The form of triclasiclib and its preparation method

Abstract

An advantageously isolated form of troracizil (2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-6'-one), for example in the form of the dihydrochloride salt or the dihydrochloride dihydrate.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 039,372, filed on June 15, 2020, U.S. Patent Application No. 17 / 097,854, filed on November 13, 2020, and U.S. Provisional Application No. 63 / 180,578, filed on April 27, 2021. The entire contents of each of these applications are hereby incorporated by reference for all purposes. Technical Field

[0003] The present invention provides an advantageously isolated morphic form of trilaciclib (2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one), for example in the form of a free base or a pharmaceutically acceptable salt thereof, for example a dihydrochloride salt or a dihydrochloride dihydrate. Background Art

[0004] U.S. Patent Nos. 8,598,186, 8,598,197, 9,957,276, 10,189,849 and 10,189,850 and corresponding WO 2012 / 061156 assigned to G1 Therapeutics, Inc. describe a class of N-(heteroaryl)-pyrrolo[3,2-d]pyrimidin-2-amine cyclin-dependent kinase inhibitors including 2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one (Compound 1) having the formula

[0005]

[0006] The synthetic procedure for preparing Compound 1 is described in US 2019 / 135820 and WO 2020 / 041770, both of which are assigned to G1 Therapeutics, Inc. Compound 1 dihydrochloride is COSELA TM The active ingredient in COSELA TM It was approved for commercial sale by the U.S. Food and Drug Administration on February 12, 2021, for the reduction of chemotherapy-induced bone marrow suppression when administered prior to a platinum / etoposide-containing regimen or a topotecan-containing regimen for extensive-stage small cell lung cancer.

[0007] Compound 1 is called "G1T28" or "trilacizumab". It temporarily arrests normal cells to prevent chemotherapy-induced bone marrow suppression and improve anti-tumor efficacy. For example, it can be used in patients with small cell lung cancer (SCLC) receiving topotecan chemotherapy, and in combination with etoposide and carboplatin in SCLC. For example, it can also be used in combination with carboplatin, etoposide and atezolizumab (a PD-L1 inhibitor) in small cell lung cancer (SCLC). Based on the bone marrow protection data of SCLC patients, trilaciclib has received breakthrough therapy designation (BTD) from the U.S. Food and Drug Administration (FDA) (see, for example, Weiss et al., "Myelopreservation with the CDK4 / 6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib / randomized phase II trial," Annals of Oncology 30:1613-1621 (2019); Daniel et al., "Trilaciclib decreases myelosuppression in extensive-stage small cell lung cancer (ES-SCLC) patients receiving first-line chemotherapy plus atezolizumab," ESMO 2019 Congress Poster Abstract #1742PD). Compound 1 is also used in combination with the neoadjuvant treatment standard of care for breast cancer in human clinical trials for the treatment of triple-negative breast cancer. Summary of the invention

[0008] It has been discovered that Compound 1 (2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one) as the dihydrochloride salt can be prepared in a highly purified, advantageous form.

[0009]

[0010] This highly purified, favorable morphology is represented as "pattern 1". Pattern 1 is a highly crystalline form of compound 1 as a dihydrochloride salt. Compared with other morphologies, pattern 1 exhibits excellent stability. For example, in competitive slurry experiments (see Example 10), pattern 1 is the main morphological structure formed by compound 1 as a dihydrochloride salt. In the manufacture of compound 1 as a dihydrochloride salt, pattern 1 also has favorable properties. For example, pattern 1 can be prepared on a large scale via crystallization of compound 1 in a heated HCl solution. Pattern 1 can also be formed from other crystalline or amorphous forms of compound 1 via recrystallization.

[0011] Compound 1 Pattern 1 may be in the form of a dihydrochloride dihydrate. Pattern 1 typically initially forms a dihydrochloride dihydrate and may eventually revert to a dihydrochloride dihydrate even after being dried when exposed to air. Regardless of the water content, Pattern 1 may retain its representative XRPD peaks, which will be described in more detail below. For example, if a form of Compound 1 is prepared as described herein to form Pattern 1 and then dried, the representative XRPD peaks before and after drying will remain the same.

[0012] Compound 1 is the approved drug triclasiclib, which is marketed under the trade name COSELA TM It is sold and used in certain embodiments as a bone marrow protectant to protect healthy cells, especially hematopoietic cells, during chemotherapy. It is intended to be administered by intravenous injection so that it can quickly enter the bloodstream just before chemotherapy is administered, which is also usually administered by IV injection. However, Compound 1 free base is not very soluble in water and is almost insoluble in DMSO. In addition, it becomes more insoluble as the pH increases. The pH of blood is usually 7.35-7.45, which is weakly alkaline. The pH of phosphate buffered saline is usually 7.2-7.4. Compound 1 free base is not very soluble at this pH and therefore presents a variety of problems. Most importantly, a large amount of Compound 1 is required to achieve a therapeutic effect. The typical dose is 240mg / m 2 And it is estimated that the dosage of normal adults is about 300mg.Due to the lack of solubility in water, a dilute solution in a large amount of liquid is needed to provide the free base compound 1 of this dosage, which will need to spend a long time to give, which is inconsistent with how it should be delivered.Compound 1IV is usually completed in about 30 minutes (20-60 minutes), which means that the drug must be concentrated in IV liquid, rather than dilute.In addition, when free base compound 1 is injected into blood, since blood is weakly alkaline, it is indeed possible that at least some of it is separated out from solution.This can cause problems and loss of activity at the injection site due to drug deposition.

[0013] It has been found that an IV solution of compound 1 for injection into cancer patients to protect healthy cells or for anti-tumor purposes can be achieved by administering it as a dihydrochloride. This makes it possible to achieve the desired therapeutic effect because it can be delivered directly to the bloodstream in a concentrated form. In a major embodiment, the IV solution is prepared from a lyophilized powder comprising compound 1 dihydrochloride, mannitol and citric acid.

[0014] In certain embodiments, the IV solution of compound 1 is prepared by a solid pharmaceutical composition, which is optionally formulated into a composition for lyophilization and then dried. In certain embodiments, the composition includes compound 1 in the form of dihydrochloride, such as compound 1 dihydrochloride mode 1. The composition may also include one or more suitable excipients, such as fillers, buffers and / or one or more pH adjusting agents. In certain embodiments, the filler is a suitable sugar, such as mannitol. In certain embodiments, the buffer is a suitable weak acid or weak base with one or more acidic or basic units. In certain embodiments, the buffer is a weak acid with two or more acidic units, such as citric acid. In certain embodiments, the composition includes NaOH, HCl and / or NaCl as a pH adjusting agent (NaOH and / or HCl) or residual salt (NaCl) from pH adjustment.

[0015] It has also been found that freeze-dried compound 1 dihydrochloride compositions comprising mannitol and citric acid can be prepared, which are crystalline and easily characterized by X-ray powder diffraction (XRPD). In certain embodiments, the freeze-dried compound 1 dihydrochloride composition comprises about 250 to 350 mg, about 275 to 325 mg, or more particularly about 300 mg of compound 1, wherein the weight of 300 mg corresponds to free alkali (i.e., about 349 mg of compound 1 in the form of dihydrochloride). In a main embodiment, the compound 1 in the freeze-dried composition is a crystalline dihydrochloride in the form of pattern 1. In other embodiments, the compound 1 in the freeze-dried composition is in the form of different pharmaceutically acceptable salts, 30%, 40% or a mixture of pharmaceutically acceptable salts. In certain embodiments, the compound 1 in the freeze-dried composition is in the form of a mixture of different patterns or patterns. In certain embodiments, the lyophilized compound 1 composition comprises at least about 10%, 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of Compound 1 dihydrochloride salt pattern 1 relative to other forms of Compound 1 in the composition. In certain embodiments, the lyophilized compound 1 composition comprises at least about 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% of Compound 1 dihydrochloride salt pattern 1 relative to other components of the lyophilized composition.

[0016] The lyophilized Compound 1 dihydrochloride composition described in Example 28 contains mannitol and citric acid and is characterized in that Fig.100 The XRPD pattern shown in . Other suitable excipients may be added as appropriate or mannitol and / or citric acid may be replaced with other suitable excipients to achieve the desired effect. In certain embodiments, the compound 1 dihydrochloride composition is lyophilized, and in other embodiments, it is dried using another technique. In certain embodiments, the compound 1 dihydrochloride composition comprises mannitol, for example, at least about 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, or 400 mg mannitol or about 200 to 400 mg, 225 to 375 mg, 250 to 350 mg, 275 to 325 mg, or 300 mg mannitol. In certain embodiments, the compound 1 dihydrochloride composition comprises citric acid, for example, at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, or 150 mg citric acid or about 15 to 145 mg, 30 to 130 mg, 45 to 105 mg, 60 to 90 mg, or 75 mg citric acid. In certain embodiments, the compound 1 dihydrochloride composition comprises one or more additional salts formed by adjusting the pH of a bulk solution, the bulk solution being dried to form a composition, the additional salts being, for example, various sodium salts of sodium chloride and / or citric acid.

[0017] In a specific embodiment, the lyophilized Compound 1 dihydrochloride composition comprises about 349 mg of Compound 1 Model 1 dihydrochloride (equivalent to about 300 mg of trexacil free base), about 50-100 mg, about 60-80 mg or more particularly about 76 mg of citric acid monohydrate and about 280-320 mg, for example 300 mg of mannitol.

[0018] The lyophilized compound 1 composition can be reconstituted in a suitable solvent, such as water, which can contain other excipients, such as sodium chloride or glucose. In certain embodiments, the lyophilized compound 1 composition is reconstituted in at least about 10, 11, 12, 13, 14, 15, 16, 17, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mL of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2% sodium chloride solution, such as about 0.9% sodium chloride solution. In certain embodiments, the lyophilized Compound 1 composition is reconstituted in about 14 to 25, 15 to 24, 16 to 23, 17 to 22, 17.5 to 21.5, 18 to 21, 18.5 to 20.5, 19 to 20, or 19.5 mL of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2% sodium chloride solution, e.g., about 0.9% sodium chloride solution. In certain embodiments, the lyophilized Compound 1 composition is reconstituted in at least about 10, 11, 12, 13, 14, 15, 16, 17, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mL of at least about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10% glucose solution, e.g., about 5% glucose solution. In certain embodiments, the lyophilized Compound 1 composition is reconstituted in about 14 to 25, 15 to 24, 16 to 23, 17 to 22, 17.5 to 21.5, 18 to 21, 18.5 to 20.5, 19 to 20, or 19.5 mL of about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10% glucose solution, e.g., about 5% glucose solution.

[0019] In certain aspects of the invention, isolated Compound 1 Mode 1 is used to make a lyophilized form, which is then formulated with a suitable solvent such as phosphate buffered saline for administration to a patient, for example, by intravenous delivery. In another embodiment, it can be formulated into a parenteral dosage form. This dosage form can be used, for example, for subcutaneous administration.

[0020] In certain embodiments, Compound 1 Pattern 1 is in the form of a dihydrochloride salt. In certain embodiments, Compound 1 Pattern 1 as a dihydrochloride salt can be used to treat any patient responsive to treracili, including for bone marrow protection or as an anti-tumor agent.

[0021] In certain embodiments, Compound 1 Pattern 1 is in the form of a dihydrochloride dihydrate. In certain embodiments, Compound 1 Pattern 1 in the form of a dihydrochloride dihydrate can be used to treat any patient responsive to treracili, including for bone marrow protection or as an anti-tumor agent.

[0022] Other forms of Compound 1 as a dihydrochloride salt have also been identified. Patterns 2 and 3 are also highly crystalline forms of Compound 1 as a dihydrochloride salt. Pattern 4 is a crystalline solvate of Compound 1 as a dihydrochloride salt with acetonitrile. Pattern 5 is a crystalline form of Compound 1 as a dihydrochloride salt. Pattern 6 is a metastable form of Compound 1 as a dihydrochloride salt. Pattern 11 is a crystalline form of Compound 1 as a dihydrochloride salt hemihydrate.

[0023] The forms of Compound 1 as a free base have also been identified. Patterns 8 and 10 are crystalline forms of Compound 1 as a free base. Pattern 9 is a crystalline form of Compound 1 as a free base, which may be a solvate or a hydrate.

[0024] In certain embodiments, Pattern 1 is the most stable form of Compound 1 as the dihydrochloride salt and is formed by competitive slurry experiments with Pattern 2 or Pattern 3.

[0025] Compound 1 is typically administered to patients in an intravenous formulation. However, solid forms of triclasiclib may be important because they can be used to achieve desired manufacturing purity and / or performance and may also be important for solid-state shelf life prior to formulation or for solid dosage forms for therapeutic delivery.

[0026] In view of the therapeutic importance of Compound 1 (triraciclib) for the medical treatment of patients with proliferative disorders such as tumors or cancer, it would be beneficial to provide such an advantageous solid form of the compound that would aid in the success or performance of the compound during manufacture, storage, formulation and / or administration. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 is the XRPD diffraction pattern of crystalline mode 1. The crystal structure was obtained using the method described in Example 1 and the peaks are shown in Table 1. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0028] Figure 2is a PLM image of crystalline mode 1. This image was obtained using the method described in Example 5. Mode 1 material appears highly crystalline under PLM imaging, with non-polarized material shown on the left and polarized material shown on the right.

[0029] Figure 3 Thermogravimetric / differential thermal (TG / DTA) thermogram for crystallization mode 1. The TG / DTA thermogram for mode 1 was obtained as described in Example 6. An initial mass loss of approximately 6% from the start of heating is associated with the loss of surface moisture. Two mass losses of approximately 7% were observed from approximately 200°C (peak at 218°C) and 300°C (peak at 343°C).

[0030] Figure 4 is a differential scanning calorimetry (DSC) thermogram of crystallization mode 1. The DSC thermogram of crystallization mode 1 was obtained as described in Example 7. DSC analysis showed two broad endothermic peaks at approximately 65°C (peak at 130°C) and 245°C (peak at 277°C). A sharp melting endothermic peak was observed starting from 330°C (peak at 341°C).

[0031] Figure 5 The results from a moisture sorption experiment for Mode 1 are shown for Dynamic Vapor Sorption (DVS) analysis. The DVS analysis for Mode 1 was obtained as described in Example 3. The material was found to be stable and XRPD analysis of a dried sample at the end of the experiment confirmed Mode 1. Mode 1 sorbed 3.00 wt % at 40% RH (relative humidity) and 4.00 wt % at 90% RH. The x-axis is relative humidity measured in percent and the y-axis is the weight of water in the material measured in percent.

[0032] Figure 6 The dynamic vapor sorption (DVS) kinetics for mode 1 are obtained as described in Example 3. The sample was subjected to a relative humidity (RH) variation curve from 40-90% in 10% increments at 25°C, and the sample was held at each step until a stable weight was reached (dm / dt 0.004%, minimum step length 30 minutes, maximum step length 500 minutes). After the adsorption cycle was completed, the sample was dried to 0% RH using the same procedure and then returned to 40% RH for a second adsorption cycle. Two cycles were performed. According to the DVS, the material exhibited hygroscopicity, with a mass increase of 4% between 0% and 90% RH. During the desorption cycle, the material was dehydrated.

[0033] Figure 7Comparison of XRPD diffractograms of Mode 1 and Mode 1 after DVS. The diffractogram of Mode 1 was obtained as described in Example 1; the diffractogram of Mode 1 after DVS was obtained as described in Example 11. According to DVS, the material exhibits hygroscopicity with a mass increase of 4% between 0% and 90% RH. During the desorption cycle, the material dehydrated. XRPD analysis after DVS in Mode 1 showed no changes. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0034] Figure 8 Comparison of XRPD diffraction pattern of Mode 1 prior to solvent solubility studies with XRPD diffraction patterns of Mode 1 material generated for various solvent solubility studies. The diffraction pattern was obtained as described in Example 1 and the studies were performed as described in Example 13. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0035] Fig. 9 Comparison of XRPD diffraction pattern of Mode 1 prior to solvent solubility studies with XRPD diffraction patterns of Mode 1 material generated for various solvent solubility studies. The diffraction pattern was obtained as described in Example 1 and the studies were performed as described in Example 13. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0036] Fig.10 Comparison of XRPD diffraction patterns of Mode 2 generated for various solvent solubility studies. The diffraction patterns were obtained as described in Example 1 and the studies were performed as described in Example 13. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0037] Fig.11 Comparison of XRPD diffraction patterns of Mode 2 generated for various solvent solubility studies. The diffraction patterns were obtained as described in Example 1 and the studies were performed as described in Example 13. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0038] Fig.12 Comparison of XRPD diffraction patterns of Mode 3 generated for various solvent solubility studies. The diffraction patterns were obtained as described in Example 1 and the studies were performed as described in Example 13. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0039] Fig.13 Comparison of XRPD diffraction patterns of Mode 1 and Mode 4 generated for solubility studies in MeCN. The diffraction patterns were obtained as described in Examples 1 and 4, and the studies were performed as described in Example 13. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0040] Fig.14Comparison of Mode 2 and Mode 5 XRPD diffraction patterns generated for various solvent systems. The diffraction patterns were obtained as described in Example 1 and studies were performed as described in Example 13. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0041] Fig.15 Comparison of Mode 2 and Mode 6 XRPD diffraction patterns generated for various solvent systems. The diffraction patterns were obtained as described in Example 1 and studies were performed as described in Example 13. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0042] Fig.16 Comparison of XRPD diffractograms of Mode 1 before and after ripening experiments in various solvent systems. The diffractograms were obtained as described in Example 1 and the studies were performed as described in Example 21. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0043] Fig.17 Comparison of XRPD diffractograms of Mode 2 before and after ripening experiments in various solvent systems. The diffractograms were obtained as described in Example 1 and the studies were performed as described in Example 21. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0044] Fig.18 Comparison of XRPD diffractograms of Mode 2 before and after ripening experiments in various solvent systems. The diffractograms were obtained as described in Example 1 and the studies were performed as described in Example 21. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0045] Fig.19 Comparison of XRPD diffractograms of Mode 3 before and after ripening experiments in isopropanol and ethanol. The diffractograms were obtained as described in Example 1 and the studies were performed as described in Example 21. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0046] Fig. 20 Comparison of XRPD diffractograms of Mode 4 before and after ripening experiments in acetonitrile. The diffractograms were obtained as described in Example 4 and the studies were performed as described in Example 21. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0047] Fig.21 Comparison of the XRPD diffractograms of Mode 5 before and after the ripening experiment in methyl isobutyl ketone. The diffractograms were obtained as described in Example 1 and the studies were performed as described in Example 21. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0048] Fig. 22Comparison of XRPD diffraction patterns generated for ripening experiments in various solvent systems. The diffraction patterns were obtained as described in Example 1 and the studies were performed as described in Example 21. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0049] Fig.23 Comparison of the XRPD Mode 1 diffraction pattern with diffraction patterns produced from aging experiments in various solvent systems after drying. The diffraction pattern was obtained as described in Example 1 and the study was performed as described in Example 21. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0050] Fig.24 Comparison of the XRPD Mode 1 diffraction pattern after drying with diffraction patterns generated from ripening experiments in various solvent systems. The diffraction pattern was obtained as described in Example 1 and the study was performed as described in Example 21. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0051] Fig.25 Comparison of the XRPD Mode 2 diffraction pattern after drying with diffraction patterns generated from ripening experiments in various solvent systems. The diffraction pattern was obtained as described in Example 1 and the study was performed as described in Example 21. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0052] Fig.26 Comparison of the XRPD Mode 3 diffraction pattern after drying with diffraction patterns generated from ripening experiments in various solvent systems. The diffraction pattern was obtained as described in Example 1 and the study was performed as described in Example 21. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0053] Fig. 27 Comparison of XRPD Mode 3 diffraction pattern after drying, Mode 4 diffraction pattern and diffraction patterns produced by ripening experiments in various solvent systems. The diffraction patterns were obtained as described in Examples 1 and 4, and the studies were performed as described in Example 21. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0054] Fig.28 Comparison of the XRPD Mode 3 diffractogram, Mode 6 diffractogram after drying and the diffractogram produced by ripening in heptane. The diffractograms were obtained as described in Example 1 and the studies were performed as described in Example 21. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0055] Fig.29 Comparison of XRPD pattern 5 after drying with diffraction patterns produced by ripening in various solvents. The diffraction patterns were obtained as described in Example 1 and the studies were performed as described in Example 21. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0056] Fig.30 Comparison of the XRPD diffraction pattern of mode 1 and the solid left after the evaporation experiment. The diffraction pattern was obtained as described in Example 1. The solid was obtained as described in Example 13. The sample was uncovered and placed in a cabinet to allow evaporation. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0057] Fig.31 Comparison of the XRPD diffraction pattern of mode 3 and the solid left after the evaporation experiment. The diffraction pattern was obtained as described in Example 1. The solid was obtained as described in Example 13. The sample was uncovered and placed in a cabinet to allow evaporation. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0058] Fig.32 Comparison of Mode 3 with the XRPD diffractogram of a solid produced by adding methyl tert-butyl ether (t-BME) to 2,2,2-trifluoroethanol. The diffractogram was obtained as described in Example 1. The solid was obtained as described in Example 13. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0059] Fig.33 Thermogravimetric / differential thermal (TG / DTA) thermograms of Mode 2 small-scale material. The TG / DTA thermograms of Mode 2 were obtained as described in Example 6. An initial mass loss of approximately 3% from the start of heating was associated with the loss of surface moisture. Two mass losses of approximately 7% were observed from approximately 222°C (peak at 239°C), 318°C (peak at 340°C), and 345°C (peak at 325°C). The x-axis is temperature (°C) and the y-axis is TG (%).

[0060] Fig.34 Thermogravimetric / differential thermal (TG / DTA) thermograms of Mode 3 small-scale material. The TG / DTA thermograms of Mode 3 were obtained as described in Example 6. An initial mass loss of approximately 2.6% from the start of heating was associated with the loss of surface moisture. Two mass losses of approximately 6.6% were observed from approximately 222°C (peak at 229°C), 311°C (peak at 317°C), and 343°C (peak at 345°C). The x-axis is temperature (°C) and the y-axis is TG (%).

[0061] Fig.35 Thermogravimetric / differential thermal (TG / DTA) thermogram of Mode 5 small-scale material. The TG / DTA thermogram of Mode 5 was obtained as described in Example 6. An initial mass loss of approximately 3.4% from the start of heating was associated with the loss of surface moisture. Three mass losses of approximately 7.3% were observed from approximately 206°C (peak at 216°C), 284°C (peak at 321°C), and 343°C (peak at 345°C). The x-axis is temperature (°C) and the y-axis is TG (%).

[0062] Fig.36 Comparison of XRPD patterns of small and scaled-up materials for Mode 2 and Mode 6. When the Mode 2 synthesis is scaled up, it produces a mixture of Mode 6 and Mode 2, as shown in the XRPD diffraction pattern. The diffraction pattern was obtained as described in Example 1. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0063] Fig.37 PLM image of a mixture of Mode 2 and Mode 6 produced for an amplification attempt. PLM imaging of the Mode 2 / 6 mixture was obtained as described in Example 5. The Mode 2 / 6 amplified material appears highly crystalline under PLM imaging, with non-polarized material shown on the left and polarized material shown on the right.

[0064] Fig.38 Thermogravimetric / differential thermal (TG / DTA) thermogram of a mixture of Mode 2 and Mode 6 generated for an amplification attempt. An initial mass loss of approximately 3.6% from the start of heating is associated with the loss of surface moisture. Two mass losses of approximately 6.3% are observed from approximately 211°C and 310°C (peak at 321°C). The x-axis is temperature (°C) and the y-axis is TG (%).

[0065] Fig.39 Differential Scanning Calorimetry (DSC) thermogram of a mixture of Mode 2 and Mode 6 generated for scale-up attempts. The DSC thermogram of the Mode 2 / 6 mixture was obtained as described in Example 7. The DSC analysis showed two broad endotherms at approximately 55.9°C (peak at 131°C) and 267°C (peak at 295°C). A sharp melting endotherm was observed starting at 336°C.

[0066] Fig.40 Gravimetric vapor sorption (GVS) isotherm plot of a mixture of Mode 2 and Mode 6 generated for scale-up attempts. The GVS isotherm plot of the Mode 2 / 6 mixture was obtained as described in Example 2. The mixture of Mode 2 and Mode 6 adsorbed 4.00 wt% at 40% RH (relative humidity) and 7.00 wt% at 90% RH. The x-axis is the relative humidity measured in percent and the y-axis is the weight of water in the material measured in percent.

[0067] Fig.41Gravimetric vapor sorption (GVS) kinetics of a mixture of Mode 2 and Mode 6 generated for the scale-up attempt. The GVS isotherm of the Mode 2 / 6 mixture was obtained as described in Example 2. The sample was subjected to a relative humidity (RH) variation curve from 40-90% in 10% increments at 25°C, holding the sample at each step until a stable weight was reached (dm / dt 0.004%, minimum step length 550 minutes, maximum step length 900 minutes). After the adsorption cycle was completed, the sample was dried to 0% RH using the same procedure and then returned to 40% RH for a second adsorption cycle. Two cycles were performed. According to DVS, the material exhibited hygroscopicity with an 8% mass increase between 0% and 90% RH. During the desorption cycle, the material was dehydrated.

[0068] Fig.42 Comparison of XRPD diffraction patterns of Mode 1, Mode 2 magnification and Mode 2 magnification after DVS. The diffraction patterns were obtained as described in Example 1. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0069] Fig.43 Comparison of small scale and enlarged XRPD diffraction patterns of Mode 3 in dry and wet form. The diffraction patterns were obtained as described in Example 1. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0070] Fig.44 PLM image of a Mode 3 magnified material. The Mode 3 magnified material appears highly crystalline under PLM imaging as described in Example 5. The non-polarized material is shown on the left and the polarized material is shown on the right.

[0071] Fig.45 TG / DTA thermogram for mode 3 scaled-up material. The TG / DTA thermogram for mode 3 scaled-up material was obtained as described in Example 6. The TG / DTA shows two peaks at 199°C and 345°C. The initial mass loss of about 8% from the start of heating is associated with the loss of surface moisture. Two mass losses of about 7% are observed from about 199°C and 343°C (peak at 345°C). The x-axis is temperature (°C) and the y-axis is TG (%).

[0072] Fig.46 Differential Scanning Calorimetry (DSC) thermogram of scaled-up material for Mode 3. The DSC thermogram for Mode 3 was obtained as described in Example 7. The DSC analysis showed three broad endothermic peaks at approximately 168°C (peak at 189°C), 251°C (peak at 264°C), and 272°C (peak at 296°C). A sharp melting endothermic peak was observed starting at 337°C (peak at 343°C).

[0073] Fig.47DVS isotherm plot of scaled-up material for Mode 3. The DVS isotherm plot for Mode 3 was obtained as described in Example 3. According to DVS, the material exhibits hygroscopicity with a mass increase of 4% between 0% and 90% RH. During the desorption cycle, the material loses water.

[0074] Fig.48 DVS kinetics for scaled-up material for Mode 3. The DVS kinetics for Mode 3 were obtained as described in Example 3. The sample was subjected to a relative humidity (RH) profile of 40-90% in 10% increments at 25°C, holding the sample at each step until a stable weight was reached (mass change 0.004%, minimum step length 650 minutes, maximum step length 1050 minutes). After the adsorption cycle was completed, the sample was dried to 0% RH using the same procedure and then returned to 40% RH for a second adsorption cycle. Two cycles were performed. According to DVS, the material exhibited hygroscopicity with a mass increase of 4% between 0% and 90% RH. During the desorption cycle, the material was dehydrated.

[0075] Fig.49 Comparison of XRPD diffraction patterns of a material before and after DVS for Mode 3 magnification. The diffraction patterns were obtained as described in Example 1. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0076] Fig.50 Comparison of XRPD diffraction patterns of Mode 5 from small-scale and scaled-up experiments. The diffraction patterns were obtained as described in Example 1. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0077] Fig.51 Comparison of XRPD diffraction patterns of Mode 5 from small-scale and scaled-up experiments after a repeat process. The diffraction patterns were obtained as described in Example 1. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0078] Fig.52 Comparison of XRPD diffraction patterns of Mode 2 in various one-week stability studies. The diffraction patterns were obtained as described in Example 1. The stability studies compared Mode 2 and Mode 2 after one week at ambient temperature and 80°C, respectively. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts. Repeated magnification.

[0079] Fig.53 Comparison of XRPD diffraction patterns of Mode 2 in various one-week stability studies. Diffraction patterns were obtained as described in Example 1. The stability studies compared Mode 2, Mode 2 scale-up, and Mode 2 at 40°C. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts. The scale-up was repeated.

[0080] Fig.54 Figure 1 is a comparison of XRPD diffraction patterns of Pattern 3 in various one-week stability studies. The diffraction patterns were obtained as described in Example 1. The stability studies compared Pattern 3 and Pattern 3 after one week at ambient temperature, 40°C, and 80°C, respectively. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0081] Fig.55 Comparison of XRPD diffraction patterns generated for competitive slurry experiments for Mode 1 mixed with Modes 2 and 3. The diffraction patterns were obtained as described in Example 1 following the procedure of Example 11. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0082] Fig.56 Comparison of XRPD diffraction patterns generated for competitive slurry experiments for Mode 1 mixed with Modes 2 and 3. The diffraction patterns were obtained as described in Example 1 following the procedure of Example 11. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0083] Fig.57 Comparison of XRPD diffraction patterns generated for competitive slurry experiments for Mode 1 mixed with Modes 2 and 3. The diffraction patterns were obtained as described in Example 1 following the procedure of Example 11. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0084] Fig.58 Comparison of XRPD diffraction patterns generated for competitive slurry experiments for Mode 1 mixed with Modes 2 and 3. The diffraction patterns were obtained as described in Example 1 following the procedure of Example 11. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0085] Fig.59 Comparison of XRPD diffraction patterns generated for competitive slurry experiments for Mode 1 mixed with Modes 2 and 3. The diffraction patterns were obtained as described in Example 1 following the procedure of Example 11. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0086] Fig.60 Comparison of the XRPD diffraction patterns of Mode 7 before and after the thermodynamic solubility experiment. The thermodynamic solubility experiment is described in Example 22. The diffraction pattern was obtained using the procedure of Example 1. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0087] Fig.61 is the XRPD diffraction pattern of Mode 7. The diffraction pattern of Mode 7 was obtained as described in Example 1. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0088] Fig.62is a PLM image at 200x magnification of Mode 7. The PLM image of Mode 7 was obtained as described in Example 5. The birefringent sample under polarized light is shown at the bottom and the unpolarized light of the sample is shown at the top.

[0089] Fig.63 TG / DTA thermogram for mode 7. The TG / DTA thermogram for mode 7 was obtained as described in Example 6. The thermogram shows a weight loss of 6.2% between 150 and 340° C. and decomposition of the sample above 350° C. The thermogram also shows that the sample starts to melt at 340° C. with a peak at 345° C. The x-axis is temperature measured in degrees Celsius and the y-axis is intensity measured in DTAuV on the left and TG% on the right.

[0090] Fig.64 The DSC first heating thermogram for mode 7. The DSC thermogram for mode 7 was obtained as described in Example 7. During the first heating, the thermogram shows a sample melting event at 335°C with a peak at 338°C (consistent with the TG / DTA data). The x-axis is temperature measured in degrees Celsius and the y-axis is intensity measured in DSC mW.

[0091] Fig.65 is the DSC cooling thermogram for mode 7. The DSC thermogram for mode 7 was obtained as described in Example 7. The thermogram shows no significant thermal events during the cooling cycle. The x-axis is the temperature measured in degrees Celsius and the y-axis is the intensity measured in DSC mW.

[0092] Fig.66 is the DSC second heating thermogram of crystallization mode 7. The DSC thermogram of mode 7 was obtained as described in Example 7. The second heating contains a melting event starting at 333°C with a peak at 339°C. Melting may not be complete during the initial heating cycle. The x-axis is temperature measured in degrees Celsius and the y-axis is intensity measured in DSC mW.

[0093] Fig.67 Comparison of XRPD diffraction patterns from pH solubility studies at various pHs for Mode 7. Material produced at pH 4 was identified as Mode 8. The diffraction pattern was obtained as described in Example 1 and the pH experiments were as described in Example 16. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0094] Fig.68 is a comparison of XRPD diffraction patterns from pH solubility studies at various pHs for Mode 7. The diffraction patterns for Mode 7 were obtained as described in Example 1 and Example 16. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0095] Fig.69Comparison of XRPD diffraction patterns from pH solubility studies of Mode 7 in various pH solvent systems. The diffraction patterns of Mode 7 were obtained as described in Example 1 and Example 16. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0096] Fig.70 is a comparison of XRPD diffractograms produced by crystallization set 1. Crystallization was performed as described in Example 17. This comparison shows pattern 7 and the forms produced by various concentrations in various pH solvent systems. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0097] Fig.71 is a comparison of the XRPD diffraction patterns produced by crystallization sets 2 and 3. Crystallization was performed as described in Example 18 and Example 19. This comparison shows Pattern 7 and the forms produced by various concentrations in various pH solvent systems. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0098] Fig.72 is a comparison of the XRPD diffraction patterns produced by crystallization sets 2 and 3. Crystallization was performed as described in Example 18 and Example 19. This comparison shows Pattern 7 and the forms produced by various concentrations in various pH solvent systems. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0099] Fig.73 is a comparison of XRPD diffraction patterns produced by crystallization set 4. Crystallization was performed as described in Example 20. This comparison shows pattern 7 and the forms produced by various concentrations in various pH solvent systems. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0100] Fig.74 are PLM images corresponding to the material obtained from Experiment 1 of Example 23. The polarized samples are shown in the bottom row and the non-polarized samples are shown in the top row.

[0101] Fig.75 is a PLM image corresponding to the material obtained from Experiment 2 of Example 23. PLM imaging was obtained as described in Example 5. The polarized sample is shown on the right and the unpolarized sample is shown on the left.

[0102] Fig.76 is a PLM image corresponding to the material obtained from Experiment 3 of Example 23. PLM imaging was obtained as described in Example 5. The polarized sample is shown on the right and the unpolarized sample is shown on the left.

[0103] Fig.77are PLM images corresponding to the material obtained from Experiment 4 of Example 23. PLM imaging was obtained as described in Example 5. Polarized samples are shown in the bottom row and unpolarized samples are shown in the top row.

[0104] Fig.78 are PLM images corresponding to the material obtained from Experiment 5 of Example 23. PLM images were obtained as described in Example 5. Polarized samples are shown in the bottom row and non-polarized samples are shown in the top row.

[0105] Fig.79 is a PLM image corresponding to the material obtained from Experiment 7 of Example 23. The PLM imaging was obtained as described in Example 5. The polarized sample is shown on the right and the unpolarized sample is shown on the left.

[0106] Fig.80 are PLM images corresponding to the material obtained from Experiment 6 of Example 23. PLM imaging was obtained as described in Example 5. Polarized samples are shown in the bottom row and non-polarized samples are shown in the top row.

[0107] Fig.81 is a PLM image corresponding to the material obtained from Experiment 8 of Example 23. The polarized sample is shown on the right and the non-polarized sample is shown on the left.

[0108] Fig.82 is a PLM image corresponding to the material obtained from Experiment 9 of Example 23. The PLM imaging was obtained as described in Example 5. The polarized sample is shown on the right and the unpolarized sample is shown on the left.

[0109] Fig.83 are PLM images corresponding to the material obtained from Experiment 10 of Example 23. Polarized samples are shown in the bottom row and non-polarized samples are shown in the top row.

[0110] Fig.84 is a PLM image corresponding to the material obtained from Experiment 11 of Example 23. The polarized sample is shown on the right and the non-polarized sample is shown on the left.

[0111] Fig.85 is a PLM image corresponding to the material obtained from Experiment 12 of Example 23. The material was identified as Mode 9. The polarized samples are shown in the bottom row and the unpolarized samples are shown in the top row.

[0112] Fig.86 is a PLM image at 200x magnification of crystalline mode 10. PLM imaging of crystalline mode 7 was obtained as described in Example 5. Polarized samples are shown in the bottom row and non-polarized samples are shown in the top row.

[0113] Fig.87is the TG / DTA thermogram of mode 9. The TG / DTA thermogram of mode 9 was obtained as described in Example 6. Mode 9 exhibits a large weight loss of 24.3% from the start of heating to 150°C. Mode 9 exhibits a second mass loss of 15 wt% between 75°C and 154°C. The DT trace identifies two endothermic events associated with mass loss, the first showing a start at 37°C with a peak at 66.2°C; the second starting at 122°C with a peak at 128°C; and the third and last endothermic event in the DT trace (sample melting) is observed to start at 326°C with a peak at 330°C. The x-axis is the temperature measured in degrees Celsius, the y-axis is the intensity measured in DTAuV on the left, and TG% on the right.

[0114] Fig.88 is the TG / DTA thermogram for mode 10. The TG / DTA thermogram was obtained as described in Example 6. The thermogram shows a minimum weight loss of 0.1% weight loss between 150 and 340°C from the start of heating. The sample shows degradation above 320°C. The thermogram also shows two peaks, the first starting at 199 and peaking at 206; the second starting at 327°C and peaking at 331°C. The x-axis is temperature measured in degrees Celsius, the y-axis is intensity measured in DTAuV on the left and TG% on the right.

[0115] Fig.89 is the XRPD diffraction pattern of crystalline mode 8. The crystal structure was obtained using the method described in Example 1 and the peaks are shown in Table 1. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0116] Fig.90 is the crystal structure of Mode 11. The crystal structure was solved as described in Example 25. Non-hydrogen atoms are shown with thermal ellipsoids set at a 50% probability level.

[0117] Fig.91 is the crystal structure of mode 11, with hydrogen bonds depicted. The crystal structure was solved as described in Example 25. Non-hydrogen atoms are shown with thermal ellipsoids set at a 50% probability level.

[0118] Fig.92 is the crystal structure of Mode 11, with the view set to the a-axis of the unit cell. The crystal structure was solved as described in Example 25. Non-hydrogen atoms are shown with thermal ellipsoids set at a 50% probability level.

[0119] Fig.93 is the crystal structure of Mode 11 with the view set to the b-axis of the unit cell. The crystal structure was solved as described in Example 25. Non-hydrogen atoms are shown with thermal ellipsoids set at a 50% probability level.

[0120] Fig.94 is the crystal structure of Mode 11 with the view set to the c-axis of the unit cell. The crystal structure was solved as described in Example 25. Non-hydrogen atoms are shown with thermal ellipsoids set at a 50% probability level.

[0121] Fig.95 is the crystal structure of mode 11 with the view set to a null view of the a-axis. The crystal structure was solved as described in Example 25. Non-hydrogen atoms are shown with thermal ellipsoids set at a 50% probability level.

[0122] Fig.96 : Comparison of the simulated XRPD pattern of Mode 11 with the XRPD pattern of Mode 1. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts.

[0123] Fig.97 is the crystal structure of Model 1 generated by x-ray crystallography discussed in Example 27.

[0124] Fig.98 is the crystal structure of Model 1 generated by x-ray crystallography discussed in Example 27, in which hydrogen bonds are clearly shown.

[0125] Fig.99 The experimentally determined XRPD diffraction pattern for mode 1 corresponds to Fig.97 . The difference between the two lines is shown in the bottom line. Since the bottom line is almost flat, the simulation strongly indicates that the crystal structure corresponds to the XRPD pattern.

[0126] Fig.100 : is the XRPD diffraction pattern of a lyophilized Compound 1 dihydrochloride composition comprising mannitol and citric acid. Crystallization was performed as described in Example 28 and Table 42. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts. DETAILED DESCRIPTION

[0127] It is not possible to predict in advance whether a compound exists in more than one solid form, or in which salt or solvate form it exists, or, if one or more solid forms do exist, what the various properties of any solid form might be, or whether those properties would be advantageous for a therapeutic dosage form. As an example, the drug ritonavir is active in one morphological form and inactive in another, and the inactive form is more stable.

[0128] Compound 1 is the approved drug triclasiclib, which is marketed under the trade name COSELA TMIt is sold and used in certain embodiments as a bone marrow protectant to protect healthy cells, especially hematopoietic cells, during chemotherapy. It is intended to be administered by intravenous injection so that it can quickly enter the bloodstream just before chemotherapy is administered, which is also usually administered by IV injection. However, Compound 1 free base is not very soluble in water and is almost insoluble in DMSO. In addition, it becomes more insoluble as the pH increases. The pH of blood is usually 7.35-7.45, which is weakly alkaline. The pH of phosphate buffered saline is usually 7.2-7.4. Compound 1 is not very soluble at this pH and therefore presents a variety of problems. Most importantly, a large amount of Compound 1 is required to achieve a therapeutic effect. The typical dose is 240mg / m 2 And it is estimated that the dosage of normal adults is about 300mg.Due to the lack of solubility in water, a dilute solution in a large amount of liquid is needed to provide the free base compound 1 of this dosage, which will need to spend a long time to give, which is inconsistent with how it should be delivered.Compound 1IV is usually completed in about 30 minutes (20-60 minutes), which means that the drug must be concentrated in IV liquid, rather than dilute.In addition, when free base compound 1 is injected into blood, since blood is weakly alkaline, it is indeed possible that at least some of it is separated out from solution.This can cause problems and loss of activity at the injection site due to drug deposition.

[0129] It has been found that an IV solution of Compound 1 for injection into cancer patients to protect healthy cells or for anti-tumor use can be achieved by administering it as dihydrochloride or dihydrochloride dihydrate. This makes it possible to achieve the expected therapeutic effect because it can be delivered directly to the bloodstream in a concentrated form. In a major embodiment, the IV solution is prepared from a lyophilized powder comprising Compound 1 dihydrochloride, mannitol and citric acid.

[0130] In certain embodiments, the IV solution of compound 1 is prepared by a solid pharmaceutical composition, which is optionally dried by lyophilization. In certain embodiments, the composition comprises compound 1 in the form of dihydrochloride, such as compound 1 dihydrochloride mode 1. The composition may also include suitable excipients, such as fillers, buffers and / or one or more pH adjusting agents. In certain embodiments, the filler is a suitable sugar, such as mannitol. In certain embodiments, the buffer is a suitable weak acid or weak base with one or more acidic or basic sites. In certain embodiments, the buffer is a weak acid with two or more acidic sites, such as citric acid. In certain embodiments, the composition comprises NaOH, HCl and / or NaCl as a pH adjusting agent (NaOH and / or HCl) or residual salt (NaCl) from pH adjustment.

[0131] It has also been found that the freeze-dried compound 1 dihydrochloride composition comprising mannitol and citric acid is crystalline and easy to characterize by X-ray powder diffraction (XRPD). In certain embodiments, the freeze-dried compound 1 dihydrochloride composition comprises about 250 to 350mg, about 275 to 325mg or more particularly about 300mg of compound 1, wherein the weight of 300mg corresponds to free alkali. In a main embodiment, the compound 1 in the freeze-dried composition is a crystalline dihydrochloride in the form of pattern 1 herein. In other embodiments, the compound 1 in the freeze-dried composition is in the form of different pharmaceutically acceptable salts or a mixture of pharmaceutically acceptable salts. In certain embodiments, the compound 1 in the freeze-dried composition is in the form of a mixture of different patterns or patterns. In certain embodiments, the lyophilized Compound 1 composition comprises at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of Compound 1 dihydrochloride salt pattern 1 relative to other forms of Compound 1. In certain embodiments, the lyophilized Compound 1 composition comprises at least about 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% of Compound 1 dihydrochloride salt pattern 1 relative to other components of the lyophilized composition.

[0132] The lyophilized Compound 1 dihydrochloride composition described in Example 28 contains mannitol and citric acid and is characterized in that Fig.100The XRPD pattern shown in . Other suitable excipients may be added or replaced with other suitable excipients to achieve the desired effect. In certain embodiments, the compound 1 dihydrochloride composition is lyophilized. In other embodiments, it is dried using another technique. In certain embodiments, the compound 1 dihydrochloride composition comprises mannitol, for example, at least about 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, or 400 mg mannitol or about 200 to 400 mg, 225 to 375 mg, 250 to 350 mg, 275 to 325 mg, or 300 mg mannitol, or at least about 200 370, 380, 390, or 400 mg of mannitol. In certain embodiments, the compound 1 dihydrochloride composition comprises citric acid, for example, about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, or 150 mg citric acid or about 15 to 145 mg, 30 to 130 mg, 45 to 105 mg, 60 to 90 mg, 75 mg citric acid, or at least about 10, 15, 20, 25, 30, 130, 135, 140, 145, or 150 mg of citric acid, or up to about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, or 150 mg of citric acid. In certain embodiments, the compound 1 dihydrochloride composition comprises one or more additional salts formed by adjusting the pH of a bulk solution that is dried to form a composition, such as sodium chloride and / or various sodium salts of citric acid.

[0133] In a specific embodiment, the lyophilized Compound 1 dihydrochloride composition comprises about 349 mg of Compound 1 Model 1 dihydrochloride (equivalent to about 300 mg of trexacil free base), about 50-100 mg, about 60-80 mg or more particularly about 76 mg of citric acid monohydrate and about 280-320 mg, for example 300 mg of mannitol.

[0134] The lyophilized compound 1 composition can be reconstituted in a suitable solvent, such as water, which can contain other excipients, such as sodium chloride or glucose. In certain embodiments, the lyophilized compound 1 composition is reconstituted in at least about 10, 11, 12, 13, 14, 15, 16, 17, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mL of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2% sodium chloride solution, such as about 0.9% sodium chloride solution. In certain embodiments, the lyophilized Compound 1 composition is reconstituted in at least about 14 to 25, 15 to 24, 16 to 23, 17 to 22, 17.5 to 21.5, 18 to 21, 18.5 to 20.5, 19 to 20, or 19.5 mL of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2% sodium chloride solution, e.g., about 0.9% sodium chloride solution. In certain embodiments, the lyophilized Compound 1 composition is reconstituted in at least about 10, 11, 12, 13, 14, 15, 16, 17, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mL of at least about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10% glucose solution, e.g., about 5% glucose solution. In certain embodiments, the lyophilized Compound 1 composition is reconstituted in about 14 to 25, 15 to 24, 16 to 23, 17 to 22, 17.5 to 21.5, 18 to 21, 18.5 to 20.5, 19 to 20, or 19.5 mL of about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10% glucose solution, e.g., about 5% glucose solution.

[0135] Pattern 1, Pattern 2 and Pattern 3 are highly crystalline forms of compound 1 as a dihydrochloride salt. Pattern 1 is a useful dihydrochloride dihydrate form of compound 1. Pattern 4 is a crystalline solvate of compound 1 as a dihydrochloride salt with acetonitrile. Pattern 5 is a crystalline form of compound 1 as a dihydrochloride salt. Pattern 6 is a metastable form of compound 1 as a dihydrochloride salt. Pattern 7 is a highly crystalline form of compound 1 as a free base. Patterns 8 and 10 are crystalline forms of compound 1 as a free base. Pattern 9 is a crystalline form of compound 1 as a free base, which may be a solvate or a hydrate. Pattern 11 is a crystalline form of compound 1 as a dihydrochloride hemihydrate.

[0136] In certain embodiments, Pattern 1 dihydrochloride dihydrate is the most stable morphological form of Compound 1 as a dihydrochloride salt and can be formed by competitive slurry experiments with Pattern 2 or Pattern 3. In certain embodiments, regardless of its water content, Pattern 1 is the most stable morphological form of Compound 1 as a dihydrochloride salt and can be formed by competitive slurry experiments with Pattern 2 or Pattern 3. In certain embodiments, Pattern 7 is the most stable morphological form of Compound 1 as a free base.

[0137] Pattern 1 dihydrochloride dihydrate has a variety of therapeutic advantages over other morphological forms of compound 1. For example, Pattern 1 dihydrochloride dihydrate is easier to use in intravenous solutions. In addition, higher concentrations of Pattern 1 dihydrochloride dihydrate can be obtained in water and / or DMSO.

[0138] Pattern 1 dihydrochloride dihydrate has various manufacturing advantages over other morphological forms of Compound 1. For example, Pattern 1 dihydrochloride dihydrate generally has increased shelf stability, thermodynamic stability, and / or solubility in water over other morphological forms of Compound 1. In other embodiments, the manufacture of Pattern 1 dihydrochloride dihydrate is reproducibly more scalable than the manufacture of other morphological forms of Compound 1.

[0139] In certain aspects of the invention, the dihydrate is optionally isolated in mode 1 for the manufacture of a lyophilized form, which is then formulated with a suitable solvent such as phosphate buffered saline to be administered to a patient, for example, by intravenous delivery. In an alternative embodiment, it can be formulated into a parenteral dosage form. The dosage form can be used, for example, for subcutaneous administration.

[0140] In certain aspects of the invention, the isolated mode 2 is used to make a lyophilized form, which is then formulated with a suitable solvent such as phosphate buffered saline to be administered to a patient, for example, by intravenous delivery. In an alternative embodiment, it can be formulated into a parenteral dosage form. The dosage form can be used, for example, for subcutaneous administration.

[0141] In certain aspects of the invention, the isolated mode 3 is used to make a lyophilized form, which is then formulated with a suitable solvent such as phosphate buffered saline to be administered to a patient, for example, by intravenous delivery. In an alternative embodiment, it can be formulated into a parenteral dosage form. This dosage form can be used, for example, for subcutaneous administration.

[0142] In certain aspects of the invention, the isolated mode 7 is used to make a lyophilized form, which is then formulated with a suitable solvent such as phosphate buffered saline to be administered to a patient, for example, by intravenous delivery. In an alternative embodiment, it can be formulated into a parenteral dosage form. This dosage form can be used, for example, for subcutaneous administration.

[0143] Mode 1

[0144] The present invention provides an isolated morphological form of Compound 1 as a dihydrochloride salt, which has been designated as Pattern 1 herein.

[0145] Compound 1 Pattern 1 may be in the form of a dihydrochloride dihydrate. Pattern 1 is typically initially in the form of a dihydrochloride dihydrate after formation, and may eventually revert to a dihydrochloride dihydrate even after being dried when exposed to air. Regardless of the water content, Pattern 1 may retain its representative XRPD peaks, which will be described in more detail below. For example, if a morphological form of Compound 1 is prepared as described herein to form Pattern 1 and then dried, the representative XRPD peaks before and after drying will remain the same.

[0146] Surprisingly, it was found that pattern 1 could be dissolved in the composition for lyophilization and reformed after drying.

[0147] In certain embodiments, Compound 1 Pattern 1 is in the form of a dihydrochloride dihydrate morphology. In certain embodiments, the present invention provides a composition of Compound 1 that is a dihydrochloride dihydrate. In certain embodiments, the present invention provides a composition of Compound 1 Pattern 1 that is a dihydrochloride dihydrate.

[0148] In certain embodiments, Compound 1 Pattern 1 dihydrochloride dihydrate is more stable than other hydrate forms of Compound 1. In another embodiment, Compound 1 Pattern 1 dihydrochloride dihydrate may be more stable than a non-hydrate form of Compound 1. Compound 1 Pattern 1 in the form of dihydrochloride dihydrate may be superior to anhydrous, monohydrate or even trihydrate forms of Compound 1 Pattern 1. For example, the dihydrate form of Compound 1 Pattern 1 dihydrochloride has increased shelf stability, thermodynamic stability and / or solubility in water over anhydrous, monohydrate or even trihydrate forms of Compound 1 Pattern 1. In other embodiments, the manufacture of Pattern 1 dihydrochloride dihydrate is cheaper, faster and / or more scalable than the manufacture of anhydrous, monohydrate or even trihydrate forms of Compound 1 Pattern 1.

[0149] In certain embodiments, Compound 1, optionally in the form of a dihydrate, is characterized by Figure 1 In one embodiment, Compound 1, optionally in the form of a dihydrate, has an XRPD pattern substantially similar to that shown in . In one embodiment, Pattern 1 of Compound 1, optionally in the form of a dihydrate, is characterized in that the XRPD pattern comprises at least three 2θ values ​​selected from about 9.6±0.2°, about 21.3±0.2°, about 19.8±0.2°, about 12.2±0.2°, about 24.0±0.2°, about 26.1±0.2°, about 19.3±0.2°, about 17.6±0.2°, and about 28.6±0.2°. In one embodiment, Pattern 1 of Compound 1, optionally in the form of a dihydrate, is characterized in that the XRPD pattern comprises a peak with a 2θ value of about 9.6±0.2°.

[0150] In certain embodiments, Compound 1 Pattern 1, optionally in the form of a dihydrate, is characterized by a 6% ± 3% weight loss when the sample is initially heated. In certain embodiments, Compound 1 Pattern 1, optionally in the form of a dihydrate, is characterized by a 7% ± 3% weight loss between about 200°C and about 230°C. In certain embodiments, Compound 1 Pattern 1 is characterized by a second 7% ± 3% weight loss between about 300°C and about 380°C.

[0151] Compound 1 pattern 1 can be prepared using selective crystallization. The method can be carried out by treating a solution of compound 1 in the form of a dihydrochloride salt containing one or more suitable solvents, optionally in the presence of one or more seed crystals containing compound 1 pattern 1, under conditions that provide crystallization of compound 1 pattern 1. If the solvent used is water or contains water, the resulting compound 1 pattern 1 is generally a dihydrochloride dihydrate. Selective crystallization can be carried out in any suitable solvent. For example, it can be carried out in an aprotic solvent or a mixture thereof. Examples of usable aprotic solvents include tetrahydrofuran, dichloromethane, nitromethane and dioxane. In another embodiment, compound 1 pattern 1 is prepared from a protic solvent. Examples of usable protic solvents include water, methanol and ethanol. In certain embodiments, compound 1 pattern 1 is prepared from a mixture of aprotic solvents and protic solvents, such as a mixture of acetonitrile and water.

[0152] The selective crystallization may be performed, for example, at a temperature in the range of about 20° C. to about 65° C. In another embodiment, the selective crystallization may be performed, for example, at a temperature in the range of about 35° C. to about 45° C. or at about 40° C.

[0153] In one embodiment, Compound 1 Pattern 1, optionally in the form of a dihydrate, is produced by crystallization or recrystallization in an acidic solution. For example, Compound 1 Pattern 1 can be produced in aqueous hydrochloric acid.

[0154] In one embodiment, Compound 1 Mode 1 is prepared by heating Compound 1 to about 80°C and stirring for at least 30 minutes. The resulting solution is filtered into a reactor preheated to about 80°C, and the reaction mixture is cooled to about 70°C. Preheated (about 70°C) purified water is added and the reaction mixture is cooled to below 20°C under agitation. Compound 1 Mode 1 can be isolated by filtration, washed with purified water and acetone, and dried in vacuo at elevated temperatures.

[0155] In certain embodiments, Compound 1 Pattern 1, optionally as a dihydrate, is sieved using a mill. In certain embodiments, the sieved Compound 1 Pattern 1 material is formulated for parenteral administration to a patient.

[0156] In certain embodiments, Compound 1, optionally as a dihydrate, Pattern 1 is characterized by an XRPD pattern comprising at least 2 peaks selected from about 9.6±0.2°, about 12.2±0.2°, about 19.8±0.2°, about 21.2±0.2°, about 23.9±0.2°, and about 26.1±0.2°.

[0157] In certain embodiments, Compound 1, optionally in the form of a dihydrate, Pattern 1 is characterized by an XRPD pattern comprising at least 3 peaks selected from about 9.6±0.2°, about 12.2±0.2°, about 19.8±0.2°, about 21.2±0.2°, about 23.9±0.2°, and about 26.1±0.2°.

[0158] In certain embodiments, Compound 1, optionally in the form of a dihydrate, Pattern 1 is characterized by an XRPD pattern comprising at least 4 peaks selected from about 9.6±0.2°, about 12.2±0.2°, about 19.8±0.2°, about 21.2±0.2°, about 23.9±0.2°, and about 26.1±0.2°.

[0159] In certain embodiments, Compound 1, optionally in the form of a dihydrate, Pattern 1 is characterized by an XRPD pattern comprising at least 5 peaks selected from about 9.6±0.2°, about 12.2±0.2°, about 19.8±0.2°, about 21.2±0.2°, about 23.9±0.2°, and about 26.1±0.2°.

[0160] In certain embodiments, Compound 1, optionally as a dihydrate, Pattern 1 is characterized by an XRPD pattern comprising 2θ values ​​selected from about 9.6±0.2°, about 12.2±0.2°, about 19.8±0.2°, about 21.2±0.2°, about 23.9±0.2°, and about 26.1±0.2°.

[0161] In certain embodiments, Compound 1, optionally as a dihydrate, Pattern 1 is characterized in that the XRPD pattern comprises all or at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 2θ values ​​within ±0.4° 2θ of a peak selected from:

[0162] a. 9.6, 21.3, 19.8, 12.2, 24.0, 26.1, 19.3, 17.6, 28.6, 15.3, 23.2, 20.3, 22.7, 27.1, 21.0, 17.0, 10.1, 16.0, 26.8, 31.4, 13.8, 32.3, 32.9, 20.7, 18.7, and 27.6 ° 2θ; or

[0163] b. 9.6, 21.3, 19.8, 12.2, 24.0, 26.1, 19.3, 17.6, 28.6, 15.3, 23.2, 20.3, 22.7, 27.1, 21.0, 17.0, 10.1, 16.0, 26.8, 31.4, 13.8, 32.3, 32.9, 20.7, and 18.7° 2θ; or

[0164] c. 9.6, 21.3, 19.8, 12.2, 24.0, 26.1, 19.3, 17.6, 28.6, 15.3, 23.2, 20.3, 22.7, 27.1, 21.0, 17.0, 10.1, 16.0, 26.8, 31.4, 13.8, 32.3, 32.9, and 20.7° 2θ; or

[0165] d. 9.6, 21.3, 19.8, 12.2, 24.0, 26.1, 19.3, 17.6, 28.6, 15.3, 23.2, 20.3, 22.7, 27.1, 21.0, 17.0, 10.1, 16.0, 26.8, 31.4, 13.8, 32.3, and 32.9 ° 2θ; or

[0166] 9.6, 21.3, 19.8, 12.2, 24.0, 26.1, 19.3, 17.6, 28.6, 15.3, 23.2, 20.3, 22.7, 27.1, 21.0, 17.0, 10.1, 16.0, 26.8, 31.4, 13.8, and 32.3° 2θ; or

[0167] f. 9.6, 21.3, 19.8, 12.2, 24.0, 26.1, 19.3, 17.6, 28.6, 15.3, 23.2, 20.3, 22.7, 27.1, 21.0, 17.0, 10.1, 16.0, 26.8, 31.4, and 13.8° 2θ; or

[0168] g. 9.6, 21.3, 19.8, 12.2, 24.0, 26.1, 19.3, 17.6, 28.6, 15.3, 23.2, 20.3, 22.7, 27.1, 21.0, 17.0, 10.1, 16.0, 26.8, and 31.4 ° 2θ; or

[0169] h. 9.6, 21.3, 19.8, 12.2, 24.0, 26.1, 19.3, 17.6, 28.6, 15.3, 23.2, 20.3, 22.7, 27.1, 21.0, 17.0, 10.1, 16.0, and 26.8 ° 2θ; or

[0170] 9.6, 21.3, 19.8, 12.2, 24.0, 26.1, 19.3, 17.6, 28.6, 15.3, 23.2, 20.3, 22.7, 27.1, 21.0, 17.0, 10.1, and 16.0° 2θ; or

[0171] 9.6, 21.3, 19.8, 12.2, 24.0, 26.1, 19.3, 17.6, 28.6, 15.3, 23.2, 20.3, 22.7, 27.1, 21.0, 17.0, and 10.1 ° 2θ; or

[0172] k. 9.6, 21.3, 19.8, 12.2, 24.0, 26.1, 19.3, 17.6, 28.6, 15.3, 23.2, 20.3, 22.7, 27.1, 21.0, and 17.0° 2θ; or

[0173] 1.9.6, 21.3, 19.8, 12.2, 24.0, 26.1, 19.3, 17.6, 28.6, 15.3, 23.2, 20.3, 22.7, 27.1, and 21.0 degrees 2θ; or

[0174] m. 9.6, 21.3, 19.8, 12.2, 24.0, 26.1, 19.3, 17.6, 28.6, 15.3, 23.2, 20.3, 22.7 and 27.1 ° 2θ; or

[0175] n.9.6, 21.3, 19.8, 12.2, 24.0, 26.1, 19.3, 17.6, 28.6, 15.3, 23.2, 20.3 and 22.7° 2θ; or

[0176] 9.6, 21.3, 19.8, 12.2, 24.0, 26.1, 19.3, 17.6, 28.6, 15.3, 23.2 and 20.3° 2θ; or

[0177] p. 9.6, 21.3, 19.8, 12.2, 24.0, 26.1, 19.3, 17.6, 28.6, 15.3 and 23.2° 2θ; or

[0178] q. 9.6, 21.3, 19.8, 12.2, 24.0, 26.1, 19.3, 17.6, 28.6 and 15.3° 2θ; or

[0179] r. 9.6, 21.3, 19.8, 12.2, 24.0, 26.1, 19.3, 17.6 and 28.6° 2θ; or

[0180] s. 9.6, 21.3, 19.8, 12.2, 24.0, 26.1, 19.3 and 17.6° 2θ; or

[0181] t. 9.6, 21.3, 19.8, 12.2, 24.0, 26.1 and 19.3° 2θ; or

[0182] u.9.6, 21.3, 19.8, 12.2, 24.0 and 26.1°2θ;

[0183] v. Any of the above peak lists, where °2θ is + 0.1; or

[0184] w. Any of the above peak lists, where °2θ is + 0.2; or

[0185] x. Any of the above peak lists, where °2θ is + 0.3.

[0186] In one embodiment, Compound 1 Pattern 1, optionally in a dihydrate, is characterized by the above XRPD pattern and is further characterized by no peaks with a relative intensity of greater than 15% between 4 and 9° 2θ. In one embodiment, Compound 1 Pattern 1, optionally in a dihydrate, is characterized by the above XRPD pattern and is further characterized by no peaks with a relative intensity of greater than 10% between 4 and 9° 2θ. In one embodiment, Compound 1 Pattern 1, optionally in a dihydrate, is characterized by the above XRPD pattern and is further characterized by no peaks with a relative intensity of greater than 5% between 4 and 9° 2θ. In one embodiment, Compound 1 Pattern 1, optionally in a dihydrate, is characterized by the above XRPD pattern and is further characterized by no peaks with a relative intensity of greater than 3% between 4 and 9° 2θ.

[0187] In certain embodiments, Compound 1 Pattern 1, which is optionally a dihydrate, is used to prepare amorphous Compound 1 as a dihydrochloride. For example, amorphous Compound 1 as a dihydrochloride can be formed by freeze-drying or spray-drying of Compound 1 Pattern 1, which is optionally a dihydrate. The amorphous dihydrochloride can have a higher purity than that prepared directly by a known synthetic method. In addition, the advantage of first preparing Compound 1 Pattern 1, which is optionally a dihydrate, and then converting it into an amorphous material may be that the overall shelf life of the product is thus increased.

[0188] In certain embodiments, Compound 1 Pattern 1, which is optionally a dihydrate, is used to prepare amorphous Compound 1 as a mono-HCl salt. For example, amorphous Compound 1 as a mono-HCl salt can be formed by dissolving Compound 1 Pattern 1 and changing the pH of the solution, followed by removal of the solvent. The amorphous mono-HCl salt can have a higher purity than that prepared directly by known synthetic methods. In addition, the advantage of first preparing Compound 1 Pattern 1, which is optionally a dihydrate, and then converting it into an amorphous material may be that the overall shelf life of the product is increased.

[0189] In certain embodiments, Compound 1 Pattern 1, optionally in the form of a dihydrate, is used to prepare amorphous Compound 1 as a free base. The amorphous free base may have a higher purity than that prepared directly by known synthetic methods. In addition, the advantage of first preparing Compound 1 Pattern 1, optionally in the form of a dihydrate, and then converting it into an amorphous material may be that the overall shelf life of the product is thereby increased.

[0190] In certain embodiments, Compound 1 Pattern 1, optionally in the form of a dihydrate, is used to prepare a liquid solution suitable for intravenous administration of Compound 1. The liquid solution of Compound 1 may have a higher purity than that prepared directly by known synthetic methods. In addition, the advantage of first preparing Compound 1 Pattern 1, optionally in the form of a dihydrate, and then converting it into a liquid solution may be that the overall shelf life of the product is thereby increased.

[0191] In certain embodiments, Compound 1 Pattern 1, which is optionally a dihydrate, is lyophilized. In these embodiments, Compound 1 Pattern 1, which is optionally a dihydrate, may be optionally mixed with one or more suitable excipients before or after lyophilization. For example, in certain embodiments, the present invention provides a solid lyophilized composition comprising Compound 1 Pattern 1, which is optionally a dihydrate. In certain embodiments, the present invention provides a solid lyophilized composition comprising Compound 1 Pattern 1, which is optionally a dihydrate, mannitol, and citric acid. In certain embodiments, the present invention provides a solid lyophilized composition comprising Compound 1 Pattern 1 dihydrochloride dihydrate, mannitol, and citric acid.

[0192] Non-limiting embodiments of the invention

[0193] 1. In certain embodiments, a crystalline compound of the following structure is provided:

[0194]

[0195] It is the dihydrochloride salt, optionally in the form of a dihydrate.

[0196] Other non-limiting embodiments include:

[0197] 2. The crystalline compound of embodiment 1, characterized in that the X-ray powder diffraction (XRPD) pattern comprises at least three 2θ values ​​selected from 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°.

[0198] 3. The crystalline compound of embodiment 2, wherein the XRPD pattern comprises at least four 2θ values ​​selected from 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°.

[0199] 4. The crystalline compound of embodiment 2, wherein the XRPD pattern comprises at least five 2θ values ​​selected from 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°.

[0200] 5. The crystalline compound of embodiment 2, wherein the XRPD pattern comprises at least six 2θ values ​​selected from 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°.

[0201] 6. The crystalline compound of embodiment 2, wherein the XRPD pattern comprises a 2θ value of at least 9.6±0.2°.

[0202] 7. The crystalline compound of embodiment 2, wherein the XRPD pattern comprises 2θ values ​​of at least 9.6±0.2°, 19.8±0.2°, and 21.3±0.2°.

[0203] 8. In certain embodiments, a lyophilized powder prepared from the crystalline compound of embodiment 1 is provided.

[0204] 9. The lyophilized powder of embodiment 8, wherein the crystalline compound of embodiment 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three 2θ values ​​selected from 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2°, and 28.6±0.2°.

[0205] 10. The lyophilized powder of embodiment 9, wherein the crystalline compound of embodiment 1 is characterized by an XRPD pattern comprising at least four 2θ values ​​selected from 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°.

[0206] 11. The lyophilized powder of embodiment 9, wherein the crystalline compound of embodiment 1 is characterized in that the XRPD pattern comprises at least five 2θ values ​​selected from 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°.

[0207] 12. The lyophilized powder of embodiment 9, wherein the crystalline compound of embodiment 1 is characterized in that the XRPD pattern comprises at least six 2θ values ​​selected from 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°.

[0208] 13. The lyophilized powder of embodiment 9, wherein the crystalline compound of embodiment 1 is characterized by an XRPD pattern comprising a 2θ value of at least 9.6±0.2°.

[0209] 14. The lyophilized powder of embodiment 9, wherein the crystalline compound of embodiment 1 is characterized by an XRPD pattern comprising 2θ values ​​of at least 9.6±0.2°, 19.8±0.2°, and 21.3±0.2°.

[0210] 15. In certain embodiments, a pharmaceutical composition comprising the crystalline compound of embodiment 1 and a pharmaceutically acceptable excipient is provided.

[0211] 16. The pharmaceutical composition of embodiment 15, wherein the pharmaceutical composition is suitable for intravenous delivery.

[0212] 17. The pharmaceutical composition of embodiment 15, comprising about 200 mg to about 600 mg of the crystalline compound of embodiment 1.

[0213] 18. The pharmaceutical composition of embodiment 15, comprising about 300 mg of the crystalline compound of embodiment 1.

[0214] 19. The pharmaceutical composition of embodiment 15, comprising about 150 mg / m 2 About 350 mg / m 2 The dosage of the crystalline compound of embodiment 1.

[0215] 20. The pharmaceutical composition of embodiment 15, further comprising about 300 mg mannitol and about 76 mg citric acid.

[0216] 21. The pharmaceutical composition of embodiment 15, comprising about 240 mg / m 2 The dosage of the crystalline compound of embodiment 1.

[0217] 22. In certain embodiments, a pharmaceutically acceptable reconstitution solution of the lyophilized powder of embodiment 8 is provided.

[0218] 23. The pharmaceutical solution of embodiment 23, wherein the solution is an aqueous solution.

[0219] 24. The pharmaceutical solution of embodiment 23, wherein the pharmaceutical composition is suitable for intravenous delivery.

[0220] 25. The pharmaceutical solution of embodiment 23, comprising about 200 mg to about 600 mg of the lyophilized powder of embodiment 8.

[0221] 26. The pharmaceutical solution of embodiment 23, comprising about 300 mg of the lyophilized powder of embodiment 8.

[0222] 27. The pharmaceutical solution of embodiment 23, comprising about 150 mg / m 2 About 350 mg / m 2 The lyophilized powder dosage of embodiment 8.

[0223] 28. The pharmaceutical solution of embodiment 23, further comprising about 300 mg mannitol and about 76 mg citric acid.

[0224] 29. The pharmaceutical solution of embodiment 23, further comprising sodium hydroxide or hydrochloric acid.

[0225] 30. The pharmaceutical solution of embodiment 23, comprising about 240 mg / m 2 The lyophilized powder dosage of embodiment 8.

[0226] 31. A lyophilized powder comprising a compound of the following structure:

[0227]

[0228] It is a dihydrochloride salt, which optionally includes a hydrate.

[0229] 32. The lyophilized powder of embodiment 31, wherein the compound is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three 2θ values ​​selected from 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2°, and 28.6±0.2°.

[0230] 33. The lyophilized powder of embodiment 31, wherein the compound is characterized by an XRPD pattern comprising at least four 2θ values ​​selected from 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°.

[0231] 34. The lyophilized powder of embodiment 31, wherein the compound is characterized by an XRPD pattern comprising at least five 2θ values ​​selected from 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2°, and 28.6±0.2°.

[0232] 35. The lyophilized powder of embodiment 31, wherein the compound is characterized by an XRPD pattern comprising at least six 2θ values ​​selected from 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2°, and 28.6±0.2°.

[0233] 36. The lyophilized powder of embodiment 31, wherein the compound is characterized by an XRPD pattern comprising a 2θ value of at least 9.6±0.2°.

[0234] 37. The lyophilized powder of embodiment 31, wherein the compound is characterized by an XRPD pattern comprising 2θ values ​​of at least 9.6±0.2°, 19.8±0.2°, and 21.3±0.2°.

[0235] Additional embodiments

[0236] 1. In one embodiment, a crystalline compound of the following structure is provided:

[0237]

[0238] It is the dihydrochloride salt.

[0239] 2. The crystalline compound of embodiment 1, characterized in that the X-ray powder diffraction (XRPD) pattern comprises at least three 2θ values ​​selected from 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°.

[0240] 3. The crystalline compound of embodiment 2, wherein the XRPD pattern comprises at least four 2θ values ​​selected from 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°.

[0241] 4. The crystalline compound of embodiment 2, wherein the XRPD pattern comprises at least five 2θ values ​​selected from 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°.

[0242] 5. The crystalline compound of embodiment 2, wherein the XRPD pattern comprises at least six 2θ values ​​selected from 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°.

[0243] 6. The crystalline compound of embodiment 2, wherein the XRPD pattern comprises a 2θ value of at least 9.6±0.2°.

[0244] 7. The crystalline compound of embodiment 2, wherein the XRPD pattern comprises 2θ values ​​of at least 9.6±0.2°, 19.8±0.2°, and 21.3±0.2°.

[0245] 8. A composition comprising the crystalline compound of any one of embodiments 1-7, mannitol and citric acid.

[0246] 9. A pharmaceutical composition comprising the crystalline compound of any one of embodiments 1-7 and a pharmaceutically acceptable excipient.

[0247] 10. The pharmaceutical composition of embodiment 9, wherein the pharmaceutically acceptable excipient comprises mannitol.

[0248] 11. The pharmaceutical composition of embodiment 9, wherein the pharmaceutically acceptable excipient comprises citric acid.

[0249] 12. The pharmaceutical composition of embodiment 9, wherein the pharmaceutically acceptable excipients comprise mannitol and citric acid.

[0250] 13. The pharmaceutical composition of embodiment 9, comprising about 200-600 mg of the crystalline compound.

[0251] 14. The pharmaceutical composition of embodiment 9, comprising about 300 mg of the crystalline compound.

[0252] 15. The pharmaceutical composition of embodiment 9, comprising about 349 mg of the crystalline compound.

[0253] 16. The pharmaceutical composition of embodiment 10, comprising about 250-350 mg mannitol.

[0254] 17. The pharmaceutical composition of embodiment 10, comprising about 300 mg of mannitol.

[0255] 18. The pharmaceutical composition of embodiment 11, comprising about 50-100 mg citric acid.

[0256] 19. The pharmaceutical composition of embodiment 11, comprising about 76 mg citric acid.

[0257] 20. The pharmaceutical composition of embodiment 12, comprising about 250-350 mg mannitol.

[0258] 21. The pharmaceutical composition of embodiment 12, comprising about 300 mg of mannitol.

[0259] 22. The pharmaceutical composition of embodiment 12, comprising about 50-100 mg citric acid.

[0260] 23. The pharmaceutical composition of embodiment 12, comprising about 76 mg citric acid.

[0261] 24. The pharmaceutical composition of embodiment 12, comprising about 300 mg mannitol and about 76 mg citric acid.

[0262] 25. The pharmaceutical composition of embodiment 24, comprising about 300 mg of the crystalline compound.

[0263] 26. The pharmaceutical composition of embodiment 12, comprising about 150 mg / m 2 About 350 mg / m 2 of the crystalline compound dosage.

[0264] 27. The pharmaceutical composition of embodiment 12, comprising about 240 mg / m 2 of the crystalline compound dosage.

[0265] 28. A pharmaceutical composition formed by dissolving the pharmaceutical composition of any one of embodiments 1 to 27 in a solvent.

[0266] 29. The pharmaceutical composition of embodiment 28, wherein the solvent is water.

[0267] 30. The pharmaceutical composition according to embodiment 28, wherein the solvent is an aqueous sodium chloride solution.

[0268] 31. The pharmaceutical composition of embodiment 30, wherein the sodium chloride concentration is between about 0.1% and 2%.

[0269] 32. The pharmaceutical composition of embodiment 30, wherein the sodium chloride concentration is about 0.9%.

[0270] 33. The pharmaceutical composition according to embodiment 28, wherein the solvent is an aqueous solution of glucose.

[0271] 34. The pharmaceutical composition of embodiment 33, wherein the glucose concentration is between about 1% and 10%.

[0272] 35. The pharmaceutical composition of embodiment 33, wherein the glucose concentration is about 5%.

[0273] 36. The pharmaceutical composition of any one of embodiments 28 to 35, wherein about 10 to 30 mL of solvent is present.

[0274] 37. The pharmaceutical composition of any one of embodiments 28 to 35, wherein about 19.5 mL of solvent is present.

[0275] 38. A method of treating a disorder mediated by CDK4 or CDK6, the method comprising administering to a patient in need thereof an effective amount of a compound of the pharmaceutical composition of any one of embodiments 1-37.

[0276] 39. A method of treating cancer, comprising administering to a patient in need thereof an effective amount of a compound of the pharmaceutical composition of any one of embodiments 1-37.

[0277] 40. A method of reducing the effects of chemotherapy on healthy cells in a patient being treated for cancer or abnormal cell proliferation, the method comprising administering to the subject an effective amount of at least one chemotherapeutic agent and an effective amount of a compound of the pharmaceutical composition of any one of embodiments 1-37.

[0278] 41. The method according to embodiment 40, wherein the healthy cells are hematopoietic stem cells or hematopoietic progenitor cells.

[0279] 42. The method of any one of embodiments 40-41, wherein the chemotherapeutic agent is carboplatin.

[0280] 43. The method of any one of embodiments 40-41, wherein the chemotherapeutic agent is cisplatin.

[0281] 44. The method according to any one of embodiments 42-43, wherein the method further comprises administering etoposide.

[0282] 45. The method of any one of embodiments 40-41, wherein the chemotherapeutic agent is topotecan.

[0283] 46. ​​The method according to any one of embodiments 38-45, wherein the patient is a human.

[0284] Preparation of Compound 1 Mode 1

[0285] In certain embodiments, compound 1 pattern 1 in the form of dihydrochloride dihydrate in a formulation is provided. In certain embodiments, the formulation comprises about 300-400 mg, about 350-400 mg, about 360-380 mg, or more particularly about 373 mg compound 1 pattern 1 dihydrochloride dihydrate, about 50-100, about 60-80, or more particularly about 76 mg citric acid monohydrate, and about 250-350 mg, about 280-320 mg, or more particularly about 300 mg mannitol, and optionally sodium hydroxide and / or hydrochloric acid to adjust pH as needed. In particular, 373 mg dihydrochloride dihydrate will provide 300 mg of treracili free base.

[0286] In certain embodiments, the formulation is lyophilized after Compound 1 Pattern 1 in the form of a dihydrochloride dihydrate is mixed with citric acid and mannitol. In certain embodiments, the formulation comprises lyophilized Compound 1 Pattern 1 in the form of a dihydrochloride dihydrate mixed with citric acid and mannitol, wherein the citric acid and mannitol are added after Compound 1 Pattern 1 in the form of a dihydrochloride dihydrate is lyophilized.

[0287] In certain embodiments, Compound 1 Pattern 1 in the form of a dihydrochloride salt in a formulation is provided. In certain embodiments, the formulation comprises about 300-400 mg, about 350-400 mg, or about 360-380 mg, or more particularly about 373 mg of Compound 1 Pattern 1 dihydrochloride dihydrate, about 50-100, about 60-80, or more particularly about 76 mg of citric acid monohydrate, and about 250-350 mg, about 280-320 mg, or more particularly about 300 mg of mannitol, and optionally sodium hydroxide and / or hydrochloric acid to adjust the pH as needed for reconstitution.

[0288] In certain embodiments, the formulation is sterile.

[0289] In certain embodiments, the formulation is lyophilized after Compound 1 Pattern 1 in the form of a dihydrochloride dihydrate is mixed with citric acid and mannitol. In certain embodiments, the formulation comprises lyophilized Compound 1 Pattern 1 in the form of a dihydrochloride mixed with citric acid and mannitol, wherein the citric acid and mannitol are added after Compound 1 Pattern 1 in the form of a dihydrochloride dihydrate is lyophilized.

[0290] In certain embodiments, a formulation is provided, wherein the formulation is prepared by lyophilizing about 300-400 mg, about 350-400 mg, or about 360-380 mg, or more particularly about 373 mg of compound 1 mode 1 dihydrochloride dihydrate, about 50-100, about 60-80, or more particularly about 76 mg of citric acid monohydrate and about 250-350 mg, about 280-320 mg, or more particularly about 300 mg of mannitol, and optionally sodium hydroxide and / or hydrochloric acid (to adjust pH as needed). In another embodiment, the formulation is produced by lyophilizing compound 1 mode 1 after mixing compound 1 mode 1 with about 50-100 mg, about 60-80 mg, or more particularly about 76 mg of citric acid monohydrate and about 280-320 mg, more particularly about 300 mg of mannitol.

[0291] Any of the above formulations can be reconstituted with about 5-100, 5-50, 10-30, about 10-25, or more particularly about 19.5 mL of sterile water, phosphate buffered saline, dilute sugar or another saline solution. In a non-limiting embodiment, the reconstitution solution is a sterile sodium chloride solution, for example containing about 0.9% NaCl, or a sterile sugar solution, for example, about 5% glucose solution. The resulting reconstitution solution will have any amount of trexacil required for the intended purpose, for example, about 5-50 mg / mL, about 10-25 mg / mL, or even about 15 mg / mL of trexacil. In certain embodiments, the resulting solution is then diluted prior to parenteral administration such as intravenous delivery.

[0292] Non-limiting examples of typical quality standards and drug functions are provided in the table below.

[0293]

[0294] NF = National Formulary; USP = United States Pharmacopoeia; Ph.Eur. = European Pharmacopoeia; N / A = not applicable; qs = s.s.

[0295] a The target solution weight filled into the vial before lyophilization was 12.252 g (12 mL).

[0296] b Amount calculated as free base (equivalent to 373 mg of Compound 1 Pattern 1 dihydrochloride dihydrate).

[0297] cIf necessary, it can be used to adjust the pH of the bulk solution.

[0298] d is used to dissolve the components and then removed during the lyophilization process.

[0299] eVacuum regulation using nitrogen as inert gas at the end of the lyophilization process.

[0300] The resulting formulation may be supplied in any suitable container, for example, in a 20 mL (Type 1) clear glass vial sealed with a 20 mm grey neoprene stopper and secured with a 20 mm aluminium outer seal and a plastic flip seal.

[0301] In certain embodiments, the solid dosage form is reconstituted with at least about 5-100, 5-50, 10-30, about 10-25, or more particularly about 19.5 mL of about 0.9% NaCl solution or sterile sugar solution (e.g., about 5% glucose solution), sodium hydroxide and / or hydrochloric acid is added to adjust the pH, and the reconstituted solution is then diluted to a suitable dose for administration to a person in need thereof, e.g., about 200-300 mg / m 2 , for example 240mg / m 2 dosage.

[0302] Chemical Description and Terminology

[0303] The compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0304] The terms "a" and "an" do not indicate a limitation of quantity, but rather indicate the presence of at least one of the referenced item. The term "or" means "and / or". Unless otherwise indicated herein, the recitation of a range of values ​​is intended merely to serve as a shorthand method of individually referring to each individual value falling within the range, and each individual value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included in the range and are independently combinable.

[0305] Unless otherwise specified herein or clearly contradicted by context, all methods described herein can be performed in any suitable order. Unless otherwise stated, the use of any and all examples or exemplary language (e.g., "such as") is intended to illustrate and not to limit the scope of the invention.

[0306] An "active agent" is a compound (including compounds disclosed herein), element, or mixture that, when administered to a patient alone or in combination with another compound, element, or mixture, will directly or indirectly impart a physiological effect to the patient. Indirect physiological effects may occur via metabolites or other indirect mechanisms.

[0307] "Deuteration (deuteration / deuterated)" refers to that hydrogen is replaced with deuterium so that deuterium exists beyond natural abundance and is therefore "enriched". 50% enrichment means that the content of deuterium rather than hydrogen at the designated position is 50%. For the sake of clarity, it is confirmed that the term "enrichment" as used herein does not refer to the enrichment percentage exceeding natural abundance. In other embodiments, at least 80%, at least 90% or at least 95% deuterium enrichment will be present at one or more designated deuterated positions. In other embodiments, at designated deuterated positions or indicated multiple positions, at least 96%, at least 97%, at least 98% or at least 99% deuterium enrichment will be present. In the absence of pointing out the contrary, the deuterium enrichment in the designated position of the compound described herein is at least 90%.

[0308] "Dosage form" refers to the unit of administration of an active agent. Non-limiting examples of dosage forms include tablets, capsules, injections, suspensions, liquids, intravenous solutions, emulsions, creams, ointments, suppositories, inhalable dosage forms, transdermal dosage forms, and the like.

[0309] A "pharmaceutical composition" is a composition comprising at least one active agent (such as an active compound disclosed herein or a salt of one of them) and at least one other substance (such as a carrier). A pharmaceutical composition optionally contains more than one active agent. A "pharmaceutical combination" or "combination therapy" refers to the administration of at least two active agents, and in one embodiment, three or four or more active agents, which may be combined in a single dosage form or provided together in separate dosage forms, optionally together with instructions for using the active agents together to treat a condition.

[0310] "Pharmaceutically acceptable salts" include derivatives of disclosed compounds, wherein the parent compound is modified by preparing its inorganic and organic, suitably non-toxic acid or base addition salts. The salts of the compounds of the present invention can be synthesized from the parent compound containing an alkaline or acidic part by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as a hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg or K) or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or in an organic solvent or in a mixture of the two. Pharmaceutically acceptable salts may be in the form of pure crystals or a single crystal form, or may be used in a non-crystalline or amorphous, glassy or vitreous form or a mixture thereof. In an alternative embodiment, the active compound may be provided in the form of a solvate.

[0311] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali metal or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts include conventional non-toxic salts and quaternary ammonium salts of the parent compound, for example, formed from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, and the like; and those derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH 2 )n-COOH (wherein n is 0-4) and the like. Additional lists of suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., p. 1418 (1985).

[0312] The term "carrier" refers to a diluent, excipient or vehicle with which the active compound is provided.

[0313] "Pharmaceutically acceptable excipient" refers to an excipient that can be used to prepare a pharmaceutical composition / combination that is generally safe, substantially non-toxic, and neither biologically undesirable nor otherwise undesirable. As used in this application, "pharmaceutically acceptable excipient" includes one and more than one such excipient.

[0314] A "patient" or "host" is a human or non-human animal, including but not limited to a simian, avian, feline, canine, bovine, equine, or porcine animal in need of medical treatment. Medical treatment may include treatment of an existing condition, such as a disease or disorder, or prophylactic or diagnostic treatment. In a particular embodiment, the patient or host is a human patient. Any condition that is responsive to triclasiclib in a patient, such as a host, may be treated, including for bone marrow protection or as an anti-tumor agent.

[0315] As used herein, the term "isolated" refers to a material in substantially pure form. An isolated compound does not have other components that would substantially affect the properties of the compound. In particular embodiments, the isolated form is at least 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99% pure.

[0316] Pharmaceutical compositions and dosage forms

[0317] In certain aspects of the present invention, a formulation is provided, wherein the formulation is prepared by mixing Pattern 1 Compound 1 with an excipient for lyophilization. As a non-limiting example, about 300 to 400 mg, about 350-400 mg, or more particularly about 373 mg of Compound 1 Pattern 1 dihydrochloride dihydrate (equivalent to about 300 mg of treracili free base) with about 50-100 mg, about 60-80 mg, or more particularly about 76 mg of citric acid monohydrate and about 250-350 mg, about 280-320 mg, or more particularly about 300 mg of mannitol and optionally sodium hydroxide and / or hydrochloric acid to adjust pH as needed. In another embodiment, the formulation is produced by lyophilizing Compound 1 Pattern 1 after mixing Compound 1 Pattern 1 with about 50-100 mg, about 60-80 mg, or more specifically about 76 mg of citric acid monohydrate and about 250-350 mg, about 280-320 mg, or more specifically about 300 mg of mannitol and optionally sodium hydroxide and / or hydrochloric acid (to adjust the pH as needed).

[0318] The formulation can be reconstituted with sterile water, and in a non-limiting embodiment, about 10-30, or more particularly about 5-100, 5-50, 10-30, about 10-25, or more particularly about 19.5 mL of sterile water, phosphate buffered saline, dilute sugar or another saline solution. In a non-limiting embodiment, the reconstitution solution is a sterile sodium chloride solution, for example, containing about 0.9% NaCl, or a sterile sugar solution, for example, about 5% glucose solution. The resulting reconstitution solution will have any amount of trexacil required for the intended purpose, for example, about 5-50 mg / mL, about 10-25 mg / mL or even about 15 mg / mL of trexacil. In certain embodiments, the resulting solution is then diluted before parenteral administration such as intravenous delivery.

[0319] Any suitable method that will achieve the desired therapeutic result can be used to administer the isolated compound 1 pattern 1 described herein or its substituted salt, isotope analog or prodrug to the host in an effective amount to treat any of the conditions described herein. Of course, the amount and time of the isolated compound 1 pattern 1 administered will depend on the host receiving treatment, the instructions of the supervising medical expert, the time course of exposure, the mode of administration, the pharmacokinetic properties of the specific active compound, and the judgment of the prescribing physician. Therefore, due to the differences between hosts and hosts, the dosage given below is a guide dosage, and the doctor can determine the dosage of the compound that the doctor believes is suitable for the treatment of the host. When considering the degree of treatment required, the doctor can balance multiple factors such as the age and weight of the host, the presence of previous diseases, and the presence of other diseases.

[0320] The pharmaceutical composition can be formulated into any pharmaceutically useful form, typically a parenteral formulation, such as an intravenous, intramuscular, subcutaneous or intradermal formulation. Other alternative formulations include oral, transdermal or intranasal formulations. For example, the pharmaceutical composition can be in the form of an IV bag or vial for injection, a pill, a capsule, a tablet, a transdermal patch, a subcutaneous patch, a dry powder, an inhalation formulation, in a medical device, a suppository, a buccal or sublingual formulation. Some dosage forms, such as tablets and capsules, are subdivided into unit doses of suitable size, wherein containing an appropriate amount of active ingredient, such as an effective amount to achieve the desired purpose.

[0321] In certain embodiments, the pharmaceutical composition is in the form of a composition containing at least about 50 mg / m 2 About 800 mg / m 2 , about 100mg / m 2 About 600 mg / m 2 , about 100mg / m 2 About 500 mg / m 2 , about 100mg / m 2 About 400 mg / m 2 , about 100mg / m 2 About 350 mg / m 2 , about 150mg / m 2 About 350 mg / m 2 , about 200mg / m 2 About 350 mg / m 2 , or about 200 mg / m 2 About 300 mg / m 2 In one embodiment, the pharmaceutical composition is in the form of about 240 mg / m 2 dosage form.

[0322] The therapeutically effective dose of the isolated compound 1 pattern 1 described herein will be determined by a healthcare practitioner based on the patient's condition, size and age, and route of delivery. In a non-limiting embodiment, a dose of about 0.1 to about 200 mg / kg has therapeutic efficacy, all weights being calculated based on the weight of the active compound. In some embodiments, the dose can be an amount of the isolated compound 1 pattern 1 required to provide a serum concentration of the active compound of up to about 10 nM, 50 nM, 100 nM, 200 nM, 300 nM, 400 nM, 500 nM, 600 nM, 700 nM, 800 nM, 900 nM, 1 μM, 5 μM, 10 μM, 20 μM, 30 μM or 40 μM.

[0323] In certain embodiments, the pharmaceutical composition is in a dosage form containing about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of active compound and optionally about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg, e.g., about 300 mg to about 400 mg of isolated Compound 1, Pattern 1, measured as the free base or a salt thereof, in a unit dosage form, e.g., a unit dosage form for parenteral delivery, such as an IV bag. Examples are dosage forms having at least 5, 10, 15, 20, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of active compound or a salt thereof. The pharmaceutical composition may also contain isolated Compound 1 Pattern 1 and the additional active agent in a molar ratio to achieve a desired result.

[0324] The isolated Compound 1 Mode 1 disclosed herein or used as described herein can be administered parenterally, intravenously, orally, topically, by inhalation or spray, sublingually, via implants (including ocular implants), transdermally, via buccal administration, rectally, intramuscularly, by inhalation, intraaortically, intracranially, subdermally, intraperitoneally, subcutaneously, nasally, sublingually or rectally or by other means in dosage unit formulations containing conventional pharmaceutically acceptable carriers.

[0325] According to the method disclosed in the present invention, a parenteral dosage form can be prepared from compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate. The dosage form may contain any pharmaceutically acceptable excipient, such as a liquid excipient. Non-limiting examples of liquid excipients include phosphate-buffered saline, non-buffered or buffered saline (e.g., NaCl solution without a buffer), sugar solution (e.g., glucose solution), or a combination thereof as needed. When prepared for parenteral administration, compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, can be dissolved in a suitable liquid excipient as a concentrated solution. This concentrated solution of compound 1 can then be diluted with the same or different liquid excipients to a suitable dose for treating a person in need thereof. In certain embodiments, the pH of the solution (before or after dilution) is adjusted with a pH adjusting agent (e.g., HCl or NaOH). In certain embodiments, an additional therapeutic agent or non-therapeutic agent is added to the solution before administration or to extend the shelf life.

[0326] According to the methods disclosed in the present invention, oral administration can be in any desired form, in which the isolated compound 1 pattern 1 is stable as a solid. In certain embodiments, the isolated compound 1 pattern 1 is delivered in solid micron particles or nanoparticles. When administered by inhalation, the isolated compound 1 pattern 1 can be in the form of a plurality of solid particles or droplets having any desired particle size, for example, from about 0.01, 0.1 or 0.5 to about 5, 10, 20 or more microns, and optionally from about 1 to about 2 microns. The isolated compound 1 pattern 1 disclosed in the present invention has good pharmacokinetic and pharmacodynamic properties, for example, when administered by oral or intravenous routes.

[0327] The pharmaceutical preparation may comprise the isolated Compound 1 Pattern 1 described herein or an alternative pharmaceutically acceptable salt thereof in any pharmaceutically acceptable carrier.

[0328] Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to make them suitable for administration to the patient being treated. The carrier may be inert or may have its own pharmaceutical benefits. The amount of carrier used with the compound is sufficient to provide the actual amount of material administered per unit dose of the compound.

[0329] Classes of carriers include, but are not limited to, binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavoring agents, glidants, lubricants, preservatives, stabilizers, surfactants, tablets, and wetting agents. Some carriers may be listed in more than one category, for example, vegetable oils may be used as lubricants in some formulations and as diluents in other formulations. Exemplary pharmaceutically acceptable carriers include sugars, starches, cellulose, powdered astragalus, malt, gelatin; talc and vegetable oils. Optional active agents may be included in the pharmaceutical composition that do not substantially interfere with the activity of the compounds of the invention.

[0330] Depending on the intended mode of administration, the pharmaceutical composition may be in a solid form or semisolid dosage form in which the isolated Compound 1 Pattern 1 is stable, such as tablets, suppositories, pills, capsules, powders, etc., preferably in a unit dosage form suitable for single administration of precise doses. The composition will contain an effective amount of the selected drug and a pharmaceutically acceptable carrier, and may also contain other pharmaceutical agents, adjuvants, diluents, buffers, etc.

[0331] Therefore, the compositions of the present disclosure can be used as pharmaceutical preparations, including those suitable for oral (including buccal and sublingual), rectal, nasal, topical, pulmonary, vaginal administration or in a form suitable for administration by inhalation or insufflation. The preferred mode of administration is oral administration using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, saccharin sodium, talcum, cellulose, glucose, sucrose, magnesium carbonate, etc.

[0332] In yet another embodiment, for the use of penetration enhancing excipients, it includes polymers such as: polycations (chitosan and its quaternary ammonium derivatives, poly-L-arginine, aminated gelatin); polyanions (N-carboxymethyl chitosan, polyacrylic acid); thiolated polymers (carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosan-thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugates).

[0333] For oral administration, the composition is usually in the form of tablets or capsules. Tablets and capsules are preferred oral administration forms. Tablets and capsules for oral use may contain one or more commonly used carriers such as lactose and corn starch. Lubricants such as magnesium stearate are usually added. Usually, the composition of the present disclosure can be combined with oral non-toxic pharmaceutically acceptable inert carriers such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc. Moreover, when necessary or necessary, suitable binders, lubricants, disintegrants and colorants can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, wax, etc. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrators include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

[0334] In addition to the active compound or its salt, the pharmaceutical preparation may also contain other additives, such as pH adjusting additives. In particular, useful pH adjusting agents include acids such as hydrochloric acid, alkalis or buffers such as sodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodium borate or sodium gluconate. In addition, the preparation may contain an antimicrobial preservative. Useful antimicrobial preservatives include methylparaben, propylparaben and benzyl alcohol. When the preparation is placed in a vial designed for multi-dose use, an antimicrobial preservative is usually used. The pharmaceutical preparation described herein can be lyophilized using techniques well known in the art.

[0335] For oral administration, pharmaceutical compositions can take the form of tablets, pills, capsules, powders, etc. Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate can be used together with various disintegrants such as starch (e.g., potato starch or tapioca starch) and some composite silicates and binding agents such as polyvinyl pyrrolidone, sucrose, gelatin and gum arabic. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talcum are usually very useful for tableting. Solid compositions of similar types can be used as fillers in soft and hard filled gelatin capsules.

[0336] Also provided are pharmaceutical formulations that provide controlled release of the compounds described herein, including through the use of degradable polymers as known in the art.

[0337] As used herein, the term "pharmaceutically acceptable salts" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with a host (e.g., a human host) without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use, as well as zwitterionic forms of the presently disclosed subject compounds, where possible.

[0338] In an alternative embodiment, Compound 1 Pattern 1 is not an HCl salt, but a salt as described below.

[0339] In one embodiment, the additional therapeutic agent described in the Combinations section below is administered as a pharmaceutically acceptable salt, such as the salts described below.

[0340] Therefore, the term "salt" refers to relatively non-toxic inorganic and organic acid addition salts of compounds disclosed in the present invention. These salts can be prepared in the final separation and purification process of the compound, or by reacting the purified compound in its free base form with a suitable organic acid or inorganic acid alone and separating the salt so formed. Basic compounds can form a wide range of different salts with various inorganic and organic acids. The acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid in a conventional manner to produce a salt. The free base form can be regenerated by contacting the salt form with a base in a conventional manner and separating the free base. The free base form may be different from their corresponding salt forms in certain physical properties such as solubility in polar solvents. Pharmaceutically acceptable base addition salts can be formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides, or organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, calcium, etc. Examples of suitable amines include, but are not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine. Base addition salts of acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base in a conventional manner to produce a salt. The free acid form may be regenerated by contacting the salt form with an acid in a conventional manner and isolating the free acid. The free acid forms may differ somewhat from their corresponding salt forms in certain physical properties, such as solubility in polar solvents.

[0341] Salts can be prepared from inorganic acid sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorus, etc. Representative salts include hydrobromates, hydrochlorides, sulfates, bisulfates, nitrates, acetates, oxalates, valerates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, phosphates, toluenesulfonates, citrates, maleates, fumarates, succinates, tartrates, naphthoates, methanesulfonates, glucoheptonates, lactobionates, lauryl sulfonates, and isethionates, etc. Salts can also be prepared from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like.

[0342] Pharmaceutically acceptable salts may include cations based on alkali metals and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. Also encompassed are salts of amino acids such as arginine salts, gluconates, galacturonates, etc. See, e.g., Berge et al., J. Pharm. Sci., 1977, 66, 1-19, which is incorporated herein by reference.

[0343] Formulations suitable for rectal administration are generally presented as unit dose suppositories. These can be prepared by mixing the disclosed active compound with one or more conventional solid carriers, such as cocoa butter, and then shaping the resulting mixture.

[0344] Formulations suitable for topical application to the skin preferably take the form of ointments, creams, lotions, pastes, gels, sprays, aerosols or oils that maintain the stability of the isolated Compound 1 Pattern 1. Useful carriers include petrolatum, lanolin, polyethylene glycol, alcohol, skin penetration enhancers, and combinations of two or more thereof.

[0345] The pharmaceutical composition suitable for transdermal administration can be presented as discrete patches, and these patches are suitable for keeping close contact with the epidermis of the recipient for a long time. The preparation suitable for transdermal administration can also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6): 318 (1986)) and is generally in the form of an optionally buffered active compound aqueous solution. In one embodiment, microneedle patches or devices are provided to deliver drugs through biological tissue or enter biological tissue, particularly skin. Microneedle patches or devices allow drugs to be delivered through or enter skin or other tissue barriers with clinically relevant speeds, with minimal or no damage, pain or stimulation to the damage, pain or stimulation of tissue.

[0346] Preparations suitable for administration to the lungs can be delivered by a wide range of passive breath-driven and active power-driven single / multi-dose dry powder inhalers (DPIs). The devices most commonly used for respiratory delivery include nebulizers, metered dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. The selection of suitable pulmonary delivery devices depends on parameters such as the properties of the drug and its preparation, the site of action, and the pathophysiology of the lungs.

[0347] It has been found that an IV solution of Compound 1 for injection into cancer patients to protect healthy cells or for anti-tumor use can be achieved by administering it as dihydrochloride or dihydrochloride dihydrate. This makes it possible to achieve the expected therapeutic effect because it can be delivered directly to the bloodstream in a concentrated form. In a major embodiment, the IV solution is prepared from a lyophilized powder comprising Compound 1 dihydrochloride, mannitol and citric acid.

[0348] In certain embodiments, the IV solution of compound 1 is prepared by a solid pharmaceutical composition, which is optionally dried by lyophilization. In certain embodiments, the composition comprises compound 1 in the form of dihydrochloride, such as compound 1 dihydrochloride mode 1. The composition may also include suitable excipients, such as fillers, buffers and / or one or more pH adjusting agents. In certain embodiments, the filler is a suitable sugar, such as mannitol. In certain embodiments, the buffer is a suitable weak acid or weak base with one or more acidic or basic sites. In certain embodiments, the buffer is a weak acid with two or more acidic sites, such as citric acid. In certain embodiments, the composition comprises NaOH, HCl and / or NaCl as a pH adjusting agent (NaOH and / or HCl) or residual salt (NaCl) from pH adjustment.

[0349] It has also been found that the freeze-dried compound 1 dihydrochloride composition comprising mannitol and citric acid is crystalline and easy to characterize by X-ray powder diffraction (XRPD). In certain embodiments, the freeze-dried compound 1 dihydrochloride composition comprises about 250 to 350mg, about 275 to 325mg or more particularly about 300mg of compound 1, wherein the weight of 300mg corresponds to free alkali. In a main embodiment, the compound 1 in the freeze-dried composition is a crystalline dihydrochloride in the form of pattern 1 herein. In other embodiments, the compound 1 in the freeze-dried composition is in the form of different pharmaceutically acceptable salts or a mixture of pharmaceutically acceptable salts. In certain embodiments, the compound 1 in the freeze-dried composition is in the form of a mixture of different patterns or patterns. In certain embodiments, the lyophilized Compound 1 composition comprises at least about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of Compound 1 dihydrochloride salt pattern 1 relative to other forms of Compound 1.

[0350] The lyophilized Compound 1 dihydrochloride composition described in Example 28 contains mannitol and citric acid and is characterized in that Fig.100The XRPD pattern shown in . Other suitable excipients may be added or replaced with other suitable excipients to achieve the desired effect. In certain embodiments, the compound 1 dihydrochloride composition is lyophilized, and in other embodiments, it is dried using another technique. In certain embodiments, the compound 1 dihydrochloride composition comprises mannitol, such as at least about 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, or 400 mg mannitol or about 200 to 400 mg, 225 to 375 mg, 250 to 350 mg, 275 to 325 mg, or 300 mg mannitol, or at least about 200 370, 380, 390, or 400 mg of mannitol. In certain embodiments, the compound 1 dihydrochloride composition comprises citric acid, for example, about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, or 150 mg citric acid or about 15 to 145 mg, 30 to 130 mg, 45 to 105 mg, 60 to 90 mg, 75 mg citric acid, or at least about 10, 15, 20, 25, 30, 130, 135, 140, 145, or 150 mg of citric acid, or up to about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, or 150 mg of citric acid. In certain embodiments, the compound 1 dihydrochloride composition comprises one or more additional salts formed by adjusting the pH of a bulk solution that is dried to form a composition, such as sodium chloride and / or various sodium salts of citric acid.

[0351] In a specific embodiment, the lyophilized Compound 1 dihydrochloride composition comprises about 349 mg of Compound 1 Model 1 dihydrochloride (equivalent to about 300 mg of trexacil free base), about 50-100 mg, about 60-80 mg or more particularly about 76 mg of citric acid monohydrate and about 280-320 mg, for example 300 mg of mannitol.

[0352] In certain aspects of the invention, isolated Compound 1 Mode 1 is used to make a lyophilized form, which is then formulated with a suitable solvent such as phosphate buffered saline for administration to a patient, for example, by intravenous delivery. In another embodiment, it can be formulated into a parenteral dosage form. This dosage form can be used, for example, for subcutaneous administration.

[0353] Favorable pharmaceutical forms of Trilacizide for effective treatment

[0354] In certain embodiments, a morphological form of Compound 1, such as Compound 1 dihydrochloride dihydrate, is used to produce an intravenous formulation as a bone marrow protector or is optionally administered together with chemotherapy for the treatment of cancer in conjunction with the standard of care for the cancer being treated. The standard of care for treating a particular cancer includes the use of a therapy approved by a regulatory agency such as the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the China National Medical Products Administration (NMPA) for the cancer being treated. In other embodiments, a pharmaceutical formulation as described herein is selected and managed by the patient's health care physician.

[0355] In certain embodiments, methods of treating a CDK4 / 6-mediated disorder, such as any disorder or method described below, are provided, wherein an IV solution comprising Compound 1, mannitol, and citric acid is administered to a patient, wherein the IV solution is formed by reconstituting a lyophilized Compound 1 dihydrochloride composition comprising mannitol and citric acid. In certain embodiments, the lyophilized composition comprises Compound 1 dihydrochloride, Model 1.

[0356] (i) Bone marrow protection

[0357] When used as a bone marrow protector, it can be applied as taught in WO 2014 / 144326, WO 2016 / 040848, WO 2018 / 106729 or PCT / US20 / 38557. For example, in certain embodiments, compound 1 pattern 1 dihydrochloride dihydrate or an intravenous solution prepared therefrom is applied every day of the treatment cycle of chemotherapy. For example, if chemotherapy is given on the 1st day, 2nd day and / or 3rd day of the treatment cycle, intravenous solution is also applied on the 1st day, 2nd day and / or 3rd day of the treatment cycle (for example, on the 1st day or the 1st day and the 2nd day of the treatment cycle). In another embodiment, intravenous solution is applied on the 1st and 8th day of a 21-day treatment cycle, as a non-limiting example, in combination with gemcitabine, carboplatin or topotecan.

[0358] In certain embodiments, the isolated compound 1 pattern 1 of the present invention reduces the effects of chemotherapeutic agent toxicity on CDK4 / 6 replication-dependent healthy cells such as hematopoietic stem cells and hematopoietic progenitor cells (collectively referred to as HSPCs) and / or renal epithelial cells in a subject (usually, a human) who will, is, or has been exposed to a chemotherapeutic agent (usually, a DNA damaging agent).

[0359] In one embodiment, the subject has been exposed to a chemotherapeutic agent, and using the intravenous solution described herein, the subject's CDK4 / 6 replication-dependent healthy cells are placed in G1 arrest after exposure to reduce, for example, DNA damage. In one embodiment, the compound is at least 1 / 2 hour, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 20 hours or more after exposure to the chemotherapeutic agent. In an alternative embodiment, compound 1 mode 1 dihydrochloride dihydrate or an intravenous solution prepared therefrom is administered at least 1 / 2 hour, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 20 hours or more before exposure to the chemotherapeutic agent. In certain embodiments, Compound 1 Pattern 1 dihydrochloride dihydrate or an intravenous solution prepared therefrom is administered about 4 hours prior to chemotherapy.

[0360] In one embodiment, an intravenous solution prepared from Compound 1 Pattern 1 dihydrochloride dihydrate is administered in combination with a chemotherapeutic agent, including but not limited to treatment regimens in which the chemotherapeutic agent is administered on days 1-3 every 21 days; days 1-3 every 28 days; day 1 every 3 weeks; days 1, 8, and 15 every 28 days; day 1 and day 8 every 28 days; day 1 and day 8 every 21 days; days 1-5 every 21 days; 1 day per week for 6-8 weeks; day 1, day 22, and day 43; day 1 and day 2 of each week; days 1-4 and days 22-25; days 1-4, days 22-25, and days 43-46; and similar type regimens, wherein the CDK4 / 6-replication-dependent cells are arrested in the G1 phase during exposure to the chemotherapeutic agent.

[0361] In one embodiment, isolated Compound 1 Pattern 1 can allow for dose intensification in medically relevant chemotherapy (e.g., more treatments can be given in a fixed period of time), which will translate into better efficacy. Thus, the methods disclosed herein can result in less toxic and more effective chemotherapy regimens.

[0362] In some embodiments, the use of isolated compound 1 pattern 1 described herein can result in reduced or greatly limited off-target effects, for example, related to the inhibition of kinases other than CDK4 and / or CDK6, such as CDK2. In addition, in certain embodiments, the use of isolated compound 1 pattern 1 described herein should not induce cell cycle arrest in CDK4 / 6 replication-independent cells.

[0363] In some embodiments, the use of the isolated compound 1 pattern 1 described herein reduces the risk of undesirable off-target effects, including but not limited to long-term toxicity, antioxidant effects and estrogenic effects. Antioxidant effects can be determined by standard assays known in the art. For example, a compound without significant antioxidant effects is a compound that does not significantly remove free radicals such as oxygen free radicals. The antioxidant effects of a compound can be compared with compounds with known antioxidant activity such as genistein. Therefore, a compound without significant antioxidant activity can be a compound with less than about 2, 3, 5, 10, 30 or 100 times antioxidant activity relative to genistein. Estrogenic activity can also be determined via known assays. For example, a non-estrogenic compound is a compound that does not significantly bind to and activate estrogen receptors. A compound with greatly limited estrogenic effects can be a compound with less than about 2, 3, 5, 10, 20 or 100 times estrogenic activity relative to a compound with estrogenic activity such as genistein.

[0364] Compound 1 Mode 1, for example, Compound 1 Mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, can be administered to a patient parenterally (e.g., intravenously) prior to administration of immune response induction chemotherapy such as ICD induction chemotherapy. In some embodiments, Compound 1 is administered up to about 24 hours or less, or up to about 20, 15, 10, 5 or 4 hours or less, for example, about 30-60 minutes or less, prior to administration of chemotherapy. In some embodiments, Compound 1 is administered approximately 22 to 26 hours prior to administration of chemotherapy, and is administered again about 4 hours or less, for example, about 30-60 minutes or less, prior to administration of chemotherapy. In some embodiments, the dose of Compound 1 administered is between about 180 and about 280 mg / m 2 For example, the dosage is up to about 100, 125, 150, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, or 280 mg / m 2 Or any dosage between these numbers, as determined by a healthcare practitioner as appropriate. In a particular embodiment, the dosage is about 240 mg / m 2 .

[0365] Typically, compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate, or a preparation produced therefrom, is administered to a subject prior to treatment with a chemotherapeutic agent so that its concentration reaches a peak serum level before or during treatment with a chemotherapeutic agent, allowing the proliferation of immune effector cells to be inhibited, thereby protecting them from the harmful effects of chemotherapy. In some embodiments, compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate, or a preparation produced therefrom, is administered simultaneously or close to exposure to a chemotherapeutic agent. Alternatively, if it is necessary to reduce immune effector cell damage associated with exposure to a chemotherapeutic agent, a CDK4 / 6 inhibitor described herein may be administered after exposure to a chemotherapeutic agent. In one embodiment, an aqueous solution produced by compound 1 pattern 1 is administered to a patient in need thereof.

[0366] In some embodiments, Compound 1 Pattern 1, e.g., Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation derived therefrom, is administered to a subject less than about 24 hours, about 20 hours, about 16 hours, about 12 hours, about 8 hours, about 4 hours, about 2.5 hours, about 2 hours, about 1 hour, about 1 / 2 hour, or less prior to treatment with a chemotherapeutic agent. In a particular embodiment, Compound 1 Pattern 1, e.g., Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation derived therefrom, is administered about 1 / 2 hour prior to administration of a chemotherapeutic agent.

[0367] In some embodiments, Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation produced therefrom, is administered to a subject twice before the administration of chemotherapy. For example, in some embodiments, Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation produced therefrom, is administered about 18 to 28 hours before the administration of chemotherapy, and then administered again less than about 4 hours, about 2.5 hours, about 2 hours, about 1 hour, about 1 / 2 hour or less before treatment with the chemotherapeutic agent. In a particular embodiment, Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation produced therefrom, is administered about 22 to 26 hours before the administration of the chemotherapeutic agent and administered again about 1 / 2 hour or less before the administration of the chemotherapeutic agent.

[0368] In certain embodiments, Compound 1 Mode 1, such as Compound 1 Mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, is administered prior to or concurrently with the administration of a chemotherapeutic agent, wherein the chemotherapeutic agent is administered, for example, on days 1-3 every 21 days; on days 1-3 every 28 days; on day 1 every 3 weeks; on days 1, 8, and 15 every 28 days; on days 1 and 8 every 28 days; on days 1 and 8 every 21 days; on days 1-5 every 21 days; on day 1 every week for 6-8 weeks; on days 1, 22, and 43; on days 1 and 2 every week; on days 1-4 and 22-25; on days 1-4, 22-25, and 43-46; and similar types of chemotherapy regimens. In some embodiments, Compound 1 Mode 1, such as Compound 1 Mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, is administered prior to or concurrently with the administration of a chemotherapeutic agent at least once during a chemotherapy treatment regimen. In some embodiments, Compound 1 Mode 1, such as Compound 1 Mode 1 dihydrochloride dihydrate, or a formulation derived therefrom, is administered prior to or concurrently with one or more administrations of a chemotherapeutic agent during a chemotherapeutic treatment regimen. In one embodiment, Compound 1 Mode 1, such as Compound 1 Mode 1 dihydrochloride dihydrate, or a formulation derived therefrom, is administered prior to or concurrently with each administration of a chemotherapeutic agent during a chemotherapeutic treatment regimen.

[0369] In some embodiments, compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a preparation produced therefrom, is administered before or simultaneously with each administration of a chemotherapeutic agent during, for example, a standard chemotherapy protocol such as a 21-day cycle. After the standard chemotherapy protocol is stopped, compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a preparation produced therefrom, can also be administered alone at a maintenance dose. In some embodiments, compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a preparation produced therefrom, is also administered once a week for at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 26, 52, 104 weeks or longer. In some embodiments, compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a preparation produced therefrom, is administered once every 21 days after the chemotherapy protocol is stopped. In one embodiment, Compound 1 Pattern 1, e.g., Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation derived therefrom, is a fast-acting, short half-life CDK4 / 6 inhibitor.

[0370] In some embodiments, Compound 1 Mode 1, e.g., Compound 1 Mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, is administered with a chemotherapeutic agent in a maintenance therapy treatment regimen after standard chemotherapy procedures have been discontinued. Maintenance therapy can include continuing a drug given as part of a first-line or previous regimen (continuation maintenance) or treatment with a new drug (conversion maintenance).

[0371] In some embodiments, Compound 1 Mode 1, such as Compound 1 Mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, is also administered in a maintenance treatment regimen, wherein Compound 1 Mode 1, such as Compound 1 Mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, is administered in combination with a reduced maintenance dose of chemotherapy at regular dosing intervals, such as, but not limited to, once a week, once every two weeks, once every three weeks, once every month, once every six weeks, once every two months, once every three months, or once every six months after completion of the initial chemotherapy treatment. In some embodiments, Compound 1 Mode 1, such as Compound 1 Mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, is administered with the same drug used in the previous chemotherapy treatment phase. In some embodiments, Compound 1 Mode 1, such as Compound 1 Mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, is administered with a different chemotherapeutic agent used in the previous chemotherapy treatment phase.

[0372] Standard cancer chemotherapy can promote tumor immunity in two main ways: (i) inducing immunogenic cell death as part of its intended therapeutic effect; (ii) destroying the strategies used by tumors to evade immune responses. A large amount of data shows that some chemotherapy drugs mediate their anti-tumor effects at least in part by inducing immunogenic cell death at their standard doses and schedules (see, for example, Emens et al., Chemotherapy: friend of foe to cancer vaccines? Curr Opin Mol Ther 2001; 3: 77–84; Vanmeerbeek et al., Trial Watch: Chemotherapy-Induced Immunogenic Cell Death in Immuni-Oncology. Oncoimmunology Vol. 9, No. 1 2020: e1703449, both of which are incorporated herein by reference).

[0373] Immunogenic cell death (ICD) is a type of cell death characterized by, for example, cell surface translocation of calreticulin (CRT), extracellular release of ATP and high-mobility group box 1 protein (HMBG1), and stimulation of type I interferon (IFN) responses. ICD in cancer cells may trigger anticancer immune responses. A variety of chemotherapeutic agents can induce ICD, as indicated by alterations in the abundance and composition of tumor-infiltrating lymphocytes (TILs).

[0374] In response to ICD induction chemotherapy, tumor cells expose CRT on the cell surface before death and release damage-associated molecular pattern (DAMP) molecules such as ATP during apoptosis or HMGB1 during secondary necrosis. These DAMPs stimulate the recruitment of dendritic cells (DC) into the tumor bed, the uptake and processing of tumor antigens, and optimal antigen presentation to T cells. The cross-priming of CD8+T-cells is triggered by mature DCs and γδT-cells in an IL-1β and IL-17 dependent manner. The primed CTLs then trigger a direct cytotoxic response to kill the remaining tumor cells by generating IFN-γ, perforin-1, and granzyme B. In certain embodiments, compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate, or a preparation produced therefrom, is used in combination with ICD induction chemotherapy for bone marrow protection.

[0375] ICD induction chemotherapy used in the present invention includes alkylating agents such as cyclophosphamide, trabectedin, temozolomide, melphalan, dacarbazine and oxaliplatin; antimetabolites such as methotrexate, mitoxantrone, gemcitabine and 5-fluorouracil (5-FU); cytotoxic antibiotics such as bleomycin and anthracyclines, including doxorubicin, daunorubicin, epirubicin, idarubicin and valrubicin; taxanes such as paclitaxel, cabazitaxel and docetaxel; topoisomerase inhibitors such as topotecan, irinotecan and etoposide; platinum compounds such as carboplatin and cisplatin; anti-microtubule vinca alkaloid agents such as vinblastine, vincristine, vinorelbine and vindesine. Other ICD induction chemotherapy includes bortezomib (a 26S proteasome subunit inhibitor), nitrogen mustard, diazocine, mitomycin C, fludarabine and cytarabine. In some embodiments, ICD induction chemotherapy is selected from idarubicin, epirubicin, doxorubicin, mitoxantrone, oxaliplatin, bortezomib, gemcitabine and cyclophosphamide and combinations thereof. In an alternative embodiment, the chemotherapy administered can induce an immune response, and tumor immunity can be regulated by a mechanism different from immunogenic cell death. Various chemotherapy drugs can regulate the activity of different immune cell subsets or the immune phenotype of tumor cells by enhancing antigen presentation, enhancing the expression of costimulatory molecules (including B7.1 (CD80) and B7.2 (CD86)), downregulating checkpoint molecules such as programmed death ligand 1 (PD-L1), or promoting tumor cell death through fas, perforin or granzyme B pathways. Chemotherapy that modulates tumor immunity can be achieved by: abrogating myeloid-derived suppressor cell (MDSC) activity, such as gemcitabine, 5-fluorouracil, cisplatin, and doxorubicin; abrogating Treg activity, such as cyclophosphamide, 5-fluorouracil; paclitaxel, cisplatin, and fludarabine; enhancing T-cell cross-priming, such as gemcitabine and anthracyclines such as doxorubicin, daunorubicin, epirubicin, valrubicin, and idarubicin; enhancing dendritic cell activation, such as anthracyclines, taxanes, cyclophosphamide, vinca alkaloids, methotrexate, and mitomycin C; promoting an antitumor CD4+ T-cell phenotype, such as cyclophosphamide and paclitaxel; and promoting tumor cell recognition and lysis, such as cyclophosphamide, 5-fluorouracil, paclitaxel, doxorubicin, cisplatin, and cytarabine.

[0376] In some embodiments, a method of selecting a patient or patient population for cancer treatment is provided, wherein the cancer treatment comprises administering Compound 1 Mode 1, such as Compound 1 Mode 1 dihydrochloride dihydrate, or a formulation derived therefrom, in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenicity, and if so, administering an effective amount of an alkylating agent such as cyclophosphamide, trabectedin, temozolomide, melphalan, dacarbazine, or oxaliplatin; an antimetabolite such as methotrexate, mitoxantrone, gemcitabine, or the like. , 5-fluorouracil (5-FU); cytotoxic antibiotics such as bleomycin or anthracyclines such as doxorubicin, daunorubicin, epirubicin, idarubicin or valrubicin; taxanes such as paclitaxel, cabazitaxel and docetaxel; topoisomerase inhibitors such as topotecan, irinotecan and etoposide; platinum compounds such as carboplatin and cisplatin; anti-microtubule vinca alkaloids such as vinblastine, vincristine, vinorelbine and vindesine; bortezomib; nitrogen mustard; diazonone; fludarabine; mitomycin C; and cytarabine are combined to administer to the patient an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a preparation produced therefrom. In some embodiments, compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a preparation produced therefrom, is administered in combination with chemotherapy, excluding the administration of an immune checkpoint inhibitor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressive immune tumor. In some embodiments, the patient has an altered-barrier immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature". In some embodiments, the patient has a tumor that is PD-L1 positive.

[0377] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, to the patient in combination with an effective amount of cyclophosphamide. In some embodiments, administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in combination with cyclophosphamide does not include administering an immune checkpoint inhibitor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has a modified-immunosuppressive immune tumor. In some embodiments, the patient has a modified-blocking immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0378] In some embodiments, a method of selecting a patient or patient population for cancer treatment is provided, the cancer treatment comprising administering a CDK4 / 6 inhibitor with chemotherapy in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering to the patient an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in combination with an effective amount of trabectedin. In some embodiments, the administration of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in combination with trabectedin does not include the administration of an immune checkpoint inhibitor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressive immune tumor. In some embodiments, the patient has an altered-barrier immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as high "IFN-γ signature" or high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0379] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, to the patient in combination with an effective amount of temozolomide. In some embodiments, administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in combination with temozolomide does not include administering an immune checkpoint inhibitor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has a modified-immunosuppressive immune tumor. In some embodiments, the patient has a modified-barrier immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0380] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering Compound 1 Mode 1, such as Compound 1 Mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of Compound 1 Mode 1, such as Compound 1 Mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, to the patient in combination with an effective amount of melphalan. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressive immune tumor. In some embodiments, the patient has an altered-barrier immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0381] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering a CDK4 / 6 inhibitor and chemotherapy in a manner that increases the progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, to the patient in combination with an effective amount of dacarbazine. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressive immune tumor. In some embodiments, the patient has an altered-barrier immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature". In some embodiments, the patient has a PD-L1-positive tumor.

[0382] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, to the patient in combination with an effective amount of oxaliplatin. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressive immune tumor. In some embodiments, the patient has an altered-barrier immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0383] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, to the patient in combination with an effective amount of methotrexate. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressive immune tumor. In some embodiments, the patient has an altered-barrier immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0384] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering a CDK4 / 6 inhibitor and chemotherapy in a manner that increases the progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in combination with an effective amount of 5-fluorouracil (5-FU). In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressive immune tumor. In some embodiments, the patient has an altered-barrier immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0385] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, to the patient in combination with an effective amount of gemcitabine. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressive immune tumor. In some embodiments, the patient has an altered-barrier immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature."

[0386] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, to the patient in combination with an effective amount of mitoxantrone. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressive immune tumor. In some embodiments, the patient has an altered-barrier immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0387] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering a CDK4 / 6 inhibitor and chemotherapy in a manner that increases the progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, to the patient in combination with an effective amount of doxorubicin. In some embodiments, the administration of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in combination with doxorubicin does not include the administration of an immune checkpoint inhibitor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressive immune tumor. In some embodiments, the patient has an altered-barrier immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as high "IFN-γ signature" or high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0388] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, to the patient in combination with an effective amount of daunorubicin. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressive immune tumor. In some embodiments, the patient has an altered-barrier immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0389] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, to the patient in combination with an effective amount of idarubicin. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressive immune tumor. In some embodiments, the patient has an altered-barrier immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0390] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, to the patient in combination with an effective amount of valrubicin. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressive immune tumor. In some embodiments, the patient has an altered-barrier immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0391] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering a CDK4 / 6 inhibitor and chemotherapy in a manner that increases the progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of Compound 1 Mode 1, such as Compound 1 Mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in combination with an effective amount of epirubicin to the patient. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressive immune tumor. In some embodiments, the patient has an altered-barrier immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature". In some embodiments, the patient has a PD-L1-positive tumor.

[0392] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a preparation produced therefrom, in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a preparation produced therefrom, to the patient in combination with an effective amount of bleomycin. In some embodiments, administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a preparation produced therefrom, in combination with bleomycin does not include administering an immune checkpoint inhibitor. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has a modified-immunosuppressive immune tumor. In some embodiments, the patient has a modified-blocking immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature."

[0393] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, to the patient in combination with an effective amount of bortezomib. In some embodiments, administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in combination with bortezomib does not include administering an immune checkpoint inhibitor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has a modified-immunosuppressive immune tumor. In some embodiments, the patient has a modified-blocking immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0394] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, to the patient in combination with an effective amount of paclitaxel. In some embodiments, administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in combination with paclitaxel does not include administering an immune checkpoint inhibitor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has a modified-immunosuppressive immune tumor. In some embodiments, the patient has a modified-blocking immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0395] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, to the patient in combination with an effective amount of docetaxel, compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom. In some embodiments, administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in combination with docetaxel does not include administering an immune checkpoint inhibitor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has a modified-immunosuppressive immune tumor. In some embodiments, the patient has an altered-barrier immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0396] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, to the patient in combination with an effective amount of cabazitaxel. In some embodiments, administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in combination with cabazitaxel does not include administering an immune checkpoint inhibitor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressive immune tumor. In some embodiments, the patient has an altered-blocking immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0397] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering a CDK4 / 6 inhibitor with chemotherapy in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering to the patient an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in combination with an effective amount of topotecan. In some embodiments, the administration of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in combination with topotecan does not include the administration of an immune checkpoint inhibitor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressive immune tumor. In some embodiments, the patient has an altered-barrier immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as high "IFN-γ signature" or high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0398] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, to the patient in combination with an effective amount of etoposide. In some embodiments, administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in combination with etoposide does not include administering an immune checkpoint inhibitor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has a modified-immunosuppressive immune tumor. In some embodiments, the patient has a modified-blocking immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0399] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, to the patient in combination with an effective amount of irinotecan. In some embodiments, administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in combination with irinotecan does not include administering an immune checkpoint inhibitor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has a modified-immunosuppressive immune tumor. In some embodiments, the patient has a modified-blocking immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0400] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, to the patient in combination with an effective amount of cisplatin. In some embodiments, administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in combination with cisplatin does not include administering an immune checkpoint inhibitor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has a modified-immunosuppressive immune tumor. In some embodiments, the patient has a modified-blocking immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0401] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, to the patient in combination with an effective amount of carboplatin. In some embodiments, administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in combination with carboplatin does not include administering an immune checkpoint inhibitor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has a modified-immunosuppressive immune tumor. In some embodiments, the patient has a modified-blocking immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0402] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a preparation produced therefrom, in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a preparation produced therefrom, to the patient in combination with an effective amount of vinblastine. In some embodiments, administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a preparation produced therefrom, in combination with vinblastine does not include administering an immune checkpoint inhibitor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has a modified-immunosuppressive immune tumor. In some embodiments, the patient has a modified-blocking immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0403] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a preparation produced therefrom, in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a preparation produced therefrom, to the patient in combination with an effective amount of vincristine. In some embodiments, administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a preparation produced therefrom, in combination with vincristine does not include administering an immune checkpoint inhibitor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has a modified-immunosuppressive immune tumor. In some embodiments, the patient has a modified-blocking immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0404] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, to the patient in combination with an effective amount of vinorelbine. In some embodiments, administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in combination with vinorelbine does not include administering an immune checkpoint inhibitor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has a modified-immunosuppressive immune tumor. In some embodiments, the patient has a modified-blocking immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0405] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, to the patient in combination with an effective amount of vindesine. In some embodiments, administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in combination with vindesine does not include administering an immune checkpoint inhibitor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has a modified-immunosuppressive immune tumor. In some embodiments, the patient has a modified-blocking immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0406] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering Compound 1 Mode 1, such as Compound 1 Mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of Compound 1 Mode 1, such as Compound 1 Mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, to the patient in combination with an effective amount of diazaquinone. In some embodiments, administering Compound 1 Mode 1, such as Compound 1 Mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in combination with diazaquinone does not include administering an immune checkpoint inhibitor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressive immune tumor. In some embodiments, the patient has an altered-barrier immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0407] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a preparation produced therefrom, in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a preparation produced therefrom, to the patient in combination with an effective amount of nitrogen mustard. In some embodiments, administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a preparation produced therefrom, in combination with nitrogen mustard does not include administering an immune checkpoint inhibitor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has a modified-immunosuppressive immune tumor. In some embodiments, the patient has a modified-blocking immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0408] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a preparation produced therefrom, in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a preparation produced therefrom, to the patient in combination with an effective amount of mitomycin C. In some embodiments, administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a preparation produced therefrom, in combination with mitomycin C does not include administering an immune checkpoint inhibitor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has a modified-immunosuppressive immune tumor. In some embodiments, the patient has a modified-barrier immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0409] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, to the patient in combination with an effective amount of fludarabine. In some embodiments, administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in combination with fludarabine does not include administering an immune checkpoint inhibitor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has a modified-immunosuppressive immune tumor. In some embodiments, the patient has a modified-blocking immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0410] In some embodiments, a method of selecting a patient or a patient population for cancer treatment is provided, the cancer treatment comprising administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in a manner that increases progression-free survival or overall survival of the patient or patient population, the method comprising determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenicity sensitive to CDK4 / 6 inhibitor treatment, or immunogenic, and if so, administering an effective amount of compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, to the patient in combination with an effective amount of cytarabine. In some embodiments, administering compound 1 mode 1, such as compound 1 mode 1 dihydrochloride dihydrate, or a formulation produced therefrom, in combination with cytarabine does not include administering an immune checkpoint inhibitor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has a modified-immunosuppressive immune tumor. In some embodiments, the patient has a modified-blocking immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-γ dominant" category cancer. In some embodiments, the patient has a tumor classified as a high "IFN-γ signature" or a high "extended immune signature." In some embodiments, the patient has a tumor that is PD-L1 positive.

[0411] In any of the above embodiments, the patient to be treated has been determined to have cancer, and the cancer has a surrounding microenvironment that is favorable for immunomodulation, immunogenic, or immunogenic to CDK4 / 6 inhibitor treatment. Therefore, if the cancer meets the categories as described herein, the patient may be suitable for the described treatment. In some embodiments, the cancer to be treated is selected from breast cancer, including but not limited to estrogen receptor (ER)-positive breast cancer and triple-negative breast cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, classical Hodgkin lymphoma (cHL), diffuse large B-cell lymphoma, bladder cancer, primary mediastinal B-cell lymphoma (PBMCL), urothelial carcinoma, high microsatellite instability (MSI-H) solid tumors, mismatch repair deficiency (dMMR) solid tumors, stomach or gastroesophageal junction (GEJ) adenocarcinoma, esophageal squamous cell carcinoma, cervical cancer, endometrial cancer, bile duct cancer, hepatocellular carcinoma, Merkel cell carcinoma, renal cell carcinoma, ovarian cancer, anal canal cancer, colorectal cancer, skin melanoma and melanoma.

[0412] In some embodiments, a checkpoint inhibitor is not administered to the patient.

[0413] In some embodiments, a checkpoint inhibitor is administered to the patient.

[0414] (ii) Anti-tumor therapy

[0415] In addition to being useful for preparing advantageous intravenous solutions for bone marrow protection, Compound 1 Pattern 1 dihydrochloride dihydrate can also be used to treat abnormal cell proliferation disorders, inflammatory disorders, immune disorders, or autoimmune disorders.

[0416] In certain aspects, a method of treating a proliferative disorder in a host (including a human) is provided, comprising administering isolated Compound 1, e.g., in the form of a dihydrochloride dihydrate, optionally in a pharmaceutically acceptable carrier. Non-limiting examples of disorders include tumors, cancers, disorders associated with abnormal cell proliferation, inflammatory disorders, immune disorders, and autoimmune disorders.

[0417] In one embodiment, Compound 1 Mode 1 is administered parenterally. For bone marrow protection, the administration may be performed daily or with treatment holidays.

[0418] When administered to a host (including humans) in an effective amount to treat tumors, cancers (solid cancer, non-solid cancer, diffuse cancer, blood cancer, etc.), abnormal cell proliferation, immune disorders, inflammatory disorders, blood disorders, myeloproliferative disorders or lymphoproliferative disorders such as B-cell or T-cell lymphoma, multiple myeloma, breast cancer, prostate cancer, AML, ALL, ACL, lung cancer, pancreatic cancer, colon cancer, skin cancer, melanoma, Waldenstrom's macroglobulinemia, Wiskott-Aldrich syndrome or post-transplant lymphoma Proliferative disorders; autoimmune disorders, such as lupus, Crohn's disease, Addison's disease, celiac disease, dermatomyositis, Graves' disease, thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis or type I diabetes; cardiac dysfunction diseases, including hypercholesterolemia; infectious diseases, including viral and / or bacterial infections; inflammatory patients, including asthma, chronic peptic ulcers, tuberculosis, rheumatoid arthritis, periodontitis, ulcerative colitis or hepatitis, compound 1 mode 1 can be used as a therapeutic agent in a certain dosage form.

[0419] Exemplary proliferative disorders include, but are not limited to, benign growths, neoplasms, tumors, cancers (Rb positive or Rb negative), autoimmune disorders, inflammatory disorders, graft versus host disease, and fibrotic disorders.

[0420] Non-limiting examples of cancers that can be treated according to the present invention include, but are not limited to, acoustic neuroma, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelioma, angiosarcoma), appendix cancer, benign monoclonal gammopathy, bile duct cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., breast adenocarcinoma, breast papillary carcinoma, breast carcinoma, medullary carcinoma of the breast), brain cancer (e.g., meningioma; gliomas such as astrocytoma, oligodendroglioma; medulloblastoma), bronchial carcinoma, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal cancer), ... adenocarcinoma), epithelial cancer, ependymoma, endothelial sarcoma (e.g., Kaposi sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma), Ewing's sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), familial eosinophilia, gallbladder cancer, gastric cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma), oral cancer (e.g., oral squamous cell carcinoma (OSCC), pharyngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal carcinoma, oropharyngeal cancer)), hematopoietic cancer (e.g., leukemia such as acute lymphoblastic leukemia, Leukemia (ALL) - also known as acute lymphocytic leukemia or acute lymphoid leukemia (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL); lymphomas such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL)) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., "Waldenstein's macroglobulinemia"), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma;and T-cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); a mixture of one or more leukemias / lymphomas as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumor, immune cell amyloid leiomyoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myeloid metaplasia (AMM) (also known as myelofibrosis (MF)), chronic idiopathic myelofibrosis, chronic myelofibrosis (CMF), myelofibrosis ( ... neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibromas (e.g., neurofibromatosis (NF) type 1 or 2, schwannomatosis), neuroendocrine cancers (e.g., gastroenteropancreatic neuroendocrine tumors (GEP-NET), carcinoid tumors), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumor), penile cancer (e.g., Paget's disease of the penis and scrotum), pineal tumors, primary neuroectodermal tumors (PNT), prostate cancer (e.g., , prostate adenocarcinoma), rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small intestine cancer (e.g., appendix cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland cancer, sweat gland cancer, synovioma, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid cancer), urethral cancer, vaginal cancer, and vulvar cancer (e.g., Paget's disease of the vulva). ;

[0421] In certain aspects, the present invention includes the use of an effective amount of isolated Compound 1 Pattern 1 or a pharmaceutically acceptable salt, prodrug or isotopic variant thereof, optionally in a pharmaceutical composition, for treating a host (usually a human) suffering from a selected cancer, tumor, hyperproliferative disease, or inflammatory or immune disorder. Compound 1 Pattern 1 also has anti-T-cell proliferation activity. In view of the shortage of drugs for T-cell cancer and abnormal proliferation, the determination of such a use represents a substantial improvement in the medical treatment of these diseases.

[0422] In another embodiment, the disorder is myelodysplastic syndrome (MDS).

[0423] In certain embodiments, the cancer is a hematopoietic cancer. In certain embodiments, the hematopoietic cancer is a lymphoma. In certain embodiments, the hematopoietic cancer is a leukemia. In certain embodiments, the leukemia is acute myeloid leukemia (AML).

[0424] In certain embodiments, the proliferative disorder is a myeloproliferative neoplasm.In certain embodiments, the myeloproliferative neoplasm (MPN) is primary myelofibrosis (PMF).

[0425] In certain embodiments, cancer is a solid tumor. As used herein, a solid tumor refers to an abnormal tissue mass that is generally free of cysts or fluid areas. Different types of solid tumors are named after the type of cells that form them. Examples of classes of solid tumors include, but are not limited to, sarcomas, carcinomas, and lymphomas, as described above. Other examples of solid tumors include, but are not limited to, squamous cell carcinoma, colon cancer, breast cancer, prostate cancer, lung cancer, liver cancer, pancreatic cancer, and melanoma.

[0426] In certain embodiments, the condition treated with Compound 1 Mode 1 is a condition associated with abnormal cell proliferation.

[0427] Abnormal cell proliferation, particularly hyperproliferation, can be caused by a variety of factors, including genetic mutations, infection, exposure to toxins, autoimmune disorders, and induction of benign or malignant tumors.

[0428] There are many skin disorders associated with excessive cell proliferation. For example, psoriasis is a benign disease of the human skin that is typically characterized by plaques covered with thickened scales. The disease is caused by an unexplained increase in the proliferation of epidermal cells. Chronic eczema is also associated with significant excessive proliferation of the epidermis. Other diseases caused by excessive proliferation of skin cells include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratosis, basal cell carcinoma, and squamous cell carcinoma.

[0429] Other hyperproliferative cell disorders include vascular proliferative disorders, fibrotic disorders, autoimmune disorders, graft-versus-host disease, tumors and cancer.

[0430] Vascular proliferative disorders include angiogenic and vasculogenic disorders. Proliferation of smooth muscle cells during the development of plaques in vascular tissue leads to, for example, restenosis, retinopathy, and atherosclerosis. Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions.

[0431] Fibrotic conditions are generally due to abnormal formation of the extracellular matrix. Examples of fibrotic conditions include cirrhosis and mesangial proliferative cell disorders. Cirrhosis is characterized by an increase in extracellular matrix components leading to the formation of liver scarring. Cirrhosis can cause diseases such as hardening of the liver. Increased extracellular matrix leading to liver scarring can also be caused by viral infections such as hepatitis. Fat cells appear to play a major role in cirrhosis.

[0432] Mesangial disorders are caused by abnormal proliferation of mesangial cells. Mesangial hyperproliferative cell disorders include various human kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, transplant rejection and glomerulopathy.

[0433] Another disease with a proliferative component is rheumatoid arthritis. Rheumatoid arthritis is generally considered an autoimmune disease and is believed to be associated with the activity of autoreactive T cells and is caused by autoantibodies produced against collagen and IgE.

[0434] Other conditions that may include an abnormal cell proliferation component include Bechet's syndrome, acute respiratory distress syndrome (ARDS), ischemic heart disease, post-dialysis syndrome, leukemia, acquired immunodeficiency syndrome, vasculitis, lipid histiocytosis, septic shock, and general inflammation.

[0435] In certain embodiments, the compounds of the present invention and their pharmaceutically acceptable derivatives or pharmaceutically acceptable preparations containing these compounds can also be used to prevent and treat HBV infection and other related patients such as anti-HBV antibody positive and HBV-positive patients, chronic liver inflammation caused by HBV, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis and fatigue. These compounds or preparations can also be used prophylactically to prevent or delay the progression of clinical diseases in individuals who are anti-HBV antibody or HBV-antigen positive or have been exposed to HBV.

[0436] In certain embodiments, the disorder is associated with an immune response.

[0437] Skin contact hypersensitivity and asthma are just two examples of immune responses that may be associated with significant morbidity. Others include atopic dermatitis, eczema, Sjögren's syndrome (including keratoconjunctivitis sicca secondary to Sjögren's syndrome), alopecia areata, allergic reactions due to arthropod bite reactions, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. These conditions may cause any one or more of the following symptoms or signs: itching, swelling, redness, blisters, crusting, ulcers, pain, scaling, cracking, hair loss, scarring, or fluid exudation involving the skin, eyes, or mucous membranes.

[0438] In atopic dermatitis and eczema in general, immune-mediated leukocyte infiltration (particularly of monocytes, lymphocytes, neutrophils, and eosinophils) into the skin contributes significantly to the pathogenesis of these diseases. Chronic eczema is also associated with marked hyperproliferation of the epidermis. Immune-mediated leukocyte infiltration also occurs at sites other than the skin, such as in the airways in asthma and in the tear glands of the eye in keratoconjunctivitis sicca.

[0439] In a non-limiting embodiment, the compounds of the present invention are used as topical agents for the treatment of contact dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjögren's syndrome (including keratoconjunctivitis sicca secondary to Sjögren's syndrome), alopecia areata, allergic reactions caused by arthropod bite reactions, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. This new method can also be used to reduce the infiltration of malignant leukocytes to the skin in diseases such as mycosis fungoides. These compounds can also be used to treat aquagenic dry eyes (such as immune-mediated keratoconjunctivitis) in patients suffering from them by topical application of the compounds to the eyes.

[0440] Throughout the specification, the term "neoplasia" or "cancer" is used to refer to the pathological process that leads to the formation and growth of cancerous or malignant tumors, i.e., abnormal tissue (solid) or cells (non-solid) that grow by cell proliferation, usually faster than normal, and continue to grow after the stimulus that triggered the new growth has ceased. Malignant tumors show a partial or complete lack of structural organization and functional coordination with normal tissues, and most invade surrounding tissues, can metastasize to several sites, may recur after attempted removal, and may cause the death of the patient unless adequately treated. As used herein, the term neoplasia is used to describe all cancerous disease states, and includes or encompasses pathological processes associated with malignant hematogenous, ascites, and solid tumors. Exemplary cancers that can be treated by the compounds disclosed herein, alone or in combination with at least one additional anticancer agent, include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma and renal cell carcinoma, bladder cancer, head cancer, kidney cancer and neck cancer; leukemia; benign and malignant lymphomas, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative disorders; sarcomas, including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma , glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma and neurothecoma; colorectal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratoma.

[0441] Additional cancers that can be treated using the compounds disclosed herein include, for example, acute myeloid leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), adenocarcinoma, adenosarcoma, adrenal carcinoma, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma, basal cell carcinoma, B-cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, intestinal cancer, brain cancer, brain stem glioma, breast cancer, triple (estrogen, progesterone and HER-2) negative breast cancer, double negative breast cancer (negative for two of estrogen, progesterone and HER-2), single negative (negative for one of estrogen, progesterone and HER-2), estrogen receptor positive, HER2 negative breast cancer. cancer, estrogen receptor negative breast cancer, estrogen receptor positive breast cancer, metastatic breast cancer, luminal A breast cancer, luminal B breast cancer, Her2 negative breast cancer, HER2 positive or negative breast cancer, progesterone receptor negative breast cancer, progesterone receptor positive breast cancer, recurrent breast cancer, carcinoid tumor, cervical cancer, bile duct cancer, chondrosarcoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, Ewing's sarcoma, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal Carcinoid of the tract, Gastrointestinal stromal tumor (GIST), Germ cell tumor glioblastoma multiforme (GBM), Glioma, Hairy cell leukemia, Head and neck cancer, Hemangioendothelioma, Hodgkin lymphoma, Hypopharyngeal cancer, Infiltrating ductal carcinoma (IDC), Infiltrating lobular carcinoma (ILC), Inflammatory breast cancer (IBC), Intestinal cancer, Intrahepatic bile duct cancer, Infiltrating / invasive breast cancer, Islet cell carcinoma, Jaw cancer, Kaposi's sarcoma, Kidney cancer, Laryngeal cancer, Leiomyosarcoma, Leptomeningeal metastasis, Leukemia, Lip cancer, Liposarcoma, Liver cancer, Lobular carcinoma in situ, Low-grade astrocytoma, Lung cancer, Lymph node cancer, Lymphoma, Male breast cancer, Medullary carcinoma, Medulloblastoma, Melanoma, Meningioma, Merkel cell carcinoma, Mesenchymal chondrosarcoma, Mesenchymal mesothelioma, metastatic breast cancer, metastatic melanoma, metastatic squamous neck cancer, mixed glioma, monodermal teratoma, oral cancer, mucinous carcinoma, mucosal melanoma, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, nasal cancer, nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumor (NET), non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oat cell carcinoma, eye cancer, eye melanoma, oligodendroglioma, mouth cancer, oral cancer, oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian primary peritoneal cancer, ovarian sex cord stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer,Peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal region tumor, pineoblastoma, pituitary adenocarcinoma, primary central nervous system (CNS) lymphoma, prostate cancer, colorectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, osteosarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cord cancer, spinal cancer, spinal cord cancer, squamous cell carcinoma, gastric cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma / thymic cancer, thyroid cancer, tongue cancer, tonsil cancer, transitional cell carcinoma, fallopian tube cancer, renal tubular cancer, undiagnosed Cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-cell lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-BALL, pre-B lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, Philadelphia chromosome-positive CML, juvenile monocytic leukemia (JMML), acute promyelocytic leukemia (AML subtype), large granular lymphocytic leukemia, adult T- chronic leukemia, diffuse large B-cell lymphoma, follicular lymphoma; mucosa-associated lymphoid tissue lymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large B-cell lymphoma, nodal marginal zone B-cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary effusion lymphoma; or lymphomatoid granuloma; B-cell prolymphocytic leukemia; unclassified splenic lymphoma / leukemia, splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacytic lymphoma; heavy chain disease, e.g., alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease; plasma cell myeloma, bone solitary plasmacytoma of the bone; extraosseous plasmacytoma; primary cutaneous follicle center lymphoma, T cell / histiocyte-rich large B cell lymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV) + DLBCL in the elderly; primary mediastinal (thymic) large B cell lymphoma, leg-type primary cutaneous DLBCL, ALK + large B cell lymphoma, plasma cell lymphoma; HHV8-related multicentric large B cell lymphoma, Castleman's disease; or unclassified B-cell lymphoma with features between diffuse large B cell lymphoma and classical Hodgkin lymphoma.

[0442] In another aspect, a method of increasing BIM expression (e.g., BCLC2L11 expression) is provided to induce apoptosis in a cell, comprising contacting a compound of the present invention or a pharmaceutically acceptable composition, salt, isotope analog or prodrug thereof with a cell. In certain embodiments, the method is an in vitro method. In certain embodiments, the method is an in vivo method. BCL2L11 expression is strictly regulated in cells. BCL2L11 encodes BIM, a pro-apoptotic protein. BCL2L11 is downregulated in many cancers, BIM is inhibited in many cancers, including chronic myeloid leukemia (CML) and non-small cell lung cancer (NSCLC), and inhibition of BCL2L11 expression can confer resistance to tyrosine kinase inhibitors. See, e.g., Ng et al., Nat. Med. (2012) 18: 521–528.

[0443] In yet another aspect, a method of treating a condition associated with angiogenesis, such as a diabetic condition (e.g., diabetic retinopathy), an inflammatory condition (e.g., rheumatoid arthritis), macular degeneration, obesity, atherosclerosis, or a proliferative disorder is provided, the method comprising administering to a subject in need thereof a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof.

[0444] In certain embodiments, the disease associated with angiogenesis is macular degeneration. In certain embodiments, a method of treating macular degeneration is provided, comprising administering a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog or prodrug thereof to a subject in need thereof.

[0445] In certain embodiments, the condition associated with angiogenesis is obesity. As used herein, "obesity" and "obesity" as used herein refer to Class I obesity, Class II obesity, Class III obesity, and pre-obesity (e.g., "overweight") as defined by the World Health Organization. In certain embodiments, a method for treating obesity is provided, comprising administering a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof to a subject in need thereof.

[0446] In certain embodiments, the disease associated with angiogenesis is atherosclerosis. In certain embodiments, a method of treating atherosclerosis is provided, comprising administering a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog or prodrug thereof to a subject in need thereof.

[0447] In certain embodiments, the condition associated with angiogenesis is a proliferative disorder. In certain embodiments, a method of treating a proliferative disorder is provided, comprising administering to a subject in need thereof a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog or prodrug thereof.

[0448] In an alternative embodiment, the compound is administered at about 50 mg / m 2 About 800 mg / m 2 , about 100mg / m 2 About 600 mg / m 2 , about 100mg / m 2 About 500 mg / m 2 , about 100mg / m 2 About 400 mg / m 2 , about 100mg / m 2 About 350 mg / m 2 , about 150mg / m 2 About 350 mg / m 2 , about 200mg / m 2 About 350 mg / m 2 , or about 200 mg / m 2 About 300 mg / m 2 dosage administration.

[0449] The isolated Compound 1 Pattern 1 can be used alone or in combination with another compound of the present invention or another biologically active agent in an effective amount to treat a host, such as a human, suffering from a disorder as described herein.

[0450] The isolated Compound 1 Pattern 1 described herein can be used alone or in combination with another compound of the present invention or another biologically active agent in an effective amount to treat a host, such as a human, suffering from a disorder as described herein.

[0451] The term "biologically active agent" is used to describe an agent other than a selected compound according to the invention, which can be used in conjunction with or alternately with a compound of the invention to achieve a desired therapeutic outcome. In one embodiment, the compound of the invention and the biologically active agent are administered in such a manner that they have in vivo activity over overlapping time periods, such as having Cmax, Tmax, AUC or other pharmacokinetic parameters that overlap over time periods. In another embodiment, the separated compound 1 mode 1 and the biologically active agent are administered to a host in need thereof, which do not have overlapping pharmacokinetic parameters, however, one has a therapeutic effect on the therapeutic efficacy of the other.

[0452] In some aspects of this embodiment, the bioactive agent is an immunomodulator, including but not limited to checkpoint inhibitors, as non-limiting examples, including PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, V domain Ig inhibitors of T-cell activation (VISTA) inhibitors, small molecules, peptides, nucleotides or other inhibitors. In some aspects, the immunomodulator is an antibody, such as a monoclonal antibody.

[0453] PD-1 inhibitors that block the interaction of PD-1 and PD-L1 by binding to the PD-1 receptor and thereby inhibit immunosuppression include, for example, nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab, AMP-224 (AstraZeneca and MedImmune), PF-06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1 (Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR-042 (Tesaro), and the PD-L1 / VISTA inhibitor CA-170 (Curis Inc.). PD-L1 inhibitors that block the interaction of PD-1 and PD-L1 by binding to the PD-L1 receptor and thereby inhibit immunosuppression include, for example, atezolizumab (Tecentriq), durvalumab (AstraZeneca and MedImmune), KN035 (Alphamab), and BMS-936559 (Bristol-Myers Squibb). CTLA-4 checkpoint inhibitors that bind to CTLA-4 and inhibit immunosuppression include, but are not limited to, ipilimumab, tremelimumab (AstraZeneca and MedImmune), AGEN1884, and AGEN2041 (Agenus). LAG-3 checkpoint inhibitors include, but are not limited to, BMS-986016 (Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (Prima BioMed), LAG525 (Novartis), and the dual inhibitor of PD-1 and LAG-3 MGD013 (MacroGenics). An example of a TIM-3 inhibitor is TSR-022 (Tesaro).

[0454] In yet another embodiment, the isolated compound 1 pattern 1 as described herein can be administered in combination or alternation with an effective amount of an estrogen inhibitor to treat abnormal tissues of the female reproductive system such as breast cancer, ovarian cancer, endometrial cancer or uterine cancer, wherein the estrogen inhibitor includes but is not limited to SERM (selective estrogen receptor modulator), SERD (selective estrogen receptor degrader), complete estrogen receptor degrader or another form of partial or complete estrogen antagonist or agonist. Some anti-estrogens such as raloxifene and tamoxifen retain some estrogen-like effects, including estrogen-like stimulation of uterine growth, and also in some cases, actually stimulate the estrogen-like effect of tumor growth during breast cancer progression. In contrast, fulvestrant is a complete anti-estrogen agent with limited estrogen-like effects on the uterus and is effective for tamoxifen-resistant tumors. Non-limiting examples of anti-estrogen compounds are provided in WO 2014 / 19176 assigned to Astra Zeneca, WO 2013 / 090921, WO 2014 / 203129, WO 2014 / 203132, and US 2013 / 0178445 assigned to Olema Pharmaceuticals, and U.S. Pat. Nos. 9,078,871, 8,853,423, and 8,703,810, and US 2015 / 0005286, WO 2014 / 205136, and WO 2014 / 205138.

[0455] Additional non-limiting examples of anti-estrogen compounds include: SERMS such as anordrin, bazedoxifene, broparestriol, chlorfenestrol, clomiphene citrate, cyclofenil, lasofoxifene, ormeloxifene, raloxifene, tamoxifen, toremifene, and fulvestrant; aromatase inhibitors such as aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane, and letrozole; and antigonadotropins such as leuprolide, cetrorelix, allylestradiol, chlormadinone acetate, cyproterone acetate, delmadinone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, progesterone, and spironolactone. Other estrogen ligands that can be used according to the present invention are described in the following documents: U.S. Patent Nos. 4,418,068; 5,478,847; 5,393,763; and 5,457,117, WO2011 / 156518, U.S. Patent Nos. 8,455,534 and 8,299,112, U.S. Patent Nos. 9,078,871; 8,853,423; 8,703,810; US 2015 / 0005286; and WO 2014 / 205138, US2016 / 0175289, US2015 / 0258080, WO 2014 / 191726, WO2012 / 084711; WO 2002 / 013802; WO 2002 / 004418; WO 2002 / 003992; WO 2002 / 003991; WO2002 / 003990; WO 2002 / 003989; WO 2002 / 003988; WO 2002 / 003986; WO 2002 / 003977; WO2002 / 003976; WO 2002 / 003975; WO 2006 / 078834; US 6821989; US 2002 / 0128276; US6777424; US 2002 / 0016340; US 6326392; US 6756401; US ​​2002 / 0013327; US 6512002;US6632834;US 2001 / 0056099; US 6583170; US 6479535; WO 1999 / 024027; US 6005102; EP0802184; US 5998402; US 5780497, US 5880137, WO 2012 / 048058 and WO 2007 / 087684.

[0456] In another embodiment, the isolated compound 1 pattern 1 described herein can be administered in combination or alternation with an effective amount of an androgen (such as testosterone) inhibitor to treat abnormal tissues of the male reproductive system such as prostate cancer or testicular cancer, and the androgen inhibitor includes but is not limited to a selective androgen receptor modulator, a selective androgen receptor degrader, a complete androgen receptor degrader, or another form of partial or complete androgen antagonist. In one embodiment, prostate cancer or testicular cancer is androgen resistant. Non-limiting examples of anti-androgen compounds are provided in WO 2011 / 156518 and U.S. Patent Nos. 8,455,534 and 8,299,112. Other non-limiting examples of anti-androgen compounds include: enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topilutamide, abiraterone acetate, and cimetidine.

[0457] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of abiraterone acetate (Zytiga) to treat abnormal tissue of the male reproductive system.

[0458] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of abiraterone acetate (Zytiga) to treat prostate cancer.

[0459] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of enzalutamide to treat prostate cancer.

[0460] In one embodiment, the bioactive agent is an ALK inhibitor. Examples of ALK inhibitors include, but are not limited to, crizotinib, alectinib, ceritinib, TAE684 (NVP-TAE684), GSK1838705A, AZD3463, ASP3026, PF-06463922, entrectinib (RXDX-101), and AP26113.

[0461] In one embodiment, the bioactive agent is an EGFR inhibitor. Examples of EGFR inhibitors include erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilotrif), rociletinib (CO-1686), osimertinib (Tagrisso), omotinib (Olita), naquotinib (ASP8273), nazartinib (EGF816), PF-06747775 (Pfizer), icotinib (BPI-2009), neratinib (HKI-272; PB272); avitinib (AC 0010), EAI045, tasotinib (TH-4000; PR-610), PF-06459988 (Pfizer), tesevatinib (XL647; EXEL-7647; KD-019), transtinib, WZ-3146, WZ8040, CNX-2006, dacomitinib (PF-00299804; Pfizer), brigatinib (Alunbrig), lorlatinib, and PF-06747775 (PF7775).

[0462] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of afatinib dimaleate (Gilotrif) to treat non-small cell lung cancer.

[0463] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of Alectinib (Alecensa) to treat non-small cell lung cancer.

[0464] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of ceritinib (Zykadia) to treat non-small cell lung cancer.

[0465] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of crizotinib (Xalkori) to treat non-small cell lung cancer.

[0466] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of osimertinib (Tagrisso) to treat non-small cell lung cancer.

[0467] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of brigatinib (Alunbrig) to treat non-small cell lung cancer.

[0468] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of lorlatinib to treat non-small cell lung cancer.

[0469] In one embodiment, the bioactive agent is a HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, trastuzumab enalapril, and pertuzumab.

[0470] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of lapatinib ditosylate to treat breast cancer.

[0471] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of lapatinib ditosylate to treat HER2+ breast cancer.

[0472] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of PF7775 to treat non-small cell lung cancer.

[0473] In one embodiment, the bioactive agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutuzumab, rituximab, ofatumumab, ibritumomab tiuxetan, tositumomab, and ocrelizumab.

[0474] In one embodiment, the bioactive agent is a JAK3 inhibitor. Examples of JAK3 inhibitors include tofacitinib.

[0475] In one embodiment, the bioactive agent is a BCL-2 inhibitor. Examples of BCL-2 inhibitors include venetoclax, ABT-199 (4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl)-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), 1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide) (navitoclax), ABT-263 ((R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[l,l'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl) 1-[(4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazol-2-ylamino)phenyl]- ... cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylic acid ethyl ester, nilotinib-d3, TW-37 (N-[4-[[2-(1,1-dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(1-methylethyl)phenyl]methyl]benzamide), apogossypolone (ApoG2), HA14-1, AT101, sabutoclax, gambogic acid or G3139 (Oblimersen).

[0476] In certain aspects, a treatment regimen is provided comprising administering Compound 1, Mode 1, in combination with at least one additional chemotherapeutic agent. The combinations disclosed herein can be administered to obtain a beneficial, additive or synergistic effect in the treatment of abnormal cell proliferative disorders.

[0477] In a specific embodiment, the treatment regimen comprises administering isolated Compound 1 Mode 1 in combination with at least one kinase inhibitor. In one embodiment, the at least one kinase inhibitor is selected from a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton's tyrosine kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof.

[0478] PI3k inhibitors that can be used in the present invention are well known. Examples of PI3 kinase inhibitors include, but are not limited to, wortmannin, demethylglycin, perifosine, idelalisib, Pictilisib, Palomid 529, ZSTK474, PWT33597, CUDC-907 and AEZS-136, duvelisib, GS-9820, BKM120, GDC-0032 (Taselisib), (2-[4-[2-(2-isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine -9-yl] pyrazol-1-yl]-2-methylpropionamide), MLN-1117 ((2R)-1-phenoxy-2-butane hydrogen (S)-methylphosphonate; or methyl (oxo) {[(2R)-l-phenoxy-2-butane]oxy}phosphonium)), BYL-719 ((2S)-N1-[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide), GSK2126458 (2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolyl]-3-pyridinyl}benzenesulfonamide) (omipalisib), TGX-221 ( (±)-7-methyl-2-(morpholin-4-yl)-9-(l-phenylaminoethyl)-pyrido[l,2-a]-pyrimidin-4-one), GSK2636771 (2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-lH-benzo[d]imidazole-4-carboxylic acid dihydrochloride), KIN-193 ((R)-2-((l-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid), TGR-1202 / RP5264, GS-9820 ((S)-l-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-hydroxypropan-1-one), G S-1101 (5-fluoro-3-phenyl-2-([S)]-1-[9H-purin-6-ylamino]-propyl)-3H-quinazolin-4-one), AMG-319, GSK-2269557, SAR245409 (N-(4-(N-(3-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide), BAY80-6946 (2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[l,2-c]quinaz), AS252424 (5-[l-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-methyl -(Z)-ylidene]-thiazolidine-2,4-dione), CZ24832 (5-(2-amino-8-fluoro-[l,2,4]triazolo[l,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide), Buparicib (5-[2,6-Di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine), GDC-0941 (2-(lH-indazol-4-yl)-6-[[4-(methylsulfonyl)-l-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine), GDC-0980 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (also known as RG7422)), SF1126 ((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentaoxo-1-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholino-4-ium)- 2-oxa-7,10,13,16-tetraazaoctadecane-18-acid ester), PF-05212384 (N-[4-[[4-(dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-(4,6-di-4-morpholinyl-l,3,5-triazine-2-yl)phenyl]urea) (gedatolisib), LY3023414, BEZ235 (2-methyl-2- {4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl}propionitrile) (dactolisib), XL-765 (N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide) and GSK1059615 ( 5-[[4-(4-pyridyl)-6-quinolyl]methylene]-2,4-thiazolidinedione), PX886 ([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylene]-5-hydroxy-9-(methoxymethyl)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindeno[4,5h]isochromene-10-yl] acetate (also known as sonolisib), LY294002, AZD8186, PF-4989216, pilaralisib, GNE-317, PI-3065, PI-103, NU7441 (KU-57788), HS 173, VS-5584 (SB2343), CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75, PIK-93, AS-605240, BGT226 (NVP-BGT226), AZD6482, voxtalisib, alpelisib, IC-87114, TGI100713, CH5132799, PKI-402, copanlisib (BAY 80-6946), XL 147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine), AS-252424, AS-604850, apitolisib (GDC-0980; RG7422) and the structures described in WO2014 / 071109. In one embodiment, the isolated compound 1 mode 1 is used in combination with a PIk3 inhibitor in a single dosage form. ,

[0479] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of apilisib to treat solid tumors.

[0480] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of apilisib to treat abnormal tissue of the female reproductive system.

[0481] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of apilisib to treat breast cancer.

[0482] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of Kupanisib hydrochloride (Aliqopa) to treat lymphoma.

[0483] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of kupanisib hydrochloride (Aliqopa) to treat follicular lymphoma.

[0484] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of Zydelig to treat chronic lymphocytic leukemia.

[0485] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of Zydelig to treat non-Hodgkin lymphoma, including follicular B-cell non-Hodgkin lymphoma or small lymphocytic lymphoma.

[0486] BTK inhibitors for use in the present invention are well known. Examples of BTK inhibitors include ibrutinib (also known as PCI-32765) (Imbruvica TM)(1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one), dianilinopyrimidine-based inhibitors such as AVL-101 and AVL-291 / 292 (N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide) (Avila Therapeutics) (see U.S. Patent Publication No. 2011 / 0117073, the entire contents of which are incorporated herein), dasatinib ([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide], LFM-A13 (α-cyano-β-hydroxy-β-methyl-N-(2,5-dibromophenyl)acrylamide), GDC-0834 ([RN-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide], CGI-560 4-(tert-butyl)-N-(3-(8-(phenylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)benzamide, CGI-1746(4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide), CNX-774(4-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpicolinamide), CTA056(7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxaline- 6(5H)-one), GDC-0834 ((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), GDC-0837 ((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607(4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), QL-47 (1-(1-acryloyldihydroindolin-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naphthyridin-2(1H)-one), and RN486 (6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one), as well as other molecules capable of inhibiting BTK activity, such as Akinleye et al., Journal of Those BTK inhibitors disclosed in Hematology & Oncology, 2013, 6:59, the entire contents of which are incorporated herein by reference. In one embodiment, an effective amount of isolated Compound 1 Mode 1 is used in combination with a BTK inhibitor in a single dosage form.

[0487] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of Ibrutinib (Imbruvica) to treat chronic lymphocytic leukemia.

[0488] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of Imbruvica to treat lymphoma, including small lymphocytic lymphoma, mantle cell lymphoma, marginal zone lymphoma, or Waldenstrom's macroglobulinemia.

[0489] Syk inhibitors useful in the present invention are well known and include, for example, cerdulatinib (4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide), entospletinib (6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine), fotantinib ([6-({5-fluoro-2-[(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyrazin-8-amine]), 6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate), BAY 61-3606 (2-(7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino)nicotinamide HCl), RO9021 (6-[(1R,2S)-2-amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide), imatinib (Gleevac; 4-[(4-methylpiperazin-1-yl)methyl]-N-( 4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide), staurosporine, GSK143 (2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide), PP2 (1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), PRT -060318 (2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide), PRT-062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), R112 (3,3'-((5-fluoropyrimidine-2, 4-diyl)bis(azanediyl))diphenol), R348 (3-ethyl-4-methylpyridine), R406 (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one), piceatannol (3-hydroxyresveratrol), YM193306 (see Singh et al.,Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643), 7-azaindole, piceatannol, ER-27319 (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the entire contents of which are incorporated herein), Compound D (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the entire contents of which are incorporated herein), PRT060318 (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the entire contents of which are incorporated herein), luteolin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the entire contents of which are incorporated herein), apigenin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the entire contents of which are incorporated herein), quercetin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the entire contents of which are incorporated herein), fisetin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the entire contents of which are incorporated herein), myricetin (see Singh et al.,Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the entire contents of which are incorporated herein), Morin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the entire contents of which are incorporated herein). In one embodiment, an effective amount of the isolated compound 1 mode 1 is used in combination with a Syk inhibitor in a single dosage form. ,

[0490] In one embodiment, the at least one additional chemotherapeutic agent is a protein cell death-1 (PD-1) inhibitor. PD-1 inhibitors are known in the art and include, for example, nivolumab (BMS), pembrolizumab (Merck), pidilizumab (CureTech / Teva), AMP-244 (Amplimmune / GSK), BMS-936559 (BMS) and MEDI4736 (Roche / Genentech). In one embodiment, an effective amount of isolated Compound 1 Mode 1 is used in combination with a PD-1 inhibitor in a single dosage form.

[0491] In one embodiment, the at least one additional chemotherapeutic agent is a B-cell lymphoma 2 (Bcl-2) protein inhibitor. BCL-2 inhibitors are known in the art and include, for example, ABT-199 (4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), ABT-737 (4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), [(4-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino]-3-nitrophenyl]sulfonylbenzamide), ABT-263 ((R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[l,l'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino]-3-nitrophenyl]sulfonylbenzamide yl)-3 ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide), GX15-070 (methanesulfonic acid obakla, (2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrol-2-yl) methylene]-4-methoxypyrrol-2-ylidene] indole; methanesulfonic acid))), 2-methoxy-antimycin A3, YC137 (4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazol-2-ylamino)-phenyl ester), pog osin, ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate, nilotinib-d3, TW-37 (N-[4-[[2-(1,1-dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(1-methylethyl)phenyl]methyl]benzamide), Apogossypolone (ApoG2) or G3139 (Oblimersen). In one embodiment, an effective amount of the isolated compound 1 mode 1 is used in combination with at least one BCL-2 inhibitor in a single dosage form.

[0492] In one embodiment, the combination described herein can be further used in combination with another therapeutic agent to treat cancer. The second therapy can be immunotherapy. As discussed in more detail below, an effective amount of separated compound 1 mode 1 can be conjugated with an antibody, a radioactive agent, or other targeting agents that direct the compound to diseased or abnormally proliferating cells. In another embodiment, the combination is used in combination with another drug or biological agent (such as an antibody) to improve the therapeutic efficacy by a combined or synergistic approach. In one embodiment, the combination can be used with T-cell vaccination, which generally involves immunization with inactivated autoreactive T cells to eliminate cancer cell populations as described herein. In another embodiment, the combination is used in combination with a bispecific T-cell engager (BiTE), which is an antibody designed to simultaneously bind to endogenous T cells and specific antigens on cancer cells as described herein, thereby connecting two types of cells.

[0493] In one embodiment, the bioactive agent is a MEK inhibitor. MEK inhibitors are well known and include, for example, trametinib / GSK1120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H-yl}phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pimasertib / AS703026 / MSC 1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973 (l-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidine-3-ol), refactinib / BAY869766 / RDEA119 (N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6 -methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide), PD-0325901 (N-[(2R)-2,3-dihydroxypropyloxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide), TAK733 ((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162 (5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide), R05126766 (3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one), WX-554, R04987655 / CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl) AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide), U0126-EtOH, PD184352 (CI-1040), GDC-0623, BI-847325, cobimetinib, PD98059, BIX 02189, BIX 02188, bimetinib, SL-327, TAK-733, PD318088.

[0494] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of bimetinib to treat melanoma, including BRAF-mutant melanoma and NRAS-mutant melanoma.

[0495] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of Cobimetinib (Cotellic) to treat melanoma, including BRAF-mutant melanoma and NRAS-mutant melanoma.

[0496] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of bimetinib to treat ovarian cancer.

[0497] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of selumetinib to treat non-small cell lung cancer.

[0498] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of selumetinib to treat thyroid cancer.

[0499] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of trametinib (Mekinist) to treat thyroid cancer.

[0500] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of trametinib (Mekinist) to treat melanoma.

[0501] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of trametinib (Mekinist) to treat non-small cell lung cancer.

[0502] In one embodiment, the bioactive agent is a Raf inhibitor. Raf inhibitors are known and include, for example, vemurafenib (N-[3-[[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide), sorafenib tosylate (4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide; 4-methylbenzenesulfonate), AZ628 (3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)- benzamide), NVP-BHG712 (4-methyl-3-(1-methyl-6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-N-(3-(trifluoromethyl)phenyl)benzamide), RAF-265 (1-methyl-5-[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine), 2-Bromoaldisine (2-bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine -4,8-dione), Raf kinase inhibitor IV (2-chloro-5-(2-phenyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)phenol), sorafenib N-oxide (4-[4-[[[[4-chloro-3(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide 1-oxide), PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ 628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120, and GX818 (conafenib).

[0503] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of dabrafenib (Tafinlar) to treat thyroid cancer.

[0504] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of dabrafenib (Tafinlar) to treat melanoma.

[0505] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of dabrafenib (Tafinlar) to treat non-small cell lung cancer.

[0506] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of contrafenib to treat melanoma, including BRAF-mutant melanoma.

[0507] In one embodiment, additional therapy is a monoclonal antibody (MAb). Some MAbs stimulate immune responses, thereby destroying cancer cells. Similar to antibodies naturally produced by B cells, these MAbs "cover" the surface of cancer cells, thereby triggering the immune system to destroy them. For example, bevacizumab targets vascular endothelial growth factor (VEGF), a protein secreted by tumor cells and other cells in the tumor microenvironment, which will promote the development of tumor blood vessels. When combined with bevacizumab, VEGF cannot interact with its cell receptors, thereby preventing the signal transduction that causes new blood vessel growth. Similarly, cetuximab and panitumumab target epidermal growth factor receptor (EGFR), and trastuzumab targets human epidermal growth factor receptor 2 (HER-2). MAbs that bind to cell surface growth factor receptors prevent the targeted receptors from sending their normal growth-promoting signals. They may also trigger apoptosis and activate the immune system to destroy tumor cells.

[0508] Another group of cancer therapeutic MAbs are immunoconjugates. These MAbs, sometimes called immunotoxins or antibody-drug conjugates, consist of antibodies attached to cell-killing substances such as plant or bacterial toxins, chemotherapeutic drugs, or radioactive molecules. The antibody locks onto its specific antigen on the surface of the cancer cell, and the cell-killing substance is taken up by the cell. FDA-approved conjugated MAbs that work in this way include trastuzumab, which targets the HER-2 molecule to deliver the drug DM1, which inhibits cell proliferation, to metastatic breast cancer cells that express HER-2.

[0509] T cell immunotherapy engineered to recognize cancer cells via bispecific antibodies (bsAbs) or chimeric antigen receptors (CARs) is an approach that has the potential to eliminate both dividing and non- / slowly dividing subpopulations of cancer cells.

[0510] By simultaneously recognizing the target antigen and the activating receptor on the surface of the immune effector cell, bispecific antibodies offer the opportunity to redirect immune effector cells to kill cancer cells. Another approach is to generate chimeric antigen receptors by fusing the extracellular antibody to the intracellular signaling domain. Chimeric antigen receptor engineered T cells are able to specifically kill tumor cells in an MHC-independent manner.

[0511] In some embodiments, the combination can be further administered to the subject in combination with other chemotherapeutic agents. If convenient, the combination described herein can be administered simultaneously with another chemotherapeutic agent to simplify the treatment regimen. In some embodiments, the combination and other chemotherapeutic agents can be provided in a single formulation. In one embodiment, the compound described herein is used in combination with other agents in the treatment regimen. Such agents may include but are not limited to tamoxifen, midazolam, letrozole, bortezomib, anastrozole, goserelin, mTOR inhibitors, PI3 kinase inhibitors, mTOR-PI3K dual inhibitors, MEK inhibitors, RAS inhibitors, ALK inhibitors, HSP inhibitors (e.g., HSP70 and HSP 90 inhibitors or combinations thereof), BCL-2 inhibitors, apoptosis-inducing compounds, AKT inhibitors, including but not limited to MK-2206, GSK690693, perifosine, (KRX-0401), GDC-0068, triciribine, AZD5363, honokiol, PF-04691502 and ipatasertib, miltefosine; PD-1 inhibitors, including but not limited to nivolumab, CT-011, MK-3475, BMS936558, and AMP-514 or FLT-3 inhibitors, including but not limited to P406, dovitinib, quizartinib (AC220), Amuvatinib (MP-470), tandutinib (MLN518), ENMD-2076 and KW-2449, or combinations thereof.

[0512] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of ipatasertib to treat breast cancer, including triple-negative breast cancer.

[0513] In one embodiment, the bioactive agent is an mTOR inhibitor. Examples of mTOR inhibitors include, but are not limited to, vistusertib and rapamycin and its analogs, everolimus (Afinitor), temsirolimus, lidaformolimus, sirolimus and rifolimus. Examples of MEK inhibitors include, but are not limited to, trametinib / GSK1120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidine-1(2H-yl}phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pimasertib / AS703026 / MSC 1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973 (l-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidine-3-ol), rivatinib / BAY869766 / RDEA119 (N-(3,4-difluoro-2 -(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide), PD-0325901 (N-[(2R)-2,3-dihydroxypropyloxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide), TAK733 ((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyridine pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162 (5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide), R05126766 (3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one), WX-554, R04987655 / CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazin-2-yl)methyl)benzamide) or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide).

[0514] In one embodiment, the bioactive agent is a RAS inhibitor. Examples of RAS inhibitors include, but are not limited to, Reolysin and siG12D LODER.

[0515] In one embodiment, the bioactive agent is an ALK inhibitor. Examples of ALK inhibitors include, but are not limited to, crizotinib, AP26113, and LDK378.

[0516] In one embodiment, the bioactive agent is an HSP inhibitor. HSP inhibitors include, but are not limited to, geldanamycin or 17-N-allylamino-17-demethoxygeldanamycin (17AAG) and radicicol. In a particular embodiment, the compounds described herein are administered in combination with letrozole and / or tamoxifen. Other chemotherapeutic agents that can be used in combination with the compounds described herein include, but are not limited to, chemotherapeutic agents that do not require cell cycle activity to exert their anti-tumor effects.

[0517] Additional biologically active compounds include, for example, everolimus, trabectedin, nab-paclitaxel, TLK286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, Enzastaurin, Vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, laser kinase inhibitors, PIK-1 modulators, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, focal adhesion kinase, Map kinase (mek) inhibitors, VEGF trap antibodies, pemetrexed, panitumumab, amrubicin, ogavuzumab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zalimumab, edotecarin, hanfangji A, rubitecan, patozuzuril, oblimersen, tesimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, Cilengitide, Gimatecan, IL13-PE38QQR, INO 1001, IPdR 1KRX-0402, Lucanthone, LY317615, Newdi, Vitspan, Rta 744, Sdx 102, talampanel, atrasentan, Xr311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposome doxorubicin, 5′-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, celecoxib; PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-disodium salt heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, irinotecan simestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258); 3-[5-(methylsulfonylpiperidinylmethyl)-indolyl-quinolone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PK I-166, GW-572016, Ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, scopolamine hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, BCG vaccine, doxorubicin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone ketone, flutamide, Gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, nitrogen mustard, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, prilocybin, porphine, procarbazine, raltitrexed, rituximab, streptozotocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, retinoic acid, vindesine, 13-cis retinoic acid, phenylalanine mustard, uracil mustard, estramustine, hexamethylmelamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin,Calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neivastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimetidine, trastuzumab, denileukin-toxin conjugate, gefitinib, bortezomib, paclitaxel, paclitaxel without polyoxyethylene castor oil, docetaxel, epithilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, dapoxetine statins, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol acetate, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, NK-1 Receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, ethylenediamine, erythropoietin, platelet-derived growth factor receptor alpha (PDGFR-α) antibody, epoetin alpha, darbepoetin alpha and mixtures thereof.

[0518] In one embodiment, an effective amount of the isolated Compound 1 Pattern 1 described herein can be used in combination with a PARP inhibitor selected from niraparib tosylate monohydrate (Zejula), olaparib (Lynparza), rucaparib camphorsulfonate (Rubraca), and talazoparib.

[0519] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of niraparib tosylate monohydrate (Zejula) to treat abnormal tissues of the female reproductive system, including epithelial ovarian cancer or fallopian tube cancer.

[0520] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of niraparib tosylate monohydrate (Zejula) to treat peritoneal cancer.

[0521] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of Lynparza to treat abnormal tissues of the female reproductive system, including breast cancer, ovarian cancer, epithelial ovarian cancer, or fallopian tube cancer.

[0522] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of Lynparza to treat BRAC1 or BRAC2 mutant breast cancer.

[0523] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of Lynparza to treat HER2- breast cancer.

[0524] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of Olaparib (Lynparza) to treat peritoneal cancer.

[0525] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of rucaparib camphorsulfonate (Rubraca) to treat abnormal tissues of the female reproductive system, including breast cancer, ovarian cancer, epithelial ovarian cancer, or fallopian tube cancer.

[0526] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of rucaparib camphorsulfonate (Rubraca) to treat peritoneal cancer.

[0527] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of talazoparib to treat abnormal tissues of the female reproductive system, including breast cancer, ovarian cancer, epithelial ovarian cancer, or fallopian tube cancer.

[0528] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of talazoparib to treat BRAC1 or BRAC2 mutant breast cancer.

[0529] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of Olaratumab to treat soft tissue sarcoma.

[0530] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of savotinib to treat adenocarcinoma.

[0531] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of savotinib to treat non-small cell lung cancer.

[0532] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of savotinib to treat renal cell carcinoma.

[0533] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of vistusertib to treat advanced breast cancer.

[0534] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of vistusertib to treat advanced breast cancer.

[0535] In one embodiment, an effective amount of the isolated compound 1 described herein can be used in combination with a chemotherapeutic agent selected from but not limited to the following: imatinib mesylate Dasatinib Nilotinib Bosutinib Trastuzumab Pertuzumab (PerjetaTM), Lapatinib Gefitinib Erlotinib Cetuximab Panitumumab Vandetanib Vemurafenib Vorinostat Romidepsin Bexarotene Alitretinoin Retinoic acid Carfilzomib (KyprolisTM), pralatrexate Bevacizumab Aflibercept Sorafenib Sunitinib Pazopanib Regorafenib and cabozantinib (Cometriq TM ).

[0536] In one embodiment, an effective amount of the isolated Compound 1 Schematic 1 described herein can be used in combination with a CD4 / 6 inhibitor, including pomacetinib (Versenio), palbociclib (Ibrance), or triclasiclib.

[0537] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of Versenio to treat breast cancer.

[0538] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of Versenio to treat HR+HER2- breast cancer.

[0539] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of palbociclib (Ibrance) to treat breast cancer.

[0540] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of palbociclib (Ibrance) to treat HR+HER2- breast cancer.

[0541] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of palbociclib (Ibrance) to treat breast cancer.

[0542] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of palbociclib (Ibrance) to treat metastatic triple-negative breast cancer.

[0543] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of palbociclib (Ibrance) to treat small cell lung cancer.

[0544] In one embodiment, an effective amount of Compound 1, Mode 1, is combined with an effective amount of S-malate cabozantinib (Cometriq TM ) are administered in combination to treat thyroid cancer.

[0545] In one embodiment, an effective amount of Compound 1, Mode 1, is combined with an effective amount of S-cabozantinib maleate (Cometriq TM ) are administered in combination to treat renal cell carcinoma.

[0546] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of dasatinib (Sprycel) to treat leukemia, including acute lymphoblastic leukemia or chronic myeloid leukemia.

[0547] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of dasatinib (Sprycel) to treat prostate cancer.

[0548] In one embodiment, an effective amount of Compound 1 Mode 1 is combined with an effective amount of erlotinib Administered in combination to treat prostate cancer.

[0549] In one embodiment, an effective amount of Compound 1 Mode 1 is combined with an effective amount of gefitinib Administered in combination to treat prostate cancer.

[0550] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of imatinib mesylate (Gleevec) to treat leukemia, including acute lymphoblastic leukemia, chronic eosinophilic leukemia, hypereosinophilic syndrome, or chronic myeloid leukemia.

[0551] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of trastuzumab (Herceptin) to treat adenocarcinoma.

[0552] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of trastuzumab (Herceptin) to treat breast cancer, including HER2+ breast cancer.

[0553] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of imatinib mesylate (Gleevec) to treat tumors, including but not limited to dermatofibrosarcoma protuberans and gastrointestinal stromal tumors.

[0554] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of imatinib mesylate (Gleevec) to treat myelodysplasia / myeloproliferative neoplasms.

[0555] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of imatinib mesylate (Gleevec) to treat systemic mastocytosis.

[0556] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of nilotinib (Tasigna) to treat chronic myeloid leukemia, including Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML).

[0557] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of pazopanib hydrochloride (Votrient) to treat renal cell carcinoma.

[0558] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of pazopanib hydrochloride (Votrient) to treat soft tissue sarcoma.

[0559] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of regorafenib (Stivarga) to treat colorectal cancer.

[0560] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of regorafenib (Stivarga) to treat gastrointestinal stromal tumors.

[0561] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of regorafenib (Stivarga) to treat hepatocellular carcinoma.

[0562] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of sorafenib tosylate (Nexavar) to treat cancer, including hepatocellular carcinoma or renal cell carcinoma.

[0563] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of sunitinib malate (Sutent) to treat gastrointestinal stromal tumors.

[0564] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of sunitinib malate (Sutent) to treat pancreatic cancer.

[0565] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of sunitinib malate (Sutent) to treat renal cell carcinoma.

[0566] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of Vemurafenib (Zelboraf) to treat Erdheim-Chester disease.

[0567] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of Zelboraf to treat melanoma.

[0568] In certain aspects, the additional therapeutic agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic agent, an additional therapeutic agent, or an immunosuppressive agent.

[0569] Suitable chemotherapeutic agents include, but are not limited to, radioactive molecules, toxins (also known as cytotoxins or cytotoxic agents), which include any agent that is detrimental to the viability of cells, agents, and liposomes or other vesicles containing chemotherapeutic compounds. Common anticancer agents include: vincristine Liposomal vincristine Daunorubicin (daunorubicin or Doxorubicin Cytosine arabinoside (ara-C or L-Asparaginase or PEG-L-asparaginase (pegaspargase or Etoposide (VP-16), Teniposide 6-Mercaptopurine (6-MP or Methotrexate, cyclophosphamide Prednisone, dexamethasone (Decadron), imatinib Dasatinib Nilotinib Bosutinib and ponatinib (Iclusig TMExamples of additional suitable chemotherapeutic agents include, but are not limited to, 1-dehydrotestosterone, 5-fluorouracil dacarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, doxorubicin, aldesleukin, alkylating agents, allopurinol sodium, hexamethylmelamine, amifostine, anastrozole, anthramycin (AMC), antimitotic agents, cis-dichlorodiamine platinum (II) (DDP) cisplatin), diaminodichloroplatinum, anthracyclines, antibiotics, antimetabolites, asparaginase, BCG live (for intravesical use), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, leucovorin calcium, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), chlorambucil, cisplatin, cladribine, colchicine, conjugated estrogens, cyclophosphamide, Cyclothosphamide, cytarabine, cytarabine, cytochalasin B, carboxysin, dacarbazine, dactinomycin, dactinomycin (formerly actinomycin), daunorubicin HCl, daunorubicin citrate, denileukin diftitox, dexrazoxane, dibromomannitol, dihydroxy anthracin dione, docetaxel, dolasetron mesylate, doxorubicin HCl, dronabinol, Escherichia coli L-asparaginase, cephalothin, epoetin-α, Erwinia L-asparaginase, esterified estrogens, estradiol, estramustine sodium phosphate, ethidium bromide, ethinyl estradiol, etidronate sodium, epotocin, epotocin phosphate, filgrastim, floxuridine, fluconazole, fludarabine phosphate, fluorouracil, flutamide, folinic acid, gemcitabine HCl, glucocorticoids, goserelin acetate, gramicidin D, granisetron HCl, hydroxyurea, idarubicin HCl, ifosfamide, interferon α-2b, irinotecan HCl, letrozole, formyl Calcium tetrahydrofolate, leuprolide acetate, levamisole HCl, lidocaine, lomustine, maytansine, methotrexate HCl, medroxyprogesterone acetate, megestrol acetate, melphalan HCl, mercaptopurine, mesna, methotrexate, methyltestosterone, mithramycin, mitomycin C, mitotane, mitoxantrone, nilutamide, octreotide acetate, ondansetron HCl, paclitaxel, pamidronate disodium, pentostatin, pilocarpine HCl, primycin, polyphenprosan 20 with carmustine implant, porfimer sodium, procaine, procarbazine HCL, propranolol, rituximab, sargramostim, streptozocin, tamoxifen, paclitaxel, teniposide, tenoposide, testolactone, tetracaine, thiopental chlorambucil chlorambucil), thioguanine, thiotepa, topotecan HCl, toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.

[0570] In one embodiment, an effective amount of Compound 1 Mode 1 is combined with an effective amount of Bosutinib Administered in combination to treat chronic myeloid leukemia (CML).

[0571] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of Ponatinib Hydrochloride (Iclusig) to treat leukemia, including acute lymphoblastic leukemia and chronic myeloid leukemia.

[0572] Additional therapeutic agents that can be administered in combination with the compounds disclosed herein can include bevacizumab, sunitinib, sorafenib, 2-methoxyestradiol or 2ME2, fenacote, vatalanib, vandetanib, aflibercept, volociximab, edamasumab (MEDI-522), cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, dovitinib, fentolimumab, Atacicept, rituximab, alemtuzumab, aldesleukin, atezolizumab, tocilizumab, temsirolimus, everolimus, rucamumab, dasizumab, HLL1, huN901-DM1, atimod, natalizumab, bortezomib, carfilzomib, marizomib, tansiracin, saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate, belinstat, par Binastat, mapatumumab, lexalimumab, dulanamine, ABT-737, oblimersen, plitidepsin, tapimod, P276-00, enzastaurin, tipifarnib, perifosine, imatinib, dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib, bazedoxifene, AZD4547, rilotumumab, oxaliplatin (Eloxatin), PD0332991, ribociclib (LEE011), pomacetinib (LY2835219), HDM201, fulvestrant (Faslodex), exemestane (Aromasin), PIM447, ruxolitinib (INC424), BGJ398, necituzumab, pemetrexed (Alimta), and ramucirumab (IMC-1121B).

[0573] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of everolimus (Afinitor) to treat breast cancer.

[0574] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of everolimus (Afinitor) to treat HR+, HER2- breast cancer.

[0575] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of everolimus (Afinitor) to treat pancreatic cancer.

[0576] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of everolimus (Afinitor) to treat gastrointestinal cancer.

[0577] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of everolimus (Afinitor) to treat lung cancer.

[0578] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of everolimus (Afinitor) to treat renal cell carcinoma.

[0579] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of everolimus (Afinitor) to treat astrocytoma, including subependymal giant cell astrocytoma.

[0580] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of Fulvestrant (Faslodex) to treat breast cancer.

[0581] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of Fulvestrant (Faslodex) to treat HR+, HER2- breast cancer.

[0582] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of ramucirumab to treat adenocarcinoma.

[0583] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of ramucirumab to treat non-small cell lung cancer.

[0584] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of ramucirumab to treat colorectal cancer.

[0585] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of ribociclib (Kisqali) to treat breast cancer.

[0586] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of ribociclib (Kisqali) to treat HR+ and HER2- breast cancer.

[0587] In certain aspects of the invention, the compounds described herein may be used in combination with at least one IDH1 or IDH2 inhibitor. In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of Ensidipin Mesylate (Idhifa) to treat acute myeloid leukemia.

[0588] In certain aspects of the invention, the compounds described herein may be used in combination with at least one fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor. In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of erdafitinib to treat urothelial carcinoma, including metastatic urothelial carcinoma.

[0589] In certain aspects of the invention, the compounds described herein may be used in combination with at least one ERK inhibitor.

[0590] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of SCH772984 to treat melanoma, including BRAF-mutant melanoma or NRAS-mutant melanoma.

[0591] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of ulixertinib to treat melanoma, including uveal melanoma.

[0592] In one embodiment, an effective amount of Compound 1 Mode 1 is administered in combination with an effective amount of ulixertinib to treat pancreatic cancer.

[0593] In certain aspects of the invention, the compounds described herein may be used in combination with at least one immunosuppressant. The immunosuppressant is preferably selected from a calcineurin inhibitor, such as cyclosporine or an ascomycin, such as cyclosporine A. FK506 (tacrolimus), pimecrolimus, mTOR inhibitors such as rapamycin or its derivatives such as sirolimus Everolimus Temsirolimus, zotarolimus, umbilolimus-7, umbilolimus-9, rapamycin analogs, such as lidaformolimus, azathioprine, campath 1H, S1P receptor modulators, such as fingolimod or its analogs, anti-IL-8 antibodies, mycophenolic acid or a salt thereof, such as sodium salt, or a prodrug thereof, such as mycophenolate mofetil OKT3 (ORTHOCLONE ), prednisone, Buquina sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyspermanguanine, treperolimus, leflunomide CTLAI-Ig, anti-CD25, anti-IL2R, basiliximab Daclizumab Mizoribine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, ), CTLA4lg (abatacept), belatacept, LFA3lg, etanercept (by Immunex Adalimumab Infliximab Anti-LFA-1 antibody, natalizumab Enmolumab, gavilimumab, antithymocyte immunoglobulin, cilizumab, afacept, efalizumab, podesan, mesalamine, doxorubicin, codeine phosphate, benolate, fenbufen, naproxen, diclofenac, etodolac, and indomethacin, aspirin, and ibuprofen.

[0594] In certain embodiments, a compound described herein is administered to a subject prior to treatment with another chemotherapeutic agent, during treatment with another chemotherapeutic agent, after administration of another chemotherapeutic agent, or a combination thereof.

[0595] In some embodiments, an effective amount of isolated Compound 1, Pattern 1, may be administered to a subject so that other chemotherapeutic agents may be administered at higher doses (increased chemotherapy dose intensity) or more frequently (increased chemotherapy dose density). Dose-dense chemotherapy is a chemotherapy treatment plan in which the intervals between drug administrations are shorter than those of a standard chemotherapy treatment plan. Chemotherapy dose intensity refers to the unit dose of chemotherapy administered per unit time. The dose intensity may be increased or decreased by changing the administered dose, the administration time interval, or both.

[0596] In one embodiment of the invention, the compounds described herein may be administered in a coordinated regimen with another agent such as a non-DNA damaging targeted anti-tumor agent or a hematopoietic growth factor agent. It has recently been reported that delayed administration of hematopoietic growth factors can produce serious side effects. For example, the use of EPO family growth factors has been associated with arterial hypertension, cerebral convulsions, hypertensive encephalopathy, thromboembolism, iron deficiency, flu-like syndrome, and venous thrombosis. G-CSF family growth factors have been associated with splenomegaly and rupture, respiratory distress syndrome, allergic reactions, and sickle cell complications. Thus, in one embodiment, the use of the compounds or methods described herein is combined with the use of hematopoietic growth factors, including but not limited to granulocyte colony stimulating factor (G-CSF, sold for example as Neupogen (filgrastim), Neulasta (pegylated filgrastim) or Lenograstim), granulocyte-macrophage colony stimulating factor (GM-CSF, sold for example as moragastim and sarmograstim (Leukine)), M-CSF (macrophage colony stimulating factor), thrombopoietin (megakaryocyte growth factor (MGDF), sold for example as romiplostim and eltrombopag), interleukin (IL)-12, interleukin-3, interleukin-11 (lipogenesis inhibitory ... or oprelvekin), SCF (stem cell factor, cyan factor, kit-ligand or KL) and erythropoietin (EPO) and their derivatives (sold as, for example, epoetin-α, such as Darbopoetin, Epocept, Nanokine, Epofit, Epogin, Eprex and Procrit; epoetin-β, sold as, for example, NeoRecormon, Recormon and Micera), epoetin-δ (sold as, for example, Dynepo), epoetin-ω (sold as, for example, Epomax), epoetin ζ (sold as, for example, Silapo and Reacrit) and, for example, Epocept, EPOTrust, Erypro Safe, Repoeitin, Vintor, Epofit, Erykine, Wepox, Espogen, Relipoeitin, Shanpoietin, Zyrop and EPIAO). In one embodiment, an effective amount of isolated compound 1 Mode 1 is administered prior to administration of the hematopoietic growth factor. In one embodiment, the hematopoietic growth factor is administered at a time such that the effect of the compound on the HSPC has disappeared. In one embodiment, the growth factor is administered at least 20 hours after administra...

Claims

1. A crystalline compound having the following structure: It is the dihydrochloride dihydrate, Features The XRPD pattern comprises at least eight 2θ values ​​selected from 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2°, and 28.6±0.2°.

2. The crystalline compound of claim 1, wherein the XRPD pattern comprises 2θ values ​​of 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2°, and 28.6±0.2°.

3. The crystalline compound of claim 1, wherein the XRPD pattern comprises a 2θ value of at least 9.6±0.2°.

4. The crystalline compound of claim 1, wherein the XRPD pattern comprises 2θ values ​​of at least 9.6±0.2°, 19.8±0.2°, and 21.3±0.2°.

5. A freeze-dried powder comprising a compound of the following structure: It is the dihydrochloride dihydrate, Features The XRPD pattern comprises at least eight 2θ values ​​selected from 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2°, and 28.6±0.2°.

6. The lyophilized powder of claim 5, wherein the compound is characterized by an XRPD pattern comprising 2θ values ​​of 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2°, and 28.6±0.2°.

7. The lyophilized powder of claim 5, wherein the compound is characterized by an XRPD pattern comprising a 2θ value of at least 9.6 ± 0.2°.

8. The lyophilized powder of claim 5, wherein the compound is characterized by an XRPD pattern comprising 2θ values ​​of at least 9.6±0.2°, 19.8±0.2°, and 21.3±0.2°.

9. A pharmaceutically acceptable reconstitution solution for the lyophilized powder of claim 5.

10. The reconstitution solution of claim 9, wherein the reconstitution solution is an aqueous solution.

11. The reconstituted solution of claim 10, wherein the reconstituted solution is suitable for intravenous delivery.

12. The reconstituted solution of claim 10, comprising 200 mg to 600 mg of the lyophilized powder.

13. The reconstituted solution of claim 10, comprising 300 mg of the lyophilized powder.

14. The reconstituted solution of claim 10, comprising 150 mg / m 2 Up to 350 mg / m 2 of freeze-dried powder dose.

15. The reconstituted solution of claim 10, comprising 240 mg / m 2 of freeze-dried powder dose.

16. The reconstituted solution of claim 10, further comprising 300 mg mannitol and 76 mg citric acid.

17. The reconstitution solution of claim 10, further comprising sodium hydroxide or hydrochloric acid.

18. Use of the crystalline compound of any one of claims 1-4, the lyophilized powder of any one of claims 5-8, and the reconstituted solution of any one of claims 9-17 for the manufacture of a medicament for treating a disorder mediated by CDK4 or CDK6 in a patient in need thereof.

19. Use of the crystalline compound of any one of claims 1-4, the lyophilized powder of any one of claims 5-8, and the reconstituted solution of any one of claims 9-17 for the manufacture of a medicament for treating cancer in a patient in need thereof, wherein the cancer is selected from breast cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, classical Hodgkin lymphoma, diffuse large B-cell lymphoma, bladder cancer, primary mediastinal B-cell lymphoma, urothelial carcinoma, high microsatellite instability solid tumors, mismatch repair deficient solid tumors, gastric or gastroesophageal junction adenocarcinoma, esophageal squamous cell carcinoma, cervical cancer, endometrial cancer, bile duct cancer, hepatocellular carcinoma, Merkel cell carcinoma, renal cell carcinoma, ovarian cancer, anal canal cancer, colorectal cancer and melanoma.

20. Use of the crystalline compound of any one of claims 1-4, the lyophilized powder of any one of claims 5-8, and the reconstituted solution of any one of claims 9-17 for the manufacture of a medicament for reducing the effects of chemotherapy on healthy cells in a patient undergoing cancer treatment, wherein the patient is administered an effective amount of at least one chemotherapeutic agent and an effective amount of the crystalline compound of any one of claims 1-4.

21. Use of the crystalline compound of any one of claims 1-4, the lyophilized powder of any one of claims 5-8, and the reconstituted solution of any one of claims 9-17 for the manufacture of a medicament for reducing the effects of chemotherapy on healthy cells in a patient being treated for an abnormal cell proliferative disorder, wherein the patient is administered an effective amount of at least one chemotherapeutic agent and an effective amount of the crystalline compound of any one of claims 1-4.

22. The use according to claim 20 or 21, wherein the healthy cells are hematopoietic stem cells or hematopoietic progenitor cells.

23. The use of claim 20 or 21, wherein the chemotherapeutic agent is carboplatin.

24. The use of claim 20 or 21, wherein the chemotherapeutic agent is cisplatin.

25. The use of claim 20 or 21, further comprising administering etoposide.

26. The use of claim 20 or 21, wherein the chemotherapeutic agent is topotecan.

27. The use of claim 20 or 21, wherein the patient is a human.

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