TWI906312B - Morphic forms of trilaciclib and methods of manufacture thereof - Google Patents

Abstract

An advantageous isolated morphic form of trilaciclib which is 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 di-hydrochloride salt or a dihydrochloride, dihydrate.

Description

Types and manufacturing methods of triclaccib

The present invention provides an advantageously isolated form of trilaciclib, which is 2'-((5-(4-methylpiperidin-1-yl)pyridin-2-yl)amino)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrro[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 in the form of a dihydrochloride or a dihydrochloride dihydrate.

The U.S. Patents 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]pyrimidine-2-amine cytokinin-dependent kinase inhibitors, including 2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrrolo[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-6'-one (compound 1) It has the following formula: .

The synthetic procedure for preparing compound 1 is described in US 2019/135820 and WO 2020/041770, both of which have been licensed to G1 Therapeutics, Inc. Compound 1 dihydrochloride is the active ingredient in COSELA ^™ , ^which was approved by the US Food and Drug Administration on February 12, 2021, for the purpose of reducing chemotherapy-induced myelosuppression when administered prior to platinum/etoposide or topotecan-containing regimens for the treatment of metastatic small cell lung cancer.

Compound 1 is known as "G1T28" or "triclasigli". It temporarily arrests normal cells to prevent chemotherapy-induced myelosuppression and can improve antitumor efficacy. It can be used, for example, in patients with small cell lung cancer (SCLC) receiving topotecan chemotherapy, and in combination with etoposide and carboplatin for SCLC. It can also be used, for example, in combination with carboplatin, etoposide, and atezolizumab (a PD-L1 inhibitor) for small cell lung cancer (SCLC). Based on bone marrow preservation data from patients with SCLC, trilaciclib was granted Breakthrough Therapy Designation (BTD) by 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 undergoing human clinical trials for the treatment of triple-negative breast cancer, in conjunction with standard care for neoadjuvant therapy in breast cancer.

It has been found that compound 1 (2'-((5-(4-methylpiperidin-1-yl)pyridin-2-yl)amino)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrro[1',2'1,5]pyrrolo[2,3-d]pyrimidine]-6'-one), in dihydrochloride form, can be prepared in a highly purified and favorable form.

This highly purified and advantageous form is indicated by "Pattern 1". Pattern 1 is a highly crystalline form of compound 1 in the form of a dihydrochloride. Pattern 1 exhibits superior stability compared to other forms. For example, in competitive slurry experiments (see Example 10), Pattern 1 is the primary structural form of compound 1 in the form of a dihydrochloride. Pattern 1 also possesses advantageous properties in the manufacture of compound 1 in the form of a dihydrochloride. For example, Pattern 1 can be mass-produced by crystallization of compound 1 in a heated HCl solution. Pattern 1 can also be formed from other forms or amorphous forms of compound 1 by recrystallization.

Compound 1, pattern 1, can be in the form of a dihydrochloride dihydrate. Pattern 1 typically initially forms a dihydrochloride dihydrate and can eventually revert to it even after drying and exposure to air. Regardless of water content, pattern 1 maintains its representative XRPD peaks, as described in more detail below. For example, if compound 1 is prepared in the form of pattern 1 as described herein and subsequently dried, the representative XRPD peaks will remain the same before and after drying.

Compound 1 is the approved drug trilacizate, marketed under the brand name COSELA ^™ and used in some practices as a bone marrow preserver to protect healthy cells, particularly hematopoietic cells, during chemotherapy. It is intended to be administered intravenously to rapidly establish blood flow before chemotherapy, typically via IV. However, the free base of Compound 1 is insoluble in water and practically insoluble in DMSO. Furthermore, it becomes less soluble as pH increases. Blood typically has a pH of 7.35 to 7.45, which is slightly alkaline. Phosphate-blended saline typically has a pH of 7.2 to 7.4. The free base of Compound 1 is not very soluble at these pH levels, and this can lead to various problems. Most importantly, a large dose of Compound 1 is required to achieve therapeutic effect. The typical dose is 240 mg/ ^m² , which can be estimated at approximately 300 mg for a normal adult. Because it has no solubility in water, a dilute solution will be used in a large volume of fluid to provide this dose of the free alkali compound 1. This results in a conflict between how it should be delivered and the need for prolonged administration. Compound 1 IV is typically administered over approximately 30 minutes (20 to 60 minutes) , meaning the drug must be concentrated, not diluted, in the IV fluid. Furthermore, when the free alkali compound 1 is injected into the bloodstream, there is a real possibility that at least some of it may leak out of the solution due to the slightly alkaline nature of blood. This can cause problems at the injection site due to drug deposition and loss of activity.

It has been found that an IV solution of compound 1 , intended for injection into cancer patients to preserve healthy cells or for anti-excessive purposes, can be administered by dispensing it in dihydrochloride form. This achieves the desired therapeutic effect because it can be delivered directly and rapidly into the bloodstream in concentrated form. In one primary embodiment, the IV solution is prepared from a freeze-dried powder comprising compound 1 dihydrochloride, mannitol, and citric acid.

In some embodiments, the IV solution of compound 1 is prepared from a solid pharmaceutical composition, which is formulated as appropriate for freeze-drying and subsequently dried. In some embodiments, the composition includes compound 1 in the form of a dihydrochloride, such as compound 1 dihydrochloride pattern 1. The composition may also include one or more suitable excipients, such as builders, buffers, and/or one or more pH adjusters. In some embodiments, the builder is a suitable sugar, such as mannitol. In some embodiments, the buffer is a suitable weak acid or weak base having one or more acidic or basic units. In some embodiments, the buffer is a weak acid having two or more acidic units, such as citric acid. In some embodiments, the composition includes NaOH, HCl and/or NaCl as pH adjusters (NaOH and/or HCl) or residual salts (NaCl) derived from pH adjustment.

It was also found that the freeze-dried compound 1 dihydrochloride composition containing mannitol and citric acid can be prepared as a crystalline form and is readily characterized by X-ray powder diffraction (XRPD). In some embodiments, the freeze-dried compound 1 dihydrochloride composition contains about 250 to 350 mg, about 275 to 325 mg, or more specifically about 300 mg of compound 1 , wherein the weight of 300 mg corresponds to the free base (i.e., about 349 mg of compound 1 in the form of dihydrochloride). In a primary embodiment, compound 1 in the freeze-dried composition is a crystalline dihydrochloride characterized as shown in Figure 1. In other embodiments, compound 1 in the freeze-dried composition is in the form of 30%, 40%, or a mixture of pharmaceutically acceptable salts. In some embodiments, compound 1 in the freeze-dried composition is in the form of different patterns or mixtures of patterns. In some embodiments, the freeze-dried compound 1 composition contains 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 pattern 1 relative to other forms of compound 1 in the composition. In some embodiments, the freeze-dried compound 1 composition comprises at least about 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75% or 80% of compound 1 dihydrochloride pattern 1 relative to other components of the freeze-dried composition.

The freeze-dried compound 1 dihydrochloride composition described in Example 28 contains mannitol and citric acid and is characterized by the XRPD pattern shown in Figure 100. Other suitable excipients may be added or mannitol and/or citric acid may be substituted to achieve the desired effect. In some embodiments, the compound 1 dihydrochloride composition is freeze-dried; in others, it is dried using a different technique. In some 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 of mannitol, or about 200 to 400 mg, 225 to 375 mg, 250 to 350 mg, 275 to 325 mg or 300 mg of mannitol. In some 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 of citric acid, or about 15 to 145 mg, 30 to 130 mg, 45 to 105 mg, 60 to 90 mg or 75 mg of citric acid. In some embodiments, the compound 1 dihydrochloride composition comprises one or more additional salts formed by adjusting the pH of a bulk solution, which is then dried to form the composition, such as sodium chloride and/or various sodium citrate salts.

In one specific embodiment, the freeze-dried compound 1 dihydrochloride composition comprises about 349 mg of compound 1 pattern 1 dihydrochloride (equivalent to about 300 mg of trilactone free base), about 50 to 100 mg, about 60 to 80 mg or more specifically about 76 mg of citrate monohydrate, and about 280 to 320 mg, such as 300 mg of mannitol.

The freeze-dried compound 1 can be restored in a suitable solvent (e.g., water), which may include other adjuvants such as sodium chloride or dextrose. In some embodiments, the freeze-dried compound 1 is reduced 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, for example about 0.9% sodium chloride solution. In some embodiments, the freeze-dried compound 1 is restored 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, for example, about 0.9% sodium chloride solution. In some embodiments, the freeze-dried compound 1 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, or 10% dextrose solution, for example, about 5% dextrose solution. In some embodiments, the freeze-dried compound 1 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, or 10% dextrose solution, for example, about 5% dextrose solution.

In some embodiments of the invention, the isolated compound 1 (pattern 1) is used to produce a freeze-dried form, which is then formulated with a suitable solvent, such as phosphate-rehydrated saline, for administration to a patient, for example, by intravenous delivery. In another embodiment, it can be formulated as a non-enteric dosage form. This dosage form can be used, for example, for subcutaneous administration.

In some embodiments, compound 1 , pattern 1, is in the form of a dihydrochloride. In some embodiments, compound 1, pattern 1, in the form of a dihydrochloride, can be used to treat any condition responding to triazepam, including for bone marrow preservation or as an anti-abortive agent.

In some embodiments, Compound 1, Pattern 1, is in the form of a dihydrochloride dihydrate. In some embodiments, Compound 1 , Pattern 1, in the form of a dihydrochloride dihydrate, can be used to treat any condition responding to triazepam, including for bone marrow preservation or as an anti-excess agent.

Other forms of compound 1 in the form of dihydrochloride have also been identified. Figures 2 and 3 show highly crystalline forms of compound 1 in the form of dihydrochloride. Figure 4 shows a crystalline solvent complex of compound 1 in the form of dihydrochloride and acetonitrile. Figure 5 shows a crystalline form of compound 1 in the form of dihydrochloride. Figure 6 shows a metastable form of compound 1 in the form of dihydrochloride. Figure 11 shows a crystalline form of compound 1 in the form of a dihydrochloride hemihydrate.

The morphological forms of compound 1 in the form of a free base have also been identified. Figures 8 and 10 show the crystalline forms of compound 1 in the form of a free base. Figure 9 shows the crystalline forms of compound 1 in the form of a free base, which can be a solvent compound or a hydrate.

In some embodiments, pattern 1 is the most stable form of compound 1 in the form of a dihydrochloride and is formed by pattern 2 or pattern 3 in a competing slurry experiment.

Compound 1 is typically administered to patients as an intravenous formulation. However, the solid form of triasidrili can be important because it can be used to achieve the required manufacturing purity and/or efficacy, and can also be important for the solid shelf life before reconstitution or in solid dosage forms used for treatment delivery.

Given the therapeutic importance of compound 1 (triclasidil) for the medical treatment of patients with proliferative conditions (such as tumors or cancer), it is beneficial to provide this advantageous solid form that contributes to the success or efficacy of the compound during its manufacture, storage, formulation and/or administration.

Cross-reference to related applications

This application claims the interests in U.S. Provisional Application No. 63/039,372, filed June 15, 2020, and U.S. Provisional Application No. 63/180,578, filed April 27, 2021. The entire contents of those applications are incorporated herein by reference in all respects.

It is impossible to predict in advance whether a compound exists in more than one solid form, or if one or more do exist, to what extent they exist as salts or solvents, or in any solid form, or whether those properties are favorable for therapeutic formulation. As an example, the drug ritonavir is active in one form and inert in another, with the inert form being more stable.

Compound 1 is the approved drug triasidrili, marketed under the brand name COSELA ^™ and used in some practices as a bone marrow preserver to protect healthy cells, particularly hematopoietic cells, during chemotherapy. It is intended to be administered intravenously to rapidly establish blood flow before chemotherapy, typically via IV. However, the free base of compound 1 is insoluble in water and practically insoluble in DMSO. Furthermore, it becomes less soluble with increasing pH. Blood typically has a pH of 7.35 to 7.45, which is slightly alkaline. Phosphate-blended saline typically has a pH of 7.2 to 7.4. Compound 1 is not very soluble at these pH levels, and this can lead to various problems. Most importantly, a large dose of Compound 1 is required to achieve therapeutic effect. The typical dose is 240 mg/ ^m² , which can be estimated at approximately 300 mg for a normal adult. Because it has no solubility in water, a dilute solution will be used in a large volume of fluid to provide this dose of the free alkali compound 1. This results in a conflict between how it should be delivered and the need for prolonged administration. Compound 1 IV is typically administered over approximately 30 minutes (20 to 60 minutes) , meaning the drug must be concentrated, not diluted, in the IV fluid. Furthermore, when the free alkali compound 1 is injected into the bloodstream, there is a real possibility that at least some of it may leak out of the solution due to the slightly alkaline nature of blood. This can cause problems at the injection site due to drug deposition and loss of activity.

It has been found that an IV solution of compound 1 , intended for injection into cancer patients to preserve healthy cells or for anti-reproductive purposes, can be administered by dispensing it in the form of a dihydrochloride or a dihydrate of the dihydrochloride. This achieves the desired therapeutic effect because it can be delivered directly and rapidly into the bloodstream in a concentrated form. In one primary embodiment, the IV solution is prepared from a freeze-dried powder comprising compound 1 dihydrochloride, mannitol, and citric acid.

In some embodiments, the IV solution of compound 1 is prepared from a solid pharmaceutical composition, which is dried by freeze-drying as appropriate. In some embodiments, the composition includes compound 1 in the form of a dihydrochloride, such as compound 1 dihydrochloride pattern 1. The composition may also include suitable excipients, such as build-up agents, buffers, and/or one or more pH adjusters. In some embodiments, the build-up agent is a suitable sugar, such as mannitol. In some embodiments, the buffer is a suitable weak acid or weak base having one or more acidic or basic sites. In some embodiments, the buffer is a weak acid having two or more acidic sites, such as citric acid. In some embodiments, the composition includes NaOH, HCl and/or NaCl as pH adjusters (NaOH and/or HCl) or residual salts (NaCl) derived from pH adjustment.

It was also found that the freeze-dried compound 1 dihydrochloride composition containing mannitol and citric acid is crystalline and readily characterized by X-ray powder diffraction (XRPD). In some embodiments, the freeze-dried compound 1 dihydrochloride composition contains about 250 to 350 mg, about 275 to 325 mg, or more specifically about 300 mg of compound 1 , wherein the weight of 300 mg corresponds to the free base. In one main embodiment, compound 1 in the freeze-dried composition is a crystalline dihydrochloride characterized herein as in Figure 1. In other embodiments, compound 1 in the freeze-dried composition is in the form of different pharmaceutically acceptable salts or mixtures of pharmaceutically acceptable salts. In some embodiments, compound 1 in the freeze-dried composition is in the form of different patterns or mixtures of patterns. In some embodiments, the freeze-dried compound 1 composition contains 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 pattern 1 relative to other forms of compound 1. In some embodiments, the freeze-dried compound 1 composition contains at least about 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% of compound 1 dihydrochloride pattern 1 relative to other components of the freeze-dried composition.

The freeze-dried compound 1 dihydrochloride composition described in Example 28 contains mannitol and citric acid and is characterized by the XRPD pattern shown in Figure 100. Other suitable excipients may be added or mannitol and/or citric acid may be substituted to achieve the desired effect. In some embodiments, the compound 1 dihydrochloride composition is freeze-dried. In other embodiments, a different technique is used to dry it. In some 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 of mannitol, or about 200 to 400 mg, 225 to 375 mg, 250 to 350 mg, 275 to 325 mg or 300 mg of mannitol. mg of mannitol, or 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 of mannitol, or up to about 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390 or 400 mg of mannitol. In some 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 of citric acid, or about 15 to 145 mg, 30 to 130 mg, 45 to 105 mg, 60 to 90 mg, 75 mg or more. 10 mg of citric acid, or 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 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 some embodiments, the compound 1 dihydrochloride composition comprises one or more additional salts formed by adjusting the pH of a bulk solution, which is then dried to form the composition, such as sodium chloride and/or various sodium citrate salts.

In one specific embodiment, the freeze-dried compound 1 dihydrochloride composition comprises about 349 mg of compound 1 pattern 1 dihydrochloride (equivalent to about 300 mg of triacetyl free base), about 50 to 100 mg, about 60 to 80 mg or more specifically about 76 mg of citrate monohydrate, and about 280 to 320 mg, such as 300 mg of mannitol.

The freeze-dried compound 1 can be restored in a suitable solvent (e.g., water), which may include other adjuvants such as sodium chloride or dextrose. In some embodiments, the freeze-dried compound 1 is restored 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, for example about 0.9% sodium chloride solution. In some embodiments, the freeze-dried compound 1 is restored 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, for example, about 0.9% sodium chloride solution. In some embodiments, the freeze-dried compound 1 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, or 10% dextrose solution, for example, about 5% dextrose solution. In some embodiments, the freeze-dried compound 1 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, or 10% dextrose solution, for example, about 5% dextrose solution.

Figures 1, 2, and 3 also represent highly crystalline forms of compound 1 in the form of a dihydrochloride. Figure 1 shows a suitable dihydrate form of compound 1 in the form of a dihydrochloride. Figure 4 shows a crystalline solvent compound of compound 1 in the form of a dihydrochloride and acetonitrile. Figure 5 shows a crystalline form of compound 1 in the form of a dihydrochloride. Figure 6 shows a metastable form of compound 1 in the form of a dihydrochloride. Figure 7 shows a highly crystalline form of compound 1 in the form of a free base. Figures 8 and 10 show crystalline forms of compound 1 in the form of a free base. Figure 9 shows a crystalline form of compound 1 in the form of a free base, which can be a solvent compound or a hydrate. Figure 11 shows the crystalline form of compound 1 as a dihydrochloride hemihydrate.

In some embodiments, Figure 1, the dihydrochloride dihydrate, is the most stable form of compound 1 in dihydrochloride form and can be formed using Figure 2 or Figure 3 in a competing paste experiment. In some embodiments, Figure 1, regardless of its water content, is the most stable form of compound 1 in dihydrochloride form and can be formed using Figure 2 or Figure 3 in a competing paste experiment. In some embodiments, Figure 7 is the most stable form of compound 1 in free base form.

Compared to other forms of compound 1 , pattern 1 dihydrochloride dihydrate offers several therapeutic advantages. For example, pattern 1 dihydrochloride dihydrate is easier to use in intravenous solutions. Furthermore, higher concentrations of pattern 1 dihydrochloride dihydrate can be achieved in water and/or DMSO.

Compared to other forms of Compound 1 , the dihydrochloride dihydrate of Figure 1 offers several manufacturing advantages. For example, compared to other forms of Compound 1 , the dihydrochloride dihydrate of Figure 1 typically exhibits increased storage stability, thermodynamic stability, and/or water solubility. In other embodiments, the manufacturing of the dihydrochloride dihydrate of Figure 1 allows for more scalable and renewable production compared to other forms of Compound 1 .

In some embodiments of the invention, the separation pattern 1, where appropriate, is used to manufacture a freeze-dried form, which is then formulated with a suitable solvent, such as phosphate-rehydrated saline, for administration to a patient, for example, by intravenous delivery. In an alternative embodiment, it can be formulated as a non-enteric dosage form. This dosage form can be used, for example, for subcutaneous administration.

In some embodiments of the invention, the separation pattern 2 is used to produce a freeze-dried form, which is then formulated with a suitable solvent, such as phosphate-rehydrated saline, for administration to a patient, for example, via intravenous delivery. In an alternative embodiment, it can be formulated as a non-enteric dosage form. This dosage form can be used, for example, for subcutaneous administration.

In some embodiments of the invention, the separation pattern 3 is used to produce a freeze-dried form, which is then formulated with a suitable solvent, such as phosphate-rehydrated saline, for administration to a patient, for example, via intravenous delivery. In an alternative embodiment, it can be formulated as a non-enteric dosage form. This dosage form can be used, for example, for subcutaneous administration.

In some embodiments of the invention, the separation pattern 7 is used to produce a freeze-dried form, which is then formulated with a suitable solvent, such as phosphate-rehydrated saline, for administration to a patient, for example, via intravenous delivery. In an alternative embodiment, it can be formulated as a non-enteric dosage form. This dosage form can be used, for example, for subcutaneous administration.

Figure 1. This invention provides the isolated form of compound 1 , named Figure 1, in the form of a dihydrochloride.

Compound 1, pattern 1, can be in the form of a dihydrochloride dihydrate. Pattern 1 typically initially exists as a dihydrochloride dihydrate after formation and can eventually revert to this form even after drying and exposure to air. Regardless of water content, pattern 1 maintains its representative XRPD peaks, as described in more detail below. For example, if compound 1 is prepared in the form of pattern 1 as described herein and subsequently dried, the representative XRPD peaks will remain the same before and after drying.

Surprisingly, it was found that pattern 1 could dissolve in the composition used for freeze-drying and reformed into pattern 1 after drying.

In some embodiments, compound 1 , as shown in pattern 1, is in the form of a dihydrochloride dihydrate. In some embodiments, the present invention provides compositions of compound 1 in the form of a dihydrochloride dihydrate. In some embodiments, the present invention provides compositions of compound 1 , as shown in pattern 1, in the form of a dihydrochloride dihydrate.

In some embodiments, the dihydrate of compound 1 (designation 1) is more stable than other hydrated forms of compound 1. In another embodiment, the dihydrate of compound 1 (designation 1) may be more stable than the non-hydrated form of compound 1. The dihydrate form of compound 1 (designation 1) may be advantageous over the anhydrous monohydrate or even trihydrate form of compound 1 (designation 1). For example, the dihydrate form of compound 1 (designation 1) has improved storage stability, thermodynamic stability, and/or water solubility compared to the anhydrous monohydrate or even trihydrate form of compound 1 (designation 1). In other embodiments, the production of the dihydrochloride dihydrate of pattern 1 is cheaper, faster, and/or more scalable than the production of anhydrous monohydrate or even trihydrate form compound 1 of pattern 1 .

In some embodiments, the compound 1 in the form of a dihydrate, as appropriate, is characterized by an XRPD pattern substantially similar to the XRPD pattern illustrated in Figure 1. In one embodiment, the compound 1 in the form of a dihydrate, as appropriate, is characterized by an XRPD pattern comprising at least three 2θ values selected from the following: approximately 9.6 ± 0.2°, approximately 21.3 ± 0.2°, approximately 19.8 ± 0.2°, approximately 12.2 ± 0.2°, approximately 24.0 ± 0.2°, approximately 26.1 ± 0.2°, approximately 19.3 ± 0.2°, approximately 17.6 ± 0.2°, and approximately 28.6 ± 0.2°. In one embodiment, the compound 1 in the form of a dihydrate, as appropriate, is characterized by an XRPD pattern containing a peak with a 2θ value of approximately 9.6 ± 0.2°.

In some embodiments, Compound 1, as shown in Pattern 1 and where applicable, is characterized by a 6% ± 3% weight loss at the start of heating the sample. In some embodiments, Compound 1, as shown in Pattern 1 and where applicable, is characterized by a 7% ± 3% weight loss between about 200°C and about 230°C. In some embodiments, Compound 1 , as shown in Pattern 1 and where applicable, is characterized by a second 7% ± 3% weight loss between about 300°C and about 380°C.

Compound 1, pattern 1, can be prepared by selective crystallization. The method can be carried out by treating a solution containing one or more suitable solvents and Compound 1 in the form of a dihydrochloride in the presence of one or more seed crystals containing Compound 1 , pattern 1, to achieve the conditions for crystallizing Compound 1, pattern 1. If the solvent used is water or contains water, the resulting Compound 1 , pattern 1, is typically 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 aprotic solvents that can be used include tetrahydrofuran, dichloromethane, nitromethane, and dialkylene. In another embodiment, Compound 1, pattern 1, is prepared from a protic solvent. Examples of protic solvents that can be used include water, methanol, and ethanol. In some embodiments, compound 1, pattern 1, is prepared from a mixture of aprotic solvent and protic solvent (such as a mixture of acetonitrile and water).

Selective crystallization can be carried out at temperatures, for example, in the range of about 20°C to about 65°C. In another embodiment, selective crystallization can be carried out at temperatures, for example, in the range of about 35°C to about 45°C or at about 40°C.

In one embodiment, Compound 1, pattern 1, which is in dihydrate form, is produced by crystallization or recrystallization in an acidic solution, as appropriate. For example, Compound 1, pattern 1, can be produced in an aqueous hydrochloric acid solution.

In one embodiment, Compound 1 (Pattern 1) is produced 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 with stirring. Compound 1 (Pattern 1) can be separated by filtration, washed with purified water and acetone, and dried under vacuum at high temperature.

In some embodiments, the compound 1 pattern 1 in dihydrate form is sieved using a grinder, depending on the circumstances. In some embodiments, the sieved material of compound 1 pattern 1 is formulated for non-enteral administration to the patient.

In some embodiments, the compound 1 in the form of a dihydrate, as appropriate, is characterized in that the XRPD pattern contains at least two peaks selected from the following: 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°.

In some embodiments, the compound 1 in the form of a dihydrate, as appropriate, is characterized in that the XRPD pattern contains at least three peaks selected from the following: 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°.

In some embodiments, the compound 1 in the form of a dihydrate, as appropriate, is characterized in that the XRPD pattern contains at least four peaks selected from the following: 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°.

In some embodiments, the compound 1 in the form of a dihydrate, as appropriate, is characterized in that the XRPD pattern contains at least five peaks selected from the following: 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°.

In some embodiments, the compound 1 in the form of a dihydrate, as appropriate, is characterized in that the XRPD pattern includes 2θ values selected from the following: 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°.

In some embodiments, the compound 1 in dihydrate form, as appropriate, is characterized by an XRPD pattern comprising 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 selected from the following peaks within ±0.4°2θ: 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 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 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 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 e. 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 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 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 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 i. 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 j. 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 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 l. 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°2θ; or 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 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 o. 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 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 q. 9.6, 21.3, 19.8, 12.2, 24.0, 26.1, 19.3, 17.6, 28.6 and 15.3°2θ; or r. 9.6, 21.3, 19.8, 12.2, 24.0, 26.1, 19.3, 17.6 and 28.6°2θ; or s. 9.6, 21.3, 19.8, 12.2, 24.0, 26.1, 19.3 and 17.6°2θ; or t. 9.6, 21.3, 19.8, 12.2, 24.0, 26.1 and 19.3°2θ; or u. 9.6, 21.3, 19.8, 12.2, 24.0 and 26.1°2θ; v. where °2θ is any of the peaks in the list of peaks with an elevation of +0.1 or higher; or w. where °2θ is any of the peaks in the list of peaks with an elevation of +0.2 or higher; or x. where °2θ is any of the peaks in the list of peaks with an elevation of +0.3 or higher.

In one embodiment, the compound 1 in its dihydrate form, pattern 1, is characterized by the XRPD pattern described above, and further characterized by not having a peak with a relative intensity greater than 15% between 4° and 9°2θ. In one embodiment, the compound 1 in its dihydrate form, pattern 1, is characterized by the XRPD pattern described above, and further characterized by not having a peak with a relative intensity greater than 10% between 4° and 9°2θ. In one embodiment, the compound 1 in its dihydrate form, pattern 1, is characterized by the XRPD pattern described above, and further characterized by not having a peak with a relative intensity greater than 5% between 4° and 9°2θ. In one embodiment, the compound 1 in the form of a dihydrate, as it is, is characterized by the XRPD pattern described above and is further characterized by not having a peak with a relative intensity greater than 3% between 4 and 9°2θ.

In some embodiments, compound 1 (pattern 1), which is in dihydrate form, is used to prepare amorphous compound 1 in the form of a dihydrochloride. For example, amorphous compound 1 in the form of a dihydrochloride can be formed by freeze-drying or spray-drying compound 1 (pattern 1), which is in dihydrate form. This amorphous dihydrochloride can have a higher purity than that prepared directly by known synthetic methods. Furthermore, the advantage of first preparing compound 1 (pattern 1), which is in dihydrate form, and then converting it into an amorphous material, can thus increase the overall shelf life of the product.

In some embodiments, compound 1 (pattern 1), which is in the form of a dihydrate, is used to prepare an amorphous compound 1 in the form of a mono-HCl salt. For example, the amorphous compound 1 in the form of a mono-HCl salt can be formed by dissolving compound 1 (pattern 1) and adjusting the pH of the solution, followed by removing the solvent. This amorphous mono-HCl salt can have a higher purity than that prepared directly by known synthetic methods. Furthermore, the advantage of first preparing compound 1 (pattern 1) in the form of a dihydrate and then converting it into an amorphous material can improve the overall shelf life of the product.

In some embodiments, compound 1 (pattern 1), which is in the form of a dihydrate, is used to prepare an amorphous compound 1 in the form of a free base. This amorphous free base can have a higher purity than that prepared directly by known synthetic methods. Furthermore, the advantage of first preparing compound 1 (pattern 1), which is in the form of a dihydrate, and then converting it into an amorphous material, is that the overall shelf life of the product can be increased.

In some embodiments, Compound 1 (scheme 1), which is, where appropriate, a dihydrate, is used to prepare a liquid solution suitable for intravenous administration of Compound 1. This liquid solution of Compound 1 can have a higher purity than that prepared directly by known synthetic methods. Furthermore, the advantage of first preparing Compound 1 (scheme 1), which is, where appropriate, a dihydrate, and then converting it into a liquid solution, is that the overall shelf life of the product can be increased.

In some embodiments, Compound 1 (pattern 1), as it is in dihydrate form, is freeze-dried. In these embodiments, Compound 1 (pattern 1), as it is in dihydrate form, may be mixed with one or more suitable excipients, as it is, before or after freeze-drying. For example, in some embodiments, the invention provides a solid freeze-dried composition comprising Compound 1 (pattern 1), as it is in dihydrate form. In some embodiments, the invention provides a solid freeze-dried composition comprising Compound 1 (pattern 1), as it is in dihydrate form, mannitol, and citric acid. In some embodiments, the invention provides a solid freeze-dried composition comprising Compound 1 (pattern 1) dihydrochloride dihydrate, mannitol, and citric acid.

Non-limiting embodiments of the present invention 1. In some embodiments, a crystalline compound having the following structure is provided: It is a dihydrochloride, which may be in dihydrate form depending on the situation.

Other non-limiting embodiments include: 2. The crystalline compound of embodiment 1, characterized in that the X-ray powder diffraction (XRPD) pattern includes at least three 2θ values selected from the following: 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 Embodiment 2, wherein the XRPD pattern comprises at least four 2θ values selected from the following: 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°. 4. The crystalline compound of Embodiment 2, wherein the XRPD pattern comprises at least five 2θ values selected from the following: 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°. 5. The crystalline compound of Embodiment 2, wherein the XRPD pattern includes at least six 2θ values selected from the following: 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 crystalline compound of Embodiment 2, wherein the XRPD pattern includes at least the 2θ value of 9.6±0.2°. 7. The crystalline compound of Embodiment 2, wherein the XRPD pattern includes at least the 2θ values of 9.6±0.2°, 19.8±0.2°, and 21.3±0.2°. 8. In some embodiments, a freeze-dried powder prepared from the crystalline compound of Embodiment 1 is provided. 9. The freeze-dried powder of Example 8, wherein the crystalline compound of Example 1 is characterized in that the X-ray powder diffraction (XRPD) pattern includes at least three 2θ values selected from the following: 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°. 10. The freeze-dried powder of Example 9, wherein the crystalline compound of Example 1 is characterized in that the XRPD pattern includes at least four 2θ values selected from the following: 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°. 11. The freeze-dried powder of Example 9, wherein the crystalline compound of Example 1 is characterized in that the XRPD pattern includes at least five 2θ values selected from the following: 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°. 12. The freeze-dried powder of Embodiment 9, wherein the crystalline compound of Embodiment 1 is characterized in that the XRPD pattern includes at least six 2θ values selected from the following: 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°. 13. The freeze-dried powder of Embodiment 9, wherein the crystalline compound of Embodiment 1 is characterized in that the XRPD pattern includes at least the 2θ value of 9.6±0.2°. 14. The freeze-dried powder of Example 9, wherein the crystalline compound of Example 1 is characterized in that the XRPD pattern includes 2θ values of at least 9.6 ± 0.2°, 19.8 ± 0.2°, and 21.3 ± 0.2°. 15. In some embodiments, a pharmaceutical composition comprising the crystalline compound of Example 1 and a pharmaceutically acceptable excipient is provided. 16. The pharmaceutical composition of Example 15, wherein the pharmaceutical composition is suitable for intravenous delivery. 17. The pharmaceutical composition of Example 15, comprising about 200 mg to about 600 mg of the crystalline compound of Example 1. 18. The pharmaceutical composition of Example 15, comprising about 300 mg of the crystalline compound of Example 1. 19. A pharmaceutical composition of Example 15, comprising a dose of the crystalline compound of Example ¹ at a concentration of about 150 mg/ ^m² to about 350 mg/m². 20. A pharmaceutical composition of Example 15, further comprising about 300 mg of mannitol and about 76 mg of citric acid. 21. A pharmaceutical composition of Example 15, comprising a dose of the crystalline compound of Example ¹ at a concentration of about 240 mg/m². 22. In some embodiments, a pharmaceutically acceptable reconstitution solution of the freeze-dried powder of Example 8 is provided. 23. A pharmaceutical solution of Example 23, wherein the solution is an aqueous solution. 24. A pharmaceutical solution of Example 23, wherein the pharmaceutical composition is suitable for intravenous delivery. 25. The pharmaceutical solution of Example 23 contains approximately 200 mg to approximately 600 mg of the freeze-dried powder of Example 8. 26. The pharmaceutical solution of Example 23 contains approximately 300 mg of the freeze-dried powder of Example 8. 27. The pharmaceutical solution of Example 23 contains a dose of approximately 150 mg/ ^m² to approximately 350 mg/ ^m² of the freeze-dried powder of Example 8. 28. The pharmaceutical solution of Example 23 further contains approximately 300 mg of mannitol and approximately 76 mg of citric acid. 29. The pharmaceutical solution of Example 23 further contains sodium hydroxide or hydrochloric acid. 30. A pharmaceutical solution as in Example 23, comprising a dose of the freeze-dried powder as in Example ⁸ at approximately 240 mg/m². 31. A freeze-dried powder comprising a compound having the following structure: ; It is a dihydrochloride, which may include hydrates as appropriate. 32. The freeze-dried powder of Example 31, wherein the compound is characterized in that the X-ray powder diffraction (XRPD) pattern includes at least three 2θ values selected from the following: 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°. 34. The freeze-dried powder of Example 31, wherein the compound is characterized in that the XRPD pattern includes at least four 2θ values selected from the following: 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°. 35. The freeze-dried powder of Example 31, wherein the compound is characterized in that the XRPD pattern includes at least five 2θ values selected from the following: 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°. 36. The freeze-dried powder of Example 31, wherein the compound is characterized in that its XRPD pattern includes at least six 2θ values selected from the following: 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°. 37. The freeze-dried powder of Example 31, wherein the compound is characterized in that its XRPD pattern includes at least the 2θ value of 9.6±0.2°. 38. The freeze-dried powder of Example 31, wherein the compound is characterized in that the XRPD pattern includes 2θ values of at least 9.6±0.2°, 19.8±0.2° and 21.3±0.2°.

Additional embodiment 1. In one embodiment, a crystalline compound having the following structure is provided: ; It is a dihydrochloride. 2. The crystalline compound of Example 1 is characterized in that its X-ray powder diffraction (XRPD) pattern includes at least three 2θ values selected from the following: 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 Embodiment 2, wherein the XRPD pattern comprises at least four 2θ values selected from the following: 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°. 4. The crystalline compound of Embodiment 2, wherein the XRPD pattern comprises at least five 2θ values selected from the following: 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°. 5. The crystalline compound of Embodiment 2, wherein the XRPD pattern includes at least six 2θ values selected from the following: 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 crystalline compound of Embodiment 2, wherein the XRPD pattern includes at least the 2θ value of 9.6±0.2°. 7. The crystalline compound of Embodiment 2, wherein the XRPD pattern includes at least the 2θ values of 9.6±0.2°, 19.8±0.2°, and 21.3±0.2°. 8. A composition comprising a crystalline compound as described in any one of Examples 1 to 7, mannitol, and citric acid. 9. A pharmaceutical composition comprising a crystalline compound as described in Examples 1 to 7 and a pharmaceutically acceptable excipient. 10. A pharmaceutical composition as described in Example 9, wherein the pharmaceutically acceptable excipient comprises mannitol. 11. A pharmaceutical composition as described in Example 9, wherein the pharmaceutically acceptable excipient comprises citric acid. 12. A pharmaceutical composition as described in Example 9, wherein the pharmaceutically acceptable excipient comprises mannitol and citric acid. 13. A pharmaceutical composition as described in Example 9, comprising about 200 to 600 milligrams of the crystalline compound. 14. The pharmaceutical composition of Example 9, comprising about 300 mg of the crystalline compound. 15. The pharmaceutical composition of Example 9, comprising about 349 mg of the crystalline compound. 16. The pharmaceutical composition of Example 10, comprising about 250 to 350 mg of mannitol. 17. The pharmaceutical composition of Example 10, comprising about 300 mg of mannitol. 18. The pharmaceutical composition of Example 11, comprising about 50 to 100 mg of citric acid. 19. The pharmaceutical composition of Example 11, comprising about 76 mg of citric acid. 20. The pharmaceutical composition of Example 12, comprising about 250 to 350 mg of mannitol. 21. The pharmaceutical composition of Example 12, comprising about 300 mg of mannitol. 22. The pharmaceutical composition of Example 12 contains about 50 to 100 mg of citric acid. 23. The pharmaceutical composition of Example 12 contains about 76 mg of citric acid. 24. The pharmaceutical composition of Example 12 contains about 300 mg of mannitol and about 76 mg of citric acid. 25. The pharmaceutical composition of Example 24 contains about 300 mg of the crystalline compound. 26. The pharmaceutical composition of Example 12 contains a dose of the crystalline compound of about 150 mg/ ^m² to about 350 mg/ ^m² . 27. The pharmaceutical composition of Example 12 contains a dose of the crystalline compound of about 240 mg/ ^m² . 28. A pharmaceutical composition formed by dissolving the pharmaceutical composition of any one of Examples 1 to 27 in a solvent. 29. The pharmaceutical composition of Example 28, wherein the solvent is water. 30. The pharmaceutical composition of Example 28, wherein the solvent is an aqueous sodium chloride solution. 31. The pharmaceutical composition of Example 30, wherein the sodium chloride concentration is between about 0.1% and 2%. 32. The pharmaceutical composition of Example 30, wherein the sodium chloride concentration is about 0.9%. 33. The pharmaceutical composition of Example 28, wherein the solvent is an aqueous dextran solution. 34. The pharmaceutical composition of Example 33, wherein the dextran concentration is between about 1% and 10%. 35. The pharmaceutical composition of Example 33, wherein the dextran concentration is about 5%. 36. The pharmaceutical composition of any one of Examples 28 to 35, wherein about 10 to 30 mL of solvent is present. 37. The pharmaceutical composition of any one of Examples 28 to 35, wherein about 19.5 mL of solvent is present. 39. A method for treating a condition mediated by CDK4 or CDK6, comprising administering to a patient in need an effective amount of the compound of any one of Examples 1 to 37. 40. A method for treating cancer, comprising administering to a patient in need an effective amount of the compound of any one of Examples 1 to 37. 41. A method for reducing the effect of chemotherapy on healthy cells of a patient receiving treatment for cancer or abnormal cell proliferation, the method comprising administering to the individual an effective amount of at least one chemotherapy agent and an effective amount of a compound of a pharmaceutical composition as described in any one of Examples 1 to 37. 42. The method of Example 40, wherein the healthy cells are hematopoietic stem cells or hematopoietic precursor cells. 43. The method of any one of Examples 40 to 41, wherein the chemotherapy agent is carboplatin. 44. The method of any one of Examples 40 to 41, wherein the chemotherapy agent is cisplatin. 45. The method of any one of Examples 42 to 43, wherein the method further comprises administering etoposide. 46. The method of any of Examples 40 to 41, wherein the chemotherapy agent is topotecan. 47. The method of any of Examples 38 to 45, wherein the patient is a human.

In some embodiments, the formulation of compound 1 (Figure 1) is provided in which compound 1 (Figure 1) is in the form of dihydrochloride dihydrate. In some embodiments, the formulation comprises about 300 to 400 mg, about 350 to 400 mg, about 360 to 380 mg, or more specifically about 373 mg of dihydrochloride dihydrate of compound 1 (Figure 1), about 50 to 100, about 60 to 80, or more specifically about 76 mg of citrate monohydrate, and about 250 to 350 mg, about 280 to 320 mg, or more specifically about 300 mg of mannitol, and, as appropriate, sodium hydroxide and/or hydrochloric acid to adjust the pH as needed. Specifically, 373 mg of dihydrochloride dihydrate will provide 300 mg of triacetyl free base.

In some embodiments, the formulation is freeze-dried after being mixed with citric acid and mannitol in the form of compound 1 (pattern 1) as a dihydrochloride dihydrate. In some embodiments, the formulation comprises freeze-dried 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 the compound 1 (pattern 1) in the form of a dihydrochloride dihydrate has been freeze-dried.

In some embodiments, the formulation is provided in the form of a dihydrochloride, as shown in Figure 1. In some embodiments, the formulation comprises about 300 to 400 mg, about 350 to 400 mg, or about 360 to 380 mg, or more specifically about 373 mg of the dihydrochloride dihydrate of compound 1 (Figure 1), about 50 to 100, about 60 to 80, or more specifically about 76 mg of citrate monohydrate, and about 250 to 350 mg, about 280 to 320 mg, or more specifically about 300 mg of mannitol, and, as appropriate, sodium hydroxide and/or hydrochloric acid for adjusting the pH as needed for reduction.

In some embodiments, the preparation is sterile.

In some embodiments, the formulation is freeze-dried after being mixed with citric acid and mannitol in the form of compound 1 (pattern 1) as a dihydrochloride dihydrate. In some embodiments, the formulation comprises freeze-dried 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 the form of compound 1 (pattern 1) as a dihydrochloride dihydrate has been freeze-dried.

In some embodiments, a formulation is provided, wherein the formulation is prepared by freeze-drying about 300 to 400 mg, about 350 to 400 mg, or about 360 to 380 mg, or more specifically about 373 mg of compound 1 (Figure 1) dihydrochloride dihydrate, about 50 to 100, about 60 to 80, or more specifically about 76 mg of citric acid monohydrate, and about 250 to 350 mg, about 280 to 320 mg, or more specifically about 300 mg of mannitol, and, as appropriate, sodium hydroxide and/or hydrochloric acid to adjust the pH as needed. In another embodiment, the formulation is produced by freezing-drying compound 1 (pattern 1) after mixing it with about 50 to 100 mg, about 60 to 80 mg or more specifically about 76 mg of citric acid monohydrate and about 280 to 320 mg or more specifically about 300 mg of mannitol.

Any of the formulations described above may be reconstituted with about 5 to 100, 5 to 50, 10 to 30, about 10 to 25, or more specifically about 19.5 mL of sterile water, phosphate-buffered saline, diluted sugar, or another aqueous solution of physiological saline. In a non-limiting embodiment, the reconstituted solution is a sterile sodium chloride solution, for example containing about 0.9% NaCl, or a sterile sugar solution, such as about 5% dextrose solution. The resulting reconstituted solution will have any amount of triprazine required for the intended purpose, such as triprazine at a concentration between about 5 to 50 mg/mL, about 10 to 25 mg/mL, or even about 15 mg/mL. In some embodiments, the resulting solution is subsequently diluted before administration, such as intravenous delivery.

Non-limiting examples of typical quality standards and pharmaceutical functions are provided in the table below. Components Quantity ^a (mg) per vial Medical Function Quality Standards ^Compound 1b 300 Activator inherent Mannitol 300 Ingredients USP/Ph. Eur. Citric acid monohydrate 75.6 buffer USP/Ph. Eur. Sodium hydroxide Sufficient pH adjuster ^C NF/Ph. Eur. hydrochloric acid Sufficient pH adjuster ^C NF/Ph. Eur. Water for Injection ^d Sufficient solvent USP/Ph. Eur. Nitrogen ^e N/A Process aids NF NF = United States National Prescriptions; USP = United States Pharmacopeia; Ph. Eur. = European Pharmacopeia; N/A = Not Applicable; qs = Sufficient. a. The target weight of the solution filled into the vial before freeze-drying is 12.252 g (12 mL). b. The amount relative to the free base (equivalent to 373 mg of compound 1, pattern 1, dihydrochloride dihydrate). c. Can be used to adjust the pH of the bulk solution if necessary. d. Used to dissolve components, subsequently removed during freeze-drying. e. Nitrogen is used as an inert gas at the end of the freeze-drying process for vacuum conditioning.

The resulting formulation can be applied to any suitable container, such as a 20 mL (Type 1) clear glass vial, sealed with a 20 mm gray chloroprene rubber stopper and secured with a 20 mm aluminum outer seal with a plastic easy-pull seal.

In some embodiments, the solid formulation is reconstituted with at least about 5 to 100, 5 to 50, 10 to 30, about 10 to 25, or more specifically about 19.5 mL of about 0.9% NaCl or a sterile sugar solution, such as about 5% dextrose solution, with sodium hydroxide and/or hydrochloric acid added to adjust the pH, and then the reconstituted solution is diluted to an appropriate dose for administration to humans in need, such as at a dose of about 200 to 300 mg/ ^m² , for example 240 mg/ ^m² .

Chemical descriptions and terminology use standard nomenclature to describe compounds. Unless otherwise defined, 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 pertains.

The term "a (and an)" does not indicate a quantity limitation, but rather that at least one of the mentioned items exists. The term "or" means "and/or". Unless otherwise indicated herein, the description of value ranges is intended only as a shorthand reference for each independent value belonging to that range, and each independent value is incorporated into this specification as if it were described individually herein. All endpoints of ranges are included within the range and can be combined independently.

Unless otherwise indicated herein or otherwise clearly contradicted by the context, all methods described herein may be performed in any suitable order. Unless otherwise claimed, the use of any or all instances or illustrative language (e.g., "such as") is intended only to better illustrate and does not constitute a limitation on the scope of the invention.

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

"Deuteration" means the replacement of hydrogen with deuterium so that deuterium is present in its natural abundance and is therefore "enriched". A 50% enrichment means that at a specified location, the deuterium content is 50%, not hydrogen. For clarity, it is confirmed that the term "enrichment" as used herein does not mean an enrichment percentage higher than the natural abundance. In other embodiments, at least 80%, at least 90%, or at least 95% deuterium enrichment will be present at one or more specified deuteration sites. In other embodiments, at least 96%, at least 97%, at least 98%, or at least 99% deuterium enrichment will be present at one or more specified deuteration sites. Unless otherwise indicated, the deuterium enrichment at a specified site in the compounds described herein is at least 90%.

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

"Pharmaceutical composition" is a composition comprising at least one active agent (such as a compound or salt of one of the active compounds disclosed herein) and at least one other substance (such as a carrier). A pharmaceutical composition may contain more than one active agent. "Pharmaceutical composition" or "combination therapy" means administration of at least two active agents, and in one embodiment, three or four or more active agents, which may, as appropriate, be provided together in a single dosage form or in separate dosage forms according to instructions for use with the active agents to treat a condition.

"Pharmaceutically acceptable salts" include derivatives of the disclosed compounds, wherein the parent compound is modified by preparing its inorganic and organic, appropriately non-toxic, acidic or basic addition salts. Salts of the compounds of the invention can be synthesized from parent compounds containing basic or acidic moieties using known chemical methods. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of an appropriate base (such as hydroxides of Na, Ca, Mg, or K, carbonates, bicarbonates, or analogs), or by reacting the free basic form of these compounds with a stoichiometric amount of an appropriate acid. These reactions are typically carried out in water or in an organic solvent, or in a mixture of both. Pharmaceutically acceptable salts may be in pure crystalline or monomorphic form, or may be used in amorphous or nonmorphic, glassy or vitreous form, or mixtures thereof. In an alternative embodiment, the active compound may be provided in solvent compound form.

Examples of pharmaceutically acceptable salts include (but are not limited to) inorganic or organic acid salts with basic residues (such as amines); basic or organic salts with acidic residues (such as carboxylic acids); and similar salts. Pharmaceutically acceptable salts include commonly known nontoxic salts formed from parent compounds with, for example, nontoxic inorganic or organic acids, and quaternary ammonium salts. For example, commonly known non-toxic acids include salts derived from inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, and similar acids); and salts 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, dihydroxynaphthyl acid, maleic acid, hydroxybutyric acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-aminobenzenesulfonic acid, 2-acetylated benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, hydroxyethylsulfonic acid, HOOC-(CH2 ₎ Salts prepared from n-COOH, where n is 0 to 4, and similar acids. A list of other suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing, Easton, Pa., p. 1418 (1985).

The term "carrier" refers to a diluent, adsorbent, or mediator provided together with the active compound.

"Pharmaceutical acceptable excipients" means excipients suitable for the preparation of pharmaceutical compositions/combinations that are generally safe, adequately non-toxic, and free from biological or other impropriety. As used in the instructions, "pharmaceutical acceptable excipients" may include one or more such excipients.

"Patient" or "host" is a human or non-human animal, including (but not limited to) monkeys, birds, cats, dogs, cattle, horses, or pigs requiring medical treatment. Medical treatment may include treatment of existing conditions, such as diseases or symptoms, or preventative or diagnostic treatment. In a particular implementation, the patient or host is a human patient. Any condition in which the patient, such as the host, responds to trilacridone may be treated, including for bone marrow preservation or as an anti-inflammatory agent.

As used herein, "separation" refers to material in a substantially pure form. A separated compound does not have another component that substantially affects the properties of the compound. In certain embodiments, the separated form is at least 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99% pure.

In certain embodiments of the present invention, a formulation is provided, wherein the formulation is prepared by mixing compound 1 of pattern 1 with an excipient for cryo-drying. As a non-limiting example, 300 to 400 mg, about 350 to 400 mg, or more specifically about 373 mg of compound 1 pattern 1 dihydrochloride dihydrate (equivalent to about 300 mg of trilactone free base) and about 50 to 100 mg, about 60 to 80 mg, or more specifically about 76 mg of citrate monohydrate, and about 250 to 350 mg, about 280 to 320 mg, or more specifically about 300 mg of mannitol, and, as appropriate, sodium hydroxide and/or hydrochloric acid to adjust the pH as needed. In another embodiment, the formulation is produced by freeze-drying compound 1 (Figure 1) before mixing with about 50 to 100 mg, about 60 to 80 mg or more specifically about 76 mg of citric acid monohydrate and about 250 to 350 mg, about 280 to 320 mg or more specifically about 300 mg of mannitol, and, as appropriate, sodium hydroxide and/or hydrochloric acid to adjust the pH as needed.

This formulation can be reconstituted with sterile water, and in a non-limiting embodiment, with about 10 to 30, or more specifically about 5 to 100, 5 to 50, 10 to 30, about 10 to 25, or more specifically about 19.5 mL of sterile water, phosphate buffered saline, diluted sugar, or another aqueous solution of physiological saline. In one non-limiting embodiment, the reconstituted solution is a sterile sodium chloride solution, for example containing about 0.9% NaCl, or a sterile sugar solution, such as about 5% dextrose solution. The resulting reconstituted solution will have any amount of triprazine required for the intended purpose, such as triprazine at a concentration between about 5 to 50 mg/mL, about 10 to 25 mg/mL, or even about 15 mg/mL. In some embodiments, the resulting solution is subsequently diluted before administration via non-enteric routes, such as intravenous delivery.

The isolated compound 1 pattern 1 described herein, or its alternative salts, isotope analogs, or prodrugs, can be administered to the host in an effective dose to treat any of the conditions described herein using any suitable method to achieve the desired therapeutic outcome. Of course, the dose and timing of the administered isolated compound 1 pattern 1 will depend on the host being treated, the instructions of the supervising medical professional, the exposure time, the administration method, the pharmacokinetic properties of the specific active compound, and the prescribing physician's judgment. Therefore, due to host-to-host variability, the doses given below are guidelines, and the physician may titrate the dosage of the compound to achieve the treatment deemed appropriate for the host by the physician. When considering the required level of treatment, physicians can balance a variety of factors, such as the host's age and weight, the presence of pre-existing conditions, and the presence of other diseases.

Pharmaceutical compounds can be formulated in any pharmaceutically suitable form and are typically non-enteric compound, such as intravenous, intramuscular, subcutaneous, or intradermal compounds. Other alternative compoundings include oral, transdermal, or intranasal compounds. For example, pharmaceutical compounds can be in the form of intravenous pouches, vials, pills, capsules, tablets, transdermal patches, subcutaneous patches, dry powders, inhalation compounds, suppositories, and buccal or sublingual compounds within a medical device. Some dosage forms (such as tablets and capsules) are further subdivided into unit doses of appropriate size containing an appropriate amount of the active ingredient (e.g., an effective amount to achieve the desired effect).

In some embodiments, the pharmaceutical composition is in a dosage form containing at least about 50 mg/ ^m² to about 800 mg/ ^m² , about 100 mg/ ^m² to about 600 mg/ ^m² , about 100 mg/ ^m² to about 500 mg/ ^m² , about 100 mg/ ^m² to about 400 mg/ ^m² , about 100 mg/ ^m² to about 350 mg/ ^m² , about 150 mg/ ^m² to about 350 mg/ ^m² , about 200 mg/ ^m² to about 350 mg/ ^m² , or about 200 mg/ ^m² to about 300 mg/ ^m² . In one embodiment, the pharmaceutical composition is in a dosage form containing about 240 mg/ ^m² .

The therapeutically effective dose of isolated compound 1 (pattern 1) described herein will be determined by a healthcare professional based on the patient's condition, size and age, and route of administration. In one non-limiting embodiment, a dose of about 0.1 to about 200 mg/kg is therapeutically effective, wherein all weights are calculated based on the weight of the active compound. In some embodiments, the dose may be the amount of isolated compound 1 (pattern 1) required to provide serum concentrations 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 of the active compound.

In some embodiments, the pharmaceutical composition is in the form of an active compound 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, and, as appropriate, 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, such as about 300 mg to about 400 mg, of the isolated compound 1 in Pattern 1, which may alternatively be measured as a unit dose of free base or salt thereof, for example for non-enteric delivery, such as intravenous encapsulation. Examples include dosage forms of an active compound or its salt having a concentration of at least 5, 10, 15, 20, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg. Pharmaceutical compositions may also include a molar ratio of the isolated compound ( schema 1) to an additional active agent in a ratio to achieve the desired result.

The isolated compound 1 shown in this article or used as described herein may contain a dosage unit of a known pharmaceutically acceptable carrier and be administered non-enteric, autologous, oral, topical, by inhalation or spray, sublingual, via implantation (including ocular implantation), percutaneous, via buccal administration, via rectal, intramuscular, by inhalation, intra-aortic, intracranial, subcutaneous, intraperitoneal, subcutaneous, via nasal, sublingual, or via rectal or other means.

According to the method disclosed in this invention, a non-enteric dosage form can be prepared from compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate. This dosage form may include any pharmaceutically acceptable excipient, such as a liquid excipient. Non-limiting examples of liquid excipients include phosphate-buffered saline, unbuffered or buffered physiological saline (e.g., NaCl solution without buffer), sugar solutions (e.g., dextrose solution, or combinations thereof as needed). When prepared for non-enteric administration, Compound 1 (e.g., Compound 1 (e.g., dihydrochloride dihydrate) can be dissolved in a concentrated solution of a suitable liquid excipient. The concentrated solution of Compound 1 can then be diluted to an appropriate dose for the treatment of humans in need using the same or different liquid excipients. In some embodiments, the pH of the solution is adjusted using a pH-adjusting agent (e.g., HCl or NaOH). (Before or after dilution). In some embodiments, additional therapeutic or non-therapeutic agents are added to the solution before administration or to improve shelf life.

According to the method disclosed in this invention, oral administration can be in any desired form, wherein the isolated compound pattern 1 is stably solid. In some embodiments, the isolated compound pattern 1 is delivered as solid microparticles or nanoparticles. When administered by inhalation, the isolated compound pattern 1 can be in the form of a plurality of solid particles or droplets having any desired particle size, and for example from about 0.01, 0.1, or 0.5 to about 5, 10, 20, or larger micrometers, and in some cases from about 1 to about 2 micrometers. The isolated compound pattern 1 disclosed in this invention has good pharmacokinetic and pharmacodynamic properties, for example, when administered by oral or intravenous routes.

Pharmaceutical formulations may contain the isolated compound 1 of pattern 1 described herein or its alternative pharmaceutically acceptable salt in any pharmaceutically acceptable carrier.

The carrier includes excipients and diluents, and must possess sufficiently high purity and low toxicity to be suitable for administration to the treated patient. The carrier may be inert or may itself have pharmaceutical benefits. The amount of carrier used in conjunction with the compound is sufficient to provide the actual amount of material to be administered per unit dose of the compound.

Carriers include, but are not limited to, binders, buffers, colorants, thinners, disintegrants, emulsifiers, flavorings, lubricants, preservatives, stabilizers, surfactants, tableting agents, and humectants. Some carriers may be classified in more than one category; for example, vegetable oils can be used as lubricants in some formulations and as thinners in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, cellulose, powdered tragacanth, malt, gelatin; talc, and vegetable oils. The active agents used may be included in the pharmaceutical composition, and such active agents do not substantially interfere with the activity of the compounds of the invention.

Depending on the intended mode of administration, the pharmaceutical composition may be in a solid or semi-solid dosage form in which the isolated compound 1 of pattern 1 is stable, such as tablets, suppositories, pills, capsules, powders, or similar forms, preferably in a unit dosage form suitable for a precise single dose. The composition will comprise an effective amount of the selected drug and a pharmaceutically acceptable carrier, and may additionally include other pharmaceutical preparations, adjuvants, diluents, buffers, and the like.

Therefore, the compositions of the present invention can be administered as pharmaceutical preparations, including those suitable for oral (including cheek and sublingual), rectal, nasal, topical, pulmonary, and vaginal administration, or in forms suitable for inhalation or insufflation. A preferred method of administration is oral administration using a convenient daily dosage regimen that can be adjusted according to the severity of the ailment. For solid compositions, known non-toxic solid carriers include, for example, pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like.

In another embodiment, a penetration-enhancing adjuvant comprising polymers such as: polycationic polymers (polyglucosamine and its quaternary ammonium derivatives, poly-L-arginine, aminated gelatin); polyanionic polymers ( N -carboxymethyl polyglucosamine, polyacrylic acid); and thiolized polymers (carboxymethyl cellulose cysteine, polycarbofil cysteine, polyglucosamine thiobutylamidine, polyglucosamine thioglycolic acid, polyglucosamine glutathione complex).

For oral administration, the composition is typically in tablet or capsule form. Tablets and capsules are preferred oral administration forms. Tablets and capsules for oral use may include one or more common carriers, such as lactose and corn starch. Lubricants, such as magnesium stearate, are also usually added. Generally, the composition of the present invention 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, and similar substances. In addition, suitable binders, lubricants, disintegrants, and colorants may be incorporated into the mixture when needed or necessary. Suitable adhesives include starch, gelatin, natural sugars (such as glucose or β-lactose), corn sweeteners, natural and synthetic gums (such as gum arabic, tragali, or sodium alginate), carboxymethyl cellulose, polyethylene glycol, wax, and the like. Lubricants used in these formulations include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, succinate, and the like.

In addition to the active compound or its salt, pharmaceutical formulations may contain other additives, such as pH-adjusting additives. Specifically, suitable pH adjusters include acids, such as hydrochloric acid; and bases or buffers, such as sodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodium borate, or sodium gluconate. Furthermore, formulations may contain antimicrobial preservatives. Suitable antimicrobial preservatives include methyl paraben, propyl paraben, and benzyl alcohol. Antimicrobial preservatives are typically used when formulations are placed in vials designed for multi-dose administration. The pharmaceutical compounds described herein may be freeze-dried using techniques well known to those skilled in the art.

For oral administration, pharmaceutical compounds may be in the form of tablets, pellets, capsules, powders, and similar forms. Tablets containing: various excipients such as sodium citrate, calcium carbonate, and calcium phosphate; various disintegrants such as starch (e.g., potato or cassava starch); specific complex silicates; and binders such as polyvinylpyrrolidone, sucrose, gelatin, and gum arabic. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are commonly used for tablet manufacturing purposes. Similar types of solid compounds may also be used as fillers in soft and hard filled gelatin capsules.

It also provides pharmaceutical formulations that provide controlled release of the compounds described herein, including through the use of biodegradable polymers known in such art.

As used herein, "medically acceptable salt" means salts that, within the scope of reasonable medical judgment, are suitable for contact with a host (e.g., a human host) without abnormal toxicity, irritation, allergic reactions or similar reactions, satisfying a reasonable benefit/risk ratio, and effective for their intended use; and the zwitterionic form of the host substance disclosed in this invention (where possible).

In an alternative embodiment, compound 1, pattern 1, is not an HCl salt, but is actually a salt as described below.

In one embodiment, another treatment described in the Combination section below is administered in the form of pharmaceutically acceptable salt, such as the salt described below.

Therefore, the term "salt" refers to the relatively non-toxic inorganic and organic acid addition salts of the compounds disclosed in this invention. These salts can be prepared during the final separation and purification of the compound, or by reacting a purified compound in its free base form with a suitable organic or inorganic acid separately, and then separating the resulting salt. Basic compounds can form a variety of different salts with various inorganic and organic acids. Acid addition salts of basic compounds are prepared by conventionally contacting the free base form with a sufficient amount of the desired acid to produce salt. The free base form can be regenerated by conventionally contacting the salt form with a base and separating the free base. The free base form may differ from its individual salt forms in certain physical properties, such as solubility in polar solvents. Pharmaceutically acceptable base addition salts can be formed from metals or amines, such as alkali metals and alkaline earth metals or organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, calcium, and their analogues. Examples of suitable amines include, but are not limited to, N,N'-diphenylmethylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylreducing glucosamine, and procaine. Alkali addition salts of acidic compounds are prepared by conventionally contacting the free acid form with a sufficient amount of the desired alkali to produce salt. The free acid form can be regenerated by conventionally contacting the salt form with an acid and then separating the free acid. The free acid form may differ from its individual salt forms in certain physical properties, such as solubility in polar solvents.

Salts can be prepared from inorganic acids such as sulfates, pyrosulfates, hydrogen sulfates, sulfites, hydrogen sulfites, nitrates, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, and substances like hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorus, and their analogues. Representative salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthalenedicarboxylate, methanesulfonate, gluconate, lactobionate, laurylsulfonate, and hydroxyethanesulfonate and their similar salts. Salts can also be prepared from organic acids, such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkyl acids, hydroxyalkyl acids, alkyl diacids, aromatic acids, aliphatic sulfonic acids and aromatic sulfonic acids, and similar acids. Representative salts include acetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, octanoates, sebacic acids, trans-butenedioates, maleic anhydrides, amygdalinates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleic anhydrides, tartrates, methanesulfonates, and their analogues.

Pharmaceutically acceptable salts may include those based on the following cations: alkaline metals and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and their analogues; and non-toxic ammonium, quaternary ammonium, and amines, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and their analogues. This also includes amino acid salts, such as arginine, gluconate, galacturonate, and their analogues. See, for example, Berge et al., J. Pharm. Sci., 1977, 66, 1-19, which are incorporated herein by reference.

Formulations suitable for rectal administration are typically presented as unit dose suppositories. These formulations can be prepared by mixing the active, disclosed compound with one or more conventional solid carriers (e.g., cocoa butter) and subsequently shaping the resulting mixture.

Formulations suitable for topical application to the skin are preferably in the form of ointments, creams, lotions, pastes, gels, sprays, aerosols, or oils, maintaining the stability of the isolated compound 1 (Figure 1). Suitable carriers include petroleum jelly, lanolin, polyethylene glycol, alcohols, transdermal reinforcing agents, and combinations of two or more thereof.

Suitable pharmaceutical formulations for transdermal administration can be delivered in the form of dissociative patches adapted to maintain close contact with the recipient's epidermis for extended periods. Suitable formulations for transdermal administration can also be delivered via iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)) and, where applicable, in the form of a buffered aqueous solution, typically presenting as an active compound. In one embodiment, microneedle patches or devices are provided for delivering drugs across biological tissues (particularly the skin) or into biological tissues. Microneedle patches or devices allow drugs to be delivered across or into skin or other tissue barriers at clinically relevant rates with minimal or no tissue damage, pain, or irritation.

Lung-delivered formulations can be delivered using a wide range of passive and active electrically driven single-dose/multi-dose dry powder inhalers (DPIs). The most commonly used devices for inhalation delivery include sprays, dose-controlled inhalers, and dry powder inhalers. Several types of sprays are available, including jet sprays, ultrasonic sprays, and vibrating mesh sprays. The selection of a suitable lung delivery device depends on parameters such as the nature of the drug and its formulation, the site of action, and lung pathophysiology.

It has been found that an IV solution of compound 1 , intended for injection into cancer patients to preserve healthy cells or for anti-reproductive purposes, can be administered by dispensing it in the form of a dihydrochloride or a dihydrate of the dihydrochloride. This achieves the desired therapeutic effect because it can be delivered directly and rapidly into the bloodstream in a concentrated form. In one primary embodiment, the IV solution is prepared from a freeze-dried powder comprising compound 1 dihydrochloride, mannitol, and citric acid.

In some embodiments, the IV solution of compound 1 is prepared from a solid pharmaceutical composition, which is dried by freeze-drying as appropriate. In some embodiments, the composition includes compound 1 in the form of a dihydrochloride, such as compound 1 dihydrochloride pattern 1. The composition may also include suitable excipients, such as build-up agents, buffers, and/or one or more pH adjusters. In some embodiments, the build-up agent is a suitable sugar, such as mannitol. In some embodiments, the buffer is a suitable weak acid or weak base having one or more acidic or basic sites. In some embodiments, the buffer is a weak acid having two or more acidic sites, such as citric acid. In some embodiments, the composition includes NaOH, HCl and/or NaCl as pH adjusters (NaOH and/or HCl) or residual salts (NaCl) derived from pH adjustment.

It was also found that the freeze-dried compound 1 dihydrochloride composition containing mannitol and citric acid can be prepared as a crystalline form and is readily characterized by X-ray powder diffraction (XRPD). In some embodiments, the freeze-dried compound 1 dihydrochloride composition contains about 250 to 350 mg, about 275 to 325 mg, or more specifically about 300 mg of compound 1 , wherein the weight of 300 mg corresponds to the free base. In one main embodiment, compound 1 in the freeze-dried composition is a crystalline dihydrochloride characterized herein as in Figure 1. In other embodiments, compound 1 in the freeze-dried composition is in the form of different pharmaceutically acceptable salts or mixtures of pharmaceutically acceptable salts. In some embodiments, compound 1 in the freeze-dried composition is in the form of different patterns or mixtures of patterns. In some embodiments, the freeze-dried compound 1 composition contains, relative to other forms of compound 1 , 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 pattern 1.

The freeze-dried compound 1 dihydrochloride composition described in Example 28 contains mannitol and citric acid and is characterized by the XRPD pattern shown in Figure 100. Other suitable excipients may be added or mannitol and/or citric acid may be substituted to achieve the desired effect. In some embodiments, the compound 1 dihydrochloride composition is freeze-dried; in others, it is dried using a different technique. In some 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 of mannitol, or about 200 to 400 mg, 225 to 375 mg, 250 to 350 mg, 275 to 325 mg or 300 mg of mannitol. mg of mannitol, or 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 of mannitol, or up to about 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390 or 400 mg of mannitol. In some 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 of citric acid, or about 15 to 145 mg, 30 to 130 mg, 45 to 105 mg, 60 to 90 mg, 75 mg or more. 10 mg of citric acid, or 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 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 some embodiments, the compound 1 dihydrochloride composition comprises one or more additional salts formed by adjusting the pH of a bulk solution, which is then dried to form the composition, such as sodium chloride and/or various sodium citrate salts.

In one specific embodiment, the freeze-dried compound 1 dihydrochloride composition comprises about 349 mg of compound 1 pattern 1 dihydrochloride (equivalent to about 300 mg of triacetyl free base), about 50 to 100 mg, about 60 to 80 mg or more specifically about 76 mg of citrate monohydrate, and about 280 to 320 mg, such as 300 mg of mannitol.

In some embodiments of the invention, the isolated compound 1 (pattern 1) is used to produce a freeze-dried form, which is then formulated with a suitable solvent, such as phosphate-rehydrated saline, for administration to a patient, for example, by intravenous delivery. In another embodiment, it can be formulated as a non-enteric dosage form. This dosage form can be used, for example, for subcutaneous administration.

In some embodiments, the preferred pharmaceutical form of triasidrili used as an effective treatment , compound 1 (e.g., compound 1 dihydrochloride dihydrate), is used to produce an intravenous formulation in a bone marrow-preserving form, or alternatively, when provided in conjunction with chemotherapy to treat cancer, as appropriate, along with the standards of care for the cancer being treated. Standards of care for treating specific cancers include 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 National Medical Products Administration of China (NMPA). In other embodiments, a pharmaceutical formulation as described herein is selected and administered by the patient's attending physician.

In some embodiments, a method is provided for treating CDK4/6-mediated conditions, such as any of the conditions or methods described below, wherein an IV solution comprising compound 1 , mannitol, and citric acid is administered to the patient, wherein the IV solution is formed by reconstituted a cryo-dried compound 1 dihydrochloride composition comprising mannitol and citric acid. In some embodiments, the cryo-dried composition comprises compound 1 dihydrochloride pattern 1. (i) Bone marrow preservation

When used as a bone marrow preserver, it may be administered, for example, as taught in WO 2014/144326, WO 2016/040848, WO 2018/106729 or PCT/US20/38557. For example, in some embodiments, the dihydrochloride dihydrate of compound 1 (Figure 1) or an intravenous solution prepared therefrom is administered daily during the treatment cycle of chemotherapy. For example, if chemotherapy is administered on day 1, day 2, and/or day 3 of the treatment cycle, the intravenous solution is also administered on day 1, day 2, and/or day 3 of the treatment cycle (e.g., on day 1 or day 1 and day 2 of the treatment cycle). In another embodiment, the intravenous solution was administered on days 1 and 8 of a 21-day treatment cycle, and as a non-limiting example, it was administered in combination with gemcitabine, carboplatin, or toloxetine.

In some embodiments, the isolated compound 1 of the present invention reduces the toxicity of chemotherapeutic agents on CDK4/6 replication-dependent healthy cells in individuals (typically humans), such as hematopoietic stem cells and hematopoietic precursor cells (collectively referred to as HSPCs) and/or renal epithelial cells, who will be exposed to, are being exposed to, or have been exposed to chemotherapeutic agents (typically DNA-damaging agents).

In one embodiment, an individual has been exposed to a chemotherapy agent, and using an intravenous solution described herein, the individual's CDK4/6 replication-dependent healthy cells are placed in post-exposure G1 stasis to mitigate, for example, DNA damage. In one embodiment, the compound is administered 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 longer, following chemotherapy agent exposure. In one alternative embodiment, the dihydrate of compound 1 (Figure 1) or an intravenous solution prepared therefrom is administered at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, or longer before chemotherapy exposure. In some embodiments, the dihydrate of compound 1 (Figure 1 ) or an intravenous solution prepared therefrom is administered approximately 4 hours before chemotherapy.

In one embodiment, an intravenous solution prepared from compound 1 (Figure 1) dihydrochloride dihydrate is administered in combination with a chemotherapy agent, which includes, but is not limited to, treatment regimens in which the chemotherapy agent is administered at the following times and similar regimens: days 1 to 3 of every 21 days; days 1 to 3 of every 28 days; day 1 of every 3 weeks; days 1, 8, and 15 of every 28 days; every 28 days... On days 1 and 8; days 1 and 8 of every 21 days; days 1 to 5 of every 21 days; one day a week for 6 to 8 weeks; on days 1, 22 and 43; on days 1 and 2 of every week; days 1 to 4 and 22 to 25; days 1 to 4, 22 to 25 and 43 to 46, CDK4/6 replication-dependent cells were arrested in the G1 phase during chemotherapy.

In one embodiment, the separation of compound 1 (pattern 1) may allow for dose intensification in medically relevant chemotherapy (e.g., more treatments can be administered within a fixed time period), which will translate into better efficacy. Therefore, the method disclosed in this invention can produce less toxic and more effective chemotherapy regimens.

In some embodiments, the use of isolated compound 1 pattern 1 described herein may result in off-target effects, such as reduced or substantially limited inhibition of kinases other than CDK4 and/or CDK6 (e.g., CDK2). Furthermore, in some embodiments, the use of isolated compound 1 pattern 1 described herein should not induce cell cycle arrest in CDK4/6 replication-independent cells.

In some embodiments, the use of isolated compound 1 (schema 1) described herein reduces the risk of unwanted off-target effects, including (but not limited to) long-term toxicity, antioxidant effects, and estrogenic effects. Antioxidant effects can be determined by standard analyses known in this art. For example, compounds without significant antioxidant effects are compounds that do not significantly scavenge free radicals such as oxygen free radicals. The antioxidant activity of a compound can be compared to that of compounds with known antioxidant activity, such as genistein. Therefore, compounds without significant antioxidant activity can be compounds with antioxidant activity less than about 2, 3, 5, 10, 30, or 100 times that of genistein. Estrogenic activity can also be determined by known analyses. For example, non-estrogenous compounds are compounds that do not significantly bind to and activate estrogen receptors. Compounds that are substantially limited in their estrogenic effect can be compounds that have less than about 2, 3, 5, 10, 20 or 100 times the estrogenic activity of compounds with estrogenic activity (e.g., genistein).

Compound 1 pattern 1 (e.g., compound 1 pattern 1 dihydrochloride dihydrate) or formulations thereof may be administered to the patient non-enterically (e.g., intravenously) prior to administration of immunomodulatory chemotherapy (such as ICD-induced chemotherapy). In some practices, compound 1 is administered at most about 24 hours or less prior to chemotherapy, or at most about 20, 15, 10, 5, or 4 hours or less prior to chemotherapy, for example, about 30 to 60 minutes or less. In some practices, compound 1 is administered approximately 22 to 26 hours prior to chemotherapy, and is re-administered at about 4 hours or less prior to chemotherapy, for example, about 30 to 60 minutes or less. In some embodiments, the dosage of compound 1 administered is between about 180 and about 280 mg/ ^m² . 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/ ^m² , or any such dosage as required by a healthcare professional. In one particular embodiment, the dosage is about 240 mg/ ^m² .

Typically, Compound 1 (Scheme 1), such as Compound 1 (Scheme 1) dihydrochloride dihydrate or a formulation thereof, is administered to an individual prior to chemotherapy so that its concentration reaches peak serum levels before or during chemotherapy, thereby inhibiting the proliferation of immune effector cells and protecting them from the harmful effects of chemotherapy. In some embodiments, Compound 1 (Scheme 1), such as Compound 1 (Scheme 1) dihydrochloride dihydrate or a formulation thereof, is administered simultaneously with or near chemotherapy exposure. Alternatively, if necessary, the CDK4/6 inhibitors described herein may be administered after chemotherapy exposure to alleviate immune effector cell damage associated with chemotherapy exposure. In one embodiment, an aqueous solution generated from compound 1 (pattern 1) is administered to a patient in need.

In some embodiments, Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation thereof, is administered to an individual for 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 before chemotherapy. In one particular embodiment, Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation thereof, is administered about 1/2 hour before chemotherapy.

In some embodiments, Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation thereof, is administered to the individual twice prior to chemotherapy. For example, in some embodiments, Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation thereof, is administered between approximately 18 and 28 hours prior to chemotherapy, and then again for less than approximately 4 hours, approximately 2.5 hours, approximately 2 hours, approximately 1 hour , approximately 1/2 hour, or less prior to chemotherapy. In one particular embodiment, Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation thereof, is administered approximately 22 to 26 hours prior to the administration of the chemotherapeutic agent, and again approximately 1/2 hour or less prior to the administration of the chemotherapeutic agent.

In some embodiments, compound 1 (scheme 1), such as compound 1 (scheme 1) dihydrochloride dihydrate or a formulation thereof, is administered before or simultaneously with the chemotherapy, wherein the chemotherapy and similar regimens are administered at the following times: days 1 to 3 of every 21 days; days 1 to 3 of every 28 days; day 1 of every 3 weeks; day 28 of every 28 weeks. Day 1, Day 8 and Day 15; Day 1 and Day 8 of every 28 days; Day 1 and Day 8 of every 21 days; Days 1 to 5 of every 21 days; Day 1 of every week for 6 to 8 weeks; Day 1, Day 22 and Day 43; Day 1 and Day 2 of every week; Days 1 to 4 and Days 22 to 25; Days 1 to 4, Days 22 to 25 and Days 43 to 46. In some embodiments, Compound 1 , Pattern 1, such as Compound 1 , Pattern 1 dihydrochloride dihydrate or formulations thereof, is administered before or simultaneously with at least one administration of the chemotherapy agent during the chemotherapy regimen. In some embodiments, compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, is administered before or simultaneously with one or more doses of a chemotherapy agent during a chemotherapy regimen. In one embodiment, compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, is administered before or simultaneously with each dose of a chemotherapy agent during a chemotherapy regimen.

In some embodiments, Compound 1 , pattern 1, such as Compound 1, pattern 1 dihydrochloride dihydrate, or a formulation derived therefrom, is administered, for example, before or simultaneously with each dose of chemotherapy during a standard chemotherapy regimen, such as a 21-day cycle. After the standard chemotherapy regimen is discontinued, Compound 1 , pattern 1, such as Compound 1 , pattern 1 dihydrochloride dihydrate, or a formulation derived therefrom, may be further administered separately to maintain the dosage. In some embodiments, Compound 1 , pattern 1, such as Compound 1 , pattern 1 dihydrochloride dihydrate or a formulation thereof, is further administered once weekly 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 , pattern 1, such as Compound 1 , pattern 1 dihydrochloride dihydrate or a formulation thereof, is administered once every 21 days after discontinuation of chemotherapy. In one embodiment, Compound 1 , pattern 1, such as Compound 1 , pattern 1 dihydrochloride dihydrate or a formulation thereof, is a fast-acting, short-half-life CDK4/6 inhibitor.

In some embodiments, after the standard chemotherapy regimen is discontinued, Compound 1 (scheme 1), such as Compound 1 (scheme 1) dihydrochloride dihydrate or a formulation thereof, is administered together with the chemotherapy agent in the maintenance therapy regimen. Maintenance therapy may include the continuation of the medication given as a first-line or part of the aforementioned regimen (continuation maintenance) or treatment with a novel medication (switching maintenance).

In some embodiments, compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, is further administered as a maintenance-type treatment regimen, wherein compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, is administered together with chemotherapy at regular dosing intervals and reduced maintenance doses, such intervals including, but not limited to, once a week, once every two weeks, once every three weeks, once a month, once every six weeks, once every two months, once every three months, or once every six months after the completion of initial chemotherapy. In some embodiments, compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, is administered together with the same medication used in the previous chemotherapy phase. In some embodiments, compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, is administered together with a chemotherapy medication different from that used in the previous chemotherapy phase.

Standard cancer chemotherapy can promote tumor immunity in two main ways: (i) by inducing immunogenic cell death as part of its expected therapeutic effect; and (ii) by disrupting the strategies that tumors use to evade the immune response. Extensive data indicate that some chemotherapy drugs at standard doses and durations mediate their anti-excitatory effects at least in part by inducing immunogenic cell death (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).

Immunogenic cell death (ICD) is a type of cell death characterized by features such as cell surface displacement of calcified reticulin (CRT), extracellular release of ATP and high migration rate group 1 (HMBG1), and stimulation of type I interferon (IFN) responses. ICD in cancer cells can induce anti-cancer immune responses. Various chemotherapy agents can induce ICD, as indicated by changes in tumor-infiltrating lymphocytes (TILs), their abundance, and composition.

In response to ICD-induced chemotherapy, tumor cells expose CRTs to their cell surface before death and release damage-associated molecular pattern (DAMP) molecules, such as ATP, during apoptosis, or HMGB1 during secondary necrosis. This DAMP stimulation replenishes dendritic cells (DCs) into the tumor bed, facilitating the uptake and processing of tumor antigens and optimal antigen presentation to T cells. Cross-sensitization of CD8+ T cells is triggered by mature DCs and γδ T cells in an IL-1β and IL-17-dependent manner. Presensitized CTLs subsequently induce a cytotoxic response to kill remaining tumor cells by producing IFN-γ, perforin-1, and granzyme B. In some embodiments, compound 1 (scheme 1), such as compound 1 (scheme 1) dihydrochloride dihydrate or a formulation thereof, is combined with ICD-induced chemotherapy for bone marrow preservation.

The ICD-induced chemotherapy methods used in this invention include alkylating agents such as cyclophosphamide, trabectedin, temozolomide, melphalan, dacarbazine, and oxaliplatin; antimetabolites such as methotrexate, mitroxantrone, gemcitabine, and 5-fluorouracil (5-FU); cytotoxic antibiotics such as bleomycin; and anthraquinones, including small red... Doxorubicin, daunorubicin, epirubicin, idarubicin, and valrubicin; taxanes, such as paclitaxel, cabazitaxel, and docetaxel; topoisomerase inhibitors, such as toponotecan, irinotecan, and etoposide; platinum compounds, such as carboplatin and cisplatin; antimicrotubule vinca alkaloids, such as vincristine, vinorelbine, and vindesine. Other ICD-induced chemotherapy regimens include bortezomib, 26S proteasome subunit inhibitors, methyldi(chloroethyl)amine, diaziquone, mitomycin C, fludarabine, and cytosine arabinoside. In some embodiments, ICD-induced chemotherapy regimens are selected from idarubicin, epirubicin, cranberry, mitoxantrone, oxaliplatin, bortezomib, gemcitabine, and cyclophosphamide, and combinations thereof. In an alternative embodiment, the administered chemotherapy agent can induce an immune response that modulates tumor immunity through a mechanism different from immunogenic cell death. Different chemotherapy drugs can modulate the activity of different immune cell subsets or the immunophenotype of tumor cells by enhancing antigen presentation, enhancing the expression of co-stimulatory molecules (including B7.1 (CD80) and B7.2 (CD86)), downregulating checkpoint molecules such as planned death-ligand 1 (PD-L1), or promoting tumor cell death through the fas, perforin, or granzyme B pathway. Chemotherapy for tumor immunity can be carried out by: eliminating myeloid-derived suppressor cell (MDSC) activity, such as gemcitabine, 5-fluorouracil, cisplatin, and cranberry; eliminating Treg Activities such as cyclophosphamide, 5-fluorouracil; paclitaxel, cisplatin, and fludarabine; enhancing T cell cross-sensitization, such as gemcitabine and anthracyclines, such as cranberry, donomethoxazole, epirubicin, vararubicin, and idarubicin; enhancing dendritic cell activation, such as anthracyclines, taxanes, cyclophosphamide, vinca alkaloids, methotrexate, and mitomycin C; promoting anti-supernumerary CD4+ T cell phenotype, such as cyclophosphamide and paclitaxel; and promoting tumor cell recognition and lysis, such as cyclophosphamide, 5-fluorouracil, paclitaxel, cranberry, cisplatin, and cytosine arabinoside.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering compound 1 (design 1), such as compound 1 (design 1) dihydrochloride dihydrate or a formulation thereof, and chemotherapy in a manner that increases progression-free survival or overall survival of the patient or patient population. The method includes determining whether the cancer has an immunomodulatory, immunogenically susceptible, or immunogenic microenvironment. If so, administering to the patient an effective amount of compound 1 (design 1), such as compound 1 (design 1) dihydrochloride dihydrate or a formulation thereof, and an effective amount of the following: alkylating agents, such as cyclophosphamide, trabectedin, etc. Temozolomide, melphalan, dacarbazine, and oxaliplatin; antimetabolites, such as methotrexate, mitoxantrone, gemcitabine, and 5-fluorouracil (5-FU); cytotoxic antibiotics, such as bleomycin and anthracyclines, such as cranberry, donomethoxazole, epirubicin, idarubicin, and penrubicin; taxanes, such as paclitaxel, cabazitaxel, and... Docetaxel; topoisomerase inhibitors, such as toponotecan, irinotecan, and etoposide; platinum compounds, such as carboplatin and cisplatin; antimicrotubule vinca alkaloids, such as vincristine, vinorelbine, vinorelbine, and vindesine; bortezomib; methyldi(chloroethyl)amine; diazinon; fludarabine; mitomycin C; and cytosine arabinoside. In some embodiments, the administration of compound 1 (scheme 1), such as compound 1 (scheme 1) dihydrochloride dihydrate or formulations thereof, in combination with chemotherapy does not include the administration of immune checkpoint inhibitors. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient had a hot immunological tumor. In some embodiments, the patient had a variant-immunosuppressive immunological tumor. In some embodiments, the patient had a variant-rejection immunological tumor. In some embodiments, the patient had a cold tumor. In some embodiments, the patient had a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient had a tumor classified as high "IFN-γ characteristic" or high "amplified immune characteristic". In some embodiments, the patient had a PD-L1 positive tumor.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, to the patient or patient population in a manner that increases progression-free survival or overall survival, and chemotherapy. The method includes determining whether the cancer has an immunomodulatory, immunogenically susceptible to CDK4/6 inhibitor treatment or an immunogenic surrounding microenvironment, and if so, administering to the patient an effective amount of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of cyclophosphamide. In some embodiments, administration of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, in combination with cyclophosphamide does not involve 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 immunotumor. In some embodiments, the patient has a variant-immunosuppressive immunotumor. In some embodiments, the patient has a variant-rejection immunotumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient has a tumor classified as high "IFN-γ signature" or high "amplified immune signature". In some implementations, the patient had a PD-L1 positive tumor.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering a CDK 4/6 inhibitor and chemotherapy in a manner that increases progression-free survival or overall survival of the patient or patient population. This method includes determining whether the cancer has a favorable immunomodulatory, immunogenically susceptible, or immunogenic microenvironment to CDK 4/6 inhibitor treatment, and if so, administering to the patient an effective amount of Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of trabectedine. In some embodiments, the combination of administering Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation thereof, and trabectedine does not include the administration of an immune checkpoint inhibitor. In some embodiments, the patient had a tumor classified as immunogenic. In some embodiments, the patient had a hot immunotumor. In some embodiments, the patient had a variant-immunosuppressive immunotumor. In some embodiments, the patient had a variant-rejection immunotumor. In some embodiments, the patient had a cold tumor. In some embodiments, the patient had a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient had a tumor classified as high "IFN-γ characteristic" or high "amplified immune characteristic". In some embodiments, the patient had a PD-L1 positive tumor.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, to the patient or patient population in a manner that increases progression-free survival or overall survival, and chemotherapy. The method includes determining whether the cancer has an immunomodulatory, immunogenically susceptible to CDK4/6 inhibitor treatment or an immunogenic surrounding microenvironment, and if so, administering to the patient an effective amount of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of temozolomide. In some embodiments, administration of Compound 1 (scheme 1), such as Compound 1 (scheme 1) dihydrochloride dihydrate or formulations thereof, in combination with temozolomide does not involve administration of an immune checkpoint inhibitor. In some embodiments, the patient has an immunogenic tumor. In some embodiments, the patient has a hot immunotumor. In some embodiments, the patient has a variant-immunosuppressive immunotumor. In some embodiments, the patient has a variant-rejection immunotumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient has a tumor classified as high "IFN-γ signature" or high "amplified immune signature". In some implementations, the patient had a PD-L1 positive tumor.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, to the patient or patient population in a manner that increases progression-free survival or overall survival, along with chemotherapy. This method includes determining whether the cancer has a favorable immunomodulatory, immunogenically susceptible to CDK4/6 inhibitor treatment, or immunogenic surrounding microenvironment, and if so, administering to the patient an effective amount of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of melphalan. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immunotumor. In some embodiments, the patient had a variant-immunosuppressive immunotumor. In some embodiments, the patient had a variant-rejection immunotumor. In some embodiments, the patient had a cold tumor. In some embodiments, the patient had a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient had a tumor classified as high "IFN-γ signature" or high "amplified immune signature". In some embodiments, the patient had a PD-L1 positive tumor.

In some embodiments, a method for selecting a patient or patient population for cancer therapy is provided, comprising administering a CDK4/6 inhibitor and chemotherapy in a manner that increases progression-free survival or overall survival of the patient or patient population. This method includes determining whether the cancer has a favorable immunomodulatory, immunogenically susceptible, or immunogenic peripheral microenvironment to CDK4/6 inhibitor treatment, and if so, administering to the patient an effective amount of Compound 1 (Pattern 1), such as Compound 1 (Pattern 1) dihydrochloride dihydrate or a formulation thereof, and an effective amount of dacarbazine. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immunotumor. In some embodiments, the patient has a variant-immunosuppressive immunotumor. In some embodiments, the patient had a variant-rejection immune tumor. In some embodiments, the patient had a cold tumor. In some embodiments, the patient had a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient had a tumor classified as high "IFN-γ signature" or high "amplified immune signature". In some embodiments, the patient had a PD-L1 positive tumor.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, to the patient or patient population in a manner that increases progression-free survival or overall survival, along with chemotherapy. The method includes determining whether the cancer has a favorable immunomodulatory, immunogenically susceptible to CDK4/6 inhibitor treatment, or immunogenic surrounding microenvironment, and if so, administering to the patient an effective amount of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of oxaliplatin. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immunotumor. In some embodiments, the patient had a variant-immunosuppressive immunotumor. In some embodiments, the patient had a variant-rejection immunotumor. In some embodiments, the patient had a cold tumor. In some embodiments, the patient had a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient had a tumor classified as high "IFN-γ signature" or high "amplified immune signature". In some embodiments, the patient had a PD-L1 positive tumor.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, to the patient or patient population in a manner that increases progression-free survival or overall survival, along with chemotherapy. The method includes determining whether the cancer has a favorable immunomodulatory, immunogenically susceptible to CDK4/6 inhibitor treatment, or immunogenic microenvironment, and if so, administering to the patient an effective amount of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of methotrexate. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immunotumor. In some embodiments, the patient had a variant-immunosuppressive immunotumor. In some embodiments, the patient had a variant-rejection immunotumor. In some embodiments, the patient had a cold tumor. In some embodiments, the patient had a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient had a tumor classified as high "IFN-γ signature" or high "amplified immune signature". In some embodiments, the patient had a PD-L1 positive tumor.

In some embodiments, a method for selecting a patient or patient population for cancer therapy is provided, comprising administering a CDK4/6 inhibitor and chemotherapy in a manner that increases progression-free survival or overall survival of the patient or patient population. This method includes determining whether the cancer has a favorable immunomodulatory, immunogenically susceptible, or immunogenic peripheral microenvironment to CDK4/6 inhibitor treatment, and if so, administering to the patient an effective amount of Compound 1 (Pattern 1), such as Compound 1 (Pattern 1) dihydrochloride dihydrate or a formulation thereof, and 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 immunotumor. In some embodiments, the patient has a variant-immunosuppressive immunotumor. In some embodiments, the patient had a variant-rejection immune tumor. In some embodiments, the patient had a cold tumor. In some embodiments, the patient had a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient had a tumor classified as high "IFN-γ signature" or high "amplified immune signature". In some embodiments, the patient had a PD-L1 positive tumor.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, to the patient or patient population in a manner that increases progression-free survival or overall survival, along with chemotherapy. The method includes determining whether the cancer has a favorable immunomodulatory, immunogenically susceptible to CDK4/6 inhibitor treatment, or immunogenic microenvironment, and if so, administering to the patient an effective amount of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of gemcitabine. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immunotumor. In some embodiments, the patient had a variant-immunosuppressive immunotumor. In some embodiments, the patient had a variant-rejection immunotumor. In some embodiments, the patient had a cold tumor. In some embodiments, the patient had a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient had a tumor classified as high "IFN-γ signature" or high "amplified immune signature".

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, to the patient or patient population in a manner that increases progression-free survival or overall survival, along with chemotherapy. This method includes determining whether the cancer has a favorable immunomodulatory, immunogenically susceptible to CDK4/6 inhibitor treatment, or immunogenic microenvironment, and if so, administering to the patient an effective amount of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of mitoxantrone. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immunotumor. In some embodiments, the patient had a variant-immunosuppressive immunotumor. In some embodiments, the patient had a variant-rejection immunotumor. In some embodiments, the patient had a cold tumor. In some embodiments, the patient had a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient had a tumor classified as high "IFN-γ signature" or high "amplified immune signature". In some embodiments, the patient had a PD-L1 positive tumor.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering a CDK 4/6 inhibitor and chemotherapy in a manner that increases progression-free survival or overall survival of the patient or patient population. This method includes determining whether the cancer has a favorable immunomodulatory, immunogenically susceptible, or immunogenic microenvironment to CDK 4/6 inhibitor treatment, and if so, administering to the patient an effective amount of Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of cranberries. In some embodiments, the combination of administering Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation thereof, with cranberries does not include the administration of an immune checkpoint inhibitor. In some embodiments, the patient had a tumor classified as immunogenic. In some embodiments, the patient had a hot immunotumor. In some embodiments, the patient had a variant-immunosuppressive immunotumor. In some embodiments, the patient had a variant-rejection immunotumor. In some embodiments, the patient had a cold tumor. In some embodiments, the patient had a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient had a tumor classified as high "IFN-γ characteristic" or high "amplified immune characteristic". In some embodiments, the patient had a PD-L1 positive tumor.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, to the patient or patient population in a manner that increases progression-free survival or overall survival, along with chemotherapy. This method includes determining whether the cancer has a favorable immunomodulatory, immunogenically susceptible to CDK4/6 inhibitor treatment, or immunogenic surrounding microenvironment, and if so, administering to the patient an effective amount of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of donorrhizin. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a febrile immunotumor. In some embodiments, the patient had a variant-immunosuppressive immunotumor. In some embodiments, the patient had a variant-rejection immunotumor. In some embodiments, the patient had a cold tumor. In some embodiments, the patient had a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient had a tumor classified as high "IFN-γ signature" or high "amplified immune signature". In some embodiments, the patient had a PD-L1 positive tumor.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, to the patient or patient population in a manner that increases progression-free survival or overall survival, along with chemotherapy. The method includes determining whether the cancer has a favorable immunomodulatory, immunogenically susceptible to CDK4/6 inhibitor treatment, or immunogenic microenvironment, and if so, administering to the patient an effective amount of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of idarubicin. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a febrile immunotumor. In some embodiments, the patient had a variant-immunosuppressive immunotumor. In some embodiments, the patient had a variant-rejection immunotumor. In some embodiments, the patient had a cold tumor. In some embodiments, the patient had a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient had a tumor classified as high "IFN-γ signature" or high "amplified immune signature". In some embodiments, the patient had a PD-L1 positive tumor.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, to the patient or patient population in a manner that increases progression-free survival or overall survival, along with chemotherapy. This method includes determining whether the cancer has a favorable immunomodulatory, immunogenically susceptible to CDK4/6 inhibitor treatment, or immunogenic peripheral microenvironment, and if so, administering to the patient an effective amount of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of vararubicin. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a febrile immunotumor. In some embodiments, the patient had a variant-immunosuppressive immunotumor. In some embodiments, the patient had a variant-rejection immunotumor. In some embodiments, the patient had a cold tumor. In some embodiments, the patient had a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient had a tumor classified as high "IFN-γ signature" or high "amplified immune signature". In some embodiments, the patient had a PD-L1 positive tumor.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering a CDK4/6 inhibitor and chemotherapy in a manner that increases progression-free survival or overall survival of the patient or patient population. This method includes determining whether the cancer has a favorable immunomodulatory, immunogenically susceptible, or immunogenic peripheral microenvironment to CDK4/6 inhibitor treatment, and if so, administering to the patient an effective amount of Compound 1 (Pattern 1), such as Compound 1 (Pattern 1) dihydrochloride dihydrate or a formulation thereof, and an effective amount of epirubicin. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a febrile immunotumor. In some embodiments, the patient has a variant-immunosuppressive immunotumor. In some embodiments, the patient had a variant-rejection immune tumor. In some embodiments, the patient had a cold tumor. In some embodiments, the patient had a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient had a tumor classified as high "IFN-γ signature" or high "amplified immune signature". In some embodiments, the patient had a PD-L1 positive tumor.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, to the patient or patient population in a manner that increases progression-free survival or overall survival, and chemotherapy. The method includes determining whether the cancer has an immunomodulatory, immunogenically susceptible to CDK4/6 inhibitor treatment or an immunogenic surrounding microenvironment, and if so, administering to the patient an effective amount of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of bleomycin. In some embodiments, administration of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, in combination with bleomycin does not involve administration of an immune checkpoint inhibitor. In some embodiments, the patient has a hot immunotumor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immunotumor. In some embodiments, the patient has a variant-immunosuppressive immunotumor. In some embodiments, the patient has a variant-rejection immunotumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as C2 "IFN-γ dominant" carcinoma. In some implementations, the patient has a tumor that is classified as having high "IFN-γ signature" or high "amplified immune signature".

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, to the patient or patient population in a manner that increases progression-free survival or overall survival, and chemotherapy. The method comprises determining whether the cancer has an immunomodulatory, immunogenically susceptible to CDK4/6 inhibitor treatment or an immunogenic surrounding microenvironment, and if so, administering to the patient an effective amount of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of bortezomib. In some embodiments, administration of Compound 1 (scheme 1), such as Compound 1 (scheme 1) dihydrochloride dihydrate or a formulation thereof, in combination with bortezomib does not involve 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 immunotumor. In some embodiments, the patient has a variant-immunosuppressive immunotumor. In some embodiments, the patient has a variant-rejection immunotumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient has a tumor classified as high "IFN-γ signature" or high "amplified immune signature". In some implementations, the patient had a PD-L1 positive tumor.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, to the patient or patient population in a manner that increases progression-free survival or overall survival, and chemotherapy. The method comprises determining whether the cancer has an immunomodulatory, immunogenically susceptible to CDK4/6 inhibitor treatment or an immunogenic surrounding microenvironment, and if so, administering to the patient an effective amount of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of paclitaxel. In some embodiments, administration of Compound 1 (scheme 1), such as Compound 1 (scheme 1) dihydrochloride dihydrate or a formulation thereof, in combination with paclitaxel does not involve 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 immunotumor. In some embodiments, the patient has a variant-immunosuppressive immunotumor. In some embodiments, the patient has a variant-rejection immunotumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient has a tumor classified as high "IFN-γ signature" or high "amplified immune signature". In some implementations, the patient had a PD-L1 positive tumor.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, to the patient or patient population in a manner that increases progression-free survival or overall survival, and chemotherapy. The method comprises determining whether the cancer has an immunomodulatory, immunogenically susceptible to CDK4/6 inhibitor treatment or an immunogenic surrounding microenvironment, and if so, administering to the patient an effective amount of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of docetaxel. In some embodiments, administration of Compound 1 (scheme 1), such as Compound 1 (scheme 1) dihydrochloride dihydrate or a formulation thereof, in combination with docetaxel does not involve 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 immunotumor. In some embodiments, the patient has a variant-immunosuppressive immunotumor. In some embodiments, the patient has a variant-rejection immunotumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient has a tumor classified as high "IFN-γ signature" or high "amplified immune signature". In some implementations, the patient had a PD-L1 positive tumor.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, to the patient or patient population in a manner that increases progression-free survival or overall survival, and chemotherapy. The method includes determining whether the cancer has an immunomodulatory, immunogenically susceptible to CDK4/6 inhibitor treatment or an immunogenic surrounding microenvironment, and if so, administering to the patient an effective amount of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of cabazitaxel. In some embodiments, administration of Compound 1 (scheme 1), such as Compound 1 (scheme 1) dihydrochloride dihydrate or a formulation thereof, in combination with cabazitaxel does not involve 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 immunotumor. In some embodiments, the patient has a variant-immunosuppressive immunotumor. In some embodiments, the patient has a variant-rejection immunotumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient has a tumor classified as high "IFN-γ signature" or high "amplified immune signature". In some implementations, the patient had a PD-L1 positive tumor.

In some embodiments, a method for selecting a patient or patient population for cancer therapy is provided, comprising administering a CDK 4/6 inhibitor and chemotherapy in a manner that increases progression-free survival or overall survival of the patient or patient population. This method includes determining whether the cancer has a microenvironment favorable for immune regulation, immunogenically susceptible to CDK 4/6 inhibitor treatment, or immunogenic. If so, the patient is administered an effective amount of Compound 1 , Pattern 1, such as Compound 1, Pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of topotecan. In some embodiments, the combination of administering Compound 1 , such as Compound 1 , Pattern 1 dihydrochloride dihydrate or a formulation thereof, and topotecan does not include the administration of an immune checkpoint inhibitor. In some embodiments, the patient had a tumor classified as immunogenic. In some embodiments, the patient had a hot immunotumor. In some embodiments, the patient had a variant-immunosuppressive immunotumor. In some embodiments, the patient had a variant-rejection immunotumor. In some embodiments, the patient had a cold tumor. In some embodiments, the patient had a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient had a tumor classified as high "IFN-γ characteristic" or high "amplified immune characteristic". In some embodiments, the patient had a PD-L1 positive tumor.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, to the patient or patient population in a manner that increases progression-free survival or overall survival, and chemotherapy. The method includes determining whether the cancer has an immunomodulatory, immunogenically susceptible to CDK4/6 inhibitor treatment or an immunogenic surrounding microenvironment, and if so, administering to the patient an effective amount of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of etoposide. In some embodiments, administration of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, in combination with etoposide does not include administration of an immune checkpoint inhibitor. In some embodiments, the patient has an immunogenic tumor. In some embodiments, the patient has a hot immunotumor. In some embodiments, the patient has a variant-immunosuppressive immunotumor. In some embodiments, the patient has a variant-rejection immunotumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient has a tumor classified as high "IFN-γ signature" or high "amplified immune signature". In some implementations, the patient had a PD-L1 positive tumor.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, to the patient or patient population in a manner that increases progression-free survival or overall survival, and chemotherapy. The method includes determining whether the cancer has an immunomodulatory, immunogenically susceptible to CDK4/6 inhibitor treatment or an immunogenic surrounding microenvironment, and if so, administering to the patient an effective amount of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of irinotecan. In some embodiments, administration of Compound 1 (scheme 1), such as Compound 1 (scheme 1) dihydrochloride dihydrate or formulations thereof, in combination with irinotecan does not involve administration of an immune checkpoint inhibitor. In some embodiments, the patient has an immunogenic tumor. In some embodiments, the patient has a hot immunotumor. In some embodiments, the patient has a variant-immunosuppressive immunotumor. In some embodiments, the patient has a variant-rejection immunotumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient has a tumor classified as high "IFN-γ signature" or high "amplified immune signature". In some implementations, the patient had a PD-L1 positive tumor.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, to the patient or patient population in a manner that increases progression-free survival or overall survival, and chemotherapy. The method includes determining whether the cancer has an immunomodulatory, immunogenically susceptible to CDK4/6 inhibitor treatment or an immunogenic surrounding microenvironment, and if so, administering to the patient an effective amount of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of cisplatin. In some embodiments, administration of Compound 1 (scheme 1), such as Compound 1 (scheme 1) dihydrochloride dihydrate or a formulation thereof, in combination with cisplatin, does not include 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 immunotumor. In some embodiments, the patient has a variant-immunosuppressive immunotumor. In some embodiments, the patient has a variant-rejection immunotumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient has a tumor classified as high "IFN-γ signature" or high "amplified immune signature". In some implementations, the patient had a PD-L1 positive tumor.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, to the patient or patient population in a manner that increases progression-free survival or overall survival, and chemotherapy. The method includes determining whether the cancer has an immunomodulatory, immunogenically susceptible to CDK4/6 inhibitor treatment or an immunogenic surrounding microenvironment, and if so, administering to the patient an effective amount of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of carboplatin. In some embodiments, administration of Compound 1 (scheme 1), such as Compound 1 (scheme 1) dihydrochloride dihydrate or a formulation thereof, in combination with carboplatin does not involve 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 immunotumor. In some embodiments, the patient has a variant-immunosuppressive immunotumor. In some embodiments, the patient has a variant-rejection immunotumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient has a tumor classified as high "IFN-γ signature" or high "amplified immune signature". In some implementations, the patient had a PD-L1 positive tumor.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, to the patient or patient population in a manner that increases progression-free survival or overall survival, and chemotherapy. The method includes determining whether the cancer has an immunomodulatory, immunogenically susceptible to CDK4/6 inhibitor treatment or an immunogenic surrounding microenvironment, and if so, administering to the patient an effective amount of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of vincristine. In some embodiments, administration of Compound 1 (scheme 1), such as Compound 1 (scheme 1) dihydrochloride dihydrate or a formulation thereof, in combination with vincristine does not involve administration of an immune checkpoint inhibitor. In some embodiments, the patient has an immunogenic tumor. In some embodiments, the patient has a hot immunotumor. In some embodiments, the patient has a variant-immunosuppressive immunotumor. In some embodiments, the patient has a variant-rejection immunotumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient has a tumor classified as high "IFN-γ signature" or high "amplified immune signature". In some implementations, the patient had a PD-L1 positive tumor.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, to the patient or patient population in a manner that increases progression-free survival or overall survival, and chemotherapy. The method includes determining whether the cancer has an immunomodulatory, immunogenically susceptible to CDK4/6 inhibitor treatment or an immunogenic surrounding microenvironment, and if so, administering to the patient an effective amount of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of vincristine. In some embodiments, administration of Compound 1 (scheme 1), such as Compound 1 (scheme 1) dihydrochloride dihydrate or a formulation thereof, in combination with vincristine does not involve administration of an immune checkpoint inhibitor. In some embodiments, the patient has an immunogenic tumor. In some embodiments, the patient has a hot immunotumor. In some embodiments, the patient has a variant-immunosuppressive immunotumor. In some embodiments, the patient has a variant-rejection immunotumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient has a tumor classified as high "IFN-γ signature" or high "amplified immune signature". In some implementations, the patient had a PD-L1 positive tumor.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, to the patient or patient population in a manner that increases progression-free survival or overall survival, and chemotherapy. The method includes determining whether the cancer has an immunomodulatory, immunogenically susceptible to CDK4/6 inhibitor treatment or an immunogenic surrounding microenvironment, and if so, administering to the patient an effective amount of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of vinorelbine. In some embodiments, administration of Compound 1 (scheme 1), such as Compound 1 (scheme 1) dihydrochloride dihydrate or formulations thereof, in combination with vinorelbine does not involve administration of an immune checkpoint inhibitor. In some embodiments, the patient has an immunogenic tumor. In some embodiments, the patient has a hot immunotumor. In some embodiments, the patient has a variant-immunosuppressive immunotumor. In some embodiments, the patient has a variant-rejection immunotumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient has a tumor classified as high "IFN-γ signature" or high "amplified immune signature". In some implementations, the patient had a PD-L1 positive tumor.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, to the patient or patient population in a manner that increases progression-free survival or overall survival, and chemotherapy. The method includes determining whether the cancer has an immunomodulatory, immunogenically susceptible to CDK4/6 inhibitor treatment or an immunogenic surrounding microenvironment, and if so, administering to the patient an effective amount of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of vinblastine. In some embodiments, administration of Compound 1 (scheme 1), such as Compound 1 (scheme 1) dihydrochloride dihydrate or a formulation thereof, in combination with vinorelbine does not involve administration of an immune checkpoint inhibitor. In some embodiments, the patient has an immunogenic tumor. In some embodiments, the patient has a hot immunotumor. In some embodiments, the patient has a variant-immunosuppressive immunotumor. In some embodiments, the patient has a variant-rejection immunotumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient has a tumor classified as high "IFN-γ signature" or high "amplified immune signature". In some implementations, the patient had a PD-L1 positive tumor.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, to the patient or patient population in a manner that increases progression-free survival or overall survival, and chemotherapy. The method includes determining whether the cancer has an immunomodulatory, immunogenically susceptible to CDK4/6 inhibitor treatment or an immunogenic surrounding microenvironment, and if so, administering to the patient an effective amount of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of diazinon. In some embodiments, administration of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, in combination with diazinon does not involve administration of an immune checkpoint inhibitor. In some embodiments, the patient has an immunogenic tumor. In some embodiments, the patient has a hot immunotumor. In some embodiments, the patient has a variant-immunosuppressive immunotumor. In some embodiments, the patient has a variant-rejection immunotumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient has a tumor classified as high "IFN-γ signature" or high "amplified immune signature". In some implementations, the patient had a PD-L1 positive tumor.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, to the patient or patient population in a manner that increases progression-free survival or overall survival, and chemotherapy. The method includes determining whether the cancer has an immunomodulatory, immunogenically susceptible to CDK4/6 inhibitor treatment or an immunogenic surrounding microenvironment, and if so, administering to the patient an effective amount of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of methyldi(chloroethyl)amine. In some embodiments, administration of Compound 1 (scheme 1), such as Compound 1 (scheme 1) dihydrochloride dihydrate or a formulation thereof, in combination with methyldi(chloroethyl)amine does not involve 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 immunotumor. In some embodiments, the patient has a variant-immunosuppressive immunotumor. In some embodiments, the patient has a variant-rejection immunotumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient has a tumor classified as high "IFN-γ signature" or high "amplified immune signature". In some implementations, the patient had a PD-L1 positive tumor.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, to the patient or patient population in a manner that increases progression-free survival or overall survival, and chemotherapy. The method comprises determining whether the cancer has an immunomodulatory, immunogenically susceptible to CDK4/6 inhibitor treatment or an immunogenic surrounding microenvironment, and if so, administering to the patient an effective amount of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of mitogen C. In some embodiments, administration of Compound 1 (scheme 1), such as Compound 1 (scheme 1) dihydrochloride dihydrate or a formulation thereof, in combination with mitomycin C does not involve 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 immunotumor. In some embodiments, the patient has a variant-immunosuppressive immunotumor. In some embodiments, the patient has a variant-rejection immunotumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient has a tumor classified as high "IFN-γ signature" or high "amplified immune signature". In some implementations, the patient had a PD-L1 positive tumor.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, to the patient or patient population in a manner that increases progression-free survival or overall survival, and chemotherapy. The method includes determining whether the cancer has an immunomodulatory, immunogenically susceptible to CDK4/6 inhibitor treatment or an immunogenic surrounding microenvironment, and if so, administering to the patient an effective amount of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of fludarabine. In some embodiments, administration of Compound 1 (scheme 1), such as Compound 1 (scheme 1) dihydrochloride dihydrate or a formulation thereof, in combination with fludarabine does not involve 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 immunotumor. In some embodiments, the patient has a variant-immunosuppressive immunotumor. In some embodiments, the patient has a variant-rejection immunotumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient has a tumor classified as high "IFN-γ signature" or high "amplified immune signature". In some implementations, the patient had a PD-L1 positive tumor.

In some embodiments, a method is provided for selecting a patient or patient population for cancer therapy, comprising administering compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, to the patient or patient population in a manner that increases progression-free survival or overall survival, and chemotherapy. The method includes determining whether the cancer has an immunomodulatory, immunogenically susceptible to CDK4/6 inhibitor treatment or an immunogenic surrounding microenvironment, and if so, administering to the patient an effective amount of compound 1 pattern 1, such as compound 1 pattern 1 dihydrochloride dihydrate or a formulation thereof, and an effective amount of cytosine arabinoside. In some embodiments, administration of Compound 1 (scheme 1), such as Compound 1 (scheme 1) dihydrochloride dihydrate or a formulation thereof, in combination with cytosine arabinoside does not involve 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 immunotumor. In some embodiments, the patient has a variant-immunosuppressive immunotumor. In some embodiments, the patient has a variant-rejection immunotumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as C2 "IFN-γ dominant" carcinoma. In some embodiments, the patient has a tumor classified as high "IFN-γ signature" or high "amplified immune signature". In some implementations, the patient had a PD-L1 positive tumor.

In any of the above embodiments, the patient to be treated has been identified as having a cancer with a favorable immunomodulatory microenvironment, being immunogenic, or immunogenically susceptible to CDK 4/6 inhibitor therapy. Therefore, assuming the cancer falls into the category described herein, the patient may be a suitable candidate for the described treatment. In some embodiments, the cancer to be treated is selected from the following groups: breast cancer, including but not limited to estrogen receptor (ER)-positive and triple-negative breast cancer; non-small cell lung cancer; head and neck squamous cell carcinoma; and classic Hodgkin's lymphoma. Lymphoma (cHL); diffuse large B-cell lymphoma; bladder cancer; primary mediastinal B-cell lymphoma (PBMCL); urothelial carcinoma; microsatellite-instability (MSI-H) solid tumor; mismatch-deficient repair (dMMR) solid tumor; gastric or gastroesophageal junction (GEJ) adenocarcinoma; squamous cell carcinoma of the esophagus; 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.

In some implementations, checkpoint inhibitors are not administered to patients.

In some practices, checkpoint inhibitors are administered to patients. (i) Anti-excessive therapy

In addition to being used to produce a beneficial intravenous solution for bone marrow preservation, compound 1 (Figure 1) dihydrochloride dihydrate can also be used to treat abnormal cell proliferation disorders, inflammatory disorders, immune disorders, or autoimmune disorders.

In some embodiments, methods for treating proliferative disorders in a host (including humans) include, where appropriate, administration of a separated compound (scheme 1 ), for example, in the form of a dihydrochloride dihydrate, to a pharmaceutically acceptable carrier. Non-limiting examples of disorders include tumors, cancers, disorders related to abnormal cell proliferation, inflammatory disorders, immune disorders, and autoimmune disorders.

In one embodiment, compound 1, pattern 1, is administered non-intestinally. This administration can be performed daily or during treatment breaks for bone marrow preservation.

When administered in an effective amount to a host including humans, Compound 1 (Figure 1) is suitable as a dosage form for the treatment of tumors, cancers (solid, non-solid, diffuse, hematologic, etc.), abnormal cell proliferation, immune disorders, inflammatory disorders, hematologic disorders, myeloproliferative or lymphoproliferative disorders (such as B or T-cell lymphoma, multiple myeloma), breast cancer, prostate cancer, AML, ALL, ACL, lung cancer, pancreatic cancer, colorectal cancer, skin cancer, melanoma, Waldenstrom's macroglobulinemia, Wiskott-Aldrich syndrome, or post-transplant lymphoproliferative disorders; autoimmune diseases such as lupus, Crohn's disease, and Addison's disease. Diseases including: celiac disease, dermatomyositis, Graves' disease, thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis, or type 1 diabetes; cardiac abnormalities, including hypercholesterolemia; infectious diseases, including viral and/or bacterial infections; inflammatory conditions, including asthma, chronic gastric ulcers, tuberculosis, rheumatoid arthritis, periostitis of the dental root, ulcerative colitis, or hepatitis.

Examples of proliferative disorders include (but are not limited to) benign growths, tumors, tumors, cancers (Rb positive or Rb negative), autoimmune disorders, inflammatory disorders, graft-versus-host rejection, and fibrotic disorders.

Non-limiting examples of cancers that can be treated according to this invention include (but are not limited to) acoustic neuroma, adenocarcinoma, adrenal carcinoma, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphoendothelial sarcoma, angiosarcoma), appendiceal carcinoma, benign monoclonal gamma globulinosis, bile duct cancer (e.g., bile duct cancer), bladder cancer, and breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, breast cancer, medullary carcinoma of the breast). Brain cancer (e.g., meningioma; glioma, such as astrocytoma, oligodendroglioma; neuroblastoma), bronchial carcinoma, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), chordoma, craniopharyngioma, colorectal cancer (e.g., colorectal cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endothelial sarcoma (e.g., Kaposi's 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). Cancers include sarcoma, eye cancers (e.g., intraocular melanoma, retinal blastoma), common hypereosinophilic cancers, gallbladder cancer, gastric cancers (e.g., gastric adenocarcinoma), gastrointestinal sclerotum (GIST), head and neck cancers (e.g., head and neck squamous cell carcinoma), oral cancers (e.g., oral squamous cell carcinoma (OSCC), pharyngeal cancers (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematopoietic cancers (e.g., leukemia, such as acute lymphoblastic leukemia (ALL), also known as acute lymphoblastic leukemia or acute lymphoblastic leukemia (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), and 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 B-cell lymphoma, splenic-marginal B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma.) Lymphoma, plasma cell lymphoma (i.e., Waldenström'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) Leukemia syndrome); angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathic T-cell lymphoma, subcutaneous lipoitis-like T-cell lymphoma, pleomorphic large cell lymphoma; one or more of the mixtures of leukemia/lymphomas as described above; and multiple myeloma (MM), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastoma, immunocytoamyloidosis, renal cancer (e.g., nephroblastoma, also known as Wilms' tumor). Tumors, kidney cancer, liver cancer (e.g., hepatocellular carcinoma, malignant liver cancer), lung cancer (e.g., bronchial carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung), leiomyosarcoma (LMS), mastocytosis (e.g., generalized mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorders (MPD) (For example, polycythemia vera (PV), essential thrombocythemia (ET), unexplained myelocytic metaplasia (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic neutrophilic leukemia (CNL), eosinophilic syndrome (HE)), neuroblastoma, neurofibroma (e.g., neurofibroma (NF) type 1 or 2, Schwann cell tumors) Wannomatosis), neuroendocrine carcinomas (e.g., gastrointestinal pancreatic neuroendocrine tumors (GEP-NET), carcinoid tumors), osteosarcoma, ovarian cancers (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary carcinoma, pancreatic cancers (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous tumor (IPMN), islet cell tumors), and penile cancers (e.g., Paget's disease of the penis and scrotum). Diseases including pineal gland tumors, primitive neuroectodermal tumors (PNT), prostate cancer (e.g., prostate adenocarcinoma), rhabdomyosarcoma, salivary gland cancer, skin cancers (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small bowel cancer (e.g., appendix cancer), and soft tissue sarcomas (e.g., malignant fibrous histiocytoma (MFH)). Liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma, sebaceous gland carcinoma, sweat gland carcinoma, synovial tumor, testicular cancer (e.g., seminoma, embryonal testicular carcinoma), thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma), urethral cancer, vaginal cancer, and vulvar cancer (e.g., Paget's disease of the vulva).

In some embodiments, the invention includes the use, as appropriate, of an effective amount of isolated compound 1 (scheme 1) or a pharmaceutically acceptable salt, prodrug, or isotopic variant thereof, in a pharmaceutical composition for the treatment of a host, typically human, suffering from selected cancers, tumors, hyperproliferative conditions, or inflammatory or immune disorders. Compound 1 (scheme 1) also exhibits activity against T cell proliferation. Given the extremely small amounts of drugs targeting T-cell cancers and abnormal proliferation, the identification of such uses represents a substantial improvement in the medical treatment of these diseases.

In another implementation, the condition is myelodysplastic syndrome (MDS).

In some embodiments, the cancer is a hematopoietic carcinoma. In some embodiments, the hematopoietic carcinoma is lymphoma. In some embodiments, the hematopoietic carcinoma is leukemia. In some embodiments, the leukemia is acute myeloid leukemia (AML).

In some embodiments, the proliferative condition is myeloproliferative tumor. In some embodiments, myeloproliferative tumor (MPN) is primary myelofibrosis (PMF).

In some embodiments, cancer is a solid tumor. As used herein, a solid tumor refers to an abnormal mass of tissue that does not typically contain cystic or fluid-filled areas. Different types of solid tumors are named in relation to the type of cells that form them. As mentioned above, examples of solid tumor categories include, but are not limited to, sarcomas, carcinomas, and lymphomas. Additional 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.

In some embodiments, the condition treated with compound 1 (pattern 1) is a symptom associated with abnormal cell proliferation.

Abnormal cell proliferation, especially excessive proliferation, can occur due to various factors, including gene mutations, infection, exposure to toxins, autoimmune diseases, and the induction of benign or malignant tumors.

There are many skin conditions associated with excessive cell proliferation. For example, psoriasis is a benign human skin disease typically characterized by patches covered with thickened scales. This disease is caused by an increase in the proliferation of epidermal cells for unknown reasons. 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 commonis, actinic keratosis, basal cell carcinoma, and squamous cell carcinoma.

Other conditions of excessive cell proliferation include angiogenesis, fibrosis, autoimmune diseases, graft-versus-host rejection, tumors, and cancer.

Angiogenic disorders include angiogenesis and angiovascularization. The proliferation of smooth muscle cells during plaque development in vascular tissues leads to conditions such as restenosis, retinopathy, and atherosclerosis. Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions.

Fibrosis is usually attributed to abnormalities in the formation of the extracellular matrix. Examples of fibrosis include cirrhosis and glomerular membranous proliferative dysplasia. Cirrhosis is characterized by an increase in extracellular matrix components, leading to liver scarring. Hepatic cirrhosis causes diseases such as cirrhosis of the liver. Increased extracellular matrix leading to liver scarring can also be caused by viral infections such as hepatitis. Lipid cells appear to play a major role in cirrhosis.

Glomerular membrane disorders are caused by abnormal proliferation of glomerular membrane cells. Glomerular membrane hyperproliferative cell disorders include various human kidney diseases, such as glomerular nephritis, diabetic nephropathy, nephrotic cirrhosis, thrombotic microangiopathy syndrome, transplant rejection, and glomerular nephropathy.

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

Generally speaking, other conditions that may include abnormal proliferative components include Behcet's syndrome, acute respiratory distress syndrome (ARDS), ischemic heart disease, postdialysis syndrome, leukemia, acquired immunodeficiency syndrome, vasculitis, lipohistiocytosis, septic shock, and inflammation.

In some embodiments, the compounds of the present invention and their pharmaceutically acceptable derivatives, or pharmaceutically acceptable formulations containing such compounds, are also suitable for the prevention and treatment of HBV infection and other related conditions, such as anti-HBV antibody positivity and HBV positivity, HBV-related conditions, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis, and fatigue-induced chronic hepatitis. These compounds or formulations can also be used prophylactically to prevent or halt the development of clinical disease in individuals who are anti-HBV antibody or HBV-antigen positive or have been exposed to HBV.

In some implementations, the condition is associated with the immune response.

Skin contact hypersensitivity and asthma are two examples of immune responses that can be associated with a fairly high incidence rate. Other conditions include atopic dermatitis, eczema, Hugh Grant's syndrome, including xerotic keratoconjunctivitis secondary to Hugh Grant's syndrome, alopecia areata, allergic reactions attributable to arthropod bites, Crohn's disease, oral ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, skin lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. These conditions can cause one or more of the following symptoms or signs: itching, swelling, redness, blisters, crusting, ulceration, pain, scaling, cracking, hair loss, scarring, or fluid leakage involving the skin, eyes, or mucous membranes.

In atopic dermatitis and eczema, immune-mediated leukocyte infiltration (specifically, infiltration of monocytes, lymphocytes, neutrophils, and eosinophils) into the skin is generally important in the pathogenesis of these diseases. Chronic eczema is also associated with significant epidermal hyperplasia. Immune-mediated leukocyte infiltration also occurs in sites other than the skin, such as in the trachea of asthma and in the lacrimal glands of the eyes in xerotic keratoconjunctivitis.

In a non-limiting embodiment, the compounds of the invention are used as topical agents for the treatment of contact dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis, Hugh Grant's syndrome (including keratoconjunctivitis sicca secondary to Hugh Grant's syndrome), alopecia areata, allergic reactions attributable to arthropod bites, Crohn's disease, oral ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, skin lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. The novel method can also be applied to reduce malignant leukocyte infiltration of the skin in diseases such as mycosis fungoides. These compounds can also be used to treat dehydrated dry eye conditions (such as immune-mediated keratoconjunctivitis) in patients by topical application of the compound to the eye.

Throughout this manual, the terms "tumor" or "cancer" are used to describe the pathological process of the formation and growth of carcinogenic or malignant tumors. That is, abnormal tissue (solid) or cells (non-solid) that proliferate and grow normally more rapidly than normal and continue to grow after stimulation has induced a cessation of growth. Malignant tumors are characterized by partial or complete absence of structural tissue and functional coordination with normal tissue and most of the invasive surrounding tissue. They can metastasize to several sites, may recur after attempted removal, and can lead to patient death unless adequately treated. As used herein, the term "tumor" is used to describe all cancerous disease conditions and includes or covers the pathological processes associated with malignant hematitis, ascites, and solid tumors. Exemplary cancers that can be treated 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 cervical cancer; leukemia; benign and malignant lymphomas, specifically Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative disorders; sarcomas, including Ewing's sarcoma, angiosarcoma, and Kaposi's sarcoma. Sarcoma, liposarcoma, angiosarcoma, peripheral neuroepithelial tumor, synovial sarcoma, glioma, astrocytoma, oligodendritic glioma, ependymoma, glioblastoma, neuroblastoma, gangliocytoma, ganglioglioma, ductoblastoma, pineal cell tumor, meningioma, meningosarcoma, neurofibroma and schwannoma; colon 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, colorectal cancer, carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratoma.

Additional cancers that can be treated with the compounds disclosed in this script include, for example, acute myeloid leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adenocarcinoma, adenosarcoma, adrenal carcinoma, adrenocortical carcinoma, anal cancer, pleomorphic astrocytoma, angiosarcoma, appendiceal carcinoma, astrocytoma, basal cell carcinoma, B-cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, colon cancer, brain cancer, brainstem glioma, breast cancer, ginseng (estrogen), HER2-negative breast cancer, double-negative breast cancer (negative for estrogen, progesterone, and HER2), single-negative breast cancer (negative for one of estrogen, progesterone, and HER2), estrogen receptor-positive, HER2-negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor-positive breast cancer, metastatic breast cancer, luminal type A breast cancer, luminal type B breast cancer, HER2-negative breast cancer, HER2-positive or negative breast cancer, progesterone receptor-negative breast cancer, progesterone receptor-positive breast cancer, etc. Positive breast cancer, recurrent breast cancer, carcinoid tumor, cervical cancer, bile duct cancer, chondrosarcoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), colorectal cancer, colorectal cancer, craniopharyngioma, cortical lymphoma, skin 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 Cancer, gastrointestinal carcinoid cancer, gastrointestinal stromal tumor (GIST), germ cell tumors, glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin's lymphoma, hypopharyngeal cancer, invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), inflammatory breast cancer (IBC), colorectal cancer, intrahepatic bile duct cancer, traumatic/invasive breast cancer, pancreatic islet cell carcinoma, jaw cancer, Kaburg's sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, plenomotor membrane transferases, Leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, neuroblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymal tumor, mesothelioma, metastatic breast cancer, metastatic melanoma, metastatic squamous cervical cancer, mixed glioma, single-keratome teratoma, oral cancer, mucinous carcinoma, mucosal melanoma, multiple myeloma, mycosis fungoides, myelodylocytosis Syndrome, nasal cavity carcinoma, nasopharyngeal carcinoma, cervical cancer, neuroblastoma, neuroendocrine tumors (NETs), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cell carcinoma, eye cancer, ocular melanoma, oligodendroglioma, oral cancer, oral cavity cancer, oropharyngeal cancer, osteoblastoma, osteosarcoma, ovarian cancer, ovarian epithelial carcinoma, ovarian germ cell tumor, primary ovarian peritoneal carcinoma, ovarian sex cord-stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, sinus cancer, paranasal carcinoma Thyroid cancer, pelvic cancer, penile cancer, peripheral nerve carcinoma, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal region tumor, pineal cell carcinoma, pituitary gland cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal 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 cancer, spinal cord cancer, squamous cell carcinoma. Cancer, stomach cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma/thymic carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell carcinoma, fallopian tube cancer, tubular carcinoma, undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult-onset T-cell leukemia, prophylactic B-cell lymphoma. ALL, pre-B lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, Philadelphia chromosome-positive CML, juvenile myeloid monocytic leukemia (JMML), acute promyelocytic leukemia (AML subtype), macromyeloid lymphocytic leukemia, adult-onset T-cell chronic leukemia, diffuse large B-cell lymphoma, follicular lymphoma Lymphoma; mucosal fusion lymphotid tissue lymphoma (MALT), small cell lymphoglobulin lymphoma, large mediastinal B-cell lymphoma, nodal-marginal B-cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary exudative lymphoma; or lymphoma-like granuloma; B-cell prelymphocytic leukemia; splenic lymphoma/leukemia, indivisible Splenic diffuse red pulp small B-cell lymphoma; lymphoplasmic lymphoma; heavy chain diseases, such as alpha heavy chain disease, gamma heavy chain disease, Mu heavy chain disease, plasmacytoma, solitary plasmacytoma of bone; extraosseous plasmacytoma; primary cortical follicular center lymphoma, large B-cell lymphoma rich in T cells/histocytes, DLBCL associated with chronic inflammation; Ebola virus (EBV) in the elderly. V)+DLBCL; primary mediastinal (thymic) large B-cell lymphoma, primary cortical DLBCL, leg-type, ALK+ large B-cell lymphoma, plasmablastic lymphoma; large B-cell lymphoma arising from HHV8-associated multicentric Castileman disease; or B-cell lymphoma, unclassifiable, exhibiting characteristics between diffuse large B-cell lymphoma and classic Hodgkin's lymphoma.

In another embodiment, a method for increasing BIM expression (e.g., BCLC2L11 expression) to induce apoptosis in cells is provided, the method comprising contacting cells with a compound of the invention or a pharmaceutically acceptable combination thereof, a salt, an isotope analogue, or a prodrug. In some embodiments, the method is an in vitro method. In some embodiments, the method is an in vivo method. BCL2L11 expression is tightly regulated in cells. BCL2L11 encodes the pro-apoptotic protein BIM. BCL2L11 is downregulated in many cancers and inhibits BIM 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, for example, Ng et al., Nat. Med. (2012) 18:521-528.

In another embodiment, a method is provided for treating conditions related to angiogenesis, such as diabetes (e.g., diabetic retinopathy), inflammatory conditions (e.g., rheumatoid arthritis), macular degeneration, obesity, atherosclerosis, or proliferative conditions, comprising administering to an individual in need a compound of the invention or a pharmaceutically acceptable combination thereof, a salt, an isotope analogue, or a prodrug.

In some embodiments, the condition associated with angiogenesis is macular degeneration. In some embodiments, a method for treating macular degeneration is provided, comprising administering to an individual in need a compound of the invention or a pharmaceutically acceptable combination thereof, a salt, an isotope analogue, or a prodrug.

In some embodiments, the condition associated with angiogenesis is obesity. As used herein, "obesity" and "obesity" refer to Group I, Group II, Group III obesity, and pre-obesity (e.g., "overweight") as defined by the World Health Organization. In some embodiments, a method for treating obesity is provided, comprising administering to an individual in need a compound of the invention or a pharmaceutically acceptable combination thereof, a salt, an isotope analogue, or a prodrug.

In some embodiments, the condition associated with angiogenesis is atherosclerosis. In some embodiments, a method for treating atherosclerosis is provided, comprising administering to an individual in need a compound of the invention or a pharmaceutically acceptable combination thereof, a salt, an isotope analogue, or a prodrug.

In some embodiments, the condition associated with angiogenesis is a proliferative condition. In some embodiments, a method for treating a proliferative condition is provided, comprising administering to an individual in need a compound of the invention or a pharmaceutically acceptable combination thereof, a salt, an isotope analogue, or a prodrug.

In an alternative embodiment, the compound is administered at doses of about 50 mg/ ^m² to about 800 mg/ ^m² , about 100 mg/ ^m² to about 600 mg/ ^m² , about 100 mg/ ^m² to about 500 mg/ ^m² , about 100 mg/ ^m² to about 400 mg/ ^m² , about 100 mg/ ^m² to about 350 mg/ ^m² , about 150 mg/ ^m² to about 350 mg/ ^m² , about 200 mg/ ^m² to about 350 mg/ ^m² , or about 200 mg/ ^m² to about 300 mg/ ^m² .

The isolated compound 1 (Figure 1) can be used alone or in combination with another compound of the present invention or another bioactive agent in an effective amount to treat a host, such as a human, suffering from a condition as described herein.

The isolated compound 1 of pattern 1 described herein can be used alone or in combination with another compound of the present invention or another bioactive agent to treat a host, such as a human, suffering from the condition described herein.

The term "bioactive agent" is used to describe agents other than those selected according to the invention, which can be used in combination with or alternately with the compounds of the invention to achieve desired therapeutic results. In one embodiment, the compounds and bioactive agents of the invention are administered in vivo in a manner that allows them to be active during overlapping time periods, such as having overlapping Cmax, Tmax, AUC, or other pharmacokinetic parameters. In another embodiment, isolated compound 1 (schema 1) and bioactive agent are administered to a host in need, which do not have overlapping pharmacokinetic parameters, but one has a therapeutic effect on the therapeutic efficacy of the other.

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

PD-1 inhibitors that block the interaction between PD-1 and PD-L1 by binding to PD-1 receptors and thereby inhibiting 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 between 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 PD-1 and LAG-3 inhibitor MGD013 (MacroGenics). One example of a TIM-3 inhibitor is TSR-022 (Tesaro).

In another embodiment, the isolated compound 1 of pattern 1 described herein may be administered in combination or alternately with an effective amount of an estrogen suppressant for the treatment of abnormal tissues of the female reproductive system, such as breast cancer, ovarian cancer, endometrial cancer, or uterine cancer. The estrogen suppressant includes (but is not limited to) selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), complete estrogen receptor degraders, or other forms of partial or complete estrogen antagonists or agonists. Some anti-estrogens (such as raloxifene and tamoxifen) retain some estrogenic effects (including estrogen-like stimulation of uterine growth) and, in some cases, estrogen-like activity that actually stimulates tumor growth during breast cancer progression. In contrast, fulvestrant, a completely anti-estrogenic compound, has limited estrogen-like activity in the uterus and is effective against tamoxifen-resistant tumors. Non-limiting examples of anti-estrogenic compounds are provided in WO 2014/19176, WO2013/090921, WO 2014/203129, WO 2014/203132, assigned to Astra Zeneca, and US2013/0178445, US Patents 9,078,871, 8,853,423, and 8,703,810, assigned to Olema Pharmaceuticals, as well as US 2015/0005286, WO 2014/205136, and WO 2014/205138.

Additional non-limiting examples of anti-estrogenic compounds include: SERMS, such as aordrin, bazedoxifene, broparestriol, chlorotriarylene, and clonifene citrate. Citrate, cyclofenil, lasofoxifene, ormeloxifene, raloxifene, tamoxifen, toremifene, and fulvestrant; aromatase inhibitors, such as aminoglutethimide, testolactone, anastrozole, exemestane, faldazole, formexane, and letrozole; and antigonadotropins, such as leuprorelin, cetrorelix, allylestrenol, chloromadinone acetate, cyproterone acetate, and delmadinone acetate. Acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, progesterone and spironolactone. Other estrogen ligands that may be used in this invention are described in the following: U.S. Patents 4,418,068; 5,478,847; 5,393,763; and 5,457,117, WO2011/156518; U.S. Patents 8,455,534 and 8,299,112; U.S. Patents 9,078,871; 8,853,423; 8,703,810; US 2015/0005286; and WO 2014/205138, US2016/0175289, US2015/0258080, WO 2014/191726, WO 2012/084711; WO 2002/013802; WO 2002/004418; WO 2002/003992; WO 2002/003991; WO 2002/003990; WO 2002/003989; WO 2002/003988; WO 2002/003986; WO 2002/003977; WO 2002/003976; WO 2002/003975; WO 2006/078834; US 6821989; US 2002/0128276; US 6777424; US 2002/0016340; US 6326392; US 6756401;US 2002/0013327; US 6512002; US 6632834; US 2001/0056099; US 6583170; US 6479535; WO 1999/024027; US 6005102; EP 0802184; US 5998402; US 5780497, US 5880137, WO 2012/048058 and WO 2007/087684.

In another embodiment, the isolated compound 1 of pattern 1 described herein may be administered in combination with or alternately with an effective amount of an androgen (such as testosterone) inhibitor for the treatment of abnormal tissues of the male reproductive system, such as prostate cancer or testicular cancer. The androgen inhibitor includes (but is not limited to) selective androgen receptor modulators, selective androgen receptor degraders, complete androgen receptor degraders, or other forms of partial or complete androgen antagonists. In one embodiment, the prostate or testicular cancer is androgen-resistant. Non-limiting examples of antiandrogen compounds are provided in WO 2011/156518 and U.S. Patents 8,455,534 and 8,299,112. Additional non-limiting examples of anti-androgen compounds include: enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topilutamide, abiraterone acetate, and cimetidine.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of abiraterone acetate (Zytiga) are administered together for the treatment of abnormal tissues of the male reproductive system.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of abiraterone acetate (Zytiga) are administered together for the treatment of prostate cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of enzalutamide are administered together for the treatment of prostate cancer.

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.

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), olmutinib (Olita), naquotinib (ASP8273), nazartinib (EGF816), PF-06747775 (Pfizer), icotinib (BPI-2009), neratinib (HKI-272; PB272), avitinib (AC0010), EAI045, and tarloxotinib. (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).

In one embodiment, an effective amount of compound 1 (pattern 1) is administered in combination with an effective amount of afatinib dicis-butenedioate (Gilotrif) for the treatment of non-small cell lung cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of alectinib (Alecensa) are administered in combination for the treatment of non-small cell lung cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of celitinib (Zykadia) are administered in combination for the treatment of non-small cell lung cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of crizotinib (Xalkori) are administered in combination for the treatment of non-small cell lung cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of osimertinib (Tagrisso) are administered in combination for the treatment of non-small cell lung cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of brigatinib (Alunbrig) are administered in combination for the treatment of non-small cell lung cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of lorlatinib are administered in combination for the treatment of non-small cell lung cancer.

In one embodiment, the bioactive agent is a HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab emtansine, and pertuzumab.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of lapatinib xylenesulfonate are administered in combination for the treatment of breast cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of lapatinib dimethylsulfonate are administered in combination for the treatment of HER2+ breast cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of PF7775 are administered together for the treatment of non-small cell lung cancer.

In one embodiment, the bioactive agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutuzumab, rituximab, fatumumab, ibritumomab, tositumomab, and ocrelizumab.

In one embodiment, the bioactive agent is a JAK3 inhibitor. Examples of JAK3 inhibitors include tasocitinib.

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-dimethylcyclohexyl-1-en-1-yl]methyl]piperidin-1-yl]-N-[[[3-nitro-4-[[(tetrahydro-2H-piperan-4-yl)methyl]amino]phenyl]sulfonylurea]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), and ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperidin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylthiobut-2-yl]amino]-3-nitrophenyl]sulfonylurea). (Navitoclax), ABT-263 ((R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[l,l'-biphenyl]-2-yl)methyl)piperidin-1-yl)-N-((4-((4-pyrinyl-1-(phenylthio)but-2-yl)amino)-3((trifluoromethyl)sulfonylurea)phenyl)sulfonylurea)benzamide), GX15-070 (obatoclax mesylate, (2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrolo-2-yl)methylene]-4-methoxypyrrolo-2-yl]indole; mesylate))), 2-methoxy-antimicrobial A3, YC137 (4-(4,9-di-side-oxy-4,9-dihydronaphtho[2,3-d]thiazolyl-2-ylamino)-phenyl ester), pogosin, 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-side-oxyethyl)-4H-benzopiperan-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]benzylamine), Apogossypolone (ApoG2), HA14-1, AT101, sabutoclax, gambogic acid, or G3139 (Oblimersen).

In some embodiments, a treatment regimen is provided comprising administering a combination of compound 1 (schema 1) and at least one additional chemical agent. The combination disclosed herein may be administered for beneficial, additional, or synergistic effects in the treatment of abnormal proliferative disorders.

In a specific embodiment, the treatment regimen includes administration of a combination of isolated compound 1 (schema 1) and at least one kinase inhibitor. In one embodiment, the at least one kinase inhibitor is selected from phosphoinositol 3-kinase (PI3K) inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, or spleen tyrosine kinase (Syk) inhibitors, or combinations thereof.

PI3k inhibitors that can be used in this invention are well known. Examples of PI3 kinase inhibitors include (but are not limited to) Wortmannin, demethoxyviridin, perifosine, idelalisib, pictilisib, Palomid 529, ZSTK474, PWT33597, CUDC-907 and AEZS-136, duvelisib, GS-9820, BKM120, and GDC-0032 (taselisib). (2-[4-[2-(2-isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazol-9-yl]pyrazol-1-yl]-2-methylpropionic acid), MLN-1117 ((S)-methylphosphonate hydrogen(2R)-1-phenoxy-2-butyl ester; or methyl(sideoxy){[(2R)-1-phenoxy-2-butyl]oxy}phosphonium), BYL-719 ((2S)-N1-[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridyl]-2-thiazolyl]-1,2-pyrrolidinedimethylamine), GSK2126458 (2,4-Difluoro-N-{2-(methoxy)-5-[4-(4-tert-yl)-6-quinolinyl]-3-pyridyl}benzenesulfonamide) (omipalisib), TGX-221 ((±)-7-methyl-2-(ominolin-4-yl)-9-(1-anilinylethyl)-pyrido[l,2-a]pyrimidin-4-one), GSK2636771 (2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-ominolinyl-1H-benzo[d]imidazolium-4-carboxylic acid dihydrochloride), KIN-193 ((R)-2-((1-(7-methyl-2-pyriminyl-4-sideoxy-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid), TGR-1202/RP5264, GS-9820 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-monohelylprop-1-one), GS-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)quinolin-2-yl)aminosulfonylurea)phenyl)-3-methoxy-4-methylbenzamide), BAY80-6946 (2-amino-N-(7-methoxy-8-(3-pyrinylpropoxy)-2,3-dihydroimidazole[l,2-c]quinazon), AS 252424 (5-[1-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-methyl-(Z)-yenyl]-thiazolyl-2,4-dione), CZ 24832 (5-(2-amino-8-fluoro-[l,2,4]triazolo[l,5-a]pyridin-6-yl)-N-tert-butylpyridin-3-sulfonamide), Buparlisib (5-[2,6-di(4-hydroxyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamide), GDC-0941 (2-(lH-indazol-4-yl)-6-[[4-(methanesulfonyl)-1-piperazolyl]methyl]-4-(4-hydroxyl)thieno[3,2-d]pyrimidinyl), GDC-0980 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-N-hydroxylthiopheno[3,2-d]pyrimidin-6-yl)methyl)silyl-1-yl)-2-hydroxypropyl-1-one (also known as RG7422)), SF1126 ((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentaoxy-1-(4-(4-sideoxy-8-phenyl-4H-benzopiperan-2-yl)silyl)-4-onthium)-2-oxa-7,10,13,16-tetraazaoctadecane-18-ester), PF-05212384 (N-[4-[[4-(dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-(4,6-di-4-hydroxy-1,3,5-tris(2-yl)phenyl]urea) (gedatolisib), LY3023414, BEZ235 (2-methyl-2-{4-[3-methyl-2-sideoxy-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-dimethoxyaniline)quinolin-2-yl)aminosulfonyl)phenyl)-3-methoxy-4-methylbenzoamide) and GSK1059615 (5-[[4-(4-pyridyl)-6-quinolinyl]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-trilateraloxy-2,3,3a,9,10,11-hexahydroindo[4,5h]isobenzopiperan-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 The structure described in (GDC-0980; RG7422) and WO2014/071109. In one embodiment, compound 1 of pattern 1 is isolated and combined with a PIk3 inhibitor in a single dosage form.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of apelelis are administered together for the treatment of solid tumors.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of apelis are administered together for the treatment of abnormal tissues of the female reproductive system.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of apelis are administered together for the treatment of breast cancer.

In one embodiment, an effective amount of compound 1 (schema 1) is administered in combination with an effective amount of copanlisib hydrochloride (Aliqopa) for the treatment of lymphoma.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of cobancobacterium hydrochloride (Aliqopa) are administered together for the treatment of follicular lymphoma.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of Zydelig are administered together for the treatment of chronic lymphocytic leukemia.

In one embodiment, an effective amount of compound 1 (pattern 1) is administered in combination with an effective amount of Zydelig for the treatment of non-Hodgkin's lymphoma, including follicular B-cell non-Hodgkin's lymphoma or small lymphocytic lymphoma.

The BTK inhibitors used in this invention are well known. Examples of BTK inhibitors include ibrutinib (also known as PCI-32765) (Imbruvica™) (1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one), diphenylaminopyrimidine-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, which is incorporated herein by reference in its entirety), and dasatinib. ([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazine-1-yl)-2-methylpyrimidin-4-ylamino)thiazolyl-5-methylamine]), LFM-A13 (α-cyano-β-hydroxy-β-methyl-N-(2,5-dibromophenyl)propenylamine), GDC-0834 ([RN-(3-(6-(4-(1,4-dimethyl-3-sideoxypiperazine-2-yl)anilino)-4-methyl-5-sideoxy-4,5-dihydropyridine-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-methylamine]), CGI-560 4-(tri-butyl)-N-(3-(8-(anilino)imidazo[1,2-a]pyridine-6-yl)phenyl)benzamide, CGI-1746 (4-(tri-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(azoline-4-carbonyl)phenyl)amino)-5-sideoxy-4,5-dihydropyridine-2-yl)phenyl)benzamide), CNX-774 (4-(4-((4-((3-propenylaminophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpyridinemethylamine), CTA056 (7-Benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoline-6(5H)-one), GDC-0834 ((R)-N-(3-(6-((4-(1,4-dimethyl-3-sideoxypiperidin-2-yl)phenyl)amino)-4-methyl-5-sideoxy-4,5-dihydropyridine-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-methylamine), GDC-0837 ((R)-N-(3-(6-((4-(1,4-dimethyl-3-sideoxypiperazine-2-yl)phenyl)amino)-4-methyl-5-sideoxy-4,5-dihydropyridine-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-methylamine), 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-methylamine hydrochloride), QL-47 (1-(1-Acrylamide indoline-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6] acetidine-2(1H)-one) and RN486 (6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperidin-1-yl)-pyridin-2-ylamino]-6-sideoxy-1,6-dihydropyridin-3-yl}-phenyl)-2H-isoquinoline-1-one) and other molecules capable of inhibiting BTK activity, such as those BTK inhibitors disclosed in Akinleye et al., Journal of Hematology & Oncology, 2013, 6:59 (the entire contents of which are incorporated herein by reference). In one embodiment, the isolated compound 1 (pattern 1) is combined with a BTK inhibitor in a single dosage form.

In one embodiment, an effective amount of compound 1 (schema 1) and an effective amount of ibrutinib (Imbruvica) are administered in combination for the treatment of chronic lymphocytic leukemia.

In one embodiment, an effective amount of compound 1 ( schema 1) is administered in combination with an effective amount of ibrutinib (Imbruvica) for the treatment of lymphomas, including small lymphocytic lymphoma, mantle cell lymphoma, marginal zone lymphoma, or Waldenström's macroglobulinemia.

Syk inhibitors used in this invention are well known and include, for example, cerdulatinib (4-(cyclopropylamino)-2-((4-(4-(ethanesulfonyl)hexahydropyridine-1-yl)phenyl)amino)pyrimidin-5-methylamine), entospletinib (6-(1H-indazol-6-yl)-N-(4-olinylphenyl)imidazo[1,2-a]pyridine-8-amine), and fostamatinib. ([6-({5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl}amino)-2,2-dimethyl-3-sideoxy-2,3-dihydro-4H-pyridano[3,2-b][1,4]carbazinyl-4-yl]dihydromethyl phosphate), fotatinib disodium salt ((6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidinyl-4-yl)amino)-2,2-dimethyl-3-sideoxy-2H-pyridano[3,2-b][1,4]carbazinyl-4(3H)-yl)sodium 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)-pyrazinamide-3-carboxylic acid), imatinib (Gleevac; 4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzoamide), astrococcus, GSK143 (2-(((3R,4R)-3-aminotetrahydro-2H-piperan-4-yl)amino)-4-(p-toluidine)pyrimidine-5-methylamine), PP2 (1-(tributyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine), PRT-060318 (2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-toluidine)pyrimidine-5-methylamine), PRT-062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-methylamine hydrochloride), R112 (3,3'-((5-fluoropyrimidin-2,4-diyl)bis(azadiyl))diol), 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]carbazone-3(4H)-one), spleen pineol (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, spleen pineol, ER-27319 (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643), 7-azaindole, spleen pineol, ER-27319 (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643), 7-azaindole, spleen pineol, ER-27319 (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643). and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein by reference in full), compound D (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein by reference in full), PRT060318 (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein by reference in full), luteolin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein by reference in full), ... luteolin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein by reference in full), luteolin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein by reference in full Med. Chem. 2012, 55, 3614-3643, which is incorporated herein by reference in full), apigenin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein by reference in full), quercetin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein by reference in full), flavonoids (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, ... References 3614-3643 (in which the full text is incorporated herein by reference), myricetin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, in which the full text is incorporated herein by reference), and morin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, in which the full text is incorporated herein by reference). In one embodiment, an effective amount of the isolated compound 1 , pattern 1, is combined with a Syk inhibitor in a single dosage form.

In one embodiment, at least one additional chemotherapy agent is a protein cell-1 (PD-1) inhibitor. PD-1 inhibitors are known in the art and include, for example, nivolumab (BMS), pembrolizumab (Merck), pilithumab (CureTech/Teva), AMP-244 (Amplimmune/GSK), BMS-936559 (BMS), and MEDI4736 (Roche/Genentech). In one embodiment, an effective amount of the isolated compound 1 (schema 1) is combined with the PD-1 inhibitor in a single dosage form.

In one embodiment, at least one additional chemotherapy 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-dimethylcyclohexyl-1-en-1-yl]methyl]piperazine-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-piperan-4-yl)methyl]amino]phenyl]sulfonylurea]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazine-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylthioalkylbut-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)piperazine-1-yl)-N-((4-((4-olinyl-1-(phenylthio)but-2-yl)amino)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15-070(obatoclax methanesulfonate) mesylate), (2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrolo-2-yl)methylene]-4-methoxypyrrolo-2-yl]indole; methanesulfonic acid)), 2-methoxy-antimicrobial A3, YC137 (4-(4,9-dioxy-4,9-dihydronaphtho[2,3-d]thiazolyl-2-ylamino)-phenyl esters), pogosin, ethyl 2-amino-6-bromo-4-(1 -Cyano-2-ethoxy-2-sideoxyethyl)-4H-carbamate-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 of pattern 1 is combined in a single dosage form with at least one BCL-2 inhibitor.

In one embodiment, the combination described herein may be further combined with another cancer treatment. The second therapy may be immunotherapy. As discussed in more detail below, an effective amount of the isolated compound 1 (schema 1) may be conjugated to an antibody, radiopharmaceutical, or other targeted agent that directs the compound to diseased or abnormally proliferating cells. In another embodiment, the combination is used in combination with another pharmaceutical or biological agent (e.g., an antibody) to enhance the therapeutic efficacy of the combination or synergistic approach. In one embodiment, the combination may be used in conjunction with T-cell vaccine administration, which typically involves immunization with inactivated autoreactive T cells to eliminate cancer cell populations as described herein. In another embodiment, the combination is used in conjunction with a bispecific T cell conjugate (BiTE), which is designed to simultaneously bind to specific antigens on endogenous T cells and cancer cells as described herein, and to antibodies linking both types of cells.

In one embodiment, the bioactive agent is a MEK inhibitor. MEK inhibitors are well known and include, for example, trametinib/GSKl120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trisyloxy-3,4,6,7-tetrahydropyridino[4,3-d]pyrimidin-1(2H-yl}phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-methamide), and pimasertib/AS703026/MSC 1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isocyanamide), XL-518/GDC-0973 (1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azacyclobutanol), refamatetinib/BAY869766/RDEAl 19 (N-(3,4-difluoro-2-(2-fluoro-4-iodoaniline)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide), PD-0325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzylamine), TAK733 ((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodoanilino)-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-carboxylamine), R05126766 (3-[[3-fluoro-2-(methylaminosulfonylmethane)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxy-2-one), WX-554, R04987655/CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-sideoxy-1,2-oxoazinon-cyclohexyl)methyl)benzamide) or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-sideoxy-1,6-dihydropyridine-3-carboxamide), U0126-EtOH, PD184352 (CI-1040), GDC-0623, BI-847325, cobimetinib, PD98059, BIX 02189, BIX 02188, binimetinib, SL-327, TAK-733, PD318088.

In one embodiment, an effective amount of compound 1 (schema 1) is administered in combination with an effective amount of bemettinib for the treatment of melanoma, including BRAF-mutant melanoma and NRAS-mutant melanoma.

In one embodiment, an effective amount of compound 1 ( schema 1) is administered in combination with an effective amount of cobimetinib (Cotellic) for the treatment of melanoma, including BRAF-mutant melanoma and NRAS-mutant melanoma.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of bemettinib are administered in combination for the treatment of ovarian cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of selmetinib are administered in combination for the treatment of non-small cell lung cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of selmetinib are administered together for the treatment of thyroid cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of trametinib (Mekinist) are administered in combination for the treatment of thyroid cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of trametinib (Mekinist) are administered in combination for the treatment of melanoma.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of trametinib (Mekinist) are administered in combination for the treatment of non-small cell lung cancer.

In one embodiment, the bioactive agent is a Raf inhibitor. Raf inhibitors are known and include, for example, vemurafinib (N-[3-[[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide), sorafenib tosylate (4-methylbenzenesulfonic acid 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]aminomethylamino]phenoxy]-N-methylpyridin-2-methylamine), AZ628 (3-(2-cyanopropyl-2-yl)-N-(4-methyl-3-(3-methyl-4-sideoxy-3,4-dihydroquinazolin-6-ylamino)phenyl)benzamide), and 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]azinon-4,8-dione), Raf kinase inhibitor IV (2-chloro-5-(2-phenyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)phenol), Sorafenib N-oxide 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 (encorafenib).

In one embodiment, an effective amount of compound 1 (pattern 1) is administered in combination with an effective amount of dabrafenib (Tafinlar) for the treatment of thyroid cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) is administered in combination with an effective amount of dabrafenib (Tafinlar) for the treatment of melanoma.

In one embodiment, an effective amount of compound 1 (pattern 1) is administered in combination with an effective amount of dabrafenib (Tafinlar) for the treatment of non-small cell lung cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) is administered in combination with an effective amount of enrafenib for the treatment of melanoma, including BRAF-mutant melanoma.

In one embodiment, the adjunctive therapy is a monoclonal antibody (MAb). Some MAbs stimulate an immune response that destroys cancer cells. Similar to antibodies naturally produced by B cells, these MAbs coat the "surface of cancer cells," triggering their destruction by the immune system. For example, bevacizumab targets vascular endothelial growth factor (VEGF), a protein secreted by tumor cells and other cells in the tumor microenvironment, which promotes tumor angiogenesis. When bound to bevacizumab, VEGF cannot interact with its cellular receptors, thereby blocking the signaling pathway that induces new angiogenesis. Similarly, cetuximab and panitumumab target the epidermal growth factor receptor (EGFR), while trastuzumab targets human epidermal growth factor receptor 2 (HER-2). MAbs that bind to cell surface growth factor receptors prevent the target receptors from sending their pro-growth signals. They can also trigger apoptosis and activate the immune system to destroy tumor cells.

Another group of therapeutic MAbs for cancer are immune conjugates. These MAbs, sometimes called immunotoxins or antibody-drug conjugates, consist of antibodies that attach to cytotoxic substances (such as plant or bacterial toxins), chemotherapy drugs, or radioactive molecules. The antibody locks its specific antigen onto the surface of cancer cells, and the cytotoxic substance is absorbed by the cell. FDA-approved conjugate MAbs that work in this manner include trastuzumab-mettansine conjugate, which targets the HER-2 molecule to deliver the cell proliferation inhibitor DM1 to HER-2 in metastatic breast cancer cells.

Immunotherapy with engineered T cells that recognize cancer cells via bispecific antibodies (bsAb) or chimeric antigen receptors (CAR) can potentially eliminate cancer cell division and slow down or eliminate cancer cell subsets.

Bispecific antibodies provide an opportunity for redirected immune response cells to kill cancer cells by simultaneously recognizing target antigens and activated receptors on the surface of immune response cells. Another approach involves creating chimeric antigen receptors by fusing extracellular antibodies into intracellular signaling domains. T cells engineered with chimeric antigen receptors can specifically kill tumor cells in an MHC-independent manner.

In some embodiments, the combination may be further combined with other chemotherapeutic agents for administration to an individual. Where appropriate, the combination described herein may be administered simultaneously with another chemotherapeutic agent to simplify the treatment regimen. In some embodiments, the combination and other chemotherapeutic agents may be provided in a single formulation. In one embodiment, the compounds described herein are used in combination with other agents in the form of a treatment regimen. This class of drugs may include, but is not limited to, tamoxifen, midazolam, letrozole, bortezomib, anastrozole, goserelin, mTOR inhibitors, PI3 kinase inhibitors, dual mTOR-PI3K inhibitors, MEK inhibitors, RAS inhibitors, ALK inhibitors, HSP inhibitors (e.g., HSP70 and HSP90 inhibitors or combinations thereof), BCL-2 inhibitors, apoptosis-inducing compounds, and AKT inhibitors, including but not limited to MK-2206, GSK690693, and Perifosine. (KRX-0401), GDC-0068, Triciribine, AZD5363, Honokiol, PF-04691502, ipatasertib, and Miltefosine; PD-1 inhibitors include, but are 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.

In one embodiment, an effective amount of compound 1 (schema 1) and an effective amount of parathetide are administered together for the treatment of breast cancer, including triple-negative breast cancer.

In one embodiment, the bioactive agent is an mTOR inhibitor. Examples of mTOR inhibitors include (but are not limited to) vistusertib and rapamycin and their analogues, everolimus (Afinitor), temsirolimus, ridaforolimus, sirolimus, and deforolimus. Examples of MEK inhibitors include (but are not limited to) tametinib/GSKl120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trisyloxy-3,4,6,7-tetrahydropyridino[4,3-d]pyrimidin-l(2H-yl}phenyl)acetamide), sumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-methamide), and pimasertib/AS703026/MSC1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isocyanamide), XL-518/GDC-0973 (l-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azacyclobutanol-3-ol) (cobimetinib), Refametinib/BAY869766/RDEAl19 (N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide), PD-0325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzylamine), TAK733 ((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3d]pyrimidine-4,7(3H,8H)-dione), MEK162/ARRY438162 (5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-methylamine), R05126766 (3-[[3-fluoro-2-(methylaminosulfonylmethane)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxy-2-one), WX-554, R04987655/CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-sideoxy-1,2-oxazolidone-2-yl)methyl)benzamide) or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-sideoxy-1,6-dihydropyridine-3-methylamine).

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

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

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, 17-N-Allylamino-17-demethoxygeldanamycin) and radicicol. In certain embodiments, the compounds described herein are administered in combination with letrozole and/or tamoxifen. Other chemotherapeutic agents that may be used in combination with the compounds described herein include (but are not limited to) chemotherapeutic agents that do not require cell cycle activity for their anti-excessive effect.

Additional bioactive compounds include, for example, everolimus, trabectedin, TLK 286, AV-299, DN-101, parzopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, and AZD. 1152, Enzatolin, Vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitor, VEGFR inhibitor, Olora kinase inhibitor, PIK-1 regulator, HDAC inhibitor, c-MET inhibitor, PARP inhibitor, Cdk inhibitor, IGFR-TK inhibitor, anti-HGF antibody, focal adhesion kinase inhibitor, Map kinase (mek) inhibitor, VEGF interception antibody, pemetrexed, panitumumab, amrubicin, ozovozab (oregovomab), Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, cottonseed oil, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, Cilengitide, Gematometra, IL13-PE38QQR, INO 1001, IPdR ₁ KRX-0402, Amethionone, LY317615, Neuradiab, Vitespan, Rta 744, Sdx 102, Talampanel, Atrasentan, Xr 311, Romidesin, ADS-100380, Sunitinib, 5-Fluorouracil, Vorinostat, Etoposide, Gemcitabine, Cranberry, Lipid Cranberry, 5'-Deoxy-5-Fluorouracil, Vincristine, Temozolomide, ZK-304709, Seliciclib; PD0325901, AZD-6244, Capecitabine, L-Phenylic Acid, N-[4-[2-(2-amino-4,7-dihydro-4-sideoxy-1H-pyrrolo[2] ,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258); 3-[5-(methylsulfonylopiperidinylmethyl)-indolyl-quinolinone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate Acetate), triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, medroxyprogesterone acetate, ranoxifene, bicalutamide, flutamide, nilutamide, medroxyprogesterone acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide Hydroxamic acid, valproic acid, trichomycin A, FK-228, SU11248, sorafenib, KRN951, aminoglutenin, annsacrine, anagrelide, L-aspartate aminotransferase, BCG vaccine, adriamycin, bleomycin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladrolidine, clodronate, cyproterone acetate, cytarabine, dacarbazine, actinomycin, donomethoxazole, diethylstilbestrol, epirubicin, fludara Betaine, flucortisone, flumethasone, flutamide, glibenclamide, gemcitabine, hydroxyurea, idarubicin, isocyclophosphamide, imatinib, leuprolide, levamisole, lomustine, methyldi(chloroethyl)amine, melphalan, 6-methylpurine, messodium, methamidophos, mitomycin, mitotane, mitotane Quinones, Nirutide, Octreotide, Oxaliplatin, Pamidronate, Pensistatin, Procarbazine, Porphenem, Procarbazine, Raltitrexed, Rituximab, Strazotocin, Teniposide, Testosterone, Thalidomide, Thioguanine, Thiotepa, Retinyl acid, Vindycin, 13-cis-retinoic acid, Phenylammonium mustard, Ureaplasma Pyrimidine mustard, estradiol, hexamethylmelamine, fluorouracil, 5-deoxyuridine, cytosine arabinoside, 6-pyridine, deoxymyotrophic lateral tincture, calcitriol, vararubicin, sclerosamine, vinblastine, vinorelbine, toponotecan, lasozin, marimasitol, COL-3, squalane, BMS-275291, squalane, endothelial growth factor, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitamin, traloxifen, idoxyfene, spironolactone, finasteride, cimetidine, trastuzumab, denosumab, interleukin-1, Gefitinib, Bortezomib, Paclitaxel, Paclitaxel without Cetyl alcohol polyoxyethylene ether, Docetaxel, Ebola B, BMS-247550, BMS-310705, Traloxifen, 4-Hydroxytamoxifen, Pipenoxifene, ERA-923, Arzoxifene, Fulvestrant, Acolbifene, Lasoxifene, Idoxifene, TSE-424, HMR-3339, ZK186619, Topotecan, PTK787/ZK 222584, VX-745, PD 184352, Rapamycin, 40-O-(2-Hydroxyethyl)-Rapamycin, Tamramolis, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, Wortmannin, ZM336372, L-779, 450, PEG-filgrastim, Dabepoetin, Erythropoietin, Granulocyte Colony-Stimulating Factor, Zolendronate, Presson, Cetuximab, Granulocyte-Macrophage Colony-Stimulating Factor Histrelin, pegylated interferon α-2a, interferon α-2a, pegylated interferon α-2b, interferon α-2b, azoxybin, PEG-L-aspartate, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, medroxyprogesterone acetate, immunoglobulin, nitrogen mustard, methylphenidate, ibritgumomab Tiuxetan), androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposome danomycin, Edwina-asparaginase, strontium 89, caspopitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide olazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, platelet-derived growth factor receptor α (PDGFR-α) antibody, epidotin alfa, afadabetapenem and mixtures thereof.

In one embodiment, an effective amount of the isolated compound 1 of pattern 1 described herein may be combined with a PARP inhibitor selected from niraparib tosylate monohydrate (Zejula), olaparib (Lynparza), rucaparib camsylate (Rubraca), and talazoparib.

In one embodiment, an effective amount of compound 1 (Figure 1) is administered in combination with an effective amount of nirapanib toluene sulfonate monohydrate (Zejula) for the treatment of abnormal tissues of the female reproductive system, including ovarian epithelial cancer or fallopian tube cancer.

In one embodiment, an effective amount of compound 1 (Figure 1) and an effective amount of nirapanib toluenesulfonate monohydrate (Zejula) are administered together for the treatment of peritoneal cancer.

In one embodiment, an effective amount of compound 1 ( schema 1) is administered in combination with an effective amount of olaparib (Lynparza) for the treatment of abnormal tissues of the female reproductive system, including breast cancer, ovarian cancer, ovarian epithelial cancer, or fallopian tube cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) is administered in combination with an effective amount of olaparib (Lynparza) for the treatment of BRAC1 or BRAC2 mutated breast cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) is administered in combination with an effective amount of olaparib (Lynparza) for the treatment of HER2- breast cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) is administered in combination with an effective amount of olaparib (Lynparza) for the treatment of peritoneal cancer.

In one embodiment, an effective amount of compound 1 (schema 1) and an effective amount of lucapani camphor sulfonate (Rubraca) are administered together for the treatment of abnormal tissues of the female reproductive system, including breast cancer, ovarian cancer, ovarian epithelial cancer, or fallopian tube cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of lucapanib camphor sulfonate (Rubraca) are administered together for the treatment of peritoneal cancer.

In one embodiment, an effective amount of compound 1 (schema 1) is administered in combination with an effective amount of lazopanib for the treatment of abnormal tissues of the female reproductive system, including breast cancer, ovarian cancer, ovarian epithelial cancer, or fallopian tube cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) is administered in combination with an effective amount of prazole for the treatment of BRAC1 or BRAC2 mutated breast cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of olarumab are administered in combination for the treatment of soft tissue sarcoma.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of savorinib are administered in combination for the treatment of adenocarcinoma.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of savorinib are administered in combination for the treatment of non-small cell lung cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of savorinib are administered in combination for the treatment of renal cell carcinoma.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of vesetib are administered together for the treatment of advanced breast cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of vesetib are administered together for the treatment of advanced breast cancer.

In one embodiment, an effective amount of the isolated compound 1 of pattern 1 described herein may be combined with a chemotherapy agent selected from, but not limited to, imatinib mesylate (Gleevac®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), trastuzumab (Herceptin®), pertuzumab (Perjeta™), lapatinib (Tykerb®), gefitinib (Iressa®), erlotinib (Tarceva®), cetuximab (Erbitux®), panitumumab (Vectibix®), vandetanib (Caprelsa®), and vemurafenib. (Zelboraf®), Vorinostat (Zolinza®), Romidepsin (Istodax®), Bexarotene (Tagretin®), Alitretinoin (Panretin®), Vesanoid®, Carfilizomib (Kyprolis™), Pralatrexate (Folotyn®), Avastin®, Ziv-aflibercept (Zaltrap®), Sorafenib (Nexavar®), Sunitinib (Sutent®), Votrient®, Regorafenib (Stivarga®), and Cabozantinib (Cometriq ^™ ).

In one embodiment, an effective amount of the isolated compound 1 of pattern 1 described herein may be combined with a CD4/6 inhibitor, including abemaciclib (Versenio), palbociclib (Ibrance), or trilacidine.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of abecili (Versenio) are administered together for the treatment of breast cancer.

In one embodiment, an effective amount of compound 1 (scheme 1) and an effective amount of abecitabine (Versenio) are administered in combination for the treatment of HR+ breast cancer and HER2- breast cancer.

In one embodiment, an effective amount of compound 1 (scheme 1) and an effective amount of ipramexilate (Ibrance) are administered together for the treatment of breast cancer.

In one embodiment, an effective amount of compound 1 (schema 1) and an effective amount of palbociclib (Ibrance) are administered in combination for the treatment of HR+ breast cancer and HER2- breast cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of ipramexilate (Ibrance) are administered together for the treatment of breast cancer.

In one embodiment, an effective amount of compound 1 (schema 1) and an effective amount of ipproxil (Ibrance) are administered in combination for the treatment of metastatic triple-negative breast cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of ipramexilate (Ibrance) are administered together for the treatment of small cell lung cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of cabozantinib S-maloate (Cometriq ^™ ) are administered in combination for the treatment of thyroid cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of cabozantinib S-cis-butenedioate (Cometriq ^™ ) are administered in combination for the treatment of renal cell carcinoma.

In one embodiment, an effective amount of compound 1 ( schema 1) is administered in combination with an effective amount of dasatinib (Sprycel) for the treatment of leukemia, including acute lymphoblastic leukemia or chronic myeloid leukemia.

In one embodiment, an effective amount of compound 1 (schema 1) is administered in combination with an effective amount of dasatinib (Sprycel) for the treatment of prostate cancer.

In one embodiment, an effective amount of compound 1 (Figure 1) is administered in combination with an effective amount of erlotinib (Tarceva®) for the treatment of prostate cancer.

In one embodiment, an effective amount of compound 1 (Figure 1) is administered in combination with an effective amount of gefitinib (Iressa®) for the treatment of prostate cancer.

In one embodiment, an effective amount of compound 1 ( schema 1) is administered in combination with an effective amount of imatinib mesylate (Gleevec) for the treatment of leukemia, including acute lymphoblastic leukemia, chronic eosinophilic leukemia, eosinophilic leukemia syndrome, or chronic myeloid leukemia.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of trastuzumab (Herceptin) are administered in combination for the treatment of adenocarcinoma.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of trastuzumab (Herceptin) are administered in combination for the treatment of breast cancer, including HER2+ breast cancer.

In one embodiment, an effective amount of compound 1 ( schema 1) is administered in combination with an effective amount of imatinib mesylate (Gleevec) for the treatment of tumors, including (but not limited to) fibrosarcoma protuberans and gastrointestinal stromal tumors.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of imatinib mesylate (Gleevec) are administered in combination for the treatment of myelodyplasia/myeloproliferative tumor.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of imatinib mesylate (Gleevec) are administered in combination for the treatment of systemic mastocytosis.

In one embodiment, an effective amount of compound 1 ( schema 1) is administered in combination with an effective amount of nilotinib (Tasigna) for the treatment of chronic myeloid leukemia, including Philadelphia chromosome-positive chronic myeloid leukemia (Ph+CML).

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of pazopanib hydrochloride (Votrient) are administered in combination for the treatment of renal cell carcinoma.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of pazopanib hydrochloride (Votrient) are administered in combination for the treatment of soft tissue sarcoma.

In one embodiment, an effective amount of compound 1 (pattern 1) is administered in combination with an effective amount of regorafenib (Stivarga) for the treatment of colorectal cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) is administered in combination with an effective amount of regorafenib (Stivarga) for the treatment of gastrointestinal stromal tumors.

In one embodiment, an effective amount of compound 1 (pattern 1) is administered in combination with an effective amount of regorafenib (Stivarga) for the treatment of hepatocellular carcinoma.

In one embodiment, an effective amount of compound 1 (schema 1) is administered in combination with an effective amount of sorafenib tosylate (Nexavar) for the treatment of cancers, including hepatocellular carcinoma or renal cell carcinoma.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of sunitinib malate (Sutent) are administered in combination for the treatment of gastrointestinal stromal tumors.

In one embodiment, an effective amount of compound 1 (schema 1) and an effective amount of sunitinib malate (Sutent) are administered in combination for the treatment of pancreatic cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of sunitinib malate (Sutent) are administered in combination for the treatment of renal cell carcinoma.

In one embodiment, an effective amount of compound 1 (scheme 1) is administered in combination with an effective amount of vemurafenib (Zelboraf) for the treatment of Erdheim-Chester disease.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of vemurafenib (Zelboraf) are administered in combination for the treatment of melanoma.

In some cases, the additional treatment is an anti-inflammatory agent, a chemotherapy agent, a radiation therapy adjunct, or an immunosuppressant.

Suitable chemotherapeutic agents include (but are not limited to) radioactive molecules and toxins also known as cytotoxins or cytotoxic agents, including any agent that is harmful to the survival of cells, drugs, and liposomes or other vesicles containing chemotherapeutic compounds. Commonly used anticancer drugs include: vincristine (Oncovin®) or lipoic vincristine (Marqibo®), daunomycin (daunomycin or Cerubidine®) or adriamycin®, cytarabine (cytosine arabinoside, ara-C or Cytosar®), L-aspartame (Elspar®) or PEG-L-aspartame (pegaspargase or Oncaspar®), etoposide (VP-16), teniposide (Vumon®), 6-phenylpurine (6-MP or Purinethol®), methotrexate, cyclophosphamide (Cytoxan®), presbyron, dexamethasone (Decadron), and imatinib. (Gleevec®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), and ponatinib (Iclusig™). Examples of additional suitable chemotherapy agents include (but are not limited to) 1-dehydrotestosterone, 5-fluorouracil, dacarbazine, 6-purine, 6-thioguanine, actinomycin D, adenomycin, aldesleukin, alkylating agents, allopurinol sodium, hexamethylmelamine, amifostine, anastrozole, anthramycin (AMC), antimitotic agents, cis-dichlorodiamine platinum(II) (DDP) (cis-platinum), diamine dichloroplatinum, anthracycline, antibiotics, antimetabolites, aspartate aminotransferase, and BCG for injection. Live (intrabladder), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, calcium leucouorin, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), chlorambucil, cisplatin, cladrin, colchicine, conjugated estrogen, cyclophosphamide, cyclothosphamide, cytarabine, cytochalasin B, cytoxan, dacarbazine, actinomycin D, actinomycin D (Formerly actinomycin), daunirubicin HCl, daunorucbicin citrate, dinitroleukin, dexrazoxane, dibromomannitol, dihydroxyanthracin dione, docetaxel, dolasidium mesylate, cranberry HCl, dronabinol, E. coli L-asparaginase, emetine, epperine-α, Erwinia L-asparaginase, esterified estrogen, estradiol, sodium estradiol phosphate, ethidium bromide, ethinyl estradiol estradiol), etidronate, etoposide citrororum factor, etoposide phosphate, filgrastim, fluorouridine, fluconazole, fludarabine phosphate, fluorouracil, flutamide, folate, gemcitabine HCl, glucocorticoids, goserelin acetate, gramicidin D, granisequinone HCl, hydroxyurea, adapalene HCl, isocyclophosphamide, interferon α-2b, irinotecan HCl, letrozole, leucovorin calcium), leuprolide acetate, levamisole HCl, lidocaine, lomustine, maytansinoid, methyldichloroethylamine HCl, medroxyprogesterone acetate, megestrol acetate, melphalan HCl, mecaptipurine, messodium, methyltestosterone, methyltestosterone, styramine, mitomycin C, mitotane, mitoxantrone, nirumide, octreotide acetate, ondansetron HCl, paclitaxel, disodium pamidronate, pentostatin, pirocarpine HCl, plimycin, polifeprosan 20 with carmustine implant Implant), porfimer sodium, procaine, procarbazine HCl, propranolol, rituximab, sargramostim, streptozotocin, tamoxifen, taxol, teniposide, testrolide, tetracaine, thioepa chlorambucil, thioguanine, thiotepa, toremifene citrate, trastuzumab, retinoic acid, valrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.

In one embodiment, an effective amount of compound 1 (Figure 1) is administered in combination with an effective amount of bosutinib (Bosulif®) for the treatment of chronic myeloid leukemia (CML).

In one embodiment, an effective amount of compound 1 (schema 1) is administered in combination with an effective amount of ponatinib hydrochloride (Iclusig) for the treatment of leukemia, including acute lymphoblastic leukemia or chronic myeloid leukemia.

Other treatments that can be administered in combination with the compounds disclosed herein may include bevacizumab, sutinib, sorafenib, 2-methoxyestradiol or 2ME2, finasunate, vatalani, vandetanib, aflibercept, volociximab, and etaracizumab. (MEDI-522), Cirungiline, Erlotinib, Cetuximab, Panitumumab, Gefitinib, Trastuzumab, Dovitinib, Figizumab, Atacicept, Rituximab, Aldesleukine, Atlizumab, Tocilizumab, Tamramolis, Everolis, Lucatumumab, Dacetuzumab, HLL1, HuN901-DM1, Atiprimadone, Natalizumab, Bortezomib, Carfilzomib, Marizomib, Tanespimycin, Saquinavir Mesylate mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate sulfate), belinostat, panobinostat, mapatumumab, lexatumumab, dulanermin, ABT-737, olimerson, plitidepsin, talmapimod, P276-00, enzastaurin, tepifenabine, perifolfen, imatinib, dasatinib, lenalidomide, tharidomide, simvastatin, celecoxib, bardoxifene, AZD4547, rilotumumab, oxaliplatin (Eloxatin), PD0332991, ribociclib (LEE011), amebaciclib. (LY2835219), HDM201, fulvestrant (Faslodex), exemestane (Aromasin), PIM447, ruxolitinib (INC424), BGJ398, necitumumab, pemetrexed (Alimta), and ramucirumab (IMC-1121B).

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of everolimus (Afinitor) are administered together for the treatment of breast cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of everolimus (Afinitor) are administered in combination for the treatment of HR+ breast cancer and HER2- breast cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of everolimus (Afinitor) are administered in combination for the treatment of pancreatic cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of everolimus (Afinitor) are administered in combination for the treatment of gastrointestinal cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of everolimus (Afinitor) are administered together for the treatment of lung cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of everolimus (Afinitor) are administered in combination for the treatment of renal cell carcinoma.

In one embodiment, an effective amount of compound 1 (pattern 1) is administered in combination with an effective amount of everolimus (Afinitor) for the treatment of astrocytomas, including subependymal giant cell astrocytomas.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of fulvestrant (Faslodex) are administered in combination for the treatment of breast cancer.

In one embodiment, an effective amount of compound 1 (schema 1) and an effective amount of fulvestrant (Faslodex) are administered in combination for the treatment of HR+ breast cancer and HER2- breast cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of ramorumab are administered in combination for the treatment of adenocarcinoma.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of ramorumab are administered in combination for the treatment of non-small cell lung cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of ramorumab are administered in combination for the treatment of colorectal cancer.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of libocili (Kisqali) are administered in combination for the treatment of breast cancer.

In one embodiment, an effective amount of compound 1 (schema 1) is administered in combination with an effective amount of libocitric acid (Kisqali) for the treatment of HR+ breast cancer and HER2- breast cancer.

In some embodiments of the present invention, the compounds described herein may be combined with at least one IDH1 or IDH2 inhibitor. In one embodiment, an effective amount of compound 1 (Figure 1) is administered in combination with an effective amount of edhifa mesylate for the treatment of acute myeloid leukemia.

In some embodiments of the present invention, the compounds described herein may be combined with at least one fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor. In one embodiment, an effective amount of compound 1 (Figure 1) is administered in combination with an effective amount of erdatinib for the treatment of urothelial carcinoma, including metastatic urothelial carcinoma.

In some embodiments of the present invention, the compounds described herein may be combined with at least one ERK inhibitor.

In one embodiment, an effective amount of compound 1 (schema 1) and an effective amount of SCH772984 are administered together for the treatment of melanoma, including BRAF-mutant melanoma or NRAS-mutant melanoma.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of uritinib are administered together for the treatment of melanoma, including uveal melanoma.

In one embodiment, an effective amount of compound 1 (pattern 1) and an effective amount of uritinib are administered in combination for the treatment of pancreatic cancer.

In certain embodiments of the present invention, the compounds described herein may be combined with at least one immunosuppressant. The immunosuppressant is preferably selected from the group consisting of: calcineurin inhibitors, such as cyclosporin or ascomycin, such as cyclosporine A (NEORAL®), FK506 (tacrolimus), and pimecrolimus; mTOR inhibitors, such as rapamycin or its derivatives (e.g., sirolimus (RAPAMUNE®), everolimus (Certican®), tamsulosin, zotarolimus, biolimus-7, and biolimus-9); and rapalogs (e.g., sifomooxin, azathioprine, and campath 1H). 1H); S1P receptor modulators, such as fingolimod or its analogues, anti-IL-8 antibodies, mycophenolic acids or their salts (e.g., sodium salts) or their prodrugs, such as mycophenolate mofetil (CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), presbyron, ATGAM®, THYMOGLOBULIN®, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1, deoxyspergualin, tresperimus, leflunomide, ARAVA®, CTLAI-Ig, anti-CD25, anti-IL2R, basiliximab. SIMULECT®, Daclizumab (ZENAPAX®), mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, Elidel®), CTLA4lg (abatacept), belacept, LFA3lg, etanercept (sold through Immunex as Enbrel®), adalimumab (Humira®), infliximab (Remicade®), anti-LFA-1 antibody, natalizumab (Antegren®), Enlimomab, Gavilimomab, Antithymocyte Immunoglobulin, Siplizumab, Alefacept, Efaizumab, Pentasa, Mesalazine, Asacol, Codeine Phosphate, Benorylate, Fenbufen, Naprosyn, Diclofenac, Etodolac, Indomethacin, Aspirin, and Ibuprofen.

In some embodiments, the compound described herein is administered to the individual before, during, after, or in combination with another chemotherapeutic agent.

In some embodiments, an effective amount of isolated compound 1 (Figure 1) may be administered to an individual, allowing for the administration of other chemotherapeutic agents at higher doses (increased chemotherapeutic dose intensity) or more frequently (increased chemotherapeutic dose density). Dosage-intensive chemotherapy is a chemotherapy regimen in which drugs are administered for shorter periods between treatments compared to a standard chemotherapy regimen. Chemotherapy dose intensity refers to the amount of chemotherapy administered per unit time. Dosage intensity can be increased or decreased by varying the administered dose, the interval between administrations, or both.

In one embodiment of the present invention, the compounds described herein may be administered in synergistic regimens with another agent (such as a non-DNA-damage-targeting anti-excipient or a hematopoietic growth factor agent). Inappropriate administration of hematopoietic growth factors has recently been reported to have serious side effects. For example, the use of the EPO family of growth factors has been associated with arterial hypertension, cerebral spasm, hypertensive encephalopathy, thromboembolism, iron deficiency, flu-like syndrome, and venous thrombosis. The G-CSF family of growth factors has been associated with splenomegaly and rupture, respiratory distress syndrome, allergic reactions, and sickle cell complications. Therefore, in one embodiment, the compounds or methods described herein are used in combination with hematopoietic growth factors, including (but not limited to) granulocyte colony-stimulating factor (G-CSF, such as those sold as Neupogen (filgrastin), Neulasta (peg-filgrastin), or lenograstin), granulocyte-macrophage colony-stimulating factor (GM-CSF, such as those sold as molgramostim and sargramostim (Leukine), M-CSF (macrophage colony-stimulating factor), thrombopoietin (megakaryocytic growth factor (MGDF), such as those sold as Romiplostim and Eltrombopag), interleukin (IL)-12, interleukin-3, and interleukin-11. (Adipogenesis inhibitor or oprelvekin), SCF (stem factor, steel factor, mantle-ligand or KL) and erythropoietin (EPO) and its derivatives (e.g., epoetin-α is sold as Darbopoetin, Epocept, Nanokine, Epofit, Epogin, Eprex and Procrit; epoetin-β is sold as NeoRecormon, Recordon and Micera), epoetin-δ (sold as Dynepo), epoetin-Ω (sold as Epomax), epoetin-ζ (sold as Silapo and Reacrit) and e.g., 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 (Figure 1) is administered before the administration of the hematopoietic growth factor. In one embodiment, the administration of the hematopoietic growth factor is timed, allowing the compound's effect on HSPC to dissipate. In one embodiment, the growth factor is administered at least 20 hours after the administration of the compound described herein.

If necessary, multiple doses of the compound described herein may be administered to an individual. Alternatively, a single dose of the compound described herein may be administered to an individual.

In some embodiments of the invention, the compounds disclosed herein can be advantageously administered in combination with any treatment regimen requiring radiation therapy, chemotherapy, or other treatments. In additional embodiments, the compounds disclosed herein can be advantageously administered in combination with treatments targeting autoimmune diseases. Example 1. X - ray powder diffraction (XRPD)

XRPD analysis was performed on a PANalytical X'pert Pro, scanning the sample between 3° and 35° 2θ. The material was gently abraded to release any agglomerates and mounted on a porous disc supported by a Kapton or Mylar polymer film. The porous plate was then placed in a diffractometer and analyzed using Cu K radiation (α1λ = 1.54060 Å; α2 = 1.54443 Å; β = 1.39225 Å; α1:α2 ratio = 0.5) in transmission mode (step 0.0130° 2θ). The above techniques are used to generate the images in Figures 1, 7, 8 to 19, 21 to 32, 36, 38, 42, 43, 49 to 59, 61, 67 to 69 and 89.

Table 1 below provides a list of XRPD peaks for Pattern 1, which has a relative intensity peak >10%. The XRPD of Pattern 1 shows sharp peaks, indicating that the sample is composed of a crystalline material. Significant peaks were observed in the XRPD of Pattern 1 at approximately 9.6 ± 0.2°, approximately 12.2 ± 0.2°, approximately 15.3 ± 0.2°, approximately 17.6 ± 0.2°, approximately 19.3 ± 0.2°, approximately 19.8 ± 0.2°, approximately 21.3 ± 0.2°, approximately 22.7 ± 0.2°, approximately 24.0 ± 0.2°, approximately 26.1 ± 0.2°, and approximately 28.6 ± 0.2°. Table 1. List of XRPD Peaks for Pattern 1 Position [°2θ] Spacing [Å] Relative strength [%] 9.57 9.24 100.0 10.12 8.74 16.80 12.20 7.26 57.10 13.82 6.41 14.30 15.33 5.78 27.70 15.99 5.54 16.60 17.00 5.22 17.80 17.56 5.05 31.70 18.71 4.74 11.50 19.28 4.60 35.70 19.84 4.47 65.40 20.30 4.37 23.30 20.71 4.29 11.80 20.98 4.23 17.90 21.27 4.18 89.10 22.71 3.91 20.90 23.19 3.84 24.70 23.97 3.71 53.30 26.06 3.42 37.00 26.76 3.33 16.40 27.09 3.29 18.20 27.56 3.24 11.30 28.61 3.12 30.20 31.38 2.85 14.90 32.30 2.77 13.60 32.87 2.72 13.00

In some embodiments, the form is pattern 1 and is characterized in that the XRPD pattern includes at least two peaks selected from the following: approximately 9.6±0.2°, approximately 12.2±0.2°, approximately 15.3±0.2°, approximately 17.6±0.2°, approximately 19.3±0.2°, approximately 19.8±0.2°, approximately 21.2±0.2°, approximately 22.7±0.2°, approximately 23.9±0.2°, approximately 26.1±0.2° and approximately 28.6±0.2°.

In some embodiments, the form is pattern 1 and is characterized in that the XRPD pattern includes at least three peaks selected from the following: approximately 9.6±0.2°, approximately 12.2±0.2°, approximately 15.3±0.2°, approximately 17.6±0.2°, approximately 19.3±0.2°, approximately 19.8±0.2°, approximately 21.2±0.2°, approximately 22.7±0.2°, approximately 23.9±0.2°, approximately 26.1±0.2°, and approximately 28.6±0.2°.

In some embodiments, the form is pattern 1 and is characterized in that the XRPD pattern includes at least four peaks selected from the following: approximately 9.6±0.2°, approximately 12.2±0.2°, approximately 15.3±0.2°, approximately 17.6±0.2°, approximately 19.3±0.2°, approximately 19.8±0.2°, approximately 21.2±0.2°, approximately 22.7±0.2°, approximately 23.9±0.2°, approximately 26.1±0.2°, and approximately 28.6±0.2°.

In some embodiments, the form is pattern 1 and is characterized in that the XRPD pattern includes at least 5 peaks selected from the following: approximately 9.6±0.2°, approximately 12.2±0.2°, approximately 15.3±0.2°, approximately 17.6±0.2°, approximately 19.3±0.2°, approximately 19.8±0.2°, approximately 21.2±0.2°, approximately 22.7±0.2°, approximately 23.9±0.2°, approximately 26.1±0.2° and approximately 28.6±0.2°.

In some embodiments, the form is pattern 1 and is characterized in that the XRPD pattern includes at least 6 peaks selected from the following: approximately 9.6±0.2°, approximately 12.2±0.2°, approximately 15.3±0.2°, approximately 17.6±0.2°, approximately 19.3±0.2°, approximately 19.8±0.2°, approximately 21.2±0.2°, approximately 22.7±0.2°, approximately 23.9±0.2°, approximately 26.1±0.2° and approximately 28.6±0.2°.

In some embodiments, the form is pattern 1 and is characterized in that the XRPD pattern includes at least 7 peaks selected from the following: approximately 9.6±0.2°, approximately 12.2±0.2°, approximately 15.3±0.2°, approximately 17.6±0.2°, approximately 19.3±0.2°, approximately 19.8±0.2°, approximately 21.2±0.2°, approximately 22.7±0.2°, approximately 23.9±0.2°, approximately 26.1±0.2° and approximately 28.6±0.2°.

In some embodiments, the form is pattern 1 and is characterized in that the XRPD pattern includes at least 8 peaks selected from the following: approximately 9.6±0.2°, approximately 12.2±0.2°, approximately 15.3±0.2°, approximately 17.6±0.2°, approximately 19.3±0.2°, approximately 19.8±0.2°, approximately 21.2±0.2°, approximately 22.7±0.2°, approximately 23.9±0.2°, approximately 26.1±0.2° and approximately 28.6±0.2°.

In some embodiments, the form is pattern 1 and is characterized in that the XRPD pattern includes at least 9 peaks selected from the following: approximately 9.6±0.2°, approximately 12.2±0.2°, approximately 15.3±0.2°, approximately 17.6±0.2°, approximately 19.3±0.2°, approximately 19.8±0.2°, approximately 21.2±0.2°, approximately 22.7±0.2°, approximately 23.9±0.2°, approximately 26.1±0.2° and approximately 28.6±0.2°.

In some embodiments, the form is pattern 1 and is characterized in that the XRPD pattern includes at least 10 peaks selected from the following: approximately 9.6±0.2°, approximately 12.2±0.2°, approximately 15.3±0.2°, approximately 17.6±0.2°, approximately 19.3±0.2°, approximately 19.8±0.2°, approximately 21.2±0.2°, approximately 22.7±0.2°, approximately 23.9±0.2°, approximately 26.1±0.2° and approximately 28.6±0.2°.

In some embodiments, the form is pattern 1 and is characterized in that the XRPD pattern includes 2θ values selected from the following: approximately 9.6 ± 0.2°, approximately 12.2 ± 0.2°, approximately 15.3 ± 0.2°, approximately 17.6 ± 0.2°, approximately 19.3 ± 0.2°, approximately 19.8 ± 0.2°, approximately 21.2 ± 0.2°, approximately 22.7 ± 0.2°, approximately 23.9 ± 0.2°, approximately 26.1 ± 0.2°, and approximately 28.6 ± 0.2°.

Table 2 below provides the XRPD results for Figure 2. The XRPD peaks indicate that the sample is composed of crystalline material. Significant peaks were observed in the XRPD of Figure 2 at 6.7±0.2°, 11.1±0.2°, 16.3±0.2°, 17.2±0.2°, 18.2±0.2°, 19.8±0.2°, 20.4±0.2°, 20.6±0.2°, 26.4±0.2°, and 27.3±0.2°. Table 2. XRPD peaks of Figure 2. Position [°2θ] Spacing [Å] Relative strength [%] 6.77 13.050 100 11.15 7.933 58.67 14.06 6.300 14.44 14.77 5.996 24.21 15.08 5.875 19.26 16.29 5.442 63.87 16.96 5.227 26.73 17.24 5.144 36.62 18.19 4.878 39.51 19.81 4.482 36.17 20.42 4.350 33.11 20.64 4.303 31.36 21.55 4.125 23.41 22.72 3.914 22.54 23.11 3.849 28.74 24.90 3.576 16.55 25.55 3.486 14.30 26.41 3.375 99.54 27.28 3.269 49.45 28.46 3.137 27.85 30.35 2.945 10.69

In some embodiments, the form is pattern 2 and is characterized in that the XRPD pattern includes at least two peaks selected from the following: 6.7±0.2°, 11.1±0.2°, 16.3±0.2°, 17.2±0.2°, 18.2±0.2°, 19.8±0.2°, 20.4±0.2°, 20.6±0.2°, 26.4±0.2° and 27.3±0.2°.

In some embodiments, the form is pattern 2 and is characterized in that the XRPD pattern includes at least three peaks selected from the following: 6.7±0.2°, 11.1±0.2°, 16.3±0.2°, 17.2±0.2°, 18.2±0.2°, 19.8±0.2°, 20.4±0.2°, 20.6±0.2°, 26.4±0.2° and 27.3±0.2°.

In some embodiments, the form is pattern 2 and is characterized in that the XRPD pattern includes at least four peaks selected from the following: 6.7±0.2°, 11.1±0.2°, 16.3±0.2°, 17.2±0.2°, 18.2±0.2°, 19.8±0.2°, 20.4±0.2°, 20.6±0.2°, 26.4±0.2° and 27.3±0.2°.

In some embodiments, the form is pattern 2 and is characterized in that the XRPD pattern includes at least 5 peaks selected from the following: 6.7±0.2°, 11.1±0.2°, 16.3±0.2°, 17.2±0.2°, 18.2±0.2°, 19.8±0.2°, 20.4±0.2°, 20.6±0.2°, 26.4±0.2° and 27.3±0.2°.

In some embodiments, the form is pattern 2 and is characterized in that the XRPD pattern includes at least 6 peaks selected from the following: 6.7±0.2°, 11.1±0.2°, 16.3±0.2°, 17.2±0.2°, 18.2±0.2°, 19.8±0.2°, 20.4±0.2°, 20.6±0.2°, 26.4±0.2° and 27.3±0.2°.

In some embodiments, the form is pattern 2 and is characterized in that the XRPD pattern contains at least 7 peaks selected from the following: 6.7±0.2°, 11.1±0.2°, 16.3±0.2°, 17.2±0.2°, 18.2±0.2°, 19.8±0.2°, 20.4±0.2°, 20.6±0.2°, 26.4±0.2° and 27.3±0.2°.

In some embodiments, the form is pattern 2 and is characterized in that the XRPD pattern contains at least 8 peaks selected from the following: 6.7±0.2°, 11.1±0.2°, 16.3±0.2°, 17.2±0.2°, 18.2±0.2°, 19.8±0.2°, 20.4±0.2°, 20.6±0.2°, 26.4±0.2° and 27.3±0.2°.

In some embodiments, the form is pattern 2 and is characterized in that the XRPD pattern contains at least 9 peaks selected from the following: 6.7±0.2°, 11.1±0.2°, 16.3±0.2°, 17.2±0.2°, 18.2±0.2°, 19.8±0.2°, 20.4±0.2°, 20.6±0.2°, 26.4±0.2° and 27.3±0.2°.

In some embodiments, the form is pattern 2, characterized in that the XRPD pattern includes 2θ values selected from the following: 6.7±0.2°, 11.1±0.2°, 16.3±0.2°, 17.2±0.2°, 18.2±0.2°, 19.8±0.2°, 20.4±0.2°, 20.6±0.2°, 26.4±0.2°, and 27.3±0.2°.

Table 4 below provides the XRPD results for Figure 5. Significant peaks were observed at 6.3±0.2°, 6.8±0.2°, 8.1±0.2°, 11.2±0.2°, 16.2±0.2°, 26.5±0.2°, 27.4±0.2°, 27.8±0.2°, and 28.6±0.2° in the XRPD of Figure 5.

Table 3 below provides the XRPD results of a scaled-up analysis of Figure 3. The XRPD peaks indicate that the sample is composed of crystalline material. Significant peaks were observed in the scaled-up XRPD of Figure 3 at approximately 8.1 ± 0.2°, 14.8 ± 0.2°, 16.5 ± 0.2°, 18.2 ± 0.2°, 19.7 ± 0.2°, 24.8 ± 0.2°, 25.6 ± 0.2°, and 27.7 ± 0.2°. Table 3. XRPD peaks of Figure 3. Position [°2θ] Spacing [Å] Relative strength [%] 8.12 10.885 100 16.50 5.371 59.88 24.84 3.584 40.08 14.80 5.986 37.36 18.16 4.884 33.40 27.72 3.218 31.65 25.56 3.485 28.53 19.74 4.497 27.61 17.13 5.177 27.38 12.99 6.817 26.27 15.98 5.548 25.23 22.20 4.005 21.04 26.76 3.331 19.56 24.30 3.662 19.00 31.30 2.858 18.31 5.13 17.212 17.64 29.87 2.992 13.67 33.15 2.703 11.17 29.06 3.073 10.28

In some embodiments, the form is pattern 3, characterized in that the XRPD pattern includes at least two peaks selected from the following: 8.1±0.2°, 14.8±0.2°, 16.5±0.2°, 18.1±0.2°, 19.7±0.2°, 24.84±0.2° and 27.7±0.2°.

In some embodiments, the form is pattern 3, characterized in that the XRPD pattern includes at least three peaks selected from the following: 8.1±0.2°, 14.8±0.2°, 16.5±0.2°, 18.1±0.2°, 19.7±0.2°, 24.84±0.2° and 27.7±0.2°.

In some embodiments, the form is pattern 3, characterized in that the XRPD pattern includes at least four peaks selected from the following: 8.1±0.2°, 14.8±0.2°, 16.5±0.2°, 18.1±0.2°, 19.7±0.2°, 24.84±0.2° and 27.7±0.2°.

In some embodiments, the form is pattern 3, characterized in that the XRPD pattern includes at least 5 peaks selected from the following: 8.1±0.2°, 14.8±0.2°, 16.5±0.2°, 18.1±0.2°, 19.7±0.2°, 24.84±0.2° and 27.7±0.2°.

In some embodiments, the form is pattern 3, characterized in that the XRPD pattern includes at least 6 peaks selected from the following: 8.1±0.2°, 14.8±0.2°, 16.5±0.2°, 18.1±0.2°, 19.7±0.2°, 24.84±0.2° and 27.7±0.2°.

In some embodiments, the form is pattern 3, characterized in that the XRPD pattern includes 2θ values selected from the following: 8.1±0.2°, 14.8±0.2°, 16.5±0.2°, 18.1±0.2°, 19.7±0.2°, 24.84±0.2° and 27.7±0.2°.

Table 4 below provides the XRPD results for Pattern 4. The XRPD shows sharp peaks, indicating that the sample is composed of crystalline material. The table below shows the peaks with a relative intensity >10% for Pattern 4. Significant peaks were observed in the XRPD of Pattern 4 at approximately 6.3±0.2°, 6.8±0.2°, 8.1±0.2°, 11.2±0.2°, 16.2±0.2°, 26.5±0.2°, 27.4±0.2°, 27.8±0.2°, and 28.6±0.2°. Table 4. XRPD peaks of Pattern 4. Position [°2θ] Spacing [Å] Relative strength [%] 6.36 13.896 35.99 6.79 13.009 95.80 8.11 10.903 41.76 11.21 7.892 49.51 13.59 6.518 13.93 14.12 6.274 16.30 14.87 5.960 23.31 15.16 5.843 23.61 16.24 5.457 70.61 17:30 5.125 31.55 18.27 4.855 36.30 18.98 4.677 17.47 19.89 4.464 28.00 20.49 4.334 26.21 20.72 4.288 27.97 21.65 4.105 17.94 22.82 3.897 17.26 23.21 3.833 24.78 24.76 3.595 19.75 25.63 3.476 17.12 26.53 3.360 100 27.41 3.254 56.04 27.85 3.203 37.88 28.61 3.120 41.94 29.39 3.039 12.96 30.02 2.977 13.48 30.42 2.939 16.39 31.42 2.847 10.75 32.50 2.755 13.49 33.07 2.709 12.96

In some embodiments, the form is pattern 5 and is characterized in that the XRPD pattern includes at least two peaks selected from the following: 6.3±0.2°, 6.8±0.2°, 8.1±0.2°, 11.2±0.2°, 16.2±0.2°, 26.5±0.2°, 27.4±0.2°, 27.8±0.2° and 28.6±0.2°.

In some embodiments, the form is pattern 5 and is characterized in that the XRPD pattern includes at least three peaks selected from the following: 6.3±0.2°, 6.8±0.2°, 8.1±0.2°, 11.2±0.2°, 16.2±0.2°, 26.5±0.2°, 27.4±0.2°, 27.8±0.2° and 28.6±0.2°.

In some embodiments, the form is pattern 5 and is characterized in that the XRPD pattern includes at least four peaks selected from the following: 6.3±0.2°, 6.8±0.2°, 8.1±0.2°, 11.2±0.2°, 16.2±0.2°, 26.5±0.2°, 27.4±0.2°, 27.8±0.2° and 28.6±0.2°.

In some embodiments, the form is pattern 5 and is characterized in that the XRPD pattern contains at least 5 peaks selected from the following: 6.3±0.2°, 6.8±0.2°, 8.1±0.2°, 11.2±0.2°, 16.2±0.2°, 26.5±0.2°, 27.4±0.2°, 27.8±0.2° and 28.6±0.2°.

In some embodiments, the form is pattern 5 and is characterized in that the XRPD pattern contains at least 6 peaks selected from the following: 6.3±0.2°, 6.8±0.2°, 8.1±0.2°, 11.2±0.2°, 16.2±0.2°, 26.5±0.2°, 27.4±0.2°, 27.8±0.2° and 28.6±0.2°.

In some embodiments, the form is pattern 5 and is characterized in that the XRPD pattern contains at least 7 peaks selected from the following: 6.3±0.2°, 6.8±0.2°, 8.1±0.2°, 11.2±0.2°, 16.2±0.2°, 26.5±0.2°, 27.4±0.2°, 27.8±0.2° and 28.6±0.2°.

In some embodiments, the form is pattern 5 and is characterized in that the XRPD pattern contains at least 8 peaks selected from the following: 6.3±0.2°, 6.8±0.2°, 8.1±0.2°, 11.2±0.2°, 16.2±0.2°, 26.5±0.2°, 27.4±0.2°, 27.8±0.2° and 28.6±0.2°.

In some embodiments, the form is pattern 5 and is characterized in that the XRPD pattern includes 2θ values selected from the following: 6.3±0.2°, 6.8±0.2°, 8.1±0.2°, 11.2±0.2°, 16.2±0.2°, 26.5±0.2°, 27.4±0.2°, 27.8±0.2° and 28.6±0.2°.

Table 5 below provides the XRPD results for Pattern 6, which exhibits a sharp peak, indicating that the sample is composed of a crystalline material. The peaks in the table below are selected from those with a relative intensity >10% for Pattern 6. Significant peaks were observed in the XRPD of Pattern 6 at approximately 6.7 ± 0.2°, 11.1 ± 0.2°, 16.26 ± 0.2°, 26.3 ± 0.2°, and 27.2 ± 0.2°. Table 5. Scale-up XRPD peaks for Pattern 6. Position [°2θ] Spacing [Å] Relative strength [%] 6.77 13.051 100 9.54 9.273 15.73 11.15 7.938 55.43 14.74 6.012 12.56 16.26 5.452 55.44 16.94 5.234 21.60 17.23 5.146 32.11 18.16 4.885 33.45 19.78 4.490 33.56 20.39 4.355 24.11 20.62 4.308 23.52 21.20 4.192 18.54 21.51 4.131 14.66 22.68 3.920 14.28 23.08 3.853 27.52 23.91 3.721 12.10 24.85 3.582 11.69 26.02 3.424 20.04 26.36 3.381 83.70 27.26 3.271 42.92 28.43 3.140 27.55

In some embodiments, the morphology is pattern 6 and is characterized in that the XRPD pattern contains at least two peaks selected from the following: 6.7±0.2°, 11.1±0.2°, 16.26±0.2°, 26.3±0.2° and 27.2±0.2°.

In some embodiments, the morphology is pattern 6 and is characterized in that the XRPD pattern contains at least three peaks selected from the following: 6.7±0.2°, 11.1±0.2°, 16.26±0.2°, 26.3±0.2° and 27.2±0.2°.

In some embodiments, the morphology is pattern 6 and is characterized in that the XRPD pattern contains at least four peaks selected from the following: 6.7±0.2°, 11.1±0.2°, 16.26±0.2°, 26.3±0.2° and 27.2±0.2°.

In some embodiments, the form is pattern 6 and is characterized in that the XRPD pattern includes 2θ values selected from the following: 6.7±0.2°, 11.1±0.2°, 16.26±0.2°, 26.3±0.2° and 27.2±0.2°.

Example 2. Using general techniques of gravity vapor adsorption (GVS) , approximately 10 to 20 mg of sample was placed in the mesh tray of a gas phase adsorption balance and loaded into a Hiden Analytical IGASorp moisture adsorption analyzer. The sample was subjected to a slow temperature increase profile from 40 to 90% relative humidity (RH) in 10% increments, maintaining the sample at 25°C until a stable weight was obtained in each step (98% of steps completed, minimum step 30 min, maximum step 60 min). After the adsorption cycle was completed, the sample was dried to 0% RH using the same procedure, and finally restored to a starting point of 40% RH. Three cycles were performed. The hygroscopic properties of the sample were determined by plotting the weight changes during the adsorption/desorption cycles. The above techniques are used to generate the images in Figures 40 and 41.

Table 6 below provides the list of GVS data for Figure 1, showing the difference in water vapor absorption between the adsorption and desorption isotherms. The hygroscopic properties of the sample are determined by plotting the weight changes during the adsorption/desorption cycles. Table 6. List of GVS data for Figure 1 Target (RH (%)) Quality change (%) - ref Adsorption Desorption Cycle 1 0 0.180 10 2.320 20 2.820 30 3.110 40 3.420 3.340 50 3.560 3.580 60 3.720 3.730 70 3.800 3.820 80 3.920 3.970 90 4.160 4.160 Cycle 2 0 0.180 0.000 10 2.300 2.240 20 2.770 2.680 30 3.030 3.020 40 3.290 3.260 50 3.470 3.500 60 3.660 3.670 70 3.780 3.780 80 3.900 3.890 90 4.080 4.080 Cycle 3 0.000 0.000 10.000 2.250 20,000 2.740 30,000 3.020 40,000 3.220

In some embodiments, the sample undergoes a slow temperature rise profile from 40 to 90% relative humidity (RH) in 10% increments.

In some embodiments, at least two adsorption cycles are performed.

In some embodiments, three adsorption cycles are performed.

Table 7 below provides the GVS data for the mixtures of Figures 2 and 6, showing the difference in water vapor absorption between the adsorption and desorption isotherms. The hygroscopic properties of the samples were determined by plotting the weight changes during the adsorption/desorption cycles. Table 7. GVS data for the mixtures of Figures 2 and 6 Target (RH (%)) Quality change (%) - ref Adsorption Desorption Cycle 1 0 0.000 10 3.118 20 3.734 30 4.148 40 4.737 4.497 50 5.420 4.806 60 7.044 5.181 70 6.346 5.653 80 6.770 6.343 90 7.898 7.898 Cycle 2 0 0.000 0.059 10 2.731 3.200 20 3.470 3.820 30 3.969 4.205 40 4.353 4.512 50 4.661 4.848 60 4.999 5.157 70 5.436 5.572 80 5.976 6.181 90 7.039 7.039 Cycle 3 0 0.059 10 2.708 20 3.502 30 4.027 40 4.335

In some embodiments, the sample undergoes a slow temperature rise profile from 40 to 90% relative humidity (RH) in 10% increments.

In some embodiments, at least two adsorption cycles are performed.

In some embodiments, three adsorption cycles are performed.

Example 3 : Dynamic Vapor Adsorption (DVS) Approximately 10 to 20 mg of sample was placed in the mesh tray of a gas phase adsorption balance and mounted on a DVS Intrinsic dynamic gas phase adsorption balance using Surface Measurement Systems. The sample was subjected to a slow temperature increase profile from 40 to 90% relative humidity (RH) in 10% increments, maintaining the sample at 25°C until a stable weight was obtained (dm/dt 0.004%, minimum step 30 min, maximum step 500 min). After the adsorption cycle was complete, the sample was dried to 0% RH using the same procedure and then restored to 40% RH using a second adsorption cycle. Two cycles were performed. The hygroscopic properties of the sample were determined by plotting the weight change during the adsorption/desorption cycles. XRPD analysis was then performed on any remaining solids. The above techniques were used to generate the images shown in Figures 5, 6, 47, and 48. Table 8 provides the results of the scaled-up list of DVS data for Figure 3. Target (RH (%)) Quality change (%) - ref Adsorption Desorption Delay Cycle 1 0 0.000 10 0.863 20 1.274 30 1.818 40 2.516 2.223 -0.292 50 2.780 2.491 -0.289 60 2.970 2.727 -0.242 70 3.115 2.940 -0.175 80 3.288 3.171 -0.117 90 3.555 3.555 Cycle 2 0 0.000 0.075 10 0.831 0.885 0.054 20 1.198 1.290 0.091 30 1.468 1.711 0.243 40 1.853 1.977 0.124 50 2.092 2.171 0.080 60 2.271 2.337 0.066 70 2.461 2.510 0.050 80 2.700 2.717 0.018 90 3.093 3.093 Cycle 3 0 0.075 10 0.861 20 1.198 30 1.443 40 1.757

The material exhibits hygroscopicity according to DVS, with a mass increase of approximately 4% at 90% RH. During desorption cycles, the material loses mass, possibly due to loss of surface water present in the sample and crystallization of amorphous components. The material adsorbs 2.5 wt% water at 40% RH, 3.1 wt% water at 60% RH, and 3.5 wt% water at 90% RH.

In some embodiments, at least two adsorption cycles are performed. In some embodiments, three adsorption cycles are performed.

Example 4. The XRPD analysis of the >5% relative intensity peaks in Figure 4 was performed on a PANalytical X'pert Pro, scanning the sample between 3° and 35° 2θ. The material was gently abraded to release any agglomerates and mounted on a porous disc supported by a Kapton or Mylar polymer film. The porous plate was then placed in a diffractometer and analyzed using a 40 kV/40 mA generator setting with Cu K radiation (α1λ = 1.54060 Å; α2 = 1.54443 Å; β = 1.39225 Å; α1:α2 ratio = 0.5) running in transmission mode (step 0.0130° 2θ). The images in Figures 13, 20, and 27 were produced using this technique.

Table 9 below provides the XRPD results for Figure 4, which exhibits sharp peaks, indicating that the sample is composed of a crystalline material. Significant peaks were observed at 6.1±0.2°, 15.0±0.2°, 27.5±0.2°, and 28.1±0.2° in the XRPD of Figure 4. Table 9. XRPD Peaks of Figure 4 Position [°2θ] Spacing [Å] Relative strength [%] 6.13 14.416 100 9.55 9.265 20.37 14.64 6.049 14.50 15.03 5.896 21.29 17.84 4.971 12.89 18.44 4.811 12.04 20.24 4.387 6.94 21.25 4.181 10.22 21.97 4.046 5.55 25.73 3.462 6.79 26.42 3.374 6.40 27.55 3.238 29.60 28.15 3.170 29.11 29.61 3.017 6.00

In some embodiments, the morphology is pattern 4 and is characterized in that the XRPD pattern contains at least two peaks selected from the following: 6.1±0.2°, 15.0±0.2°, 27.5±0.2° and 28.1±0.2°.

In some embodiments, the form is pattern 4 and is characterized in that the XRPD pattern contains at least three peaks selected from the following: 6.1±0.2°, 15.0±0.2°, 27.5±0.2° and 28.1±0.2°.

In some embodiments, the form is pattern 4 and is characterized in that the XRPD pattern includes 2θ values selected from the following: 6.1±0.2°, 15.0±0.2°, 27.5±0.2° and 28.1±0.2°.

Example 5. PLM Imaging PLM imaging was performed in the presence of crystallinity (birefringence). PLM imaging was measured using an Olympus BX50 polarizing microscope equipped with a Motic camera and image capture software (Motic Images Plus 2.0). Unless otherwise stated, all images were recorded using a 20× objective. The images in Figures 2, 37, 44, 62, and 74 through 86 were produced using the above techniques.

Example 6 : Pyrogravimetric Analysis (TGA) Approximately 5 mg of material was weighed and placed in an open aluminum pan, loaded into a simultaneous pyrogravimetric/differential thermal analyzer (TG/DTA), and maintained at room temperature. The sample was then heated from 20°C to 300°C at a rate of 10°C/min. During this time, changes in sample weight and any differential thermal events (DTA) were recorded. Nitrogen gas at a flow rate of 300 ^cm³ /min was used as the purge gas. The images in Figures 3, 33, 34, 35, 38, 45, 63, 87, and 88 were generated using this technique.

Example 7 : Differential Scanning Calorimetry (DSC) Approximately 5 mg of material was weighed into a DSC aluminum pan and non-hermetically sealed with a puncture-type aluminum cap. The sample pan was then placed in a Seiko DSC6200 (equipped with a cooler) and cooled to 20°C. Once a stable heat flow was obtained, the sample and reference material were heated to 360°C at a scan rate of 10°C/min, and the resulting heat flow was monitored. Nitrogen gas with a flow rate of 50 ^cm³ /min was used as the purge gas. The images in Figures 4, 39, 46, 64, 65, and 66 were generated using this technique.

Example 8. Crystallization and Competitive Slurry Experiment: A competitive slurry experiment was conducted using approximately 10 mg of Pattern 1. Mixtures of Pattern 2/6 and Pattern 3 were weighed and added to a 1.5 mL glass bottle. Samples were prepared using 100 µL aliquots of solvent until a flowing slurry was formed. The samples were stirred at ambient temperature for 48 hours. A second set of samples was stirred at 60°C for 48 hours. All samples were collected, and the solids were separated and analyzed by XRPD. The images in Figures 50, 51, and 55-59 were generated using the above techniques. Table 10. Results and Observations of the Competitive Slurry Experiment. Sample Input materials solvent Solvent volume (μL) temperature Observation results XRPD format 1 1 + 2 + 3 EtOH 1000 environment Yellow paste 1 2 1 + 2 + 3 MEK 1000 environment Yellow paste 1 and trace amounts 2 3 1 + 2 + 3 2N HCl 1000 environment Yellow paste 1 4 1 + 2 + 3 IPA 1000 environment Yellow paste 1 and trace amounts 2 5 1 + 2 + 3 MeCN/Water (97:3 % v/v) 1000 environment Yellow paste 1 6 1 + 2 + 3 Acetone/water (85:15 % v/v) 1000 environment Yellow paste 1 7 1 + 2 + 3 EtOH 1000 60℃ Yellow paste 1 8 1 + 2 + 3 MEK 1000 60℃ Yellow paste A mixture of 1, 2 and 3 9 1 + 2 + 3 2N HCl 1000 60℃ Yellow paste 1 and trace amounts 2 10 1 + 2 + 3 IPA 1000 60℃ Yellow paste 1 and trace amounts 2 11 1 + 2 + 3 MeCN/Water (97:3 % v/v) 1000 60℃ Yellow paste 1 12 1 + 2 + 3 Acetone/water (85:15 % v/v) 1000 60℃ Yellow paste 1

Example 9. XRPD Analysis Following DVS Experiment XRPD analysis was performed on a PANalytical X'pert pro, scanning the sample between 3° and 35° 2θ. The material was gently abraded to release any agglomerates and mounted on a porous disc supported by a Kapton or Mylar polymer film. Subsequently, the porous plate was placed in a diffractometer and analyzed using Cu K radiation (α1λ = 1.54060 Å; α2 = 1.54443 Å; β = 1.39225 Å; α1:α2 ratio = 0.5) running in transmission mode (step 0.0130° 2θ).

The sample after DVS was analyzed using XRPD. After DVS, the sample was analyzed using XRPD to confirm any changes in the material. The above techniques were used to generate the images shown in Figures 7, 42, and 49.

Example 10. Stability Study After 1 Week: A stability study was conducted using approximately 10 mg of material. Two samples were prepared for XRPD and HPLC analysis. One sample set was capped and stored under ambient light, temperature, and humidity. Another sample set was capped and stored in an oven at 80°C. A third sample set (75%) was opened and stored in a desiccator containing sodium chloride solution at 40°C. After 7 days, the samples were collected and analyzed by XRPD and HPLC. The images in Figures 52, 53, and 54 were generated using these techniques.

Example 11. Solvent Solubility Systems: Solvent solubility experiments were conducted using various solvents provided in Tables 11, 12, and 13 to determine solid formation. Known volumes of aliquots of solvent (typically 5 volumes) were added to approximately 10 mg of amorphous compound 1 in dihydrochloride form. Between each addition, the mixture was checked for dissolution; if no significant dissolution was observed, the mixture was heated to approximately 40°C and checked again. This procedure was continued until dissolution was observed or until 100 volumes of solvent had been added. All observed solids were separated and analyzed by XRPD.

Examples of solvents include, but are not limited to, 1,4-diethane, methanol, ethanol, propanol, butanol, butanone, ethoxyethanol, trifluoroethanol, methyl-THF, acetone, acetonitrile, anisole, chlorobenzene, DMSO, DMF, cumene, dichloromethane, ethyl acetate, ethylene glycol, heptane, isopropyl acetate, nitromethane, n-methylpyrrolidone, MIBK, t-BME, tetrahydrofuran, toluene, water, and mixtures thereof. The above techniques are used to produce the images shown in Figures 8, 9, 10, 11, 12, and 14. Table 11. Approximate solubility results from solvent screening. Sample solvent Approximate solubility (mg/mL) 1 1,4-Dimethyl ether <5 2 1-Butanol <5 3 2,2,2-Trifluoroethanol >200 4 2-Butanone <5 5 2-Ethoxyethanol <5 6 2-MethylTHF <5 7 2-Propanol Approximately 5 8 acetone <5 9 Acetonitrile <5 10 Acetonitrile/water (90:10 % v/v) <5 11 aniline <5 12 chlorobenzene <5 13 DMSO Approximately 5 14 DMF <5 15 Isopropylbenzene Approximately 5 16 dichloromethane <5 17 ethanol Approximately 5 18 Ethanol/water (85:15 % v/v) <5 19 Ethyl acetate <5 20 Ethylene glycol 50 twenty one heptane <5 twenty two Isopropyl acetate <5 twenty three methanol Approximately 5 twenty four Methanol/water (95:5 % v/v) 20 25 Nitromethane 33 26 N-methylpyrrolidone <5 27 Methyl isobutyl ketone <5 28 Tertiary butyl methyl ether <5 29 Tetrahydrofuran <5 30 Tetrahydrofuran/water (99:1 % v/v) <5 31 Toluene <5 32 Deionized water >200 Table 12. XRPD results from solvent solubility screening Sample solvent XRPD 1 1,4-Dimethyl ether Pattern 1 2 1-Butanol Pattern 2 3 2,2,2-Trifluoroethanol Pattern 3 4 2-Butanone Pattern 2 5 2-Ethoxyethanol Pattern 2 6 2-MethylTHF Pattern 2 7 2-Propanol Pattern 2 8 acetone Pattern 5 9 Acetonitrile Pattern 4 10 Acetonitrile/water (90:10 % v/v) Pattern 1 11 aniline Pattern 6 12 chlorobenzene Amorphous 13 DMSO Amorphous 14 DMF Amorphous 15 Isopropylbenzene Pattern 2 16 dichloromethane Pattern 1 17 ethanol Pattern 1 18 Ethanol/water (85:15 % v/v) Pattern 1 19 Ethyl acetate Pattern 2 20 Ethylene glycol Non-solid twenty one heptane Pattern 3 twenty two Isopropyl acetate Pattern 2 twenty three methanol Pattern 1 twenty four Methanol/water (95:5 % v/v) Pattern 1 25 Nitromethane Pattern 1 26 N-methylpyrrolidone Pattern 2 27 Methyl isobutyl ketone Pattern 2 28 Tertiary butyl methyl ether Pattern 5 29 Tetrahydrofuran Pattern 1 30 Tetrahydrofuran/water (99:1 % v/v) Pattern 1 31 Toluene Pattern 2 32 water Non-solid

After removing the initial solids, the dissolved sample was opened and allowed to evaporate. This produced the diffraction patterns shown in Figures 30 and 31. Table 13. Observational results from the evaporation experiment. Sample Solvent system Observation results after evaporation 1 1,4-Dimethyl ether Non-solid 2 Acetone/water (20:80 % v/v) yellow solid 3 2,2,2-Trifluoroethanol yellow solid 4 2-Butanone Non-solid 5 2-Propanol Non-solid 6 acetone Non-solid 7 Acetonitrile Non-solid 8 Acetonitrile/water (90:10 % v/v) Non-solid 9 dichloromethane Non-solid 10 ethanol A small amount of yellow solid 11 Ethanol/water (85:15 % v/v) A small amount of yellow solid 12 Ethyl acetate Non-solid 13 heptane Non-solid 14 Isopropyl acetate Non-solid 15 methanol Non-solid 16 Methanol/water (95:5 % v/v) A small amount of yellow solid 17 2N HCl Non-solid 18 Methyl isobutyl ketone Non-solid 19 Tertiary butyl methyl ether Non-solid 20 Tetrahydrofuran Non-solid twenty one Toluene Non-solid

Example 12. Reverse Solvent Addition Experiment The reverse solvent addition experiment was conducted using a selected reverse solvent (e.g., t-BME) that separates each sample onto the material solution until precipitation was observed or 1 mL of reverse solvent was added. Samples were stored at approximately 5°C to promote precipitation, and any observed solids were collected and analyzed by XRPD, as provided in Tables 14 and 15. The material solution was prepared using the solvent system listed in Example 13. The above techniques were used to produce the image shown in Figure 32. Table 14. Observational Results from the Reverse Solvent Addition Experiment Sample Solvent system Anti-solvent Anti-solvent volume (μL) Observation results after adding AS 1 1,4-Dimethyl ether t-BME 1000 Clear colorless solution 2 Acetone/water (20:80 % v/v) t-BME 1000 Clear colorless solution 3 2,2,2-Trifluoroethanol t-BME 500 yellow solid 4 2-Butanone t-BME 1000 Clear colorless solution 5 2-Ethoxyethanol t-BME 1000 Clear colorless solution 6 2-Propanol t-BME 1000 Clear colorless solution 7 acetone t-BME 1000 Clear colorless solution 8 Acetonitrile t-BME 1000 Clear colorless solution 9 Acetonitrile/water (90:10 % v/v) t-BME 1000 Clear colorless solution 10 aniline t-BME 1000 Clear colorless solution 11 Isopropylbenzene t-BME 1000 Clear colorless solution 12 dichloromethane t-BME 1000 Clear colorless solution 13 ethanol t-BME 1000 Clear colorless solution 14 Ethanol/water (85:15 % v/v) t-BME 1000 Clear colorless solution 15 Ethyl acetate t-BME 1000 Clear colorless solution 16 heptane t-BME 1000 Clear colorless solution 17 Isopropyl acetate t-BME 1000 Clear colorless solution 18 methanol t-BME 1000 Clear colorless solution 19 Methanol/water (95:5 % v/v) t-BME 1000 Clear colorless solution 20 2N HCl t-BME 1000 Clear colorless solution twenty one Methyl isobutyl ketone t-BME 1000 Clear colorless solution twenty two Tertiary butyl methyl ether heptane 1000 Clear colorless solution twenty three Tetrahydrofuran t-BME 1000 Clear colorless solution twenty four Toluene t-BME 1000 Clear colorless solution Table 15. Solids observed from the anti-solvent addition experiment Sample Solvent system Anti-solvent XRPD 1 1,4-Dimethyl ether t-BME Non-solid 2 Acetone/water (20:80 % v/v) t-BME Non-solid 3 2,2,2-Trifluoroethanol t-BME Pattern 3 4 2-Butanone t-BME Non-solid 5 2-Ethoxyethanol t-BME Non-solid 6 2-Propanol t-BME Non-solid 7 acetone t-BME Non-solid 8 Acetonitrile t-BME Non-solid 9 Acetonitrile/water (90:10 % v/v) t-BME Non-solid 10 aniline t-BME Non-solid 11 Isopropylbenzene t-BME Non-solid 12 dichloromethane t-BME Non-solid 13 ethanol t-BME Non-solid 14 Ethanol/water (85:15 % v/v) t-BME Non-solid 15 Ethyl acetate t-BME Non-solid 16 heptane t-BME Non-solid 17 Isopropyl acetate t-BME Non-solid 18 methanol t-BME Non-solid 19 Methanol/water (95:5 % v/v) t-BME Non-solid 20 2N HCl t-BME Non-solid twenty one Methyl isobutyl ketone t-BME Non-solid twenty two Tertiary butyl methyl ether heptane Non-solid twenty three Tetrahydrofuran t-BME Non-solid twenty four Toluene t-BME Non-solid

Example 13. Scale-up of Figures 2 , 3 , and 5 : Figure 2 was scaled up to approximately 500 mg of amorphous compound 1 in the form of diHCl salt by adding 100 µL of MEK aliquots until a flowing slurry was formed. The slurry was then cyclically heated between ambient temperature and 40°C for approximately 72 hours. Samples were collected, and aliquots of the slurry were analyzed by XRPD. The solids were then separated and vacuum-dried at 40°C for approximately 4 hours. The resulting material was a mixture of Figures 2 and 6.

Figure 3 shows the scale-up process, where approximately 500 mg of amorphous compound 1 in the form of diHCl salt was added to aliquots of ethanol (100 µL each) until a flowing slurry was formed. The slurry was then cyclically cooled between ambient temperature and 40°C for approximately 72 hours. Samples were collected, and aliquots of the slurry were analyzed by XRPD. The solids were then separated and vacuum-dried at 40°C for approximately 4 hours.

Figure 5 shows the process of scaling up to approximately 500 mg of amorphous compound 1 in the form of diHCl salt by adding 100 µL of ethanol to an aliquot of the sample, until a flowing slurry was formed. The slurry was then cyclically heated between ambient temperature and 40°C for approximately 72 hours. Samples were collected, and aliquots of the slurry were analyzed by XRPD. The solid was then separated and vacuum-dried at 40°C for approximately 4 hours. The resulting material was then reslurried in 10 mL of methyl isobutyl ketone for 24 hours. Aliquots of the slurry were analyzed by XRPD. The solid was then separated and vacuum-dried at 40°C for approximately 4 hours. The dried material was analyzed by XRPD.

Example 14. pH Solubility and pH Solvent System : pH solubility experiments were conducted on solid pattern 7 at pH 2 to pH 13. A total of 12 vials containing 100 mg of pattern 7 and 500 µL of 66% DMSO:33% THF (% v/v) were used to prepare slurries. The initial pH of each slurry was measured using a pH meter. The pH of each vial was adjusted to the desired pH using aliquots of acetic acid or 1 M sodium hydroxide solution. If dissolution was observed at the selected pH, additional solid pattern 7 was added to the vial until the slurry was maintained or a maximum of 500 mg was added. The pH was then readjusted as needed. The recovered solids were determined to have high purity (area %), with most experiments yielding values of 99.5% and 99.4%. The purity values did not differ significantly across pH values, but the solids were derived from pH 4, with an area purity of 99.9%. Concentration analysis of the mother liquor showed that the concentration values generally decreased (i.e., solubility decreased) as the system pH increased. Sticky, highly viscous slurries were observed at pH 4 and pH 8. The above techniques were used to produce the diffraction patterns shown in Figures 67, 68, and 69.

Example 15. Crystallization in Group 1 : Small-scale crystallization experiments were conducted on Pattern 7 using Group 1 to determine the effect of altering the initial concentration of Pattern 7 in the DMSO/THF solvent systems provided in Tables 16 and 17. Several concentrations of Pattern 7 in DMSO/THF were prepared, with initial concentrations of 100, 150, and 200 mg/mL. Samples were prepared in a volume of 66% DMSO:33% THF (% v/v) and Pattern 7 (200 mg) was added at an appropriate initial concentration. Acetic acid (100 μL aliquots) was added to each sample at ambient temperature until dissolution was achieved. At each of the three concentrations, solid crystallization was achieved from solution by using a) a 1:1 equivalence ratio of acetic acid and alkali (1 M sodium hydroxide solution), or b) adjusting the final pH to 12 using 1 M sodium hydroxide solution. The pH of the solution was measured using a pH meter and adjusted to pH 12 using 1 M sodium hydroxide solution.

The sample group was stirred for approximately 18 hours at ambient temperature using an electromagnetic stirrer plate. After approximately 18 hours, stirring was stopped, and the supernatant was filtered using a 0.45 μm PVDF syringe and a syringe. The concentration of the supernatant was analyzed by HPLC. The remaining slurry in the vials was transferred to centrifuge tubes using a 0.22 μm nylon filter, and the solids were separated by centrifugation. For purity, the recovered solids were analyzed by XRPD, PLM, and HPLC. The images in Figures 70 and 71 were generated using the above techniques. Table 16. Group 1: pH 12 Initial free base mass (mg) Starting volume (DMSO:THF 66/33) mL) Initial concentration (mg/mL) Added acetic acid (mL) Add 1 M NaOH solution (mL) Final pH 200 2 100 2.4 39 12.26 200 1.3 150 1.8 33.5 12.13 200 1 200 1.2 twenty three 12.31 Table 17. Group 1: 1:1 acid to alkali ratio Initial volume (DMSO:THF 66/33) mL Initial concentration (mg/mL) Added acetic acid (mL) Acetic acid equivalent Add 1 M NaOH solution (mL) Final pH 2 100 2.4 94 42.1 12.42 1.3 150 1.8 70.5 31.6 12.22 1 200 1.2 47 twenty one 12.02

Example 16. Crystallization Group 2 conducted small-scale crystallization experiments on Figure 7, focusing on the optimal pH range of Figure 7, as provided in Table 18. The initial concentration of the crystallization experiments in Group 2 was reduced to 44 mg/mL and the final pH was also reduced from 12 to 7 in order to reduce the volume of alkali required.

Samples (1 and 2) were prepared by adding Figure 7 (200 mg), DMSO (3 mL), and THF (1.6 mL) to form slurries. The resulting slurries were heated to 70°C using a temperature control block. Acetic acid was added until dissolved. The experiment was maintained at 70°C for 1 hour. After 1 hour, Sample 1 was added to 100 μL aliquots of 1 M sodium hydroxide solution until the experiment reached pH 7. The experiment was then cooled from 70°C to 25°C at a rate of 0.25°C/min. Sample 2 solution was cooled from 70°C to 25°C at a rate of 0.25°C/min. Once the experiment reached 25°C, 1 M sodium hydroxide solution was added to 100 μL aliquots until the experiment reached pH 7. The two samples were stirred for approximately 18 hours at ambient temperature using an electromagnetic stirrer plate. After approximately 18 hours, stirring was stopped, and the supernatant was filtered using a 0.45 μm PVDF syringe and a syringe. The concentration of the supernatant was analyzed by HPLC. The remaining slurry from each sample was transferred to a 0.22 μM nylon centrifuge tube, and the solids were separated by centrifugation. The recovered solids were analyzed for purity by XRPD, PLM, and HPLC. The above techniques were used to produce the second and third diffraction patterns in Figure 72. Table 18. Group 2 small bottle Experiment FB mass (mg) Initial volume (DMSO:THF 66/33) Initial concentration (mg/mL) Added acetic acid (mL) Add 1 M sodium hydroxide solution (mL) Final pH 1 Add 1 M sodium hydroxide 200 4.57 44 2.85 mL 52.5 7.06 2 Add 1 M sodium hydroxide 200 4.57 44 2.85 mL 52.5 7.38

Example 17. Crystallization Group 3 : Small-scale crystallization experiments were conducted on Pattern 7 using Group 3 (see Table 19) to determine the inoculation effect, employing both cooling and isothermal processing. Samples (1 and 2) were prepared by adding Pattern 7 (200 mg) and 1 mL of 66% DMSO:33% THF (% v/v) to form a slurry. Acetic acid was added to 100 μL aliquots at ambient temperature until dissolution was observed. Sodium hydroxide solution (1 M) was added to 100 μL aliquots until pH reached pH 5. Subsequently, 4 mg (2%) of Pattern 7 inoculation solution was used, and the pH was further adjusted with 1 M sodium hydroxide solution until pH 7 was obtained. Sample 1 was stirred for approximately 18 hours at ambient temperature using an electromagnetic stirrer plate. Sample 2 was cooled at 5°C at 0.1°C/min and stirred for approximately 18 hours. After approximately 18 hours, stirring was stopped and the supernatant of each sample was filtered using a 0.45 μm PVDF syringe and a syringe. The concentration of the supernatant was analyzed by HPLC. The residual slurry from each sample was transferred to a 0.22 μM nylon filter centrifuge tube, and the solids were separated by centrifugation. The recovered solids were analyzed for purity by XRPD, PLM, and HPLC. The above techniques were used to produce diffraction patterns 3 and 4 in Figure 72. Table 19. Group 3 small bottle Experiment Initial concentration (mg/mL) Added acetic acid (mL) Add 1 M sodium hydroxide solution (mL) to achieve pH 5. pH Add 1 M sodium hydroxide solution (mL) to achieve pH 7. Final pH 1 Environmental mixing 200 1.3 18 5.07 5.7 7.18 2 Cool while stirring. 200 1.3 18 5.09 5.5 7.04

Example 18. Crystallization Group 4 : Small-scale crystallization was performed on Pattern 7 using higher concentrations (5M and 10M) of sodium hydroxide solution (see Table 20) to reduce the volume required to achieve the desired pH. Samples were prepared by adding 200 mg of Pattern 7 and 1 mL of 66% DMSO:33% THF (% v/v) at ambient temperature to form a slurry. Acetic acid was added to 100 μL aliquots at ambient temperature until dissolution was observed. Subsequently, sodium hydroxide solution (5 M) was added to 100 μL aliquots until the system pH reached pH 5. The inoculation solution (4 mg or 2%) was then used as shown in Figure 7, and the pH of the sample was adjusted to pH 7 by adding sodium hydroxide solution (NaOH); vial 1 contained 5 M NaOH and vial 2 contained 10 M NaOH. The sample was stirred for approximately 18 hours at ambient temperature using an electromagnetic stirrer plate. After approximately 18 hours, stirring was stopped, and any solids were separated by vacuum filtration using a Büchner funnel and Whatman Grade 1 filter paper. The recovered solids were analyzed for purity by XRPD, PLM, and HPLC, and the concentration of the supernatant was analyzed by HPLC. The above techniques were used to produce the diffraction pattern shown in Figure 73. Table 20. Group 4 small bottle Experiment Initial concentration (mg/mL) Added acetic acid (mL) Add sodium hydroxide solution (mL) to achieve pH 5. pH Add sodium hydroxide solution (mL) to achieve pH 7. Final pH 1 5 M sodium hydroxide 200 1.3 1.45 5 3.1 7.05 2 10 M sodium hydroxide 200 1.3 0.51 5 1.6 7.02

Example 19. Maturity Experiment : 100 μL aliquots of the selected solvent were added to 40 mg of amorphous material (Pattern 1) until a flowing slurry was formed, as provided in Tables 21 and 22. The slurry was cyclically heated between ambient temperature and 40°C for 72 hours. Samples were then collected, and the observed solids were separated and analyzed by XRPD.

The samples were then dried and reanalyzed using XRPD. For drying, the XRPD tray was placed in an oven at 40°C for approximately 4 hours, after which the dried samples were analyzed using XRPD. The diffraction patterns shown in Figures 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, and 29 were generated using this technique. Table 21 shows the observation results from the mature experiment. Sample Solvent system Solvent volume (μL) Initial observation results Observation results after maturity 1 1,4-Dimethyl ether 1000 Yellow paste Pale yellow paste 2 Acetone/water (20:80 % v/v) 500 Yellow paste Yellow paste 3 2,2,2-Trifluoroethanol 200 Yellow paste yellow solution 4 2-Butanone 1000 Yellow paste Yellow paste 5 2-Ethoxyethanol 1000 Pale yellow paste Yellow paste 6 2-Propanol 1000 Yellow paste Pale yellow paste 7 acetone 1300 Yellow paste Pale yellow paste 8 Acetonitrile 1300 Yellow paste Pale yellow paste 9 Acetonitrile/water (90:10 % v/v) 1000 Yellow paste Yellow paste 10 aniline 1200 Yellow paste Yellow paste 11 Isopropylbenzene 1200 Yellow paste Yellow paste 12 dichloromethane 700 Yellow paste Pale yellow paste 13 ethanol 700 Yellow paste Yellow paste 14 Ethanol/water (85:15 % v/v) 1300 Pale yellow paste Yellow paste 15 Ethyl acetate 1500 Pale yellow paste Yellow paste 16 heptane 1500 Yellow paste Yellow paste 17 Isopropyl acetate 400 Yellow paste Yellow paste 18 methanol 300 Pale yellow paste Yellow paste 19 Methanol/water (95:5 % v/v) 400 Pale yellow paste Yellow paste 20 2N HCl 1500 Pale yellow paste Yellow paste twenty one Methyl isobutyl ketone 1500 Yellow paste Yellow paste twenty two Tertiary butyl methyl ether 1500 Yellow paste Yellow paste twenty three Tetrahydrofuran 1500 Yellow paste Yellow paste twenty four Toluene 1500 Yellow paste Pale yellow paste Table 22. XRPD results after maturation experiments Sample Solvent system Mature XRPD XRPD after drying 1 1,4-Dimethyl ether Switch to 2 Switch to 2 2 Acetone/water (20:80 % v/v) Insufficient solids Insufficient solids 3 2,2,2-Trifluoroethanol Non-solid Non-solid 4 2-Butanone Pattern 2 Pattern 2 5 2-Ethoxyethanol Pattern 2 Pattern 2 6 2-Propanol Pattern 3 Pattern 3 7 acetone Pattern 2 Pattern 2 8 Acetonitrile Pattern 4 Pattern 2 9 Acetonitrile/water (90:10 % v/v) Pattern 1 Pattern 1 10 aniline Weak patterns 5. Has additional peaks 11 Isopropylbenzene Weak patterns 5. Has additional peaks 12 dichloromethane Pattern 2 Pattern 2 13 ethanol Figure 3 (Amorphous halogen) Pattern 3 14 Ethanol/water (85:15 % v/v) Pattern 1 (Highly Crystalline) Pattern 1 (Highly Crystalline) 15 Ethyl acetate Figure 2 (Amorphous halogen) Pattern 5 16 heptane Weak patterns Pattern 3 and Pattern 6 17 Isopropyl acetate Pattern 2 Pattern 2 18 methanol Pattern 1 (Highly Crystalline) Pattern 1 (Highly Crystalline) 19 Methanol/water (95:5 % v/v) Pattern 1 Pattern 1 20 2N HCl Pattern 1 Pattern 1 twenty one Methyl isobutyl ketone Pattern 5 Pattern 5 twenty two Tertiary butyl methyl ether Weak patterns Weak patterns twenty three Tetrahydrofuran Pattern 2 Pattern 2 twenty four Toluene Weak patterns Pattern 5

Example 20. Thermodynamic Solubility: Thermodynamic solubility of samples 1, 2/6 mixture, 3, amorphous diHCl salt, and 7 in water at pH 4.2 is shown in Table 23. All samples were prepared at 30 mg/mL. Initial observations were obtained. Samples were stirred at ambient temperature for approximately 24 hours. Samples were collected and observations were obtained. Solids observed by centrifugation were observed. The mother liquor from the filtered samples was analyzed by HPLC. A pH 4.3 solution was prepared by diluting glacial acetic acid (11.6 mL) to 100 mL in deionized water, followed by the addition of sodium acetate (1.07 g) and acetic acid solution (5.9 mL). A total of 500 mL solution was prepared with deionized water, and the pH was then adjusted to 4.2. The image shown in Figure 60 was generated using this technique. Table 23 shows the observations and results from the thermodynamic solubility experiment. Sample form Observation results at T=0 hours Observation results at T=24 hours 1 Pattern 1 Yellow paste yellow solution 2 Pattern 2/6 Yellow solution (dissolves upon addition) yellow solution 3 Pattern 3 Yellow solution (dissolves upon addition) yellow solution 4 Amorphous diHCl Yellow solution (dissolves upon addition) yellow solution 5 Pattern 7 grayish-white slurry grayish-white paste

Example 21. Overview of Crystallization Experiments on Compound 1 Free Alkali Material An overview of the experiments from Examples 17, 18, 19, and 20 is shown in Table 24 below. Table 24: Overview of Crystallization Conditions Group Experiment Initial concentration Alkali used Target pH for sedimentation Experimental Overview 1 1 100 1M 12 Add sodium hydroxide to pH 12 2 100 1M 12 Acid to base ratio of 1:1 3 150 1M 12 Add sodium hydroxide to pH 12 4 150 1M 12 Acid to base ratio of 1:1 5 200 1M 12 Add sodium hydroxide to pH 12 6 200 1M 12 Acid to base ratio of 1:1 2 7 44 mg/mL 1M 7 After adding DMSO/THF, the experiment was heated to 70°C. After cooling to 25°C, alkali was added. 8 44 mg/mL 1M 7 After adding DMSO/THF, the experiment was heated to 70°C. After cooling to 25°C, alkali was added. 3 9 200 mg/mL 1M 7 The experiment was conducted at pH 5 (2%). The environment was stirred after inoculation. 10 200 mg/mL 1M 7 The experiment was conducted at pH 5 (2%). After inoculation, the cells were cooled to 5°C. 4 11 200 mg/mL 5M 7 The experiment was conducted at pH 5 (2%). The environment was stirred after inoculation. 12 200 mg/mL 10M 7 The experiment was conducted at pH 5 (2%). The environment was stirred after inoculation.

Example 22. Formation of Figure 11 : A saturated solution of compound 1 ,diHCl was prepared in N,N'-dimethylacetamide at ambient temperature, and the solution was subsequently cooled from 60°C to 25°C at a rate of 0.1°C/min. The sample was kept at ambient temperature until larger crystals were obtained (approximately two weeks). During attempts to perform polarized light microscopy, the crystals dissolved again after stirring the solution. The solution was placed in a refrigerator for one week to promote crystal growth, but no crystals appeared. Finally, approximately 10 drops of acetone were added as a reverse solvent, and crystals were obtained.

Example 23. Single Crystal X -ray Analysis of Pattern 11 : A suitable crystal of Pattern 11 was selected and mounted in a ring using paratone oil. Data was collected using a Bruker D8 Venture diffractometer equipped with a Photon III detector operating in off mode at 100(2) K with Cu-Kα radiation (1.54178 Å). The structure was dissolved in the Olex2 software package with the ShelXT (intrinsically phased) structure solution program and improved using the ShelXL3 improvement package with least squares minimization. Data in triclinic space group P-1 was collected, dissolved, and improved.

All non-hydrogen atoms are located in the Fourier map with improved positions, followed by an description of the anisotropic thermal migrations of all non-hydrogen atoms. Within this structure, two complete G1T28 dihydrochloride units are improved. All fully occupied hydrogen atoms are placed in their calculated positions using a fixed Uiso riding model at 1.2x (for all CH, _CH2 , and NH groups) and 1.5x (for all _CH3 groups). All partially occupied hydroxyl hydrogen atoms are located in the Fourier map with improved positions and occupancy.

The highest residual Fourier peak is considered to be approximately 0.54 ^e.Å⁻³ from C(1), approximately 1.19 Å, and the deepest Fourier aperture is considered to be -0.29 ^e.Å⁻³ from Cl(2), approximately 0.63 Å.

The crystallographic parameters of improved crystal data pattern 11 are described in Table 25 below. C ₂₄ H ₃₃ Cl ₂ N ₈ O _1.5 (M = 528.48 g/mol): Triclinic crystal, space group P-1 (No. 2), a = 12.2824(2) Å, b = 14.5593(3) Å, c = 15.9459(3) Å, α = 72.0580(10)°, β = 85.7150(10)°, γ = 74.6560(10)°, V = 2616.05(9) Å3, Z = 4, T = 100.0 K, μ(CuKα) = 2.523 mm-1, D calculated = 1.342 g/cm ³ , measured 77718 reflection (6.598° ≤ 2Θ ≤ 149.518°), 10714 unique (R _int) =0.0685, R _sigma =0.0357), which are used in all calculations. The final R ¹ is 0.0461 (I＞2σ(I)) and wR ₂ is 0.1363 (all data). Table 25. Crystallographic parameters of improved pattern 11. Figure 11 ( diHCl hemihydrate ) Empirical formula C ₂₄ H ₃₃ Cl ₂ N ₈ O _1.5 Formulas 528.48 Temperature/K 100 Crystal system Triclinic crystal Space Group P-1 a/Å 12.2824(2) b/Å 14.5593(3) c/Å 15.9459(3) α/° 72.0580(10) β/° 85.7150(10) γ/° 74.6560(10) Volume/Å ³ 2616.05(9) Z 4 ρcalcg/ ^cm³ 1.342 μ/mm ^-1 2.523 F(000) 1116 Crystal size/mm ³ 0.18×0.08×0.02 Radiation CuKα (λ = 1.54178) Data collection range 2Θ/° 6.598 to 149.518 Indicator range -15 ≤ h ≤ 15, -18 ≤ k ≤ 18, -19 ≤ l ≤ 19 Collection of Reflections 77718 Independent reflection 10714 [Rint = 0.0685, Rsigma = 0.0357] Data/Limitations/Parameters 10714/0/633 ^F2 fit score 1.038 The final R-index is [I＞=2σ (I)]. R1 = 0.0461, wR2 = 0.1260 Final R-index [All Data] R1 = 0.0613, wR2 = 0.1363 Maximum difference peak/pore/e Å ^-3 0.54/-0.29

Example 24. The single-crystal determination results in Figure 11 show that the hemihydrate of compound 1 in the form of a dihydrochloride is highly crystalline and has the following unit cell size: Triclinic P-1 a=12.2824(2) A a=72.0580(10) ^o b=14.5593(3) A b=85.7150(10) ^o c=15.9459(3) A a=74.6560(10) ^o Volume = 2,616.05 (9) A ³ Z = 4, Z' = 2

This asymmetric unit contains two complete compound 1 units and two chloride ions. Solvent masking was calculated, and 91.1 electrons were found in the interstices of the unit cell within a volume of 341.0 ų. This corresponds to 45.5 electrons per asymmetric unit and 22.75 electrons per G1T28 unit. This is consistent with the presence of an additional chloride ion and water molecule, accounting for 50% of each G1T28 molecule, for a total of 44 electrons per asymmetric unit. The solvent masking was removed to determine the location of disordered chlorides found in the channels intersecting the unit cell at the cell origin.

The final improved parameters are as follows: R _₁ [I > 2σ(I)] = 4.61% GooF (fitness) = 1.038 wR_₂ (all data) = 13.63% R _{_int} = 6.85%

The encapsulation within the structure is highly efficient, hence the moderate density of 1.342 g/ ^cm³ . The solvent mask is applied along the a-axis containing disordered solvent and relative ions to the channel.

The discrete hydrogen binding motif is indicated in the asymmetric unit, as shown in Figure 90. Hydrogen bonds are formed between protonated piperidine (H(29) or H29)') and the chloride ion (Cl(1) or Cl(2)) and between amide hydrogen (H(3) or H(3)') and the chloride ion (Cl(1) or Cl(2)), wherein H(29)…Cl(1) / H(29)'…Cl(2) and Cl(1)…H(3)' /Cl(2)…H(3) are measured to be 2.08(3) / 2.10(3) and 2.40(3) / 2.36(3) Å, respectively.

Besides the observed discrete cage-like hydrogen bonds, the pyrimidines and bridging amines appear to exhibit clear bonding. This interaction was found to be of moderate strength, measured at 2.15 (2) Å between N (9) and H (19), forming the R22 (8) motif. There is no evidence of π-π interactions; the main driving force for crystallization is via hydrogen bond formation, as described above. The remaining intermolecular interactions in the structure consist of van de Waal interactions. Simulated XRPD diffraction patterns have been calculated and compared with the experimental diffraction pattern of Figure 11 (Figure 96, see Tables 26 and 27). The diffraction patterns are inconsistent with each other. Table 26. List of simulated peaks for Figure 11. Number Position [°2θ] Spacing [Å] Altitude [cts] Relative strength [%] 1 5.8209 15.17080 2075.83 20.53 2 6.5936 13.39452 10112.42 100 3 7.3734 11.97972 7190.89 71.11 4 9.2538 9.54913 52.20 0.52 5 10.0260 8.81529 3409.28 33.71 6 11.1511 7.92828 189.13 1.87 7 11.6573 7.58514 3732.39 36.91 8 12.7374 6.94428 1333.24 13.18 9 13.9012 6.36539 99.45 0.98 10 14.7220 6.01229 1164.27 11.51 11 15.0305 5.88958 2108.97 20.86 12 15.1432 5.84602 1602.37 15.85 13 15.9841 5.54030 3119.67 30.85 14 16.5233 5.36071 1270.96 12.57 15 16.7700 5.28239 445.67 4.41 16 17.5939 5.03682 326.19 3.23 17 17.8378 4.96850 2822.86 27.91 18 18.5352 4.78310 994.29 9.83 19 18.9219 4.68623 1632.15 16.14 20 19.0676 4.65074 3212.03 31.76 twenty one 19.4254 4.56589 860.64 8.51 twenty two 19.9606 4.44465 2694.80 26.65 twenty three 20.5317 4.32229 179.94 1.78 twenty four 20.8288 4.26130 750.55 7.42 25 21.4583 4.13769 905.33 8.95 26 21.6452 4.10237 471.94 4.67 27 22.0978 4.01937 297.14 2.94 28 22.4959 3.94913 6503.85 64.32 29 23.1964 3.83144 1588.05 15.70 30 23.9311 3.71545 236.96 2.34 31 24.1998 3.67479 1260.44 12.46 32 24.3822 3.64771 524.70 5.19 33 25.0249 3.55548 711.00 7.03 34 25.6050 3.47621 114.77 1.13 35 26.2507 3.39216 712.98 7.05 36 26.5654 3.35268 1069.11 10.57 37 27.1874 3.27737 990.66 9.80 38 27.3587 3.25725 428.86 4.24 39 28.0072 3.18327 272.76 2.70 40 28.3983 3.14033 132.18 1.31 41 28.6382 3.11455 569.96 5.64 42 28.7733 3.10024 600.54 5.94 43 29.3735 3.03825 603.26 5.97 44 30.1575 2.96103 250.17 2.47 45 30.6752 2.91221 206.57 2.04 46 30.8126 2.89955 297.80 2.94 47 31.0668 2.87640 306.34 3.03 48 31.5495 2.83348 181.12 1.79 49 31.7273 2.81801 153.60 1.52 50 32.3419 2.76584 316.57 3.13 51 32.6990 2.73645 406.20 4.02 52 32.9597 2.71539 220.82 2.18 53 33.2544 2.69201 443.02 4.38 54 33.5207 2.67123 254.44 2.52 55 34.0803 2.62863 397.79 3.93 56 34.2787 2.61387 121.68 1.20 57 34.6959 2.58339 141.94 1.40 58 34.9584 2.56459 81.57 0.81 Table 27. Peak of highest intensity simulated XRPD diffraction pattern in Figure 11 Number Position [°2θ] Spacing [Å] Altitude [cts] Relative strength [%] 1 5.8209 15.17080 2075.83 20.53 2 6.5936 13.39452 10112.42 100 3 7.3734 11.97972 7190.89 71.11 4 10.0260 8.81529 3409.28 33.71 5 11.6573 7.58514 3732.39 36.91 6 12.7374 6.94428 1333.24 13.18 7 14.7220 6.01229 1164.27 11.51 8 15.0305 5.88958 2108.97 20.86 9 15.1432 5.84602 1602.37 15.85 10 15.9841 5.54030 3119.67 30.85 11 16.5233 5.36071 1270.96 12.57 12 17.8378 4.96850 2822.86 27.91 13 18.5352 4.78310 994.29 9.83 14 18.9219 4.68623 1632.15 16.14 15 19.0676 4.65074 3212.03 31.76 16 19.9606 4.44465 2694.80 26.65 17 22.4959 3.94913 6503.85 64.32 18 23.1964 3.83144 1588.05 15.70 19 24.1998 3.67479 1260.44 12.46 20 26.5654 3.35268 1069.11 10.57

Example 24. Single Crystal Solution of Figure 11. The coordinates and analytical parameters of the single crystal solution of Figure 11 are provided in Table 28 below: Table 28. Atomic Coordinates of Figure 11 atom x y z U(eq) Cl1 5968.1(4) 7961.9(3) 4715.8(3) 27.07(11) C1 1379.6(14) 3923.2(13) 3199.1(11) 19.8(3) C2 1218.2(16) 3038.6(14) 3983.3(12) 26.1(4) N3 774.0(15) 2331.4(13) 3714.7(12) 31.5(4) O4 971.0(13) 1287.2(11) 2877.5(10) 34.9(3) C4 1166.4(16) 2015.1(14) 3018.8(13) 27.5(4) C5 1874.1(16) 2601.6(14) 2413.9(13) 26.2(4) C6 2426.2(17) 2431.5(14) 1680.0(13) 26.9(4) C7 2955.6(15) 3223.7(13) 1311.4(12) 22.5(4) C8 3664.2(15) 3494.8(13) 608.8(12) 23.1(4) N9 4016.6(12) 4321.3(11) 440.4(10) 21.1(3) N29 4003.8(12) 9560.7(12) 3720.1(10) 21.3(3) C10 3637.3(14) 4904.4(13) 979.8(11) 18.7(3) N11 2977.4(12) 4724.2(11) 1682.7(10) 20.4(3) C12 2670.0(14) 3867.6(13) 1847.7(12) 20.4(3) N13 2042.9(13) 3467.9(11) 2543.4(10) 22.4(3) C14 2044.9(15) 4496.8(14) 3537.7(12) 24.5(4) C15 1312.3(17) 5098.3(15) 4115.2(13) 28.9(4) C16 251.5(18) 5779.1(15) 3624.6(14) 34.5(5) C17 -434.0(17) 5198.0(17) 3339.0(14) 34.7(5) C18 273.0(16) 4603.2(15) 2759.6(13) 28.2(4) N19 4016.4(13) 5755.4(11) 750.7(10) 21.2(3) C20 3786.8(15) 6505.3(13) 1157.8(11) 19.8(3) N21 4545.5(12) 7047.4(11) 996.8(10) 20.1(3) C22 4444.0(15) 7740.1(12) 1413.9(11) 19.8(3) C23 3596.1(14) 7936.8(12) 2007.6(12) 19.6(3) C24 2757.8(15) 7413.6(14) 2111.0(13) 24.8(4) C25 2842.4(15) 6706.2(14) 1684.8(13) 24.1(4) N26 3518.6(12) 8641.4(11) 2473.3(10) 20.6(3) C27 4464.3(17) 9099.2(15) 2348.5(13) 27.6(4) C28 4219.2(19) 9942.0(15) 2762.0(13) 31.3(4) C29 3811.0(17) 10355.8(15) 4159.4(15) 30.6(4) C30 3039.5(16) 9086.1(15) 3850.9(14) 28.1(4) C31 3300.8(16) 8258.1(14) 3421.1(12) 24.6(4) Cl2 -741.1(4) 1809.4(4) 5414.3(3) 27.98(12) N29 1143.4(13) 213.1(12) 6499.5(11) 24.6(3) C1' 3792.0(14) 5843.2(13) 6922.0(11) 19.3(3) C2' 4910.9(15) 6136.6(14) 6681.8(13) 24.4(4) N3' 4798.2(14) 7190.1(13) 6583.2(11) 27.5(3) O4' 4185.4(12) 8516.1(10) 7119.1(10) 31.8(3) C4' 4219.5(15) 7648.1(14) 7149.6(13) 24.5(4) C5' 3557.2(15) 7054.1(13) 7803.5(12) 22.6(4) C6' 2966.3(16) 7280.4(14) 8502.0(12) 24.5(4) C7' 2371.0(15) 6530.8(13) 8862.6(12) 21.6(4) C8' 1584.2(16) 6339.9(14) 9522.5(12) 23.2(4) N9' 1139.3(13 5562.6(11 9667.3(10) 22.0(3) C10' 1494.7(14 4960.0(13 9141.7(11) 18.9(3) N11' 2217.1(12 5071.8(11 8477.9(10) 19.3(3) C12' 2644.0(14 5861.3(13 8350.9(11) 19.2(3) N13' 3390.2(12 6168.8(11 7711.9(10) 19.8(3) C14' 2901.2(15 6362.3(13 6191.8(12) 22.5(4) C15' 3229.4(16 6008.9(14 5374.4(12) 26.4(4) C16' 3477.5(16 4872.2(14 5606.1(13) 27.0(4) C17' 4368.2(16 4352.5(14 6324.6(12) 25.1(4) C18' 4018.2(15 4703.1(13 7141.7(12) 23.5(4) N19' 1005.7(13 4170.4(11 9346.8(10) 21.2(3) C20' 1207.6(14 3410.0(13 8956.3(11) 19.2(3) N21' 342.1(12) 3005.5(11 8986.5(10) 21.6(3) C22' 455.3(15) 2284.2(13 8601.9(12) 21.2(3) C23' 1418.4(14 1932.0(13 8165.0(11) 19.8(3) C24' 2339.9(15 2319.0(13 8190.6(13) 23.3(4) C25' 2250.1(14 3050.6(13 8589.9(12) 22.2(4) N26' 1524.6(12 1195.2(11 7724.3(10) 20.4(3) C27' 1809.5(16 1545.0(14 6785.6(13) 25.9(4) C28' 2109.2(16 684.7(15) 6391.2(14) 27.4(4) C29' 1380.1(18 -613.6(16) 6098.7(16) 34.2(5) C30' 843.8(17) -116.7(14) 7447.6(13) 27.6(4) C31' 562.4(15) 759.4(13) 7821.8(12) 22.9(4) Table 29. Non-isotropic displacement parameters of Figure 11 (A ² x 10 ³ ). The non-isotropic displacement factor exponent is in the following form: -2π ² [h ² a ^{* 2} U ₁₁ + 2hka * b * U ₁₂ + ...] atom U11 U22 U33 U23 U13 U12 Cl1 25.4(2) 33.0(2) 23.3(2) -7.14(18) 3.64(1 - C1 19.5(8) 25.8(9) 18.1(8) -10.7(7) 6.5(6) -9.4(7) C2 27.7(9) 30.7(10) 22.5(9) -8.0(8) 4.1(7) -12.7(8) N3 39.1(9) 33.2(9) 30.5(9) -12.5(7) 15.3(8) -23.6(8) O4 47.7(8) 31.1(7) 35.6(8) -13.6(6) 13.9(7) -25.9(7) C4 31.5(9) 25.7(9) 29.3(10) -8.5(8) 6.8(8) -15.9(8) C5 30.5(9) 24.1(9) 29.0(10) -11.1(8) 8.6(8) -14.2(8) C6 34.9(10) 22.6(9) 28.8(10) -12.0(8) 9.5(8) -14.1(8) C7 27.4(9) 21.4(8) 22.6(9) -10.7(7) 5.6(7) -9.7(7) C8 29.8(9) 22.5(8) 22.0(9) -12.2(7) 6.5(7) -10.3(7) N9 25.9(7) 23.0(7) 19.7(7) -10.7(6) 6.3(6) -11.4(6) N29 19.9(7) 26.2(8) 23.9(8) -14.1(6) 3.9(6) -9.1(6) C10 21.3(8) 20.2(8) 17.7(8) -7.7(7) 3.2(6) -9.1(6) N11 23.5(7) 24.1(7) 18.8(7) -10.1(6) 6.7(6) -12.2(6) C12 21.6(8) 22.8(8) 19.8(8) -7.9(7) 5.3(7) -10.0(7) N13 26.1(7) 23.7(7) 23.2(8) -11.7(6) 9.5(6) -13.1(6) C14 23.0(8) 32.9(10) 21.9(9) -10.7(8) 4.2(7) -12.7(7) C15 34.5(10) 34.7(10) 23.6(9) -14.1(8) 8.0(8) -14.8(8) C16 41.6(11) 30.6(10) 28.1(10) -9.8(8) 10.7(9) -5.4(9) C17 25.1(9) 41.3(12) 31.9(11) -11.0(9) 0.8(8) 1.2(8) C18 23.7(9) 35.8(10) 23.6(9) -8.4(8) 0.5(7) -6.1(8) N19 25.9(7) 22.4(7) 20.9(8) -11.2(6) 8.8(6) -12.8(6) C20 23.2(8) 19.7(8) 18.4(8) -6.6(7) 1.1(7) -7.9(6) N21 25.4(7) 20.8(7) 17.2(7) -7.2(6) 4.0(6) -10.4(6) C22 23.8(8) 19.0(8) 19.5(8) -5.8(7) 2.3(7) -10.9(7) C23 21.3(8) 16.4(8) 23.1(9) -7.6(7) -1.6(7) -5.7(6) C24 18.4(8) 27.9(9) 33.6(10) -16.7(8) 6.5(7) -8.0(7) C25 19.5(8) 25.9(9) 33.5(10) -15.9(8) 4.7(7) -10.0(7) N26 22.2(7) 21.3(7) 23.0(8) -11.0(6) 3.3(6) -9.1(6) C27 38.0(10) 34.2(10) 23.2(9) -16.2(8) 13.2(8) -24.8(9) C28 47.0(12) 30.7(10) 25.4(10) -11.4(8) 6.1(9) -23.3(9) C29 28.6(9) 33.6(10) 40.5(12) -25.3(9) 3.8(8) -10.2(8) C30 23.2(9) 37.1(10) 36.1(11) -23.9(9) 11.8(8) -15.7(8) C31 28.1(9) 27.4(9) 26.2(10) -15.4(8) 12.2(7) -15.0(7) Cl2 22.4(2) 37.4(2) 24.8(2) -8.01(18) 4.76(1 - N29' 21.3(7) 30.2(8) 29.1(9) -18.4(7) 4.1(6) -8.0(6) C1' 19.7(8) 23.0(8) 17.2(8) -8.3(7) 5.1(6) -7.5(6) C2' 19.5(8) 30.7(9) 26.3(9) -11.8(8) 5.0(7) -9.2(7) N3' 29.1(8) 32.1(9) 26.8(8) -9.8(7) 9.6(7) -18.6(7) O4' 35.6(7) 28.4(7) 36.3(8) -10.6(6) 8.4(6) -17.8(6) C4' 24.0(8) 26.7(9) 26.0(9) -7.5(7) 2.1(7) -12.6(7) C5' 23.8(8) 24.0(9) 24.3(9) -9.5(7) 3.8(7) -11.7(7) C6' 29.4(9) 25.7(9) 24.5(9) -11.0(7) 5.3(7) -14.4(7) C7' 25.7(8) 23.0(8) 20.9(9) -10.8(7) 3.5(7) -10.4(7) C8' 29.4(9) 25.6(9) 22.2(9) -14.2(7) 7.0(7) -13.1(7) N9' 26.2(7) 24.2(7) 20.9(8) -11.2(6) 7.5(6) -12.0(6) C10' 20.4(8) 20.5(8) 18.1(8) -8.0(7) 2.0(6) -7.2(6) N11' 20.0(7) 23.2(7) 18.5(7) -9.3(6) 3.5(6) -9.0(6) C12' 17.8(7) 23.5(8) 18.6(8) -8.1(7) 2.8(6) -7.9(6) N13' 21.0(7) 22.8(7) 19.6(7) -9.6(6) 5.3(6) -9.7(6) C14' 21.7(8) 24.7(9) 23.1(9) -9.5(7) 2.6(7) -7.2(7) C15' 30.3(9) 28.7(9) 20.1(9) -6.9(7) 1.2(7) -8.1(8) C16' 29.4(9) 30.1(10) 25.7(10) -13.5(8) 8.3(8) -10.8(8) C17' 28.1(9) 23.0(9) 25.5(9) -10.2(7) 11.0(7) -8.0(7) C18' 25.7(9) 20.6(8) 22.4(9) -6.3(7) 5.9(7) -4.7(7) N19' 23.2(7) 24.9(7) 22.2(8) -13.0(6) 9.7(6) -12.8(6) C20' 22.4(8) 20.4(8) 17.1(8) -6.8(6) 3.3(6) -8.9(6) N21' 24.6(7) 24.1(7) 21.1(7) -10.9(6) 8.0(6) -11.9(6) C22' 24.7(8) 23.8(8) 20.7(9) -9.5(7) 5.6(7) -13.3(7) C23' 23.2(8) 19.2(8) 19.3(8) -7.6(7) 2.0(7) -7.7(7) C24' 18.5(8) 24.4(9) 29.3(10) -13.0(7) 4.3(7) -4.4(7) C25' 19.2(8) 23.9(9) 28.2(9) -12.1(7) 1.9(7) -8.7(7) N26' 21.8(7) 22.6(7) 21.7(8) -11.9(6) 3.8(6) -8.7(6) C27' 29.5(9) 28.7(9) 26.4(10) -15.3(8) 11.6(7) -14.0(8) C28' 24.4(9) 34.7(10) 32.7(10) -20.9(9) 9.1(8) -13.1(8) C29' 31.5(10) 39.1(11) 47.3(13) -32.2(10) 6.9(9) -13.6(9) C30' 32.9(10) 25.5(9) 30.7(10) -13.7(8) 5.3(8) -13.4(8) C31' 26.5(9) 24.7(9) 24.1(9) -12.4(7) 5.8(7) -13.1(7) N29' 21.3(7) 30.2(8) 29.1(9) -18.4(7) 4.1(6) -8.0(6) C1' 19.7(8) 23.0(8) 17.2(8) -8.3(7) 5.1(6) -7.5(6) C2' 19.5(8) 30.7(9) 26.3(9) -11.8(8) 5.0(7) -9.2(7) N3' 29.1(8) 32.1(9) 26.8(8) -9.8(7) 9.6(7) -18.6(7) O4' 35.6(7) 28.4(7) 36.3(8) -10.6(6) 8.4(6) -17.8(6) C4' 24.0(8) 26.7(9) 26.0(9) -7.5(7) 2.1(7) -12.6(7) C5' 23.8(8) 24.0(9) 24.3(9) -9.5(7) 3.8(7) -11.7(7) C6' 29.4(9) 25.7(9) 24.5(9) -11.0(7) 5.3(7) -14.4(7) C7' 25.7(8) 23.0(8) 20.9(9) -10.8(7) 3.5(7) -10.4(7) C8' 29.4(9) 25.6(9) 22.2(9) -14.2(7) 7.0(7) -13.1(7) N9' 26.2(7) 24.2(7) 20.9(8) -11.2(6) 7.5(6) -12.0(6) C10' 20.4(8) 20.5(8) 18.1(8) -8.0(7) 2.0(6) -7.2(6) N11' 20.0(7) 23.2(7) 18.5(7) -9.3(6) 3.5(6) -9.0(6) C12' 17.8(7) 23.5(8) 18.6(8) -8.1(7) 2.8(6) -7.9(6) N13' 21.0(7) 22.8(7) 19.6(7) -9.6(6) 5.3(6) -9.7(6) C14' 21.7(8) 24.7(9) 23.1(9) -9.5(7) 2.6(7) -7.2(7) C15' 30.3(9) 28.7(9) 20.1(9) -6.9(7) 1.2(7) -8.1(8) C16' 29.4(9) 30.1(10) 25.7(10) -13.5(8) 8.3(8) -10.8(8) C17' 28.1(9) 23.0(9) 25.5(9) -10.2(7) 11.0(7) -8.0(7) C18' 25.7(9) 20.6(8) 22.4(9) -6.3(7) 5.9(7) -4.7(7) N19' 23.2(7) 24.9(7) 22.2(8) -13.0(6) 9.7(6) -12.8(6) C20' 22.4(8) 20.4(8) 17.1(8) -6.8(6) 3.3(6) -8.9(6) N21' 24.6(7) 24.1(7) 21.1(7) -10.9(6) 8.0(6) -11.9(6) C22' 24.7(8) 23.8(8) 20.7(9) -9.5(7) 5.6(7) -13.3(7) C23' 23.2(8) 19.2(8) 19.3(8) -7.6(7) 2.0(7) -7.7(7) C24' 18.5(8) 24.4(9) 29.3(10) -13.0(7) 4.3(7) -4.4(7) C25' 19.2(8) 23.9(9) 28.2(9) -12.1(7) 1.9(7) -8.7(7) N26' 21.8(7) 22.6(7) 21.7(8) -11.9(6) 3.8(6) -8.7(6) C27' 29.5(9) 28.7(9) 26.4(10) -15.3(8) 11.6(7) -14.0(8) C28' 24.4(9) 34.7(10) 32.7(10) -20.9(9) 9.1(8) -13.1(8) C29' 31.5(10) 39.1(11) 47.3(13) -32.2(10) 6.9(9) -13.6(9) C30' 32.9(10) 25.5(9) 30.7(10) -13.7(8) 5.3(8) -13.4(8) C31' 26.5(9) 24.7(9) 24.1(9) -12.4(7) 5.8(7) -13.1(7) Table 30. Key length of pattern 11 atom atom Length /Å atom atom Length /Å C1 C2 1.539(2) N29' C28' 1.495(2) C1 N13 1.487(2) N29' C29' 1.484(2) C1 C14 1.537(2) N29' C30' 1.488(2) C1 C18 1.524(3) C1' C2' 1.533(2) C2 N3 1.465(2) C1' N13' 1.485(2) N3 C4 1.339(3) C1' C14' 1.528(2) O4 C4 1.233(2) C1' C18' 1.539(2) C4 C5 1.475(2) C2' N3' 1.463(2) C5 C6 1.364(3) N3' C4' 1.338(2) C5 N13 1.408(2) O4' C4' 1.239(2) C6 C7 1.421(2) C4' C5' 1.479(2) C7 C8 1.390(2) C5' C6' 1.362(3) C7 C12 1.417(2) C5' N13' 1.409(2) C8 N9 1.329(2) C6' C7' 1.424(2) N9 C10 1.363(2) C7' C8' 1.389(2) N29 C28 1.486(2) C7' C12' 1.416(2) N29 C29 1.489(2) C8' N9' 1.334(2) N29 C30 1.494(2) N9' C10' 1.363(2) C10 N11 1.333(2) C10' N11' 1.328(2) C10 N19 1.373(2) C10' N19' 1.376(2) N11 C12 1.341(2) N11' C12' 1.340(2) C12 N13 1.369(2) C12' N13' 1.369(2) C14 C15 1.543(2) C14' C15' 1.533(2) C15 C16 1.511(3) C15' C16' 1.530(3) C16 C17 1.518(3) C16' C17' 1.516(3) C17 C18 1.527(3) C17' C18' 1.534(2) N19 C20 1.393(2) N19' C20' 1.390(2) C20 N21 1.336(2) C20' N21' 1.336(2) C20 C25 1.401(2) C20' C25' 1.406(2) N21 C22 1.345(2) N21' C22' 1.344(2) C22 C23 1.387(2) C22' C23' 1.387(2) C23 C24 1.407(2) C23' C24' 1.399(2) C23 N26 1.421(2) C23' N26' 1.428(2) C24 C25 1.377(2) C24' C25' 1.377(2) N26 C27 1.458(2) N26' C27' 1.473(2) N26 C31 1.472(2) N26' C31' 1.460(2) C27 C28 1.518(3) C27' C28' 1.519(2) C30 C31 1.516(2) C30' C31' 1.519(2) Table 31. Key Angles of Pattern 11 atom atom atom angle ​ atom atom atom angle ​ N13 C1 C2 105.39(14) C29' N29' C28' 111.90(14) N13 C1 C14 111.19(13) C29' N29' C30' 112.09(16) N13 C1 C18 107.77(14) C30' N29' C28' 109.99(15) C14 C1 C2 107.44(15) C2' C1' C18' 108.89(14) C18 C1 C2 113.32(15) N13' C1' C2' 104.98(13) C18 C1 C14 111.60(15) N13' C1' C14' 109.06(14) N3 C2 C1 112.63(15) N13' C1' C18' 110.78(14) C4 N3 C2 122.86(16) C14' C1' C2' 112.98(14) N3 C4 C5 115.08(16) C14' C1' C18' 110.05(14) O4 C4 N3 123.95(17) N3' C2' C1' 112.38(15) O4 C4 C5 120.96(18) C4' N3' C2' 122.79(16) C6 C5 C4 128.19(17) N3' C4' C5' 114.67(16) C6 C5 N13 110.69(15) O4' C4' N3' 123.90(17) N13 C5 C4 121.11(16) O4' C4' C5' 121.36(17) C5 C6 C7 106.47(16) C6' C5' C4' 128.25(17) C8 C7 C6 137.25(17) C6' C5' N13' 110.60(15) C8 C7 C12 115.52(15) N13' C5' C4' 120.95(16) C12 C7 C6 107.21(15) C5' C6' C7' 106.45(16) N9 C8 C7 121.79(16) C8' C7' C6' 136.96(17) C8 N9 C10 117.04(15) C8' C7' C12' 115.55(15) C28 N29 C29 111.98(15) C12' C7' C6' 107.36(15) C28 N29 C30 109.42(15) N9' C8' C7' 121.54(16) C29 N29 C30 112.00(14) C8' N9' C10' 117.10(15) N9 C10 N19 113.54(15) N9' C10' N19' 113.09(15) N11 C10 N9 127.31(15) N11' C10' N9' 127.35(15) N11 C10 N19 119.14(15) N11' C10' N19' 119.56(15) C10 N11 C12 113.82(14) C10' N11' C12' 113.82(14) N11 C12 C7 124.37(16) N11' C12' C7' 124.61(15) N11 C12 N13 126.83(16) N11' C12' N13' 126.81(15) N13 C12 C7 108.80(14) N13' C12' C7' 108.58(14) C5 N13 C1 121.69(14) C5' N13' C1' 121.28(14) C12 N13 C1 129.83(14) C12' N13' C1' 130.41(14) C12 N13 C5 106.71(14) C12' N13' C5' 106.96(14) C1 C14 C15 111.95(14) C1' C14' C15' 111.80(15) Table 32. Key Angles of Continuous Pattern 11 atom atom atom angle ​ atom atom atom angle ​ C16 C15 C14 110.47(16) C16' C15' C14' 111.55(15) C15 C16 C17 111.59(17) C17' C16' C15' 111.64(16) C16 C17 C18 110.50(17) C16' C17' C18' 110.55(15) C1 C18 C17 112.70(16) C17' C18' C1' 111.87(15) C10 N19 C20 128.14(15) C10' N19' C20' 127.48(15) N19 C20 C25 124.39(15) N19' C20' C25' 123.57(15) N21 C20 N19 114.26(15) N21' C20' N19' 114.77(15) N21 C20 C25 121.34(16) N21' C20' C25' 121.60(16) C20 N21 C22 118.67(15) C20' N21' C22' 118.62(15) N21 C22 C23 124.36(15) N21' C22' C23' 124.05(15) C22 C23 C24 115.77(15) C22' C23' C24' 116.36(15) C22 C23 N26 124.13(15) C22' C23' N26' 124.19(15) C24 C23 N26 120.06(15) C24' C23' N26' 119.43(15) C25 C24 C23 120.58(16) C25' C24' C23' 120.60(16) C24 C25 C20 118.84(16) C24' C25' C20' 118.47(16) C23 N26 C27 115.10(14) C23' N26' C27' 112.98(14) C23 N26 C31 113.71(14) C23' N26' C31' 114.98(14) C27 N26 C31 109.67(14) C31' N26' C27' 109.96(14) N26 C27 C28 110.71(15) N26' C27' C28' 110.61(15) N29 C28 C27 110.27(15) N29' C28' C27' 109.76(14) N29 C30 C31 109.70(14) N29' C30' C31' 110.37(15) N26 C31 C30 111.14(15) N26' C31' C30' 110.07(14) Table 33. Location of hydrogen in Figure 11 atom x y z U(eq) atom x y Z U(eq) H2 1952.82 2684.00 4287.21 31 H29 560(20) 692(18) 6199(16) 29 H2 692.24 3296.46 4408.15 31 H2' 5477.81 5719.97 7147.31 29 H3 290(20) 2055(18) 4088(17) 38 H2' 5189.48 5999.15 6122.69 29 H6 2451.78 1890.37 1458.87 32 H3' 5130(20 7539(18 6144(16) 33 H8 3903.14 3078.05 238.95 28 H6' 2953.53 7829.77 8708.09 29 H29 4630(19 9044(17) 3990(15) 26 H8' 1357.40 6772.85 9879.05 28 H14 2330.99 4958.46 3028.79 29 H14 2805.30 7092.82 6025.24 27 H14 2703.91 4017.82 3886.35 29 H14 2169.10 6223.95 6415.63 27 H15 1107.50 4633.61 4664.44 35 H15 2606.17 6321.08 4936.54 32 H15 1748.76 5501.07 4278.38 35 H15 3906.18 6227.17 5103.58 32 H16 458.50 6273.83 3098.44 41 H16 2773.98 4662.18 5805.18 32 H16 -214.76 6147.55 4009.52 41 H16 3740.12 4667.85 5072.76 32 H17 - 5666.28 3006.91 42 H17 5097.07 4500.45 6103.61 30 H17 -689.43 4736.56 3865.85 42 H17 4471.84 3621.32 6485.66 30 H18 -171.39 4192.92 2617.73 34 H18 4624.61 4376.30 7592.81 28 H18 440.12 5073.20 2198.81 34 H18 3327.54 4497.13 7393.07 28 H19 4530(20 5778(16) 399(15) 25 H19 410(20) 4234(16) 9628(15) 25 H22 4989.26 8119.89 1293.93 twenty four H22 -162.62 1997.61 8631.02 25 H24 2127.98 7549.40 2477.86 30 H24 3033.65 2074.81 7930.26 28 H25 2270.39 6360.61 1747.02 29 H25 2878.04 3306.40 8617.03 27 H27 4603.62 9362.95 1710.35 33 H27 2456.74 1846.14 6723.87 31 H27 5153.40 8588.81 2620.46 33 H27 1158.30 2064.81 6461.48 31 H28 4870.71 10241.40 2673.81 38 H28 2280.62 933.41 5757.37 33 H28 3550.90 10467.89 2471.64 38 H28 2788.87 182.57 6690.01 33 H29 3108.17 10859.93 3935.86 46 H29 2084.80 - 6345.00 51 H29 4443.11 10670.00 4033.98 46 H29 1453.35 -345.66 5459.06 51 H29 3754.81 10060.90 4797.45 46 H29 758.50 -940.55 6227.50 51 H30 2344.25 9593.22 3586.92 34 H30 1485.34 -641.08 7780.47 33 H30 2910.10 8809.41 4488.97 34 H30 185.78 -404.85 7512.32 33 H31 3971.22 7734.39 3710.35 30 H31 -101.53 1270.66 7507.69 27 H31 2655.36 7951.83 3502.74 30 H31 370.70 530.13 8453.40 27

Example 25. Diffraction data of an XRD1 beamline (Lausi et al., 2015) with a standard single-crystal configuration was collected using the single-crystal X- ray crystallization experimental conditions of Figure 1. The experimental setup was housed in a hygrometer with a κ geometry, fully controllable from a remote location. A nitrogen stream was supplied to characterize the sample diffraction properties at 100 K via rotational crystallization (via an Oxford Cryostream 700 from Oxford Cryosystems Ltd., Oxford, UK).

Data was acquired using a monochromatic wavelength of 0.6199 Å on a Pilatus 6M hybrid pixel area detector (DECTRIS Ltd., Baden-Daettwil, Switzerland). Crystals were immersed in NHV oil (Jena Bioscience, Jena, Germany), placed on kapton rings (MiTeGen, Ithaca, USA) at room temperature, and then rapidly frozen in liquid nitrogen. The diffraction characteristics of 15 different crystals were evaluated—all crystals exhibited as thin, yellow needle-like structures less than 50 to 80 mm in their longest direction. Most samples diffracted approximately 0.9 to 1 Å, but a very few diffracted at most approximately 0.7 to 0.8 Å. Standard Ω-scan XRD data were collected on the optimal diffraction site until radiation damage began to significantly degrade data quality. An oscillation range of 0.5° was selected for optimal Bragg peak separation. The same crystal form was found in three batches of crystals from all suppliers.

The structure was solved directly using SHELX-2014/7 (Sheldrick, G. M., 2015a) and improved using the least-squares full matrix improvement of SHELXL-2014/7 (Sheldrick, G. M., 2015b). All H atoms, except those bonded to N or O atoms, are included in the geometry. In the final improvement cycle, a large peak of approximately 2 e/Å3 was found near the ClB atom. This is interpreted as a partial symptom of this atom. The improvement revealed that the symptom could be established at approximately 0.9 and approximately 0.1. This symptom affects the water molecule (O1W); therefore, to maintain the model, the complete H1W1 was preserved using the AFIX card (AFIX 1) and thermal parameters at 150% of the adjacent O atom.

HR-XRPD data were collected at room temperature using Cu Kα1 radiation (1.54056 Å) with a germanium monochromator on a D8 advanced diffractometer. Diffraction data were collected in the 2θ range of 2 to 41.5°. Detector scans were performed on a solid-state LynxEye detector at a scan rate of 5 sec/step, with each step being 0.016°. Samples were measured in an 8 mm long glass capillary with an outer diameter of 0.3 mm.

The first calculation step involves finding the unit cell parameters using the LSI index of an indexing program (Coelho, 2003; Coelho and Kern, 2005). The space group is selected based on reflection conditions and compound knowledge. The whole powder pattern decomposition method (Pawley, 1981) is used to improve cell parameters, purity, and instrument parameters.

For the Rietveld calculation, cellular parameters were obtained from room temperature measurements, while atomic positions and their thermal parameters were obtained from single-crystal measurement files (CIF) at 100 K. During the improvement process, the following parameters were modified: - Cellular constant; - Background; - Instrument geometry; - Zero shift; - Absorption.

No changes were made to atomic positions or thermal motion parameters throughout the entire process. The following fitting criteria were used: • Y_{_o,m} and Y _{_c,m} are the observed and calculated data at data point m, respectively; • M is the number of data points; • The number of P parameters; • w_{_m} is the weighting given for data point m used in statistical analysis, given by w_m = 1/σ(Y _{_o,m} )^², where σ(Y _{_o,m} ) is the error of Y _{_o,m}. ; ;

The resulting crystal structure is shown in the simulation comparisons in Figures 97, 98, and 99, which demonstrate a close agreement between the predicted and experimental diffraction patterns.

Example 26. Figure 1 shows a single crystal depicting compound 1 dihydrochloride crystallizing as a yellow columnar crystal in the monoclinic central symmetry space group P21/c. In the asymmetric unit, one dication (API2+), two chloride ions, and two water molecules were found (overall ratio 1:2:2).

As can be seen in Figure 97, the molecule is packed onto the N atom (N2) of the basic amine and onto the N atom (N10) of the pyridine. The molecule adopts an expanded (spread) configuration.

The crystal is held together by intermolecular H-bond interactions (see Figure 98). One of the chloride ions (ClA) interacts directly with the positively charged N atom (N2). The second chloride ion (ClB) acts as a bridge between the two water molecules (see Figure 97).

However, this ClB also interacts with another amine N atom (N14) via an N bond. In the crystal, all water molecules act as donors and hydrogen bond acceptors, while the N atom preferably acts only as a donor. The only acceptor of the H bond is the N16 atom, and in this case, the interaction is intramolecular.

The intermolecular H-bond network extends throughout the three dimensions, thus generating a 3D structure. HR-XRPD data and Ritter-Wade analysis of the starting material delivered by the G1 treatment allowed for the acquisition of cellular parameters at room temperature and revealed that the host material is composed of a pure form without any detectable crystalline impurities. In Figure 1, crystallization occurs in the centrally symmetric space group P21/c as a dication associated with two chloride ions. Two water molecules are also observed in the asymmetric unit. The results are listed in Table 34. Table 34. Single-crystal data for Figure 1. Pattern 1 Single Crystal Empirical formula [(C ₂₄ H ₃₂ N ₈ O)Cl ₂ •2H ₂ O] Formulas 555.51 T [K] 100(2) K λ [Å] 0.61993 Å Crystal system Monoclinic crystal Space Group P 21/c unit cell size a [Å] 22.118(4) [22.2447(9)] b [Å] 6.9060(14) [6.9472(4)] c [Å] 18.431(4) [18.5906(8)] β [°] 109.58(3) [109.407(2)] V[Å ³ ] 2652.5(10) [2709.7(4)] Z 4 DC [g/ ^cm³ ] 1.391 [mm ^-1 ] 0.199 F(000) 1176 Crystal size [ ^mm³ ] 0.07×0.02×0.01 The θ range used for data collection [°] 1.9 to 27.6. Collection of Reflections 45308 Independent reflection 9184 [Rint = 0.1141] Completeness to θ=25.242° [%] 99.8 Absorption correction without Maximum and minimum transmission 0.992 and 0.978 Data/Limitations/Parameters 9183/0/367 ^F2 fit score 1.019 The final R-index is [I > 2(I)]. R ₁ = 0.0609, wR₂ = 0.1271 R-index (All Data) R ₁ = 0.1366, wR₂ = 0.1603 Absolute configuration Extinction coefficient n/a Maximum diffraction peak and valley [e/Å ³ ] 0.355 and -0.471 Table 35. Hydrogen bonds in single-crystal structures from Figure 1 DH...A DH [Å] H...A [Å] D...A [Å] DH …A [°] O(1W)-H(1W2)...ClA ⁱ 1.08 2.20 3.246(3) 162 O(1W)-H(1W1)...ClB 1.16(5) 1.92(6) 3.064(3) 168(4) O(2W)-H(2W1)...O(1W) 0.86(2) 1.90(2) 2.752(4) 167(2) O(2W)-H(2W2)...ClB ⁱⁱ 0.88(3) 2.20(3) 3.075(3) 170(2) N(2)-H(2)...ClA 0.94(3) 2.13(3) 3.044(2) 163(3) N(10)-H(10)...O(2W) 0.95(4) 2.08(4) 2.827(3) 135(3) N(10)-H(10)...N(16) 0.95(4) 2.05(4) 2.713(3) 125(3) N(14)-H(14)...ClB ⁱⁱⁱ 0.78(2) 2.45(3) 3.218(2) 171(3) N(23)-H(23)...O(22) ^IV 0.87(3) 1.95(3) 2.814(3) 176(2) Table 36. Final parameters of Rett Wade in Figure 1 2θ range ( ^o ) 2 to 41.5 R _exp 1.94 R _wp 3.05 R _p 2.36 GOF 1.57 R _Brag 1.29 Impurities, other forms [%] Below the detection limit

Example 27. X -ray Powder Diffraction (XRPD) XRPD analysis was performed on a PANalytical X'pert pro, scanning the free base sample between 3 and 35° 2θ. The material was gently ground to release any agglomerates and loaded onto a porous disc supported by a Kapton or Mylar polymer film. The porous plate was then placed in the diffractometer and analyzed using Cu K radiation (α1λ = 1.54060 Å; α2 = 1.54443 Å; β = 1.39225 Å; α1:α2 ratio = 0.5) running in transmission mode (step 0.0130° 2θ).

Table 37 below provides a list of XRPD peaks for Pattern 7, which has a relative intensity peak >10%. The XRPD of Pattern 7 exhibits sharp peaks, indicating that the sample is composed of a crystalline material. Significant peaks were observed in the XRPD of Pattern 7 at approximately 5.8±0.2°, 10.9±0.2°, 11.8±0.2°, 15.2±0.2°, 15.6±0.2°, 17.6±0.2°, 18.1±0.2°, 18.7±0.2°, 19.3±0.2°, 21.6±0.2°, 22.7±0.2°, 23.3±0.2°, and 24.6±0.2°. Table 37. List of XRPD peaks for Pattern 7. Position [°2θ] Altitude [cts] Maintain FWHM [°2θ] Spacing [Å] Relative strength [%] 5.8473 7100.68 0.0768 15.11477 100.00 7.5415 466.35 0.0768 11.72267 6.57 10.8993 2345.84 0.1023 8.11763 33.04 11.7793 2076.64 0.1279 7.51310 29.25 14.3833 227.29 0.1023 6.15820 3.20 15.2147 884.88 0.0895 5.82352 12.46 15.6354 1009.60 0.0895 5.66775 14.22 15.9906 516.06 0.1151 5.54265 7.27 16.6298 252.87 0.1023 5.33102 3.56 17.5834 825.28 0.0895 5.04399 11.62 18.0629 1476.22 0.1279 4.91116 20.79 18.2780 645.99 0.0895 4.85384 9.10 18.6556 1724.82 0.1407 4.75644 24.29 19.2537 4278.41 0.1151 4.61001 60.25 19.9143 184.16 0.1279 4.45855 2.59 21.0463 515.45 0.0768 4.22124 7.26 21.6098 3110.68 0.1407 4.11243 43.81 22.1211 283.04 0.1023 4.01851 3.99 22.7282 1065.70 0.0895 3.91254 15.01 23.3148 2921.40 0.1407 3.81540 41.14 23.6006 520.09 0.0768 3.76984 7.32 24.0363 142.34 0.1535 3.70249 2.00 24.5873 908.96 0.1535 3.62075 12.80 24.8731 374.85 0.1279 3.57978 5.28 25.1286 307.79 0.1023 3.54397 4.33 27.1701 678.40 0.2047 3.28213 9.55 29.1007 332.84 0.1791 3.06864 4.69 29.6940 173.72 0.2558 3.00867 2.45 30.2169 163.05 0.1279 2.95779 2.30 31.4442 135.77 0.2558 2.84508 1.91 33.2805 241.46 0.1791 2.69218 3.40 33.9789 188.22 0.3070 2.63843 2.65

In some embodiments, the form is pattern 7, characterized in that the XRPD pattern includes at least two peaks selected from the following: 5.8±0.2°, 10.9±0.2°, 11.8±0.2°, 15.2±0.2°, 15.6±0.2°, 17.6±0.2°, 18.1±0.2°, 18.7±0.2°, 19.3±0.2°, 21.6±0.2°, 22.7±0.2°, 23.3±0.2°, and 24.6±0.2°.

In some embodiments, the form is pattern 7, characterized in that the XRPD pattern includes at least three peaks selected from the following: 5.8±0.2°, 10.9±0.2°, 11.8±0.2°, 15.2±0.2°, 15.6±0.2°, 17.6±0.2°, 18.1±0.2°, 18.7±0.2°, 19.3±0.2°, 21.6±0.2°, 22.7±0.2°, 23.3±0.2°, and 24.6±0.2°.

In some embodiments, the form is pattern 7, characterized in that the XRPD pattern includes at least four peaks selected from the following: 5.8±0.2°, 10.9±0.2°, 11.8±0.2°, 15.2±0.2°, 15.6±0.2°, 17.6±0.2°, 18.1±0.2°, 18.7±0.2°, 19.3±0.2°, 21.6±0.2°, 22.7±0.2°, 23.3±0.2°, and 24.6±0.2°.

In some embodiments, the form is pattern 7, characterized in that the XRPD pattern includes at least 5 peaks selected from the following: 5.8±0.2°, 10.9±0.2°, 11.8±0.2°, 15.2±0.2°, 15.6±0.2°, 17.6±0.2°, 18.1±0.2°, 18.7±0.2°, 19.3±0.2°, 21.6±0.2°, 22.7±0.2°, 23.3±0.2°, and 24.6±0.2°.

In some embodiments, the form is pattern 7, characterized in that the XRPD pattern includes at least 6 peaks selected from the following: 5.8±0.2°, 10.9±0.2°, 11.8±0.2°, 15.2±0.2°, 15.6±0.2°, 17.6±0.2°, 18.1±0.2°, 18.7±0.2°, 19.3±0.2°, 21.6±0.2°, 22.7±0.2°, 23.3±0.2°, and 24.6±0.2°.

In some embodiments, the form is pattern 7, characterized in that the XRPD pattern contains at least 7 peaks selected from the following: 5.8±0.2°, 10.9±0.2°, 11.8±0.2°, 15.2±0.2°, 15.6±0.2°, 17.6±0.2°, 18.1±0.2°, 18.7±0.2°, 19.3±0.2°, 21.6±0.2°, 22.7±0.2°, 23.3±0.2°, and 24.6±0.2°.

In some embodiments, the form is pattern 7, characterized in that the XRPD pattern contains at least 8 peaks selected from the following: 5.8±0.2°, 10.9±0.2°, 11.8±0.2°, 15.2±0.2°, 15.6±0.2°, 17.6±0.2°, 18.1±0.2°, 18.7±0.2°, 19.3±0.2°, 21.6±0.2°, 22.7±0.2°, 23.3±0.2°, and 24.6±0.2°.

In some embodiments, the form is pattern 7, characterized in that the XRPD pattern contains at least 9 peaks selected from the following: 5.8±0.2°, 10.9±0.2°, 11.8±0.2°, 15.2±0.2°, 15.6±0.2°, 17.6±0.2°, 18.1±0.2°, 18.7±0.2°, 19.3±0.2°, 21.6±0.2°, 22.7±0.2°, 23.3±0.2°, and 24.6±0.2°.

In some embodiments, the form is pattern 7, characterized in that the XRPD pattern contains at least 10 peaks selected from the following: 5.8±0.2°, 10.9±0.2°, 11.8±0.2°, 15.2±0.2°, 15.6±0.2°, 17.6±0.2°, 18.1±0.2°, 18.7±0.2°, 19.3±0.2°, 21.6±0.2°, 22.7±0.2°, 23.3±0.2°, and 24.6±0.2°.

In some embodiments, the form is pattern 7, characterized in that the XRPD pattern contains at least 11 peaks selected from the following: 5.8±0.2°, 10.9±0.2°, 11.8±0.2°, 15.2±0.2°, 15.6±0.2°, 17.6±0.2°, 18.1±0.2°, 18.7±0.2°, 19.3±0.2°, 21.6±0.2°, 22.7±0.2°, 23.3±0.2°, and 24.6±0.2°.

In some embodiments, the form is pattern 7, characterized in that the XRPD pattern contains at least 12 peaks selected from the following: 5.8±0.2°, 10.9±0.2°, 11.8±0.2°, 15.2±0.2°, 15.6±0.2°, 17.6±0.2°, 18.1±0.2°, 18.7±0.2°, 19.3±0.2°, 21.6±0.2°, 22.7±0.2°, 23.3±0.2°, and 24.6±0.2°.

In some embodiments, the form is pattern 7, characterized in that the XRPD pattern includes 2θ values selected from the following: 5.8±0.2°, 10.9±0.2°, 11.8±0.2°, 18.1±0.2°, 18.7±0.2°, 19.3±0.2°, 21.6±0.2°, 23.3±0.2° and 25.6±0.2°.

Table 38 below provides a list of XRPD peaks for Pattern 8, which has a relative intensity peak of >10%. The sharp peaks observed in the XRPD of Pattern 8 indicate that the sample is composed of crystalline material. Significant peaks were observed in the XRPD at approximately 4.0±0.2°, 7.4±0.2°, 10.8±0.2°, 15.8±0.2°, 16.4±0.2°, 17.3±0.2°, 18.5±0.2°, 18.7±0.2°, 19.3±0.2°, 19.6±0.2°, 20.0±0.2°, 20.9±0.2°, 21.6±0.2°, 21.9±0.2°, 23.0±0.2°, 23.5±0.2°, 23.8±0.2°, 24.2±0.2°, 25±0.2°, and 29.9±0.2° in Figure 8. Table 38 lists the XRPD peaks in Figure 8. Position [°2θ] Altitude [cts] Maintain FWHM [°2θ] Spacing [Å] Relative strength [%] 4.0480 347.38 0.0768 21.82815 11.93 7.4108 547.85 0.0640 11.92907 18.82 8.1013 187.49 0.0512 10.91390 6.44 9.3731 222.58 0.0640 9.43567 7.65 10.7926 549.61 0.0768 8.19763 18.88 15.2279 177.64 0.1023 5.81849 6.10 15.7970 398.88 0.1279 5.61015 13.70 16.4382 1158.24 0.0895 5.39272 39.79 17.2971 593.58 0.1023 5.12682 20.39 18.4863 2910.63 0.1151 4.79963 100.00 18.7442 1043.18 0.1151 4.73417 35.84 19.3171 921.07 0.1407 4.59503 31.64 19.5765 482.48 0.1151 4.53473 16.58 20.0240 820.68 0.1023 4.43439 28.20 20.9059 353.65 0.1791 4.24928 12.15 21.6070 931.36 0.1023 4.11294 32.00 21.8743 671.04 0.1279 4.06328 23.05 23.0044 345.45 0.1023 3.86617 11.87 23.4827 2080.97 0.2047 3.78850 71.50 23.8209 1125.13 0.1151 3.73548 38.66 24.1806 1401.67 0.0640 3.68072 48.16 25.5457 846.89 0.1151 3.48704 29.10 26.3518 179.23 0.1279 3.38217 6.16 29.5376 209.55 0.2303 3.02424 7.20 29.9908 375.55 0.1791 2.97957 12.90 31.0626 118.34 0.1535 2.87915 4.07 32.4502 89.31 0.2047 2.75914 3.07 33.1940 118.10 0.1535 2.69900 4.06 33.9568 101.24 0.1535 2.64010 3.48

In some embodiments, the form is pattern 8, characterized in that the XRPD pattern includes at least two peaks selected from the following: 4.0±0.2°, 7.4±0.2°, 10.8±0.2°, 15.8±0.2°, 16.4±0.2°, 17.3±0.2°, 18.5±0.2°, 18.7±0.2°, 19.3±0.2°, 19.6±0.2°, 20.0±0.2°, 20.9±0.2°, 21.6±0.2°, 21.9±0.2°, 23.0±0.2°, 23.5±0.2°, 23.8±0.2°, 24.2±0.2°, 25.±0.2°, and 29.9±0.2°.

In some embodiments, the form is pattern 8, characterized in that the XRPD pattern includes at least three peaks selected from the following: 4.0±0.2°, 7.4±0.2°, 10.8±0.2°, 15.8±0.2°, 16.4±0.2°, 17.3±0.2°, 18.5±0.2°, 18.7±0.2°, 19.3±0.2°, 19.6±0.2°, 20.0±0.2°, 20.9±0.2°, 21.6±0.2°, 21.9±0.2°, 23.0±0.2°, 23.5±0.2°, 23.8±0.2°, 24.2±0.2°, 25.±0.2°, and 29.9±0.2°.

In some embodiments, the form is pattern 8, characterized in that the XRPD pattern includes at least 5 peaks selected from the following: 4.0±0.2°, 7.4±0.2°, 10.8±0.2°, 15.8±0.2°, 16.4±0.2°, 17.3±0.2°, 18.5±0.2°, 18.7±0.2°, 19.3±0.2°, 19.6±0.2°, 20.0±0.2°, 20.9±0.2°, 21.6±0.2°, 21.9±0.2°, 23.0±0.2°, 23.5±0.2°, 23.8±0.2°, 24.2±0.2°, 25.±0.2°, and 29.9±0.2°.

In some embodiments, the form is pattern 8, characterized in that the XRPD pattern includes at least 7 peaks selected from the following: 4.0±0.2°, 7.4±0.2°, 10.8±0.2°, 15.8±0.2°, 16.4±0.2°, 17.3±0.2°, 18.5±0.2°, 18.7±0.2°, 19.3±0.2°, 19.6±0.2°, 20.0±0.2°, 20.9±0.2°, 21.6±0.2°, 21.9±0.2°, 23.0±0.2°, 23.5±0.2°, 23.8±0.2°, 24.2±0.2°, 25.±0.2°, and 29.9±0.2°.

In some embodiments, the form is pattern 8, characterized in that the XRPD pattern contains at least 9 peaks selected from the following: 4.0±0.2°, 7.4±0.2°, 10.8±0.2°, 15.8±0.2°, 16.4±0.2°, 17.3±0.2°, 18.5±0.2°, 18.7±0.2°, 19.3±0.2°, 19.6±0.2°, 20.0±0.2°, 20.9±0.2°, 21.6±0.2°, 21.9±0.2°, 23.0±0.2°, 23.5±0.2°, 23.8±0.2°, 24.2±0.2°, 25.±0.2°, and 29.9±0.2°.

In some embodiments, the form is pattern 8, characterized in that the XRPD pattern contains at least 11 peaks selected from the following: 4.0±0.2°, 7.4±0.2°, 10.8±0.2°, 15.8±0.2°, 16.4±0.2°, 17.3±0.2°, 18.5±0.2°, 18.7±0.2°, 19.3±0.2°, 19.6±0.2°, 20.0±0.2°, 20.9±0.2°, 21.6±0.2°, 21.9±0.2°, 23.0±0.2°, 23.5±0.2°, 23.8±0.2°, 24.2±0.2°, 25.±0.2°, and 29.9±0.2°.

In some embodiments, the form is pattern 8, characterized in that the XRPD pattern contains at least 13 peaks selected from the following: 4.0±0.2°, 7.4±0.2°, 10.8±0.2°, 15.8±0.2°, 16.4±0.2°, 17.3±0.2°, 18.5±0.2°, 18.7±0.2°, 19.3±0.2°, 19.6±0.2°, 20.0±0.2°, 20.9±0.2°, 21.6±0.2°, 21.9±0.2°, 23.0±0.2°, 23.5±0.2°, 23.8±0.2°, 24.2±0.2°, 25.±0.2°, and 29.9±0.2°.

In some embodiments, the form is pattern 8, characterized in that the XRPD pattern contains at least 15 peaks selected from the following: 4.0±0.2°, 7.4±0.2°, 10.8±0.2°, 15.8±0.2°, 16.4±0.2°, 17.3±0.2°, 18.5±0.2°, 18.7±0.2°, 19.3±0.2°, 19.6±0.2°, 20.0±0.2°, 20.9±0.2°, 21.6±0.2°, 21.9±0.2°, 23.0±0.2°, 23.5±0.2°, 23.8±0.2°, 24.2±0.2°, 25.±0.2°, and 29.9±0.2°.

In some embodiments, the form is pattern 8, characterized in that the XRPD pattern contains at least 17 peaks selected from the following: 4.0±0.2°, 7.4±0.2°, 10.8±0.2°, 15.8±0.2°, 16.4±0.2°, 17.3±0.2°, 18.5±0.2°, 18.7±0.2°, 19.3±0.2°, 19.6±0.2°, 20.0±0.2°, 20.9±0.2°, 21.6±0.2°, 21.9±0.2°, 23.0±0.2°, 23.5±0.2°, 23.8±0.2°, 24.2±0.2°, 25.±0.2°, and 29.9±0.2°.

In some embodiments, the form is pattern 8, characterized in that the XRPD pattern contains at least 19 peaks selected from the following: 4.0±0.2°, 7.4±0.2°, 10.8±0.2°, 15.8±0.2°, 16.4±0.2°, 17.3±0.2°, 18.5±0.2°, 18.7±0.2°, 19.3±0.2°, 19.6±0.2°, 20.0±0.2°, 20.9±0.2°, 21.6±0.2°, 21.9±0.2°, 23.0±0.2°, 23.5±0.2°, 23.8±0.2°, 24.2±0.2°, 25.±0.2°, and 29.9±0.2°.

In some embodiments, the form is pattern 8, characterized in that the XRPD pattern includes 2θ values selected from the following: 4.0±0.2°, 7.4±0.2°, 10.8±0.2°, 15.8±0.2°, 16.4±0.2°, 17.3±0.2°, 18.5±0.2°, 18.7±0.2°, 19.3±0.2°, 19.6±0.2°, 20.0±0.2°, 20.9±0.2°, 21.6±0.2°, 21.9±0.2°, 23.0±0.2°, 23.5±0.2°, 23.8±0.2°, 24.2±0.2°, 25.±0.2°, and 29.9±0.2°.

Table 39 below provides a list of XRPD peaks for Pattern 9, which has a relative intensity peak of >10%. The sharp peaks observed in the XRPD of Pattern 9 indicate that the sample is composed of crystalline material. Significant peaks were observed in the XRPD at approximately 11.4±0.2°, 11.5±0.2°, 12.8±0.2°, 16.3±0.2°, 16.9±0.2°, 19.0±0.2°, 22.5±0.2°, 24.0±0.2°, 24.7±0.2°, 25.0±0.2°, 25.2±0.2°, 25.6±0.2°, 26.9±0.2°, 28.2±0.2°, 29.2±0.2°, 29.6±0.2°, 29.7±0.2°, 29.8±0.2°, 32.5±0.2°, 32.6±0.2°, and 33.6±0.2° in Figure 9. Table 39. List of XRPD peaks in Figure 9. Position [°2θ] Altitude [cts] Maintain FWHM [°2θ] Spacing [Å] Relative strength [%] 3.3241 66.84 0.6140 26.58015 1.22 5.8249 435.60 0.0768 15.17296 7.95 10.8757 163.63 0.0768 8.13513 2.98 11.2250 455.75 0.0384 7.88278 8.31 11.3768 2582.29 0.0256 7.77792 47.10 11.4550 3239.65 0.0512 7.72505 59.09 11.7506 125.87 0.1023 7.53135 2.30 12.7555 911.61 0.0768 6.94019 16.63 16.2943 579.18 0.0640 5.44001 10.56 16.9724 5482.56 0.0640 5.22416 100.00 18.3347 317.87 0.0768 4.83897 5.80 19.0290 1955.36 0.0512 4.66393 35.67 21.6233 209.25 0.1023 4.10989 3.82 22.5372 3327.96 0.0640 3.94525 60.70 23.0204 228.23 0.0895 3.86352 4.16 23.3310 202.17 0.1023 3.81279 3.69 24.0081 1586.58 0.0768 3.70676 28.94 24.7459 1138.05 0.0512 3.59790 20.76 25.0321 671.51 0.0512 3.55741 12.25 25.1807 628.82 0.0384 3.53675 11.47 25.6410 589.48 0.0512 3.47430 10.75 26.8890 774.68 0.0384 3.31581 14.13 27.3292 336.97 0.1535 3.26339 6.15 28.1945 1400.08 0.0768 3.16518 25.54 29.2218 587.48 0.0768 3.05620 10.72 29.5880 578.30 0.0468 3.01670 10.55 29.6825 2105.96 0.0624 3.00731 38.41 29.7556 2789.47 0.0512 3.00258 50.88 30.8547 227.32 0.0768 2.89808 4.15 31.3680 103.61 0.1791 2.85182 1.89 32.5428 1281.07 0.0624 2.74922 23.37 32.6311 1246.75 0.0468 2.74880 22.74 33.0463 389.09 0.0468 2.70848 7.10 33.1273 426.22 0.0468 2.70204 7.77 33.6270 830.91 0.0624 2.66302 15.16 34.2293 196.40 0.1248 2.61753 3.58 34.4200 366.04 0.0468 2.60346 6.68 34.5206 224.05 0.0468 2.60256 4.09

In some embodiments, the form is pattern 9, characterized in that the XRPD pattern includes at least two peaks selected from the following: 11.4±0.2°, 11.5±0.2°, 12.8±0.2°, 16.3±0.2°, 16.9±0.2°, 19.0±0.2°, 22.5±0.2°, 24.0±0.2°, 24.7±0.2°, 25.0±0.2°, 25.2±0.2°, 25.6±0.2°, 26.9±0.2°, 28.2±0.2°, 29.2±0.2°, 29.6±0.2°, 29.7±0.2°, 29.8±0.2°, 32.5±0.2°, 32.6±0.2°, and 33.6±0.2°.

In some embodiments, the form is pattern 9, characterized in that the XRPD pattern includes at least three peaks selected from the following: 11.4±0.2°, 11.5±0.2°, 12.8±0.2°, 16.3±0.2°, 16.9±0.2°, 19.0±0.2°, 22.5±0.2°, 24.0±0.2°, 24.7±0.2°, 25.0±0.2°, 25.2±0.2°, 25.6±0.2°, 26.9±0.2°, 28.2±0.2°, 29.2±0.2°, 29.6±0.2°, 29.7±0.2°, 29.8±0.2°, 32.5±0.2°, 32.6±0.2°, and 33.6±0.2°.

In some embodiments, the form is pattern 9, characterized in that the XRPD pattern includes at least 5 peaks selected from the following: 11.4±0.2°, 11.5±0.2°, 12.8±0.2°, 16.3±0.2°, 16.9±0.2°, 19.0±0.2°, 22.5±0.2°, 24.0±0.2°, 24.7±0.2°, 25.0±0.2°, 25.2±0.2°, 25.6±0.2°, 26.9±0.2°, 28.2±0.2°, 29.2±0.2°, 29.6±0.2°, 29.7±0.2°, 29.8±0.2°, 32.5±0.2°, 32.6±0.2°, and 33.6±0.2°.

In some embodiments, the form is pattern 9, characterized in that the XRPD pattern includes at least 7 peaks selected from the following: 11.4±0.2°, 11.5±0.2°, 12.8±0.2°, 16.3±0.2°, 16.9±0.2°, 19.0±0.2°, 22.5±0.2°, 24.0±0.2°, 24.7±0.2°, 25.0±0.2°, 25.2±0.2°, 25.6±0.2°, 26.9±0.2°, 28.2±0.2°, 29.2±0.2°, 29.6±0.2°, 29.7±0.2°, 29.8±0.2°, 32.5±0.2°, 32.6±0.2°, and 33.6±0.2°.

In some embodiments, the form is pattern 9, characterized in that the XRPD pattern contains at least 9 peaks selected from the following: 11.4±0.2°, 11.5±0.2°, 12.8±0.2°, 16.3±0.2°, 16.9±0.2°, 19.0±0.2°, 22.5±0.2°, 24.0±0.2°, 24.7±0.2°, 25.0±0.2°, 25.2±0.2°, 25.6±0.2°, 26.9±0.2°, 28.2±0.2°, 29.2±0.2°, 29.6±0.2°, 29.7±0.2°, 29.8±0.2°, 32.5±0.2°, 32.6±0.2°, and 33.6±0.2°.

In some embodiments, the form is pattern 9, characterized in that the XRPD pattern contains at least 11 peaks selected from the following: 11.4±0.2°, 11.5±0.2°, 12.8±0.2°, 16.3±0.2°, 16.9±0.2°, 19.0±0.2°, 22.5±0.2°, 24.0±0.2°, 24.7±0.2°, 25.0±0.2°, 25.2±0.2°, 25.6±0.2°, 26.9±0.2°, 28.2±0.2°, 29.2±0.2°, 29.6±0.2°, 29.7±0.2°, 29.8±0.2°, 32.5±0.2°, 32.6±0.2°, and 33.6±0.2°.

In some embodiments, the form is pattern 9, characterized in that the XRPD pattern contains at least 13 peaks selected from the following: 11.4±0.2°, 11.5±0.2°, 12.8±0.2°, 16.3±0.2°, 16.9±0.2°, 19.0±0.2°, 22.5±0.2°, 24.0±0.2°, 24.7±0.2°, 25.0±0.2°, 25.2±0.2°, 25.6±0.2°, 26.9±0.2°, 28.2±0.2°, 29.2±0.2°, 29.6±0.2°, 29.7±0.2°, 29.8±0.2°, 32.5±0.2°, 32.6±0.2°, and 33.6±0.2°.

In some embodiments, the form is pattern 9, characterized in that the XRPD pattern contains at least 15 peaks selected from the following: 11.4±0.2°, 11.5±0.2°, 12.8±0.2°, 16.3±0.2°, 16.9±0.2°, 19.0±0.2°, 22.5±0.2°, 24.0±0.2°, 24.7±0.2°, 25.0±0.2°, 25.2±0.2°, 25.6±0.2°, 26.9±0.2°, 28.2±0.2°, 29.2±0.2°, 29.6±0.2°, 29.7±0.2°, 29.8±0.2°, 32.5±0.2°, 32.6±0.2°, and 33.6±0.2°.

In some embodiments, the form is pattern 9, characterized in that the XRPD pattern contains at least 17 peaks selected from the following: 11.4±0.2°, 11.5±0.2°, 12.8±0.2°, 16.3±0.2°, 16.9±0.2°, 19.0±0.2°, 22.5±0.2°, 24.0±0.2°, 24.7±0.2°, 25.0±0.2°, 25.2±0.2°, 25.6±0.2°, 26.9±0.2°, 28.2±0.2°, 29.2±0.2°, 29.6±0.2°, 29.7±0.2°, 29.8±0.2°, 32.5±0.2°, 32.6±0.2°, and 33.6±0.2°.

In some embodiments, the form is pattern 9, characterized in that the XRPD pattern contains at least 19 peaks selected from the following: 11.4±0.2°, 11.5±0.2°, 12.8±0.2°, 16.3±0.2°, 16.9±0.2°, 19.0±0.2°, 22.5±0.2°, 24.0±0.2°, 24.7±0.2°, 25.0±0.2°, 25.2±0.2°, 25.6±0.2°, 26.9±0.2°, 28.2±0.2°, 29.2±0.2°, 29.6±0.2°, 29.7±0.2°, 29.8±0.2°, 32.5±0.2°, 32.6±0.2°, and 33.6±0.2°.

In some embodiments, the form is pattern 9, characterized in that the XRPD pattern includes 2θ values selected from the following: 11.4±0.2°, 11.5±0.2°, 12.8±0.2°, 16.3±0.2°, 16.9±0.2°, 19.0±0.2°, 22.5±0.2°, 24.0±0.2°, 24.7±0.2°, 25.0±0.2°, 25.2±0.2°, 25.6±0.2°, 26.9±0.2°, 28.2±0.2°, 29.2±0.2°, 29.6±0.2°, 29.7±0.2°, 29.8±0.2°, 32.5±0.2°, 32.6±0.2°, and 33.6±0.2°.

Table 40 below provides a list of XRPD peaks for Pattern 10, which has a relative intensity peak >10%. The XRPD of Pattern 10 exhibits sharp peaks, indicating that the sample is composed of a crystalline material. Significant peaks were observed in the XRPD of Pattern 10 at approximately 8.6±0.2°, 8.8±0.2°, 18.8±0.2°, 22.8±0.2°, 28.4±0.2°, 30.0±0.2°, 30.6±0.2°, 30.7±0.2°, 31.1±0.2°, 31.3±0.2°, and 33.4±0.2°. Table 40. List of XRPD peaks for Pattern 10. Position [°2θ] Altitude [cts] Maintain FWHM [°2θ] Spacing [Å] Relative strength [%] 5.8105 111.76 0.1023 15.21055 3.02 8.4576 348.24 0.0512 10.45487 9.42 8.6052 938.19 0.0384 10.27586 25.37 8.8323 3698.48 0.0895 10.01221 100.00 10.8959 47.29 0.1535 8.12011 1.28 11.7796 49.97 0.2047 7.51285 1.35 17.7257 115.24 0.2047 5.00383 3.12 18.7729 461.23 0.0768 4.72700 12.47 19.2217 201.82 0.1279 4.61762 5.46 19.8311 260.56 0.1023 4.47708 7.04 21.6431 180.47 0.1279 4.10617 4.88 22.7827 March 1974 0.1023 3.90330 53.37 23.3096 166.09 0.1535 3.81624 4.49 24.3184 133.94 0.1279 3.66017 3.62 26.3881 331.12 0.1023 3.37760 8.95 26.7437 104.59 0.1535 3.33350 2.83 27.6105 180.69 0.1535 3.23079 4.89 28.3607 1012.39 0.0895 3.14701 27.37 30.0318 3097.78 0.1279 2.97559 83.76 30.4202 255.52 0.0768 2.93848 6.91 30.6379 1479.82 0.0468 2.91568 40.01 30.7217 2244.78 0.0512 2.91033 60.69 31.1380 428.31 0.0895 2.87236 11.58 31.3221 416.14 0.1279 2.85589 11.25 31.9484 263.81 0.0512 2.80132 7.13 32.4521 119.39 0.1279 2.75899 3.23 33.1508 177.25 0.0768 2.70241 4.79 33.4324 1032.02 0.1151 2.68030 27.90 34.3039 136.16 0.1535 2.61417 3.68 34.6150 319.87 0.2047 2.59138 8.65

In some embodiments, the form is pattern 10, characterized in that the XRPD pattern includes at least two peaks selected from the following: 8.6±0.2°, 8.8±0.2°, 18.8±0.2°, 22.8±0.2°, 28.4±0.2°, 30.0±0.2°, 30.6±0.2°, 30.7±0.2°, 31.1±0.2°, 31.3±0.2° and 33.4±0.2°.

In some embodiments, the form is pattern 10, characterized in that the XRPD pattern includes at least three peaks selected from the following: 8.6±0.2°, 8.8±0.2°, 18.8±0.2°, 22.8±0.2°, 28.4±0.2°, 30.0±0.2°, 30.6±0.2°, 30.7±0.2°, 31.1±0.2°, 31.3±0.2° and 33.4±0.2°.

In some embodiments, the form is pattern 10, characterized in that the XRPD pattern includes at least five peaks selected from the following: 8.6±0.2°, 8.8±0.2°, 18.8±0.2°, 22.8±0.2°, 28.4±0.2°, 30.0±0.2°, 30.6±0.2°, 30.7±0.2°, 31.1±0.2°, 31.3±0.2° and 33.4±0.2°.

In some embodiments, the form is pattern 10, characterized in that the XRPD pattern includes at least 7 peaks selected from the following: 8.6±0.2°, 8.8±0.2°, 18.8±0.2°, 22.8±0.2°, 28.4±0.2°, 30.0±0.2°, 30.6±0.2°, 30.7±0.2°, 31.1±0.2°, 31.3±0.2° and 33.4±0.2°.

In some embodiments, the form is pattern 10, characterized in that the XRPD pattern includes at least nine peaks selected from the following: 8.6±0.2°, 8.8±0.2°, 18.8±0.2°, 22.8±0.2°, 28.4±0.2°, 30.0±0.2°, 30.6±0.2°, 30.7±0.2°, 31.1±0.2°, 31.3±0.2° and 33.4±0.2°.

In some embodiments, the form is pattern 10, characterized in that the XRPD pattern includes 2θ values selected from the following: 8.6±0.2°, 8.8±0.2°, 18.8±0.2°, 22.8±0.2°, 28.4±0.2°, 30.0±0.2°, 30.6±0.2°, 30.7±0.2°, 31.1±0.2°, 31.3±0.2°, and 33.4±0.2°.

Example 28. Freeze-dried powder X -ray powder diffraction (XRPD) analysis of the freeze-dried compositions described in Table 41 below. Table 41 Freeze-dried compositions Components Quantity ^a (mg) per vial Medical Function Quality Standards ^Compound 1b 300 Activator inherent Mannitol 300 Ingredients USP/Ph. Eur. Citric acid monohydrate 75 buffer USP/Ph. Eur. Sodium hydroxide Sufficient pH adjuster ^C NF/Ph. Eur. hydrochloric acid Sufficient pH adjuster ^C NF/Ph. Eur. Water ^d Sufficient solvent USP/Ph. Eur. Nitrogen ^e N/A Process aids NF NF = United States National Prescriptions; USP = United States Pharmacopeia; Ph. Eur. = European Pharmacopeia; N/A = Not Applicable; qs = Sufficient. a. The target weight of the solution filled into the vial before freeze-drying is 12.252 g (12 mL). b. The amount relative to the free base (equivalent to 373 mg of compound 1, pattern 1, dihydrochloride dihydrate). c. Can be used to adjust the pH of the bulk solution if necessary. d. Used to dissolve components, subsequently removed during freeze-drying. e. Nitrogen is used as an inert gas at the end of the freeze-drying process for vacuum conditioning.

The freeze-dried compositions described in Table 41 can be prepared by mixing mannitol and citric acid monohydrate in the mass ratios described in Table 41. Where appropriate, the pH of the solution is adjusted with hydrochloric acid and sodium hydroxide to achieve a pH between 3.5 and 5, typically between 4.1 and 4.3.

Representative kilogram-scale preparation of the freeze-dried composition from Table 41 is provided as follows: Mannitol (4 kg) is slowly added to a tank of water for injection (WFI) grade water (130 kg). The mannitol dispensing container is rinsed with 500 mL of WFI and the material is added to the tank and mixed until the mannitol is completely dissolved. Then, citric acid monohydrate (1 kg) is added to the tank and the dispensing container is rinsed with 200 mL of WFI. The resulting solution is mixed until completely dissolved. A sample of the solution is taken and the pH is checked (2.26), and then adjusted by slowly adding 2800 mL of 5N NaOH. The pH is checked again (6.56) and an additional 100 mL of 5N NaOH is added. The pH was checked again (7.2), and then 100 mL of 1N HCl solution was added to produce a solution with a pH of 6.98. An additional 100 mL of 1N HCl solution was added to produce a final pH of 6.85. Compound 1 dihydrochloride dihydrate (4.92 kg) was then slowly added to the mixed solution. The compound 1 dihydrochloride dihydrate application vessel was washed three times with a total of 1 L of WFI and then mixed for 30 minutes. The pH of the solution was obtained (4.44), and then the pH was adjusted by continuously adding 1N HCl (a total of 890 mL) to a final pH of (4.30). Additional WFI was then added until the tank contained 163.4 kg of material. The solution was then mixed for an additional 20 minutes and stored overnight at room temperature. The bulk solution was then aspirated through a filter into another tank, where samples were collected for analytical purposes.

The filtered solution was then loaded into appropriately sized vials. The freeze-drying apparatus plates were then pre-cooled to 5°C, and the vials were placed on the plates. Freeze-drying was performed at the following temperatures and under vacuum: Step number stage temperature pressure Time (hh:mm ) 1 Loading 5℃ Atmospheric pressure N/A 2 frozen 5℃ Atmospheric pressure 00:10 3 -42℃ Atmospheric pressure 00:47 4 -42℃ Atmospheric pressure 05:00 5 -17℃ Atmospheric pressure 00:25 6 -17℃ Atmospheric pressure 05:00 7 -42℃ Atmospheric pressure 00:25 8 -42℃ Atmospheric pressure 05:00 9 Empty -42℃ 150 milliton N/A 10 First drying -42℃ 150 milliton 00:15 11 -14℃ 150 milliton 00:28 12 -14℃ 150 milliton 69:00 13 Secondary drying 36℃ 150 milliton 00:50 14 36℃ 150 milliton 06:00 15 20℃ 150 milliton 00:15 16 Pre-inflate (with _N2 ) 20℃ 11 psi N/A 17 Cut in line 20℃ 1000 psi N/A Total length Approximately 94 hours

After the cycle was completed, the freeze-drying chamber was purged with nitrogen gas filtered through the 0.22 μm sterile freeze-drying filter. The freeze-dried sample of this material was then analyzed by XRPD.

XRPD analysis was performed on a Bruker D8 advanced powder X-ray diffraction system by placing the sample in the center of a zero-background holder coated with a thin layer of petroleum paste, followed by flattening the sample with a glass slide.

Use the following instrument parameters for the X-ray diffraction system: General parameters Scan mode Continuous PSD Fast Time for each step 1 second (valid for 192 seconds) Scanning range 2 to 40θ Step size 0.05θ Sample rotation 15 revolutions per minute CuKalpha rotation 40kV: 40mA Scan type Coupled 2θ/θ Primary beam optical components Diverging Narrow Seam/Double Primary Narrow Seam 0.6 mm Primary narrow gap installation without Primary soller slit 2.5θ Secondary beam optical components Secondary Soler slot/detector optical component mount 2 2.5θ Detector optical component mounting component 1 tunnel Detector narrow opening/secondary narrow opening mount without Anti-scattering narrow gaps / dual secondary narrow gaps 3mm blade exist Detector opening 2.940θ

The XRPD image is shown in Figure 100.

Table 42 below provides a list of peaks with a relative intensity of >10% for the freeze-dried compound 1 dihydrochloride composition containing the above-mentioned mannitol and citric acid. XRPD of the freeze-dried compound 1 dihydrochloride composition shows sharp peaks, indicating that the sample remains crystalline after freeze-drying. Significant peaks were observed at approximately 9.8±0.4°, 18.9±0.4°, 19.5±0.4°, 20.5±0.4°, 21.2±0.4°, 22.2±0.4°, 23.5±0.4°, 24.7±0.4°, 25.4±0.4°, 31.8±0.4°, and 36.2±0.4°2θ in the XRPD pattern of the freeze-dried compound 1 dihydrochloride composition containing mannitol and citric acid. The XRPD patterns exhibit several peaks of compound 1 and clearly show the formation of compound 1 pattern 1 during the freeze-drying process. Table 42 lists the XRPD peaks with a relative intensity >10% for the freeze-dried compound 1 dihydrochloride composition containing mannitol and citric acid. angle Relative strength [%] 9.753 100 18.858 15.2 19.507 13.0 20.458 86.6 21.159 32.1 22.158 29.2 23.459 11.8 24.710 30.0 25.410 27.7 31.763 44.0 36.165 19.5

In some embodiments, the freeze-dried compound 1 dihydrochloride composition is characterized by an XRPD pattern containing at least two peaks selected from the following: 9.8±0.4°, 18.9±0.4°, 19.5±0.4°, 20.5±0.4°, 21.2±0.4°, 22.2±0.4°, 23.5±0.4°, 24.7±0.4°, 25.4±0.4°, 31.8±0.4°, and 36.2±0.4°2θ.

In some embodiments, the freeze-dried compound 1 dihydrochloride composition is characterized by an XRPD pattern containing at least three peaks selected from the following: 9.8±0.4°, 18.9±0.4°, 19.5±0.4°, 20.5±0.4°, 21.2±0.4°, 22.2±0.4°, 23.5±0.4°, 24.7±0.4°, 25.4±0.4°, 31.8±0.4°, and 36.2±0.4°2θ.

In some embodiments, the freeze-dried compound 1 dihydrochloride composition is characterized by an XRPD pattern containing at least four peaks selected from the following: 9.8±0.4°, 18.9±0.4°, 19.5±0.4°, 20.5±0.4°, 21.2±0.4°, 22.2±0.4°, 23.5±0.4°, 24.7±0.4°, 25.4±0.4°, 31.8±0.4°, and 36.2±0.4°2θ.

In some embodiments, the freeze-dried compound 1 dihydrochloride composition is characterized by an XRPD pattern containing at least five peaks selected from the following: 9.8±0.4°, 18.9±0.4°, 19.5±0.4°, 20.5±0.4°, 21.2±0.4°, 22.2±0.4°, 23.5±0.4°, 24.7±0.4°, 25.4±0.4°, 31.8±0.4°, and 36.2±0.4°2θ.

In some embodiments, the freeze-dried compound 1 dihydrochloride composition is characterized by an XRPD pattern containing at least six peaks selected from the following: 9.8±0.4°, 18.9±0.4°, 19.5±0.4°, 20.5±0.4°, 21.2±0.4°, 22.2±0.4°, 23.5±0.4°, 24.7±0.4°, 25.4±0.4°, 31.8±0.4°, and 36.2±0.4°2θ.

In some embodiments, the freeze-dried compound 1 dihydrochloride composition is characterized by an XRPD pattern containing at least seven peaks selected from the following: 9.8±0.4°, 18.9±0.4°, 19.5±0.4°, 20.5±0.4°, 21.2±0.4°, 22.2±0.4°, 23.5±0.4°, 24.7±0.4°, 25.4±0.4°, 31.8±0.4°, and 36.2±0.4°2θ.

In some embodiments, the freeze-dried compound 1 dihydrochloride composition is characterized by an XRPD pattern containing at least eight peaks selected from the following: 9.8±0.4°, 18.9±0.4°, 19.5±0.4°, 20.5±0.4°, 21.2±0.4°, 22.2±0.4°, 23.5±0.4°, 24.7±0.4°, 25.4±0.4°, 31.8±0.4°, and 36.2±0.4°2θ.

In some embodiments, the freeze-dried compound 1 dihydrochloride composition is characterized by an XRPD pattern containing at least nine peaks selected from the following: 9.8±0.4°, 18.9±0.4°, 19.5±0.4°, 20.5±0.4°, 21.2±0.4°, 22.2±0.4°, 23.5±0.4°, 24.7±0.4°, 25.4±0.4°, 31.8±0.4°, and 36.2±0.4°2θ.

In some embodiments, the freeze-dried compound 1 dihydrochloride composition is characterized by an XRPD pattern containing at least 10 peaks selected from the following: 9.8±0.4°, 18.9±0.4°, 19.5±0.4°, 20.5±0.4°, 21.2±0.4°, 22.2±0.4°, 23.5±0.4°, 24.7±0.4°, 25.4±0.4°, 31.8±0.4°, and 36.2±0.4°2θ.

In some embodiments, the freeze-dried compound 1 dihydrochloride composition is characterized by an XRPD pattern containing at least the following peaks: 9.8±0.4°, 18.9±0.4°, 19.5±0.4°, 20.5±0.4°, 21.2±0.4°, 22.2±0.4°, 23.5±0.4°, 24.7±0.4°, 25.4±0.4°, 31.8±0.4°, and 36.2±0.4°2θ.

In some embodiments, the freeze-dried compound 1 dihydrochloride composition is characterized by an XRPD pattern containing a peak at 9.8 ± 0.4°2θ.

In some embodiments, the freeze-dried compound 1 dihydrochloride composition is characterized by an XRPD pattern containing a peak at 20.5 ± 0.4°2θ.

In some embodiments, ±0.4°2θ is ±0.3°2θ or ±0.2°2θ.

This specification has been described with reference to embodiments of the present invention. However, those skilled in the art will understand that various modifications and variations can be made without departing from the scope of the present invention as set forth in the claims below. Therefore, this specification should be viewed in an illustrative rather than restrictive sense, and all such modifications are intended to be included within the scope of the present invention.

Figure 1 is the XRPD diffraction pattern of crystalline pattern 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. Figure 2 is a PLM image of crystalline pattern 1. The image was obtained using the method described in Example 5. The material in pattern 1 is highly crystalline under PLM imaging, with the non-polarized material shown on the left and the polarized material shown on the right. Figure 3 is the pyrolysis gravimetric/differential thermal (TG/DTA) thermal analysis plot of crystalline pattern 1. The TG/DTA thermal analysis plot of pattern 1 was obtained as described in Example 6. Approximately 6% of the initial mass loss from heating is related to surface moisture loss. Two mass losses of approximately 7% were observed, peaking at approximately 200°C at 218°C and peaking at approximately 300°C at 343°C. Figure 4 shows the differential scanning calorimetry (DSC) thermal analysis plot for crystallization pattern 1. The DSC thermal analysis plot for crystallization pattern 1 was obtained as described in Example 7. The DSC analysis shows two broad endothermic events, peaking at approximately 65°C at 130°C and peaking at 245°C at 277°C. Rapid melting endothermic events were observed starting from 330°C, peaking at 341°C. Figure 5 shows the dynamic vapor adsorption (DVS) analysis of the results of the moisture adsorption experiment for pattern 1. The DVS analysis for pattern 1 was obtained as described in Example 3. The material was found to be stable, and XRPD analysis of the dried sample at the end of the experiment confirmed Pattern 1. Pattern 1 shows adsorption of 3.00 wt% at 40% RH and 4.00 wt% at 90% RH. The x-axis represents the relative humidity as a percentage, and the y-axis represents the weight of water in the material as a percentage. Figure 6 shows the dynamic vapor adsorption (DVS) kinetics of Pattern 1. The DVS of Pattern 1 was obtained as described in Example 3. The sample was subjected to a slow temperature increase from 40% to 90% relative humidity in 10% increments, and in each step, the sample was held at 25°C until a stable weight (dm/dt 0.004%, minimum step 30 min, maximum step 500 min) was obtained. After the adsorption cycle was completed, the sample was dried to 0% RH using the same procedure and then restored to 40% RH using a second adsorption cycle. Two cycles were performed. The material exhibited hygroscopicity according to DVS, with a mass increase of 4% between 0% and 90% RH. During the desorption cycle, the material was dehydrated. Figure 7 shows a comparison of Pattern 1 after DVS and the XRPD diffraction pattern of Pattern 1. The diffraction pattern of Pattern 1 was obtained as described in Example 1; and Pattern 1 after DVS was obtained as described in Example 11. The material exhibited hygroscopicity according to DVS, with a mass increase of 4% between 0% and 90% RH. During the desorption cycle, the material was dehydrated. XRPD analysis after DVS showed no change in Pattern 1. The x-axis represents 2θ measured in degrees, and the y-axis represents intensity measured in counts. Figure 8 compares the XRPD diffraction plot of Pattern 1 before the solvent solubility study with that of Pattern 1 material generated from various solvent solubility studies. The diffraction plot was obtained as described in Example 1, and the study was conducted as described in Example 13. The x-axis represents 2θ measured in degrees, and the y-axis represents intensity measured in counts. Figure 9 compares the XRPD diffraction plot of Pattern 1 before the solvent solubility study with that of Pattern 1 material generated from various solvent solubility studies. The diffraction plot was obtained as described in Example 1, and the study was conducted as described in Example 13. The x-axis represents 2θ measured in degrees, and the y-axis represents intensity measured in counts. Figure 10 compares the XRPD diffraction plots of Pattern 2 generated from studies of the solubility of various solvents. The diffraction plots were obtained as described in Example 1, and the study was conducted as described in Example 13. The x-axis represents 2θ measured in degrees, and the y-axis represents intensity measured in counts. Figure 11 compares the XRPD diffraction plots of Pattern 2 generated from studies of the solubility of various solvents. The diffraction plots were obtained as described in Example 1, and the study was conducted as described in Example 13. The x-axis represents 2θ measured in degrees, and the y-axis represents intensity measured in counts. Figure 12 compares the XRPD diffraction plots of Pattern 3, generated from solubility studies of various solvents. The diffraction plots were obtained as described in Example 1, and the studies were conducted as described in Example 13. The x-axis represents 2θ measured in degrees, and the y-axis represents intensity measured in counts. Figure 13 compares the XRPD diffraction plots of Pattern 1 and Pattern 4, generated from solubility studies in MeCN. The diffraction plots were obtained as described in Examples 1 and 4, and the studies were conducted as described in Example 13. The x-axis represents 2θ measured in degrees, and the y-axis represents intensity measured in counts. Figure 14 compares the XRPD diffraction plots of Pattern 2 and Pattern 5, generated from various solvent systems. The diffraction pattern was obtained as described in Example 1 and studied as described in Example 13. The x-axis represents 2θ measured in degrees and the y-axis represents intensity measured in counts. Figure 15 compares XRPD diffraction patterns 2 and 6 generated from various solvent systems. The diffraction pattern was obtained as described in Example 1 and studied as described in Example 13. The x-axis represents 2θ measured in degrees and the y-axis represents intensity measured in counts. Figure 16 compares the XRPD diffraction pattern of pattern 1 before and after maturation experiments in various solvent systems. The diffraction pattern was obtained as described in Example 1 and studied as described in Example 21. The x-axis represents 2θ measured in degrees, and the y-axis represents intensity measured in counts. Figure 17 compares the XRPD diffraction plots of Pattern 2 before and after maturation experiments in various solvent systems. The diffraction plots were obtained as described in Example 1, and the study was conducted as described in Example 21. The x-axis represents 2θ measured in degrees, and the y-axis represents intensity measured in counts. Figure 18 compares the XRPD diffraction plots of Pattern 2 before and after maturation experiments in various solvent systems. The diffraction plots were obtained as described in Example 1, and the study was conducted as described in Example 21. The x-axis represents 2θ measured in degrees, and the y-axis represents intensity measured in counts. Figure 19 compares the XRPD diffraction patterns of Pattern 3 before and after maturation experiments in isopropanol and ethanol. The diffraction patterns were obtained as described in Example 1 and studied as described in Example 21. The x-axis represents 2θ measured in degrees and the y-axis represents intensity measured in counts. Figure 20 compares the XRPD diffraction patterns of Pattern 4 before and after maturation experiments in acetonitrile. The diffraction patterns were obtained as described in Example 4 and studied as described in Example 21. The x-axis represents 2θ measured in degrees and the y-axis represents intensity measured in counts. Figure 21 compares the XRPD diffraction patterns of Pattern 5 before and after maturation experiments in methyl isobutyl ketone. The diffraction pattern was obtained as described in Example 1 and studied as described in Example 21. The x-axis represents 2θ measured in degrees and the y-axis represents intensity measured in counts. Figure 22 shows a comparison of XRPD diffraction patterns generated from mature experiments in various solvent systems. The diffraction pattern was obtained as described in Example 1 and studied as described in Example 21. The x-axis represents 2θ measured in degrees and the y-axis represents intensity measured in counts. Figure 23 shows a comparison of XRPD pattern 1 diffraction pattern and diffraction pattern generated from mature experiments in various solvent systems after drying. The diffraction pattern was obtained as described in Example 1 and studied as described in Example 21. The x-axis represents 2θ measured in degrees, and the y-axis represents intensity measured in counts. Figure 24 compares the diffraction pattern 1 and the diffraction pattern generated from mature experiments in various solvent systems after drying. The diffraction pattern was obtained as described in Example 1, and the study was conducted as described in Example 21. The x-axis represents 2θ measured in degrees, and the y-axis represents intensity measured in counts. Figure 25 compares the diffraction pattern 2 and the diffraction pattern generated from mature experiments in various solvent systems after drying. The diffraction pattern was obtained as described in Example 1, and the study was conducted as described in Example 21. The x-axis represents 2θ measured in degrees, and the y-axis represents intensity measured in counts. Figure 26 compares the XRPD pattern 3 diffraction plot and the diffraction plot generated from mature experiments in various solvent systems after drying. The diffraction plot was obtained as described in Example 1, and the study was conducted as described in Example 21. The x-axis represents 2θ measured in degrees, and the y-axis represents intensity measured in counts. Figure 27 compares the XRPD pattern 3 diffraction plot, pattern 4 diffraction plot, and the diffraction plot generated from mature experiments in various solvent systems after drying. The diffraction plot was obtained as described in Examples 1 and 4, and the study was conducted as described in Example 21. The x-axis represents 2θ in degrees and the y-axis represents intensity in counts. Figure 28 compares the diffraction patterns 3 and 6 of the XRPD generated after drying and maturation in heptane. The diffraction patterns were obtained as described in Example 1 and studied as described in Example 21. The x-axis represents 2θ in degrees and the y-axis represents intensity in counts. Figure 29 compares the diffraction patterns 5 of the XRPD generated after drying and maturation in various solvents. The diffraction patterns were obtained as described in Example 1 and studied as described in Example 21. The x-axis represents 2θ in degrees and the y-axis represents intensity in counts. Figure 30 compares the XRPD diffraction pattern of Figure 1 with the solid residue left after the evaporation experiment. The diffraction pattern was obtained as described in Example 1. The solid residue was obtained as described in Example 13. The sample was kept open and placed in a chamber to allow evaporation. The x-axis is 2θ measured in degrees and the y-axis is the intensity measured in counts. Figure 31 compares the XRPD diffraction pattern of Figure 3 with the solid residue left after the evaporation experiment. The diffraction pattern was obtained as described in Example 1. The solid residue was obtained as described in Example 13. The sample was kept open and placed in a chamber to allow evaporation. The x-axis is 2θ measured in degrees and the y-axis is the intensity measured in counts. Figure 32 compares the XRPD diffraction pattern of Pattern 3 with that of the solid produced by adding tributyl methyl ether (t-BME) to 2,2,2-trifluoroethanol. The diffraction pattern was obtained as described in Example 1. The solid was obtained as described in Example 13. The x-axis represents 2θ measured in degrees and the y-axis represents strength measured in counts. Figure 33 shows the pyrolysis gravimetric/differential thermal (TG/DTA) thermal analysis of the small-scale material of Pattern 2. The TG/DTA thermal analysis of Pattern 2 was obtained as described in Example 6. The initial mass loss of approximately 3% from the start of heating is related to surface moisture loss. Two types of mass loss, approximately 7%, were observed at approximately 222°C (peak at 239°C), 318°C (peak at 340°C), and 345°C (peak at 325°C). The x-axis is in temperature (°C) and the y-axis is TG (%). Figure 34 is the pyrolysis gravimetric/differential thermal analysis (TG/DTA) plot of the small-scale material in Figure 3. The TG/DTA plot of Figure 3 was obtained as described in Example 6. The initial mass loss of approximately 2.6% from the start of heating is related to surface moisture loss. Two types of mass loss, approximately 6.6%, were observed at approximately 222°C (peak at 229°C), 311°C (peak at 317°C), and 343°C (peak at 345°C). The x-axis represents temperature (°C) and the y-axis represents TG (%). Figure 35 shows the pyrolysis gravimetric/differential thermal analysis (TG/DTA) plot of the small-scale material in Figure 5. The TG/DTA plot of Figure 5 was obtained as described in Example 6. Approximately 3.4% of the initial mass loss from the start of heating is related to surface moisture loss. Three mass losses of approximately 7.3% were observed, peaking at approximately 206°C at 216°C, at 284°C at 321°C, and at 343°C at 345°C. The x-axis represents temperature (°C) and the y-axis represents TG (%). Figure 36 compares the XRPD plots of the small-scale and scale-up materials in Figures 2 and 6. When pattern 2 is scaled up, it produces a mixture of pattern 6 and pattern 2, as shown in the XRPD diffraction pattern. The diffraction pattern is obtained as described in Example 1. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts. Figure 37 is a PLM image of the mixture of pattern 2 and pattern 6 produced by the scale-up attempt. The PLM image of the pattern 2/6 mixture is obtained as described in Example 5. The scale-up materials of pattern 2/6 are highly crystalline in the PLM image, with the unpolarized material shown on the left and the polarized material shown on the right. Figure 38 is a pyrolysis gravimetric/differential thermal (TG/DTA) thermal analysis plot of the mixture of pattern 2 and pattern 6 produced by the scale-up attempt. The initial mass loss of approximately 3.6% from the start of heating is related to surface moisture loss. Two mass losses of approximately 6.3% were observed at approximately 211°C and a peak of 310°C at 321°C. The x-axis is in temperature (°C) and the y-axis is TG (%). Figure 39 shows the differential scanning calorimetry (DSC) thermal analysis of the mixture of patterns 2 and 6 produced by the scale-up experiment. The DSC thermal analysis of the mixture of patterns 2/6 was obtained as described in Example 7. The DSC analysis shows two broad endothermic processes, peaking at approximately 55.9°C at 131°C and peaking at 267°C at 295°C. Rapid melting endothermic processes were observed from 336°C onwards. Figure 40 shows the gravitational vapor adsorption (GVS) isotherm of the mixture of Pattern 2 and Pattern 6, obtained from a scale-up experiment. The GVS isotherm of the Pattern 2/6 mixture was obtained as described in Example 2. The mixture of Pattern 2 and Pattern 6 adsorbed 4.00 wt% at 40% RH and 7.00 wt% at 90% RH. The x-axis represents the relative humidity measured as a percentage, and the y-axis represents the weight of water in the material measured as a percentage. Figure 41 shows the gravitational vapor adsorption (GVS) kinetics of the mixture of Pattern 2 and Pattern 6, obtained from a scale-up experiment. The GVS isotherm of the Pattern 2/6 mixture was obtained as described in Example 2. The sample was subjected to a slow temperature increase from 40% to 90% relative humidity (RH) in 10% increments. In each step, the sample was held at 25°C until a stable weight was obtained (dm/dt 0.004%, minimum step 550 min, maximum step 900 min). After the adsorption cycle, the sample was dried to 0% RH using the same procedure and then restored to 40% RH using a second adsorption cycle. Two cycles were performed. The material exhibited hygroscopicity according to DVS, with a mass increase of 8% between 0% and 90% RH. During the desorption cycle, the material was dehydrated. Figure 42 compares the scale-up XRPD diffraction patterns of Figures 1 and 2, and the scale-up XRPD diffraction pattern of Figure 2 after DVS. The diffraction pattern was obtained as described in Example 1. The x-axis represents 2θ measured in degrees, and the y-axis represents intensity measured in counts. Figure 43 compares the XRPD diffraction patterns of Pattern 3 at small scale and Pattern 3 at scale adjusted in dry and humid conditions. The diffraction pattern was obtained as described in Example 1. The x-axis represents 2θ measured in degrees, and the y-axis represents intensity measured in counts. Figure 44 shows a PLM image of the scale-up material of Pattern 3. The scale-up material of Pattern 3 exhibits high crystalline structure under PLM imaging as described in Example 5. The unpolarized material is shown on the left, and the polarized material is shown on the right. Figure 45 shows the TG/DTA thermal analysis diagram of the scale-up material of Pattern 3. As described in Example 6, the scale-up TG/DTA thermal analysis plot of Pattern 3 was obtained. The TG/DTA shows two peaks at 199°C and 345°C. Approximately 8% of the initial mass loss from the start of heating is related to surface moisture loss. Two mass losses of approximately 7% were observed at approximately 199°C and 343°C, which peaks at 345°C. The x-axis is in temperature (°C) and the y-axis is TG (%). Figure 46 is the differential scanning calorimetry (DSC) thermal analysis plot of the scale-up material of Pattern 3. The DSC thermal analysis plot of Pattern 3 was obtained as described in Example 7. The DSC analysis shows three broad endothermic peaks at approximately 168°C (peaking at 189°C), 251°C (peaking at 264°C), and 272°C (peaking at 296°C). Rapid melting and endothermic reaction were observed starting at a peak temperature of 337°C, reaching 343°C. Figure 47 shows the DVS isotherm of the scaled-up material in Figure 3. The DVS isotherm of Figure 3 was obtained as described in Example 3. The material exhibits hygroscopicity according to DVS, with a mass increase of 4% between 0% and 90% RH. The material dehydrates during the desorption cycle. Figure 48 shows the DVS kinetic curve of the scaled-up material in Figure 3. The DVS kinetic curve of Figure 3 was obtained as described in Example 3. The sample was subjected to a slow temperature increase from 40% to 90% relative humidity (RH) in 10% increments, maintaining the sample at 25°C until a stable weight was obtained (mass change 0.004%, minimum step 650 min, maximum step 1050 min) in each step. After the adsorption cycle was complete, the sample was dried to 0% RH using the same procedure and then restored to 40% RH using a second adsorption cycle. Two cycles were performed. The material exhibited hygroscopicity according to DVS, with a mass increase of 4% between 0% and 90% RH. The material was dehydrated during the desorption cycle. Figure 49 shows a comparison of the XRPD diffraction patterns of the material at scale 3 before and after DVS. The diffraction patterns were obtained as described in Example 1. The x-axis represents 2θ in degrees and the y-axis represents intensity in counts. Figure 50 compares the XRPD diffraction patterns of Pattern 5 from small-scale and scale-up experiments. The diffraction patterns were obtained as described in Example 1. The x-axis represents 2θ in degrees and the y-axis represents intensity in counts. Figure 51 compares the XRPD diffraction patterns of Pattern 5 from small-scale and scale-up experiments in a repeating process. The diffraction patterns were obtained as described in Example 1. The x-axis represents 2θ in degrees and the y-axis represents intensity in counts. Figure 52 compares the XRPD diffraction patterns of Pattern 2 in various one-week stability studies. Diffraction plots were obtained as described in Example 1. Stability studies compared plots 2 and 2 after one week at ambient temperature and at 80°C. The x-axis represents 2θ measured in degrees, and the y-axis represents intensity measured in counts. Repeated scale-up. Figure 53 compares the XRPD diffraction plots of plot 2 in various one-week stability studies. Diffraction plots were obtained as described in Example 1. Stability studies compared plot 2, plot 2 at scale, and plot 2 at 40°C. The x-axis represents 2θ measured in degrees, and the y-axis represents intensity measured in counts. Repeated scale-up. Figure 54 compares the 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 temperatures of 40°C and 80°C, respectively. The x-axis represents 2θ in degrees and the y-axis represents intensity in counts. Figure 55 compares the XRPD diffraction patterns generated from competing slurry experiments of Pattern 1, which is a mixture of Patterns 2 and 3. After performing the procedure to form Example 11, the diffraction pattern was obtained as described in Example 1. The x-axis represents 2θ in degrees and the y-axis represents intensity in counts. Figure 56 compares the XRPD diffraction patterns generated from competing slurry experiments of Pattern 1, which is combined with Patterns 2 and 3. After implementing the procedure to form Example 11, the diffraction pattern is obtained as described in Example 1. The x-axis is 2θ measured in degrees and the y-axis is the intensity measured in counts. Figure 57 compares the XRPD diffraction patterns generated from competing slurry experiments of Pattern 1, which is combined with Patterns 2 and 3. After implementing the procedure to form Example 11, the diffraction pattern is obtained as described in Example 1. The x-axis is 2θ measured in degrees and the y-axis is the intensity measured in counts. Figure 58 compares the XRPD diffraction patterns generated from competing slurry experiments of Pattern 1, which is combined with Patterns 2 and 3. After implementing the procedure to form Example 11, the diffraction pattern is obtained as described in Example 1. The x-axis is 2θ measured in degrees and the y-axis is the intensity measured in counts. Figure 59 compares the XRPD diffraction patterns generated from competing slurry experiments of Pattern 1, which is combined with Patterns 2 and 3. After implementing the procedure to form Example 11, the diffraction pattern is obtained as described in Example 1. The x-axis is 2θ measured in degrees and the y-axis is the intensity measured in counts. Figure 60 compares the XRPD diffraction plots of Pattern 7 before and after the thermodynamic solubility experiment. The thermodynamic solubility experiment is described in Example 22. The diffraction plots were obtained using a procedure from Example 1. The x-axis represents 2θ measured in degrees and the y-axis represents intensity measured in counts. Figure 61 shows the XRPD diffraction plot of Pattern 7. The diffraction plot of Pattern 7 was obtained as described in Example 1. The x-axis represents 2θ measured in degrees and the y-axis represents intensity measured in counts. Figure 62 shows the PLM image of Pattern 7 at 200× magnification. The PLM image of Pattern 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. Figure 63 is the TG/DTA thermal analysis plot of Figure 7. The TG/DTA thermal analysis plot of Figure 7 was obtained as described in Example 6. The thermal analysis plot shows a 6.2% weight loss between 150 and 340°C and sample decomposition above 350°C. The thermal analysis plot also shows the melting of the sample under conditions that begin at 340°C and reach a peak at 345°C. The x-axis represents temperature measured in degrees Celsius, and the y-axis represents intensity measured in DTA µV on the left and TG% on the right. Figure 64 is the DSC thermal analysis plot of Figure 7 after the first heating. The DSC thermal analysis plot of Figure 7 was obtained as described in Example 7. The thermal analysis plot shows the sample melting event at 335°C and the peak at 338°C during the first heating period (consistent with the TG/DTA data). The x-axis represents temperature measured in degrees Celsius, and the y-axis represents intensity measured in DSC mW. Figure 65 is the DSC thermal analysis plot for the first cooling of Figure 7. The DSC thermal analysis plot for Figure 7 was obtained as described in Example 7. The thermal analysis plot does not show significant thermal events during the cooling cycle. The x-axis represents temperature measured in degrees Celsius, and the y-axis represents intensity measured in DSC mW. Figure 66 is the DSC thermal analysis plot for the second heating of crystallization pattern 7. The DSC thermal analysis plot for Figure 7 was obtained as described in Example 7. The second heating includes a melting event starting at 333°C and a peak at 339°C. Incomplete melting may occur during the initial thermal cycle. The x-axis represents temperature measured in degrees Celsius, and the y-axis represents intensity measured in DSC mW. Figure 67 compares the XRPD diffraction plots from Figure 7 for pH solubility studies at various pH levels. The material produced at pH 4 is identified as Figure 8. The diffraction plot was obtained as described in Example 1, and the pH experiment was conducted as described in Example 16. The x-axis represents 2θ measured in degrees Celsius, and the y-axis represents intensity measured in count. Figure 68 compares the XRPD diffraction plots from Figure 7 for pH solubility studies at various pH levels. The diffraction plot for Figure 7 was obtained as described in Examples 1 and 16. The x-axis represents 2θ measured in degrees, and the y-axis represents intensity measured in counts. Figure 69 shows a comparison of XRPD diffraction plots from Pattern 7 for pH solubility studies in various pH solvent systems. The diffraction plots for Pattern 7 were obtained as described in Examples 1 and 16. The x-axis represents 2θ measured in degrees, and the y-axis represents intensity measured in counts. Figure 70 shows a comparison of XRPD diffraction plots generated from the first group of crystals. Crystallization was performed as described in Example 17. The comparison shows Pattern 7 and its forms generated from various concentrations in various pH solvent systems. The x-axis represents 2θ measured in degrees, and the y-axis represents intensity measured in counts. Figure 71 compares the XRPD diffraction patterns generated from the second and third groups of crystals. Crystallization was performed as described in Examples 18 and 19. The comparison shows the patterns 7 and forms generated 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. Figure 72 compares the XRPD diffraction patterns generated from the second and third groups of crystals. Crystallization was performed as described in Examples 18 and 19. The comparison shows the patterns 7 and forms generated 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. Figure 73 is a comparison of the XRPD diffraction patterns generated from the fourth group of crystals. Crystallization was performed as described in Example 20. The comparison shows the patterns 7 and forms generated 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. Figure 74 is a PLM image corresponding to the material obtained from Experiment 1 of Example 23. Polarized samples are shown in the bottom column and unpolarized samples are shown in the top column. Figure 75 is a PLM image corresponding to the material obtained from Experiment 2 of Example 23. The PLM image was obtained as described in Example 5. Polarized samples are shown on the right and unpolarized samples are shown on the left. Figure 76 is a PLM image corresponding to the material obtained in Experiment 3 of Example 23. The PLM image was obtained as described in Example 5. Polarized samples are shown on the right and unpolarized samples are shown on the left. Figure 77 is a PLM image corresponding to the material obtained in Experiment 4 of Example 23. The PLM image was obtained as described in Example 5. Polarized samples are shown in the bottom column and unpolarized samples are shown in the top column. Figure 78 is a PLM image corresponding to the material obtained in Experiment 5 of Example 23. The PLM image was obtained as described in Example 5. Polarized samples are shown in the bottom column and unpolarized samples are shown in the top column. Figure 79 is a PLM image corresponding to the material obtained in Experiment 7 of Example 23. The PLM image was obtained as described in Example 5. Polarized samples are shown on the right and unpolarized samples on the left. Figure 80 is a PLM image of the material obtained from Experiment 6 of Example 23. The PLM image was obtained as described in Example 5. Polarized samples are shown in the bottom column and unpolarized samples are shown in the top column. Figure 81 is a PLM image of the material obtained from Experiment 8 of Example 23. Polarized samples are shown on the right and unpolarized samples are shown on the left. Figure 82 is a PLM image of the material obtained from Experiment 9 of Example 23. The PLM image was obtained as described in Example 5. Polarized samples are shown on the right and unpolarized samples are shown on the left. Figure 83 is a PLM image of the material obtained from Experiment 10 of Example 23. Polarized samples are shown in the bottom column and unpolarized samples are shown in the top column. Figure 84 is a PLM image corresponding to the material obtained from Experiment 11 of Example 23. Polarized samples are shown on the right and unpolarized samples are shown on the left. Figure 85 is a PLM image corresponding to the material obtained from Experiment 12 of Example 23. This material is identified as pattern 9. Polarized samples are shown in the bottom column and unpolarized samples are shown in the top column. Figure 86 is a PLM image of crystal pattern 10 at 200× magnification. A PLM image of crystal pattern 7 was obtained as described in Example 5. Polarized samples are shown in the bottom column and unpolarized samples are shown in the top column. Figure 87 is a TG/DTA thermal analysis diagram of pattern 9. The TG/DTA thermal analysis plot of Figure 9 was obtained as described in Example 6. Figure 9 shows a significant weight loss of 24.3% from the start of heating up to 150°C. Figure 9 shows a second mass loss of 15 wt.% between 75°C and 154°C. The DT trace identified two endothermic events associated with the mass loss that first started at 37°C and peaked at 66.2°C; a second endothermic event that started at 122°C and peaked at 128°C; and a third and final endothermic event (sample melting) observed in the DT trace that started at 326°C and peaked at 330°C. The x-axis represents temperature measured in degrees Celsius, and the y-axis represents intensity measured in DTAuV on the left and TG% on the right. Figure 88 shows the TG/DTA thermal analysis plot of Figure 10. The TG/DTA thermal analysis plot was obtained as described in Example 6. The thermal analysis plot shows the minimum weight loss of 0.1% between 150°C and 340°C from the start of heating. The sample shows degradation above 320°C. The thermal analysis plot also shows two peaks, the first starting at 199°C and reaching a peak at 206°C; and the second starting at 327°C and reaching a peak at 331°C. The x-axis represents temperature measured in degrees Celsius, and the y-axis represents intensity measured in DTAuV on the left and TG% on the right. Figure 89 is the XRPD diffraction pattern of crystal pattern 8. The crystal structure was obtained using the method described in Example 1, and the peak values are shown in Table 1. The x-axis represents 2θ measured in degrees Celsius, and the y-axis represents intensity measured in counts. Figure 90 shows the crystal structure of pattern 11. It is a dissolved crystal structure as described in Example 25. Non-hydrogen atoms are shown as thermal ellipses with a set probability level of 50%. Figure 91 shows the crystal structure of pattern 11 with the depicted hydrogen bond. It is a dissolved crystal structure as described in Example 25. Non-hydrogen atoms are shown as thermally elliptical shapes with a probability level set at 50%. Figure 92 shows the crystal structure of pattern 11, where the view is set along the a-axis of the unit cell. The dissolved crystal structure is as described in Example 25. Non-hydrogen atoms are shown as thermally elliptical shapes with a probability level set at 50%. Figure 93 shows the crystal structure of pattern 11, where the view is set along the b-axis of the unit cell. The dissolved crystal structure is as described in Example 25. Non-hydrogen atoms are shown as thermally elliptical shapes with a probability level set at 50%. Figure 94 shows the crystal structure of pattern 11, where the view is set along the c-axis of the unit cell. The dissolved crystal structure is as described in Example 25. Non-hydrogen atoms are shown as thermally elliptical shapes with a probability level set at 50%. Figure 95 shows the crystal structure of Pattern 11, with the view set as a void view along the a-axis. It is a dissolved crystal structure as described in Example 25. Non-hydrogen atoms are shown as thermal ellipses with a probability level set at 50%. Figure 96 compares the simulated XRPD pattern of Pattern 11 with the XRPD pattern of Pattern 1. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in counts. Figure 97 shows the crystal structure of Pattern 1 generated from the X-ray crystallization discussed in Example 27. Figure 98 shows the crystal structure of Pattern 1 generated from the X-ray crystallization discussed in Example 27, where hydrogen bonds are clearly shown. Figure 99 is an overlay of the experimentally determined XRPD diffraction pattern of pattern 1 and the simulated diffraction pattern corresponding to the crystal structure shown in Figure 97. The difference between these two lines is shown on the bottom line. Because the bottom line is nearly flat, the simulation strongly indicates that the crystal structure corresponds to the XRPD pattern. Figure 100 is an XRPD diffraction pattern of a freeze-dried compound 1 dihydrochloride composition containing mannitol and citric acid. Crystallization was carried out 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.

Claims (56)

A crystalline compound having the following structure: It is a dihydrochloride dihydrate, wherein the X-ray powder diffraction (XRPD) pattern contains at least eight 2θ values selected from the following: 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°. The crystalline compound of claim 1, wherein the XRPD pattern includes a 2θ value of at least 9.6 ± 0.2°. The crystalline compound of claim 1, wherein the XRPD pattern includes 2θ values of at least 9.6±0.2°, 19.8±0.2° and 21.3±0.2°. The crystalline compound of claim 1, wherein the XRPD pattern includes the following 2θ values: 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°. A composition comprising a crystalline compound as described in any one of claims 1 to 4, mannitol, and citric acid. A pharmaceutical composition comprising a crystalline compound as described in any of claims 1 to 4 and a pharmaceutically acceptable excipient. The pharmaceutical composition of claim 6, wherein the pharmaceutically acceptable excipient comprises mannitol. The pharmaceutical composition of claim 6, wherein the pharmaceutically acceptable excipient comprises citric acid. For example, in the pharmaceutical composition of claim 6, the pharmaceutically acceptable excipient comprises mannitol and citric acid. The pharmaceutical composition of claim 6 contains approximately 200 to 600 milligrams of the crystalline compound. The pharmaceutical composition of claim 6 contains approximately 300 milligrams of the crystalline compound. The pharmaceutical composition of claim 6 contains approximately 349 milligrams of the crystalline compound. The pharmaceutical composition, such as claim 7, contains approximately 250 to 350 mg of mannitol. The pharmaceutical composition, such as claim 7, contains approximately 300 mg of mannitol. The pharmaceutical composition described in claim 8 contains approximately 50 to 100 mg of citric acid. The pharmaceutical composition described in claim 8 contains approximately 76 mg of citric acid. The pharmaceutical composition, such as claim 9, contains approximately 250 to 350 mg of mannitol. The pharmaceutical composition, such as claim 9, contains approximately 300 mg of mannitol. The pharmaceutical composition, such as claim 9, contains approximately 50 to 100 mg of citric acid. The pharmaceutical composition in claim 9 contains approximately 76 mg of citric acid. The pharmaceutical composition described in claim 9 contains approximately 300 mg of mannitol and approximately 76 mg of citric acid. The pharmaceutical composition of claim 21 contains approximately 300 milligrams of the crystalline compound. The pharmaceutical composition of claim 9 comprises the crystalline compound in doses ranging from about 150 mg/m2 to about 350 mg/m2. The pharmaceutical composition of claim 9 contains a dose of the crystalline compound of approximately 240 mg/m2. A pharmaceutical composition formed by dissolving a pharmaceutical composition as described in any one of claims 6 to 24 in a solvent. For example, in the pharmaceutical composition of claim 25, the solvent is water. The pharmaceutical composition of claim 25, wherein the solvent is an aqueous sodium chloride solution. The pharmaceutical composition of claim 27, wherein the sodium chloride concentration is between about 0.1% and 2%. The pharmaceutical composition of claim 27, wherein the sodium chloride concentration is about 0.9%. The pharmaceutical composition of claim 25, wherein the solvent is an aqueous solution of dextran. For example, the pharmaceutical composition of claim 30, wherein the concentration of dextran is between about 1% and 10%. For example, in the pharmaceutical composition of claim 30, the concentration of the dextran is about 5%. The pharmaceutical composition of any of claims 25 to 32 contains approximately 10 to 30 mL of solvent. The pharmaceutical composition of any of claims 25 to 32 contains approximately 19.5 mL of solvent. The use of a crystalline compound of any one of claims 1 to 4, a composition of claim 5, or a pharmaceutical composition of any one of claims 6 to 32 in the preparation of a medicine for treating a condition mediated by CDK4 or CDK6 in patients in need. Use of a crystalline compound of any one of claims 1 to 4, a composition of claim 5, or a pharmaceutical composition of any one of claims 6 to 32 in the preparation of a medicament for the treatment of cancer in patients in need. Use of a crystalline compound of any one of claims 1 to 4, a composition of claim 5, or a pharmaceutical composition of any one of claims 6 to 32 in the preparation of a medicament for reducing the effect of chemotherapy on healthy cells in patients receiving treatment for cancer or abnormal cell proliferation. For the purposes described in claim 37, the healthy cells are hematopoietic stem cells or hematopoietic precursor cells. For the purpose of claim 37, wherein the chemical treatment is carboplatin. For the purposes described in claim 37, the chemical treatment is cisplatin. The use of any of claims 39 to 40, wherein the chemotherapy agent further comprises etoposide. For the purpose described in claim 37, the chemical treatment is topotecan. For the purposes of request item 37, where the patient is human. A freeze-dried powder comprising a compound having the following structure: It is a dihydrochloride dihydrate, wherein the X-ray powder diffraction (XRPD) pattern of the compound includes at least eight 2θ values selected from the following: 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°. The freeze-dried powder of claim 44, wherein the XRPD pattern of the compound includes a 2θ value of at least 9.6 ± 0.2°. The freeze-dried powder of claim 44, wherein the XRPD pattern of the compound includes 2θ values of at least 9.6±0.2°, 19.8±0.2° and 21.3±0.2°. For example, the freeze-dried powder of claim 44, wherein the XRPD pattern of the compound includes the following 2θ values: 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°. A pharmaceutically acceptable reconstitution solution of a freeze-dried powder as described in any of claims 44 to 47. For example, the medical solution in claim 48, wherein the solution is an aqueous solution. The pharmaceutical solution of claim 49, wherein the pharmaceutical composition is suitable for intravenous delivery. The medical solution, as described in claim 49, contains approximately 200 mg to approximately 600 mg of the freeze-dried powder. The medical solution in claim 49 contains approximately 300 mg of the freeze-dried powder. The medical solution, as described in claim 49, contains a dose of the freeze-dried powder ranging from approximately 150 mg/m² to approximately 350 mg/m². The medical solution in claim 49 contains a dose of the freeze-dried powder of approximately 240 mg/m². The medical solution in claim 49 further contains approximately 300 mg of mannitol and approximately 76 mg of citric acid. The medical solution in claim 49 further includes sodium hydroxide or hydrochloric acid.