TW202214650A - 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

Form and manufacturing method of TRILACICLIB

The present invention provides trilaciclib in an advantageous isolated form, which is 2'-((5-(4-methylpipericlib-1-yl)pyridin-2-yl)amino)-7' ,8'-Dihydro-6'H-spiro[cyclohexane-1,9'-pyrido[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-6' - a ketone, eg in the form of the free base or a pharmaceutically acceptable salt thereof, eg in the form of the dihydrochloride or the dihydrochloride dihydrate.

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

.

Synthetic procedures to prepare Compound 1 are described in US 2019/135820 and WO 2020/041770, both assigned to G1 Therapeutics, Inc.. Compound 1 dihydrochloride is the active ingredient in ^{COSELA™ ,} which was approved for commercial sale by the US Food and Drug Administration on February 12, 2021, for use in diffusion Chemotherapy-induced myelosuppression was reduced when previously administered with a platinum/etoposide-containing regimen or a topotecan-containing regimen in stage small cell lung cancer.

Compound 1 is referred to as "G1T28" or "tralaciride". It temporarily arrests normal cells to prevent chemotherapy-induced myelosuppression and may improve antitumor efficacy. It can be used, for example, in patients with small cell lung cancer (SCLC) who are receiving topotecan chemotherapy, and in combination with etoposide and carboplatin for SCLC. It can also be used in small cell lung cancer (SCLC), eg, in combination with carboplatin, etoposide, and atezolizumab (PD-L1 inhibitors). Tralaciride was granted Breakthrough Therapy Designation (BTD) by the U.S. Food and Drug Administration (FDA) based on bone marrow preservation data from patients with SCLC (see, e.g., 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 in human clinical trials for the treatment of triple-negative breast cancer, in combination with standard care for breast cancer neoadjuvant therapy.

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'-pyrido[1',2'1,5]pyrrolo[2,3-d]pyrimidin]-6'-one) can be highly purified, Favorable form of preparation.

This highly purified, favorable form has been indicated as "Pattern 1". Pattern 1 is a highly crystalline form of Compound 1 in the form of the dihydrochloride salt. Pattern 1 exhibits excellent stability when compared to other modalities. For example, in a competitive slurry experiment (see Example 10), Pattern 1 was the predominant shaped-type structure of Compound 1 in the form of the dihydrochloride salt. Pattern 1 also has advantageous properties in the manufacture of Compound 1 in the form of the dihydrochloride salt. For example, Pattern 1 can be produced on a large scale via the crystallization of Compound 1 in heated HCl solution. Pattern 1 can also be formed from other morphological or non-morphic forms of Compound 1 via recrystallization.

Compound 1 Pattern 1 may be in the form of dihydrochloride dihydrate. Pattern 1 typically initially forms dihydrochloride dihydrate and can eventually revert to dihydrochloride dihydrate upon exposure to air even after drying. Pattern 1 maintained its representative XRPD peak regardless of water content, as described in more detail below. For example, if a morphological form of Compound 1 was prepared as described herein to form Pattern 1 and then dried, the representative XRPD peak would remain the same before and after drying.

Compound 1 is an approved drug, tralaciride, sold under the brand name COSELA ^(TM) and used in certain embodiments as a bone marrow preservative to protect healthy cells, especially hematopoietic cells, during chemotherapy. It is intended to be administered by intravenous injection for rapid access to blood flow immediately prior to the administration of chemotherapy, usually also by IV injection. However, Compound 1 free base is insoluble in water and also barely soluble in DMSO. Furthermore, it becomes less soluble as the pH increases. Blood usually has a pH of 7.35 to 7.45, which is slightly alkaline. Phosphate buffered saline typically has a pH of 7.2 to 7.4. Compound 1 free base is not very soluble at this pH, and thus various problems can arise. Most importantly, large amounts of Compound 1 are required to achieve therapeutic effects. A typical dose is 240 mg/ ^m2 and can be estimated as a dose of about 300 mg for a normal adult. Since there is no solubility in water, a dilute solution would be employed in bulk fluids to provide this dose of the free base Compound 1 , which would have to be administered over an extended period of time in conflict with how it should be delivered. Compound 1 IV is typically administered over about 30 minutes (20 to 60 minutes), which means that the drug must be concentrated, not diluted, in the IV fluid. Furthermore, when the free base Compound 1 is injected into blood, there is a real possibility that at least some of it will fall out of solution due to the fact that blood is slightly alkaline. 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 for injection into cancer patients to preserve healthy cells or for anti-neoplastic use can be achieved by administering it as the dihydrochloride salt. This achieves the desired therapeutic effect, as it can be rapidly delivered directly into the bloodstream in a concentrated form. In a primary embodiment, the IV solution is prepared from a freeze-dried powder comprising Compound 1 dihydrochloride, mannitol, and citric acid.

In certain embodiments, the IV solution of Compound 1 is prepared from a solid pharmaceutical composition that is optionally formulated into a composition for lyophilization and subsequently dried. In certain embodiments, the composition includes Compound 1 in the form of a dihydrochloride salt, eg, Compound 1 Dihydrochloride Pattern 1 . The composition may also include one or more suitable excipients such as bulking agents, buffering agents and/or one or more pH adjusting agents. In certain embodiments, the bulking agent is a suitable sugar, such as mannitol. In certain embodiments, the buffer is a suitable weak acid or base with one or more acidic or basic units. In certain embodiments, the buffer is a weak acid with two or more acidic units, such as citric acid. In certain embodiments, the composition includes NaOH, HCl, and/or NaCl as pH adjusters (NaOH and/or HCl) or residual salts (NaCl) from pH adjustment.

It was also found that freeze-dried Compound 1 dihydrochloride compositions comprising mannitol and citric acid can be prepared as crystalline and readily characterized by X-ray powder diffraction (XRPD). In certain embodiments, the lyophilized Compound 1 dihydrochloride composition comprises 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 (ie about 349 mg of Compound 1 as the dihydrochloride salt). In a primary embodiment, Compound 1 in the freeze-dried composition is a crystalline dihydrochloride salt in the form characterized as Pattern 1 . In other embodiments, Compound 1 in the lyophilized composition is in the form of different pharmaceutically acceptable salts 30%, 40%, or a mixture of pharmaceutically acceptable salts. In certain embodiments, Compound 1 in the freeze-dried composition is in different patterns or mixtures of patterns. In certain embodiments, the lyophilized Compound 1 composition comprises at least about 10%, 20%, 30%, 40%, 45%, 50%, 55%, 60% relative to other forms of Compound 1 in the composition , 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% Compound 1 Dihydrochloride Pattern 1. In certain embodiments, the freeze-dried Compound 1 composition comprises at least about 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, relative to the other components of the freeze-dried composition, 75% or 80% Compound 1 Dihydrochloride Pattern 1.

The freeze-dried Compound 1 dihydrochloride composition described in Example 28 contained mannitol and citric acid and was characterized by the XRPD pattern shown in FIG. 100 . Other suitable excipients may be added or substituted for mannitol and/or citric acid as appropriate to achieve the desired effect. In certain embodiments, the Compound 1 dihydrochloride salt composition is freeze-dried, in other embodiments, it is dried using another technique. In certain embodiments, the Compound 1 dihydrochloride composition comprises mannitol, eg, 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 certain embodiments, the Compound 1 dihydrochloride composition comprises citric acid, eg, 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 certain embodiments, the Compound 1 dihydrochloride composition comprises one or more additional salts formed by adjusting the pH of the bulk solution, which is dried to form the composition, such as sodium chloride and/or various citric acids sodium salt.

In a specific embodiment, the lyophilized Compound 1 dihydrochloride composition comprises about 349 mg of Compound 1 Pattern 1 dihydrochloride (equivalent to about 300 mg of tralaciride free base), 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, eg, 300 mg, of mannitol.

The lyophilized Compound 1 composition can be reconstituted in a suitable solvent, such as water, which may include other excipients, such as sodium chloride or dextrose. In certain embodiments, the lyophilized Compound 1 composition is at least about 10,11,12,13,14,15,16,17,18.5,19,19.5,20,20.5,21,21.5,22,23, 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 of 24, 25, 26, 27, 28, 29, or 30 mL , 1.8, 1.9 or 2% sodium chloride solution, for example about 0.9% sodium chloride solution. In certain embodiments, the lyophilized Compound 1 composition is at 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. 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, eg about 0.9% Reconstituted in sodium chloride solution. In certain embodiments, the lyophilized Compound 1 composition is at least about 10,11,12,13,14,15,16,17,18.5,19,19.5,20,20.5,21,21.5,22,23, 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 of 24, 25, 26, 27, 28, 29, or 30 mL , 9, 9.5, 10% dextrose solution, eg about 5% dextrose solution for reconstitution. In certain embodiments, the lyophilized Compound 1 composition is at 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. about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10% dextrose solution, eg about 5% Reconstituted in dextrose solution.

In certain aspects of the invention, isolated Compound 1 Pattern 1 is used to manufacture a lyophilized form that is subsequently formulated with a suitable solvent such as phosphate buffered saline for administration to a patient, eg, by intravenous delivery . In another embodiment, it can be formulated into a parenteral dosage form. Such dosage forms can be used, for example, for subcutaneous administration.

In certain embodiments, Compound 1 Pattern 1 is in the dihydrochloride salt form. In certain embodiments, Compound 1 Pattern 1 in the dihydrochloride salt form can be used to treat any condition responsive to tralaciride, including for bone marrow preservation or as an anti-neoplastic agent.

In certain embodiments, Compound 1 Pattern 1 is in the dihydrochloride dihydrate form. In certain embodiments, Compound 1 Pattern 1 in the form of the dihydrochloride salt dihydrate can be used to treat any condition responsive to tralaciride, including for bone marrow preservation or as an anti-neoplastic agent.

Other isoforms of Compound 1 in the form of the dihydrochloride salt have also been identified. Pattern 2 and Pattern 3 are also highly crystalline forms of Compound 1 in the form of the dihydrochloride salt. Pattern 4 is a crystalline solvate of Compound 1 and acetonitrile as the dihydrochloride salt. Pattern 5 is a crystalline form of Compound 1 in the form of the dihydrochloride salt. Pattern 6 is a metastable form of Compound 1 in the form of the dihydrochloride salt. Pattern 11 is a crystalline form of Compound 1 in the form of the dihydrochloride salt hemihydrate.

An isomorphic form of Compound 1 has also been identified in the free base form. Pattern 8 and Pattern 10 are crystalline forms of Compound 1 in free base form. Pattern 9 is a crystalline form of Compound 1 in the free base form, which may be a solvate or a hydrate.

In certain embodiments, Pattern 1 is the most stable form of Compound 1 in the dihydrochloride salt form and is formed with either Pattern 2 or Pattern 3 by a competitive slurry experiment.

Compound 1 is typically administered to patients in an intravenous formulation. However, the solid form of tralaciride can be important as it can be used to achieve the desired manufacturing purity and/or potency, and can also be important for solid state shelf life prior to formulation or in solid dosage forms for therapeutic delivery .

In view of the therapeutic importance of Compound 1 (tralaciride) for the medical treatment of patients suffering from proliferative disorders such as tumors or cancers, provision to aid in the success or efficacy of the compound during manufacture, storage, formulation and/or administration This advantageous solid form of .

Cross-references to related applications

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

It is not possible to predict in advance whether a compound will exist in more than one solid form, or if one or more does exist, to what extent it exists as a salt or solvate or the various properties of any solid form may be available, or whether the properties are beneficial for therapeutic dosage forms. As an example, the drug ritonavir is active in one morphological form and inert in another, and the inert form is more stable.

Compound 1 is an approved drug, tralaciride, sold under the brand name COSELA ^(TM) and used in certain embodiments as a bone marrow preservative to protect healthy cells, especially hematopoietic cells, during chemotherapy. It is intended to be administered by intravenous injection for rapid access to blood flow immediately prior to the administration of chemotherapy, usually also by IV injection. However, Compound 1 free base is insoluble in water and also barely soluble in DMSO. Furthermore, it becomes less soluble as the pH increases. Blood usually has a pH of 7.35 to 7.45, which is slightly alkaline. Phosphate buffered saline typically has a pH of 7.2 to 7.4. Compound 1 is not very soluble at this pH and thus various problems can arise. Most importantly, large amounts of Compound 1 are required to achieve therapeutic effects. A typical dose is 240 mg/ ^m2 and can be estimated as a dose of about 300 mg for a normal adult. Since there is no solubility in water, a dilute solution would be employed in bulk fluids to provide this dose of the free base Compound 1 , which would have to be administered over an extended period of time in conflict with how it should be delivered. Compound 1 IV is typically administered over about 30 minutes (20 to 60 minutes), which means that the drug must be concentrated, not diluted, in the IV fluid. Furthermore, when the free base Compound 1 is injected into blood, there is a real possibility that at least some of it will fall out of solution due to the fact that blood is slightly alkaline. 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 for injection into cancer patients to preserve healthy cells or for anti-neoplasia can be achieved by administering it as the dihydrochloride salt or the dihydrochloride salt dihydrate. This achieves the desired therapeutic effect, as it can be rapidly delivered directly into the bloodstream in a concentrated form. In a primary embodiment, the IV solution is prepared from a freeze-dried powder comprising Compound 1 dihydrochloride, mannitol, and citric acid.

In certain embodiments, IV solutions of Compound 1 are prepared from solid pharmaceutical compositions, which are optionally dried by lyophilization. In certain embodiments, the composition includes Compound 1 in the form of a dihydrochloride salt, eg, Compound 1 Dihydrochloride Pattern 1 . The composition may also include suitable excipients such as bulking agents, buffering agents and/or one or more pH adjusting agents. In certain embodiments, the bulking agent is a suitable sugar, such as mannitol. In certain embodiments, the buffer is an appropriate weak acid or base with one or more acidic or basic sites. In certain embodiments, the buffer is a weak acid with two or more acidic sites, such as citric acid. In certain embodiments, the composition includes NaOH, HCl, and/or NaCl as pH adjusters (NaOH and/or HCl) or residual salts (NaCl) from pH adjustment.

The freeze-dried Compound 1 dihydrochloride salt composition comprising mannitol and citric acid was also found to be crystalline and readily characterized by X-ray powder diffraction (XRPD). In certain embodiments, the lyophilized Compound 1 dihydrochloride composition comprises 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 a primary embodiment, Compound 1 in the lyophilized composition is a crystalline dihydrochloride salt in the form characterized herein as Pattern 1 . In other embodiments, Compound 1 in the lyophilized composition is in the form of different pharmaceutically acceptable salts or mixtures of pharmaceutically acceptable salts. In certain embodiments, Compound 1 in the freeze-dried composition is in different patterns or mixtures of patterns. In certain embodiments, the lyophilized Compound 1 composition comprises at least about 10 %, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% Compound 1 Dihydrochloride Pattern 1. In certain embodiments, the freeze-dried Compound 1 composition comprises at least about 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, relative to the other components of the freeze-dried composition, 75% or 80% Compound 1 Dihydrochloride Pattern 1.

The freeze-dried Compound 1 dihydrochloride composition described in Example 28 contained mannitol and citric acid and was characterized by the XRPD pattern shown in FIG. 100 . Other suitable excipients may be added or substituted for mannitol and/or citric acid as appropriate to achieve the desired effect. In certain embodiments, the Compound 1 dihydrochloride composition is lyophilized. In other embodiments, it is dried using another technique. In certain embodiments, the Compound 1 dihydrochloride composition comprises mannitol, eg, 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, 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 certain embodiments, the Compound 1 dihydrochloride composition comprises citric acid, eg, 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 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 certain embodiments, the Compound 1 dihydrochloride composition comprises one or more additional salts formed by adjusting the pH of the bulk solution, which is dried to form the composition, such as sodium chloride and/or various citric acids sodium salt.

In a specific embodiment, the lyophilized Compound 1 dihydrochloride composition comprises about 349 mg of Compound 1 Pattern 1 dihydrochloride (equivalent to about 300 mg of tralaciride free base), 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, eg, 300 mg, of mannitol.

The freeze-dried Compound 1 composition can be reconstituted in a suitable solvent, such as water, which may include other excipients, such as sodium chloride or dextrose. In certain embodiments, the lyophilized Compound 1 composition is 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, eg about 0.9% sodium chloride solution for reconstitution. In certain embodiments, the lyophilized Compound 1 composition is 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 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 to restore. In certain embodiments, the lyophilized Compound 1 composition is at least about 10,11,12,13,14,15,16,17,18.5,19,19.5,20,20.5,21,21.5,22,23, 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 of 24, 25, 26, 27, 28, 29, or 30 mL , 9, 9.5, 10% dextrose solution, eg about 5% dextrose solution for reconstitution. In certain embodiments, the lyophilized Compound 1 composition is at 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. about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10% dextrose solution, eg, about 5% Reconstituted in dextrose solution.

Pattern 1, Pattern 2, and Pattern 3 are also highly crystalline forms of Compound 1 in the form of the dihydrochloride salt. Pattern 1 is a suitable dihydrochloride dihydrate form of Compound 1. Pattern 4 is a crystalline solvate of Compound 1 and acetonitrile as the dihydrochloride salt. Pattern 5 is a crystalline form of Compound 1 in the form of the dihydrochloride salt. Pattern 6 is a metastable form of Compound 1 in the form of the dihydrochloride salt. Pattern 7 is a highly crystalline form of Compound 1 in the free base form. Pattern 8 and Pattern 10 are crystalline forms of Compound 1 in free base form. Pattern 9 is a crystalline form of Compound 1 in the free base form, which may be a solvate or a hydrate. Pattern 11 is a crystalline form of Compound 1 in the form of the dihydrochloride salt hemihydrate.

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

Pattern 1 dihydrochloride dihydrate has various therapeutic advantages over other forms of compound 1 . For example, Pattern 1 dihydrochloride dihydrate is easier to use in intravenous solutions. Additionally, higher concentrations of Pattern 1 dihydrochloride dihydrate can be achieved in water and/or DMSO.

Compared to other forms of compound 1 , pattern 1 dihydrochloride dihydrate has several manufacturing advantages. For example, Pattern 1 dihydrochloride dihydrate typically has increased storage stability, thermodynamic stability, and/or water solubility compared to other forms of Compound 1 . In other embodiments, the manufacture of Pattern 1 dihydrochloride dihydrate is reproducibly more scalable than other morphological forms of Compound 1 .

In certain aspects of the invention, the isolated pattern 1, optionally in the form of a dihydrate, is used to make a lyophilized form that is then formulated with a suitable solvent such as phosphate buffered saline, for example, by intravenous Internal delivery is administered to the patient. In an alternative embodiment, it may be formulated into a parenteral dosage form. Such dosage forms can be used, for example, for subcutaneous administration.

In certain aspects of the invention, the isolated pattern 2 is used to manufacture a freeze-dried form that is then formulated with a suitable solvent such as phosphate buffered saline for administration to a patient, eg, by intravenous delivery. In an alternative embodiment, it may be formulated into a parenteral dosage form. Such dosage forms can be used, for example, for subcutaneous administration.

In certain aspects of the invention, the isolated pattern 3 is used to manufacture a freeze-dried form that is subsequently formulated with a suitable solvent, such as phosphate buffered saline, for administration to a patient, eg, by intravenous delivery. In an alternative embodiment, it may be formulated into a parenteral dosage form. Such dosage forms can be used, for example, for subcutaneous administration.

In certain aspects of the invention, the isolated pattern 7 is used to manufacture a freeze-dried form that is subsequently formulated with a suitable solvent, such as phosphate buffered saline, for administration to a patient, eg, by intravenous delivery. In an alternative embodiment, it may be formulated into a parenteral dosage form. Such dosage forms can be used, for example, for subcutaneous administration.

Pattern 1 An isolated form of Compound 1 designated Pattern 1 is provided herein in the form of the dihydrochloride salt.

Compound 1 Pattern 1 may be in the form of dihydrochloride dihydrate. Pattern 1 is typically initially in the form of the dihydrochloride dihydrate after formation and can eventually revert to the dihydrochloride dihydrate upon exposure to air even after drying. Pattern 1 maintained its representative XRPD peak regardless of water content, as described in more detail below. For example, if a morphological form of Compound 1 was prepared as described herein to form Pattern 1 and then dried, the representative XRPD peak would remain the same before and after drying.

It was unexpectedly found that Pattern 1 could be dissolved in the composition used for freeze drying and re-formed Pattern 1 after drying.

In certain embodiments, Compound 1 Pattern 1 is in the dihydrochloride dihydrate form. In certain embodiments, the present invention provides compositions of Compound 1 in the form of the dihydrochloride salt dihydrate. In certain embodiments, the present invention provides compositions of Compound 1 Pattern 1 in the form of the dihydrochloride salt dihydrate.

In certain embodiments, Compound 1 Pattern 1 dihydrochloride dihydrate is more stable than other hydrate forms of Compound 1 . In another embodiment, Compound 1 Pattern 1 dihydrochloride dihydrate may be more stable than the non-hydrated form of Compound 1 . Compound 1 Pattern 1 in the form of the dihydrochloride salt dihydrate may be advantageous for the anhydrous monohydrate or even trihydrate form of Compound 1 Pattern 1. For example, the dihydrate form of Compound 1 Pattern 1 dihydrochloride has improved storage stability, thermodynamic stability and/or water solubility compared to the anhydrous monohydrate or even trihydrate form of Compound 1 Pattern 1 . In other embodiments, making Pattern 1 dihydrochloride dihydrate is cheaper, faster and/or more scalable than making anhydrous monohydrate or even trihydrate versions of Compound 1 Pattern 1 .

In certain embodiments, Compound 1 Pattern 1 , optionally in the form of a dihydrate, is characterized by an XRPD pattern substantially similar to the XRPD pattern illustrated in FIG. 1 . In one embodiment, Compound 1 , optionally in the form of a dihydrate, Pattern 1 is characterized by an XRPD pattern comprising at least three 2Θ values selected from the group consisting of: about 9.6±0.2°, about 21.3±0.2°, about 19.8±0.2 °, about 12.2±0.2°, about 24.0±0.2°, about 26.1±0.2°, about 19.3±0.2°, about 17.6±0.2°, and about 28.6±0.2°. In one embodiment, Compound 1 , optionally in the dihydrate form, Pattern 1 is characterized by an XRPD pattern comprising a peak with a 2[Theta] value of about 9.6±0.2[deg.].

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

Compound 1 Pattern 1 can be prepared using selective crystallization. The method can be carried out by optionally treating a solution comprising one or more suitable solvents and Compound 1 in the form of a dihydrochloride salt in the presence of one or more seed crystals comprising Compound 1 Pattern 1 to provide crystals of Compound 1 Pattern 1 conditions of. If the solvent used is 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 aprotic solvents or mixtures thereof. Examples of aprotic solvents that can be used include tetrahydrofuran, dichloromethane, nitromethane, and diethane. 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 certain embodiments, Compound 1 Pattern 1 is prepared from aprotic solvents and mixtures of protic solvents, such as a mixture of acetonitrile and water.

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

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

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 was filtered into a reactor preheated to about 80°C, and the reaction mixture was cooled to about 70°C. Preheated (about 70°C) purified water was added and the reaction mixture was cooled to below 20°C with stirring. Compound 1 pattern 1 can be isolated by filtration, washed with purified water and acetone, and dried under vacuum at high temperature.

In certain embodiments, Compound 1 Pattern 1, optionally in the dihydrate form, is sieved using a mill. In certain embodiments, the sieved Compound 1 Pattern 1 material is formulated for parenteral administration to a patient.

In certain embodiments, Compound 1 , optionally in a dihydrate form, Pattern 1 is characterized by an XRPD pattern comprising at least 2 peaks selected from the group consisting of: 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 certain embodiments, Compound 1 , optionally in a dihydrate form, Pattern 1 is characterized by an XRPD pattern comprising at least 3 peaks selected from the group consisting of: 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 certain embodiments, Compound 1 , optionally in a dihydrate form, Pattern 1 is characterized by an XRPD pattern comprising at least 4 peaks selected from the group consisting of: 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 certain embodiments, Compound 1 , optionally in the dihydrate form, Pattern 1 is characterized by an XRPD pattern comprising at least 5 peaks selected from the group consisting of: 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 certain embodiments, Compound 1 , optionally in a dihydrate form, Pattern 1 is characterized in that the XRPD pattern comprises a 2Θ value selected from the group consisting of: 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 certain embodiments, Compound 1 , optionally in the dihydrate form, Pattern 1 is characterized by an XRPD pattern comprising all or at least 2, 3, 4, 5, 6 within ±0.4° 2Θ of a peak selected from the group consisting of , 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20° 2θ values: 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. , 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 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. 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. 23.2, 20.3, 22.7, 27.1, 21.0, 17.0, 10.1, and 16.0° 2θ; or j. , 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, 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; 26.1 °2θ; v. where °2θ is any of the above peak list of +0.1; or w. where °2θ is any of the above peak list of +0.2; or x. where °2θ is +0.3 above the peak list either.

In one embodiment, Compound 1 , optionally in the dihydrate form, Pattern 1 is characterized by the XRPD pattern described above and is further characterized by no peaks greater than 15% relative intensity between 4 and 9° 2Θ . In one embodiment, Compound 1 , optionally in the dihydrate form, Pattern 1 is characterized by the XRPD pattern described above and is further characterized by no peaks greater than 10% relative intensity between 4 and 9° 2Θ . In one embodiment, Compound 1 , optionally in the dihydrate form, Pattern 1 is characterized by the XRPD pattern described above and is further characterized by no peaks greater than 5% relative intensity between 4 and 9° 2Θ . In one embodiment, Compound 1 , optionally in the dihydrate form, Pattern 1 is characterized by the XRPD pattern described above and is further characterized by no peaks greater than 3% relative intensity between 4 and 9° 2Θ .

In certain embodiments, Compound 1 , optionally in the form of the dihydrate, Pattern 1 is used to prepare the amorphous Compound 1 in the form of the dihydrochloride salt. For example, amorphous Compound 1 in the form of the dihydrochloride salt can be formed from freeze-dried or spray-dried Compound 1 Pattern 1, as appropriate, in the form of the dihydrate. This amorphous dihydrochloride salt can be of higher purity than it can be prepared directly by known synthetic methods. In addition, the advantage of first preparing Compound 1 Pattern 1, optionally in the dihydrate form, and then converting it to an amorphic material may be that the overall shelf life of the product is thus increased.

In certain embodiments, Compound 1 Pattern 1, optionally in the form of the dihydrate, is used to prepare the amorphous Compound 1 in the form of the mono-HCl salt. For example, amorphous Compound 1 can be formed as a mono-HCl salt by dissolving Compound 1 Pattern 1 and adjusting the pH of the solution followed by removal of the solvent. This amorphous mono-HCl salt can be of higher purity than it can be prepared directly by known synthetic methods. Additionally, the advantage of first preparing Compound 1 Pattern 1, optionally in the dihydrate form, and then converting it to an amorphic material may be an increase in the overall shelf life of the product.

In certain embodiments, Compound 1 Pattern 1, optionally in the dihydrate form, is used to prepare the amorphous Compound 1 in the free base form. This amorphous free base can be of higher purity than it can be prepared directly by known synthetic methods. In addition, the advantage of first preparing Compound 1 Pattern 1, optionally in the dihydrate form, and then converting it to an amorphic material may be that the overall shelf life of the product is thus increased.

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

In certain embodiments, Compound 1 Pattern 1, optionally in the dihydrate form, is freeze-dried. In these embodiments, Compound 1 Pattern 1, optionally in the form of a dihydrate, may optionally be mixed with one or more suitable excipients before or after lyophilization. For example, in certain embodiments, the present invention provides a solid freeze-dried composition comprising Compound 1 Pattern 1, optionally in the form of a dihydrate. In certain embodiments, the present invention provides a solid freeze-dried composition comprising Compound 1 Pattern 1 optionally as a dihydrate, mannitol, and citric acid. In certain embodiments, the present invention provides a solid freeze-dried composition comprising Compound 1 Pattern 1 dihydrochloride dihydrate, mannitol, and citric acid.

； 其為二鹽酸鹽，視情況呈二水合物形式。 Non-Limiting Embodiments of the Invention 1. In certain embodiments, crystalline compounds having the following structure are provided:

; it is the dihydrochloride salt, optionally in the form of the dihydrate.

； 其為二鹽酸鹽，其視情況包括水合物。 32.  如實施例31之冷凍乾燥粉末，其中該化合物之特徵在於X射線粉末繞射(XRPD)圖案包含至少三個選自以下之2θ值：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°及28.6±0.2°。 34.  如實施例31之冷凍乾燥粉末，其中該化合物之特徵在於XRPD圖案包含至少四個選自以下之2θ值：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°及28.6±0.2°。 35.  如實施例31之冷凍乾燥粉末，其中該化合物之特徵在於XRPD圖案包含至少五個選自以下之2θ值：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°及28.6±0.2°。 36.  如實施例31之冷凍乾燥粉末，其中該化合物之特徵在於XRPD圖案包含至少六個選自以下之2θ值：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°及28.6±0.2°。 37.  如實施例31之冷凍乾燥粉末，其中該化合物之特徵在於XRPD圖案包含至少9.6±0.2°之該2θ值。 38.  如實施例31之冷凍乾燥粉末，其中該化合物之特徵在於XRPD圖案包含至少9.6±0.2°、19.8±0.2°及21.3±0.2°之該2θ值。 Other non-limiting examples include: 2. The crystalline compound of Example 1, characterized in that the X-ray powder diffraction (XRPD) pattern comprises at least three 2Θ values selected from the group consisting of: 9.6±0.2°, 21.3±0.2° , 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°. 3. The crystalline compound of embodiment 2, wherein the XRPD pattern comprises at least four 2θ values selected from the group consisting of: 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°. 4. The crystalline compound of embodiment 2, wherein the XRPD pattern comprises at least five 2θ values selected from the group consisting of: 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°. 5. The crystalline compound of embodiment 2, wherein the XRPD pattern comprises at least six 2θ values selected from the group consisting of: 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°. 6. The crystalline compound of embodiment 2, wherein the XRPD pattern comprises the 2Θ value of at least 9.6±0.2°. 7. The crystalline compound of embodiment 2, wherein the XRPD pattern comprises the 2Θ values of at least 9.6±0.2°, 19.8±0.2°, and 21.3±0.2°. 8. In certain embodiments, a freeze-dried powder prepared from the crystalline compound of Example 1 is provided. 9. The freeze-dried powder of embodiment 8, wherein the crystalline compound of embodiment 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three 2θ values selected from the group consisting of: 9.6±0.2°, 21.3±0.2 °, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°. 10. The freeze-dried powder of embodiment 9, wherein the crystalline compound of embodiment 1 is characterized by an XRPD pattern comprising at least four 2θ values selected from the group consisting of: 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°. 11. The freeze-dried powder of embodiment 9, wherein the crystalline compound of embodiment 1 is characterized by an XRPD pattern comprising at least five 2θ values selected from the group consisting of: 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°. 12. The freeze-dried powder of embodiment 9, wherein the crystalline compound of embodiment 1 is characterized by an XRPD pattern comprising at least six 2θ values selected from the group consisting of: 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°. 13. The freeze-dried powder of embodiment 9, wherein the crystalline compound of embodiment 1 is characterized by an XRPD pattern comprising the 2Θ value of at least 9.6±0.2°. 14. The freeze-dried powder of embodiment 9, wherein the crystalline compound of embodiment 1 is characterized by an XRPD pattern comprising at least 9.6±0.2°, 19.8±0.2° and 21.3±0.2° of the 2Θ values. 15. In certain embodiments, pharmaceutical compositions comprising the crystalline compound of Example 1 and a pharmaceutically acceptable excipient are provided. 16. The pharmaceutical composition of embodiment 15, wherein the pharmaceutical composition is suitable for intravenous delivery. 17. The pharmaceutical composition of embodiment 15, comprising about 200 mg to about 600 mg of the crystalline compound of embodiment 1. 18. The pharmaceutical composition of embodiment 15, comprising about 300 mg of the crystalline compound of embodiment 1. 19. The pharmaceutical composition of embodiment 15, comprising the crystalline compound of embodiment 1 in a dose of about 150 mg/m ² to about 350 mg/m ² . 20. The pharmaceutical composition of embodiment 15, further comprising about 300 mg of mannitol and about 76 mg of citric acid. 21. The pharmaceutical composition of embodiment 15, comprising the crystalline compound of embodiment ¹ at a dose of about 240 mg/m2. 22. In certain embodiments, a pharmaceutically acceptable reconstituted solution of the freeze-dried powder of Example 8 is provided. 23. The pharmaceutical solution of embodiment 23, wherein the solution is an aqueous solution. 24. The pharmaceutical solution of embodiment 23, wherein the pharmaceutical composition is suitable for intravenous delivery. 25. The pharmaceutical solution of embodiment 23, comprising about 200 mg to about 600 mg of the freeze-dried powder of embodiment 8. 26. The pharmaceutical solution of embodiment 23, comprising about 300 mg of the lyophilized powder of embodiment 8. 27. The pharmaceutical solution of embodiment 23, comprising the freeze-dried powder of embodiment 8 in a dose of about 150 mg/m ² to about 350 mg/m ² . 28. The pharmaceutical solution of embodiment 23, further comprising about 300 mg of mannitol and about 76 mg of citric acid. 29. The pharmaceutical solution of embodiment 23, further comprising sodium hydroxide or hydrochloric acid. 30. The pharmaceutical solution of embodiment 23 comprising the freeze-dried powder of embodiment ⁸ at a dose of about 240 mg/m. 31. A freeze-dried powder comprising a compound having the following structure:

; which is the dihydrochloride salt, which optionally includes the hydrate. 32. The freeze-dried powder of embodiment 31, wherein the compound is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three 2θ values selected from the group consisting of: 9.6±0.2°, 21.3±0.2°, 19.8±0.2 °, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°. 34. The freeze-dried powder of embodiment 31, wherein the compound is characterized by an XRPD pattern comprising at least four 2θ values selected from the group consisting of: 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°. 35. The freeze-dried powder of embodiment 31, wherein the compound is characterized by an XRPD pattern comprising at least five 2θ values selected from the group consisting of: 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°. 36. The freeze-dried powder of embodiment 31, wherein the compound is characterized by an XRPD pattern comprising at least six 2θ values selected from the group consisting of: 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°. 37. The freeze-dried powder of embodiment 31, wherein the compound is characterized by an XRPD pattern comprising the 2Θ value of at least 9.6±0.2°. 38. The freeze-dried powder of embodiment 31, wherein the compound is characterized by an XRPD pattern comprising the 2Θ values of at least 9.6±0.2°, 19.8±0.2°, and 21.3±0.2°.

； 其為二鹽酸鹽。 2.   如實施例1之結晶化合物，其特徵在於X射線粉末繞射(XRPD)圖案包含至少三個選自以下之2θ值：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°及28.6±0.2°。 3.   如實施例2之結晶化合物，其中該XRPD圖案包含至少四個選自以下之2θ值：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°及28.6±0.2°。 4.   如實施例2之結晶化合物，其中該XRPD圖案包含至少五個選自以下之2θ值：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°及28.6±0.2°。 5.   如實施例2之結晶化合物，其中該XRPD圖案包含至少六個選自以下之2θ值：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°及28.6±0.2°。 6.   如實施例2之結晶化合物，其中該XRPD圖案包含至少9.6±0.2°之該2θ值。 7.   如實施例2之結晶化合物，其中該XRPD圖案包含至少9.6±0.2°、19.8±0.2°及21.3±0.2°之該2θ值。 8.   一種組合物，其包含如實施例1至7中任一項之結晶化合物、甘露糖醇及檸檬酸。 9.   一種醫藥組合物，其包含如實施例1至7之結晶化合物及醫藥學上可接受之賦形劑。 10.  如實施例9之醫藥組合物，其中該醫藥學上可接受之賦形劑包含甘露糖醇。 11.  如實施例9之醫藥組合物，其中該醫藥學上可接受之賦形劑包含檸檬酸。 12.  如實施例9之醫藥組合物，其中該醫藥學上可接受之賦形劑包含甘露糖醇及檸檬酸。 13.  如實施例9之醫藥組合物，其包含約200至600毫克之該結晶化合物。 14.  如實施例9之醫藥組合物，其包含約300毫克之該結晶化合物。 15.  如實施例9之醫藥組合物，其包含約349毫克之該結晶化合物。 16.  如實施例10之醫藥組合物，其包含約250至350 mg之甘露糖醇。 17.  如實施例10之醫藥組合物，其包含約300 mg之甘露糖醇。 18.  如實施例11之醫藥組合物，其包含約50至100 mg之檸檬酸。 19.  如實施例11之醫藥組合物，其包含約76 mg之檸檬酸。 20.  如實施例12之醫藥組合物，其包含約250至350 mg之甘露糖醇。 21.  如實施例12之醫藥組合物，其包含約300 mg之甘露糖醇。 22.  如實施例12之醫藥組合物，其包含約50至100 mg之檸檬酸。 23.  如實施例12之醫藥組合物，其包含約76 mg之檸檬酸。 24.  如實施例12之醫藥組合物，其包含約300 mg之甘露糖醇及約76 mg之檸檬酸。 25.  如實施例24之醫藥組合物，其包含約300毫克之該結晶化合物。 26.  如實施例12之醫藥組合物，其包含約150 mg/m ²至約350 mg/m ²之劑量的該結晶化合物。 27.  如實施例12之醫藥組合物，其包含約240 mg/m ²之劑量的該結晶化合物。 28.  一種醫藥組合物，其藉由將如實施例1至27中任一項之醫藥組合物溶解於溶劑中來形成。 29.  如實施例28之醫藥組合物，其中該溶劑為水。 30.  如實施例28之醫藥組合物，其中該溶劑為氯化鈉水溶液。 31.  如實施例30之醫藥組合物，其中該氯化鈉濃度在約0.1%與2%之間。 32.  如實施例30之醫藥組合物，其中該氯化鈉濃度為約0.9%。 33.  如實施例28之醫藥組合物，其中該溶劑為右旋糖水溶液。 34.  如實施例33之醫藥組合物，其中該右旋糖濃度在約1%與10%之間。 35.  如實施例33之醫藥組合物，其中該右旋糖濃度為約5%。 36.  如實施例28至35中任一項之醫藥組合物，其中存在約10至30 mL之溶劑。 37.  如實施例28至35中任一項之醫藥組合物，其中存在約19.5 mL之溶劑。 39.  一種治療藉由CDK4或CDK6介導之病症之方法，其包含向有需要之患者投與有效量的如實施例1至37中任一項之醫藥組合物之化合物。 40.  一種治療癌症之方法，其包含向有需要之患者投與有效量的如實施例1至37中任一項之醫藥組合物之化合物。 41.  一種降低化學療法對正在接受癌症或異常細胞增殖治療之患者的健康細胞之影響的方法，該方法包含向該個體投與有效量之至少一種化學治療劑及有效量之如實施例1至37中任一項之醫藥組合物之化合物。 42.  如實施例40之方法，其中該等健康細胞為造血幹細胞或造血前驅細胞。 43.  如實施例40至41中任一項之方法，其中該化學治療劑為卡鉑。 44.  如實施例40至41中任一項之方法，其中該化學治療劑為順鉑。 45.  如實施例42至43中任一項之方法，其中該方法進一步包含投與依託泊苷。 46.  如實施例40至41中任一項之方法，其中該化學治療劑為拓樸替康。 47.  如實施例38至45中任一項之方法，其中該患者為人類。 Additional Embodiments 1. In one embodiment, there is provided a crystalline compound having the structure:

; which is the dihydrochloride. 2. The crystalline compound of embodiment 1, characterized in that the X-ray powder diffraction (XRPD) pattern comprises at least three 2θ values selected from the group consisting of: 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2± 0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°. 3. The crystalline compound of embodiment 2, wherein the XRPD pattern comprises at least four 2θ values selected from the group consisting of: 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°. 4. The crystalline compound of embodiment 2, wherein the XRPD pattern comprises at least five 2θ values selected from the group consisting of: 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°. 5. The crystalline compound of embodiment 2, wherein the XRPD pattern comprises at least six 2θ values selected from the group consisting of: 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°. 6. The crystalline compound of embodiment 2, wherein the XRPD pattern comprises the 2Θ value of at least 9.6±0.2°. 7. The crystalline compound of embodiment 2, wherein the XRPD pattern comprises the 2Θ values of at least 9.6±0.2°, 19.8±0.2°, and 21.3±0.2°. 8. A composition comprising the crystalline compound of any one of embodiments 1 to 7, mannitol and citric acid. 9. A pharmaceutical composition comprising the crystalline compound of embodiments 1 to 7 and a pharmaceutically acceptable excipient. 10. The pharmaceutical composition of embodiment 9, wherein the pharmaceutically acceptable excipient comprises mannitol. 11. The pharmaceutical composition of embodiment 9, wherein the pharmaceutically acceptable excipient comprises citric acid. 12. The pharmaceutical composition of embodiment 9, wherein the pharmaceutically acceptable excipients comprise mannitol and citric acid. 13. The pharmaceutical composition of embodiment 9, comprising about 200 to 600 mg of the crystalline compound. 14. The pharmaceutical composition of embodiment 9, comprising about 300 mg of the crystalline compound. 15. The pharmaceutical composition of embodiment 9, comprising about 349 mg of the crystalline compound. 16. The pharmaceutical composition of embodiment 10, comprising about 250 to 350 mg of mannitol. 17. The pharmaceutical composition of embodiment 10, comprising about 300 mg of mannitol. 18. The pharmaceutical composition of embodiment 11, comprising about 50 to 100 mg of citric acid. 19. The pharmaceutical composition of embodiment 11, comprising about 76 mg of citric acid. 20. The pharmaceutical composition of embodiment 12, comprising about 250 to 350 mg of mannitol. 21. The pharmaceutical composition of embodiment 12, comprising about 300 mg of mannitol. 22. The pharmaceutical composition of embodiment 12, comprising about 50 to 100 mg of citric acid. 23. The pharmaceutical composition of embodiment 12, comprising about 76 mg of citric acid. 24. The pharmaceutical composition of embodiment 12, comprising about 300 mg of mannitol and about 76 mg of citric acid. 25. The pharmaceutical composition of embodiment 24, comprising about 300 mg of the crystalline compound. 26. The pharmaceutical composition of embodiment 12, comprising the crystalline compound in a dose of about 150 mg/m ² to about 350 mg/m ² . 27. The pharmaceutical composition of embodiment 12, comprising the crystalline compound at a dose of about 240 mg/m ² . 28. A pharmaceutical composition formed by dissolving the pharmaceutical composition of any one of embodiments 1 to 27 in a solvent. 29. The pharmaceutical composition of embodiment 28, wherein the solvent is water. 30. The pharmaceutical composition of embodiment 28, wherein the solvent is an aqueous sodium chloride solution. 31. The pharmaceutical composition of embodiment 30, wherein the sodium chloride concentration is between about 0.1% and 2%. 32. The pharmaceutical composition of embodiment 30, wherein the sodium chloride concentration is about 0.9%. 33. The pharmaceutical composition of embodiment 28, wherein the solvent is an aqueous dextrose solution. 34. The pharmaceutical composition of embodiment 33, wherein the dextrose concentration is between about 1% and 10%. 35. The pharmaceutical composition of embodiment 33, wherein the dextrose concentration is about 5%. 36. The pharmaceutical composition of any one of embodiments 28 to 35, wherein about 10 to 30 mL of solvent is present. 37. The pharmaceutical composition of any one of embodiments 28 to 35, wherein about 19.5 mL of solvent is present. 39. A method of treating a condition mediated by CDK4 or CDK6, comprising administering to a patient in need thereof an effective amount of a compound of the pharmaceutical composition of any one of embodiments 1-37. 40. A method of treating cancer comprising administering to a patient in need thereof an effective amount of a compound of the pharmaceutical composition of any one of embodiments 1-37. 41. A method of reducing the effect of chemotherapy on healthy cells in a patient undergoing treatment for cancer or abnormal cell proliferation, the method comprising administering to the individual an effective amount of at least one chemotherapeutic agent and an effective amount of an agent such as embodiment 1 to A compound of the pharmaceutical composition of any one of 37. 42. The method of embodiment 40, wherein the healthy cells are hematopoietic stem cells or hematopoietic precursor cells. 43. The method of any one of embodiments 40 to 41, wherein the chemotherapeutic agent is carboplatin. 44. The method of any one of embodiments 40 to 41, wherein the chemotherapeutic agent is cisplatin. 45. The method of any one of embodiments 42-43, wherein the method further comprises administering etoposide. 46. The method of any one of embodiments 40 to 41, wherein the chemotherapeutic agent is topotecan. 47. The method of any one of embodiments 38 to 45, wherein the patient is a human.

Formulations of Compound 1 Pattern 1 In certain embodiments, Compound 1 Pattern 1 is provided as a dihydrochloride salt dihydrate in a formulation. In certain 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 Compound 1 Pattern 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 are selected to adjust pH as required. Specifically, 373 mg of the dihydrochloride salt dihydrate would provide 300 mg of tralaciride free base.

In certain embodiments, the formulations are freeze-dried after compound 1 Pattern 1 in the form of the dihydrochloride salt dihydrate is combined with citric acid and mannitol. In certain embodiments, a formulation comprises lyophilized Compound 1 Pattern 1 mixed with citric acid and mannitol in the form of the dihydrochloride salt dihydrate, wherein the citric acid and mannitol are in the form of the dihydrochloride salt Compound 1 Pattern 1 in the dihydrate form was added after lyophilization.

In certain embodiments, Compound 1 Pattern 1 is provided as the dihydrochloride salt in the formulation. In certain 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 Compound 1 Pattern 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 chosen to adjust pH as needed for reconstitution.

In certain embodiments, this formulation is sterile.

In certain embodiments, the formulations are freeze-dried after compound 1 Pattern 1 in the form of the dihydrochloride salt dihydrate is combined with citric acid and mannitol. In certain embodiments, a formulation comprises freeze-dried Compound 1 Pattern 1 mixed with citric acid and mannitol in the form of the dihydrochloride salt, wherein the citric acid and mannitol are in the form of the dihydrochloride salt dihydrate Compound 1 pattern 1 in the form was added after lyophilization.

In certain 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 Pattern 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 Prepared with 300 mg of mannitol, and optionally sodium hydroxide and/or hydrochloric acid to adjust pH as needed. In another embodiment, the formulation consists of combining Compound 1 Pattern 1 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 was mixed followed by lyophilization of Compound 1 Pattern 1 to produce.

Any of the formulations described above can be prepared 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, diluting sugar, or Another physiological saline solution was restored. In one non-limiting example, the reconstitution solution is a sterile sodium chloride solution, eg, containing about 0.9% NaCl, or a sterile sugar solution, eg, about 5% dextrose solution. The resulting reconstituted solution will have any amount of tralaciride required for the intended purpose, such as between about 5 to 50 mg/mL, about 10 to 25 mg/ml, or even about 15 mg/mL of tralaciride. In certain embodiments, the resulting solution is subsequently diluted prior to parenteral administration, such as intravenous delivery.

Non-limiting examples of typical quality standards and medicinal functions are provided in the table below. component Quantity per viala ⁽ mg) Medicine function quality standard ^Compound 1b 300 active agent inherent Mannitol 300 bulking agent 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 Sufficient solvent USP/Ph. Eur. Nitrogen ^e N/A Process assistance NF NF=United States National Formulary; USP=United States Pharmacopoeia; Ph. Eur.=European Pharmacopoeia; N/A=not applicable; qs=sufficient a target weight of solution to fill the vial prior to lyophilization is 12.252 g (12 mL). b Amount relative to free base (equivalent to 373 mg of Compound 1 Pattern 1 dihydrochloride dihydrate). c Can be used to adjust bulk solution pH if necessary. d Used to dissolve components and subsequently removed during freeze-drying. e Use nitrogen as the inert gas at the end of the freeze-drying process for vacuum conditioning.

The resulting formulation can be supplied in any suitable container, such as a 20 mL (Type 1) clear glass vial, sealed with a 20 mm grey neobutyl rubber stopper and secured with a 20 mm aluminum outer seal with a plastic snap seal.

In certain embodiments, solid formulations are formulated 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 sterile sugar solution, such as about 5 The % dextrose solution is reconstituted, sodium hydroxide and/or hydrochloric acid are added to adjust the pH, and the reconstituted solution is then diluted to an appropriate dosage for administration to a human in need, eg, at about 200 to 300 mg/m ² , eg, 240 mg /m ² dose.

Chemical Descriptions and Terminology Standard nomenclature is used 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 belongs.

The term "a (a and an)" does not denote a limitation of quantity, but rather denotes that there is at least one of the referenced item. The term "or" means "and/or". Unless otherwise indicated herein, the recitation of ranges of values is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated into this specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable.

All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any or all examples or illustrative language (eg, "such as") is intended only to better illustrate and not to limit the scope of the invention unless otherwise claimed.

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

"Deuteration and deuteration" means the replacement of hydrogen by deuterium such that deuterium is present in natural abundance and is therefore "enriched." 50% enriched means that at a given position, the content of deuterium is 50%, not hydrogen. For the sake of clarity, it is demonstrated that the term "enriched" as used herein does not mean a percentage of enrichment above natural abundance. In other embodiments, there will be at least 80%, at least 90%, or at least 95% enrichment in deuterium at one or more of the designated deuterated positions. In other embodiments, there will be at least 96%, at least 97%, at least 98%, or at least 99% enrichment in deuterium at one or more of the designated deuterated positions. In the absence of indication to the contrary, the deuterium enrichment in the indicated positions of the compounds described herein is at least 90%.

"Dosage form" means the unit of administration of the active agent. Non-limiting examples of dosage forms include lozenges, capsules, injections, suspensions, liquids, intravenous solutions, emulsions, creams, ointments, suppositories, inhalable forms, transdermal forms, and the like.

A "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. Pharmaceutical compositions optionally contain more than one active agent. "Pharmaceutical composition" or "combination therapy" refers to the administration of at least two active agents, and in one embodiment, three or four or more active agents, as appropriate, together with the active agents for treating a disorder The instructions are provided in combination in a single dosage form or together in separate dosage forms.

"Pharmaceutically acceptable salts" include derivatives of the disclosed compounds wherein the parent compound has been modified by preparing inorganic and organic, suitable non-toxic, acid or base addition salts thereof. Salts of the compounds of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by combining the free acid forms of these compounds with a stoichiometric amount of an appropriate base (such as a hydroxide, carbonate, bicarbonate or the like of Na, Ca, Mg or K) reaction, or prepared by reacting the free base form of these compounds with a stoichiometric amount of the appropriate acid. These reactions are usually carried out in water or organic solvents, or in a mixture of the two. Pharmaceutically acceptable salts may be in pure crystalline or monomorphic form, or may be used in amorphous or amorphous, glassy or vitreous form, or mixtures thereof. In an alternative embodiment, the active compound may be provided as a solvate.

Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts include conventional nontoxic and quaternary ammonium salts of the parent compound with, for example, nontoxic inorganic or organic acids. By way of example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and those derived from organic acids such as acetic, propionic , succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzene Formic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane Disulfonic acid, oxalic acid, isethionic acid, HOOC-( _CH2 )n-COOH, where n is from 0 to 4, and salts prepared from similar acids). A list of other suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., p. 1418 (1985).

The term "carrier" means a diluent, excipient or vehicle with which the active compound is provided.

"Pharmaceutically acceptable excipient" means an excipient suitable for use in the preparation of pharmaceutical compositions/combinations that is generally safe, sufficiently non-toxic, and neither biologically nor otherwise inappropriate. "Pharmaceutically acceptable excipient" as used in the specification includes both one such excipient and more than one such excipient.

A "patient" or "host" is a human or non-human animal, including but not limited to monkeys, birds, cats, dogs, cows, horses or pigs in need of medical treatment. Medical treatment can include treatment of an existing condition, such as a disease or disorder, or prophylactic or diagnostic treatment. In a specific embodiment, the patient or host is a human patient. Any condition in a patient, such as a host, responsive to tralaciride can be treated, including for bone marrow preservation or as an anti-neoplastic agent.

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

Pharmaceutical Compositions and Dosage Forms In certain aspects of the present invention, a formulation is provided, wherein the formulation is prepared for lyophilization by admixing Compound 1 of Pattern 1 with an excipient. 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 traraceril free base) 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 mannose alcohol, and optionally sodium hydroxide and/or hydrochloric acid to adjust pH as needed. In another embodiment, the formulation consists of 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 optionally sodium hydroxide and/or hydrochloric acid to adjust pH as needed, were produced by freeze-drying Compound 1 Pattern 1 prior to mixing.

Sterile water can be used for this formulation, and in non-limiting examples, 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 Reconstitute with 19.5 mL of sterile water, phosphate buffered saline, diluted sugar or another physiological saline solution. In one non-limiting example, the reconstitution solution is a sterile sodium chloride solution, eg, containing about 0.9% NaCl, or a sterile sugar solution, eg, about 5% dextrose solution. The resulting reconstituted solution will have any amount of tralaciride required for the intended purpose, such as between about 5 to 50 mg/mL, about 10 to 25 mg/ml, or even about 15 mg/mL of tralaciride. In certain embodiments, the resulting solution is subsequently diluted prior to parenteral administration, such as intravenous delivery.

Isolated Compound 1 Pattern 1 described herein, or a surrogate salt, isotopic analog or prodrug thereof, can be administered to a host in an effective amount to treat any of the disorders described herein using any suitable method that achieves the desired therapeutic result . Of course, the amount and timing of isolated Compound 1 Pattern 1 administered will depend on the host being treated, the instructions of the supervising medical professional, the duration of exposure, the mode of administration, the pharmacokinetic properties of the particular active compound, and the judgment of the prescribing physician. Depends. Therefore, due to host-to-host variability, the dosages given below are guidelines and the dosage of the compound can be titrated by the physician to achieve treatment deemed appropriate for the host by the physician. In considering the level of treatment required, the physician can balance factors such as the age and weight of the host, the status of pre-existing disease, and the status of other diseases.

Pharmaceutical compositions can be formulated in any pharmaceutically acceptable form, and are typically parenteral formulations such as intravenous, intramuscular, subcutaneous or intradermal formulations. Other alternative formulations include oral, transdermal or intranasal formulations. For example, the pharmaceutical composition can be in an intravenous bag, vial for injection, pill, capsule, lozenge, transdermal patch, subcutaneous patch, dry powder, inhalation formulation, suppository, buccal or sublingual in a medical device Formulations. Some dosage forms, such as troches and capsules, are subdivided into suitably sized unit doses containing appropriate quantities of the active component, eg, an effective amount to achieve the desired purpose.

In certain embodiments, the pharmaceutical composition is in a form containing at least about 50 mg/m ² to about 800 mg/m ² , about 100 mg/m ² to about 600 mg/m ² , about 100 mg/m ² to about 500 mg/m 2 mg/m ² , about 100 mg/m ² to about 400 mg/m ² , about 100 mg/m ² to about 350 mg/m ² , about 150 mg/m ² to about 350 mg/m ² , about 200 mg /m ² to about 350 mg/m ² or a dosage form of about 200 mg/m ² to about 300 mg/m ² . 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 practitioner based on the patient's condition, size and age, and route of delivery. In one non-limiting example, doses of about 0.1 to about 200 mg/kg, wherein all weights are calculated based on the weight of the active compound, have therapeutic efficacy. In some embodiments, the dose may provide 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 The amount of isolated Compound 1 Pattern 1 required for serum concentrations of active compound of , 10 μM, 20 μM, 30 μM or 40 μM.

In certain embodiments, the pharmaceutical compositions contain from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of the active compound and optionally about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg, such as about 300 mg to about 400 mg of isolated compound 1 pattern 1 , which may alternatively be measured as the free base or a salt thereof in unit dosage form, eg, for parenteral delivery, such as intravenous packs. Examples are dosage forms having at least 5, 10, 15, 20, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700 or 750 mg of active compound or a salt thereof. The pharmaceutical composition may also include a molar ratio of the isolated Compound 1 Pattern 1 to the additional active agent in a ratio that achieves the desired result.

Isolated Compound 1 Pattern 1 disclosed or used herein can be formulated parenterally, autologously, orally, topically, by inhalation or nebulization in dosage unit formulations containing conventional pharmaceutically acceptable carriers , sublingual, via implants (including ocular implants), percutaneous, via buccal administration, rectal, intramuscular, inhalation, intra-aortic, intracranial, subcutaneous, intraperitoneal, subcutaneous, nasal, lingual administered subcutaneously or rectally or by other means.

According to the methods disclosed herein, parenteral dosage forms can be prepared from Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate. Such dosage forms may include any pharmaceutically acceptable excipients, such as liquid excipients. Non-limiting examples of liquid excipients include phosphate buffered saline, unbuffered or buffered physiological saline (eg, unbuffered NaCl solution), sugar solutions (eg, dextrose solution), or combinations thereof as desired. When prepared For parenteral administration, Compound 1 Pattern 1 (eg, Compound 1 Pattern 1 dihydrochloride dihydrate) can be dissolved in a concentrated solution in a suitable liquid excipient. Subsequent conversion with the same or a different liquid excipient can be used. This concentrated solution of Compound 1 is diluted to an appropriate dose for the treatment of humans in need. In certain embodiments, the pH of the solution is adjusted (before or after dilution) with a pH adjusting reagent such as HCl or NaOH. In certain embodiments, additional therapeutic or non-therapeutic agents are added to the solution prior to administration or to improve shelf life.

According to the methods disclosed herein, oral administration can be in any desired form, wherein the isolated compound 1 pattern 1 is stable as a solid. In certain embodiments, Isolated Compound 1 Pattern 1 is delivered as solid microparticles or nanoparticles. When administered via inhalation, Isolated Compound 1 Pattern 1 may be in the form of a plurality of solid particles or droplets of any desired particle size, and for example, from about 0.01, 0.1 or 0.5 to about 5, 10, 20 or more microns, And from about 1 to about 2 microns as appropriate. Isolated Compound 1 Pattern 1 as disclosed in the present invention has good pharmacokinetic and pharmacodynamic properties, eg, when administered by oral or intravenous routes.

Pharmaceutical formulations can comprise isolated Compound 1 Pattern 1 described herein, or a pharmaceutically acceptable salt thereof in its stead, in any pharmaceutically acceptable carrier.

The carrier includes excipients and diluents, and must be of sufficiently high purity and sufficiently low toxicity to make it suitable for administration to the patient being treated. The carrier may be inert or may itself have a pharmaceutical benefit. The amount of carrier employed in connection with the compound is sufficient to provide an actual amount of material for administration based on a unit dose of the compound.

Carrier classes include, but are not limited to, binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavoring agents, gliding agents, lubricants, preservatives, stabilizers, surfactants, lozenges, and wetting agents agent. Some carriers may fall into more than one category, eg vegetable oils may be used as lubricants in some formulations and as diluents in others. Exemplary pharmaceutically acceptable carriers include sugar, starch, cellulose, powdered tragacanth, malt, gelatin; talc and vegetable oils. Optionally, active agents that do not substantially interfere with the activity of the compounds of the present invention may be included in the pharmaceutical compositions.

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 pattern 1 is stabilized, such as lozenges, suppositories, pills, capsules, powders, or the like, preferably in the form of A unit dosage form is administered in a single dose of precise dosage. The composition will include an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier and may additionally include other pharmaceutical agents, adjuvants, diluents, buffers, and the like.

Accordingly, the compositions of the present invention can be administered as pharmaceutical formulations, including those suitable for oral (including buccal and sublingual), rectal, nasal, topical, pulmonary, vaginal administration or in forms suitable for oral (including buccal and sublingual), rectal, nasal, topical, pulmonary, vaginal administration These pharmaceutical formulations are administered in the form thereof by inhalation or insufflation. The preferred mode of administration is oral administration using a convenient daily dosage regimen that can be adjusted according to the degree of affliction. For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like .

In yet another embodiment, to use penetration enhancing excipients comprising polymers such as: polycationic (polyglucosamine and its quaternary ammonium derivatives, poly-L-arginine, aminated gelatin); polyanions ( N -carboxymethylpolyglucosamine, polyacrylic acid); and thiolated polymers (carboxymethylcellulose cysteine, polycarbophil cysteine, polyglucosamine sulfur butylamidine, polyglucosamine thioglycolic acid, polyglucosamine glutathione conjugate).

For oral administration, the compositions will usually take the form of a tablet or capsule. Tablets and capsules are the preferred forms of oral administration. Tablets and capsules for oral use may include one or more conventional carriers such as lactose and corn starch. Lubricants, such as magnesium stearate, are also often added. Generally, the compositions 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, Combination of mannitol, sorbitol and the like. Furthermore, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars (such as glucose or beta-lactose), corn sweeteners, natural and synthetic gums (such as acacia, tragacanth or sodium alginate), carboxymethyl cellulose, poly Glycols, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, sangel and the like.

In addition to the active compounds or salts thereof, the pharmaceutical formulations may contain other additives, such as pH adjusting additives. In particular, suitable pH adjusting agents include acids such as hydrochloric acid; bases or buffers such as sodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodium borate or sodium gluconate. In addition, the formulations may contain antimicrobial preservatives. Suitable antimicrobial preservatives include methylparaben, propylparaben, and benzyl alcohol. When formulations are placed in vials designed for multi-dose use, antimicrobial preservatives are typically employed. The pharmaceutical compounds described herein can be lyophilized using techniques well known to those skilled in the art.

For oral administration, the pharmaceutical compositions can be in the form of lozenges, pills, capsules, powders, and the like. Tablets are used containing various excipients such as sodium citrate, calcium carbonate, and calcium phosphate, and various disintegrants such as starches (eg, potato or tapioca), and certain complex silicates, and such Binding agent of polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are generally suitable for tableting purposes. Solid compositions of a similar type can also be employed as fillers in the form of soft and hard filled gelatin capsules.

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

The term "pharmaceutically acceptable salts" as used herein refers to salts which, within the scope of sound medical judgment, are suitable for use in contact with a host (eg, a human host) without abnormal toxicity, irritation, allergic response and similar responses, meeting a reasonable benefit/risk ratio and being effective for its intended use; and the zwitterionic forms of the host substances disclosed herein, if possible.

In an alternate embodiment, Compound 1 Pattern 1 is not the HCl salt, but is actually the salt described below.

In one embodiment, the other therapeutic agent described in the Combination Section below is administered in the form of a pharmaceutically acceptable salt, eg, the salt described below.

Thus, the term "salt" refers to the relatively nontoxic inorganic and organic acid addition salts of the compounds disclosed herein. These salts can be prepared during the final isolation and purification of the compound, or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Basic compounds are capable of forming various salts with various inorganic and organic acids. Acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in a conventional manner. The free base form can be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner. The free base forms may differ from their respective 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 and alkaline earth metals or organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines include, but are not limited to, N,N'-diphenylmethylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylreduced glucamine, and Procaine. Base addition salts of acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in a conventional manner. The free acid form can be regenerated by contacting the salt form with the acid and isolating the free acid in a conventional manner. The free acid form may differ from its respective salt form in certain physical properties, such as solubility in polar solvents.

Salts can be selected from inorganic acids sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride , bromide, iodide, such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorus and the like are prepared. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, lauric acid Salt, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthalate acid salts, mesylate, glucoheptonate, lactobionate, lauryl sulfonate and isethionate salts and the like. Salts can also be made from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic sulfonic and aromatic sulfonic acids, and the like. Acid preparation. Representative salts include acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate , maleate, mandelic, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, Tosylate, phenylacetate, citrate, lactate, maleate, tartrate, mesylate and the like.

Pharmaceutically acceptable salts may include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like; and non-toxic ammonium, quaternary ammonium, and amines, including but not limited to ammonium , tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. Also contemplated are salts of amino acids, such as arginine, gluconate, galacturonate, and the like. See, eg, Berge et al., J. Pharm. Sci., 1977, 66, 1-19, incorporated herein by reference.

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

Formulations suitable for topical application to the skin are preferably in the form of ointments, creams, lotions, ointments, gels, sprays, aerosols or oils that maintain the stability of Isolated Compound 1 Pattern 1. Carriers that can be used include petroleum gum, lanolin, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.

Pharmaceutical compositions suitable for transdermal administration may be presented in discrete patches adapted to remain in intimate contact with the epidermis of the recipient for extended periods of time. Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, eg, Pharmaceutical Research 3(6):318 (1986)) and usually in the form of an optionally buffered aqueous solution of the active compound. In one embodiment, a microneedle patch or device is provided for delivering drugs across or into biological tissue, particularly skin. Microneedle patches or devices allow drug delivery across or into skin or other tissue barriers at clinically relevant rates with minimal or no tissue damage, pain or irritation.

Formulations suitable for administration to the lung can be delivered by a wide range of passive breath-actuated and active electrically actuated single-dose/multi-dose dry powder inhalers (DPIs). The devices most commonly used for respiratory delivery include nebulizers, metered dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. Selection of an appropriate pulmonary delivery device depends on parameters such as the nature of the drug and its formulation, site of action, and lung pathophysiology.

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

In certain embodiments, IV solutions of Compound 1 are prepared from solid pharmaceutical compositions, which are optionally dried by lyophilization. In certain embodiments, the composition includes Compound 1 in the form of a dihydrochloride salt, eg, Compound 1 Dihydrochloride Pattern 1. The composition may also include suitable excipients such as bulking agents, buffering agents and/or one or more pH adjusting agents. In certain embodiments, the bulking agent is a suitable sugar, such as mannitol. In certain embodiments, the buffer is an appropriate weak acid or base with one or more acidic or basic sites. In certain embodiments, the buffer is a weak acid with two or more acidic sites, such as citric acid. In certain embodiments, the composition includes NaOH, HCl, and/or NaCl as pH adjusters (NaOH and/or HCl) or residual salts (NaCl) from pH adjustment.

It was also found that freeze-dried Compound 1 dihydrochloride compositions comprising mannitol and citric acid can be prepared as crystalline and readily characterized by X-ray powder diffraction (XRPD). In certain embodiments, the lyophilized Compound 1 dihydrochloride composition comprises 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 a primary embodiment, Compound 1 in the lyophilized composition is a crystalline dihydrochloride salt in the form characterized herein as Pattern 1 . In other embodiments, Compound 1 in the lyophilized composition is in the form of different pharmaceutically acceptable salts or mixtures of pharmaceutically acceptable salts. In certain embodiments, Compound 1 in the freeze-dried composition is in different patterns or mixtures of patterns. In certain embodiments, the lyophilized Compound 1 composition comprises at least about 1 %, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% Compound 1 Dihydrochloride Pattern 1.

The freeze-dried Compound 1 dihydrochloride composition described in Example 28 contained mannitol and citric acid and was characterized by the XRPD pattern shown in FIG. 100 . Other suitable excipients may be added or substituted for mannitol and/or citric acid as appropriate to achieve the desired effect. In certain embodiments, the Compound 1 dihydrochloride salt composition is freeze-dried, in other embodiments, it is dried using another technique. In certain embodiments, the Compound 1 dihydrochloride composition comprises mannitol, eg, 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, 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 certain embodiments, the Compound 1 dihydrochloride composition comprises citric acid, eg, 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 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 certain embodiments, the Compound 1 dihydrochloride composition comprises one or more additional salts formed by adjusting the pH of the bulk solution, which is dried to form the composition, such as sodium chloride and/or various citric acids sodium salt.

In a specific embodiment, the lyophilized Compound 1 dihydrochloride composition comprises about 349 mg of Compound 1 Pattern 1 dihydrochloride (equivalent to about 300 mg of tralaciride free base), 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, eg, 300 mg, of mannitol.

In certain aspects of the invention, isolated Compound 1 Pattern 1 is used to manufacture a lyophilized form that is subsequently formulated with a suitable solvent such as phosphate buffered saline for administration to a patient, eg, by intravenous delivery . In another embodiment, it can be formulated into a parenteral dosage form. Such dosage forms can be used, for example, for subcutaneous administration.

Beneficial Pharmaceutical Forms of Tralaciride for Effective Therapy In certain embodiments, a form of Compound 1 (eg, Compound 1 dihydrochloride dihydrate) is used to generate an intravenous formulation in a bone marrow-preserving form, Or alternatively when provided with chemotherapy for the treatment of cancer, as appropriate with the standard of care for the cancer being treated. The standard of care for the treatment of a specific cancer includes the use of a therapy approved by a regulatory agency for the cancer being treated, such as the US Food and Drug Administration (FDA), European Medicines Agency (EMA) or China's National Medical Products Administration (NMPA). In other embodiments, a pharmaceutical formulation as described herein is selected and administered by the patient's nursing physician.

In certain embodiments, there is provided a method of treating a CDK4/6 mediated disorder, such as any one of the disorders or methods described below, wherein the patient is administered a compound comprising Compound 1 , mannitol and citric acid An IV solution, wherein the IV solution was formed by reconstituting a freeze-dried Compound 1 dihydrochloride composition comprising mannitol and citric acid. In certain embodiments, the freeze-dried composition comprises Compound 1 Dihydrochloride Pattern 1. (i) Bone marrow preservation

When used as a bone marrow preservative, it can be administered, for example, as taught in WO 2014/144326, WO 2016/040848, WO 2018/106729 or PCT/US20/38557. For example, in certain embodiments, Compound 1 Pattern 1 dihydrochloride dihydrate, or an intravenous solution prepared therefrom, is administered daily during a treatment cycle in which chemotherapy is administered. For example, if chemotherapy is administered on days 1, 2, and/or 3 of the treatment cycle, the intravenous solution is also administered on days 1, 2, and/or 3 of the treatment cycle (eg on Day 1 or Day 1 and Day 2 of a treatment cycle). In another embodiment, the intravenous solution is administered on days 1 and 8 of a 21-day treatment cycle, and by way of non-limiting example, in combination with gemcitabine, carboplatin, or topotecan.

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

In one embodiment, the individual has been exposed to a chemotherapeutic agent, and the CDK4/6 replication-dependent healthy cells of the individual are placed in post-exposure G1 arrest to mitigate, eg, DNA damage using the intravenous solutions described herein. In one embodiment, at least ½ hour, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 10 hours after exposure to the chemotherapeutic agent The compound is administered for hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 20 hours or more. In an alternative embodiment, at least ½ hour, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least Compound 1 pattern 1 dihydrochloride dihydrate or an intravenous solution prepared therefrom is administered for 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 20 hours or more. In certain embodiments, Compound 1 Pattern 1 dihydrochloride dihydrate, or an intravenous solution prepared therefrom, is administered about 4 hours prior to chemotherapy.

In one embodiment, an intravenous solution prepared from Compound 1 Pattern 1 dihydrochloride dihydrate is administered in combination with a chemotherapeutic agent, including but not limited to a treatment in which the chemotherapeutic agent is administered at the following times Programs and similar types of programs: 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 ; 1st and 8th days of every 28 days; 1st and 8th days of every 21 days; 1st to 5th days of every 21st days; 1 day of a week for 6 to 8 weeks; 22 days and 43 days; 1st and 2nd days of the week; 1st to 4th days and 22nd to 25th days; 1st to 4th days, 22nd to 25th days and 43rd to 46th days, of which CDK4/ 6 Replication-dependent cells arrest in G1 phase during chemotherapeutic agents.

In one embodiment, isolated Compound 1 Pattern 1 may allow for dose intensification in medically relevant chemotherapy (eg, more therapy may be administered over a fixed period of time), which will translate into better efficacy. Thus, the methods disclosed herein can result in less toxic and more effective chemotherapy regimens.

In some embodiments, use of Isolated Compound 1 Pattern 1 described herein can result in reduced or substantially limited off-target effects, eg, associated with inhibition of kinases other than CDK4 and/or CDK6, such as CDK2. Furthermore, in certain embodiments, the use of Isolated Compound 1 Pattern 1 described herein should not induce cell cycle arrest in CDK4/6 replication-independent cells.

In some embodiments, the use of Isolated Compound 1 Pattern 1 described herein reduces the risk of undesired off-target effects including, but not limited to, long-term toxicity, antioxidant effects, and estrogenic effects. Antioxidative effects can be determined by standard assays known in the art. For example, compounds that do not have significant antioxidant effects enable compounds that do not significantly scavenge free radicals such as oxygen radicals. The antioxidant effects of the compounds are comparable to compounds with known antioxidant activity, such as genistein. Thus, a compound that does not have significant antioxidant activity can be a compound that has less than about 2, 3, 5, 10, 30 or 100 times the antioxidant activity relative to genistein. Estrogenic activity can also be determined by known assays. For example, non-estrogenic compounds are compounds that do not significantly bind and activate estrogen receptors. A compound that is substantially limited in estrogenic effect can be a compound that has less than about 2, 3, 5, 10, 20, or 100 times the estrogenic activity relative to a compound having estrogenic activity (eg, genistein).

Compound 1 pattern 1 (eg, Compound 1 pattern 1 dihydrochloride dihydrate) or formulations derived therefrom can be administered parenterally (eg, intravenously) prior to administration of immune response-inducing chemotherapy, such as ICD-induced chemotherapy inside) administered to the patient. In some embodiments, up to about 24 hours or less, or up to about 20, 15, 10, 5, or 4 hours or less, eg, about 30 to 60 minutes or less, is administered before chemotherapy is administered with compound 1 . In some embodiments, Compound 1 is administered approximately 22 to 26 hours prior to administration of chemotherapy, and re-administered approximately 4 hours or less, eg, approximately 30 to 60 minutes or less prior to administration of chemotherapy with compound 1 . In some embodiments, the dose of Compound 1 administered is between about 180 and about 280 mg/ ^m2 . For example, the dose 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 dose in between these numbers as determined by the healthcare practitioner. In a specific embodiment, the dose is about 240 mg/m ² .

Typically, Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, is administered to an individual prior to treatment with the chemotherapeutic agent such that its concentration is prior to or during treatment with the chemotherapeutic agent Achieving peak serum levels inhibits the proliferation of immune effector cells, thus protecting them from the deleterious effects of chemotherapy. In some embodiments, Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation derived therefrom, is administered concurrently with or proximate to exposure to the chemotherapeutic agent. Alternatively, the CDK4/6 inhibitors described herein can be administered after exposure to a chemotherapeutic agent, if necessary, to alleviate immune effector cell damage associated with chemotherapeutic agent exposure. In one embodiment, the aqueous solution produced from Compound 1 Pattern 1 is administered to a patient in need.

In some embodiments, 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, Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation derived therefrom, is administered to the subject for about ½ hour or less. In a particular embodiment, Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, is administered about ½ hour prior to administration of the chemotherapeutic agent.

In some embodiments, Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation derived therefrom, is administered to the individual twice prior to administration of chemotherapy. For example, in some embodiments, Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, is administered between about 18 and 28 hours prior to administration of chemotherapy, and then administer Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride, again less than about 4 hours, about 2.5 hours, about 2 hours, about 1 hour, about ½ hour or less prior to treatment with the chemotherapeutic agent Dihydrate or formulations derived therefrom. In a particular embodiment, Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, is administered between about 22 and 26 hours prior to administration of the chemotherapeutic agent, and again Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, is administered about ½ hour or less prior to administration of the chemotherapeutic agent.

In certain embodiments, Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation prepared therefrom, is administered prior to or concurrently with the administration of the chemotherapeutic agent, wherein the administration is as follows The chemotherapeutic agent and similar types of regimens: Days 1-3 every 21 days; Days 1-3 every 28 days; Day 1 every 3 weeks; Days 1, 8, and 28 days Day 15; Days 1 and 8 of every 28 days; Days 1 and 8 of every 21 days; Days 1 to 5 of every 21 days; 1 day of the week for 6 to 8 weeks; Day 22 and Day 43; Day 1 and 2 of the week; Day 1 to 4 and Day 22 to 25; Day 1 to 4, Day 22 to 25 and Day 43 to 46. In some embodiments, Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation derived therefrom, is prior to or concurrent with at least one administration of a chemotherapeutic agent during a chemotherapeutic treatment regimen. vote. In some embodiments, Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, is during a chemotherapeutic treatment regimen prior to one or more administrations of the chemotherapeutic agent or at the same time. In one embodiment, Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, is during a chemotherapeutic treatment regimen prior to or concurrent with each administration of a chemotherapeutic agent vote.

In some embodiments, Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation derived therefrom, for example, during a standard chemotherapy protocol such as a 21-day cycle, at each time of the chemotherapeutic agent before or at the same time as the vote. Compound 1 pattern 1, eg, Compound 1 pattern 1 dihydrochloride dihydrate, or formulations derived therefrom, may be further administered alone at a maintenance dose after cessation of standard chemotherapy protocols. In some embodiments, Compound 1 Pattern 1, eg Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom is further administered once a week for at least 3, 4, 5, 6, 7, 8, 9 , 10, 11, 12, 13, 14, 15, 16, 26, 52, 104 weeks or longer. In some embodiments, Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation derived therefrom, is administered every 21 days after the cessation of the chemotherapeutic protocol. In one embodiment, Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation derived therefrom, is a fast-acting short half-life CDK4/6 inhibitor.

In some embodiments, Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation derived therefrom, is administered with a chemotherapeutic agent in a maintenance therapy regimen following cessation of a standard chemotherapy regimen . Maintenance therapy may include continuation of an agent given as first line or as part of a previous regimen (continuation maintenance) or treatment with a novel agent (switch maintenance).

In some embodiments, Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation derived therefrom, is further administered in a maintenance-type treatment regimen, wherein Compound 1 Pattern 1, eg, Compound 1 Pattern 1 1 Dihydrochloride dihydrate or formulations derived therefrom are administered with reduced maintenance doses of chemotherapy at regular dosing intervals including, but not limited to, weekly, biweekly after completion of initial chemotherapy treatment Once, every three weeks, monthly, every six weeks, every two months, every three months, or every six months. In some embodiments, Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation resulting therefrom, is administered with the same agent used in the previous chemotherapy treatment session. In some embodiments, Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation derived therefrom, is administered with a different chemotherapeutic agent than was used in the previous chemotherapy treatment session.

Standard cancer chemotherapy can promote tumor immunity in two main ways: (i) by inducing immunogenic cell death as part of its intended therapeutic effect; and (ii) by destroying tumors as a strategy for evading immune responses. Extensive data suggest that some chemotherapeutic drugs at their standard doses and schedules mediate their anti-neoplastic effects, at least in part, by inducing immunogenic cell death (see, eg, 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 incorporated by reference in this article).

Immunogenic cell death (ICD) is a type of cell death characterized by cell surface displacement such as calreticulin (CRT), extracellular release of ATP and high mobility group box 1 (HMBG1) and interference with type I Stimulation of IFN (IFN) responses. ICD in cancer cells can trigger anti-cancer immune responses. Various chemotherapeutic agents can induce ICD as indicated by changes in tumor infiltrating lymphocytes (TILs), abundance and composition.

In response to ICD-inducing chemotherapeutics, tumor cells expose CRT on the cell surface prior to death and release damage-associated molecular pattern (DAMP) molecules, such as ATP, during apoptosis, or HMGB1 during secondary necrosis. These DAMP stimulations recruit dendritic cells (DCs) into the tumor bed, uptake and processing of tumor antigens, and optimal antigen presentation to T cells. Cross-priming of CD8+ T cells is triggered by mature DCs and γδ T cells in an IL-1β and IL-17-dependent manner. The primed CTLs then induce a cytotoxic response to kill the remaining tumor cells via production of IFN-γ, perforin-1 and granzyme B. In certain embodiments, Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation derived therefrom, is used in combination with ICD-inducing chemotherapy for bone marrow preservation.

ICD induction chemotherapy used in the present invention includes alkylating agents such as cyclophosphamide, trabectedin, temozolomide, melphalan, dacarbazine and oxa oxaliplatin; antimetabolites such as methotrexate, mitroxantrone, gemcitabine, and 5-fluorouracil (5-FU); cytotoxic antibiotics such as bleomycin (bleomycin) and anthracyclines, including doxorubicin, daunorubicin, epirubicin, idarubicin, and valrubicin; taxanes , such as paclitaxel, cabazitaxel and docetaxel; topoisomerase inhibitors such as topotecan, irinotecan and etoposide; platinum compounds such as carboplatin and cis Platinum; anti-microtubule vinca alkaloid agents such as vinblastine, vincristine, vinorelbine and vindesine. Other ICD induction chemotherapies include bortezomib, inhibitors of the 26S proteasome subunit, methylbis(chloroethyl)amine, diaziquone, mitomycin C, fludarabine and Cytosine arabinoside. In some embodiments, the ICD induction chemotherapy is selected from the group consisting of idarubicin, epirubicin, cranberries, mitoxantrone, oxaliplatin, bortezomib, gemcitabine, and cyclophosphamide, and combinations thereof. In an alternative embodiment, administered chemotherapeutic agents capable of inducing an immune response may modulate tumor immunity by mechanisms other than immunogenic cell death. Different chemotherapeutic agents can enhance the expression of costimulatory molecules including B7.1 (CD80) and B7.2 (CD86), downregulate checks such as planned death-ligand 1 (PD-L1) by enhancing antigen presentation Dot molecule or promotion of tumor cell death via fas, perforin or granzyme B pathways to modulate the activity of different immune cell subsets or the immunophenotype of tumor cells Modulation of tumor immunity Chemotherapy can be performed by: abrogating myeloid-derived suppression Factor cell (MDSC) activity, such as gemcitabine, 5-fluorouracil, cisplatin, and cranberries; abrogates Treg activity, such as cyclophosphamide, 5-fluorouracil; paclitaxel, cisplatin, and fludarabine; enhances T-cell crossover Sensitization, eg, gemcitabine and anthracyclines, such as cranberries, daunorubicin, epirubicin, varrubicin, and idarubicin; enhances dendritic cell activation, eg, anthracyclines, taxanes, Cyclophosphamide, vinca alkaloids, methotrexate, and mitomycin C; promote anti-neoplastic CD4+ T cell phenotypes, such as cyclophosphamide and paclitaxel; and promote tumor cell recognition and lysis, such as cyclophosphamide Phosphatamide, 5-fluorouracil, paclitaxel, cranberries, cisplatin, and cytosine arabinoside.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy, comprising administering Compound 1 Pattern 1, eg, Compound 1 , in a manner that increases progression-free survival or overall survival in the patient or patient population Pattern 1 Dihydrochloride dihydrate or formulations therefrom and chemotherapy, the method comprising, determining whether the cancer has favorable immunomodulation, is immunogenically susceptible to CDK4/6 inhibitor treatment or is immune the native surrounding microenvironment, and if so, administer to the patient an effective amount of Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, and an effective amount of each of the following : alkylating agents such as cyclophosphamide, trabectedin, temozolomide, melphalan, dacarbazine, and oxaliplatin; antimetabolites such as methotrexate, mitoxantrone, gemcitabine and 5-Fluorouracil (5-FU); cytotoxic antibiotics such as bleomycin and anthracyclines such as cranberries, daunomycin, epirubicin, idarubicin, and valrubicin; taxanes , such as paclitaxel, cabazitaxel, and docetaxel; topoisomerase inhibitors, such as topotecan, irinotecan, and etoposide; platinum compounds, such as carboplatin and cisplatin; anti-microtubule vinca Alkaloid agents such as vinblastine, vincristine, vinorelbine, and vindesine; bortezomib; methylbis(chloroethyl)amine; deacrquinone; fludarabine; mitomycin C; and Cytosine arabinoside. In some embodiments, administration of Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation derived therefrom in combination with chemotherapy 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 febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy, comprising administering Compound 1 Pattern 1, eg, Compound 1 , in a manner that increases progression-free survival or overall survival in the patient or patient population Pattern 1 Dihydrochloride dihydrate or formulations therefrom and chemotherapy, the method comprising, determining whether the cancer has favorable immunomodulation, is immunogenically susceptible to CDK4/6 inhibitor treatment or is immune the native surrounding microenvironment, and if so, administer to the patient an effective amount of Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, and an effective amount of cyclophosphine Amide. In some embodiments, administering Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation derived therefrom in combination with cyclophosphamide, does not include administering an immune checkpoint inhibitor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy comprising administering a CDK 4/6 inhibitor and a chemical in a manner that increases progression-free survival or overall survival of the patient or patient population Therapy, the method comprising, determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, is immunogenic, is susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective An amount of Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, and an effective amount of Trabectedin. In some embodiments, administration of Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation produced therefrom in combination with trabectedin 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 febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy, comprising administering Compound 1 Pattern 1, eg, Compound 1 , in a manner that increases progression-free survival or overall survival in the patient or patient population Pattern 1 Dihydrochloride dihydrate or formulations therefrom and chemotherapy, the method comprising, determining whether the cancer has favorable immunomodulation, is immunogenically susceptible to CDK4/6 inhibitor treatment or is immune The native surrounding microenvironment, and if so, an effective amount of Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, and an effective amount of temozolomide are administered to the patient. In some embodiments, administering Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation derived therefrom, in combination with temozolomide does not include administering an immune checkpoint inhibitor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy, comprising administering Compound 1 Pattern 1, eg, Compound 1 , in a manner that increases progression-free survival or overall survival in the patient or patient population Pattern 1 Dihydrochloride dihydrate or formulations therefrom and chemotherapy, the method comprising, determining whether the cancer has favorable immunomodulation, is immunogenically susceptible to CDK4/6 inhibitor treatment or is immune the native surrounding microenvironment, and if so, administer to the patient an effective amount of Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, and an effective amount of melphalan . In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy comprising administering a CDK 4/6 inhibitor and a chemical in a manner that increases progression-free survival or overall survival of the patient or patient population Therapy, the method comprising, determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, is immunogenic, is susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective An amount of Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, and an effective amount of dacarbazine. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy, comprising administering Compound 1 Pattern 1, eg, Compound 1 , in a manner that increases progression-free survival or overall survival in the patient or patient population Pattern 1 Dihydrochloride dihydrate or formulations therefrom and chemotherapy, the method comprising, determining whether the cancer has favorable immunomodulation, is immunogenically susceptible to CDK4/6 inhibitor treatment or is immune the native surrounding microenvironment, and if so, administer to the patient an effective amount of Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, and an effective amount of Oxa Liplatin. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy, comprising administering Compound 1 Pattern 1, eg, Compound 1 , in a manner that increases progression-free survival or overall survival in the patient or patient population Pattern 1 Dihydrochloride dihydrate or formulations therefrom and chemotherapy, the method comprising, determining whether the cancer has favorable immunomodulation, is immunogenically susceptible to CDK4/6 inhibitor treatment or is immune the native surrounding microenvironment, and if so, administer to the patient an effective amount of Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, and an effective amount of methylamine Pterin. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy comprising administering a CDK 4/6 inhibitor and a chemical in a manner that increases progression-free survival or overall survival of the patient or patient population Therapy, the method comprising, determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, is immunogenic, is susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective An amount of Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, 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 febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy, comprising administering Compound 1 Pattern 1, eg, Compound 1 , in a manner that increases progression-free survival or overall survival in the patient or patient population Pattern 1 Dihydrochloride dihydrate or formulations therefrom and chemotherapy, the method comprising, determining whether the cancer has favorable immunomodulation, is immunogenically susceptible to CDK4/6 inhibitor treatment or is immune The native surrounding microenvironment, and if so, an effective amount of Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, and an effective amount of gemcitabine are administered to the patient. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature."

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy, comprising administering Compound 1 Pattern 1, eg, Compound 1 , in a manner that increases progression-free survival or overall survival in the patient or patient population Pattern 1 Dihydrochloride dihydrate or formulations therefrom and chemotherapy, the method comprising, determining whether the cancer has favorable immunomodulation, is immunogenically susceptible to CDK4/6 inhibitor treatment or is immune the native 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 derived therefrom, and an effective amount of Mitotrope Anthraquinone. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy comprising administering a CDK 4/6 inhibitor and a chemical in a manner that increases progression-free survival or overall survival of the patient or patient population Therapy, the method comprising, determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, is immunogenic, is susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective An amount of Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation therefrom, and an effective amount of cranberries. In some embodiments, administering Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation produced therefrom in combination with cranberries does not include administering an immune checkpoint inhibitor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy, comprising administering Compound 1 Pattern 1, eg, Compound 1 , in a manner that increases progression-free survival or overall survival in the patient or patient population Pattern 1 Dihydrochloride dihydrate or formulations therefrom and chemotherapy, the method comprising, determining whether the cancer has favorable immunomodulation, is immunogenically susceptible to CDK4/6 inhibitor treatment or is immune the native surrounding microenvironment, and if so, administer to the patient an effective amount of Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, and an effective amount of Daunuo Mycin. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy, comprising administering Compound 1 Pattern 1, eg, Compound 1 , in a manner that increases progression-free survival or overall survival in the patient or patient population Pattern 1 Dihydrochloride dihydrate or formulations therefrom and chemotherapy, the method comprising, determining whether the cancer has favorable immunomodulation, is immunogenically susceptible to CDK4/6 inhibitor treatment or is immune the native 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 derived therefrom, and an effective amount of idarub star. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy, comprising administering Compound 1 Pattern 1, eg, Compound 1 , in a manner that increases progression-free survival or overall survival in the patient or patient population Pattern 1 Dihydrochloride dihydrate or formulations therefrom and chemotherapy, the method comprising, determining whether the cancer has favorable immunomodulation, is immunogenically susceptible to CDK4/6 inhibitor treatment or is immune the native 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 derived therefrom, and an effective amount of Varrox than stars. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy comprising administering a CDK 4/6 inhibitor and a chemical in a manner that increases progression-free survival or overall survival of the patient or patient population Therapy, the method comprising, determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, is immunogenic, is susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective An amount of Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, 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 immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy, comprising administering Compound 1 Pattern 1, eg, Compound 1 , in a manner that increases progression-free survival or overall survival in the patient or patient population Pattern 1 Dihydrochloride dihydrate or formulations therefrom and chemotherapy, the method comprising, determining whether the cancer has favorable immunomodulation, is immunogenically susceptible to CDK4/6 inhibitor treatment or is immune the native surrounding microenvironment, and if so, administer to the patient an effective amount of Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, and an effective amount of Bole Mycin. In some embodiments, administration of Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation produced therefrom in combination with bleomycin does not include administration of an immune checkpoint inhibitor. In some embodiments, the patient has a febrile immune tumor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature."

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy, comprising administering Compound 1 Pattern 1, eg, Compound 1 , in a manner that increases progression-free survival or overall survival in the patient or patient population Pattern 1 Dihydrochloride dihydrate or formulations therefrom and chemotherapy, the method comprising, determining whether the cancer has favorable immunomodulation, is immunogenically susceptible to CDK4/6 inhibitor treatment or is immune the native surrounding microenvironment, and if so, administer to the patient an effective amount of Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, and an effective amount of bortezol Meter. In some embodiments, administration of Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation produced therefrom in combination with bortezomib 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 febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy, comprising administering Compound 1 Pattern 1, eg, Compound 1 , in a manner that increases progression-free survival or overall survival in the patient or patient population Pattern 1 Dihydrochloride dihydrate or formulations therefrom and chemotherapy, the method comprising, determining whether the cancer has favorable immunomodulation, is immunogenically susceptible to CDK4/6 inhibitor treatment or is immune the native 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 derived therefrom, and an effective amount of paclitaxel . In some embodiments, administration of Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation produced therefrom in combination with paclitaxel 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 febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy, comprising administering Compound 1 Pattern 1, eg, Compound 1 , in a manner that increases progression-free survival or overall survival in the patient or patient population Pattern 1 Dihydrochloride dihydrate or formulations therefrom and chemotherapy, the method comprising, determining whether the cancer has favorable immunomodulation, is immunogenically susceptible to CDK4/6 inhibitor treatment or is immune the native 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 derived therefrom, and an effective amount of Docere He races. In some embodiments, administration of Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation produced therefrom in combination with docetaxel 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 febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy, comprising administering Compound 1 Pattern 1, eg, Compound 1 , in a manner that increases progression-free survival or overall survival in the patient or patient population Pattern 1 Dihydrochloride dihydrate or formulations therefrom and chemotherapy, the method comprising, determining whether the cancer has favorable immunomodulation, is immunogenically susceptible to CDK4/6 inhibitor treatment or is immune the native surrounding microenvironment, and if so, administer to the patient an effective amount of Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, and an effective amount of cabazita race. In some embodiments, administration of Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation produced therefrom in combination with cabazitaxel 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 febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy comprising administering a CDK 4/6 inhibitor and a chemical in a manner that increases progression-free survival or overall survival of the patient or patient population Therapy, the method comprising, determining whether the cancer has a surrounding microenvironment that is favorable for immunomodulation, is immunogenic, is susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective An amount of Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, and an effective amount of Topotecan. In some embodiments, administration of Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation produced therefrom in combination with topotecan 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 febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy, comprising administering Compound 1 Pattern 1, eg, Compound 1 , in a manner that increases progression-free survival or overall survival in the patient or patient population Pattern 1 Dihydrochloride dihydrate or formulations therefrom and chemotherapy, the method comprising, determining whether the cancer has favorable immunomodulation, is immunogenically susceptible to CDK4/6 inhibitor treatment or is immune the native 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 derived therefrom, and an effective amount of Etopo glycosides. In some embodiments, administration of Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation produced therefrom in combination with etoposide 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 febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy, comprising administering Compound 1 Pattern 1, eg, Compound 1 , in a manner that increases progression-free survival or overall survival in the patient or patient population Pattern 1 Dihydrochloride dihydrate or formulations therefrom and chemotherapy, the method comprising, determining whether the cancer has favorable immunomodulation, is immunogenically susceptible to CDK4/6 inhibitor treatment or is immune the native 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 derived therefrom, and an effective amount of Iritinib Kang. In some embodiments, administration of Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation produced therefrom in combination with irinotecan 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 febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy, comprising administering Compound 1 Pattern 1, eg, Compound 1 , in a manner that increases progression-free survival or overall survival in the patient or patient population Pattern 1 Dihydrochloride dihydrate or formulations therefrom and chemotherapy, the method comprising, determining whether the cancer has favorable immunomodulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immune the native surrounding microenvironment, and if so, administer to the patient an effective amount of Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, and an effective amount of cisplatin . In some embodiments, administration of Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation derived therefrom, 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 febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy, comprising administering Compound 1 Pattern 1, eg, Compound 1 , in a manner that increases progression-free survival or overall survival in the patient or patient population Pattern 1 Dihydrochloride dihydrate or formulations therefrom and chemotherapy, the method comprising, determining whether the cancer has favorable immunomodulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immune the native surrounding microenvironment, and if so, administer to the patient an effective amount of Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, and an effective amount of carboplatin . In some embodiments, administration of Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation derived therefrom, in combination with carboplatin 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 febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy, comprising administering Compound 1 Pattern 1, eg, Compound 1 , in a manner that increases progression-free survival or overall survival in the patient or patient population Pattern 1 Dihydrochloride dihydrate or formulations therefrom and chemotherapy, the method comprising, determining whether the cancer has favorable immunomodulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immune the native surrounding microenvironment, and if so, administer to the patient an effective amount of Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, and an effective amount of vinblastine . In some embodiments, administration of Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation produced therefrom in combination with vinblastine, 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 febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy, comprising administering Compound 1 Pattern 1, eg, Compound 1 , in a manner that increases progression-free survival or overall survival in the patient or patient population Pattern 1 Dihydrochloride dihydrate or formulations therefrom and chemotherapy, the method comprising, determining whether the cancer has favorable immunomodulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immune the native surrounding microenvironment, and if so, administer to the patient an effective amount of Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, and an effective amount of Vinblastine alkali. In some embodiments, administration of Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation produced therefrom in combination with vincristine 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 febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy, comprising administering Compound 1 Pattern 1, eg, Compound 1 , in a manner that increases progression-free survival or overall survival in the patient or patient population Pattern 1 Dihydrochloride dihydrate or formulations therefrom and chemotherapy, the method comprising, determining whether the cancer has favorable immunomodulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immune the native surrounding microenvironment, and if so, administer to the patient an effective amount of Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, and an effective amount of Vinorelbine coast. In some embodiments, administration of Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation produced therefrom in combination with Vinorelbine 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 febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy, comprising administering Compound 1 Pattern 1, eg, Compound 1 , in a manner that increases progression-free survival or overall survival in the patient or patient population Pattern 1 Dihydrochloride dihydrate or formulations therefrom and chemotherapy, the method comprising, determining whether the cancer has favorable immunomodulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immune the native surrounding microenvironment, and if so, administer to the patient an effective amount of Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, and an effective amount of Vinca pungent. In some embodiments, administration of Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation produced therefrom in combination with Vindesine 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 febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy, comprising administering Compound 1 Pattern 1, eg, Compound 1 , in a manner that increases progression-free survival or overall survival in the patient or patient population Pattern 1 Dihydrochloride dihydrate or formulations therefrom and chemotherapy, the method comprising, determining whether the cancer has favorable immunomodulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immune the native surrounding microenvironment, and if so, administer to the patient an effective amount of Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, and an effective amount of acridine Quinone. In some embodiments, administration of Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation produced therefrom in combination with Dezaquinone 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 febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy, comprising administering Compound 1 Pattern 1, eg, Compound 1 , in a manner that increases progression-free survival or overall survival in the patient or patient population Pattern 1 Dihydrochloride dihydrate or formulations therefrom and chemotherapy, the method comprising, determining whether the cancer has favorable immunomodulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immune the native surrounding microenvironment, and if so, administer to the patient an effective amount of Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, and an effective amount of methyl Di(chloroethyl)amine. In some embodiments, administration of Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom in combination with methylbis(chloroethyl)amine does not include administration of an immunoassay point inhibitor. In some embodiments, the patient has a tumor classified as immunogenic. In some embodiments, the patient has a febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy, comprising administering Compound 1 Pattern 1, eg, Compound 1 , in a manner that increases progression-free survival or overall survival in the patient or patient population Pattern 1 Dihydrochloride dihydrate or formulations therefrom and chemotherapy, the method comprising, determining whether the cancer has favorable immunomodulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immune the native surrounding microenvironment, and if so, administer to the patient an effective amount of Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, and an effective amount of Mitochondrial Mycin C. In some embodiments, administration of Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation produced therefrom in combination with Mitomycin C 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 febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy, comprising administering Compound 1 Pattern 1, eg, Compound 1 , in a manner that increases progression-free survival or overall survival in the patient or patient population Pattern 1 Dihydrochloride dihydrate or formulations therefrom and chemotherapy, the method comprising, determining whether the cancer has favorable immunomodulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immune the native surrounding microenvironment, and if so, administer to the patient an effective amount of Compound 1 Pattern 1, such as Compound 1 Pattern 1 dihydrochloride dihydrate or a formulation derived therefrom, and an effective amount of Fludax Rabin. In some embodiments, administration of Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation produced therefrom in combination with fludarabine 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 febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In some embodiments, there is provided a method of selecting a patient or patient population for cancer therapy, comprising administering Compound 1 Pattern 1, eg, Compound 1 , in a manner that increases progression-free survival or overall survival in the patient or patient population Pattern 1 Dihydrochloride dihydrate or formulations therefrom and chemotherapy, the method comprising, determining whether the cancer has favorable immunomodulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immune the native 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 derived therefrom, and an effective amount of cytosine arabinoside. In some embodiments, administration of Compound 1 Pattern 1, eg, Compound 1 Pattern 1 dihydrochloride dihydrate, or a formulation produced therefrom in combination with cytosine arabinoside 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 febrile immune tumor. In some embodiments, the patient has a variant-immunosuppressive immune tumor. In some embodiments, the patient has a variant-rejective immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor classified as a C2 "IFN-gamma dominant" type of cancer. In some embodiments, the patient has a tumor classified as high "IFN-gamma signature" or high "amplified immune signature." In some embodiments, the patient has a tumor that is positive for PD-L1.

In any of the above embodiments, it has been determined that the patient to be treated has a cancer with a surrounding microenvironment that is favorable for immunomodulation, is immunogenic, or is immunogenically susceptible to CDK 4/6 inhibition effects of drug treatment. Thus, given that the cancer fits into a category as described herein, a patient may be eligible for the described treatment. In some embodiments, the cancer to be treated is selected from the group consisting of: breast cancer, including but not limited to estrogen receptor (ER)-positive breast cancer and triple-negative breast cancer; non-small cell lung cancer; head and neck squamous cell cancer ; classic Hodgkin lymphoma (cHL); diffuse large B-cell lymphoma; bladder cancer; primary mediastinal B-cell lymphoma (PBMCL); urothelial carcinoma; microsatellite hyperinstability ( MSI-H) solid tumors; mismatch inadequate repair (dMMR) solid tumors; gastric or gastroesophageal junction (GEJ) adenocarcinomas; squamous cell carcinoma of the esophagus; cervical cancer; endometrial cancer; cholangiocarcinoma; liver cell carcinoma; Merkel cell carcinoma; renal cell carcinoma; ovarian carcinoma; anal canal carcinoma; colorectal carcinoma; skin cortical melanoma and melanoma.

In some embodiments, the checkpoint inhibitor is not administered to the patient.

In some embodiments, a checkpoint inhibitor is administered to the patient. (i) Anti-neoplastic therapy

In addition to being used to generate advantageous intravenous solutions for bone marrow preservation, Compound 1 Pattern 1 dihydrochloride dihydrate can also be used to treat abnormal cell proliferation disorders, inflammatory disorders, immune disorders, or autoimmune disorders.

In certain aspects, there is provided a method of treating a proliferative disorder in a host, including a human, comprising administering, optionally, isolated Compound 1 Pattern 1 in a pharmaceutically acceptable carrier, eg, as a dihydrochloride salt Dihydrate form. Non-limiting examples of disorders include tumors, cancers, disorders associated with abnormal cell proliferation, inflammatory disorders, immune disorders, and autoimmune disorders.

In one embodiment, Compound 1 Pattern 1 is administered parenterally. This administration can be performed daily or over a treatment holiday for bone marrow preservation.

When administered in an effective amount to a host, including humans, Compound 1 Pattern 1 is useful as a therapeutic agent in dosage form to treat tumors, cancer (solid, non-solid, diffuse, blood, etc.), abnormal cell proliferation, immune disorders, Inflammatory disorders, blood 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 disorders such as lupus, Crohn's disease Crohn's Disease, Addison disease, celiac disease, dermatomyositis, Graves' disease, thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis, or type I Diabetes; Cardiac disorders, including hypercholesterolemia; Infectious diseases, including viral and/or bacterial infections; Inflammatory conditions, including asthma, chronic gastric ulcers, tuberculosis, rheumatoid arthritis, tooth root Periostitis, ulcerative colitis, or hepatitis.

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

Non-limiting examples of cancers that can be treated in accordance with the present invention include, but are not limited to, acoustic neuroma, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma (eg, lymphangiosarcoma, lymphendothelioma, angiosarcoma), appendix cancer, Benign monoclonal gamma globulin disease, bile cancer (eg cholangiocarcinoma), bladder cancer, breast cancer (eg breast adenocarcinoma, breast papillary carcinoma, breast cancer, breast myeloid carcinoma), brain cancer (eg meningioma) Gliomas, e.g., astrocytoma, oligodendroglioma; medulloblastoma), bronchial carcinoma, carcinoid, cervical carcinoma (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma tumor, colorectal cancer (eg, colorectal cancer, rectal cancer, colorectal adenocarcinoma), epithelial cancer, ependymoma, endothelial sarcoma (eg, Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), Endometrial cancer (eg, uterine cancer, uterine sarcoma), esophageal cancer (eg, adenocarcinoma of the esophagus, Barrett's adenocarinoma, Ewing's sarcoma), eye cancer (eg, intraocular melanoma) , retinoblastoma), common hypereosinophilia, gallbladder cancer, gastric cancer (e.g. gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g. head and neck squamous cell carcinoma, oral cancer (e.g. oral cavity) Squamous cell carcinoma (OSCC), throat cancer (eg, laryngeal, pharyngeal, nasopharyngeal, oropharyngeal cancer), hematopoietic cancer (eg, leukemia, such as acute lymphoblastic leukemia (ALL), also known as acute lymphoblastic leukemia Blastic 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), 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) (eg, B-cell NHL, such as diffuse large cell lymphoma (DLCL) (eg, 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 (eg, mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (ie, "Waldenstrom's macrosphere") proteinemia”), 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, cezalea) Syndrome (Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathic T-cell lymphoma, subcutaneous adipitis-like T-cell lymphoma, pleomorphic large cell lymphoma ); a mixture of one or more leukemias/lymphomas as described above; and multiple myeloma (MM)), heavy chain disease (eg, alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammation Myofibroblastic tumor, immune cell amyloidosis, kidney cancer (eg, Wilms tumor, also known as Wilms' tumor, renal cell carcinoma), liver cancer (eg, hepatocellular carcinoma (HCC) , malignant liver cancer), lung cancer (eg bronchial carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma), leiomyosarcoma (LMS), mastocytosis (eg systemic mastocytosis) ), myelodysplastic syndromes (MDS), mesothelioma, myeloproliferative disorders (MPDs) (e.g. polycythemia vera (PV), essential thrombocythemia (ET), unexplained myeloid metaplasia (AMM) ), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic neutrophilic leukemia (CNL), eosinophilia syndrome (HE)), neuroblastoma, neurofibroma ( For example, neurofibromatosis (NF) type 1 or 2, schwannomatosis), neuroendocrine carcinoma (eg gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid), osteosarcoma, ovarian cancer ( e.g. cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g. pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumor), penile cancer ( Examples include Paget's disease of the penis and scrotum, pineal tumor, primitive neuroectodermal tumor (PNT), prostate cancer (eg prostate adenocarcinoma), rhabdomyosarcoma, salivary gland cancer, skin cancer (eg Squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC), small bowel cancer (e.g. appendix), soft tissue sarcoma (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, testicular embryonal carcinoma), thyroid cancer ( Examples are papillary thyroid cancer, papillary thyroid cancer (PTC), medullary thyroid cancer), urethral cancer, vaginal cancer, and vulvar cancer (eg, Paget's disease of the vulva).

In certain aspects, the present invention includes the use of an effective amount of isolated Compound 1 Pattern 1, or a pharmaceutically acceptable salt, prodrug or isotopic variant thereof, optionally present in a pharmaceutical composition, for A host, usually a human, is treated with a selected cancer, tumor, hyperproliferative condition, or inflammatory or immune disorder. Compound 1 pattern 1 was also active on T cell proliferation. Given the very small number of drugs targeting T cell cancer and abnormal proliferation, the identification of such uses represents a substantial improvement in medical therapy for these diseases.

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

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

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

In certain embodiments, the cancer is a solid tumor. As used herein, a solid tumor refers to an abnormal mass of tissue that typically does not contain cysts or areas of fluid. Different types of solid tumors are named with respect to the type of cells that form them. As noted above, examples of solid tumor classes 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 certain embodiments, the condition treated with Compound 1 Pattern 1 is a condition associated with abnormal cell proliferation.

Abnormal cell proliferation, especially hyperproliferation, can occur due to a variety of factors, including genetic mutation, infection, exposure to toxins, autoimmune disorders, and induction of benign or malignant tumors.

There are a variety of skin disorders associated with cellular hyperproliferation. For example, psoriasis is a benign human skin disease generally characterized by plaques covered by thickened scales. The disease is caused by increased proliferation of epidermal cells of unknown cause. Chronic eczema is also associated with marked hyperproliferation of the epidermis. Other diseases caused by excessive proliferation of skin cells include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratosis, basal cell carcinoma and squamous cell carcinoma.

Other hyperproliferative cell disorders include vascular proliferative disorders, fibrotic disorders, autoimmune disorders, graft versus host rejection, tumors, and cancer.

Angioproliferative disorders include angiogenesis and angiogenic disorders. The proliferation of smooth muscle cells during the development of plaques in vascular tissue causes, for example, restenosis, retinopathy, and atherosclerosis. Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions.

Fibrotic disorders are often attributed to abnormal formation of the extracellular matrix. Examples of fibrotic disorders include liver cirrhosis and mesangial proliferative cell disorders. Liver cirrhosis is characterized by an increase in extracellular matrix components, leading to the formation of liver scarring. Hepatic cirrhosis can cause diseases such as cirrhosis of the liver. Liver scarring due to increased extracellular matrix can also be caused by viral infections such as hepatitis. Adipocytes appear to play a major role in cirrhosis.

Mesangial disorders result from abnormal proliferation of mesangial cells. Mesangial hyperproliferative cell disorders include various human kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, transplant rejection, and glomerulopathy.

Another disease with a proliferative component is rheumatoid arthritis. Rheumatoid arthritis is generally regarded as an autoimmune disease that is thought to be associated with the activity of autoreactive T cells and caused by autoantibodies raised against collagen and IgE.

In general, other conditions that may include abnormal cell proliferative components include Behçet's syndrome, acute respiratory distress syndrome (ARDS), ischemic heart disease, post-dialysis syndrome, leukemia, acquired immunodeficiency syndrome, vasculitis, Lipid histiocytosis, septic shock, and inflammation.

In certain embodiments, the compounds of the present invention and pharmaceutically acceptable derivatives thereof or pharmaceutically acceptable formulations containing such compounds are also useful in the prevention and treatment of HBV infection and other related conditions, such as anti- HBV antibody positive and HBV positive conditions, chronic hepatitis caused by HBV, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis and fatigue. These compounds or formulations may also be used prophylactically to prevent or arrest the development of clinical disease in individuals who are anti-HBV antibody or HBV-antigen positive or have been exposed to HBV.

In certain embodiments, the condition is associated with an immune response.

Skin contact hypersensitivity and asthma are just two examples of immune responses that can be associated with considerable morbidity. Other diseases include atopic dermatitis, eczema, Sjogren's syndrome including dry keratoconjunctivitis secondary to Sjogren's syndrome, alopecia areata, anaphylaxis due to arthropod bite reaction, Crohn's disease, Aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis and drug eruption. These conditions can cause any one or more of the following symptoms or symptoms: itching, swelling, redness, blisters, crusting, ulcers, pain, scaling, cracking, hair loss, scarring or involving the skin, eyes or secretion of body fluids from the mucous membranes.

In atopic dermatitis and eczema, in general, immune-mediated infiltration of leukocytes (specifically monocytes, lymphocytes, neutrophils and eosinophils) into the skin contributes to the onset of these diseases mechanism is important. Chronic eczema is also associated with marked hyperproliferation of the epidermis. Immune-mediated leukocyte infiltration also occurs in sites other than the skin, such as in the trachea in asthma and in the lacrimal gland of the eye in keratoconjunctivitis sicca.

In a non-limiting embodiment, the compounds of the present invention are used for the treatment of contact dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis, Sugarcan's syndrome (including dryness secondary to Sugarcan's syndrome) Keratoconjunctivitis), alopecia areata, allergic reactions due to arthropod bite reactions, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, cutaneous lupus erythematosus, hard Topical agent for dermatitis, vaginitis, proctitis and drug eruption. The novel method may also be applicable to reduce skin infiltration by malignant leukocytes in diseases such as mycosis fungoides. These compounds may also be used to treat dehydration-type dry eye conditions (such as immune-mediated keratoconjunctivitis) in patients afflicted with the compounds by topical administration of the compounds to the eye.

The terms "neoplasia" or "cancer" are used throughout this specification to refer to the pathological process of the formation and growth of carcinogenic or malignant neoplasms, that is, abnormal tissue (solid) or cells (non-solid) that grow by cellular proliferation Growth is usually more rapid than normal and continues after stimulation has triggered new growth to stop. Malignant neoplasms exhibit a partial or complete lack of structural tissue and functional coordination with normal tissue and most aggressive surrounding tissue, may metastasize to several sites, may recur after attempted removal and unless adequately treated may lead to Patient died. As used herein, the term neoplasia is used to describe all cancerous disease conditions and encompasses or encompasses pathological processes associated with hematologic malignancies, ascites, and solid tumors. Exemplary cancers that can be treated by the compounds disclosed herein, alone or in combination with at least one additional anticancer agent, include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma, bladder cancer, Cancers of the head, kidney and neck; leukemias; benign and malignant lymphomas, specifically Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative disorders; sarcomas, including Ewing's Sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, angiosarcoma, peripheral neuroepithelial tumor, synovial sarcoma, glioma, astrocytoma, oligodendritic glioma, ependyma tumor, glioblastoma, neuroblastoma, gangliocytoma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, 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, stomach cancer, liver cancer, colorectal cancer, carcinosarcoma, Hodgkin disease, Wilms' tumor, and teratoma.

Additional cancers that can be treated using the compounds disclosed herein include, for example, acute granular leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adenocarcinoma, adenosarcoma, adrenal carcinoma, adrenal cortex Carcinoma, anal cancer, pleomorphic astrocytoma, angiosarcoma, appendix cancer, astrocytoma, basal cell carcinoma, B cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, bowel cancer, brain cancer , brain stem glioma, breast cancer, ginseng (estrogen, progesterone and HER-2) negative breast cancer, double negative breast cancer (both of estrogen, progesterone and HER-2 are negative), single negative (estrogen, progesterone and HER-2 negative) , progesterone and HER-2 negative), 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, recurrent breast cancer, carcinoid, cervical cancer, cholangiocarcinoma , chondrosarcoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), colorectal cancer, colorectal cancer, craniopharyngioma, cortical lymphoma, cutaneous melanoma, diffuse astrocytoma, breast duct Carcinoma in situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, Ewing's sarcoma, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, Gastrointestinal carcinoid cancer, gastrointestinal stromal tumor (GIST), germ cell tumor glioblastoma pleomorphism (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin's lymphoma, Hypopharyngeal carcinoma, Infiltrating ductal carcinoma (IDC), Infiltrating lobular carcinoma (ILC), Inflammatory breast carcinoma (IBC), Intestinal carcinoma, Intrahepatic cholangiocarcinoma, Traumatic/invasive breast carcinoma, Islet cell carcinoma, Jaw carcinoma, Carborg sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, leptomeningeal transferase, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, Medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymal tumor, mesothelioma, metastatic breast cancer, metastatic melanoma, metastatic squamous neck cancer, Mixed glioma, monoblastoma teratoma, oral cancer, mucinous carcinoma, mucosal melanoma, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal cancer, neck cancer, nerve blastoma, neuroendocrine tumors (NETs), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cell carcinoma, eye cancer, eye melanoma, oligodendroglioma, oral cancer, Oral cancer, oropharyngeal cancer, osteosarcoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian primary peritoneal carcinoma, ovarian sex cord stromal tumor, Paget's disease, pancreas cancer, papillary cancer, sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, Peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal region tumor, pineoblastoma, 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 bowel cancer, spine cancer, spine cancer, spinal cord cancer , squamous cell carcinoma, gastric cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma/thymus cancer, thyroid cancer, tongue cancer, tonsil cancer, transitional cell cancer, fallopian tube cancer, tubular cancer, undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T cell lineage acute lymphoblastic leukemia (T-ALL), T cell lineage lymphoblastic lymphoma (T -LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-B ALL, pre-B lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, juvenile myelomonocytic leukemia (JMML), acute promyelocytic leukemia (AML subtype), large granular lymphocytic leukemia, adult T-cell chronic leukemia, diffuse large B-cell lymphoma, filter Alveolar lymphoma; mucosa-associated lymphoid tissue lymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large B-cell lymphoma, nodal marginal zone B-cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL) ); intravascular large B-cell lymphoma; primary exudative lymphoma; or lymphoma-like granuloma; B-cell prelymphoid leukemia; splenic lymphoma/leukemia, unclassifiable splenic diffuse red pulp small B-cell Lymphoma; lymphoplasmacytic lymphoma; heavy chain disease such as alpha heavy chain disease, gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone; extraosseous plasmacytoma; primary Cortical follicular center lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV) + DLBCL in the elderly; primary mediastinal (thymus) Large B-cell lymphoma, primary cortical DLBCL, leg-type, ALK+ large B-cell lymphoma, plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease; or B-cell lymphoma, unclassifiable, with intermediate features between diffuse large B-cell lymphoma and classic Hodgkin's lymphoma.

In another aspect, there is provided a method of increasing BIM expression (eg, BCLC2L11 expression) to induce apoptosis in a cell, the method comprising simulating a compound of the invention or a pharmaceutically acceptable composition, salt, isotope thereof The substance or prodrug is brought into contact with the cells. In certain embodiments, the method is an in vitro method. In certain 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 and inhibits BIM in many cancers, including chronic myelogenous leukemia (CML) and non-small cell lung cancer (NSCLC), and inhibition of BCL2L11 expression may confer resistance to tyrosine kinase inhibitors resistance. See, eg, Ng et al., Nat. Med. (2012) 18:521-528.

In yet another aspect, there is provided a method of treating angiogenesis-related conditions, such as diabetic conditions (eg, diabetic retinopathy), inflammatory conditions (eg, rheumatoid arthritis), macular degeneration, obesity, atherosclerosis a sclerosing or proliferative disorder, the method comprising administering to an individual in need thereof a compound of the present invention, or a pharmaceutically acceptable composition, salt, isotopic analog or prodrug thereof.

In certain embodiments, the condition associated with angiogenesis is macular degeneration. In certain embodiments, there is provided a method of treating macular degeneration comprising administering to an individual in need thereof a compound of the present invention, or a pharmaceutically acceptable composition, salt, isotopic analog or prodrug thereof.

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

In certain embodiments, the condition associated with angiogenesis is atherosclerosis. In certain embodiments, there is provided a method of treating atherosclerosis comprising administering to an individual in need thereof a compound of the present invention, or a pharmaceutically acceptable composition, salt, isotopic analog or prodrug thereof.

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

In an alternative embodiment, the compound is administered at about 50 mg/m ² to about 800 mg/m ² , about 100 mg/m ² to about 600 mg/m ² , about 100 mg/m ² to about 500 mg/m ² , about 100 mg/m ² to about 400 mg/m ² , about 100 mg/m ² to about 350 mg/m ² , about 150 mg/m ² to about 350 mg/m ² , about 200 mg/m ² to A dose of about 350 mg/m ² or about 200 mg/m ² to about 300 mg/m ² is administered.

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

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

The term "bioactive agent" is used to describe agents other than selected compounds according to the present invention, which can be used in combination or in alternation with the compounds of the present invention to achieve the desired therapeutic result. In one embodiment, the compounds and bioactive agents of the present invention are administered in such a way that they are active in vivo during overlapping time periods, eg, with overlapping time periods Cmax, Tmax, AUC, or another pharmacokinetic parameter . In another embodiment, isolated Compound 1 Pattern 1 and a biologically active agent, which do not have overlapping pharmacokinetic parameters, yet one is therapeutic for the therapeutic efficacy of the other, are administered to a host in need thereof Influence.

In certain aspects of this embodiment, the biologically active agent is an immunomodulatory agent, which includes, but is not limited to, checkpoint inhibitors, including, by way of non-limiting example, 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 certain aspects, the immunomodulatory agent is an antibody, such as a monoclonal antibody.

PD-1 inhibitors that block the interaction of PD-1 and PD-L1 by binding to the PD-1 receptor and in turn suppress immunosuppression include, for example, nivolumab (Opdivo), pembrolizumab 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 PD-L1/VISTA inhibitor CA-170 (Curis Inc.). PD-L1 inhibitors that block the interaction of PD-1 and PD-L1 by binding to the PD-L1 receptor and in turn suppress immunosuppression include, for example, atezolizumab (Tecentriq), Deva Durvalumab (AstraZeneca and MedImmune), KN035 (Alphamab) and BMS-936559 (Bristol-Myers Squibb). CTLA-4 checkpoint inhibitors that bind to CTLA-4 and suppress 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), an example of a TIM-3 inhibitor is TSR-022 (Tesaro).

In yet another embodiment, isolated Compound 1 Pattern 1 described herein can be administered in combination or alternating with an effective amount of an estrogen inhibitor for the treatment of abnormal tissues of the female reproductive system, such as breast cancer, ovarian cancer, Endometrial cancer or uterine cancer, the estrogen inhibitor including but not limited to selective estrogen receptor modulator (SERM), selective estrogen receptor degrader (SERD), complete estrogen receptor degrader or another form of partial or complete estrogen antagonist or agonist. Some antiestrogens (eg, raloxifene and tamoxifen) retain some estrogenic effects (including estrogenic stimulation of uterine growth) and, in some cases, actually during breast cancer progression estrogenic activity that stimulates tumor growth. In contrast, the fully antiestrogen fulvestrant (fulvestrant) has limited effect on estrogenic activity in the uterus and is effective in tamoxifen-resistant tumors. Non-limiting examples of antiestrogen compounds are provided in WO 2014/19176, WO2013/090921, WO 2014/203129, WO 2014/203132, assigned to Astra Zeneca, and US2013/0178445 and US Pat. No. 9,078,871, assigned to Olema Pharmaceuticals Nos. 8,853,423 and 8,703,810 and US 2015/0005286, WO 2014/205136 and WO 2014/205138.

Additional non-limiting examples of antiestrogenic compounds include: SERMS such as anordrin, bazedoxifene, broparestriol, chlorotriarylethene, clomiphene citrate (clomiphene citrate), cyclofenil (cyclofenil), lasofoxifene (lasofoxifene), ormeloxifene (ormeloxifene), raloxifene (raloxifene), tamoxifen, toremifene and fulvestrant fulvestrant; aromatase inhibitors such as aminoglutethimide, testolactone, anastrozole, exemestane, faderozole, formestane, and letrozole and antigonadotropins such as leuprorelin, cetrorelix, allylestrenol, chloromadinone acetate, cyproterone acetate cyproterone acetate, delmadinone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate), norethisterone acetate, progesterone and spironolactone. Other estrogen ligands that can be used in accordance with the present invention are described in: US Pat. Nos. 4,418,068; 5,478,847; 5,393,763; and 5,457,117, WO2011/156518, US Pat. US Patent No. 9,078,871; No. 8,853,423; No. 8,703,810; US 2015/0005286; WO 2002/003992; WO 2002/003991; WO 2002/003990; WO 2002/003989; WO 2002/003988; /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, isolated Compound 1 Pattern 1 described herein may be administered in combination or alternation 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 including, but not limited to, a selective androgen receptor modulator, a selective androgen receptor degrader, a complete androgen receptor degrader, or another form of partial or complete androgen antagonist. In one embodiment, the prostate or testicular cancer is androgen resistant. Non-limiting examples of anti-androgens are provided in WO 2011/156518 and US Pat. Nos. 8,455,534 and 8,299,112. Additional non-limiting examples of antiandrogens include: enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone ( canrenone), drospirenone, ketoconazole, topilutamide, abiraterone acetate and cimetidine.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of abiraterone acetate (Zytiga) for the treatment of abnormal tissue in the male reproductive system.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of abiraterone acetate (Zytiga) for the treatment of prostate cancer.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of enzalutamide 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, 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 bismaleate (Gilotrif) 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 Alecensa 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 Ceritinib (Zykadia) 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 crizotinib (Xalkori) 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 osimertinib (Tagrisso) 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 brigatinib (Alunbrig) 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 lorlatinib 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 ( pertuzumab).

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of lapatinib xylene sulfonate for the treatment of breast cancer.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of lapatinib xylene sulfonate 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 PF7775 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-dimethylcyclohex-1-ene -1-yl]methyl]piperan-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl ]sulfonyl]-2-[(lH-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), ABT-737 (4-[4-[[2-( 4-Chlorophenyl)phenyl]methyl]piperidin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylthiobutan-2- [methyl]amino]-3-nitrophenyl]sulfonylbenzamide) (navitoclax), ABT-263 ((R)-4-(4-((4'-chloro- 4,4-Dimethyl-3,4,5,6-tetrahydro-[l,l'-biphenyl]-2-yl)methyl)piperidin-1-yl)-N-((4- ((4-𠰌olinyl-1-(phenylthio)butan-2-yl)amino)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzylamide), GX15-070 (obatoclax mesylate, (2Z)-2-[(5Z)-5-[(3,5-dimethyl-lH-pyrrol-2-yl)methylene] -4-Methoxypyrrole-2-ylidene]indole; methanesulfonic acid))), 2-methoxy-antimicrobial A3, YC137 (4-(4,9-di-oxy-4, 9-dihydronaphtho[2,3-d]thiazol-2-ylamino)-phenyl ester), gossypol (pogosin), 2-amino-6-bromo-4-(1-cyano-2 -Ethoxy-2-side oxyethyl)-4H-benzopyran-3-carboxylic acid ethyl ester, Nilotinib-d3, TW-37 (N-[4-[[2- (1,1-Dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(1-methylethyl)phenyl]methyl ] benzamide), Apogossypolone (ApoG2), HA14-1, AT101, sabutoclax, gambogic acid, or G3139 (Oblimersen) ).

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

In particular embodiments, the treatment regimen comprises administering isolated Compound 1 Pattern 1 in combination with at least one kinase inhibitor. In one embodiment, the at least one kinase inhibitor is selected from a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton's tyrosine kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk ) inhibitors or combinations thereof.

PI3k inhibitors useful in the present invention are well known. Examples of PI3 kinase inhibitors include, but are not limited to, Wortmannin, demethoxyviridin, perifosine, idelalisib, picoxib Pictilisib, Palomid 529, ZSTK474, PWT33597, CUDC-907 and AEZS-136, duvelisib, GS-9820, BKM120, GDC-0032 (Taselisib )) (2-[4-[2-(2-isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2- d][1,4]Benzoxazepine-9-yl]pyrazol-1-yl]-2-methylpropionamide), MLN-1117 ((S)-methylphosphonic acid hydrogen (2R) -1-phenoxy-2-butyl ester; or methyl(side oxy){[(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-pyrrolidinamide), GSK2126458 (2,4-difluoro-N-{2-(methoxy)-5-[4-(4-pyridyl)-6-quinolinyl]- 3-Pyridinyl}benzenesulfonamide) (omipalisib), TGX-221 ((±)-7-methyl-2-(𠰌olin-4-yl)-9-(1-aniline) ylethyl)-pyrido[l,2-a]-pyrimidin-4-one), GSK2636771 (2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)- 6-𠰌olinyl-1H-benzo[d]imidazole-4-carboxylic acid dihydrochloride), KIN-193 ((R)-2-(((1-(7-methyl-2-𠰌olinyl- 4-Oxy-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-monohydroxypropan-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)sulfamonoyl)phenyl)-3-methoxy-4methylbenzyl Amine), BAY80-6946 (2-amino-N-(7-methoxy-8-(3-𠰌olinylpropoxy)-2,3-dihydroimidazo[l,2-c]quinoline) azole (quinaz)), AS 252424 (5-[1-[5-(4-Fluoro-2-hydroxy-phenyl)-furan-2-yl]-methyl-(Z)-ylidene]-thiazolidine- 2,4-dione), CZ 24832 (5-(2-amino-8-fluoro-[l,2,4]triazolo[l,5-a]pyridin-6-yl)-N-tri butylpyridine-3-sulfonamide), Buparlisib (5-[2,6-bis(4-𠰌linyl)-4-pyrimidinyl]-4-(trifluoromethyl) -2-pyridinamine), GDC-0941 (2-(lH-indazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperanyl]methyl]-4-( 4-𠰌olinyl)thieno[3,2-d]pyrimidine), GDC-0980 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl) yl-4-N-𠰌linylthieno[3,2-d]pyrimidin-6yl)methyl)𠯤-1-yl)-2-hydroxypropan-1-one (also known as RG7422)), SF1126 ((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentoxy -1-(4-(4-Oxy-8-phenyl-4H-benzopyran-2-yl)𠰌olinyl)-4-onium)-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-𠰌olinyl-1,3,5-tris𠯤-2-yl)phenyl]urea) (gedatolisib), LY3023414, BEZ235 (2-methyl) yl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinoline -1-yl]phenyl}propionitrile) (dactolisib), XL-765 (N-(3-(N-(3-(3,5-dimethoxyanilino)quinol) olin-2-yl) sulfamoyl) phenyl)-3-methoxy-4-methylbenzamide) and GSK1059615 (5-[[4-(4-pyridyl)-6-quinoline [[(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino] Methylene]-5-hydroxy-9-(methoxymethyl)-9a,11a-dimethyl-1,4,7-trioxy-2,3,3a,9,10,11- Hexahydroindeno[4,5h]isobenzopyran-10-yl]acetate (also known as sonolisib), LY294002, AZD8186, PF-4989216, pilaris (pi laralisib), GNE-317, PI-3065, PI-103, NU7441 (KU-57788), HS 173, VS-5584 (SB2343), CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75, PIK- 93, AS-605240, BGT226 (NVP-BGT226), AZD6482, voxtalisib, alpelisib, IC-87114, TGI100713, CH5132799, PKI-402, copanlisib (BAY 80-6946), XL 147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine), AS-252424, AS-604850, apitolisib ( GDC-0980; RG7422) and structures described in WO2014/071109. In one embodiment, Isolated Compound 1 Pattern 1 is combined with a PIk3 inhibitor in a single dosage form.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of Apelix for the treatment of solid tumors.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of Apelix for the treatment of abnormal tissue in the female reproductive system.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of Apelix for the treatment of breast cancer.

In one embodiment, an effective amount of Compound 1 Pattern 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 is administered in combination with an effective amount of cobacoxib hydrochloride (Aliqopa) for the treatment of follicular lymphoma.

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 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.

BTK inhibitors useful in the present 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)benzene acrylamide)) (Avila Therapeutics) (see U.S. Patent Publication No. 2011/0117073, which is incorporated herein in its entirety), Dasatinib ([N-(2-chloro-6 -Methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide] ), LFM-A13 (α-cyano-β-hydroxy-β-methyl-N-(2,5-dibromophenyl)acrylamide), GDC-0834 ([RN-(3-(6- (4-(1,4-Dimethyl-3-oxypiperidin-2-yl)anilino)-4-methyl-5-oxy-4,5-dihydropyridine-2- base)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide]), CGI-560 4-(tertiary butyl)-N- (3-(8-(anilino)imidazo[1,2-a]pyridine-6-yl)phenyl)benzylamine, CGI-1746 (4-(tertiarybutyl)-N-( 2-Methyl-3-(4-methyl-6-((4-(𠰌line-4-carbonyl)phenyl)amino)-5-oxy-4,5-dihydropyridine-2 -yl)phenyl)benzamide), CNX-774 (4-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amine yl)phenoxy)-N-picolinamide), CTA056 (7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridine- 4-yl)phenyl)-1H-imidazo[4,5-g]quinolin-6(5H)-one), GDC-0834 ((R)-N-(3-(6-((4 -(1,4-Dimethyl-3-oxypiperidin-2-yl)phenyl)amino)-4-methyl-5-oxygen-4,5-dihydropyridin-2 -yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), GDC-0837 ((R)-N-(3-( 6-((4-(1,4-Dimethyl-3-oxypiperidin-2-yl)phenyl)amino)-4-methyl-5-oxy-4,5-di Hydropyridine-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carbamide), HM -71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(( (1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), QL-47 (1-(1-propenylindolin-6-yl)-9 -(1-Methyl-1H-pyrazol-4-yl)benzo[h][1,6]pyridin-2(1H)-one) and RN486 (6-cyclopropyl-8-fluoro-2 -(2-Hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperidin-1-yl)-pyridin-2-ylamino]-6-side oxy- 1,6-Dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one) and other molecules capable of inhibiting BTK activity, such as disclosed in Akinleye et al., Journal of Hematology & Oncology, 2013, 6:59 (incorporated herein by reference in its entirety). In one embodiment, 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 Pattern 1 is administered in combination with an effective amount of Ibrutinib (Imbruvica) 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 ibrutinib (Imbruvica) for the treatment of lymphomas, including small lymphocytic lymphoma, mantle cell lymphoma, marginal zone lymphoma tumor or Waldenstrom's macroglobulinemia.

Syk inhibitors useful in the present invention are well known and include, for example, Cerdulatinib (4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)hexahydropyridine) 𠯤-1-yl)phenyl)amino)pyrimidine-5-carboxamide), entospletinib (6-(1H-indazol-6-yl)-N-(4-𠰌olinyl) Phenyl)imidazo[1,2-a]pyridin-8-amine), fostamatinib ([6-({5-fluoro-2-[(3,4,5-trimethoxy Phenyl)amino]-4-pyrimidinyl}amino)-2,2-dimethyl-3-oxy-2,3-dihydro-4H-pyrido[3,2-b][1 ,4]㗁𠯤-4-yl] methyl dihydrogen phosphate), fotatinib disodium salt ((6-((5-fluoro-2-((3,4,5-trimethoxyphenyl )amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxy-2H-pyrido[3,2-b][1,4]㗁𠯤-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)- pyridoxine-3-carboxyamide), imatinib (Gleevac; 4-[(4-methylpiperidin-1-yl)methyl]-N-(4-methyl-3-{[4-( Pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide), staurosporine, GSK143 (2-(((3R,4R)-3-aminotetrahydro-2H -Piran-4-yl)amino)-4-(p-toluidine)pyrimidine-5-carboxamide), PP2 (1-(tertiarybutyl)-3-(4-chlorophenyl) -1H-pyrazolo[3,4-d]pyrimidin-4-amine), PRT-060318 (2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m- Toluidino)pyrimidine-5-carboxamide), PRT-062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(( (1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), R112 (3,3'-((5-fluoropyrimidine-2,4-diyl)bis (nitrodiyl))diphenol), R348 (3-ethyl-4-methylpyridine), R406 (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl) )amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]㗁𠯤-3(4H)-one), white Pictaxel (3-hydroxyresveratrol), YM193306 (see Singh et al., Discovery and D evelopment of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643), 7-azaindole, piceatannol, ER-27319 (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein by reference in its entirety), 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 its entirety), 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 its entirety), 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 its entirety), apigenin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which Incorporated herein by reference in its entirety), quercetin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, incorporated herein by reference in its entirety Spleen Tyrosine Kinase (SYK) Inhibitors, J. Me d. Chem. 2012, 55, 3614-3643, which is incorporated herein by reference in its entirety), myricetin (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 its entirety), morin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, It is incorporated herein by reference in its entirety). In one embodiment, an effective amount of Isolated Compound 1 Pattern 1 is combined with a Syk inhibitor in a single dosage form.

In one embodiment, the at least one additional chemotherapeutic 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), pilizumab (CureTech/Teva), AMP-244 (Amplimmune/ GSK), BMS-936559 (BMS) and MEDI4736 (Roche/Genentech). In one embodiment, an effective amount of isolated Compound 1 Pattern 1 is combined with a PD-1 inhibitor in a single dosage form.

In one embodiment, the at least one additional chemotherapeutic agent is a B-cell lymphoma 2 (Bcl-2) protein inhibitor. BCL-2 inhibitors are known in the art and include, for example, ABT-199 (4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1 -En-1-yl]methyl]piperidin-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino] Phenyl]sulfonyl]-2-[(lH-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), ABT-737 (4-[4-[[2 -(4-Chlorophenyl)phenyl]methyl]piperidin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutane -2-yl]amino]-3-nitrophenyl]sulfonylbenzamide, ABT-263((R)-4-(4-((4'-chloro-4,4-dimethyl Base-3,4,5,6-tetrahydro-[l,l'-biphenyl]-2-yl)methyl)piperidin-1-yl)-N-((4-((4-𠰌line Base-1-(phenylthio)butan-2-yl)amino)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15-070 (Obucket Obatoclax mesylate, (2Z)-2-[(5Z)-5-[(3,5-dimethyl-lH-pyrrol-2-yl)methylene]-4-methoxy pyrrolidene-2-yl]indole; methanesulfonic acid))), 2-methoxy-antimicron A3, YC137 (4-(4,9-dioxy-4,9-dihydronaphthalene) [2,3-d]thiazol-2-ylamino)-phenyl esters), pogosin, ethyl 2-amino-6-bromo-4-(1-cyano- 2-Ethoxy-2-side oxyethyl)-4H-𠳭ene-3-carboxylate, Nilotinib-d3, TW-37(N-[4-[[2-(1,1-dimethyl ethyl)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 Isolated Compound 1 Pattern 1 is combined with at least one BCL-2 inhibitor in a single dosage form.

In one embodiment, the combinations described herein can be further combined with another therapeutic agent for the treatment of cancer. The second therapy can be immunotherapy. As discussed in more detail below, an effective amount of isolated Compound 1 Pattern 1 can bind to an antibody, radiopharmaceutical or other targeting 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 (eg, an antibody) to increase the therapeutic efficacy of the combined or synergistic approach. In one embodiment, the combination may be used with T cell vaccination, which generally involves immunization with unactivated autoreactive T cells to eliminate cancer cell populations as described herein. In another embodiment, the combination is used in combination with a bispecific T cell engager (BiTE) designed to bind to both endogenous T cells and cancer cells as described herein Specific antigens, antibodies that link two types of cells.

In one embodiment, the bioactive agent is a MEK inhibitor. MEK inhibitors are well known and include, for example, trametinib/GSK1120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]- 6,8-Dimethyl-2,4,7-trioxy-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H-yl}phenyl)ethyl amide), selumetinib (selumetinib) (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5 -Carboxamide), pimasertib/AS703026/MSC 1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl) amino)isonicotinamide), XL-518/GDC-0973 (1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl )-3-[(2S)-piperidin-2-yl]azetidin-3-ol), refametinib/BAY869766/RDEAl 19 (N-(3,4-difluoro-2 -(2-Fluoro-4-iodoanilino)-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]-benzamide), 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-carboxamide), R05126766 (3-[[3-fluoro-2-(methylaminosulfonamido)-4-pyridyl]methyl]-4- Methyl-7-pyrimidin-2-yloxypyren-2-one), WX-554, R04987655/CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amine) yl)-N-(2-hydroxyethoxy)-5-((3-oxy-1,2-oxazacyclohex-2-yl)methyl)benzamide) or AZD8330 (2- ((2-Fluoro-4-iodophenyl)amino)-N-(2hydroxyethoxy)-1,5-dimethyl-6-oxy-1,6-dihydropyridine-3- Carboxamide), U0126-EtOH, PD184352 (CI-1040), GDC-0623, BI-847325, cobimetinib, PD98059, BIX 02189, BIX 02188, bimetinib tinib), SL-327, TAK-733, PD318088.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of bemetinib for the treatment of melanoma, including BRAF-mutant melanoma and NRAS-mutant melanoma.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of cobitinib (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 is administered in combination with an effective amount of bemetinib for the treatment of ovarian cancer.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of selumetinib 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 selumetinib 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 trametinib (Mekinist) 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 trametinib (Mekinist) 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 trametinib (Mekinist) 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]pyridine-3 -yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide), sorafenib tosylate (4-methylbenzenesulfonate 4-[4-[[ 4-Chloro-3-(trifluoromethyl)phenyl]aminocarbamoylamino]phenoxy]-N-methylpyridine-2-carbamoylamine), AZ628 (3-(2-cyanopropyl) -2-yl)-N-(4-methyl-3-(3-methyl-4-oxy-3,4-dihydroquinazolin-6-ylamino)phenyl)benzyl amine), 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-imidazole-2 -yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine), 2-bromoaldisine (Bromoaldisine) (2-bromo-6 ,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione), Raf kinase inhibitor IV (2-chloro-5-(2-phenyl-5- (pyridin-4-yl)-1H-imidazol-4-yl)phenol), Sorafenib N-Oxide (4-[4-[[[[4-chloro-3(tri Fluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-picolinamide 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 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 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 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 additional therapy is a monoclonal antibody (MAb). Some MAbs stimulate immune responses that destroy 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, that promotes tumor blood vessel development. When bound to bevacizumab, VEGF is unable to interact with its cellular receptors, preventing the signaling that causes new blood vessel growth. Similarly, cetuximab and panitumumab target epidermal growth factor receptor (EGFR), and trastuzumab targets human epidermal growth factor receptor 2 (HER-2) . MAbs that bind to cell surface growth factor receptors prevent the targeted receptors from sending their signals to promote normal growth. It can also trigger apoptosis and activate the immune system to destroy tumor cells.

Another group of cancer therapeutic MAbs are immunoconjugates. These MAbs, sometimes referred to as immunotoxins or antibody-drug conjugates, consist of antibodies attached to cell-killing substances such as plant or bacterial toxins, chemotherapeutic drugs, or radioactive molecules. Antibodies latch their specific antigens on the surface of cancer cells, and cell-killing substances are taken up by the cells. FDA-approved binding MAbs that function in this manner include a trastuzumab-maytansine conjugate, which targets the HER-2 molecule to deliver the cell proliferation-inhibiting drug DM1 to HER expressing metastatic breast cancer cells -2.

Immunotherapy with T cells engineered to recognize cancer cells via bispecific antibodies (bsAbs) or chimeric antigen receptors (CARs) is an approach that potentially eliminates division of cancer cells and non/decelerates segregated subpopulations.

Bispecific antibodies provide an opportunity to redirect immune effector cells to kill cancer cells by simultaneously recognizing target antigens and activating receptors on the surface of immune effector cells. Another approach is to generate chimeric antigen receptors by fusing extracellular antibodies to intracellular signaling domains. Chimeric antigen receptor-engineered T cells are able to specifically kill tumor cells in an MHC-independent manner.

In some embodiments, the combination can be administered to an individual in further combination with other chemotherapeutic agents. If appropriate, the combinations described herein may be administered concurrently with another chemotherapeutic agent in order 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 use of the compounds described herein is combined with other pharmaceutical agents in a therapeutic regimen. Such agents may include, but are 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 (eg HSP70 and HSP90 inhibitors or combinations thereof), BCL-2 inhibitors, apoptosis-inducing compounds, AKT inhibitors, including But not limited to MK-2206, GSK690693, Perifosine (KRX-0401), GDC-0068, Triciribine, AZD5363, and Honokiol, PF-04691502, and Pata ipatasertib, Miltefosine; PD-1 inhibitors including but not limited to nivolumab, CT-011, MK-3475, BMS936558 and AMP-514 or FLT-3 inhibitors, including but not limited to Not limited to P406, Dovitinib, Quizartinib (AC220), Amuvatinib (MP-470), Tandutinib (MLN518), ENMD-2076 and KW-2449 or a combination thereof.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of Patacrotide 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 analogs, everolimus (Afinitor), temsirolimus, ridaforolimus, sirolimus and deforolimus. Examples of MEK inhibitors include, but are not limited to, trametinib/GSK1120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino] -6,8-Dimethyl-2,4,7-trioxy-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H-yl}phenyl) acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5- Formamide), pimasertib/AS703026/MSC1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino) ) isonicotinamide), XL-518/GDC-0973 (l-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)- 3-[(2S)-piperidin-2-yl]azetidin-3-ol) (cobitinib), 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]-benzamide), 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 carboxamide), R05126766 (3-[[3-fluoro-2-(methylaminosulfonamido)-4-pyridyl]methyl]-4- Methyl-7-pyrimidin-2-yloxypyren-2-one), WX-554, R04987655/CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amine) base)-N-(2-hydroxyethoxy)-5-((3-oxy-l,2-oxazacyclohexane-2yl)methyl)benzamide) or AZD8330 (2 -((2-Fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxy-l,6-dihydropyridine- 3-formamide).

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-desmethoxygeldanamycin (17AAG, 17-N-Allylamino-17- demethoxygeldanamycin) and Radicicol. In particular embodiments, the compounds described herein are administered in combination with letrozole and/or tamoxifen. Other chemotherapeutic agents that can be used in combination with the compounds described herein include, but are not limited to, chemotherapeutic agents that do not require cell cycle activity for their anti-neoplastic effects.

Additional biologically active compounds include, for example, everolimus, trabectedin, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors , VEGFR inhibitor, Olola kinase inhibitor, PIK-1 modulator, HDAC inhibitor, c-MET inhibitor, PARP inhibitor, Cdk inhibitor, IGFR-TK inhibitor, anti-HGF antibody, local focal adhesion kinase Inhibitors, Map Kinase (mek) inhibitors, VEGF intercepting antibodies, pemetrexed, panitumumab, amrubicin, oregovomab, Lep-etu, Novel Nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rupee rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR ₁ KRX-0402, carbamazepine, LY317615, Nura neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, cranberry, lipid cranberry, 5'-deoxy-5-fluorouridine, vincristine , temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7- Dihydro-4-pendoxyl-1H-pyrrolo[2 ,3-d]pyrimidin-5-yl)ethyl]benzyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene lemon acid salt, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258); 3-[5 -(Methylsulfonylpiperidinemethyl)-indolyl-quinolinone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate acetate), triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifol, bicalutamide, flutamide, nilutamide , megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, Aibi Erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, Xin Suberoyl analide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminogluten, arnsacrine, Anagrelide, L-asparaginase, Bacille Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carboplatin mustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, actinomycin, daunomycin, diethylstilbestrol, epirubicin Idarubicin, Fludarabine, Flucortisone, Flumethyltestosterone, Flutamide, Glivik, Gemcitabine, Hydroxyurea, Idarubicin, Ifosfamide, Imatinib, Leuprolide, levamisole, lomustine, methylbis(chloroethyl)amine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, Nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, prukamycin, porfim, procarbazine, raltitrexed, rituximab, streptozotocin , teniposide, testosterone, thalidomide, thioguanine, thiatepa, retinoic acid, vindesine, 13-cis-retinoic acid, chlorambucil, uracil mustard, estrammus, Hexamethylmelamine, Floxuridine, 5-Deoxyuridine, Cytosine Arabinoside, 6-Mercaptopurine, Deoxycometamycin, Calcitriol, Valor Bixing, Mithramycin, Vinblastine, Vinorelbine, Topotecan, Lazoxin, Marimastat, COL-3, Shaqailing, BMS-275291, Squalamine, Endostatin, SU5416, SU6668, EMD121974, Interleukin-12, IM862, Angiostatin, Vitacin, Traloxifene, idoxyfene, Spironolactone, Finaxon, Cimetidine, Trastuzumab, Dani Interleukin, Gefitinib, Bortezomib, Paclitaxel, Paclitaxel without Ceteth-Free, Docetaxel, Epothilone B, BMS-247550, BMS-310705, Traloxifene, 4-Hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasoxifene, idoxifene ( idoxifene), TSE-424, HMR-3339, ZK186619, topotecan, PTK787/ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin Vulcan, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779, 450, PEG-filg PEG-filgrastim, darbepoetin, erythropoietin, granule colony stimulating factor, zolendronate, prisone, cetuximab, granule macrophage colony stimulation factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacytidine, PEG-L- Asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, All-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulins, nitrogen mustard, methylprednisolone, ibritgumomab tiuxetan ), androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, rice Mitotane, Cyclosporine closporine), lipid daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, NK-1 receptor antagonists , Palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, arp Alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochloraz ( prochlorperazine), granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, platelet-derived Growth factor receptor alpha (PDGFR-alpha) antibody, epoetin alfa, darbepoetin alfa and mixtures thereof.

In one embodiment, an effective amount of Isolated Compound 1 Pattern 1 described herein can be combined with niraparib tosylate monohydrate (Zejula), olaparib A PARP inhibitor combination of (Lynparza), rucaparib camsylate (Rubraca) and talazoparib.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of niraparib tosylate monohydrate (Zejula) for the treatment of abnormal tissues of the female reproductive system, including epithelial ovarian 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 Niraparib tosylate monohydrate (Zejula) for the treatment of peritoneal 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 abnormal tissues of the female reproductive system, including breast cancer, ovarian cancer, epithelial ovarian 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 mutant 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 Pattern 1 is administered in combination with an effective amount of Lucaparib camphorsulfonate (Rubraca) for the treatment of abnormal tissues of the female reproductive system, including breast cancer, ovarian cancer, ovarian epithelium 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 Lucaparib camphorsulfonate (Rubraca) for the treatment of peritoneal cancer.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of prazopanib for the treatment of abnormal tissues of the female reproductive system, including breast cancer, ovarian cancer, epithelial ovarian 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 prazopanib for the treatment of BRAC1 or BRAC2 mutant breast cancer.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of Olamumab 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 savotinib for the treatment of adenocarcinoma.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of savotinib 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 savotinib 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 Vercetib for the treatment of advanced breast cancer.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of Vercetib for the treatment of advanced breast cancer.

In one embodiment, an effective amount of Isolated Compound 1 Pattern 1 described herein can be combined with a chemotherapeutic agent selected from the group consisting of, but not limited to, Imatinib mesylate (Gleevac®), Dasatinib (Sprycel®), Nilotinib (Tasigna®), Bosutinib (Bosulif®), Trastuzumab (Herceptin®), Pertuzumab Antibiotic (PerjetaTM), Lapatinib (Tykerb®), Gefitinib (Iressa®), Erlotinib (Tarceva®), Cetuximab (Erbitux®), Panitumumab (Vectibix) ®), Vandetanib (Caprelsa®), Vemurafenib (Zelboraf®), Vorinostat (Zolinza®), Romidepsin (Istodax®) , Bexarotene (Tagretin®), Alitretinoin (Panretin®), Vesanoid®, Carfilizomib (KyprolisTM), Pralatrexate ) (Folotyn®), Bevacizumab (Avastin®), Ziv-aflibercept (Zaltrap®), Sorafenib (Nexavar®), Sunitinib (Sutent®) ®), pazopanib (Votrient®), regorafenib (Stivarga®) and cabozantinib (Cometriq ^™ ).

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

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of Abeccil (Versenio) for the treatment of breast cancer.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of Abescilli (Versenio) for the treatment of HR+ breast cancer, HER2- breast cancer.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of Palbociclib (Ibrance) for the treatment of breast cancer.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of Palbociclib (Ibrance) for the treatment of HR+ breast cancer, HER2- breast cancer.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of Palbociclib (Ibrance) for the treatment of breast cancer.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of Palbociclib (Ibrance) for the treatment of metastatic triple negative breast cancer.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of Palbociclib (Ibrance) for the treatment of small cell lung cancer.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of Cabozantinib S-malate (Cometriq ^™ ) 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 Cabozantinib S-maleate (Cometriq ^™ ) 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 Dasatinib (Sprycel) for the treatment of leukemia, including acute lymphoblastic leukemia or chronic myelogenous leukemia.

In one embodiment, an effective amount of Compound 1 Pattern 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 Pattern 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 Pattern 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 Pattern 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, Eosinophilia syndrome or chronic myelogenous leukemia.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of Trastuzumab (Herceptin) for the treatment of adenocarcinoma.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of trastuzumab (Herceptin) for the treatment of breast cancer, including HER2+ breast cancer.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of imatinib mesylate (Gleevec) for the treatment of tumors including, but not limited to, dermatofibrosarcoma protuberance and the gastrointestinal tract stromal tumor.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of imatinib mesylate (Gleevec) for the treatment of myelodysplastic/myeloproliferative neoplasms.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of imatinib mesylate (Gleevec) for the treatment of systemic mastocytosis.

In one embodiment, an effective amount of Compound 1 Pattern 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 is administered in combination with an effective amount of pazopanib hydrochloride (Votrient) 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 pazopanib hydrochloride (Votrient) 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 Pattern 1 is administered in combination with an effective amount of Sorafenib tosylate (Nexavar) for the treatment of cancer, including hepatocellular carcinoma or renal cell carcinoma.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of sunitinib malate (Sutent) 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 sunitinib malate (Sutent) for the treatment of pancreatic cancer.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of sunitinib malate (Sutent) 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 vemurafenib (Zelboraf) for the treatment of Erdheim-Chester disease.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of vemurafenib (Zelboraf) for the treatment of melanoma.

In certain aspects, the additional therapeutic agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapy additional therapeutic agent, or an immunosuppressive agent.

Suitable chemotherapeutic agents include, but are not limited to, radioactive molecules, also known as cytotoxins or cytotoxic agents, toxins, including any that are detrimental to the survival of cells, agents, and liposomes or other vesicles containing chemotherapeutic compounds. Pharmacy. Common anticancer agents include: vincristine (Oncovin®) or lipid vincristine (Marqibo®), daunomycin (daunomycin or Cerubidine®) or cranberry (Adriamycin®), arabinoside Cytidine (cytosine arabinoside, ara-C or Cytosar®), L-asparaginase (Elspar®) or PEG-L-asparaginase (pegaspargase or Oncaspar®), Etoposide (VP-16), Teniposide (Vumon®), 6-Mercaptopurine (6-MP or Purinethol®), Methotrexate, Cyclophosphamide (Cytoxan®), Prey pine, dexamethasone (Decadron), imatinib (Gleevec®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®) and Ponatinib (Iclusig™). Examples of additional suitable chemotherapeutic agents include, but are not limited to, 1-dehydrotestosterone, 5-fluorouracil, dacarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adalimycin , aldesleukin, alkylating agents, allopurinol sodium, hexamethylmelamine, amifostine, anastrozole, anthramycin (AMC), Antimitotics, cis-dichlorodiamineplatinum (II) (DDP) (cisplatin), diaminedichloroplatinum, anthracycline, antibiotics, antimetabolites, asparaginase, injections Bacille Calmette-Guérin (BCG live) (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, calcium folic acid leucouorin), calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), chlorambucil, cisplatin, cladribine, colchicine Base (Colchicin), Conjugated Estrogen, Cyclophosphamide, Cyclothosphamide, Cytarabine, Cytarabine, Cytochalasin B, Cytoxan, Dacarb𠯤, Actinomycin d, Actinomycin d (formerly actinomycin), Daunirubicin HCl, Daunorucbicin citrate, Denileukin, Right Razoxan, dibromomannitol, dihydroxy anthracin dione, docetaxel, dolasetron mesylate, cranberry HCl, dronabinol, Escherichia coli L-aspart E. coli L-asparaginase, emetine, ebetine-alpha, Erwinia L-asparaginase, esterified estrogen, estradiol alcohol, estramustine sodium phosphate, ethidium bromide, ethinyl estradiol, etidronate, etoposide citrororum factor, Etoposide Phosphate, Filgrastim, Floxuridine, Fluconazole, Fludarabine Phosphate, Fluorouracil, Flutamide, Alfolic Acid, Gemcitabine HCl, Glucocorticoids, Goserelin Acetate, Brevibacterium D (gr amicidin D), granisetron HCl, hydroxyurea, idamycin HCl, ifosfamide, interferon alpha-2b, irinotecan HCl, letrozole, leucovorin calcium, Leuprolide Acetate, Levamisole HCl, Lidocaine, Lomustine, Maytansinoid, Methylbis(chloroethyl)amine HCl, Medroxyprogesterone Acetate, Medidin Acetate Progesterone, melphalan HCl, mercaptipurine, mesna, methotrexate, methyltestosterone, mithramycin, mitomycin C, mitotane, rice Toxantrone, Nilutamide, octreotide acetate, Ondansetron HCl, Paclitaxel, Pamidronate disodium, Pentostatin, Pilocarpine HCl, Piliomycin plimycin, polifeprosan 20 with carmustine implant, porfimer sodium, procaine, procarbazine HCl, propranolol propranolol, rituximab, sargramostim, streptozotocin, tamoxifen, taxol, teniposide, tenoposide , testosterone, tetracaine, thioepa chlorambucil, thioguanine, thioepa, topotecan HCl, toremifene citrate, trastuzumab Antibiotics, retinoic acid, valrubicin (valrubicin), vinblastine sulfate (vinblastine sulfate), vincristine sulfate (vincristine sulfate) and vinorelbine tartrate (vinorelbine tartrate).

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of Bosutinib (Bosulif®) for the treatment of chronic myelogenous leukemia (CML).

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

Additional therapeutic agents that can be administered in combination with the compounds disclosed herein can include bevacizumab, sutinib, sorafenib, 2-methoxyestradiol, or 2ME2, finasuna ( finasunate), vataranib, vandetanib, aflibercept, volociximab, etaracizumab (MEDI-522), cilengitide, etanercept Rotinib, cetuximab, panitumumab, gefitinib, trastuzumab, dovitinib, figitumumab, atacicept, rituximab mAb, alemtuzumab, aldesleukine, atlizumab, tocilizumab, temsirolimus, everolimus, lucatumumab, dacetuzumab, HLL1, huN901-DM1, atiprimod, natalizumab, bortezomib, carfilzomib, marizomib, tanspira tanespimycin, saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate, belince Belinostat, panobinostat, mapatumumab, lexatumumab, dulanermin, ABT-737, olimerson, proteus plitidepsin, talmapimod, P276-00, enzastaurin, tipifarnib, pirifoxin, imatinib, dasatinib, lenalidomide, Thalidomide, simvastatin, celecoxib, bazedoxifene, 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 is administered in combination with an effective amount of Everolimus (Afinitor) for the treatment of breast cancer.

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 HR+ breast cancer, HER2- breast cancer.

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 pancreatic cancer.

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 gastrointestinal cancer.

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 lung cancer.

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 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 astrocytoma.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of fulvestrant (Faslodex) for the treatment of breast cancer.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of fulvestrant (Faslodex) for the treatment of HR+ breast cancer, HER2- breast cancer.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of Ramucirumab for the treatment of adenocarcinoma.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of Ramucirumab 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 Ramucirumab 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 Ribocil (Kisqali) for the treatment of breast cancer.

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

In certain aspects of the invention, the compounds described herein can be combined with at least one IDH1 or IDH2 inhibitor. In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of enanib mesylate (Idhifa) for the treatment of acute myeloid leukemia.

In certain aspects of the invention, the compounds described herein can be combined with at least one fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor. In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of Erdatinib for the treatment of urothelial carcinoma, including metastatic urothelial carcinoma.

In certain aspects of the invention, the compounds described herein can be combined with at least one ERK inhibitor.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of SCH772984 for the treatment of melanoma, including BRAF mutant melanoma or NRAS mutant melanoma.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of Euritinib for the treatment of melanoma, including uveal melanoma.

In one embodiment, an effective amount of Compound 1 Pattern 1 is administered in combination with an effective amount of Uritinib for the treatment of pancreatic cancer.

In certain aspects of the invention, the compounds described herein can be combined with at least one immunosuppressive agent. Immunosuppressive agents may preferably be selected from the group consisting of calcineurin inhibitors such as cyclosporin or ascomycins such as cyclosporine A (NEORAL®), FK506 (he tacrolimus), pimecrolimus; mTOR inhibitors such as rapamycin or derivatives thereof (eg sirolimus (RAPAMUNE®), everolimus (Certican®), tannin Roolimus, zotarolimus, biolimus-7, thylimus-9), rapamycin analogs (rapalog) (e.g. difoslimus, azathioprine, campath 1H; S1P receptor modulators such as fingolimod or its analogs, anti-IL-8 antibodies, mycophenolic acid or its salts (eg sodium salts) or its prodrugs, For example, Mycophenolate Mofetil (CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), Prisone, ATGAM®, THYMOGLOBULIN®, Brequinar Sodium, OKT4, T10B9.A-3A , 33B3.1, 15-deoxyspergualin, tresperimus, Leflunomide ARAVA®, CTLAI-Ig, anti-CD25, anti-IL2R, basiliximab (Basiliximab) (SIMULECT®), Daclizumab (ZENAPAX®), mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, Elidel ®), CTLA4lg (Abatacept), belatacept, LFA3lg, etanercept (sold as Enbrel® by Immunex), adalimumab (Humira® ), infliximab (Remicade®), anti-LFA-1 antibodies, natalizumab (Antegren®), Enlimomab, gavilimomab, Antithymocyte immunoglobulin, siplizumab, Alefacept, efalizumab, pentasa, mesalaz ine), asacol, codeine phosphate, benorylate, fenbufen, naprosyn, diclofenac, etodolac ) and indomethacin, aspirin and ibuprofen.

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

In some embodiments, an effective amount of Isolated Compound 1 Pattern 1 can be administered to an individual, such that higher doses (increased chemotherapy dose intensity) or more frequent (increased chemotherapy dose intensity) other chemotherapy treatments can be administered agent. Dose-dense chemotherapy is a chemotherapy treatment plan in which drugs are given in less time between treatments than a standard chemotherapy treatment plan. Chemotherapy dose intensity represents the unit dose of chemotherapy administered per unit time. The dose intensity can be increased or decreased by altering the dose administered, the interval of administration, or both.

In one embodiment of the invention, the compounds described herein can be administered in a synergistic regimen with another agent, such as a non-DNA-damage targeting antineoplastic agent or a hematopoietic growth factor agent. It has recently been reported that untimely administration of hematopoietic growth factors may have serious side effects. For example, the EPO family of growth factors have 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 spleen enlargement and rupture, respiratory distress syndrome, allergic reactions, and sickle cell complications. Thus, 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, for example as Neupogen (filgrass) filgrastin), Neulasta (peg-filgrastim) or lenograstin (sold as lenograstin), granulosa macrophage colony stimulating factor (GM-CSF, e.g. as molgramostim ) and sargramostim (Leukine), M-CSF (macrophage colony stimulating factor), thrombopoietin (megakaryocyte growth development factor (MGDF), eg sold as Romiplostim and Eltrombopag) , interleukin (IL)-12, interleukin-3, interleukin-11 (adipogenesis inhibitory factor or oprelvekin), SCF (stem cell factor, steel factor, set-ligand or KL) and erythropoietin (EPO) and its derivatives (e.g. epoetin-alpha) sold as Darbopoetin, Epocept, Nanokine, Epofit, Epogin, Eprex and Procrit; epoetin-beta as e.g. NeoRecormon , Recormon and Micera), Ebertine-delta (sold e.g. as Dynepo), Ebertin-Omega (sold e.g. as Epomax), Ebertine zeta (sold e.g. 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 Pattern 1 is administered prior to administration of the hematopoietic growth factor. In one embodiment, hematopoietic growth factor administration is timed such that the effect of the compound on HSPCs has dissipated. In one embodiment, the growth factor is administered at least 20 hours after administration of a compound described herein.

Multiple doses of the compounds described herein can be administered to an individual, as necessary. Alternatively, a single dose of a compound described herein can be administered to an individual.

In certain aspects of the invention, the compounds disclosed herein can be advantageously administered in combination with any treatment regimen requiring radiation therapy, chemotherapy, or other therapeutic agents. In additional embodiments, the compounds disclosed herein may be advantageously administered in combination with therapeutic agents targeting autoimmune disorders. EXAMPLES Example 1. X -ray Powder Diffraction (XRPD)

XRPD analysis was performed on a PANalytical X'pert pro scanning samples between 3 and 35° 2Θ. The material was ground gently to release any agglomerates and loaded onto a porous disk supporting the sample with Kapton or Mylar polymer film. Subsequently, the multiwell plate was placed in a diffractometer with a 40 kV/40 mA generator setting using Cu K radiation (α1λ=1.54060 Å; α2=1.54443 Å) operating in transmission mode (0.0130° 2θ step size) ; β=1.39225 Å; α1:α2 ratio=0.5) for analysis. Use the above techniques to generate Figures 1, 7, 8-19, 21-32, 36, 38, 42, 43, 49-59, 61, 67-69 and Image in Figure 89.

Table 1 below provides a list of XRPD peaks for Pattern 1 with >10% relative intensity peaks. XRPD performed on pattern 1 exhibited sharp peaks, indicating that the sample was composed of crystalline material. In XRPD on pattern 1 at about 9.6±0.2°, about 12.2±0.2°, about 15.3±0.2°, about 17.6±0.2°, about 19.3±0.2°, about 19.8±0.2°, about 21.3±0.2°, Significant peaks were observed at about 22.7±0.2°, about 24.0±0.2°, about 26.1±0.2°, and about 28.6±0.2°. Table 1. XRPD Peak List 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 certain embodiments, the pattern form is Pattern 1 and is characterized in that the XRPD pattern comprises at least 2 peaks selected from the group consisting of: about 9.6±0.2°, about 12.2±0.2°, about 15.3±0.2°, about 17.6±0.2° 0.2°, about 19.3±0.2°, about 19.8±0.2°, about 21.2±0.2°, about 22.7±0.2°, about 23.9±0.2°, about 26.1±0.2°, and about 28.6±0.2°.

In certain embodiments, the pattern form is Pattern 1 and is characterized in that the XRPD pattern comprises at least 3 peaks selected from the group consisting of: about 9.6±0.2°, about 12.2±0.2°, about 15.3±0.2°, about 17.6±0.2° 0.2°, about 19.3±0.2°, about 19.8±0.2°, about 21.2±0.2°, about 22.7±0.2°, about 23.9±0.2°, about 26.1±0.2°, and about 28.6±0.2°.

In certain embodiments, the pattern form is Pattern 1 and is characterized in that the XRPD pattern comprises at least 4 peaks selected from the group consisting of: about 9.6±0.2°, about 12.2±0.2°, about 15.3±0.2°, about 17.6±0.2° 0.2°, about 19.3±0.2°, about 19.8±0.2°, about 21.2±0.2°, about 22.7±0.2°, about 23.9±0.2°, about 26.1±0.2°, and about 28.6±0.2°.

In certain embodiments, the pattern form is Pattern 1 and is characterized in that the XRPD pattern comprises at least 5 peaks selected from the group consisting of: about 9.6±0.2°, about 12.2±0.2°, about 15.3±0.2°, about 17.6±0.2° 0.2°, about 19.3±0.2°, about 19.8±0.2°, about 21.2±0.2°, about 22.7±0.2°, about 23.9±0.2°, about 26.1±0.2°, and about 28.6±0.2°.

In certain embodiments, the pattern form is Pattern 1 and is characterized in that the XRPD pattern comprises at least 6 peaks selected from the group consisting of: about 9.6±0.2°, about 12.2±0.2°, about 15.3±0.2°, about 17.6±0.2° 0.2°, about 19.3±0.2°, about 19.8±0.2°, about 21.2±0.2°, about 22.7±0.2°, about 23.9±0.2°, about 26.1±0.2°, and about 28.6±0.2°.

In certain embodiments, the pattern form is Pattern 1 and is characterized in that the XRPD pattern comprises at least 7 peaks selected from the group consisting of: about 9.6±0.2°, about 12.2±0.2°, about 15.3±0.2°, about 17.6±0.2° 0.2°, about 19.3±0.2°, about 19.8±0.2°, about 21.2±0.2°, about 22.7±0.2°, about 23.9±0.2°, about 26.1±0.2°, and about 28.6±0.2°.

In certain embodiments, the pattern form is Pattern 1 and is characterized in that the XRPD pattern comprises at least 8 peaks selected from the group consisting of: about 9.6±0.2°, about 12.2±0.2°, about 15.3±0.2°, about 17.6±0.2° 0.2°, about 19.3±0.2°, about 19.8±0.2°, about 21.2±0.2°, about 22.7±0.2°, about 23.9±0.2°, about 26.1±0.2°, and about 28.6±0.2°.

In certain embodiments, the pattern form is Pattern 1 and is characterized in that the XRPD pattern comprises at least 9 peaks selected from the group consisting of: about 9.6±0.2°, about 12.2±0.2°, about 15.3±0.2°, about 17.6±0.2° 0.2°, about 19.3±0.2°, about 19.8±0.2°, about 21.2±0.2°, about 22.7±0.2°, about 23.9±0.2°, about 26.1±0.2°, and about 28.6±0.2°.

In certain embodiments, the pattern form is Pattern 1 and is characterized in that the XRPD pattern comprises at least 10 peaks selected from the group consisting of: about 9.6±0.2°, about 12.2±0.2°, about 15.3±0.2°, about 17.6±0.2° 0.2°, about 19.3±0.2°, about 19.8±0.2°, about 21.2±0.2°, about 22.7±0.2°, about 23.9±0.2°, about 26.1±0.2°, and about 28.6±0.2°.

In certain embodiments, the pattern form is Pattern 1 and is characterized in that the XRPD pattern comprises a 2θ value selected from the group consisting of: about 9.6±0.2°, about 12.2±0.2°, about 15.3±0.2°, about 17.6±0.2° , about 19.3±0.2°, about 19.8±0.2°, about 21.2±0.2°, about 22.7±0.2°, about 23.9±0.2°, about 26.1±0.2°, and about 28.6±0.2°.

Table 2 below provides the results of XRPD performed on Pattern 2. XRPD showed sharp peaks, indicating that the sample consisted of crystalline material. In XRPD on pattern 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± Significant peaks were observed at 0.2° and 27.3±0.2°. Table 2. XRPD peaks for pattern 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 certain embodiments, the pattern form is Pattern 2 and is characterized in that the XRPD pattern comprises at least 2 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is Pattern 2 and is characterized in that the XRPD pattern comprises at least 3 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is Pattern 2 and is characterized in that the XRPD pattern comprises at least 4 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is Pattern 2 and is characterized in that the XRPD pattern comprises at least 5 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is Pattern 2 and is characterized in that the XRPD pattern comprises at least 6 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is Pattern 2 and is characterized in that the XRPD pattern comprises at least 7 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is Pattern 2 and is characterized in that the XRPD pattern comprises at least 8 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is Pattern 2 and is characterized in that the XRPD pattern comprises at least 9 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is Pattern 2 and is characterized in that the XRPD pattern comprises 2θ values selected from the group consisting of: 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 results of XRPD performed on Pattern 5. 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 XRPD on pattern 5 A prominent peak was observed at 0.2°.

Table 3 below provides the results of XRPD performed on pattern 3 scale up. XRPD showed sharp peaks, indicating that the sample consisted of crystalline material. At about 8.1±0.2°, about 14.8±0.2°, about 16.5±0.2°, about 18.2±0.2°, about 19.7±0.2°, about 24.8±0.2°, about 25.6±0.2° in XRPD on pattern 3 scale magnification Significant peaks were observed at ° and about 27.7±0.2°. Table 3. XRPD peaks for pattern 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 certain embodiments, the pattern form is Pattern 3, characterized in that the XRPD pattern comprises at least 2 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is Pattern 3, characterized in that the XRPD pattern comprises at least 3 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is Pattern 3, characterized in that the XRPD pattern comprises at least 4 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is Pattern 3, characterized in that the XRPD pattern comprises at least 5 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is Pattern 3, characterized in that the XRPD pattern comprises at least 6 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is Pattern 3, characterized in that the XRPD pattern comprises 2θ values selected from the group consisting of: 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 results of XRPD performed on Pattern 4. XRPD showed sharp peaks, indicating that the sample consisted of crystalline material. The table below shows the >10% relative intensity peaks for Pattern 4. In XRPD on pattern 4 at about 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 Significant peaks were observed at ±0.2°. Table 4. XRPD peaks for 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 certain embodiments, the pattern form is pattern 5 and is characterized in that the XRPD pattern comprises at least 2 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 5 and is characterized in that the XRPD pattern comprises at least 3 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 5 and is characterized in that the XRPD pattern comprises at least 4 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 5 and is characterized in that the XRPD pattern comprises at least 5 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 5 and is characterized in that the XRPD pattern comprises at least 6 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 5 and is characterized in that the XRPD pattern comprises at least 7 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 5 and is characterized in that the XRPD pattern comprises at least 8 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 5 and is characterized in that the XRPD pattern comprises 2θ values selected from the group consisting of: 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 results of XRPD performed on Pattern 6, which exhibited sharp peaks, indicating that the sample consisted of crystalline material. The >10% relative intensity of peak picking pattern 6 in the table below. Significant peaks were observed at about 6.7±0.2°, 11.1±0.2°, 16.26±0.2°, 26.3±0.2° and 27.2±0.2° in XRPD on pattern 6. Table 5. Pattern 6 scale-up XRPD peaks. 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 certain embodiments, the pattern form is pattern 6 and is characterized in that the XRPD pattern comprises at least 2 peaks selected from the group consisting of: 6.7±0.2°, 11.1±0.2°, 16.26±0.2°, 26.3±0.2°, and 27.2 ±0.2°.

In certain embodiments, the pattern form is pattern 6 and is characterized in that the XRPD pattern comprises at least 3 peaks selected from the group consisting of: 6.7±0.2°, 11.1±0.2°, 16.26±0.2°, 26.3±0.2°, and 27.2 ±0.2°.

In certain embodiments, the pattern form is pattern 6 and is characterized in that the XRPD pattern comprises at least 4 peaks selected from the group consisting of: 6.7±0.2°, 11.1±0.2°, 16.26±0.2°, 26.3±0.2°, and 27.2 ±0.2°.

In certain embodiments, the pattern form is pattern 6 and is characterized in that the XRPD pattern comprises 2θ values selected from the group consisting of: 6.7±0.2°, 11.1±0.2°, 16.26±0.2°, 26.3±0.2°, and 27.2±0.2 °.

Example 2. Using the general technique of Gravitational Vapor Sorption (GVS) Approximately 10 to 20 mg of sample was placed in a gas phase adsorption balance mesh pan and loaded on Hiden Analytical's IGASorp Moisture Sorption Analyzer balance. Samples were subjected to a slow ramp profile from 40 to 90% relative humidity (RH) in 10% increments, holding samples at 25°C in each step until a stable weight was obtained (98% step complete, minimum step 30 minutes, maximum steps of 60 minutes). After the adsorption cycle was completed, the samples were dried to 0% RH using the same procedure and finally returned to the starting point of 40% RH. Perform three cycles. The hygroscopic properties of the samples were determined by plotting the weight change during the adsorption/desorption cycle. The above techniques were used to generate the images in Figures 40 and 41 .

Table 6 below provides tabular GVS data for Pattern 1 showing the difference in water vapor absorption between adsorption and desorption isotherms. The hygroscopic properties of the samples were determined by plotting the weight change during the adsorption/desorption cycle. Table 6. List GVS Data for Pattern 1 Target (RH(%) Mass change (%)-ref adsorption desorption loop 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 loop 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 loop 3 0.000 0.000 10.000 2.250 20.000 2.740 30.000 3.020 40.000 3.220

In certain embodiments, the samples undergo a slow temperature ramp profile from 40 to 90% relative humidity (RH) in 10% increments.

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

In certain embodiments, three adsorption cycles are performed.

Table 7 below provides the results of the GVS data for the mixtures of Pattern 2 and Pattern 6, showing the difference in water vapor absorption between adsorption and desorption isotherms. The hygroscopic properties of the samples were determined by plotting the weight change during the adsorption/desorption cycle. Table 7. GVS Data for Pattern 2 and Pattern 6 Mixtures Target (RH(%) Mass change (%)-ref adsorption desorption loop 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 loop 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 loop 3 0 0.059 10 2.708 20 3.502 30 4.027 40 4.335

In certain embodiments, the samples undergo a slow temperature ramp profile from 40 to 90% relative humidity (RH) in 10% increments.

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

In certain embodiments, three adsorption cycles are performed.

Example 3 : Dynamic Vapor Sorption (DVS) Approximately 10 to 20 mg of sample was placed in a gas phase adsorption balance mesh pan and loaded into a DVS Intrinsic Dynamic Vapor Sorption Balance by Surface Measurement Systems. Samples were subjected to a slow ramp profile from 40 to 90% relative humidity (RH) in 10% increments, in each step, samples were held at 25°C until a stable weight (dm/dt 0.004% was obtained, minimum step size 30 min, The maximum step size is 500 minutes). After the adsorption cycle was completed, the samples were dried to 0% RH using the same procedure and then returned to 40% RH using a second adsorption cycle. Do two cycles. The hygroscopic properties of the samples were determined by plotting the weight change during the adsorption/desorption cycle. Any solids that remained were then subjected to XRPD analysis. The above techniques were used to generate the images in Figures 5, 6, 47 and 48. Table 8. Provides results of pattern 3 scale-up list DVS data. Target (RH(%) Mass change (%)-ref adsorption desorption Hysteresis loop 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 loop 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 loop 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 gain of approximately 4% at 90% RH. During the desorption cycle, the material loses mass, possibly due to the loss of surface water present in the sample and the crystallization of amorphous components present in the sample. The material adsorbed 2.5 wt% moisture at 40% RH, 3.1 wt% moisture at 60% RH and 3.5 wt% moisture at 90% RH.

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

Example 4. Listed peak picking of >5% relative intensity for pattern 4. XRPD analysis was performed on a PANalytical X'pert pro, scanning samples between 3 and 35° 2Θ. The material was ground gently to release any agglomerates and loaded onto a porous disk supporting the sample with Kapton or Mylar polymer film. Subsequently, the multiwell plate was placed in a diffractometer with a 40 kV/40 mA generator setting using Cu K radiation (α1λ=1.54060 Å; α2=1.54443 Å) operating in transmission mode (step 0.0130° 2θ). ; β=1.39225 Å; α1:α2 ratio=0.5) for analysis. The above techniques were used to generate the images in Figures 13, 20 and 27.

Table 9 below provides the results of XRPD performed on Pattern 4, which exhibited sharp peaks, indicating that the sample consisted of crystalline material. Significant peaks were observed in XRPD on pattern 4 at 6.1±0.2°, 15.0±0.2°, 27.5±0.2° and 28.1±0.2°. Table 9. XRPD peaks for pattern 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 certain embodiments, the pattern form is Pattern 4 and is characterized in that the XRPD pattern comprises at least 2 peaks selected from the group consisting of: 6.1±0.2°, 15.0±0.2°, 27.5±0.2°, and 28.1±0.2°.

In certain embodiments, the pattern form is Pattern 4 and is characterized in that the XRPD pattern comprises at least 3 peaks selected from the group consisting of: 6.1±0.2°, 15.0±0.2°, 27.5±0.2°, and 28.1±0.2°.

In certain embodiments, the pattern form is Pattern 4 and is characterized in that the XRPD pattern comprises 2Θ values selected from the group consisting of: 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 determined using an Olympus BX50 polarizing microscope equipped with a Motic camera and image capture software (Motic Images Plus 2.0). All images were recorded using a 20× objective unless otherwise stated. The above techniques were used to generate the images in Figures 2, 37, 44, 62, and 74-86.

Example 6 : Thermogravimetric Analysis (TGA) Approximately 5 mg of material was weighed into an open aluminum pan and loaded into a simultaneous thermogravimetric/differential thermal analyzer (TG/DTA) and kept at room temperature. The sample was then heated from 20°C to 300°C at a rate of 10°C/min, during which time the sample weight change and any differential thermal events (DTA) were recorded. Nitrogen at a flow rate of 300 cm ³ /min was used as the purge gas. The above techniques were used to generate the images in Figures 3, 33, 34, 35, 38, 45, 63, 87 and 88.

Example 7 : Differential Scanning Calorimetry (DSC) Approximately 5 mg of material was weighed into a DSC aluminum pan and hermetically sealed with a pierced aluminum lid. The sample pan was then loaded into a Seiko DSC6200 (equipped with a cooler), cooled and kept at 20°C. Once a stable heat flow reaction was obtained, the sample and reference were heated to 360°C at a scan rate of 10°C/min and the resulting heat flow reaction was monitored. Nitrogen at a flow rate of 50 cm ³ /min was used as the purge gas. The above techniques were used to generate the images in Figures 4, 39, 46, 64, 65 and 66.

Example 8. Crystallization and Competitive Paste Experiments A competitive paste experiment was performed using approximately 10 mg of Pattern 1. Pattern 2/6 mixture 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 flowable slurry was formed. The samples were stirred for 48 hours at ambient temperature. The second set of samples was stirred at 60°C for 48 hours. All samples were collected and solids were isolated and analyzed by XRPD. The above techniques were used to generate the images in Figures 50, 51, and 55-59. Table 10. Results and observations of competitive slurry experiments sample input material solvent Solvent volume (μL) temperature observations XRPD form 1 1 + 2 + 3 EtOH 1000 environment yellow paste 1 2 1 + 2 + 3 MEK 1000 environment yellow paste 1 and traces 2 3 1 + 2 + 3 2N HCl 1000 environment yellow paste 1 4 1 + 2 + 3 IPA 1000 environment yellow paste 1 and traces 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 Mixtures of 1, 2 and 3 9 1 + 2 + 3 2N HCl 1000 60℃ yellow paste 1 and traces 2 10 1 + 2 + 3 IPA 1000 60℃ yellow paste 1 and traces 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 after DVS experiment XRPD analysis was performed on a PANalytical X'pert pro, scanning samples between 3 and 35° 2Θ. The material was ground gently to release any agglomerates and loaded onto a porous disk supporting the sample with Kapton or Mylar polymer film. Subsequently, the multiwell plate was placed in a diffractometer with a 40 kV/40 mA generator setting using Cu K radiation (α1λ=1.54060 Å; α2=1.54443 Å) operating in transmission mode (step 0.0130° 2θ). ; β=1.39225 Å; α1:α2 ratio=0.5) for analysis.

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

Example 10. Stability study after 1 week A stability study was performed using approximately 10 mg of material. Samples were prepared in duplicate for XRPD and HPLC analysis. A set of samples was capped and stored under ambient light, ambient temperature and ambient humidity. One set of samples was capped and stored in an oven at 80°C. One set of samples (75%) was unsealed and stored at 40°C in a desiccator containing sodium chloride solution. After 7 days, samples were collected and analyzed by XRPD and HPLC. The above techniques were used to generate the images in Figures 52, 53 and 54.

Example 11. Various Solvent Solubility Systems Solvent solubility experiments were performed using various solvents as provided in Tables 11, 12 and 13 to determine solid formation. A known volume aliquot (usually 5 volumes) of solvent was added to approximately 10 mg of amorphous Compound 1 as the dihydrochloride salt. Between additions, the mixture was checked for dissolution and if there was no apparent dissolution, the mixture was heated to about 40°C and checked again. Continue this procedure until dissolution is observed or until 100 volumes of solvent have been added. All observed solids were isolated and analyzed by XRPD.

Examples of solvents include, but are not limited to, 1,4-dioxane, 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 were used to generate the images 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-Diethane <5 2 1-Butanol <5 3 2,2,2-Trifluoroethanol >200 4 2-Butanone <5 5 2-Ethoxyethanol <5 6 2-Methyl THF <5 7 2-Propanol about 5 8 acetone <5 9 Acetonitrile <5 10 Acetonitrile/Water (90:10 % v/v) <5 11 anisole <5 12 chlorobenzene <5 13 DMSO about 5 14 DMF <5 15 Cumene about 5 16 Dichloromethane <5 17 Ethanol about 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 about 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-Diethane 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-Methyl THF 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 anisole pattern 6 12 chlorobenzene Amorphous 13 DMSO Amorphous 14 DMF Amorphous 15 Cumene 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 no solids 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 no solids

After removal of the initial solids, samples where dissolution was observed were unsealed and allowed to evaporate. This produces the diffraction patterns in Figures 30 and 31 . Table 13. Observations from evaporation experiments sample Solvent system Observations after evaporation 1 1,4-Diethane no solids 2 Acetone/Water (20:80 % v/v) yellow solid 3 2,2,2-Trifluoroethanol yellow solid 4 2-Butanone no solids 5 2-Propanol no solids 6 acetone no solids 7 Acetonitrile no solids 8 Acetonitrile/Water (90:10 % v/v) no solids 9 Dichloromethane no solids 10 Ethanol A small amount of yellow solid 11 Ethanol/Water (85:15% v/v) A small amount of yellow solid 12 Ethyl acetate no solids 13 Heptane no solids 14 isopropyl acetate no solids 15 methanol no solids 16 Methanol/Water (95:5 % v/v) A small amount of yellow solid 17 2N HCl no solids 18 methyl isobutyl ketone no solids 19 tertiary butyl methyl ether no solids 20 tetrahydrofuran no solids twenty one Toluene no solids

Example 12. Antisolvent Addition Experiments Antisolvent addition experiments were performed using a selected antisolvent (eg, t-BME) layered on the substance solution in each sample until precipitation was observed or 1 mL of antisolvent was added. Samples were stored in a refrigerator at approximately 5°C to facilitate precipitation, and any observed solids were collected and analyzed by XRPD, as provided in Tables 14 and 15. Material solutions were prepared using the solvent systems listed in Example 13. The above techniques were used to generate the image in Figure 32. Table 14. Observations from antisolvent addition experiments sample Solvent system antisolvent Anti-solvent volume (μL) Observations after adding AS 1 1,4-Diethane 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 anisole t-BME 1000 clear colorless solution 11 Cumene 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 antisolvent addition experiments sample Solvent system antisolvent XRPD 1 1,4-Diethane t-BME no solids 2 Acetone/Water (20:80 % v/v) t-BME no solids 3 2,2,2-Trifluoroethanol t-BME pattern 3 4 2-Butanone t-BME no solids 5 2-Ethoxyethanol t-BME no solids 6 2-Propanol t-BME no solids 7 acetone t-BME no solids 8 Acetonitrile t-BME no solids 9 Acetonitrile/Water (90:10 % v/v) t-BME no solids 10 anisole t-BME no solids 11 Cumene t-BME no solids 12 Dichloromethane t-BME no solids 13 Ethanol t-BME no solids 14 Ethanol/Water (85:15% v/v) t-BME no solids 15 Ethyl acetate t-BME no solids 16 Heptane t-BME no solids 17 isopropyl acetate t-BME no solids 18 methanol t-BME no solids 19 Methanol/Water (95:5 % v/v) t-BME no solids 20 2N HCl t-BME no solids twenty one methyl isobutyl ketone t-BME no solids twenty two tertiary butyl methyl ether Heptane no solids twenty three tetrahydrofuran t-BME no solids twenty four Toluene t-BME no solids

Example 13. Scale-Up of Pattern 2 , Pattern 3 , and Pattern 5 Pattern 2 was scaled up to approximately 500 mg of amorphous Compound 1 as di-HCl salt by adding a 100 µL aliquot of MEK until a flowable slurry was formed . The slurry was then temperature cycled between ambient temperature and 40°C for approximately 72 hours. Samples were collected and an aliquot of the slurry was analyzed by XRPD. The solid was then isolated and dried under vacuum at 40°C for approximately 4 hours. The resulting material was a mixture of Pattern 2 and Pattern 6.

Pattern 3 was scaled up to approximately 500 mg of amorphous Compound 1 as the di-HCl salt by adding 100 μL aliquots of ethanol until a flowable slurry was formed. The slurry was then temperature cycled between ambient temperature and 40°C for approximately 72 hours. Samples were collected and an aliquot of the slurry was analyzed by XRPD. The solid was then isolated and dried under vacuum at 40°C for approximately 4 hours.

Pattern 5 was scaled up to approximately 500 mg of amorphous Compound 1 as the di-HCl salt by adding 100 μL aliquots of ethanol until a flowable slurry was formed. The slurry was then temperature cycled between ambient temperature and 40°C for approximately 72 hours. Samples were collected and an aliquot of the slurry was analyzed by XRPD. The solid was then isolated and dried under vacuum at 40°C for approximately 4 hours. This resulting material was then reslurried in 10 mL of methyl isobutyl ketone for twenty-four hours. An aliquot of the slurry was analyzed by XRPD. The solid was then isolated and vacuum dried at 40°C for approximately four hours. The dried material was analyzed by XRPD.

Example 14. pH Solubility and pH Solvent System pH solubility experiments were performed on Pattern 7 solids at pH 2 to pH 13. A total of 12 vials contained pattern 7 (100 mg) and 500 µL of 66% DMSO: 33% THF (% v/v) for making the slurry. The initial pH of each slurry was measured using a pH meter. The pH of each vial was adjusted to the desired pH using an aliquot of acetic acid or 1 M sodium hydroxide solution. If dissolution is observed at the selected pH, add additional pattern 7 solids to the vial until the slurry remains or add up to 500 mg. The pH is then readjusted as necessary. The recovered solids were determined to be of high purity (area %), with most experiments returning values of 99.5 and 99.4%. Purity values did not differ significantly between pH values, but the solids were from pH 4, where the % area purity was determined to be 99.9%. Concentration analysis of the filtered mother liquors showed that as the pH of the system increased, the concentration values generally decreased (ie, decreased solubility). Tacky, highly viscous slurries were observed at pH 4 and pH 8. The above techniques were used to generate the diffraction patterns in Figures 67, 68 and 69.

Example 15. Crystallization of Group 1 Small scale crystallization experiments were performed on Pattern 7 with Group 1 to determine the effect of varying the starting concentration of Pattern 7 in the DMSO/THF solvent system as provided in Tables 16 and 17. Pattern 7 in DMSO/THF was prepared at several concentrations with starting concentrations of 100, 150 and 200 mg/mL, respectively. Samples were prepared in a volume of 66% DMSO: 33% THF (% v/v) and pattern 7 (200 mg) was added at the appropriate starting concentration. Acetic acid (100 μL aliquots) was added to each sample at ambient temperature until dissolution was achieved. At each of the three concentrations, the final pH was adjusted to 12 from The solid crystallized from the 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 set was stirred for approximately 18 hours at ambient temperature with stirring provided via a magnetic stirrer plate. After approximately 18 hours, stirring was stopped and the supernatant was filtered using a 0.45 μm PVDF syringe filter and syringe. The concentration of the supernatant was analyzed by HPLC. The remaining slurries in the vials were separately transferred to 0.22 μm nylon filter centrifuge tubes and the solids were separated by centrifugation and the recovered solids were analyzed by XRPD, PLM and HPLC for purity. The above techniques were used to generate the images in Figures 70 and 71. Table 16. Group 1: pH 12 Starting free base mass (mg) Starting volume (DMSO:THF 66/33 mL) Initial concentration (mg/mL) Acetic acid added (mL) 1 M NaOH solution added (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 Base Ratio Starting volume (DMSO:THF 66/33) mL Initial concentration (mg/mL) Acetic acid added (mL) Acetic acid equivalent 1 M NaOH solution added (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 A small scale crystallization experiment was performed on Pattern 7, with Group 2 focusing on the optimum pH range for Pattern 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 base required.

Samples (1 and 2) were prepared by adding pattern 7 (200 mg) with DMSO (3 mL) and THF (1.6 mL) to form a slurry. The resulting slurry was heated to 70°C using a temperature control block. Acetic acid was added until dissolution was achieved. The experiment was kept at 70°C for 1 hour. After 1 hour, sample 1 was added to 1 M sodium hydroxide solution in 100 μL aliquots 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. The sample 2 solution was cooled from 70°C to 25°C at a rate of 0.25°C/min. Once this experiment reached 25°C, 1 M sodium hydroxide solution was added to 100 μL aliquots until the experiment reached pH 7. Both samples were stirred for approximately 18 hours at ambient temperature with stirring provided via a magnetic stirrer plate. After approximately 18 hours, stirring was stopped and the supernatant was filtered using a 0.45 μm PVDF syringe filter and syringe. The concentration of the supernatant was analyzed by HPLC. The remaining slurry in each sample was separately transferred to a 0.22 μM nylon filter centrifuge tube, and the solids were separated by centrifugation. The recovered solids were analyzed by XRPD, PLM and HPLC for purity. The above techniques were used to generate the 2nd and 3rd diffraction patterns in Figure 72. Table 18. Group 2 vial experiment FB mass (mg) Starting volume (DMSO:THF 66/33) Initial concentration (mg/mL) Acetic acid added (mL) Added 1 M sodium hydroxide solution (mL) final pH 1 Add 1 M sodium hydroxide 200 4.57 44 2.85mL 52.5 7.06 2 Add 1 M sodium hydroxide 200 4.57 44 2.85mL 52.5 7.38

Example 17. Crystallization Group 3 A small scale crystallization experiment was performed on Pattern 7 with Group 3 (see Table 19) to determine the seeding effect, whereby both cooling and isothermal processing were used. 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 noted. Sodium hydroxide solution (1 M) was added to 100 μL aliquots until pH reached pH 5. The solution was then seeded with 4 mg (2%) pattern 7 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 with stirring provided via a magnetic stirrer plate. Sample 2 was cooled at 0.1°C/min at 5°C and stirred for approximately 18 hours. After approximately 18 hours, stirring was stopped and each sample supernatant was filtered using a 0.45 μm PVDF syringe filter and syringe. The concentration of the supernatant was analyzed by HPLC. The remaining slurry from each sample was separately transferred to a 0.22 μM nylon filter centrifuge tube, and the solids were separated by centrifugation. The recovered solids were analyzed by XRPD, PLM and HPLC for purity. The above techniques were used to generate the 3rd and 4th diffraction patterns in Figure 72. Table 19. Group 3 vial experiment Initial concentration (mg/mL) Acetic acid added (mL) 1 M sodium hydroxide solution (mL) added to reach pH 5 pH 1 M sodium hydroxide solution (mL) added to reach pH 7 final pH 1 Ambient stirring 200 1.3 18 5.07 5.7 7.18 2 Cool with stirring 200 1.3 18 5.09 5.5 7.04

Example 18. Crystallization Set 4 was used to perform small scale crystallization on pattern 7 with set 4 (see Table 20) using higher concentrations (5M and 10M) sodium hydroxide solutions in order to reduce the volume required to reach the desired pH. A sample was prepared by adding pattern 7 (200 mg) and adding 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 noted. Sodium hydroxide solution (5 M) was then added to 100 μL aliquots until the pH of the system reached pH 5. The solution was then seeded with pattern 7 (4 mg or 2%) and the pH of the sample was adjusted to pH 7 by adding sodium hydroxide solution (NaOH); where vial 1 contained 5 M NaOH and vial 2 contained 10 M NaOH. The samples were stirred for approximately 18 hours at ambient temperature with stirring provided via a magnetic stirrer plate. After approximately 18 hours, stirring was stopped and any solid formation was isolated by vacuum filtration using a Büchner funnel and Whatman grade 1 filter paper. The recovered solids were analyzed by XRPD, PLM and HPLC for purity, and the supernatant was analyzed by HPLC for concentration. The above technique was used to generate the diffraction pattern in Figure 73. Table 20. Group 4 vial experiment Initial concentration (mg/mL) Acetic acid added (mL) Sodium hydroxide solution (mL) added to reach pH 5 pH Sodium hydroxide solution (mL) added to reach 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. Maturation experiment A 100 μL aliquot of the selected solvent was added to 40 mg of Amorphous Pattern 1 until a flowable slurry was formed, as provided in Table 21 and Table 22. The slurry was temperature cycled between ambient temperature and 40°C for 72 hours. Samples were then collected, and the observed solids were isolated and analyzed by XRPD.

The samples were then dried and reanalyzed by XRPD. For drying, the XRPD disks were placed in an oven at 40°C and allowed to dry for approximately 4 hours, after which the dried samples were analyzed by XRPD. Use the above techniques to generate diffraction in Figures 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 and 29 picture. Table 21. Observations of maturation experiments sample Solvent system Solvent volume (μL) initial observations Observations after maturity 1 1,4-Diethane 1000 yellow paste light 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 light yellow paste yellow paste 6 2-Propanol 1000 yellow paste light yellow paste 7 acetone 1300 yellow paste light yellow paste 8 Acetonitrile 1300 yellow paste light yellow paste 9 Acetonitrile/Water (90:10 % v/v) 1000 yellow paste yellow paste 10 anisole 1200 yellow paste yellow paste 11 Cumene 1200 yellow paste yellow paste 12 Dichloromethane 700 yellow paste light yellow paste 13 Ethanol 700 yellow paste yellow paste 14 Ethanol/Water (85:15% v/v) 1300 light yellow paste yellow paste 15 Ethyl acetate 1500 light yellow paste yellow paste 16 Heptane 1500 yellow paste yellow paste 17 isopropyl acetate 400 yellow paste yellow paste 18 methanol 300 light yellow paste yellow paste 19 Methanol/Water (95:5 % v/v) 400 light yellow paste yellow paste 20 2N HCl 1500 light 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 light yellow paste Table 22. XRPD results after maturation experiments sample Solvent system Mature XRPD XRPD after drying 1 1,4-Diethane Convert to 2 Convert to 2 2 Acetone/Water (20:80 % v/v) Insufficient solids Insufficient solids 3 2,2,2-Trifluoroethanol no solids no solids 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 anisole weak pattern 5, with extra peaks 11 Cumene weak pattern 5, with extra peaks 12 Dichloromethane pattern 2 pattern 2 13 Ethanol Pattern 3 (Amorphous Halogen) pattern 3 14 Ethanol/Water (85:15% v/v) Pattern 1 (Highly Crystalline) Pattern 1 (Highly Crystalline) 15 Ethyl acetate Pattern 2 (Amorphous Halogen) Pattern 5 16 Heptane weak pattern 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 pattern weak pattern twenty three tetrahydrofuran pattern 2 pattern 2 twenty four Toluene weak pattern Pattern 5

Example 20. Thermodynamic solubility Thermodynamic solubility in water at pH 4.2 was performed for Pattern 1, Pattern 2/6 mixture, Pattern 3, Amorphous DiHCl salt, and Pattern 7, as provided in Table 23. All samples were prepared at 30 mg/mL. Get the initial observations. The samples were stirred at ambient temperature for approximately 24 hours. Samples were collected and observations were made. The observed solids were isolated by centrifugation. The mother liquors from the filtered samples were 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 addition of sodium acetate (1.07 g) and acetic acid solution (5.9 mL) up to 500 mL with deionized water, followed by The pH was adjusted to 4.2. The above technique was used to generate the image in FIG. 60 . Table 23. Observations and results from thermodynamic solubility experiments sample form Observations at T=0 hours Observations 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 Di-HCl Yellow solution (dissolves upon addition) yellow solution 5 Pattern 7 off-white paste off-white paste

Example 21. Summary of Crystallization Experiments on Compound 1 Free Base Material The experiments from Examples 17, 18, 19 and 20 are summarized in Table 24 below. Table 24: Summary of crystallization conditions Group experiment starting concentration Base used target pH for precipitation Experiment overview 1 1 100 1M 12 Add sodium hydroxide to pH 12 2 100 1M 12 1:1 ratio of acid to base 3 150 1M 12 Add sodium hydroxide to pH 12 4 150 1M 12 1:1 ratio of acid to base 5 200 1M 12 Add sodium hydroxide to pH 12 6 200 1M 12 1:1 ratio of acid to base 2 7 44 mg/mL 1M 7 After addition of DMSO/THF, the experiment was heated to 70°C. Base was added after cooling to 25°C. 8 44 mg/mL 1M 7 After addition of DMSO/THF, the experiment was heated to 70°C. Base was added after cooling to 25°C. 3 9 200 mg/mL 1M 7 Experiments were inoculated at pH 5 (2%). Ambient agitation after inoculation. 10 200 mg/mL 1M 7 Experiments were inoculated at pH 5 (2%). Cool to 5°C after inoculation. 4 11 200 mg/mL 5M 7 Experiments were inoculated at pH 5 (2%). Ambient agitation after inoculation. 12 200 mg/mL 10M 7 Experiments were inoculated at pH 5 (2%). Ambient agitation after inoculation.

Example 22. Formation of Pattern 11 A saturated solution of Compound 1 diHCl was prepared in N,N'-dimethylacetamide at ambient temperature, and the solution was then cooled from 60°C to 25°C at 0.1°C/min. The samples were kept at ambient temperature until larger crystals were obtained (approximately two weeks). During attempts to perform polarized light microscopy, the crystals were redissolved after stirring the solution. The solution was placed in the refrigerator for a week to promote crystal growth, but no crystals appeared. Finally, about 10 drops of acetone were added as anti-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 were 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 structures were dissolved in the Olex2 software package with the ShelXT (intrinsically phased) structure solution program and modified with the ShelXL3 modification package using least squares minimization. Collect, dissolve and refine data in triclinic space group P-1.

All non-hydrogen atoms are located in the Fourier map and their positions are modified, and the anisotropic thermal movement of all non-hydrogen atoms is described later. Within this structure, two complete G1T28 dihydrochloride units are modified. All fully occupied hydrogen atoms were placed in the calculated positions by a factor of 1.2 (for all CH, _CH2 and NH groups) and 1.5 (for all _CH3 groups) using the riding model of fixed Uiso. All partially occupied hydroxyl hydrogen atoms are located in the Fourier diagram and improve their position and occupancy.

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

The crystallographic parameters of the crystallographic data modification 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, 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 for in all calculations. Final R1 was 0.0461 ( ^I > 2σ(I)) and _wR2 was 0.1363 (all data). Table 25. Crystallographic parameters of modified pattern 11 Pattern 11 ( Di- HCl hemihydrate ) empirical formula C ₂₄ H ₃₃ Cl ₂ N ₈ O _1.5 formula 528.48 temperature/K 100 crystal system triclinic 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/cm ³ 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) 2Θ range of data collection/° 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/qualifications/parameters 10714/0/633 Goodness of fit ^on F2 1.038 Final R index [I＞=2σ(I)] R1 = 0.0461, wR2 = 0.1260 Final R Index [all data] R1 = 0.0613, wR2 = 0.1363 Maximum differential peak/hole/e Å ^-3 0.54/-0.29

Example 24. Single crystal assay results of pattern 11 The hemihydrate of compound 1 in the form of the dihydrochloride salt was found to be extremely crystalline and had the following unit cell dimensions: 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. The solvent mask was calculated and 91.1 electrons were found in a volume of 341.0 ų in the voids in the unit cell. This corresponds to 45.5 electrons per asymmetric unit and 22.75 electrons per G1T28 type unit. This is consistent with the presence of an additional chloride ion and water molecule 50% occupied per G1T28 molecule, totaling 44 electrons per asymmetric unit. The solvent mask was removed in order to determine the location of disordered chlorides found within the channel intersecting the unit cell at the source of the cell.

The final improved parameters are as follows: R ₁ [I > 2σ(I)] = 4.61 % GooF (goodness of fit) = 1.038 wR ₂ (all data) = 13.63 % R _int = 6.85 %

The encapsulation within the structure was shown to be efficient, whereby a moderate density of 1.342 g/ ^cm3 was noted. A solvent mask is applied to the channel along the a-axis containing disordered solvent and opposing ions.

Discrete hydrogen bonding phantoms are indicated in asymmetric cells, as shown in FIG. 90 . Between protonated piperidine (H(29) or H29)') and chlorine opposite ion (Cl(1) or Cl(2)) and amide hydrogen (H(3) or H(3)') and chlorine opposite Hydrogen-bonded associations between ions (Cl(1) or Cl(2)) where H(29)…Cl(1) / H(29)’…Cl(2) and Cl(1)…H(3 )' /Cl(2)…H(3) were measured to be 2.08(3) / 2.10(3) and 2.40(3) / 2.36(3) Å, respectively.

In addition to the discrete caged hydrogen-bonded associations noted, the pyrimidines and bridged amines appear to exhibit clear associations. This interaction was found to be of moderate strength, measuring 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 system for crystallization is via hydrogen bonding, as described above. The remaining interactions between the molecules in the structure consist of van de Waal's interactions. The simulated XRPD diffraction pattern has been calculated and compared to the experimental diffraction pattern of pattern 11 (FIG. 96, see Tables 26 and 27). The diffraction patterns do not agree with each other. Table 26. XRPD Simulated Peak List for Pattern 11 Numbering position [°2θ] Spacing [Å] height [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. Highest Intensity Simulated XRPD Diffraction Pattern Peaks for Pattern 11 Numbering position [°2θ] Spacing [Å] height [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 Pattern 11 The coordinates and analytical parameters of the single crystal solution of Pattern 11 are provided in Table 28 below: Table 28. Atomic Coordinates of Pattern 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. Anisotropic displacement parameters for pattern 11 (A ² x10 ³ ). Anisotropic displacement factor exponents have the 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. Bond Lengths for 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. Bonding Angles for 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. Bonding Angles for 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. Hydrogen Positions for Pattern 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. Single Crystal X -ray Crystallization Experimental Conditions for Pattern 1 Diffraction data were collected for the XRD1 beamline (Lausi et al., 2015) in its standard single crystal configuration. The experimental setup exists in a hygrometer with kappa geometry, fully controllable from the distal end. The diffraction properties of the samples were characterized by rotational crystallization at 100K (via an Oxford Cryostream 700, Oxford Cryosystems Ltd., Oxford, UK) with a nitrogen stream supplied.

Data were 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), mounted on kapton rings (MiTeGen, Ithaca, USA) at room temperature and flash frozen in liquid nitrogen. The diffraction properties of 15 different crystals have been evaluated - all crystals appear as thin yellow needles smaller than 50 to 80 mm in the longest direction. Most samples diffracted about 0.9 to 1 Å, but very few of them diffracted at most about 0.7 to 0.8 Å. Standard "Ω-scan" XRD data have been collected on one of the best diffractions until radiation damage begins to degrade the data significantly. An oscillation range of 0.5° has been chosen for optimal Bragg peaks separation. The same crystalline form has been found in crystals from all three batches supplied.

The structure was solved by SHELX-2014/7 (Sheldrick, G. M., 2015a) using direct methods and improved by least squares full-matrix refinement using SHELXL-2014/7 (Sheldrick, G. M., 2015b). All H atoms are included in the geometry except those H atoms attached to N or O atoms. In the final improvement cycle, a large peak around 2 e/Å is found near the ClB atom. This explanation is part of the disorder of this atom. The refinement revealed that the condition can be established at about 0.9 and about 0.1. This disorder affects water molecules (O1W); therefore, to maintain the model, the intact H1W1 was maintained with an AFIX card (AFIX 1) and thermal parameters at 150% of the adjacent O atoms.

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

The first calculation step was employed by finding the unit cell parameters using the LSI-index of the indexing program (Coelho, 2003; Coelho and Kern, 2005). The space group is selected based on reflection conditions and knowledge of the compound. Cell parameters, purity, and instrument parameters were improved using the Whole Powder Pattern Decomposition method (Pawley, 1981).

For the Rietveld calculation, cell parameters were obtained from room temperature measurements, while atomic positions and their thermal parameters were obtained from single crystal measurement files (cif) at 100K. During the improvement period, the following parameters are improved: - cell constant; - background; - Instrument geometry; - zero shift; - absorb.

；

；

No atomic positions or thermal motion parameters were improved during the entire process. The following fitting criteria are 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 given value for The weighting of the data point m of the count statistics is given by wm=1/σ(Y _o,m ) ² , where σ(Y _o,m ) is the error of Y _o,m ,

;

;

The resulting crystal structures are shown in Figures 97 and 98, and in a simulation comparison in Figure 99, which shows close agreement between the predicted and experimental diffraction patterns.

Example 26. Pattern 1 Single Crystal Description Compound 1 dihydrochloride crystallized as yellow columnar crystals in the monoclinic centrosymmetric space group P21/c. In the asymmetric unit, one dication API2+, two chloride ions and two water molecules are found (overall ratio 1:2:2).

As can be seen in Figure 97, the molecules are loaded on basic amine N atoms (N2) and on pyridine N atoms (N10). The molecule adopts an expanded (unrolled) configuration.

The crystals are held 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 a crystal, all water molecules act as donors as well as hydrogen bond acceptors, while N atoms preferably act only as donors. The only acceptor for the H bond is the N16 atom and in this case the interaction is intramolecular.

The intermolecular H-bond network expands in all three dimensions and thus it produces a 3D structure. HR-XRPD data and Retwede analysis of the starting material delivered by the G1 therapeutic allowed the acquisition of cellular parameters at room temperature and revealed that the host material consisted of pure form without any detectable crystalline impurities. Pattern 1 crystallizes as a dication associated with two chloride ions in the centrosymmetric space group P21/c. Two water molecules are also found in the asymmetric unit. The results are listed in Table 34. Table 34. Single crystal data for pattern 1 Pattern 1 single crystal empirical formula [(C ₂₄ H ₃₂ N ₈ O)Cl ₂ •2H ₂ O] formula 555.51 T[K] 100(2) K λ [Å] 0.61993 Å crystal system Monoclinic 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/cm ³ ] 1.391 [mm ^-1 ] 0.199 F(000) 1176 Crystal size [mm ³ ] 0.07×0.02×0.01 θ range [°] 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 none Maximum and minimum transfers 0.992 and 0.978 data/qualifications/parameters 9183/0/367 Goodness of fit ^on F2 1.019 Final R index [I>2(I)] R1 = 0.0609, wR2 = 0.1271 R index (all data) R1 = 0.1366, wR2 = 0.1603 absolute configuration Extinction coefficient n/a Maximum diffraction peaks and valleys [e/Å ³ ] 0.355 and -0.471 Table 35. Hydrogen Bonding from Pattern 1 Single Crystal Structure 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 Retweede Parameters for Pattern 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 detection limit

Example 27. X -ray Powder Diffraction (XRPD) XRPD analysis was performed on a PANalytical X'pert pro scanning free base samples between 3 and 35° 2Θ. The material was ground gently to release any agglomerates and loaded onto a porous disk supporting the sample with Kapton or Mylar polymer film. Subsequently, the multiwell plate was placed in a diffractometer with a 40 kV/40 mA generator setting using Cu K radiation (α1λ=1.54060 Å; α2=1.54443 Å) operating in transmission mode (step 0.0130° 2θ). ; β=1.39225 Å; α1:α2 ratio=0.5) for analysis.

Table 37 below provides a list of XRPD peaks for pattern 7 with >10% relative intensity peaks. XRPD performed on pattern 7 exhibited sharp peaks, indicating that the sample consisted of crystalline material. In XRPD on pattern 7 at about 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 Significant peaks were observed at ±0.2°, 21.6±0.2°, 22.7±0.2°, 23.3±0.2° and 24.6±0.2°. Table 37. XRPD peak list for pattern 7. position [°2θ] height [cts] Maintained 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 certain embodiments, the pattern form is pattern 7 and is characterized in that the XRPD pattern comprises at least 2 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 7 and is characterized in that the XRPD pattern comprises at least 3 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 7 and is characterized in that the XRPD pattern comprises at least 4 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 7 and is characterized in that the XRPD pattern comprises at least 5 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 7 and is characterized in that the XRPD pattern comprises at least 6 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 7 and is characterized in that the XRPD pattern comprises at least 7 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 7 and is characterized in that the XRPD pattern comprises at least 8 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 7 and is characterized in that the XRPD pattern comprises at least 9 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 7 and is characterized in that the XRPD pattern comprises at least 10 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 7 and is characterized in that the XRPD pattern comprises at least 11 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 7 and is characterized in that the XRPD pattern comprises at least 12 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 7 and is characterized in that the XRPD pattern comprises 2Θ values selected from the group consisting of: 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 with >10% relative intensity peaks. XRPD performed on pattern 8 exhibited sharp peaks, indicating that the sample was composed of crystalline material. In XRPD on pattern 8 at about 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 Significant peaks were observed at ±0.2° and 29.9±0.2°. Table 38. List of XRPD peaks for pattern 8. position [°2θ] height [cts] Maintained 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 certain embodiments, the pattern form is pattern 8 and is characterized in that the XRPD pattern comprises at least 2 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 8 and is characterized in that the XRPD pattern comprises at least 3 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 8 and is characterized in that the XRPD pattern comprises at least 5 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 8 and is characterized in that the XRPD pattern comprises at least 7 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 8 and is characterized in that the XRPD pattern comprises at least 9 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 8 and is characterized in that the XRPD pattern comprises at least 11 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 8 and is characterized in that the XRPD pattern comprises at least 13 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 8 and is characterized in that the XRPD pattern comprises at least 15 peaks selected from: 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 certain embodiments, the pattern form is pattern 8 and is characterized in that the XRPD pattern comprises at least 17 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 8 and is characterized in that the XRPD pattern comprises at least 19 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 8 and is characterized in that the XRPD pattern comprises 2θ values selected from the group consisting of: 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 with >10% relative intensity peaks. XRPD performed on pattern 9 exhibited sharp peaks, indicating that the sample consisted of crystalline material. In XRPD on pattern 9 at about 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 Significant peaks were observed at ±0.2°, 32.6 ±0.2° and 33.6 ±0.2°. Table 39. XRPD peak list for pattern 9. position [°2θ] height [cts] Maintained 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 certain embodiments, the pattern form is pattern 9 and is characterized in that the XRPD pattern comprises at least 2 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 9 and is characterized in that the XRPD pattern comprises at least 3 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 9 and is characterized in that the XRPD pattern comprises at least 5 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 9 and is characterized in that the XRPD pattern comprises at least 7 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 9 and is characterized in that the XRPD pattern comprises at least 9 peaks selected from: 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 certain embodiments, the pattern form is pattern 9 and is characterized in that the XRPD pattern comprises at least 11 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 9 and is characterized in that the XRPD pattern comprises at least 13 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 9 and is characterized in that the XRPD pattern comprises at least 15 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 9 and is characterized in that the XRPD pattern comprises at least 17 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 9 and is characterized in that the XRPD pattern comprises at least 19 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 9 and is characterized in that the XRPD pattern comprises 2θ values selected from the group consisting of: 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 with >10% relative intensity peaks. XRPD performed on pattern 10 exhibited sharp peaks, indicating that the sample consisted of crystalline material. In XRPD on pattern 10 at about 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 Significant peaks were observed at ±0.2°, 31.3±0.2° and 33.4±0.2°. Table 40. List of XRPD peaks for pattern 10. position [°2θ] height [cts] Maintained 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 1974.03 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 certain embodiments, the pattern form is pattern 10 and is characterized in that the XRPD pattern comprises at least 2 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 10 and is characterized in that the XRPD pattern comprises at least 3 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 10 and is characterized in that the XRPD pattern comprises at least 5 peaks selected from: 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 certain embodiments, the pattern form is pattern 10 and is characterized in that the XRPD pattern comprises at least 7 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 10 and is characterized in that the XRPD pattern comprises at least 9 peaks selected from the group consisting of: 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 certain embodiments, the pattern form is pattern 10 and is characterized in that the XRPD pattern comprises 2θ values selected from the group consisting of: 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 powders X -ray powder diffraction (XRPD) The freeze-dried compositions described in Table 41 below were analyzed by X-ray powder diffraction. Table 41 Freeze-dried composition component Quantity per viala ⁽ mg) Medicine function quality standard ^Compound 1b 300 active agent inherent Mannitol 300 bulking agent 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 assistance NF NF=United States National Formulary; USP=United States Pharmacopoeia; Ph. Eur.=European Pharmacopoeia; N/A=not applicable; qs=sufficient a target weight of solution filled into vials prior to lyophilization is 12.252 g (12 mL). b Amount relative to free base (equivalent to 373 mg of compound 1 pattern 1 dihydrochloride dihydrate). c Can be used to adjust bulk solution pH if necessary. d Used to dissolve components and subsequently removed during freeze-drying. e Use nitrogen as the 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.

A representative kilo-scale manufacture of the freeze-dried compositions provided from Table 41: Mannitol (4 kg) was slowly added to a water for injection (WFI) grade water (130 kg) tank. Rinse the mannitol dispensing container with 500 mL of WFI and add the material to the tank and mix until the mannitol is completely dissolved. Citric acid monohydrate (1 kg) was then added to the tank and the dispensing vessel was washed with 200 mL of WFI. The resulting solution was mixed until completely dissolved. A sample of the solution was taken and the pH checked (2.26) and then adjusted by slowly adding 2800 mL of 5N NaOH. The pH was checked again (6.56) and an additional 100 mL of 5N NaOH was added. The pH was checked again (7.2), and then 100 mL of 1N HCl solution was added, resulting in a pH of 6.98 solution. An additional 100 mL of 1 N HCl solution was added resulting in a final pH of 6.85. Then Compound 1 dihydrochloride dihydrate (4.92 kg) was slowly added to the mixed solution. The Compound 1 dihydrochloride dihydrate dispensing 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 successive additions of 1N HCl (890 mL total) 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 at room temperature overnight. The bulk solution was then pumped through the filter into another tank, where a sample was collected for analytical purposes.

The filtered solution is then loaded into appropriately sized vials. The shelf of the freeze drying apparatus was then pre-cooled to 5°C and the vials were then placed on the shelf. Freeze drying at the following temperatures and vacuum cycles: step number stage temperature pressure Time (hh:mm ) 1 load 5℃ atmospheric pressure N/A 2 freezing 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 take time -42℃ 150 mTorr N/A 10 primary drying -42℃ 150 mTorr 00:15 11 -14℃ 150 mTorr 00:28 12 -14℃ 150 mTorr 69:00 13 secondary drying 36℃ 150 mTorr 00:50 14 36℃ 150 mTorr 06:00 15 20℃ 150 mTorr 00:15 16 Pre-charged (with N ₂ ) 20℃ 11psi N/A 17 Gasser 20℃ 1000psi N/A full length about 94 hours

After the cycle was complete, the freeze-drying chamber was purged with nitrogen filtered through a 0.22 μm sterile freeze-drying exit filter. A 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 jelly, after which the sample was flattened with a glass slide.

An X-ray diffraction system was performed with the following instrument parameters: General parameters scan mode Sustained PSD Fast time per step 1 second (192 seconds valid Scan range 2 to 40θ step size 0.05θ sample rotation 15 rpm CuKalpha rotation 40KV: 40mA scan type Coupling 2θ/θ Primary Beam Optics Divergent slit/Dual primary slit 0.6 mm Primary slot mount none primary soller slit 2.5θ Secondary Beam Optics Secondary Soller Slit/Detector Optics Mount 2 2.5θ Detector Optics Mount 1 tunnel Detector slit opening/secondary slit mount none Anti-scatter slit / double secondary slit 3mm blade exist detector opening 2.940θ

The XRPD image is shown in FIG. 100 .

Table 42 below provides a list of peaks with >10% relative intensity peaks for the freeze-dried Compound 1 dihydrochloride salt composition comprising mannitol and citric acid described above. XRPD performed on the freeze-dried Compound 1 dihydrochloride composition exhibited sharp peaks, indicating that the sample was still crystalline after freeze-drying. In XRPD on freeze-dried Compound 1 dihydrochloride composition at about 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 Significant peaks were observed at °, 24.7±0.4°, 25.4±0.4°, 31.8±0.4° and 36.2±0.4° 2θ. The XRPD pattern exhibited several Compound 1 Pattern 1 peaks and showed that Compound 1 Pattern 1 was formed during the freeze-drying process. Table 42. XRPD listing of peaks with >10% relative intensity for freeze-dried Compound 1 dihydrochloride salt composition comprising 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 certain embodiments, the freeze-dried Compound 1 dihydrochloride composition is characterized by an XRPD pattern comprising at least 2 peaks selected from the group consisting of: 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 certain embodiments, the freeze-dried Compound 1 dihydrochloride composition is characterized by an XRPD pattern comprising at least 3 peaks selected from the group consisting of: 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 certain embodiments, the freeze-dried Compound 1 dihydrochloride composition is characterized by an XRPD pattern comprising at least 4 peaks selected from the group consisting of: 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 certain embodiments, the freeze-dried Compound 1 dihydrochloride composition is characterized by an XRPD pattern comprising at least 5 peaks selected from the group consisting of: 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 certain embodiments, the freeze-dried Compound 1 dihydrochloride composition is characterized by an XRPD pattern comprising at least 6 peaks selected from the group consisting of: 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 certain embodiments, the freeze-dried Compound 1 dihydrochloride composition is characterized by an XRPD pattern comprising at least 7 peaks selected from the group consisting of: 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 certain embodiments, the freeze-dried Compound 1 dihydrochloride composition is characterized by an XRPD pattern comprising at least 8 peaks selected from the group consisting of: 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 certain embodiments, the freeze-dried Compound 1 dihydrochloride composition is characterized by an XRPD pattern comprising at least 9 peaks selected from the group consisting of: 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 certain embodiments, the freeze-dried Compound 1 dihydrochloride composition is characterized by an XRPD pattern comprising at least 10 peaks selected from the group consisting of: 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 certain embodiments, the freeze-dried Compound 1 dihydrochloride composition is characterized by an XRPD pattern comprising 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 certain embodiments, the freeze-dried Compound 1 dihydrochloride composition is characterized by an XRPD pattern comprising a peak at 9.8±0.4° 2Θ.

In certain embodiments, the freeze-dried Compound 1 dihydrochloride composition is characterized by an XRPD pattern comprising a peak at 20.5±0.4° 2Θ.

In certain 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, one of ordinary skill in the art appreciates that various modifications and changes can be made without departing from the scope of the invention as set forth in the claims below. Accordingly, this specification is to be regarded in an illustrative rather than a restrictive sense, and all such modifications are intended to be included within the scope of the present invention.

FIG. 1 is an XRPD diffraction diagram of the crystal 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. FIG. 2 is a PLM image of the crystalline pattern 1 . Images were obtained using the method described in Example 5. Pattern 1 material appears highly crystalline under PLM imaging, with non-polarized material shown on the left and polarized material shown on the right. FIG. 3 is a thermogravimetric/differential thermal (TG/DTA) thermogram of the crystalline pattern 1. FIG. A TG/DTA thermogram for Pattern 1 was obtained as described in Example 6. About 6% of the initial mass loss from heating was associated with surface moisture loss. Two mass losses of approximately 7% were observed at approximately 200°C, which peaked at 218°C, and 300°C, which peaked at 343°C. FIG. 4 is a differential scanning calorimetry (DSC) thermogram of the crystal pattern 1. FIG. The DSC thermogram of Crystalline Pattern 1 was obtained as described in Example 7. DSC analysis showed 2 broad endotherms of approximately 65°C peaking at 130°C and 245°C peaking at 277°C. A sharp melting endotherm was observed starting at 330°C which peaked at 341°C. 5 is a Dynamic Vapor Sorption (DVS) analysis showing the results of the moisture adsorption experiment of Pattern 1. FIG. DVS analysis of Pattern 1 was obtained as described in Example 3. The material was found to be stable and pattern 1 was confirmed by XRPD analysis of the dried sample at the end of the experiment. Pattern 1 adsorbed 3.00 wt% at 40% RH (relative humidity) and 4.00 wt% at 90% RH. The x-axis is the relative humidity measured as a percentage, and the y-axis is the water weight of the material measured as a percentage. FIG. 6 is a dynamic vapor sorption (DVS) kinetic curve of pattern 1. FIG. The DVS of Pattern 1 was obtained as described in Example 3. Samples were subjected to a slow ramp profile from 40 to 90% relative humidity (RH) in 10% increments, in each step, samples were held at 25°C until a stable weight (dm/dt 0.004% was obtained, minimum step size 30 min, The maximum step size is 500 minutes). After the adsorption cycle was complete, the samples were dried to 0% RH using the same procedure and then returned to 40% RH using a second adsorption cycle. Do two cycles. The material exhibits hygroscopicity according to DVS with a 4% mass gain between 0% and 90% RH. During the desorption cycle, the material is dehydrated. FIG. 7 is a comparison of the XRPD diffraction patterns of Pattern 1 and Pattern 1 after DVS. The diffraction pattern of Pattern 1 was obtained as described in Example 1; and Post-DVS Pattern 1 was obtained as described in Example 11. The material exhibits hygroscopicity according to DVS with a 4% mass gain between 0% and 90% RH. During the desorption cycle, the material is dehydrated. XRPD analysis after DVS showed no change in pattern 1. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 8 is a comparison of the XRPD diffraction pattern of Pattern 1 prior to solvent solubility studies and Pattern 1 materials resulting from various solvent solubility studies. Diffraction patterns were obtained as described in Example 1 and investigated as described in Example 13. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 9 is a comparison of the XRPD diffraction pattern of Pattern 1 prior to solvent solubility studies and Pattern 1 materials resulting from various solvent solubility studies. Diffraction patterns were obtained as described in Example 1 and investigated as described in Example 13. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 10 is a comparison of the XRPD diffraction patterns of Pattern 2 generated from various solvent solubility studies. Diffraction patterns were obtained as described in Example 1 and investigated as described in Example 13. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 11 is a comparison of the XRPD diffraction patterns of Pattern 2 generated from various solvent solubility studies. Diffraction patterns were obtained as described in Example 1 and investigated as described in Example 13. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 12 is a comparison of the XRPD diffraction patterns of Pattern 3 generated from various solvent solubility studies. Diffraction patterns were obtained as described in Example 1 and investigated as described in Example 13. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 13 is a comparison of the XRPD diffraction patterns of Pattern 1 and Pattern 4 resulting from solubility studies in MeCN. Diffraction patterns were obtained as described in Example 1 and Example 4 and investigated as described in Example 13. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 14 is a comparison of the XRPD diffraction patterns pattern 2 and pattern 5 produced by various solvent systems. Diffraction patterns were obtained as described in Example 1 and investigated as described in Example 13. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 15 is a comparison of XRPD diffraction patterns pattern 2 and pattern 6 produced by various solvent systems. Diffraction patterns were obtained as described in Example 1 and investigated as described in Example 13. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 16 is a comparison of the XRPD diffraction patterns of Pattern 1 before and after maturation experiments in various solvent systems. Diffraction patterns were obtained as described in Example 1 and investigated as described in Example 21. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 17 is a comparison of the XRPD diffraction patterns of Pattern 2 before and after maturation experiments in various solvent systems. Diffraction patterns were obtained as described in Example 1 and investigated as described in Example 21. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 18 is a comparison of the XRPD diffraction patterns of Pattern 2 before and after maturation experiments in various solvent systems. Diffraction patterns were obtained as described in Example 1 and investigated as described in Example 21. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 19 is a comparison of the XRPD diffraction patterns of Pattern 3 before and after maturation experiments in isopropanol and ethanol. Diffraction patterns were obtained as described in Example 1 and investigated as described in Example 21. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 20 is a comparison of the XRPD diffraction patterns of pattern 4 before and after maturation experiments in acetonitrile. Diffraction patterns were obtained as described in Example 4 and investigated as described in Example 21. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 21 is a comparison of the XRPD diffraction patterns of Pattern 5 before and after the maturation experiment in methyl isobutyl ketone. Diffraction patterns were obtained as described in Example 1 and investigated as described in Example 21. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 22 is a comparison of XRPD diffraction patterns generated from maturation experiments in various solvent systems. Diffraction patterns were obtained as described in Example 1 and investigated as described in Example 21. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 23 is a comparison of XRPD Pattern 1 diffraction patterns after drying resulting from maturation experiments in various solvent systems. Diffraction patterns were obtained as described in Example 1 and investigated as described in Example 21. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 24 is a comparison of XRPD Pattern 1 diffraction patterns after drying resulting from maturation experiments in various solvent systems. Diffraction patterns were obtained as described in Example 1 and investigated as described in Example 21. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 25 is a comparison of XRPD pattern 2 diffractograms and diffractograms generated from maturation experiments in various solvent systems after drying. Diffraction patterns were obtained as described in Example 1 and investigated as described in Example 21. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 26 is a comparison of XRPD pattern 3 diffractograms after drying resulting from maturation experiments in various solvent systems. Diffraction patterns were obtained as described in Example 1 and investigated as described in Example 21. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 27 is a comparison of the XRPD pattern 3 diffractograms, pattern 4 diffractograms and diffractograms generated from maturation experiments in various solvent systems after drying. Diffraction patterns were obtained as described in Example 1 and Example 4 and investigated as described in Example 21. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 28 is a comparison of the XRPD pattern 3 diffraction pattern, pattern 6 diffraction pattern and diffraction pattern resulting from maturation in heptane after drying. Diffraction patterns were obtained as described in Example 1 and investigated as described in Example 21. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 29 is a comparison of XRPD patterns 5 and diffraction patterns resulting from maturation in various solvents after drying. Diffraction patterns were obtained as described in Example 1 and investigated as described in Example 21. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 30 is a comparison of the XRPD diffraction pattern of Pattern 1 with the solid remaining after the evaporation experiment. Diffraction patterns were obtained as described in Example 1. Solids were obtained as described in Example 13. The samples were kept unsealed and placed in a box to allow evaporation. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 31 is a comparison of the XRPD diffraction pattern of pattern 3 with the solid remaining after the evaporation experiment. Diffraction patterns were obtained as described in Example 1. Solids were obtained as described in Example 13. The samples were kept unsealed and placed in a box to allow evaporation. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 32 is a comparison of the XRPD diffraction pattern of Pattern 3 with the solid produced by adding tertiary butyl methyl ether (t-BME) to 2,2,2-trifluoroethanol. Diffraction patterns were obtained as described in Example 1. Solids were obtained as described in Example 13. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. 33 is a thermogravimetric/differential thermal (TG/DTA) thermogram of pattern 2 small scale material. A TG/DTA thermogram for Pattern 2 was obtained as described in Example 6. About 3% of the initial mass loss from heating is associated with surface moisture loss. Two mass losses of approximately 7% were observed at approximately 222°C, which peaked at 239°C, 318°C, which peaked at 340°C, and 345°C, which peaked at 325°C. The x-axis is in temperature (°C) and the y-axis is TG (%). Figure 34 is a thermogravimetric/differential thermal (TG/DTA) thermogram of pattern 3 small scale material. A TG/DTA thermogram for Pattern 3 was obtained as described in Example 6. An initial mass loss of approximately 2.6% from heating was associated with surface moisture loss. Two mass losses of approximately 6.6% were observed at approximately 222°C, which peaked at 229°C, 311°C, which peaked at 317°C, and 343°C, which peaked at 345°C. The x-axis is in temperature (°C) and the y-axis is TG (%). 35 is a thermogravimetric/differential thermal (TG/DTA) thermogram of pattern 5 small scale material. A TG/DTA thermogram for Pattern 5 was obtained as described in Example 6. An initial mass loss of approximately 3.4% from heating was associated with surface moisture loss. Three mass losses of approximately 7.3% were observed at approximately 206°C, which peaked at 216°C, 284°C, which peaked at 321°C, and 343°C, which peaked at 345°C. The x-axis is in temperature (°C) and the y-axis is TG (%). 36 is a comparison of the XRPD patterns of the small-scale and scaled-up materials of Pattern 2 and Pattern 6. FIG. When pattern 2 is synthesized and scaled, it produces a mixture of pattern 6 and pattern 2, as shown in the XRPD diffractogram. Diffraction patterns were obtained as described in Example 1. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 37 is a PLM image of a mixture of Pattern 2 and Pattern 6 generated from a scale-up attempt. PLM imaging of the pattern 2/6 mixture was obtained as described in Example 5. Pattern 2/6 scale-up material appears highly crystalline under PLM imaging, with unpolarized material shown on the left and polarized material shown on the right. Figure 38 is a thermogravimetric/differential thermal (TG/DTA) thermogram of a mixture of Pattern 2 and Pattern 6 generated from a scale-up attempt. An initial mass loss of approximately 3.6% from heating was associated with surface moisture loss. Two mass losses of about 6.3% were observed at about 211°C and at 310°C with a peak at 321°C. The x-axis is in temperature (°C) and the y-axis is TG (%). Figure 39 is a differential scanning calorimetry (DSC) thermogram of a mixture of Pattern 2 and Pattern 6 generated from a scale-up attempt. A DSC thermogram of the Pattern 2/6 mixture was obtained as described in Example 7. DSC analysis showed 2 broad endotherms of approximately 55.9°C peaking at 131°C and 267°C peaking at 295°C. A sharp melting endotherm was observed starting from 336°C. Figure 40 is a gravity vapor sorption (GVS) isotherm for the mixture of pattern 2 and pattern 6 generated from the scale-up attempt. GVS isotherms of the pattern 2/6 mixture were obtained as described in Example 2. The mixture of pattern 2 and pattern 6 adsorbed 4.00 wt% at 40% RH (relative humidity) and 7.00 wt% at 90% RH. The x-axis is the relative humidity measured as a percentage, and the y-axis is the water weight of the material measured as a percentage. Figure 41 is a gravity vapor sorption (GVS) kinetic curve for mixtures of Pattern 2 and Pattern 6 generated from a scale-up attempt. GVS isotherms of the pattern 2/6 mixture were obtained as described in Example 2. Samples were subjected to a slow ramp profile from 40 to 90% relative humidity (RH) in 10% increments, holding samples at 25°C in each step until a stable weight was obtained (dm/dt 0.004%, minimum step size 550 min, The maximum step size is 900 minutes). After the adsorption cycle was complete, the samples were dried to 0% RH using the same procedure and then returned to 40% RH using a second adsorption cycle. Do two cycles. The material exhibits hygroscopicity according to DVS with an 8% mass gain between 0% and 90% RH. During the desorption cycle, the material is dehydrated. Figure 42 is a comparison of the scale-up XRPD diffraction patterns of Pattern 1, Pattern 2, and Pattern 2 after DVS. Diffraction patterns were obtained as described in Example 1. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 43 is a comparison of XRPD diffraction patterns of pattern 3 small scale and pattern 3 scaled dry and wet. Diffraction patterns were obtained as described in Example 1. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 44 is a PLM image of pattern 3 scale-up material. The Pattern 3 scale-up material exhibited high crystallinity under PLM imaging as described in Example 5. Non-polarizing material is shown on the left, and polarizing material is shown on the right. Figure 45 is a TG/DTA thermogram of the pattern 3 scale-up material. A TG/DTA thermogram of scale-up pattern 3 was obtained as described in Example 6. TG/DTA showed two peaks at 199°C and 345°C. About 8% of the initial mass loss from heating was associated with surface moisture loss. Two mass losses of about 7% were observed at about 199°C and at 343°C with a peak at 345°C. The x-axis is in temperature (°C) and the y-axis is TG (%). Figure 46 is a differential scanning calorimetry (DSC) thermogram of the Pattern 3 scale-up material. The DSC thermogram of Pattern 3 was obtained as described in Example 7. DSC analysis showed 3 broad endotherms of approximately 168°C peaking at 189°C, 251°C peaking at 264°C, and 272°C peaking at 296°C. A sharp melting endotherm was observed starting at 337°C which peaked at 343°C. Figure 47 is a DVS isotherm curve of pattern 3 scale-up material. The DVS isotherm for Pattern 3 was obtained as described in Example 3. The material exhibits hygroscopicity according to DVS with a 4% mass gain between 0% and 90% RH. During the desorption cycle, the material is dehydrated. Figure 48 is a DVS kinetic curve of the pattern 3 scale-up material. DVS kinetic curves for Pattern 3 were obtained as described in Example 3. Samples were subjected to a slow ramp profile from 40 to 90% relative humidity (RH) in 10% increments, holding samples at 25°C in each step until a stable weight was obtained (0.004% mass change, min step 650 min, max step size 1050 minutes). After the adsorption cycle was complete, the samples were dried to 0% RH using the same procedure and then returned to 40% RH using a second adsorption cycle. Do two cycles. The material exhibits hygroscopicity according to DVS with a 4% mass gain between 0% and 90% RH. During the desorption cycle, the material is dehydrated. Figure 49 is a comparison of the XRPD diffraction patterns of the pattern 3 scale-up material before and after DVS. Diffraction patterns were obtained as described in Example 1. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 50 is a comparison of the XRPD diffraction patterns of pattern 5 from small scale and scale up experiments. Diffraction patterns were obtained as described in Example 1. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 51 is a comparison of the XRPD diffraction patterns of Pattern 5 from small scale and scale up experiments in replicate runs. Diffraction patterns were obtained as described in Example 1. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 52 is a comparison of the XRPD diffraction patterns of Pattern 2 in various one-week stability studies. Diffraction patterns were obtained as described in Example 1. Stability studies compared Pattern 2 and Pattern 2 after 1 week at ambient temperature and at 80°C, respectively. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Repeat to scale up. Figure 53 is a comparison of the XRPD diffraction patterns of Pattern 2 in various one-week stability studies. Diffraction patterns were obtained as described in Example 1. Stability studies compare Pattern 2, Pattern 2 scale-up, and Pattern 2 at 40°C. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Repeat to scale up. Figure 54 is a comparison of the XRPD diffraction patterns of Pattern 3 in various one-week stability studies. Diffraction patterns were obtained as described in Example 1. Stability studies compared Pattern 3 and Pattern 3 after 1 week at ambient temperature of 40°C and at 80°C, respectively. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. FIG. 55 is a comparison of XRPD diffraction patterns resulting from a competitive slurry experiment of Pattern 1 mixed with Pattern 2 and Pattern 3. FIG. After carrying out the procedure to form Example 11, a diffraction pattern was obtained as described in Example 1. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. FIG. 56 is a comparison of XRPD diffraction patterns resulting from a competitive slurry experiment of Pattern 1 mixed with Pattern 2 and Pattern 3. FIG. After carrying out the procedure to form Example 11, a diffraction pattern was obtained as described in Example 1. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. FIG. 57 is a comparison of XRPD diffraction patterns resulting from a competitive slurry experiment of Pattern 1 mixed with Pattern 2 and Pattern 3. FIG. After carrying out the procedure to form Example 11, a diffraction pattern was obtained as described in Example 1. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. FIG. 58 is a comparison of XRPD diffraction patterns resulting from a competitive slurry experiment of Pattern 1 mixed with Pattern 2 and Pattern 3. FIG. After carrying out the procedure to form Example 11, a diffraction pattern was obtained as described in Example 1. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. FIG. 59 is a comparison of XRPD diffraction patterns resulting from a competitive slurry experiment of Pattern 1 mixed with Pattern 2 and Pattern 3. FIG. After carrying out the procedure to form Example 11, a diffraction pattern was obtained as described in Example 1. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 60 is a comparison of the XRPD diffraction patterns of Pattern 7 before and after the thermodynamic solubility experiment. Thermodynamic solubility experiments are described in Example 22. Diffraction patterns were obtained using the procedure from Example 1. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. FIG. 61 is the XRPD diffraction pattern of pattern 7. FIG. The diffraction pattern of pattern 7 was obtained as described in Example 1. The x-axis is 2Θ measured in degrees, and the y-axis is intensity measured in counts. Figure 62 is a PLM image of pattern 7 at 200x magnification. PLM images of pattern 7 were 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. FIG. 63 is a TG/DTA thermogram of pattern 7. FIG. A TG/DTA thermogram for Pattern 7 was obtained as described in Example 6. The thermogram shows 6.2% weight loss between 150 and 340°C and sample decomposition above 350°C. The thermogram also shows melting of the sample starting at 340°C and peaking at 345°C. The x-axis is temperature measured in degrees Celsius and the y-axis is intensity measured in DTAuV on the left and TG% on the right. FIG. 64 is the DSC first heating thermogram of pattern 7. FIG. A DSC thermogram of Pattern 7 was obtained as described in Example 7. The thermogram 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 is temperature measured in degrees Celsius and the y-axis is intensity measured in DSC mW. FIG. 65 is the DSC first cooling thermogram of pattern 7. FIG. A DSC thermogram of Pattern 7 was obtained as described in Example 7. The thermogram does not show significant thermal events in the cold cycle. The x-axis is temperature measured in degrees Celsius and the y-axis is intensity measured in DSC mW. FIG. 66 is a DSC second heating thermogram of the crystal pattern 7. FIG. A DSC thermogram of Pattern 7 was obtained as described in Example 7. The second heat contained a melting event starting at 333°C and a peak at 339°C. Incomplete melting may occur during initial thermal cycling. The x-axis is temperature measured in degrees Celsius and the y-axis is intensity measured in DSC mW. Figure 67 is a comparison of XRPD diffraction patterns from a pH solubility study of Pattern 7 at various pHs. Material produced from pH 4 was identified as pattern 8. Diffraction patterns were obtained as described in Example 1 and pH experiments were performed as described in Example 16. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 68 is a comparison of XRPD diffraction patterns from a pH solubility study of Pattern 7 at various pHs. Diffraction patterns of pattern 7 were obtained as described in Example 1 and Example 16. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 69 is a comparison of XRPD diffraction patterns from a pH solubility study of Pattern 7 at various pH solvent systems. Diffraction patterns of pattern 7 were obtained as described in Example 1 and Example 16. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 70 is a comparison of the XRPD diffraction patterns produced by crystallizing Group 1. Crystallization was performed as described in Example 17. The comparison shows patterns 7 and forms produced by various concentrations in various pH solvent systems. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 71 is a comparison of the XRPD diffraction patterns produced by crystallizing Groups 2 and 3. Crystallization was performed as described in Example 18 and Example 19. The comparison shows patterns 7 and forms produced by various concentrations in various pH solvent systems. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 72 is a comparison of the XRPD diffraction patterns produced by crystallizing Groups 2 and 3. Crystallization was performed as described in Example 18 and Example 19. The comparison shows patterns 7 and forms produced by various concentrations in various pH solvent systems. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. Figure 73 is a comparison of the XRPD diffraction patterns produced by crystallizing Group 4. Crystallization was performed as described in Example 20. The comparison shows patterns 7 and forms produced by various concentrations in various pH solvent systems. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. 74 is a PLM image corresponding to the material obtained from Experiment 1 from Example 23. Polarized samples are shown in the bottom column and unpolarized samples are shown in the top column. 75 is a PLM image corresponding to the material obtained from Experiment 2 from Example 23. PLM images were obtained as described in Example 5. Polarized samples are shown on the right and non-polarized samples are shown on the left. 76 is a PLM image corresponding to the material obtained from Experiment 3 from Example 23. PLM images were obtained as described in Example 5. Polarized samples are shown on the right and non-polarized samples are shown on the left. 77 is a PLM image corresponding to the material obtained from Experiment 4 from Example 23. PLM images were obtained as described in Example 5. Polarized samples are shown in the bottom column and non-polarized samples are shown in the top column. 78 is a PLM image corresponding to the material obtained from Experiment 5 from Example 23. PLM images were obtained as described in Example 5. Polarized samples are shown in the bottom column and non-polarized samples are shown in the top column. 79 is a PLM image corresponding to the material obtained from Experiment 7 from Example 23. PLM images were obtained as described in Example 5. Polarized samples are shown on the right and non-polarized samples are shown on the left. 80 is a PLM image corresponding to the material obtained from Experiment 6 from Example 23. PLM images were obtained as described in Example 5. Polarized samples are shown in the bottom column and unpolarized samples are shown in the top column. 81 is a PLM image corresponding to the material obtained from Experiment 8 from Example 23. Polarized samples are shown on the right and non-polarized samples are shown on the left. 82 is a PLM image corresponding to the material obtained from Experiment 9 from Example 23. PLM images were obtained as described in Example 5. Polarized samples are shown on the right and non-polarized samples are shown on the left. 83 is a PLM image corresponding to the material obtained from Experiment 10 from Example 23. Polarized samples are shown in the bottom column and unpolarized samples are shown in the top column. 84 is a PLM image corresponding to the material obtained from Experiment 11 from Example 23. Polarized samples are shown on the right and non-polarized samples are shown on the left. 85 is a PLM image corresponding to the material obtained from Experiment 12 from Example 23. This material was identified as pattern 9. Polarized samples are shown in the bottom column and non-polarized samples are shown in the top column. FIG. 86 is a PLM image of crystallized pattern 10 at 200× magnification. PLM images of crystalline pattern 7 were obtained as described in Example 5. Polarized samples are shown in the bottom column and unpolarized samples are shown in the top column. FIG. 87 is a TG/DTA thermogram of pattern 9. FIG. A TG/DTA thermogram for Pattern 9 was obtained as described in Example 6. Pattern 9 exhibited a substantial weight loss of 24.3% from the onset of heating until 150°C. Pattern 9 exhibited a second mass loss of 15 wt.% between 75°C and 154°C. The DT trace identifies two endothermic events associated with the indicated mass loss with a first onset at 37°C and a peak at 66.2°C; a second onset at 122°C and a peak at 128°C peak; and the third and final endothermic event (sample melting) in the DT trace was observed starting at 326°C and peaking at 330°C. The x-axis is temperature measured in degrees Celsius and the y-axis is intensity measured in DTAuV on the left and TG% on the right. FIG. 88 is a TG/DTA thermogram of pattern 10. FIG. TG/DTA thermograms were obtained as described in Example 6. The thermogram shows a minimum weight loss of 0.1% weight loss between 150°C and 340°C from heating onset. The samples showed degradation above 320°C. The thermogram also shows two peaks, with the first starting at 199°C and peaking at 206°C; and the second starting at 327°C and peaking at 331°C. The x-axis is temperature measured in degrees Celsius and the y-axis is intensity measured in DTAuV on the left and TG% on the right. FIG. 89 is an XRPD diffraction pattern of crystal pattern 8. FIG. 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. FIG. 90 shows the crystal structure of pattern 11. FIG. The crystal structure was dissolved as described in Example 25. Non-hydrogen atoms are shown as thermal ellipsoids with probability levels set at 50%. Figure 91 is a crystal structure with a pattern 11 of hydrogen bonding as depicted. The crystal structure was dissolved as described in Example 25. Non-hydrogen atoms are shown as thermal ellipsoids with probability levels set at 50%. Figure 92 is the crystal structure of pattern 11 with the view set to the unit cell a-axis. The crystal structure was dissolved as described in Example 25. Non-hydrogen atoms are shown as thermal ellipsoids with probability levels set at 50%. Figure 93 is the crystal structure of pattern 11, with the view set to the b-axis of the unit cell. The crystal structure was dissolved as described in Example 25. Non-hydrogen atoms are shown as thermal ellipsoids with probability levels set at 50%. Figure 94 is the crystal structure of pattern 11, where the view is set to the c-axis of the unit cell. The crystal structure was dissolved as described in Example 25. Non-hydrogen atoms are shown as thermal ellipsoids with probability levels set at 50%. FIG. 95 is the crystal structure of pattern 11, wherein the view is set to a void view of the a-axis. The crystal structure was dissolved as described in Example 25. Non-hydrogen atoms are shown as thermal ellipsoids with probability levels set at 50%. 96 is a comparison of the simulated XRPD pattern of pattern 11 and the XRPD pattern of pattern 1. FIG. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts. 97 is the crystal structure of Pattern 1 produced from the x-ray crystallization discussed in Example 27. 98 is the crystal structure of Pattern 1 resulting from the x-ray crystallization discussed in Example 27, with hydrogen bonding explicitly shown. 99 is an overlay of the experimentally determined XRPD diffraction pattern of Pattern 1 and a simulated diffraction pattern corresponding to the crystal structure shown in FIG. 97 . The difference between these two lines is shown on the bottom line. Because the bottom line is nearly flat, the simulations strongly suggest that the crystal structure corresponds to the XRPD pattern. Figure 100 is an XRPD diffraction pattern of a freeze-dried Compound 1 dihydrochloride composition comprising mannitol and citric acid. Crystallization was performed as described in Example 28 and Table 42. The x-axis is 2Θ measured in degrees and the y-axis is intensity measured in counts.

Claims (76)

A crystalline compound having the following structure:

; which is the dihydrochloride. The crystalline compound of claim 1, wherein the X-ray powder diffraction (XRPD) pattern comprises at least three 2Θ values selected from the group consisting of: 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0 ±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°. The crystalline compound of claim 2, wherein the XRPD pattern comprises at least four 2Θ values selected from the group consisting of: 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1± 0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°. The crystalline compound of claim 2, wherein the XRPD pattern comprises at least five 2θ values selected from the group consisting of: 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1± 0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°. The crystalline compound of claim 2, wherein the XRPD pattern comprises at least six 2θ values selected from the group consisting of: 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1± 0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°. The crystalline compound of claim 2, wherein the XRPD pattern comprises the 2Θ value of at least 9.6±0.2°. The crystalline compound of claim 2, wherein the XRPD pattern comprises the 2Θ values of at least 9.6±0.2°, 19.8±0.2° and 21.3±0.2°. A composition comprising the crystalline compound of any one of claims 1 to 7, mannitol and citric acid. A pharmaceutical composition comprising the crystalline compound of claims 1 to 7 and a pharmaceutically acceptable excipient. The pharmaceutical composition of claim 9, wherein the pharmaceutically acceptable excipient comprises mannitol. The pharmaceutical composition of claim 9, wherein the pharmaceutically acceptable excipient comprises citric acid. The pharmaceutical composition of claim 9, wherein the pharmaceutically acceptable excipients comprise mannitol and citric acid. The pharmaceutical composition of claim 9, comprising about 200 to 600 mg of the crystalline compound. The pharmaceutical composition of claim 9, comprising about 300 mg of the crystalline compound. The pharmaceutical composition of claim 9, comprising about 349 mg of the crystalline compound. The pharmaceutical composition of claim 10, comprising about 250 to 350 mg of mannitol. The pharmaceutical composition of claim 10, comprising about 300 mg of mannitol. The pharmaceutical composition of claim 11, comprising about 50 to 100 mg of citric acid. The pharmaceutical composition of claim 11, comprising about 76 mg of citric acid. The pharmaceutical composition of claim 12, comprising about 250 to 350 mg of mannitol. The pharmaceutical composition of claim 12, comprising about 300 mg of mannitol. The pharmaceutical composition of claim 12, comprising about 50 to 100 mg of citric acid. The pharmaceutical composition of claim 12, comprising about 76 mg of citric acid. The pharmaceutical composition of claim 12, comprising about 300 mg of mannitol and about 76 mg of citric acid. The pharmaceutical composition of claim 24, comprising about 300 mg of the crystalline compound. The pharmaceutical composition of claim 12, comprising the crystalline compound in a dose of about 150 mg/m ² to about 350 mg/m ² . The pharmaceutical composition of claim 12, comprising the crystalline compound at a dose of about 240 mg/m ² . A pharmaceutical composition formed by dissolving the pharmaceutical composition of any one of claims 1 to 27 in a solvent. The pharmaceutical composition of claim 28, wherein the solvent is water. The pharmaceutical composition of claim 28, wherein the solvent is an aqueous sodium chloride solution. The pharmaceutical composition of claim 30, wherein the sodium chloride concentration is between about 0.1% and 2%. The pharmaceutical composition of claim 30, wherein the sodium chloride concentration is about 0.9%. The pharmaceutical composition of claim 28, wherein the solvent is an aqueous dextrose solution. The pharmaceutical composition of claim 33, wherein the dextrose concentration is between about 1% and 10%. The pharmaceutical composition of claim 33, wherein the dextrose concentration is about 5%. The pharmaceutical composition of any one of claims 28 to 35, wherein about 10 to 30 mL of solvent is present. The pharmaceutical composition of any one of claims 28 to 35, wherein about 19.5 mL of solvent is present. A method of treating a condition mediated by CDK4 or CDK6, comprising administering to a patient in need thereof an effective amount of a compound of the pharmaceutical composition of any one of claims 1-37. A method of treating cancer comprising administering to a patient in need thereof an effective amount of a compound of the pharmaceutical composition of any one of claims 1-37. A method of reducing the effect of chemotherapy on healthy cells in a patient undergoing treatment for cancer or abnormal cell proliferation, the method comprising administering to the individual an effective amount of at least one chemotherapeutic agent and an effective amount of as in claims 1 to 37 The compound of any one of the pharmaceutical compositions. The method of claim 40, wherein the healthy cells are hematopoietic stem cells or hematopoietic precursor cells. The method of any one of claims 40 to 41, wherein the chemotherapeutic agent is carboplatin. The method of any one of claims 40 to 41, wherein the chemotherapeutic agent is cisplatin. The method of any one of claims 42 to 43, wherein the method further comprises administering etoposide. The method of any one of claims 40 to 41, wherein the chemotherapeutic agent is topotecan. The method of any one of claims 38 to 45, wherein the patient is a human. A crystalline compound having the following structure:

It is the dihydrochloride salt dihydrate. The crystalline compound of claim 47, wherein the X-ray powder diffraction (XRPD) pattern comprises at least three 2Θ values selected from the group consisting of: 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0 ±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°. The crystalline compound of claim 48, wherein the XRPD pattern comprises at least four 2θ values selected from the group consisting of: 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1± 0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°. The crystalline compound of claim 48, wherein the XRPD pattern comprises at least five 2θ values selected from the group consisting of: 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1± 0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°. The crystalline compound of claim 48, wherein the XRPD pattern comprises at least six 2Θ values selected from the group consisting of: 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2°, 26.1± 0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°. The crystalline compound of claim 48, wherein the XRPD pattern comprises the 2Θ value of at least 9.6±0.2°. The crystalline compound of claim 48, wherein the XRPD pattern comprises the 2Θ values of at least 9.6±0.2°, 19.8±0.2° and 21.3±0.2°. A freeze-dried powder comprising a compound having the structure:

It is the dihydrochloride salt, which optionally includes the hydrate. The freeze-dried powder of claim 54, wherein the X-ray powder diffraction (XRPD) pattern of the compound comprises at least three 2θ values selected from the group consisting of: 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2± 0.2°, 24.0±0.2°, 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°. The freeze-dried powder of claim 55, wherein the XRPD pattern of the compound comprises at least four 2Θ values selected from the group consisting of: 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2° , 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°. The freeze-dried powder of claim 55, wherein the XRPD pattern of the compound comprises at least five 2Θ values selected from the group consisting of: 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2° , 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°. The freeze-dried powder of claim 55, wherein the XRPD pattern of the compound comprises at least six 2Θ values selected from the group consisting of: 9.6±0.2°, 21.3±0.2°, 19.8±0.2°, 12.2±0.2°, 24.0±0.2° , 26.1±0.2°, 19.3±0.2°, 17.6±0.2° and 28.6±0.2°. The freeze-dried powder of claim 55, wherein the XRPD pattern of the compound comprises the 2Θ value of at least 9.6±0.2°. The freeze-dried powder of claim 55, wherein the XRPD pattern of the compound comprises the 2Θ values of at least 9.6±0.2°, 19.8±0.2° and 21.3±0.2°. A pharmaceutical composition comprising the crystalline compound of claim 1 and a pharmaceutically acceptable excipient. The pharmaceutical composition of claim 61, wherein the pharmaceutical composition is suitable for intravenous delivery. The pharmaceutical composition of claim 61, comprising from about 200 mg to about 600 mg of the crystalline compound. The pharmaceutical composition of claim 61, comprising about 300 mg of the crystalline compound. The pharmaceutical composition of claim 61, comprising the crystalline compound in a dose of about 150 mg/m ² to about 350 mg/m ² . The pharmaceutical composition of claim 61, further comprising about 300 mg of mannitol and about 76 mg of citric acid. The pharmaceutical composition of claim 61, comprising the crystalline compound at a dose of about 240 mg/m ² . A pharmaceutically acceptable reconstituted solution of the freeze-dried powder of claim 54. The pharmaceutical solution of claim 68, wherein the solution is an aqueous solution. The pharmaceutical solution of claim 69, wherein the pharmaceutical composition is suitable for intravenous delivery. The pharmaceutical solution of claim 69, comprising from about 200 mg to about 600 mg of the freeze-dried powder. The pharmaceutical solution of claim 69, comprising about 300 mg of the freeze-dried powder. The pharmaceutical solution of claim 69, comprising the freeze-dried powder in a dose of about 150 mg/m ² to about 350 mg/m ² . The pharmaceutical solution of claim 69, comprising the freeze-dried powder at a dose of about 240 mg/m ² . The pharmaceutical solution of claim 69, further comprising about 300 mg of mannitol and about 76 mg of citric acid. The pharmaceutical solution of claim 69, further comprising sodium hydroxide or hydrochloric acid.

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