Method for producing benzoates of terphenyl compounds

Abstract

A method for making the benzoate salt of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]-2-fluoro-benzonitrile, designated compound (A), and methods for using compound (A) are provided.

Description

[Technical Field]

[0001] This application claims the benefit of priority under 35 USC § 119(e) to U.S. Provisional Application No. 63 / 271,975, filed October 26, 2021, which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to a method for producing a solid benzoate salt of a compound that modulates lysine-specific histone demethylase 1A (LSD1), pharmaceutical compositions thereof, and medical uses thereof. [Background technology]

[0003] The compound 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]-2-fluoro-benzonitrile (referred to herein as compound (A)) is a potent LSD1 inhibitor and is used as an antitumor agent or an agent for the prevention and / or treatment of cancer. The multi-step synthetic route typically employed to synthesize compound (A) and / or its benzoate salts results in a final product containing impurities derived from various synthetic steps.

[0004] It is desirable that such LSD1 inhibitors can be synthesized in large quantities with good reproducibility and high purity. Summary of the Invention

[0005] The present disclosure provides a method for preparing the benzoate salt of compound (A) by solvent exchange without a solvent removal step to obtain a dry solid intermediate, which reduces impurities in the final product and is amenable to scalability. [Means for solving the problem]

[0006] The present disclosure provides a method for producing a benzoate salt of the following compound (A): [ka] (i) extracting the compound (A) from a reaction solution containing the following compound (A) into 2-methyltetrahydrofuran (2-Me THF) to obtain a 2-Me THF solution of the compound (A); [ka] (ii) solvent exchange from 2-Me THF to isopropyl alcohol (IPA) to obtain an IPA solution of compound (A); and (iii) adding benzoic acid to a solution of Compound (A) in IPA under conditions sufficient to obtain a benzoate salt of Compound (A); and a manufacturing method comprising:

[0007] The present disclosure also provides a benzoate salt of Compound (A) having a content of certain impurities less than 0.5% a / a, as described in the detailed description of the invention. [Brief explanation of the drawings]

[0008] Embodiments of the present invention will now be illustrated by way of example with reference to the accompanying drawings.

[0009] [Figure 1A] 1 is an optical microscope image (polarized light microscope, PLM) of the benzoate salt of compound (A) obtained by the process described herein.

[0010] [Figure 1B] 1 is a scanning electron microscope (SEM) image of the benzoate salt of compound (A) obtained by the process described herein. DETAILED DESCRIPTION OF THE INVENTION

[0011] 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]-2-fluoro-benzonitrile, referred to herein as compound (A), is represented by the following formula: [ka]

[0012] Compound (A) is an inhibitor of LSD1. Its synthesis and use method are described in International Publication No. WO2017 / 090756, the entire contents of which are incorporated herein by reference. Also, International Publication No. WO2021 / 095835 describes the benzoate salt of compound (A), the entire contents of which are incorporated herein by reference.

[0013] In prior art preparations, compound (A) was isolated as a dry solid before conversion to the benzoate salt. In contrast, the preparation described herein involves solvent exchange without isolating compound (A) as a free base solid. The preparation described herein provides an overall yield of 20% and is scalable and reproducible.

[0014] In the synthesis methods of compound (A) disclosed in the prior art, impurities such as the following are typically present in the final product: [ka]

[0015] Furthermore, prior art manufacturing methods have not provided benzoate salt of compound (A) with optimal morphology and / or a desired level of purity, whereas the manufacturing method described herein reduces the generation of impurities and provides better control over the morphology of the final product of benzoate salt of compound (A). 1.Definition

[0016] As used herein, the following words and phrases generally are intended to have the meanings set forth below, unless the context in which such words and phrases are used indicates otherwise.

[0017] The term "comprise" and variations thereof, such as "comprises" and "comprising," are to be construed in an open and inclusive sense, i.e., "including, but not limited to." Furthermore, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, reference to "the compound" includes a plurality of such compounds, and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0018] As used herein, the term "about" of a value or parameter includes embodiments of the value or parameter itself. In certain embodiments, the term "about" includes the indicated amount ±10%. In other embodiments, the term "about" includes the indicated amount ±5%. In certain other embodiments, the term "about" includes the indicated amount ±2.5%. In certain other embodiments, the term "about" includes the indicated amount ±1%. Additionally, the term "about X" includes the description "X".

[0019] Throughout this disclosure, recitation of numerical ranges is intended to serve as a shorthand method of referring individually to each separate value falling within the range, including the values ​​defining the range, and each separate value is incorporated herein as if it were individually recited herein.

[0020] The present specification provides a benzoate salt of Compound (A), and solvates or hydrates thereof. In one embodiment, when referring to the benzoate salt of Compound (A), and solvates or hydrates thereof, it means that at least 95 to 99% (e.g., at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.8%) of the benzoate salt of Compound (A) and solvates or hydrates thereof in the composition are in said form.

[0021] The term "solvate" refers to a complex formed by the combination of solvent molecules with solute molecules or ions. The solvent can be an organic compound, an inorganic compound, or a mixture of both. As used herein, the term "solvate" includes "hydrates" (i.e., complexes formed by the combination of water molecules with solute molecules or ions), hemihydrates, channel hydrates, and the like. Examples of solvents include, but are not limited to, methanol, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, water, and the like. In general, solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure.

[0022] The formulas or structures shown herein, including Compound (A), are intended to represent unlabeled as well as isotopically labeled forms of the compounds. For any given atom, isotopes may be present essentially in proportions according to their natural occurrence, or one or more specific atoms may be enriched with one or more isotopes using synthetic methods known to those skilled in the art. Thus, hydrogen may be, for example, 1 H, 2 H, 3 H; carbon, for example, 11 C. 12 C. 13 C. 14 C; oxygen includes, for example, 16 O. 17 O. 18 O; nitrogen includes, for example, 13 N, 14 N, 15 Contains N; sulfur, e.g. 32 S, 33 S, 34 S, 35 S, 36 S, 37 S, 38 S; fluorine includes, for example, 17 F, 18 F, 19 F; chloro includes, for example, 35 Cl, 36 Cl, 37 Cl, 38 Cl, 39 Contains Cl.

[0023] As used herein, the terms "treatment," "treatment," "therapy," and the like mean the administration of an amount of material, e.g., one or more solid, crystalline, or polymorphic forms of Compound (A) described herein, in an amount effective to prevent, alleviate, or ameliorate one or more symptoms or conditions of a disease and / or prolong the survival of the subject being treated.

[0024] The term "administration" refers to oral administration, administration as a suppository, topical contact, intravenous administration, intraperitoneal administration, intramuscular administration, intranasal administration, subcutaneous administration, or implantation of a sustained-release device (e.g., a mini-osmotic pump) into a subject. Administration may be by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other delivery modes include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like.

[0025] As used herein, the term "modulation" or "modulating" refers to the effect of changing biological activity, particularly biological activity associated with a particular biomolecule, such as LSD1. For example, an agonist or antagonist of a particular biomolecule modulates the activity of that biomolecule, e.g., LSD1, by increasing (e.g., agonist, activator) or decreasing (e.g., antagonist, inhibitor) the activity of that biomolecule. Such activity is typically measured in terms of the inhibitory concentration (IC) of the respective compound, e.g., an inhibitor or activator for LSD1. 50 ) or effective concentration (EC 50 ) is shown.

[0026] As used herein, the term "LSD1-mediated disease or condition" refers to a disease or condition in which the biological function of LSD1 and its variants influences the onset, course, and / or symptoms or condition of the disease, and / or in which modulation of LSD1 alters the onset, course, and / or symptoms or condition of the disease. LSD1-mediated diseases or conditions include diseases or conditions in which modulation of LSD1 provides a therapeutic benefit, for example, in which treatment with a compound comprising one or more solid, crystalline, or polymorphic forms of Compound (A) described herein provides a therapeutic benefit to a subject suffering from or at risk for the disease or condition.

[0027] As used herein, the term "composition" refers to a pharmaceutical preparation containing at least one pharmaceutically active compound (including any solid form) suitable for administration to a subject for therapeutic purposes. The composition may include at least one pharmaceutically acceptable ingredient to modify the form of the compound, such as a suitable carrier or excipient.

[0028] As used herein, the term "subject" or "patient" refers to a living organism treated with the compounds described herein, including, but not limited to, mammals such as humans, other primates, sport animals, commercial animals such as cattle, farm animals such as horses, or companion animals such as dogs and cats.

[0029] The term "pharmaceutically acceptable" indicates that the indicated material does not have properties that would cause a reasonable medical professional to avoid administering it to a patient, taking into account the disease or condition to be treated and the respective route of administration. For example, injectable solutions generally require that such materials be essentially sterile.

[0030] As used herein, the terms "therapeutically effective" or "effective amount" refer to a material or amount of material that is effective in preventing, alleviating, or ameliorating one or more symptoms of a disease or condition and / or prolonging the survival of the subject being treated. A therapeutically effective amount will vary depending on the compound, the disease or condition and its severity, and the age, weight, etc., of the mammal being treated. For example, an effective amount is an amount sufficient to bring about a beneficial or desired clinical result. An effective amount can be provided once in a single administration, or in an amount that provides an effective amount over several administrations. The precise determination of what constitutes an effective amount can be based on factors individual to each subject, including the subject's size, age, injury, and / or the disease or injury being treated, and the length of time since the onset of the injury or the onset of the disease. One of ordinary skill in the art can determine the effective amount for a given subject based on these considerations, as is routine in the art.

[0031] In some embodiments, "substantially pure" means that in the referenced material (e.g., Compound (A) or the benzoate salt of Compound (A)), at least 99.9% of the material is the referenced polymorph. In some embodiments, "substantially pure" means that in the referenced material (e.g., Compound (A) or the benzoate salt of Compound (A)), at least 99.5% of the material is the referenced polymorph. In some embodiments, "substantially pure" means that in the referenced material (e.g., Compound (A) or the benzoate salt of Compound (A)), at least 99% of the material is the referenced polymorph. In some embodiments, "substantially pure" means that in the referenced material (e.g., Compound (A) or the benzoate salt of Compound (A)), at least 98% of the material is the referenced polymorph. In some embodiments, "substantially pure" means that in the referenced material (e.g., Compound (A) or the benzoate salt of Compound (A)), at least 97% of the material is the referenced polymorph. In some embodiments, "substantially pure" means that at least 96% of the material is the referenced polymorph in the referenced material (e.g., Compound (A) or the benzoate salt of Compound (A)). In some embodiments, "substantially pure" means that at least 95% of the material is the referenced polymorph in the referenced material (e.g., Compound (A) or the benzoate salt of Compound (A)).

[0032] By "substantially free of aqueous NaOH" is meant that in a mixture of (A) in 2-Me THF after step (ig) described herein (e.g., a mixture consisting of (A) dissolved in 2-Me THF), the weight of NaOH in the mixture is less than 5%, less than 1%, or less than 0.1% compared to the total weight of the mixture.

[0033] In the context of using, testing, or screening compounds that are or may be modulators, the term "contacting" means that the compound is brought into sufficient proximity with a particular molecule, complex, cell, tissue, organism, or other particular substance so that a potential binding interaction and / or chemical reaction between the compound and the other particular substance can occur.

[0034] The abbreviations used in this specification have the following meanings: [Table 1] 2. Method for producing benzoate of compound (A)

[0035] In some embodiments, a method for preparing a benzoate salt of compound (A) is provided, comprising: [ka] (i) extracting compound (A) from a reaction solution containing compound (A) into 2-methyltetrahydrofuran (2-Me THF) to obtain a 2-Me THF solution of compound (A); and (ii) Solvent exchange from 2-Me THF to isopropyl alcohol (IPA) to obtain an IPA solution of compound (A); The present invention provides a manufacturing method comprising the steps of: (ii) The peroxide content in IPA is 30 ppm or less, 20 ppm or less, or 10 ppm or less.

[0036] In one embodiment, a method for producing a benzoate salt of compound (A) is provided, comprising the steps of: [ka] (i) extracting compound (A) from a reaction solution containing compound (A) into 2-methyltetrahydrofuran (2-Me THF) to obtain a 2-Me THF solution of compound (A); [ka] (ii) solvent exchange from 2-Me THF to isopropyl alcohol (IPA) to obtain an IPA solution of compound (A); and (iii) adding benzoic acid to a solution of Compound (A) in IPA under conditions sufficient to obtain a benzoate salt of Compound (A); The present invention provides a manufacturing method comprising the steps of:

[0037] In one embodiment, the method further comprises the step of recrystallizing the benzoate salt of Compound (A). The crystallization can be carried out in IPA or any other suitable solvent. Optionally, recrystallization can be carried out twice.

[0038] In some embodiments, the peroxide content of the IPA is 10 ppm or less before introducing the IPA into the reaction mixture. In some embodiments, the peroxide content of the IPA is 20 ppm or less before introducing the IPA into the reaction mixture. In some embodiments, the peroxide content of the IPA is 30 ppm or less before introducing the IPA into the reaction mixture.

[0039] In some embodiments, compound (A) in the reaction mixture is obtained by contacting compound (B) with hydrochloric acid in a solvent. [ka] In some embodiments, the solvent is methanol, hi some embodiments, the solvent is water, methanol, ethanol, isopropanol, or THF.

[0040] In some embodiments, the reaction mixture is heated to 15-50°C to deprotect compound (B) and obtain compound (A). In some embodiments, the reaction mixture is heated to 40-50°C to deprotect compound (B) and obtain compound (A). In these embodiments, the reaction mixture is stirred for 1-8 hours to deprotect compound (B) and obtain compound (A). In these embodiments, the reaction mixture is stirred for 3-6 hours to deprotect compound (B) and obtain compound (A). In these embodiments, the reaction mixture is stirred for about 5 hours to deprotect compound (B) and obtain compound (A).

[0041] In some embodiments, the step of deprotecting compound (B) to obtain compound (A) comprises: (ia) cooling the reaction mixture and adding water and methyl tert-butyl ether (MTBE) to the reaction mixture; (ib) separating the organic layer containing MTBE from the aqueous layer; (ic) adding 2-Me THF to the aqueous layer from step (ib) and adding aqueous NaOH to the mixture comprising 2-Me THF and the aqueous layer; (id) separating the organic layer containing 2-Me THF; (ie) washing the organic layer of step (id) with 20% w / w NaCl solution; (if) washing the organic layer of step (ie) with water; and (ig) optionally repeating step (if) one or more times to obtain a solution of compound (A) in 2-Me THF.

[0042] In some embodiments, in step (ia), the reaction mixture is cooled to 20-25°C and optionally stirred for about 1 hour to about 24 hours, about 1 hour to about 12 hours, about 1 hour to about 6 hours, or about 1 hour to about 4 hours before adding water and MTBE. In some embodiments, in step (ia), the reaction mixture is cooled to 20-25°C and optionally stirred for about 2 hours to about 24 hours before adding water and MTBE. In some embodiments, in step (ia), the reaction mixture is cooled to 20-25°C and optionally stirred for about 1 hour to about 2 hours before adding water and MTBE. In some embodiments, in step (ia), the reaction mixture is cooled to 20-25°C and optionally stirred for an additional period of time until the reaction is complete before adding water and MTBE.

[0043] In some embodiments, in step (ic), aqueous NaOH solution is added to the mixture until the pH is at least 13. In some embodiments, the pH is at least 12. In some embodiments, the pH is at least 11. In some embodiments, the pH is at least 10. In some embodiments, the pH is at least 9. After separating the layers in step (id), the organic layer is washed with a NaCl solution, and after layer separation, the organic layer is washed with water. This washing of the organic layer with water in step (if) removes NaOH from the organic layer after step (ie). One or more water washes may be required to obtain an organic layer comprising a 2-Me THF solution of compound (A) that is substantially free of NaOH. In some embodiments, aqueous NaOH solution is added to the mixture in step (ic) so that the pH of the mixture is about 7 to about 13, about 8 to about 13, about 9 to about 13, about 10 to about 13, about 11 to about 13, or about 12 to about 13. In some embodiments, the pH of the mixture upon addition of the aqueous NaOH solution affects the overall yield of the process for producing the benzoate salt of Compound (A). In some embodiments, removing NaOH so that residual NaOH is less than 0.1% w / w of the mixture affects the overall yield of the process for producing the benzoate salt of Compound (A).

[0044] In some embodiments, in step (iii) of converting compound (A) to a benzoate salt of compound (A), step (iii) further comprises heating the reaction mixture to a temperature of about 70°C to about 80°C and maintaining the reaction mixture at about 70°C to about 80°C for about 30 minutes to about 60 minutes. In some embodiments, the heated reaction mixture is cooled to a temperature of about 50°C to about 55°C. In some embodiments, a slurry of seed crystals of the benzoate salt of compound (A) in IPA is added to the cooled reaction mixture. In some embodiments, the seed crystals are prepared according to the methods described in International Publication No. WO 2021 / 095835.

[0045] In some embodiments, after adding the seed crystals, the reaction mixture is subjected to a cooling and heating cycle, then cooled and stirred at the cooled temperature for about 4 to 10 hours (e.g., 6 hours). In some embodiments, the cooling and heating cycle consists of an initial cooling cycle of: (iii-a) The reaction mixture is cooled to a temperature of about 10°C to about 30°C, about 16°C to about 24°C, or about 20°C over about 150 minutes to about 400 minutes, about 200 minutes to about 300 minutes, or about 200 minutes to about 250 minutes, and then stirred at the cooled temperature for about 20 minutes, about 30 minutes, about 45 minutes, or about 60 minutes.

[0046] In some embodiments, the cooling and heating cycle consists of the following cycle: (iii-b) The reaction mixture is heated to a temperature of about 60°C to about 75°C, about 65°C to about 70°C, or about 62°C to about 66°C over a period of about 200 minutes to about 400 minutes, about 250 minutes to about 350 minutes, or about 280 minutes to about 320 minutes.

[0047] In some embodiments, the cooling and heating cycles include the following additional cycles: (iii-c) The cooling and heating steps (iii-a) and (iii-b) are repeated once or twice.

[0048] In some embodiments, the cooling and heating cycles include the following additional cycles: (iii-d) The reaction mixture is cooled to a temperature of about 10°C to about 30°C, about 16°C to about 24°C, or about 20°C over about 150 minutes to about 400 minutes, about 250 minutes to about 350 minutes, or about 280 minutes to about 320 minutes, and then stirred at the cooling temperature of about 10°C to about 30°C, about 16°C to about 24°C, or about 20°C for about 2 hours to about 10 hours, about 4 hours to about 8 hours, or about 6 hours.

[0049] In some embodiments, after adding the seed crystals, the reaction mixture is subjected to a cooling and heating cycle, and then cooled to a temperature of about 16° C. to about 24° C. and stirred for about 6 hours at a temperature of about 16° C. to about 24° C. In some embodiments, the cooling and heating cycle comprises the following steps: (iii-a) cooling the reaction mixture to a temperature of about 16°C to about 24°C over about 200 minutes to about 250 minutes, and then stirring at a temperature of about 16°C to about 24°C for about 30 minutes; (iii-b) heating the reaction mixture to about 62°C to about 66°C over about 280 minutes to about 320 minutes; (iii-c) repeating the cooling and heating of steps (iii-a) and (iii-b) once or twice; and (iii-d) The reaction mixture is cooled to a temperature of about 16°C to about 24°C over about 280 to 320 minutes, and stirred at a temperature of about 16°C to about 24°C for about 6 hours.

[0050] In some embodiments of the methods for preparation described herein, the benzoate salt of compound (A) is recrystallized from ethanol, butanol, IPA, acetonitrile, TBME, ethyl acetate, isopropyl acetate, methyl ethyl ketone (MEK), proprionitrile, or toluene. In some embodiments of the methods for preparation described herein, the benzoate salt of compound (A) is first crystallized from IPA, followed by further recrystallization from IPA or other solvents, including, but not limited to, ethanol, butanol, acetonitrile, TBME, ethyl acetate, isopropyl acetate, methyl ethyl ketone (MEK), proprionitrile, or toluene.

[0051] In some embodiments of the processes described herein, the recrystallized benzoate salt of Compound (A) has a total content of any one of the following compounds, or a combination thereof, of 0.7% a / a or less, or 0.5% a / a or less, or 0.3% a / a or less: [ka]

[0052] In some embodiments, a method for preparing a benzoate salt of compound (A) is provided, comprising: [ka] (i) contacting compound (B) with hydrochloric acid to obtain compound (A); [ka] [ka] (ii) extracting compound (A) into 2-methyltetrahydrofuran (2-Me THF) to obtain a 2-Me THF solution of compound (A); (iii) performing a solvent exchange from 2-Me THF to isopropyl alcohol (IPA); (iv) adding benzoic acid to a mixture containing IPA under conditions sufficient to provide a benzoate salt of compound (A); and (v) recrystallizing the benzoate salt of compound (A); The present invention provides a manufacturing method comprising the steps of:

[0053] Provided herein is a benzoate salt of Compound (A) prepared according to any of the preparation methods described herein.

[0054] Provided herein is a benzoate salt of Compound (A) having a total content of any of the following compounds, or a combination thereof, of 0.7% a / a or less, or 0.5% a / a or less, or 0.3% a / a or less: [ka]

[0055] In some embodiments, there is provided a method for preparing a benzoate salt of Compound (A), comprising the steps of: contacting compound (C) or a salt thereof with compound (D) or a salt thereof under conditions sufficient to obtain compound (B). [ka] [ka] [ka]

[0056] In some embodiments, there is provided a method for preparing compound (C) or a salt thereof, comprising the steps of: [ka] (i) contacting compound (G) or a salt thereof with compound (F) or a salt thereof under conditions sufficient to obtain compound (E); and [ka] [ka] [ka] (ii) Deprotecting compound (E) or a salt thereof to obtain compound (C) or a salt thereof.

[0057] In some embodiments, there is provided a method for preparing compound (G) or a salt thereof, comprising the steps of: [ka] (i) contacting compound (L) or a salt thereof with compound (K) or a salt thereof under conditions sufficient to obtain compound (J); [ka] [ka] [ka] (ii) protecting compound (J) or a salt thereof to obtain compound (H) or a salt thereof; and [ka] (iii) Boronating compound (H) or a salt thereof to obtain compound (G) or a salt thereof.

[0058] In some embodiments, a method for preparing compound (A) is provided according to Scheme 1. Compound (A) can be converted to the benzoate salt of compound (A) according to the methods described herein. Scheme 1 [ka]

[0059] Compound (C) and other intermediates in Scheme 1 above can be prepared according to the methods described in U.S. Pat. No. 10,723,742, which is incorporated herein by reference. Compound (C) is coupled with compound (D) to give compound (B). Compound (B) is deprotected to give compound (A), which is then converted to the benzoate salt of compound (A) using the methods described herein. 3. Pharmaceutical Compositions, Kits, and Administration Methods

[0060] Compound (A) or a benzoate salt thereof described herein can be included in a pharmaceutical composition. In some embodiments, a pharmaceutical composition is provided that includes a benzoate salt of Compound (A) prepared according to any of the preparation methods described herein.

[0061] In some embodiments, a pharmaceutical composition is provided comprising a benzoate salt of Compound (A), wherein the total content of any one of the following compounds, or a combination thereof, is 0.7% a / a or less, or 0.5% a / a or less, or 0.3% a / a or less: [ka]

[0062] In some embodiments, a pharmaceutical composition is provided comprising a benzoate salt of Compound (A), wherein the total amount of impurities is 4.0% a / a or less.

[0063] In some embodiments, a pharmaceutical composition is provided comprising the compound (A) or its benzoate salt described herein and one or more pharmaceutically acceptable vehicles, such as carriers, adjuvants, and excipients. Suitable pharmaceutically acceptable vehicles can include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants. Such compositions are prepared by methods well known in the pharmaceutical arts. For example, they are described in Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th Edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd Edition (GS Banker & CT Rhodes, Eds.). The pharmaceutical composition can be administered alone or in combination with other therapeutic agents.

[0064] Some embodiments relate to pharmaceutical compositions comprising a therapeutically effective amount of Compound (A) or a benzoate salt thereof.

[0065] Some embodiments relate to pharmaceutical compositions comprising Compound (A) or a benzoate salt thereof described herein and one or more pharmaceutically acceptable carriers. In one embodiment, the pharmaceutical composition comprises Compound (A), wherein at least 95% of Compound (A) is the benzoate salt of Compound (A) described herein. In one embodiment, the pharmaceutical composition comprises Compound (A), wherein at least 96% of Compound (A) is the benzoate salt of Compound (A) described herein. In one embodiment, the pharmaceutical composition comprises Compound (A), wherein at least 97% of Compound (A) is the benzoate salt of Compound (A) described herein. In one embodiment, the pharmaceutical composition comprises Compound (A), wherein at least 98% of Compound (A) is the benzoate salt of Compound (A) described herein. In one embodiment, the pharmaceutical composition comprises Compound (A), wherein at least 99% of Compound (A) is the benzoate salt of Compound (A) described herein. In one embodiment, the pharmaceutical composition comprises Compound (A), wherein at least 99.5% of Compound (A) is the benzoate salt of Compound (A) described herein. In one embodiment, the pharmaceutical composition comprises Compound (A), wherein at least 99.9% of Compound (A) is the benzoate salt of Compound (A) described herein.

[0066] The benzoate salt of compound (A) described in the present specification can be processed into various forms of pharmaceutical compositions, for example, oral preparations such as tablets, capsules, granules, fine granules, powders, and dry syrups, as well as suppositories, inhalants, nasal drops, ointments, patches, and aerosols, with or without being pulverized.

[0067] In some embodiments, the composition comprises a pharmaceutically acceptable carrier or excipient, such as a filler, binder, disintegrant, lubricant, complexing agent, solubilizer, and surfactant, which may be selected to facilitate administration of Compound (A) via a particular route. Examples of carriers include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, and sucrose, starches, cellulose derivatives, gelatin, lipids, liposomes, nanoparticles, and the like. Carriers also include physiologically compatible liquids as solvents or suspensions, including, for example, sterile solutions of water for injection (WFI), saline, dextrose solution, Hank's solution, Ringer's solution, vegetable oils, mineral oils, animal oils, polyethylene glycol, liquid paraffin, and the like. Examples of excipients include colloidal silicon dioxide, silica gel, talc, magnesium silicate, calcium silicate, sodium aluminosilicate, magnesium trisilicate, powdered cellulose, macrocrystalline cellulose, carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, sodium benzoate, calcium carbonate, magnesium carbonate, aluminum stearate, calcium stearate, magnesium stearate, zinc stearate, sodium stearyl fumarate, syloid, Stearowet C, magnesium oxide, starch, sodium starch glycolate, glyceryl monostearate, glyceryl dibehenate, glyceryl palmitostearate, hydrogenated vegetable oil, hydrogenated cottonseed oil, castor oil, mineral oil, polyethylene glycol (e.g., PEG-100),4000-8000), polyoxyethylene glycol, poloxamer, povidone, crospovidone, croscarmellose sodium, alginic acid, casein, methacrylate divinylbenzene copolymer, docusate sodium, cyclodextrin (e.g., 2-hydroxypropyl-δ-cyclodextrin), polysorbate (e.g., polysorbate 80), cetrimide, TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate), magnesium lauryl sulfate, sodium lauryl sulfate, polyethylene glycol ether, difatty acid ester of polyethylene glycol, or polyoxyalkylene sorbitan fatty acid ester (e.g., polyoxyethylene sorbitan ester Tween (registered trademark)

[0033] Examples of suitable sugars include sorbitan fatty acid esters (e.g., sorbitan fatty acid esters from fatty acids such as oleic acid, stearic acid, or palmitic acid), polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters (e.g., sorbitan fatty acid esters from fatty acids such as oleic acid, stearic acid, or palmitic acid), mannitol, xylitol, sorbitol, maltose, lactose, lactose monohydrate, or lactose spray-dried, sucrose, fructose, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, dextrates, dextran, dextrose, cellulose acetate, maltodextrin, simethicone, polydextrose, chitosan, gelatin, HPMC (hydroxypropyl methylcellulose), HPC (hydroxypropyl cellulose), and hydroxyethyl cellulose.

[0068] Pharmaceutical formulations may be presented in unit dosage forms containing a predetermined amount of active ingredient per unit dose. Such units may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, and more preferably 5 mg to 100 mg of a compound of the present disclosure (as a free acid salt, solvate (including hydrate), or salt, in any form) depending on the condition being treated, the route of administration, and the age, weight, and condition of the patient. Preferred unit dosage formulations are those containing a daily dose, weekly dose, monthly dose, sub-dose, or an appropriate fraction thereof, of the active ingredient. Furthermore, such pharmaceutical formulations can be prepared by any method well known in the pharmaceutical arts.

[0069] Compound (A) or its benzoate salt is usually administered in the form of a pharmaceutical composition. Accordingly, a pharmaceutical composition is provided containing Compound (A) or its benzoate salt described herein and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants, and excipients. Suitable pharmaceutically acceptable vehicles include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants. Such compositions are prepared by methods well known in the pharmaceutical arts. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th Edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd Edition (GS Banker & CT Rhodes, Eds.).

[0070] The pharmaceutical composition may be administered in a single dose or multiple doses. The pharmaceutical composition may be administered by various methods, including, for example, rectal, buccal, intranasal, and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intraarterial injection, intravenous injection, intraperitoneal injection, parenteral administration, intramuscular injection, subcutaneous injection, oral administration, topical administration, or inhalation.

[0071] One mode of administration is parenteral administration, for example, by injection. Pharmaceutical compositions for injection include, for example, aqueous or oily suspensions or emulsions with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0072] When preparing an injection, a pH adjuster, a buffer, a stabilizer, an isotonic agent, a local anesthetic, etc. may be added to the crystalline form of compound (A) as needed, and the resulting mixture may be formulated into a subcutaneous injection, an intramuscular injection, an intravenous injection, etc. according to a conventional method.

[0073] Examples of usable pH adjusters and buffers include sodium citrate, sodium acetate, and sodium phosphate. Examples of usable stabilizers include sodium metabisulfite, EDTA, thioglycolic acid, and thiolactic acid. Examples of usable local anesthetics include procaine hydrochloride and lidocaine hydrochloride. Examples of usable isotonic agents include sodium chloride, glucose, D-mannitol, and glycerin.

[0074] Other modes of administration include oral administration. Administration can be carried out, for example, via capsules or enteric-coated tablets. When preparing pharmaceutical compositions containing at least one compound described herein or its pharmaceutically acceptable salt, isotope-enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, the active ingredient is usually diluted with an excipient and / or enclosed in such a carrier, which can be in the form of a capsule, a sachet, paper, or other container. When an excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material that serves as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (in solid or liquid medium), ointment, soft and hard gelatin capsule, sterile injection solution, and sterile packaged powder.

[0075] Oral solid formulations can be prepared as follows: excipients, optionally together with binders, disintegrants, lubricants, colorants, flavoring agents, etc., are added to the crystalline form of Compound (A), and the resulting mixture is then formulated into tablets, coated tablets, granules, powders, capsules, etc., by methods known to those skilled in the art.

[0076] Examples of excipients include lactose, sucrose, D-mannitol, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, and anhydrous silicic acid. Examples of binders include water, ethanol, 1-propanol, 2-propanol, simple syrup, liquid glucose, liquid alpha-starch, liquid gelatin, D-mannitol, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, and polyvinylpyrrolidone. Examples of disintegrants include dry starch, sodium alginate, powdered agar, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, monoglyceride stearate, and lactose. Examples of lubricants include purified talc, sodium stearate, magnesium stearate, borax, and polyethylene glycol. Examples of colorants include titanium oxide and iron oxide. Examples of flavoring agents include sucrose, bitter orange peel, citric acid, L-tartaric acid, etc. The formulations may further include wetting agents; emulsifying and suspending agents; and preservatives such as methyl- and propylhydroxybenzoates.

[0077] When preparing a liquid preparation for oral administration, a flavoring agent, a buffer, a stabilizer, a flavoring agent, etc. may be added to compound (A) or its benzoate salt described in the present specification, and the resulting mixture may be formulated into an oral liquid preparation, syrup, elixir, etc. according to a conventional method.

[0078] In this case, the same flavoring agents as those mentioned above can be used. Examples of buffering agents include sodium citrate, and examples of stabilizers include tragacanth, gum arabic, gelatin, etc. If necessary, these oral administration preparations can be coated with an enteric coating agent or the like according to methods known in the art, for example, to prolong the effect. Examples of such coating agents include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80 (registered trademark), etc.

[0079] Compositions containing compound (A) or its benzoate salt described herein can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a subject by employing procedures known in the art. Controlled-release drug delivery systems for oral administration (also referred to as controlled-release drug delivery systems) include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Another formulation used in the methods disclosed herein includes transdermal delivery devices ("patches"). Such transdermal patches can be used to infuse the compounds described herein in controlled amounts, either continuously or discontinuously. The construction and use of transdermal patches for drug delivery are well known in the art. Such patches can be constructed for continuous, pulsatile, or on-demand delivery of drugs.

[0080] To prepare solid compositions such as tablets, the primary active ingredient can be mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of Compound (A) or a benzoate salt thereof described herein. These preformulation compositions are referred to as homogeneous because the active ingredient is uniformly dispersed throughout the composition, allowing the composition to be readily subdivided into uniformly effective unit dosage forms such as tablets, pills, and capsules.

[0081] Tablets or pills of Compound (A) or its benzoate salt described herein can be coated or otherwise compounded to prolong their action or to protect them from the acidic conditions of the stomach. For example, the tablets or pills can contain an inner dosage and an outer dosage, the latter in the form of an envelope surrounding the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or be delayed in release. A variety of materials can be used for such enteric layers or coatings, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0082] In another aspect, the present disclosure provides a kit or container comprising Compound (A) or its benzoate salt, in a form described herein, or a pharmaceutical composition described herein. In some embodiments, the compound or composition is packaged, for example, in a vial, bottle, or flask, and may further be packaged, for example, in a box, envelope, or bag. The compound or composition is approved for administration to a mammal, e.g., a human, by the U.S. Food and Drug Administration or a similar regulatory agency. The compound or composition is approved for administration to a mammal, e.g., a human, for a disease or condition mediated by a bromodomain protein. The kit or container described herein can include instructions for use and / or other labeling indicating that the compound or composition is suitable or approved for administration to a mammal, e.g., a human, for a disease or condition mediated by a bromodomain protein. The compound or composition can also be packaged in unit dose or single-dose form, such as a single-dose tablet, capsule, or the like.

[0083] The dosage of the various compounds is determined by the activity of the compounds (in vitro, e.g., the C of compound (A) against the target). 50The dosage can be determined by standard procedures, taking into account factors such as the in vivo activity in animal models (e.g., in vivo activity in animal efficacy models), pharmacokinetic results in animal models (e.g., biological half-life or bioavailability), the age, size, and weight of the subject, and any disorders associated with the subject. The importance of these and other factors is well known to those of skill in the art. Generally, dosages range from about 0.01 to 50 mg / kg, and from about 0.1 to 20 mg / kg of the subject being treated. Multiple doses may be administered.

[0084] The amount of compound (A) or a benzoate thereof contained in each dosage unit form varies depending on the condition of the patient to whom compound (A) or a benzoate thereof is administered, the dosage form, etc. In general, in the case of oral preparations, injections, and suppositories, the amount of the compound of the present disclosure contained per dosage form is preferably 0.05 to 100 mg, 0.01 to 500 mg, and 1 to 100 mg, respectively.

[0085] The daily dosage of the drug in such a dosage form depends on the patient's condition, body weight, age, sex, etc. and cannot be generalized. For example, the daily dosage of the salt of Compound (A) described herein for an adult (body weight: 50 to 70 kg) can be 0.05 to 5000 mg, or 0.1 to 1000 mg; it can be administered once a day, or in divided doses 2 to 4 times a day, or according to any other appropriate administration schedule. 4. Medication

[0086] The specific dosage of compound (A) or its benzoate salt described herein for any particular subject will depend on a variety of factors, including the activity of the particular compound, age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combinations, and the severity of the particular disease in the subject being treated. For example, dosages can be expressed as milligrams of compound described herein per kg of subject body weight (mg / kg). Doses of about 0.1 to 150 mg / kg may be appropriate. In some embodiments, doses of about 0.1 to 100 mg / kg may be appropriate. In other embodiments, doses of 0.5 to 60 mg / kg may be appropriate. In some embodiments, doses of about 0.0001 to about 100 mg / kg of body weight, about 0.001 to about 50 mg of compound / kg of body weight, or about 0.01 to about 10 mg of compound / kg of body weight per day may be appropriate. Normalizing for subject weight is particularly useful when adjusting dosages between subjects of widely differing size, such as when using a drug in both pediatric and adult humans, or when converting an effective dosage in a non-human subject, such as a dog, to a dosage appropriate for a human subject. 5. Adaptive diseases and regulation of LSD1

[0087] Provided herein is a method for treating a lysine-specific histone demethylase 1A (LSD-1)-associated disease or condition in a mammal, comprising administering to the mammal a therapeutically effective amount of compound (A) or a benzoate salt thereof, as described herein, or a composition as described herein.

[0088] In some embodiments, the LSD-1-related disease or condition is cancer.

[0089] In some embodiments, the cancer is a malignant tumor.

[0090] In some embodiments, the cancer is head and neck cancer, esophageal cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, gallbladder cancer, bile duct cancer, biliary tract cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, osteosarcoma, soft tissue sarcoma, leukemia, myelodysplastic syndrome, chronic myeloproliferative disorder, malignant lymphoma, multiple myeloma, skin cancer, brain tumor, or mesothelioma.

[0091] In some embodiments, the cancer is non-small cell lung cancer, small cell lung cancer, leukemia, or myelodysplastic syndrome. In some embodiments, the cancer is acute myeloid leukemia (AML), including relapsed or refractory (r / r) AML.

[0092] In certain embodiments, the present disclosure provides the use of compound (A) or a benzoate salt thereof described herein, or any of the pharmaceutical compositions described herein, in the manufacture of a medicament for the treatment of a disease or condition described herein. In other embodiments, the present disclosure provides compound (A) or a benzoate salt thereof described herein, or any of the pharmaceutical compositions described herein, for use in the treatment of a disease or condition described herein. [Example]

[0093] The present disclosure will be further understood by reference to the following examples, which are intended to be purely exemplary of the present disclosure. The present disclosure is not limited in scope by the exemplified embodiments, which are intended merely as illustrations of single aspects of the disclosure. Any functionally equivalent method is within the scope of the present disclosure. Various modifications of the present disclosure, in addition to those described herein, will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are within the scope of the claims.

[0094] The starting materials may generally be known compounds or may be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Sigma Aldrich (St. Louis, Missouri, USA), Bachem (Torrance, California, USA), and Emka-Chemce (St. Louis, Missouri, USA). In addition, Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 2016), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 2001), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 2019), March's Advanced Organic Chemistry, (John Wiley, and Sons, 8th Edition, 2019), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989) and other standard reference texts can be produced by procedures or modified procedures thereof.

[0095] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.Proper protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting specific functional groups, are well known in the art.For example, many protecting groups are described in TW Greene and PGM Wuts, Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, 1999, and the references cited therein. Example 1: Preparation of benzoate of compound (A)

[0096] Compound (B) and 4.5 vol of methanol were added to a jacketed reactor equipped with a mechanical stirrer. The mixture was heated to approximately 45°C, if necessary, to dissolve compound (B), and then cooled to approximately 35°C. In an auxiliary vessel, 1.2 vol of water and 1.2 vol of 35% w / w HCl were mixed to prepare a 6M HCl solution. 1.3 vol of the prepared 6M HCl solution was added to the reactor while maintaining the reaction temperature at approximately 35°C.

[0097] The reaction mixture was heated to about 45°C (about 40°C to about 50°C) and stirred at about 45°C (about 40°C to about 50°C) for about 4 to 5 hours, after which completion of the reaction and the formation of Compound (A) were confirmed by HPLC. In parallel with HPLC, the reaction mixture was cooled to about 15°C to about 25°C. When in-process control indicated that 99% or more of the starting material had been consumed, the reaction was quenched as follows:

[0098] The reaction mixture was kept at about 20°C to 30°C while 10v of water was added, carefully maintaining the temperature below 30°C (heat release was observed). The reaction mixture was cooled to about 15°C to about 25°C.

[0099] 5 v of MTBE was then added to the reactor while maintaining the temperature below 30° C. The reaction mixture was cooled to about 15° C. to about 25° C. and stirred for about 15 minutes while maintaining the temperature between about 15° C. and about 25° C. (e.g., about 20° C.). The layers were allowed to settle for at least 15 minutes (e.g., 30 minutes) while maintaining the temperature between 20° C. and 25° C. The aqueous layer was then transferred to a container.

[0100] An additional 5 v of MTBE was added to the vessel while maintaining the temperature below 30° C. The reaction mixture was cooled to about 15° C. to about 25° C. and stirred for about 15 minutes while maintaining the temperature between about 15° C. to about 25° C. (e.g., about 20° C.). The layers were allowed to settle for at least 15 minutes (e.g., 30 minutes) while maintaining the temperature between 20° C. and 25° C.

[0101] The separated aqueous layer was transferred to a container. Next, 10 v of 2-methyltetrahydrofuran (2-Me THF) was added to the container. A 5 M NaOH solution containing 0.6 p of NaOH and 2.9 v of water was placed in an auxiliary container. The pH of the aqueous layer in the container was adjusted to pH ≥ 13.0 using the previously prepared 5 M NaOH solution while maintaining a temperature ≤ 35 °C.

[0102] The mixture was stirred at maximum speed for at least 10 minutes at a temperature of about 15°C to about 25°C (e.g., 20°C). Stirring was stopped and the phases were allowed to separate at a temperature of about 20°C to 25°C.

[0103] The organic layer was retained in a container. To an auxiliary container, a 20% w / w NaCl solution prepared by dissolving 1.25 pb of NaCl in 5 v of water was added. To the main container containing the organic layer, 5.0 v of the 20% w / w NaCl solution was added and stirred for at least 10 minutes at a temperature of about 15 °C to about 25 °C (e.g., 20 °C). Stirring was stopped and the layers were allowed to separate. The organic layer was retained in a container and washed at least three times with 5 v of water. If necessary, the organic layer containing 2-Me THF and Compound (A) was stored at 2 to 8 °C.

[0104] A peroxide strip was used to confirm that the peroxide content of the IPA (purchased from Ravago Chemicals) used was 10 ppm or less. The organic layer was transferred to a jacketed reactor, heated to approximately 30°C to 45°C (e.g., 35°C), and then concentrated under vacuum to a residual volume of 4–5 V. 9 V of IPA was added to the concentrated solution at approximately 30°C to 45°C (e.g., 35°C), and the mixture was concentrated under vacuum to a residual volume of 4–5 V. 9 V of IPA was added to the concentrated solution at approximately 30°C to 45°C (e.g., 35°C), and the mixture was concentrated under vacuum to a residual volume of 4–5 V. The addition of IPA and concentration was repeated until GC analysis showed 2-MeTHF ≤ 1% w / w relative to IPA, i.e., solvent exchange from 2-MeTHF to IPA was achieved.

[0105] In an auxiliary vessel, 0.28 pb of benzoic acid was dissolved in 12 v of IPA at approximately 20 ± 5 °C. The amount of benzoic acid added was calculated based on the w / w assay of Compound (A) (free base). The benzoic acid solution was added to the main reactor, and an additional 6 v of IPA was added to the main reactor. The mixture was heated to a temperature of approximately 70 °C to approximately 80 °C (e.g., 76 °C) in approximately 30 minutes, and heating was continued for an additional 15 to 30 minutes. The mixture was cooled to approximately 50 °C to approximately 55 °C (e.g., approximately 52 °C) over approximately 30 to 60 minutes. At approximately 50 °C to approximately 55 °C, 0.005 pb of seed crystals in 0.05 v IPA were added, and the mixture was stirred for approximately 10 to 15 minutes. The seed crystals were prepared according to the procedure described in WO 2021 / 095835. The mixture was then cooled to about 20°C to about 25°C over about 200 to about 250 minutes, and then stirred at about 20°C to about 25°C for about 20 to about 40 minutes. The mixture was then heated to about 62°C to about 66°C over about 280 to about 320 minutes, and cooled to about 20°C to about 25°C over about 280 to about 320 minutes, repeating the heating and cooling cycle. The mixture was then further stirred at a temperature of about 20°C to about 25°C for about 6 hours.

[0106] Annealing (heat-cool cycles) improved the overall yield of the process. This annealing eliminated the crusting issue during scale-up. Using this process, the benzoate salt of compound (A) was obtained with acceptable particle size and morphology, as shown in Figures 1A and 1B.

[0107] The slurry was filtered and the filter cake was dried in vacuo for approximately 16 hours at 40° C. A sample was analyzed by HPLC and the following impurities were found to be less than 0.5% a / a: [ka]

[0108] The sample was also analyzed to determine whether the impurity with RRT1.08 was 0.3% a / a or less, and whether the impurity with the following structure with RRT1.15 was 0.7% a / a or less. [ka]

[0109] In addition, it was confirmed by HPLC whether the content of each of the following impurities was 0.3% a / a or less. [ka] [ka]

[0110] It was confirmed by HPLC that the other impurities were 0.3% a / a or less, and the total impurities were 4.0% a / a or less. In this specification, a / a means the peak area in HPLC.

[0111] Optionally, the filter cake may be recrystallized a second time with a suitable solvent (e.g., IPA) to obtain the final product.

[0112] As described in WO 2021 / 095835, the benzoate salt of compound (A) has excellent solid stability and maintains purity for 4 weeks under test conditions. Example 2: Preparation of Compound (B) from Compound (C)

[0113] Dimethylacetamide (6.5 vol) was charged to an appropriately sized reaction vessel, followed by Compound (C). After adjusting the temperature to 0 to 5°C, 0.6 parts of Compound (D) and 0.53 parts of triethylamine were added. 1.3 parts of HATU were added in small increments, and the reaction temperature was maintained at approximately 5°C until the reaction was complete as determined by HPLC analysis. Upon completion of the reaction, isopropyl acetate (10 vol) was charged to the reaction mixture, followed by water, while maintaining the reaction temperature at approximately 25°C or below. The aqueous layer was separated and extracted with isopropyl acetate (8 vol). The combined organic layers were washed sequentially with water (10 vol), 1N hydrochloric acid (10 vol), water (10 vol), 10% aqueous sodium chloride solution (5 vol), and finally water (10 vol). The isopropyl acetate solution was repeatedly circulated through an AKS-7 charcoal pad until the color was removed. The solvent was evaporated to a residual volume of approximately 5 relative volumes, and MTBE (35 vol) was added. The temperature of the mixture was adjusted to approximately 45°C and then cooled to approximately 32°C under high-speed stirring. At this point, a solid was observed. If no solid was observed, crystallization could be initiated by further cooling or by adding a slurry of Compound (B) seed crystals. Compound (B) seed crystals can be prepared using the procedure described in U.S. Patent No. 10,723,742. Once solids were observed, high-speed stirring was maintained for approximately 4-5 hours. The suspension was then cooled to approximately 10°C and filtered. The filter cake was washed with MTBE (2 x 5 volumes) and dried at approximately 40°C to obtain Compound (B). Biological Examples Example A

[0114] As described in WO 2021 / 095835, in a pharmacokinetic (PK) study using rats, the AUC, Cmax (μM), and Tmax (hr) of three drugs, namely, Compound (A) free form, Compound (A) benzoate, and Compound (A) sorbate, were calculated. Each drug was administered to animals at a dose of 32 mg / 5 mL / kg. The AUCs of Compound (A) free form, Compound (A) benzoate, and Compound (A) sorbate were 16.04 μM hr, 16.13 μM hr, and 11.64 μM hr, respectively. The Cmax of the three test compounds was 2.56 μM, 2.68 μM, and 2.03 μM. The Tmax of the three test compounds was 4.0 hours, 2.7 hours, and 2.3 hours, respectively. Therefore, excellent drug absorption / exposure was achieved with Compound (A) benzoate. Example B

[0115] A Phase 1 study will be conducted to investigate the safety, pharmacokinetics, and preliminary activity of the benzoate salt of compound (A) as a single agent and in combination with all-trans retinoic acid (ATRA) in patients with relapsed or refractory (r / r) acute myeloid leukemia (AML).

[0116] In Part 1, Compound (A) benzoate will be administered as a monotherapy once daily (QD) on selected days of a 28-day cycle. In Part 2, Compound (A) benzoate will be administered QD on selected days of a 28-day cycle in combination with ATRA twice daily (BID). Administration will be by oral capsule.

[0117] Entry criteria include, but are not limited to, a predicted life expectancy of at least 12 weeks and stable disease capable of completing one full cycle (4 weeks) of treatment; histologically confirmed AML according to the World Health Organization (WHO) 2016 criteria and failure of all other available conventional therapies; peripheral blood or bone marrow blast counts of 5% or greater at the time of entry; disease that is refractory to standard induction chemotherapy (including but not limited to anthracycline and cytarabine combination therapy), or has relapsed after anthracycline and cytarabine combination therapy or stem cell transplantation (SCT), or is refractory to or has relapsed after first-line treatment with hypomethylating agents, alone or in combination.

[0118] Outcome measures include, but are not limited to, treatment-emergent adverse events, response rates of complete remission (CR), complete remission with incomplete hematologic recovery (CRi), partial remission (PR), complete remission with partial hematologic recovery (CRh), overall survival, and other appropriate measures.

[0119] All patents and other references cited in this specification are indicative of the level of skill of those skilled in the art to which this disclosure pertains and are incorporated by reference in their entirety, including any tables and figures, to the same extent as if each reference were individually incorporated by reference in its entirety.

[0120] Those skilled in the art will readily appreciate that the present disclosure is well adapted to obtain the objects and advantages mentioned, as well as those inherent therein. The methods, variations, and compositions described herein as preferred embodiments are exemplary and are not intended as limitations on the scope of the disclosure. Modifications and other uses from the present disclosure may occur to those skilled in the art, which are encompassed by the concept of the disclosure and defined by the scope of the claims.

Claims

1. A method for producing a benzoate of the following compound (A): 【Chemistry 1】 (i) Extracting the following compound (A) from a reaction mixture containing the compound (A) into 2-methyltetrahydrofuran (2-Me THF) to obtain a 2-Me THF solution of the compound (A), wherein the compound (A) in the reaction mixture is obtained by contacting the following compound (B) with hydrochloric acid in a solvent; 【Chemistry 2】 【Transformation 3】 (ii) performing a solvent exchange from 2-Me THF to isopropyl alcohol (IPA) to obtain an IPA solution of compound (A); and (iii) adding benzoic acid to a solution of compound (A) in IPA to obtain a benzoate salt of compound (A); A manufacturing method comprising:

2. The method of claim 1 further comprising recrystallizing the benzoate salt of compound (A).

3. 3. The method according to claim 1, wherein the peroxide content of the IPA is 10 ppm or less.

4. 10. The process of claim 1, wherein the reaction mixture is heated at a temperature of from 15°C to 50°C.

5. 10. The process of claim 1, wherein the reaction mixture is heated at a temperature of from 40°C to 50°C.

6. 6. The process of claim 1, 4, or 5, wherein the reaction mixture is stirred for 1 to 8 hours.

7. (ia) cooling the reaction mixture and adding water and methyl tertbutyl ether (MTBE) to the reaction mixture; (ib) separating the organic layer containing MTBE from the aqueous layer; (ic) adding 2-Me THF to the aqueous layer from step (ib) and adding aqueous NaOH to the mixture containing 2-Me THF and the aqueous layer; (id) separating the organic layer containing 2-Me THF; (i-e) washing the organic layer of step (i-d) with 20% w / w NaCl solution; (i-f) washing the organic layer of step (i-e) with water; and (ig) optionally repeating steps (if) once or twice or more times to obtain a solution of compound (A) in 2-Me THF; The method of claim 1 further comprising:

8. 8. The process of claim 7, wherein in step (ia), the reaction mixture is cooled to a temperature of 20° C. to 25° C. and optionally stirred for 2 hours to 24 hours before adding water and MTBE.

9. 8. The method of claim 7, wherein in step (ic), aqueous NaOH is added to the mixture until a pH of at least pH 10 is reached.

10. 8. The method according to claim 7, wherein after steps (i-g), the weight of NaOH in the 2-Me THF solution of compound (A) is less than 5%.

11. 3. The process of claim 1 or 2, wherein step (iii) further comprises heating the reaction mixture to a temperature of 70°C to 80°C and maintaining the reaction mixture at 70°C to 80°C for 30 minutes to 60 minutes.

12. The process of claim 11, wherein the reaction mixture is cooled to 50°C to 55°C.

13. 13. The process of claim 12, wherein a slurry of seed crystals of the benzoate salt of compound (A) in IPA is added to the reaction mixture.

14. The process of claim 13, wherein the reaction mixture is subjected to a cooling and heating cycle, and then cooled to a temperature of 16°C to 24°C and stirred at a temperature of 16°C to 24°C for 6 hours.

15. The method of claim 14, comprising the steps of: (iii-a) cooling the reaction mixture to a temperature of 16°C to 24°C over 200 to 250 minutes, followed by stirring at a temperature of 16°C to 24°C for 30 minutes; (iii-b) heating the reaction mixture to 62°C to 66°C over 280 to 320 minutes; (iii-c) repeating the cooling and heating steps (iii-a) and (iii-b) once or twice; and (iii-d) cooling the reaction mixture to a temperature of 16°C to 24°C over 280 to 320 minutes and stirring at a temperature of 16°C to 24°C for 6 hours.

16. The method according to claim 2, wherein the benzoate salt of compound (A) is recrystallized from ethanol, butanol, IPA, acetonitrile, methyl tert-butyl ether (MTBE), ethyl acetate, isopropyl acetate, methyl ethyl ketone (MEK), proprionitrile, or toluene.

17. 3. The method according to claim 1, wherein the benzoate of compound (A) contains 0.7% a / a or less of any of the following compounds or a combination thereof in total: 【Chemistry 4】

18. A method for producing a benzoate of the following compound (A): 【Transformation 5】 (i) contacting compound (B) with hydrochloric acid to obtain compound (A); 【Transformation 6】 【Transformation 7】 (ii) extracting compound (A) into 2-methyltetrahydrofuran (2-Me THF) to obtain a 2-Me THF solution of compound (A); (iii) performing a solvent exchange from 2-Me THF to isopropyl alcohol (IPA); (iv) adding benzoic acid to the mixture containing IPA to obtain the benzoate salt of compound (A); and (v) recrystallizing the benzoate salt of compound (A); A manufacturing method comprising:

19. A composition comprising a benzoate salt of the following compound (A): 【Transformation 8】 and a composition having a total content of any one of the following compounds or a combination thereof of 0.7% a / a or less: 【Chemistry 9】

20. A composition comprising a benzoate salt of the following compound (A): 【Chemistry 10】 A pharmaceutical composition having a total content of any one of the following compounds or a combination thereof of 0.7% a / a or less: 【Chemistry 11】

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