Compounds targeting cell states and uses thereof

Abstract

Among other things, the present disclosure provides technologies targeting KAT2. In some embodiments, the present disclosure provides technologies for reducing levels of KAT2 polypeptides in various systems. In some embodiments, the present disclosure provides technologies for treating various diseases, disorders, or conditions, including those associated with a KAT2 polypeptide such as various cancers.

Description

Attorney Docket No.: 2013405-0090COMPOUNDS TARGETING CELL STATES AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and benefit of United States Provisional Application No.63 / 764,556 filed February 27, 2025, the entirety of which is incorporated herein by reference.BACKGROUND

[0002] KAT2A (also referred to as lysine acetyltransferase 2A, general control non-depressible 5 (GCN5), etc.) and KAT2B (also referred to as lysine acetyltransferase 2B, p300 / CBP-associated factor (PCAF), etc.) are both multidomain proteins, which contain an acetyltransferase domain and a bromodomain. KAT2A and KAT2B have been implicated in certain diseases, disorders, and conditions, such as cancers, neurodegenerative diseases, and inflammation.SUMMARY

[0003] Among other things, the present disclosure provides technologies, e.g., compositions, formulations, tablets, doses, dosing regimens, etc. of Compound I for treating certain diseases, disorders, and conditions, e.g., advanced hematologic malignancies.BRIEF DESCRIPTION OF DRAWING

[0004] Figure 1 shows a useful design for Part A and Part B of a study.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0005] Certain provided technologies of the disclosure, e.g., compounds, compositions, methods, include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein.

[0006] In some embodiments, the present disclosure provides a method, comprising administering to a subject suffering from a condition, disease or disorder a dose of a compound having the structure of formula I (“Compound I”);1 of 6213326598v1Attorney Docket No.: 2013405-0090Iwherein the amount of Compound I in the dose is about 1 mg or more (e.g., about ling, 2 mg, 3 mg, 5 mg, 10 mg, 16 mg, 24 mg, 33 mg, 43 mg or more) in free base form. In some embodiments, a condition, disease or disorder is or comprises an advanced hematologic malignancy. In some embodiments, a condition, disease or disorder is or comprises acute myeloid leukemia (AML). In some embodiments, an AML is relapsed AML. In some embodiments, a AML is refractory AML. In some embodiments, a subject has not achieved an adequate response to, cannot tolerate, and / or refused all approved therapies known to be active for treatment of AML. In some embodiments, a condition, disease or disorder is relapsed or refractory AML that has relapsed after the subject received hematopoietic stem cell transplantation (HSCT).

[0007] In some embodiments, a condition, disease or disorder is or comprises myelodysplastic syndromes (MDS). In some embodiments, a MDS is relapsed MDS. In some embodiments, a MDS is refractory MDS.

[0008] In some embodiments, a subject has at least 10% blasts in bone marrow. In some embodiments, a subject has not achieved an adequate response to at least about 4 cycles of a hypomethylating agent (HMA)-containing regimen or other treatment known to be active for their disease.

[0009] In some embodiments, the MDS has relapsed after a hematopoietic stem cell transplant (HSCT).

[0010] In some embodiments, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of no more than about 2. In some embodiments, a subject has adequate hepatic function. In some embodiments, a subject has adequate renal function. In some embodiments, a subject has adequate cardiovascular function. In some embodiments, a subject has a white blood cell count of no more than about 20 x 109cells / L. In some embodiments, a subject has received another anticancer therapy, and at least 2 weeks, or at least 5 half-lives, have elapsed prior to administration of the first dose of Compound I. In some embodiments, a subject has received prior hydroxyurea treatment. In some embodiments, a subject is on hydroxyurea treatment. In some embodiments, a subject has received radiotherapy, and at least about 2 weeks have elapsed since the last radiotherapy. In some embodiments, a subject has recovered from2 of 6213326598v1Attorney Docket No.: 2013405-0090any clinically relevant effects of any prior surgery. In some embodiments, a subject has not received chimeric antigen receptor T cell therapy within about 60 days of an initial dose of Compound I. In some embodiments, a subject has not received HSCT within about 60 days of an initial dose of Compound I. In some embodiments, a subject does not have an active clinically significant graft-versus-host disease (GVHD). In some embodiments, a subject does not have another malignancy that may interfere with diagnosis and treatment of the condition, disease or disorder. In some embodiments, a subject does not have an active severe infection that requires anti-infective therapy. In some embodiments, a subject is not taking systemic strong CYP3A4 inhibitors or inducers within 14 days of the first dose of Compound I. In some embodiments, a subject is not taking proton pump inhibitor. In some embodiments, a subject is on an acidreducing agent which is not a proton pump inhibitor. In some embodiments, a subject is on an antacid or H2 blocker. In some embodiments, a subject is not taking a P-gp and breast cancer resistance protein (BCRP) inhibitor or inducer within about 14 days of the first dose of Compound I. In some embodiments, a subject does not have active hepatitis B virus (HB V) or hepatitis C virus (HCV) infections with detectable viral load. In some embodiments, a subject has not experienced AIDS related illness within the past 6 months or does not have detectable HIV viral load. In some embodiments, a subject does not have an uncontrolled intercurrent illness. In some embodiments, a subject does not have active Class III or IV cardiovascular disease within 6 months prior to the first dose of Compound I. In some embodiments, a subject is able to tolerate the administration of oral medication. In some embodiments, a subject does not have a GI dysfunction that would preclude adequate absorption, distribution, metabolism, or excretion of an oral medication. In some embodiments, a subject is not pregnant. In some embodiments, a subject is not breastfeeding.

[0011] In some embodiments, Compound I is or comprises a structure as depicted in formula IA (“Structure IA”):

[0012] In some embodiments, Compound I is or comprises a free base form of Structure IA. In some embodiments, Compound I is or comprises a salt form of Structure IA. In some embodiments, Compound I is or comprises a solvate form of Structure IA. In some embodiments, Compound I is or comprises a3 of 6213326598v1Attorney Docket No.: 2013405-0090solvate form of a salt form of Structure IA. In some embodiments, Compound I is or comprises a hydrate form of Structure IA. In some embodiments, Compound I is or comprises a hydrate form of a salt form of Structure IA.

[0013] In some embodiments, Compound I is or comprises a structure as depicted in formula IB (“Structure IB”):

[0014] In some embodiments, Compound I is or comprises a free base form of Structure IB. In some embodiments, Compound I is or comprises a salt form of Structure IB. In some embodiments, Compound I is or comprises a solvate form of Structure IB. In some embodiments, Compound I is or comprises a solvate form of a salt form of Structure IB. In some embodiments, Compound I is or comprises a hydrate form of Structure IB. In some embodiments, Compound I is or comprises a hydrate form of a salt form of Structure IB.

[0015] In some embodiments, the molar ratio of all forms of Structure IA and all forms of Structure IB in the dose is about 1:1. In some embodiments, the total amount of Structure IA free base form and Structure IB free base form in a dose is about the amount of Compound I in the dose in free base form. In some embodiments, Compound I in a dose exist in the form of Structure IA free base form or Structure IB free base form.

[0016] In some embodiments, provided methods comprise administering two or more doses of Compound I. In some embodiments, a dose is administered orally. In some embodiments, each dose is administered orally. In some embodiments, a dose is administered intravenously. In some embodiments, each dose is administered intravenously. In some embodiments, provided methods comprise administering doses of Compound I about weekly. In some embodiments, provided methods comprise administering doses of Compound I about weekly for about or at least about 4 weeks. In some embodiments, provided methods comprise administering doses of Compound I about twice weekly. In some embodiments, provided methods comprise administering doses of Compound I about twice weekly for about or at least about 4 weeks. In some embodiments, provided methods comprise administering doses of Compound I about three times4 of 6213326598v1Attorney Docket No.: 2013405-0090weekly. In some embodiments, provided methods comprise administering doses of Compound I about three times weekly for about or at least about 4 weeks.

[0017] In some embodiments, a subject is administered 4 or more doses every 28 days. In some embodiments, doses are administered in one or more cycles each of which is independently about 28 days.

[0018] In some embodiments, an amount of Compound I in a dose is about 1 mg in free base form. In some embodiments, an amount of Compound I in a dose is about 2 mg in free base form. In some embodiments, an amount of Compound I in a dose is about 3 mg in free base form. In some embodiments, an amount of Compound I in a dose is about 5 mg in free base form. In some embodiments, an amount of Compound I in a dose is about 10 mg in free base form. In some embodiments, an amount of Compound I in a dose is about 16 mg in free base form. In some embodiments, an amount of Compound I in a dose is about 24 mg in free base form. In some embodiments, an amount of Compound I in a dose is about 33 mg in free base form. In some embodiments, an amount of Compound I in a dose is about 43 mg in free base form. In some embodiments, an amount of Compound I in each dose is independently about 3 mg or more in free base form. In some embodiments, an amount of Compound I in each dose is independently about 5 mg or more in free base form. In some embodiments, an amount of Compound I in each dose is independently about 5 mg in free base form. In some embodiments, wherein in each dose Compound I exists in the same forms. In some embodiments, Compound I is administered about weekly. In some embodiments, Compound I is administered about twice weekly. In some embodiments, a method comprises administering Compound I about weekly, wherein the amount of Compound I in each dose is independently about 1 mg in free base form. In some embodiments, a method comprises administering Compound I about twice weekly, wherein the amount of Compound I in each dose is independently about 1 mg in free base form. In some embodiments, a method comprises administering Compound I about weekly, wherein the amount of Compound I in each dose is independently about 2 mg in free base form. In some embodiments, a method comprises administering Compound I about twice weekly, wherein the amount of Compound I in each dose is independently about 2 mg in free base form. In some embodiments, a method comprises administering Compound I about weekly, wherein the amount of Compound I in each dose is independently about 5 mg in free base form. In some embodiments, a method comprises administering Compound I about twice weekly, wherein the amount of Compound I in each dose is independently about 5 mg in free base form. In some embodiments, a method comprises administering Compound I about weekly, wherein the amount of Compound I in each dose is independently about 10 mg in free base form. In some embodiments, a method comprises administering Compound I about twice weekly, wherein the amount of Compound I in each dose is independently about 10 mg in free base form.5 of 6213326598v1Attorney Docket No.: 2013405-0090

[0019] In some embodiments, Compound I is administered about three times weekly. In some embodiments, a method comprises administering Compound I about three times weekly, wherein the amount of Compound I in each dose is independently about 1 mg in free base form. In some embodiments, a method comprises administering Compound I about three times weekly, wherein the amount of Compound I in each dose is independently about 2 mg in free base form. In some embodiments, a method comprises administering Compound I about three times weekly, wherein the amount of Compound I in each dose is independently about 5 mg in free base form. In some embodiments, a method comprises administering Compound I about three times weekly, wherein the amount of Compound I in each dose is independently about 10 mg in free base form.

[0020] In accordance with various embodiments, in some embodiments, provided the methods comprise assessing a polypeptide level of lysine acetyltransferase 2A (KAT2A) and / or lysine acetyltransferase 2B (KAT2B) is assessed. In some embodiments, a polypeptide level of lysine acetyltransferase 2A (KAT2A) and / or lysine acetyltransferase 2B (KAT2B) is reduced. In some embodiments, a level of H3K9 acetylation is assessed. In some embodiments, a level of H3K9 acetylation is reduced.

[0021] In some embodiments, one or more cell state signatures are assessed.

[0022] In some embodiments, one or more markers of differentiation are assessed.

[0023] In some embodiments, an assessment is performed for a population of the subjects. In some embodiments, subjects in the population receive the same dosing regimen. In some embodiments, subjects in the population receive different dosing regimen.

[0024] In some embodiments, wherein one or more peripheral blood and / or bone marrow samples are assessed. In some embodiments, one or more peripheral blood samples are assessed. In some embodiments, one or more bone marrow samples are assessed. In some embodiments, an assessment is performed: (i) about 4 hours, about 8 hours, about 12 hours, about 16 hours, about 20 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, or more days, or (ii) about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, or more weeks, or (ii)6 of 6213326598v1Attorney Docket No.: 2013405-0090or about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, or more months;after administration of a dose and before a next dose, if any, is administered.

[0025] In some embodiments, Compound I is administered in a pharmaceutical composition.

[0026] In accordance with various embodiments, the present disclosure provides tablet, comprising: a compound having the structure of formula I (“Compound I”):Ia pharmaceutically acceptable excipient.

[0027] In some embodiments, a tablet comprises a filler, a disintegrant, a binder, a lubricant, or a glidant. In some embodiments, a tablet comprises a filler, a disintegrant, a binder, a lubricant, and a glidant. In some embodiments, a tablet comprises: colloidal silicon dioxide; croscarmellose sodium; hydroxypropylcellulose; lactose monohydrate; magnesium stearate; and microcrystalline cellulose.

[0028] In some embodiments, a tablet is an immediate release tablet. In some embodiments, a tablet is film-coated. In some embodiments, a tablet is coated with a water-based color film coating. In some embodiments, a tablet is coated with a water-based Opadry II color film coating. In some embodiments, a tablet is uncoated. In some embodiments, a tablet is for oral administration.Definitions

[0029] As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0030] Unless otherwise indicated, structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including replacement of hydrogen by deuterium or tritium, or replacement of a carbon7 of 6213326598v1Attorney Docket No.: 2013405-0090by13C- or14C-enriched carbon are within the scope of this disclosure.

[0031] About: The term “about”, when used herein in reference to a value, refers to a value that is similar, in context to the referenced value. In general, those skilled in the art, familiar with the context, will appreciate the relevant degree of variance encompassed by “about” in that context. For example, in some embodiments, the term “about” may encompass a range of values that within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referred value. In some embodiments, “about” is + / — 10%. In some embodiments, “about” is + / -5%. In some embodiments, “about” is + / -2%. In some embodiments, “about” is + / -1%. In some embodiments, “about” is + / — 0.5%.

[0032] Administration: The term “administration” typically refers to the administration of a composition to a subject or system. Those of ordinary skill in the art will be aware of a variety of routes that may, in appropriate circumstances, be utilized for administration to a subject, for example a human. For example, in some embodiments, administration may be ocular, oral, parenteral, topical, etc. In some particular embodiments, administration may be bronchial (e.g., by bronchial instillation), buccal, dermal (which may be or comprise, for example, one or more of topical to the dermis, intradermal, interdermal, transdermal, etc.'), enteral, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, within a specific organ (e. g., intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), vaginal, vitreal, etc. In some embodiments, administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and / or periodic (<?.g., individual doses separated by a common period of time) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time.

[0033] Dosing regimen: Those skilled in the art will appreciate that the term “dosing regimen” may be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which is separated in time from other doses. In some embodiments, individual doses are separated from one another by a lime period of tire same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments,8 of 6213326598v1Attorney Docket No.: 2013405-0090a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (z.e., is a therapeutic dosing regimen).

[0034] “Improved,” “increased” or “reduced”: As used herein, these terms, or grammatically comparable comparative terms, indicate values that are relative to a comparable reference measurement. For example, in some embodiments, an assessed value achieved with a provided composition may be “improved” relative to that obtained with a comparable reference. Alternatively or additionally, in some embodiments, an assessed value achieved in a subject or system of interest may be “improved” relative to that obtained in the same subject or system under different conditions (e.g., prior to or after an event such as administration of a provided composition), or in a different, comparable subject (e.g., in a comparable subject or system that differs from the subject or system of interest in presence of one or more indicators of a particular disease, disorder or condition of interest, or in prior exposure to a condition or a provided composition, etc). In some embodiments, comparative terms refer to statistically relevant differences (e.g., that are of a prevalence and / or magnitude sufficient to achieve statistical relevance). Those skilled in the art will be aware, or will readily be able to determine, in a given context, a degree and / or prevalence of difference that is required or sufficient to achieve such statistical significance.

[0035] Patient or subject: As used herein, the term “patient” or “subject” refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, a patient or a subject is a human. Unless indicated otherwise herein, a subject receiving Compound I is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and / or to treat a disease, disorder, or condition.

[0036] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to a provided compound, formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, a provided compound is present in unit dose amount appropriate for administration in a regimen (e.g., therapeutic regimen) that shows a statistically significant probability of achieving a predetermined effect (e.g., therapeutic effect) when administered to a relevant population. In some embodiments, provided compositions (e.g., pharmaceutical compositions) may be specially formulated for9 of 6213326598v1Attorney Docket No.: 2013405-0090administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.

[0037] Pharmaceutically acceptable: As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0038] Pharmaceutically acceptable carrier: As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; pH buffered solutions; polyesters, polycarbonates and / or polyanhydrides; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0039] Pharmaceutically acceptable salt: As used herein, the term “pharmaceutically acceptable salt”, refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.10 of 6213326598v1Attorney Docket No.: 2013405-0090M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). In some embodiments, pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts, which are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other known methods such as ion exchange. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, nontoxic base addition salts, such as those formed by acidic groups of provided compounds with bases. Representative alkali or alkaline earth metal salts include salts of sodium, lithium, potassium, calcium, magnesium, and the like. In some embodiments, pharmaceutically acceptable salts are ammonium salts (e.g., -N(R)4+). In some embodiments, pharmaceutically acceptable salts are sodium salts. In some embodiments, pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.

[0040] Prevent or prevention: As used herein, when used in connection with the occurrence of a disease, disorder, and / or condition, refers to reducing the risk of developing the disease, disorder and / or condition and / or to delaying onset of one or more characteristics or symptoms of the disease, disorder or condition. Prevention may be considered complete when onset of a disease, disorder or condition has been delayed for a predefined period of time.

[0041] Susceptible to: An individual who is “susceptible to” a disease, disorder, and / or condition is one who has a higher risk of developing the disease, disorder, and / or condition than does a member of the general public. In some embodiments, an individual who is susceptible to a disease, disorder and / or condition may not have been diagnosed with the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition may exhibit symptoms of the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition may not exhibit symptoms of the disease, disorder, and / or condition. In some11 of 6213326598v1Attorney Docket No.: 2013405-0090embodiments, an individual who is susceptible to a disease, disorder, and / or condition will develop the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition will not develop the disease, disorder, and / or condition.

[0042] Therapeutic agent: As used herein, the phrase “therapeutic agent” refers to an agent that, when administered to a subject, has a therapeutic effect and / or elicits a desired biological and / or pharmacological effect. In some embodiments, a therapeutic agent is any substance that can be used to alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition.

[0043] Therapeutic regimen: A “therapeutic regimen”, as that term is used herein, refers to a dosing regimen whose administration across a relevant population may be correlated with a desired or beneficial therapeutic outcome.

[0044] Unit dose: The expression “unit dose” as used herein refers to an amount administered as a single dose and / or in a physically discrete unit of a pharmaceutical composition. In many embodiments, a unit dose contains a predetermined quantity of an active agent. In some embodiments, a unit dose contains an entire single dose of the agent. In some embodiments, more than one unit dose is administered to achieve a total single dose. In some embodiments, administration of multiple unit doses is required, or expected to be required, in order to achieve an intended effect. A unit dose may be, for example, a volume of liquid (e.g., an acceptable carrier) containing a predetermined quantity of one or more therapeutic agents, a predetermined amount of one or more therapeutic agents in solid form, a sustained release formulation or drug delivery device containing a predetermined amount of one or more therapeutic agents, etc. It will be appreciated that a unit dose may be present in a formulation that includes any of a variety of components in addition to the therapeutic agent(s). For example, acceptable carriers (e.g., pharmaceutically acceptable carriers), diluents, stabilizers, buffers, preservatives, etc., may be included as described infra. It will be appreciated by those skilled in the art, in many embodiments, a total appropriate daily dosage of a particular therapeutic agent may comprise a portion, or a plurality, of unit doses, and may be decided, for example, by the attending physician within the scope of sound medical judgment. In some embodiments, the specific effective dose level for any particular subject or organism may depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of specific active compound employed; specific composition employed; age, body weight, general health, sex and diet of the subject; time of administration, and rate of excretion of the specific active compound employed; duration of the treatment; drugs and / or additional therapies used in combination or coincidental with specific compound(s) employed, and like factors well known in the medical arts.

[0045] Treat: As used herein, the term “treat” (also “treatment” or “treating”) refers to any12 of 6213326598v1Attorney Docket No.: 2013405-0090administration of a therapy that partially or completely alleviates, ameliorates, relives, inhibits, delays onset of, reduces severity of, and / or reduces incidence of one or more symptoms, features, and / or causes of a particular disease, disorder, and / or condition. In some embodiments, such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder, and / or condition and / or of a subject who exhibits only early signs of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and / or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and / or condition.

[0046] As used in the present disclosure, unless otherwise clear from context, (i) the term “a” or “an” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and / or”; (iii) the terms “comprise”, “comprising”, “include” and “including” (whether used with “not limited to” or not (whether used with “not limited to” or not) may be understood to encompass itemized component(s) or step(s) whether presented by themselves or together with one or more additional components or steps; (iv) the term “another” may be understood to mean at least an additional / second one or more; (v) the terms “about” and “approximately” may be understood to permit standard variation as would be understood by those of ordinary skill in the art; and (vi) where ranges are provided, endpoints are included. As those skilled in the art appreciate, compounds may be provided, administered, or delivered in various forms, e.g., salts (e.g., pharmaceutically acceptable salts), solvates (e.g., of acid forms, base forms, salt forms, etc.), hydrates (e.g., of acid forms, base forms, salt forms, etc.), esters, prodrugs, tautomers, etc.Compound I

[0047] Among other things, the present disclosure provides compositions comprising a compound having the structure of formula I (“Compound I”):In some embodiments, the present disclosure provides pharmaceutical compositions comprising Compound I. In some embodiments, the present disclosure provides formulations of Compound I. In some embodiments, the present disclosure provides tablets comprising Compound I. In some embodiments, the13 of 6213326598v1Attorney Docket No.: 2013405-0090present disclosure provides methods for using Compound I. In some embodiments, the present disclosure provides technologies for administering or delivering Compound I, e.g., to a subject suffering from a condition, disease or disorder. In some embodiments, the present disclosure provides doses and dosing regimens for administering or delivering Compound I. In some embodiments, the present disclosure provides a method, comprising administering to a subject suffering from a condition, disease or disorder a dose of Compound I, wherein the amount of Compound I in the dose is about 3 mg or more (e.g., about 3 mg, 5 mg, 10 mg, 16 mg, 24 mg, 33 mg, 43 mg or more) in free base form. In some embodiments, the present disclosure provides a method, comprising administering to a subject suffering from a condition, disease or disorder a dose of Compound I, wherein the amount of Compound I in the dose is about 1 mg or more (e.g., about 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 16 mg, 24 mg, 33 mg, 43 mg or more) in free base form. In some embodiments, a condition, disease or disorder is or comprises an advanced hematologic malignancy. In some embodiments, a condition, disease or disorder is or comprises acute myeloid leukemia. In some embodiments, a condition, disease or disorder is or comprises myelodysplastic syndromes. In some embodiments, a condition, disease or disorder is or comprises elapsed / refractory acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). In some embodiments, a condition, disease or disorder is or comprises elapsed / refractory AML. In some embodiments, a condition, disease or disorder is or comprises elapsed AML. In some embodiments, a condition, disease or disorder is or comprises refractory AML. In some embodiments, a condition, disease or disorder is or comprises relapsed MDS. In some embodiments, a condition, disease or disorder is or comprises refractory MDS.

[0048] As used herein, Compound I can exist or be administered in one or more forms, e.g., epimers with respect to unspecified chiral center, free base form, salt forms (e.g., pharmaceutically acceptable salt forms), solvate forms (e.g., of the free base form, salt forms, etc.), etc. In some embodiments, Compound I is or comprises Structure IA, which may exist in various forms (e.g., free base form, salt forms (e.g., pharmaceutically acceptable salt forms), solvate forms (e.g., of the free base form, salt forms, etc.), etc.):N iN N N HNIn some embodiments, Compound I is or comprises Structure IB, which may exist in various forms (e.g., free base form, salt forms (e.g., pharmaceutically acceptable salt forms), solvate forms (e.g., of the free14 of 6213326598v1Attorney Docket No.: 2013405-0090base form, salt forms, etc.), etc.):oIB.In some embodiments, a composition or a dose comprising Compound I comprises Structure IA. In some embodiments, a composition or a dose comprising Compound I comprises Structure IB. In some embodiments, a composition or a dose comprising Compound I comprises Structure IA and Structure IB. In some embodiments, the molar ratio of Structure IA (all forms) and Structure IB (all forms) is about or at least about 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1 or 1:1. In some embodiments, the molar ratio of Structure IB (all forms) and Structure IA (all forms) is about or at least about 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1 or 1:1. In some embodiments, the molar percentage of Structure I A (all forms) among Compound I (all forms) is about or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95%, or about 100%. In some embodiments, the molar percentage of Structure IB (all forms) among Compound I (all forms) is about or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95%, or about 100%. In some embodiments, the molar percentage of free base form(s) are about or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95%, or about 100%. In some embodiments, the molar percentage of the free base form of Structure IA among all Structure IA forms is about or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95%, or about 100%. In some embodiments, the molar percentage of the free base form of Structure IB among all Structure IB forms is about or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95%, or about 100%. In some embodiments, a percentage is about 10%. In some embodiments, a percentage is about 20%. In some embodiments, a percentage is about 30%. In some embodiments, a percentage is about 40%. In some embodiments, a percentage is about 50%. In some embodiments, a percentage is about 60%. In some embodiments, a percentage is about 70%. In some embodiments, a percentage is about 80%. In some embodiments, a percentage is about 90%. In some embodiments, a percentage is about 100%. In some embodiments, a percentage is at least about 10%. In some embodiments, a percentage is at least about 20%. In some embodiments, a percentage is at least about 30%. In some embodiments, a percentage is at least about 40%. In some embodiments, a percentage is at least about 50%. In some embodiments, a percentage is at least about 60%. In some embodiments, a percentage is at least about 70%. In some embodiments, a percentage15 of 6213326598v1Attorney Docket No.: 2013405-0090is at least about 80%. In some embodiments, a percentage is at least about 90%. In some embodiments, a percentage is at least about 95%. In some embodiments, about or at least about 80%, 90% or 95%, or about 100% (molar percentage) of all Compound I forms in a composition or dose is the free base form of Structure I A or the free base form of Structure IB.

[0049] In some embodiments, a composition or a dose comprises Structure IA. In some embodiments, a composition or a dose comprises Structure IB. In some embodiments, a composition or a dose comprises Structure IA and Structure IB. In some embodiments, a composition or dose comprises a free base form, a salt form, or a solvate form of Structure IA. In some embodiments, a composition or dose comprises a free base form, a salt form, a solvate form of the free base, or a solvate form of a salt of Structure IA. In some embodiments, each form of Structure IA is independently a free base form, a salt form, or a solvate form of Structure IA. In some embodiments, each form of Structure IA is independently a free base form, a salt form, a solvate form of the free base, or a solvate form of a salt of Structure IA. In some embodiments, a composition or a dose comprises Structure IB. In some embodiments, a composition or dose comprises a free base form, a salt form, or a solvate form of Structure IB. In some embodiments, a composition or dose comprises a free base form, a salt form, a solvate form of the free base, or a solvate form of a salt of Structure IB. In some embodiments, each form of Structure IB is independently a free base form, a salt form, or a solvate form of Structure IB. In some embodiments, each form of Structure IB is independently a free base form, a salt form, a solvate form of the free base, or a solvate form of a salt of Structure IB. In some embodiments, each salt is independently a pharmaceutically acceptable salt. In some embodiments, each solvate is independently a pharmaceutically acceptable solvate. In some embodiments, each solvate is independently a hydrate.

[0050] Unless indicated otherwise, amount of Compound I (unless indicated otherwise, all forms of Compound I) is presented as an amount in the free base form. In some embodiments, an amount, e.g., in a composition or a dose of Compound I is about 3 mg or more (e.g., about 3 mg, 5 mg, 10 mg, 16 mg, 24 mg, 33 mg, 43 mg or more). In some embodiments, an amount, e.g., in a composition or a dose of Compound I is about 1 mg or more (e.g., about 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 16 mg, 24 mg, 33 mg, 43 mg or more). In some embodiments, an amount is about 1 mg or more. In some embodiments, an amount is about 1 mg. In some embodiments, an amount is about 2 mg or more. In some embodiments, an amount is about 2 mg. In some embodiments, an amount is about 3 mg or more. In some embodiments, an amount is about 3 mg. In some embodiments, an amount is about 5 mg or more. In some embodiments, an amount is about 5 mg. In some embodiments, an amount is about 10 mg or more. In some embodiments, an amount is about 10 mg. In some embodiments, an amount is about 16 mg or more. In some embodiments, an amount is about 16 mg. In some embodiments, an amount is about 24 mg or more. In some embodiments, an amount is about16 of 6213326598v1Attorney Docket No.: 2013405-009024 mg. In some embodiments, an amount is about 33 mg or more. In some embodiments, an amount is about 33 mg. In some embodiments, an amount is about 43 mg or more. In some embodiments, an amount is about 43 mg. In some embodiments, an amount of Structure IA (unless indicated otherwise, all forms of Structure IA) is about or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or about 100% of an amount of Compound I. In some embodiments, an amount of Structure IB (unless indicated otherwise, all forms of Structure IB) is about or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or about 100% of an amount of Compound I. In some embodiments, an amount of the free base forms of Compound I is about or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or about 100% of an amount of Compound I. In some embodiments, an amount of the free base forms of Compound I is about or at least about 80% of an amount of Compound I. In some embodiments, an amount of the free base forms of Compound I is about or at least about 90% of an amount of Compound I. In some embodiments, an amount of the free base forms of Compound I is about or at least about 95% of an amount of Compound I. In some embodiments, an amount of the free base forms of Compound I is about 100% of an amount of Compound I. In some embodiments, an amount of free base forms of Compound I, e.g., in a composition or a dose, is about 3 mg or more (e.g., about 3 mg, 5 mg, 10 mg, 16 mg, 24 mg, 33 mg, 43 mg or more). In some embodiments, an amount of free base forms of Compound I, e.g., in a composition or a dose, is about 1 mg or more (e.g., about 1 mg, about 2mg, about 3 mg, about 5 mg, about 10 mg, about 16 mg, about 24 mg, about 33 mg, about 43 mg or more). In some embodiments, an amount is about 1 mg or more. In some embodiments, an amount is about 1 mg. In some embodiments, an amount is about 2 mg or more. In some embodiments, an amount is about 2 mg. In some embodiments, an amount is about 3 mg or more. In some embodiments, an amount is about 3 mg. In some embodiments, an amount is about 5 mg or more. In some embodiments, an amount is about 5 mg. In some embodiments, an amount is about 10 mg or more. In some embodiments, an amount is about 10 mg. In some embodiments, an amount is about 16 mg or more. In some embodiments, an amount is about 16 mg. In some embodiments, an amount is about 24 mg or more. In some embodiments, an amount is about 24 mg. In some embodiments, an amount is about 33 mg or more. In some embodiments, an amount is about 33 mg. In some embodiments, an amount is about 43 mg or more. In some embodiments, an amount is about 43 mg.

[0051] In some embodiments, a free base form of Structure IA is administered. In some embodiments, a free base form of Structure IB is administered. In some embodiments, a free base form of Structure IA and a free base form of Structure IB are administered.

[0052] In some embodiments, Compound I is provided or utilized in a salt form (e.g., a pharmaceutically acceptable salt form). In some embodiments, Compound I is provided or utilized in multiple forms, one or more of which pharmaceutically acceptable forms. Various pharmaceutically17 of 6213326598v1Attorney Docket No.: 2013405-0090acceptable salt forms, e.g., those described in S. M. Berge, et al. J. Pharmaceutical Sciences, 66:1-19(1977), may be utilized in accordance with the present disclosure.

[0053] In some embodiments, Compound I is in a free base form. In some embodiments, Compound I is or comprises a salt form of Structure IA. In some embodiments, Compound I is or comprises a hydrate form of Structure IA. In some embodiments, Compound I is or comprises a hydrate form of a salt form of Structure IA. In some embodiments, Compound I is or comprises a solvate form of Structure IA. In some embodiments, Compound I is or comprises a solvate form of a salt form of Structure IA.

[0054] In some embodiments, Compound I is or comprises a salt form of Structure IB. In some embodiments, Compound I is or comprises a hydrate form of Structure IB. In some embodiments, Compound I is or comprises a hydrate form of a salt form of Structure IB. In some embodiments, Compound I is or comprises a solvate form of Structure IB. In some embodiments, Compound I is or comprises a solvate form of a salt form of Structure IB.

[0055] In some embodiments, Compound I or a form thereof is crystalline. In some embodiments, Compound I or a form thereof is amorphous.Condition, Disease or Disorder

[0056] Among other things, the present disclosure provides methods for treating a subject suffering from a condition, disease or disorder. In some embodiment provided methods comprise, administering to a subject suffering from a condition, disease or disorder a dose of Compound I.

[0057] In some embodiments, provided methods comprise, administering to a subject suffering from a condition, disease or disorder a dose of Compound I, wherein the amount of Compound I in the dose is about 0.5 mg or more (e.g., about 0.5 mg, about 3 mg, about 5 mg, about 10 mg, about 16 mg, about 24 mg, about 33 mg, about 43 mg or more) in free base form.

[0058] In some embodiments, provided methods comprise administering to a subject suffering from a condition, disease or disorder a dose of Compound I, wherein the amount of Compound I in the dose is about 1 mg or more (e.g., about 2 mg, 3 mg, 5 mg, 10 mg, 16 mg, 24 mg, 33 mg, 43 mg or more) in free base form. In some embodiments, it is about 1 mg in free base form. In some embodiments, it is about 5 mg in free base form. In some embodiments, it is about 10 mg in free base form.

[0059] In some embodiments, the present disclosure provides a dose of Compound I for use in a method for treating a subject suffering from a condition, disease or disorder, wherein the amount of Compound I in the dose is about 0.5 mg or more (e.g., about 0.5 mg, about 3 mg, about 5 mg, about 10 mg, about 16 mg, about 24 mg, about 33 mg, about 43 mg or more) in free base form.18 of 6213326598v1Attorney Docket No.: 2013405-0090

[0060] In some embodiments, the present disclosure provides a dose of Compound I for use in a method for treating a subject suffering from a condition, disease or disorder, wherein an amount of Compound I in the dose is about 1 mg or more (e.g., about 2 mg, 3 mg, 5 mg, 10 mg, 16 mg, 24 mg, 33 mg, 43 mg or more) in free base form. In some embodiments, it is about 1 mg in free base form. In some embodiments, it is about 5 mg in free base form. In some embodiments, it is about 10 mg in free base form.

[0061] In some embodiments, the present disclosure provides uses of Compound I in the manufacture of a medicament for treating a subject suffering from a condition, disease or disorder, wherein the medicament is to be administered at a dose, wherein the amount of Compound I in the dose is about 0.5 mg or more (e.g., about 0.5 mg, about 3 mg, about 5 mg, about 10 mg, about 16 mg, about 24 mg, about 33 mg, about 43 mg or more) in free base form.

[0062] In some embodiments, the present disclosure provides uses of Compound I in the manufacture of a medicament for treating a subject suffering from a condition, disease or disorder, wherein the medicament is to be administered at a dose, wherein the amount of Compound I in the dose is about 1 mg or more (e.g., about 2 mg, 3 mg, 5 mg, 10 mg, 16 mg, 24 mg, 33 mg, 43 mg or more) in free base form. In some embodiments, it is about 1 mg in free base form. In some embodiments, it is about 5 mg in free base form. In some embodiments, it is about 10 mg in free base form.Acute Myeloid Leukemia (AML)

[0063] In some embodiments, a condition, disease or disorder is or comprises an advanced hematologic malignancy. In some embodiments, a condition, disease or disorder is or comprises AML. In some embodiments, AML is relapsed AML. In some embodiments, AML is refractory AML. In some embodiments, AML is relapsed / refractory AML.

[0064] Acute myeloid leukemia (AML) is a heterogeneous group of cancers that arise from blood cell precursors in the bone marrow. In AML, malignant transformation of myeloid precursor cells leads to their uncontrolled proliferation and inability to differentiate from immature blast cells into mature blood cells. As a result, the bone marrow becomes overcrowded and is unable to produce adequate amounts of essential mature blood cells. This leads to the classic clinical manifestations of AML: bleeding and bruising (due to low platelets), infections (due to low neutrophils), and anemia (due to low red blood cell [RBC] count), among others. Though AML can occur in patients of all ages (from infants to the elderly), the median age at diagnosis is approximately 68 years and the risk of developing the disease increases with age. In the United States, there are approximately 20,800 new cases of AML diagnosed each year and the disease accounts for 1% to 2% of adult cancer deaths (SEER 2022). Prognosis differs greatly between age groups and disease related factors with 5-year overall survival (OS) reaching -50% in younger patients and < 10% in those over 60, and 5-year survival rates range from 55% to 65%, 24% to 41%, and 5% to 14% for patients19 of 6213326598v1Attorney Docket No.: 2013405-0090with favorable, intermediate, and unfavorable cytogenetics, respectively (see, e.g., Shimony et al. 2023; Pollyea et al. 2024). With a median age at diagnosis of 68 years, most patients fall into the poor prognosis category.

[0065] For decades, the standard of care for AML has been intensive cytotoxic chemotherapy (namely, cytarabine plus an anthracycline), with or without hematopoietic stem cell transplantation (HSCT)., which has typically only been available for young patients without significant comorbidities, disease that is responsive to standard therapies, and a stem cell donor. Cure of disease is achieved in less than one-third of patients; these patients are typically younger fit patients who can tolerate intensive chemo with HSCT and whose disease demonstrates favorable molecular features (see, e.g., Pollyea et al. 2024). Older patients, particularly those with treatment related or secondary AML most often do not respond to currently available therapy and have a poor median OS.

[0066] More recently, molecularly targeted therapeutic agents have become available for specific subsets of AML patients, largely as supplements to chemotherapy. These agents have not achieved significant increases in cure rates, but they have demonstrated improved survival and quality of life in the AML patient segments that they target (Lai et al. 2019).

[0067] Given the low cure rate and poor OS and quality of life in the AML population, as well as the highly toxic nature of the standard of care for the majority of patients, there remains a high degree of unmet need. There is a clear demand for continued efforts to develop drugs with lower toxicity profiles that can achieve improved survival, improved quality of life, and higher cure rates.

[0068] In some embodiments, provided methods comprise administering to a subject suffering from AML a dose of Compound I, wherein the amount of Compound I in the dose is about 0.5 mg or more (e.g., about 0.5 mg, about 3 mg, about 5 mg, about 10 mg, about 16 mg, about 24 mg, about 33 mg, about 43 mg or more) in free base form.

[0069] In some embodiments, provided methods comprise, administering to a subject suffering from AML a dose of Compound I, wherein the amount of Compound I in the dose is about 1 mg or more (e.g., about 2 mg, 3 mg, 5 mg, 10 mg, 16 mg, 24 mg, 33 mg, 43 mg or more) in free base form. In some embodiments, it is about 1 mg in free base form. In some embodiments, it is about 5 mg in free base form. In some embodiments, it is about 10 mg in free base form.

[0070] In some embodiments, the present disclosure provides a dose of Compound I for use in a method for treating a subject suffering from AML, wherein the amount of Compound I in the dose is about 0.5 mg or more (e.g., about 0.5 mg, about 3 mg, about 5 mg, about 10 mg, about 16 mg, about 24 mg, about 33 mg, about 43 mg or more) in free base form.20 of 6213326598v1Attorney Docket No.: 2013405-0090

[0071] In some embodiments, the present disclosure provides a dose of Compound I for use in a method for treating a subject suffering from AML, wherein the amount of Compound I in the dose is about 1 mg or more (e.g., about 2 mg, 3 mg, 5 mg, 10 mg, 16 mg, 24 mg, 33 mg, 43 mg or more) in free base form. In some embodiments, it is about 1 mg in free base form. In some embodiments, it is about 5 mg in free base form. In some embodiments, it is about 10 mg in free base form.

[0072] In some embodiments, the present disclosure provides uses of Compound I in the manufacture of a medicament for treating a subject suffering from AML, wherein the medicament is to be administered at a dose, wherein the amount of Compound I in the dose is about 0.5 mg or more (e.g., about 0.5 mg, about 3 mg, about 5 mg, about 10 mg, about 16 mg, about 24 mg, about 33 mg, about 43 mg or more) in free base form.

[0073] In some embodiments,, the present disclosure provides uses of Compound I in the manufacture of a medicament for treating a subject suffering from AML, wherein the medicament is to be administered at a dose, wherein the amount of Compound I in the dose is about 1 mg or more (e.g., about 2 mg, about 3 mg, 5 mg, 10 mg, 16 mg, 24 mg, 33 mg, 43 mg or more) in free base form. In some embodiments, it is about 1 mg in free base form. In some embodiments, it is about 5 mg in free base form. In some embodiments, it is about 10 mg in free base form.Myelodysplastic syndrome (MDS)

[0074] In some embodiments, a condition, disease or disorder is or comprises myelodysplastic syndromes / neoplasms (MDS). In some embodiments, MDS is relapsed MDS. In some embodiments, MDS is refractory MDS. In some embodiments, MDS is preleukemia.

[0075] MDS comprise a diverse group of clonal hematologic malignancies that manifest as 1 or more cytopenias (ie, anemia, neutropenia, and / or thrombocytopenia) typically accompanied by morphologic changes in bone marrow and blood cells. The major clinical problems in these disorders are morbidities caused by cytopenias and the potential for MDS to evolve into AML. It is mainly a disease of the elderly with an incidence of 0.1 per 100,000 per year in individuals < 40 years of age that increases to ~27 per 100,000 among individuals 70 to 79 years and further to 55.4 per 100,000 among those > 80 years of age (Greenberg et al. 2024; Sekeres and Platzbecker 2024).

[0076] Patients are broadly characterized as having lower- or higher-risk MDS based on molecular, cytogenetic, and clinical features at diagnosis, which in addition to patients’ physical status and preference ultimately guides choice of therapy. Patients who are medically fit benefit from and may achieve long-term disease-free survival with induction chemotherapy with or without HSCT similar to treatment for fit21 of 6213326598v1Attorney Docket No.: 2013405-0090patients with AML. Alternatively, the goal of care for medically unfit or frail patients who may only tolerate best supportive care or may benefit from low intensity therapy is aimed at improved quality of life.

[0077] The division between MDS and AML remains an area of debate, though it is generally accepted that patients with > 20% bone marrow blasts are classified as AML, though there may be some patients with 20% to 29% bone marrow blasts whose disease behaves more similarly to MDS than those with de novo AML.

[0078] In some embodiments, provided methods comprise, administering to a subject suffering from MDS a dose of Compound I, wherein the amount of Compound I in the dose is about 0.5 mg or more (e.g., about 3 mg, about 5 mg, about 10 mg, about 16 mg, about 24 mg, about 33 mg, about 43 mg or more) in free base form.

[0079] In some embodiments, provided methods comprise, administering to a subject suffering from MDS a dose of Compound I, wherein the amount of Compound I in the dose is about 1 mg or more (e.g., about 2 mg, 3 mg, 5 mg, 10 mg, 16 mg, 24 mg, 33 mg, 43 mg or more) in free base form. In some embodiments, it is about 1 mg in free base form. In some embodiments, it is about 5 mg in free base form. In some embodiments, it is about 10 mg in free base form.

[0080] In some embodiments, the present disclosure provides a dose of Compound I for use in a method for treating a subject suffering from MDS, wherein the amount of Compound I in the dose is about 0.5 mg or more (e.g., about 3 mg, about 5 mg, about 10 mg, about 16 mg, about 24 mg, about 33 mg, about 43 mg or more) in free base form.

[0081] In some embodiments, the present disclosure provides a dose of Compound I for use in a method for treating a subject suffering from MDS, wherein the amount of Compound I in the dose is about 1 mg or more (e.g., about 2 mg, 3 mg, 5 mg, 10 mg, 16 mg, 24 mg, 33 mg, 43 mg or more) in free base form. In some embodiments, it is about 1 mg in free base form. In some embodiments, it is about 5 mg in free base form. In some embodiments, it is about 10 mg in free base form.

[0082] In some embodiments, the present disclosure provides uses of Compound I in the manufacture of a medicament for treating a subject suffering from MDS, wherein the medicament is to be administered at a dose, wherein the amount of Compound I in the dose is about 0.5 mg or more (e.g., about 3 mg, about 5 mg, about 10 mg, about 16 mg, about 24 mg, about 33 mg, about 43 mg or more) in free base form.

[0083] In some embodiments, the present disclosure provides uses of Compound I in the manufacture of a medicament for treating a subject suffering from MDS, wherein the medicament is to be administered at a dose, wherein the amount of Compound I in the dose is about 1 mg or more (e.g., about 2 mg, 3 mg, 5 mg, 10 mg, 16 mg, 24 mg, 33 mg, 43 mg or more) in free base form. In some embodiments, it is about 122 of 6213326598v1Attorney Docket No.: 2013405-0090mg in free base form. In some embodiments, it is about 5 mg in free base form. In some embodiments, it is about 10 mg in free base form.Subject Identification

[0084] In some embodiments, Compound I may be administered to one or more subjects characterized by one or more criteria provided herein.

[0085] In some embodiments, a subject has not achieved an adequate response to, cannot tolerate, and / or refused all approved therapies known to be active for treatment of their refractory AML. In some embodiments, a subject has not achieved an adequate response to, cannot tolerate, and / or refused all approved therapies known to be active for treatment of their relapsed AML. I

[0086] In some embodiments, a subject has refractory MDS and has at least 10% or more blasts in bone marrow. In some embodiments, a subject has not achieved an adequate response to at least about 4 cycles of a hypomethylating agent (HMA)-containing regimen or other treatment known to be active for their disease. In some embodiments, a subject has at least 10% or more blasts in bone marrow and has not achieved an adequate response to at least about 4 cycles of a hypomethylating agent (HMA)-containing regimen or other treatment known to be active for their disease.

[0087] In some embodiments, a subject has relapsed MDS and has at least 10% or more blasts in bone marrow. In some embodiments, a subject has not achieved an adequate response to at least about 4 cycles of a hypomethylating agent (HMA)-containing regimen or other treatment known to be active for their disease. In some embodiments, a subject has at least 10% or more blasts in bone marrow and has not achieved an adequate response to at least about 4 cycles of a hypomethylating agent (HMA)-containing regimen or other treatment known to be active for their disease.

[0088] In some embodiments, a subject has relapsed AML that has relapsed after a subject received hematopoietic stem cell transplantation (HSCT). In some embodiments, a subject has refractory AML that has relapsed after a subject received hematopoietic stem cell transplantation (HSCT).

[0089] In some embodiments, a subject has relapsed MDS that has relapsed after a subject received hematopoietic stem cell transplantation (HSCT). In some embodiments, a subject has refractory MDS that has relapsed after a subject received hematopoietic stem cell transplantation (HSCT).

[0090] In some embodiments, a subject has an Eastern Cooperative Oncology Group (ECOG) performance status of no more than about 2.

[0091] In some embodiments, a subject is assessed for tissue function. In some embodiments, a subject is assessed for tissue function prior to administration of a dose of Compound I. In some embodiments, a subject is assessed for tissue function post-administration of a dose of Compound I. In some embodiments,23 of 6213326598v1Attorney Docket No.: 2013405-0090a subject is assessed for tissue function following administration of one or more doses a dose of Compound I.

[0092] In some embodiments, a subject has adequate tissue function prior to administration of a dose of Compound I. In some embodiments, a subject has adequate tissue function post-administration of a dose of Compound I. In some embodiments, a subject has adequate tissue function following administration of one or more doses of a dose of Compound I.

[0093] In some embodiments, a subject has adequate hepatic function. In some embodiments, adequate hepatic function can be characterized using various tests e.g., measuring aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and / or bilirubin levels in a subject. In some embodiments, a subject has a total level of AST that is less than or equal to 3 times a upper limit of a reference (e.g., a healthy physiological level or acceptable therapeutic level e.g., as determined by an expert). In some embodiments, a subject has a total level of ALT that is less than or equal to 3 times a upper limit of a reference (e.g., a healthy physiological level or acceptable therapeutic level e.g., as determined by an expert). In some embodiments, a subject has a total level of ALP that is less than or equal to 3 times the upper limit of a reference (e.g., a healthy physiological level or acceptable therapeutic level e.g., as determined by an expert). In some embodiments, a subject has a total bilirubin level that is less than about 1.5 times the upper limit of a reference (e.g., a healthy physiological level or acceptable therapeutic level e.g., as determined by an expert). In some embodiments, a subject may suffer from an additional condition, disorder, or disease (e.g., Gilbert’s Syndrome) that may result in the subject experiencing an elevated bilirubin level as compared to a reference (e.g., a healthy physiological level or acceptable therapeutic level e.g., as determined by an expert).

[0094] In some embodiments, a subject has adequate renal function. In some embodiments, adequate renal function can be characterized using various tests e.g., measuring creatinine clearance in a subject based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) glomerular function rate (GFR) estimation. In some embodiments, a subject has a creatinine clearance of at 45 mL / min or greater based on the CKD-EPI GFR estimation.

[0095] In some embodiments, a subject has adequate cardiovascular function. In some embodiments, adequate cardiovascular function can be characterized using various tests e.g., echocardiogram, electrocardiogram, etc. In some embodiments, a subject has a left ventricular ejection fraction (LVEF) of at least 40% or greater. In some embodiments, a subject has a QTc interval of less than or equal to 470 ms. In some embodiments, a measured QTc can be corrected and / or adjusted using methods known in the art e.g., Fridericia’s correction (QTcF).24 of 6213326598v1Attorney Docket No.: 2013405-0090

[0096] In some embodiments, a subject has a white blood cell count of no more than about 20 x 109cells / L.

[0097] In some embodiments, a subject has received another anticancer therapy, and at least 2 weeks, or at least 5 half-lives, have elapsed prior to administration of a first dose of Compound I.

[0098] In some embodiments, a subject has received prior hydroxyurea treatment.

[0099] In some embodiments, a subject is on hydroxyurea treatment.

[0100] In some embodiments, a subject has received radiotherapy, and at least about 2 weeks have elapsed since the last radiotherapy.

[0101] In some embodiments, a subject has recovered from any clinically relevant effects of any prior surgery.

[0102] In some embodiments, a subject has not received chimeric antigen receptor T cell therapy within about 60 days of an initial dose of Compound I.

[0103] In some embodiments, a subject has not received HSCT within about 60 days of an initial dose of Compound I.

[0104] In some embodiments, a subject does not have an active clinically significant graft- versus-host disease (GVHD).

[0105] In some embodiments, a subject does not have another malignancy that may interfere with diagnosis and treatment of the condition, disease or disorder.

[0106] In some embodiments, a subject does not have an active severe infection that requires anti-infective therapy.

[0107] In some embodiments, a subject is not taking systemic strong CYP3A4 inhibitors or inducers within 14 days of a first dose of Compound I.

[0108] In some embodiments, a subject is not taking proton pump inhibitor.

[0109] In some embodiments, a subject is on an acid-reducing agent which is not a proton pump inhibitor.

[0110] In some embodiments, a subject is on an antacid or H2 blocker.

[0111] In some embodiments, a subject is not taking a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitor or inducer within about 14 days or 5 half-lives of a first dose of Compound I. In some embodiments, a P-gp is a not a mild P-gp inhibitor. In some embodiments, a P-gp inhibitor is not isavuconazonium sulfate. In some embodiments, a P-gp inhibitor is not isavuconazole. In some embodiments, a subject can and is taking a mild P-gp inhibitor. In some embodiments, a subject can and is taking isavuconazonium sulfate. In some embodiments, a subject can and is taking isavuconazole.25 of 6213326598v1Attorney Docket No.: 2013405-0090

[0112] In some embodiments, a subject does not have active hepatitis B virus (HBV) or hepatitis C virus (HCV) infections with detectable viral load.

[0113] In some embodiments, a subject has not experienced AIDS related illness within the past 6 months or does not have detectable HIV viral load.

[0114] In some embodiments, a subject does not have an uncontrolled intercurrent illness.

[0115] In some embodiments, a subject does not have active Class III or IV cardiovascular disease within 6 months prior to a first dose of Compound I.

[0116] In some embodiments, a subject is able to tolerate the administration of oral medication.

[0117] In some embodiments, a subject does not have a GI dysfunction that would preclude adequate absorption, distribution, metabolism, or excretion of an oral medication.

[0118] In some embodiments, a subject is not pregnant. In some embodiments, a subject is not breastfeeding.Doses and Dosing Regimens

[0119] In some embodiments, an amount of Compound I in a dose is about 0.5 mg or more (e.g., about 0.5 mg, about 3 mg, about 5 mg, about 10 mg, about 16 mg, about 24 mg, about 33 mg, about 43 mg or more) in free base form. In some embodiments, an amount of Compound I in a dose is about 1 mg or more (e.g., about 2 mg, about 3 mg, about 5 mg, about 10 mg, about 16 mg, about 24 mg, about 33 mg, about 43 mg or more) in free base form.

[0120] In some embodiments, an amount of Compound I in a dose is about 0.5 mg or more in free base form. In some embodiments, an amount of Compound I in a dose is about 1 mg or more in free base form. In some embodiments, an amount of Compound I in a dose is about 2 mg or more in free base form. In some embodiments, an amount of Compound I in a dose is about 3 mg or more in free base form. In some embodiments, an amount of Compound I in a dose is about 5 mg or more in free base form. In some embodiments, an amount of Compound I in a dose is about 10 mg or more in free base form. In some embodiments, an amount of Compound I in a dose is about 16 mg or more in free base form. In some embodiments, an amount of Compound I in a dose is about 24 mg or more in free base form. In some embodiments, an amount of Compound I in a dose is about 33 mg or more in free base form. In some embodiments, an amount of Compound I in a dose is about 43 mg or more in free base form.

[0121] In some embodiments, an amount of Compound I in a dose is about 0.5 mg in free base form. In some embodiments, an amount of Compound I in a dose is about 1 mg in free base form. In some embodiments, an amount of Compound I in a dose is about 2 mg in free base form. In some embodiments, an amount of Compound I in a dose is about 3 mg in free base form. In some embodiments, an amount of26 of 6213326598v1Attorney Docket No.: 2013405-0090Compound I in a dose is about 5 mg in free base form. In some embodiments, an amount of Compound I in a dose is about 10 mg in free base form. In some embodiments, an amount of Compound I in a dose is about 16 mg in free base form. In some embodiments, an amount of Compound I in a dose is about 24 mg in free base form. In some embodiments, an amount of Compound I in a dose is about 33 mg in free base form. In some embodiments, an amount of Compound I in a dose is about 43 mg in free base form.

[0122] In some embodiments, an amount of Compound I in each dose is independently about 1 mg or more in free base form. In some embodiments, an amount of Compound I in each dose is independently about 2 mg or more in free base form.

[0123] In some embodiments, an amount of Compound I in each dose is independently about 3 mg or more in free base form. In some embodiments, an amount of Compound I in each dose is independently about 5 mg or more in free base form. In some embodiments, an amount of Compound I in each dose is independently about 10 mg in free base form.

[0124] In some embodiments, a molar ratio of all forms of Structure IA and all forms of Structure IB in a dose is about 1:1. In some embodiments, a total amount of Structure I A free base form and Structure IB free base form in a dose is about the amount of Compound I in the dose in free base form. In some embodiments, Compound I in a dose exists in the form of Structure IA free base form or Structure IB free base form.

[0125] In some embodiments, one dose is administered. In some embodiments, a dose is administered about once weekly. In some embodiments, a dose is administered about once weekly for about 4 weeks.

[0126] In some embodiments, two or more doses are administered. In some embodiments, doses are administered weekly. In some embodiments, doses are administered about twice weekly (e.g., for a 7-day period, dosing on day 1 and day 4). In some embodiments, doses are administered about twice weekly for about 4 weeks. In some embodiments, doses are administered about three times weekly (e.g., for a 7-day period, dosing on day 1, day 3 and day 5). In some embodiments, doses are administered about three times weekly for about 4 weeks.

[0127] In some embodiments, dosing regimens, e.g., doses and dosing frequency may change.

[0128] In some embodiments, a subject is administered 4 or more doses every 28 days. In some embodiments, doses are administered in one or more cycles each of which is independently about 28 days.

[0129] In some embodiments, a dose is administered orally. In some embodiments, each dose is administered orally.

[0130] In some embodiments, a dose is administered intravenously. In some embodiments, each dose is administered intravenously.27 of 6213326598v1Attorney Docket No.: 2013405-0090

[0131] In some embodiments, a dose of about 1 mg Compound I in free base form is administered about weekly. In some embodiments, a dose of 1 mg Compound I in free base form is administered weekly. In some embodiments, a dose of about 1 mg Compound I in free base form is administered about twice weekly. In some embodiments, a dose of 1 mg Compound I in free base form is administered twice weekly. In some embodiments, a dose of about 1 mg Compound I in free base form is administered about three times weekly. In some embodiments, a dose of 1 mg Compound I in free base form is administered three times weekly.

[0132] In some embodiments, a dose of about 2 mg Compound I in free base form is administered about weekly. In some embodiments, a dose of 2 mg Compound I in free base form is administered weekly. In some embodiments, a dose of about 2 mg Compound I in free base form is administered about twice weekly. In some embodiments, a dose of 2 mg Compound I in free base form is administered twice weekly. In some embodiments, a dose of about 2 mg Compound I in free base form is administered about three times weekly. In some embodiments, a dose of 2 mg Compound I in free base form is administered three times weekly.

[0133] In some embodiments, a dose of about 5 mg Compound I in free base form is administered about weekly. In some embodiments, a dose of 5 mg Compound I in free base form is administered weekly. In some embodiments, a dose of about 5 mg Compound I in free base form is administered about twice weekly. In some embodiments, a dose of 5 mg Compound I in free base form is administered twice weekly. In some embodiments, a dose of about 5 mg Compound I in free base form is administered about three times weekly. In some embodiments, a dose of 5 mg Compound I in free base form is administered three times weekly.

[0134] In some embodiments, a dose of about 10 mg Compound I in free base form is administered about weekly. In some embodiments, a dose of 10 mg Compound I in free base form is administered weekly. In some embodiments, a dose of about 10 mg Compound I in free base form is administered about twice weekly. In some embodiments, a dose of 10 mg Compound I in free base form is administered twice weekly. In some embodiments, a dose of about 10 mg Compound I in free base form is administered about three times weekly. In some embodiments, a dose of 10 mg Compound I in free base form is administered three times weekly.Assessments

[0135] In some embodiments, effects of Compound I may be assessed by various technologies.

[0136] In some embodiments, an assessment is performed prior to administration of Compound I. Such assessment, may be useful in establishing an initial level for one or more subjects.28 of 6213326598v1Attorney Docket No.: 2013405-0090

[0137] In some embodiments, a polypeptide level of lysine acetyltransferase 2A (KAT2A) and / or lysine acetyltransferase 2B (KAT2B) is assessed. In some embodiments, a polypeptide level of KAT2A and / or KAT2B is reduced. In some embodiments, KAT2A level (e.g., RNA, polypeptide, etc.) in peripheral blood and / or bone marrow is assessed. In some embodiments, KAT2B level (e.g., RNA, polypeptide, etc.) in peripheral blood and / or bone marrow is assessed.

[0138] In some embodiments, a level of H3K9 acetylation is assessed. In some embodiments, a level of H3K9 acetylation is reduced.

[0139] In some embodiments, one or more cell state signatures are assessed.

[0140] In some embodiments, one or more markers of differentiation are assessed.

[0141] In some embodiments, an assessment is performed for a population of the subjects. In some embodiments, subjects in the population receive the same dosing regimen. In some embodiments, subjects in the population receive different dosing regimen.

[0142] In some embodiments, one or more peripheral blood and / or bone marrow samples are assessed. In some embodiments, one or more peripheral blood samples are assessed. In some embodiments, one or more bone marrow samples are assessed.

[0143] In some embodiments, an assessment is performed about 4 hours, about 8 hours, about 12 hours, about 16 hours, about 20 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, or more days after administration of a dose and before a next dose, if any, is administered.

[0144] In some embodiments, an assessment is performed about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, or more weeks after administration of a dose and before a next dose, if any, is administered.

[0145] In some embodiments, an assessment is performed about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, or more months after administration of a dose and before a next dose, if any, is administered.29 of 6213326598v1Attorney Docket No.: 2013405-0090

[0146] In some embodiments, maximum tolerated dose (MTD) is assessed. In some embodiments, safety, pharmacokinetics (PK), pharmacodynamics (PD), and / or preliminary clinical activity are assessed.

[0147] In some embodiments, one or more morphological changes are assessed. In some embodiments, one or more morphological changes are assessed in a sample. In some embodiments, a sample is or comprises bone marrow. In some embodiments, a sample is or comprises bone marrow aspirate. In some embodiments, a sample is or comprises a biopsy.

[0148] In some embodiments, an assessment is performed once a subject achieves a complete remission (CR), CR with partial hematologic recovery (CRh), or CR with incomplete hematologic recovery (CRi). In some embodiments, an assessment is performed at least about every 3 months. In some embodiments, an assessment is performed at least every 3 months. In some embodiments, an assessment is performed about every 3 months. In some embodiments, an assessment is performed every 3 months. In some embodiments, an assessment is performed until a relapse. In some embodiments, an assessment is performed until a suspected relapse.Formulations

[0149] Among other things, the present disclosure provides formulations for Compound I. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound I and a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutical composition is a tablet. As described herein, Compound I may exist in various forms in a pharmaceutical composition, e.g., a tablet. In some embodiments, Compound I exists as free base forms in a pharmaceutical composition, e.g., a tablet. In some embodiments, a pharmaceutical composition, e.g. a tablet, comprises free base forms of Compound I. In some embodiments, a pharmaceutical composition, e.g. a tablet, comprises the free base forms of Structure IA. In some embodiments, a pharmaceutical composition, e.g. a tablet, comprises the free base forms of Structure IB.

[0150] In some embodiments, a pharmaceutical composition comprises a filler. In some embodiments, a pharmaceutical composition comprises a disintegrant. In some embodiments, a pharmaceutical composition comprises a binder. In some embodiments, a pharmaceutical composition comprises a lubricant. In some embodiments, a pharmaceutical composition comprises a glidant. In some embodiments, a pharmaceutical composition comprises a filler, a disintegrant, a binder, a lubricant, and a glidant. For example, in some embodiments, a pharmaceutical composition comprises one or more of microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, and colloidal silicon dioxide. In some embodiments, a tablet comprises or consists of:Compound I;30 of 6213326598v1Attorney Docket No.: 2013405-0090colloidal silicon dioxide;croscarmellose sodium;hydroxypropylcellulose;lactose monohydrate;magnesium stearate; andmicrocrystalline cellulose.

[0151] In some embodiments, a tablet comprises or consists of:one or two Compound I free base forms;colloidal silicon dioxide;croscarmellose sodium;hydroxypropylcellulose;lactose monohydrate;magnesium stearate; andmicrocrystalline cellulose.

[0152] In some embodiments, the amount of Compound I in a composition, e.g., a tablet, is about 0.5 mg. In some embodiments, the amount of Compound I in a composition, e.g., a tablet, is about 1 mg. In some embodiments, the amount of Compound I in a composition, e.g., a tablet, is about 2 mg. In some embodiments, the amount of Compound I in a composition, e.g., a tablet, is about 3 mg. In some embodiments, the amount of Compound I in a composition, e.g., a tablet, is about 5 mg. In some embodiments, the amount of Compound I in a composition, e.g., a tablet, is about 10 mg.

[0153] In some embodiments, a tablet comprises Compound I and a pharmaceutically acceptable excipient. In some embodiments, a tablet provided herein is formulated for oral administration.

[0154] In some embodiments, a tablet comprises Compound I and a pharmaceutically acceptable excipient.

[0155] In some embodiments a tablet comprises a free base form of Compound I and a pharmaceutically acceptable excipient. In some embodiments a tablet comprises a salt form of Compound I and a pharmaceutically acceptable excipient. In some embodiments a tablet comprises a hydrate from of Compound I and a pharmaceutically acceptable excipient. In some embodiments a tablet comprises a hydrate form of a salt form of Compound I and a pharmaceutically acceptable excipient. In some embodiments a tablet comprises a solvate form of Compound I and a pharmaceutically acceptable excipient. In some embodiments a tablet comprises a solvate form of a salt form of Compound I and a pharmaceutically acceptable excipient.31 of 6213326598v1Attorney Docket No.: 2013405-0090

[0156] In some embodiments, a tablet is an immediate release tablet. In some embodiments a tablet is uncoated. In some embodiments, a tablet is film-coated. In some embodiments, a tablet is coated with a water-based color film coating. In some embodiments, a tablet is coated with a water-based film coating (e.g., Opadry II color film coating).

[0157] In some embodiments, a tablet described herein comprises one or more fillers (e.g., microcrystalline cellulose, lactose monohydrate). In some embodiments, a tablet described herein comprises one or more disintegrants (e.g., croscarmellose sodium). In some embodiments, a tablet described herein comprises one or more binders (e.g., hydroxypropyl cellulose). In some embodiments, a tablet described herein comprises one or more lubricants (e.g., magnesium stearate). In some embodiments, a tablet described herein comprises one or more glidants (e.g., colloidal silicon dioxide).

[0158] In some embodiments, a tablet described herein comprises one or more fillers (e.g., microcrystalline cellulose, lactose monohydrate), a disintegrant (e.g., croscarmellose sodium), a binder (e.g., hydroxypropyl cellulose), a lubricant (e.g., magnesium stearate), and / or a glidant (e.g., colloidal silicon dioxide).

[0159] In some embodiments, a tablet comprises one or more fillers (e.g., microcrystalline cellulose, lactose monohydrate), a disintegrant (e.g., croscarmellose sodium), a binder (e.g., hydroxypropyl cellulose), a lubricant (e.g., magnesium stearate), and a glidant (e.g., colloidal silicon dioxide).

[0160] In some embodiments, a tablet described herein further comprises microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, and colloidal silicon dioxide.

[0161] In some embodiments, a pharmaceutical composition is for oral administration. In some embodiments, a composition is for intravenous administration.Compositions

[0162] The present disclosure also provides compositions that comprise or deliver a dose of Compound I. In some embodiments, the present disclosure provides compositions comprising a dose of Compound I with one or more other components. As used herein, the term “pharmaceutical composition” refers to a composition in which an active agent is formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, a pharmaceutical composition may be specially formulated for administration in a particular form (e.g., in a solid form or a liquid form), and / or may be specifically adapted for, for example: oral administration (for32 of 6213326598v1Attorney Docket No.: 2013405-0090example, as a drenche [aqueous or non-aqueous solutions or suspensions], tablet, capsule, bolus, powder, granule, paste, etc., which may be formulated specifically for example for buccal, sublingual, or systemic absorption); parenteral administration (for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation, etc.); topical application (for example, as a cream, ointment, patch or spray applied for example to skin, lungs, or oral cavity); intravaginal or intrarectal administration (for example, as a pessary, suppository, cream, or foam); ocular administration; nasal or pulmonary administration, etc.

[0163] In some embodiments, the present disclosure provides compositions comprising a dose of Compound I and a pharmaceutically acceptable carrier. In some embodiments, Compound I is in a pharmaceutically acceptable salt form. The term “pharmaceutically acceptable salt”, as used herein, refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). In some embodiments, pharmaceutically acceptable salt include nontoxic acid addition salts, which are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.

[0164] As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; pH buffered solutions; polyesters, polycarbonates33 of 6213326598v1Attorney Docket No.: 2013405-0090and / or polyanhydrides; and other non-toxic compatible substances employed in pharmaceutical formulations. In some embodiments, a pharmaceutically acceptable carrier is a buffer. In some embodiments, a pharmaceutical composition comprises a buffer. In some embodiments, a pharmaceutical composition comprises the solid components a buffer. In some embodiments, a pharmaceutical composition is re-constituted by addition of solvent, e.g., water. In some embodiments, a pharmaceutically acceptable carrier is an acidic buffer. In some embodiments, its pH is about 2-6.5, 2-6, 3-6, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6 or 6.5. In some embodiments, a pharmaceutically acceptable carrier is a citrate buffer, e.g., pH about 3.5. In some embodiments, Compound I can be formulated without using compounds such as cyclodextrins (e.g., HPBCD) to improve apparent solubility and / or dissolution rate.

[0165] In some embodiments, provided compositions comprise and / or deliver a dose of Compound I.

[0166] In some embodiments, a provided composition is a pharmaceutical composition that comprises and / or delivers a dose of Compound 1 and further comprises a pharmaceutically acceptable carrier.

[0167] The present disclosure also provides methods of preparing pharmaceutical compositions provided herein. In some embodiments, provided methods comprise (i) providing a dose of Compound I or a pharmaceutically acceptable salt thereof; and (ii) formulating the compound with suitable excipients to give a pharmaceutical composition.

[0168] The present disclosure incorporates various information, including patent application publications, patents and non-patent references, by reference; in the case of any conflict, the present disclosure will control.EXAMPLES

[0169] Various technologies can be utilized to prepare Compound I. Certain technologies are described in WO 2024 / 050078 and WO 2024 / 220843, the entirety of each of which is independently incorporated herein by reference.Example 1. Preparation of compounds and compositions.

[0170] Many technologies can be utilized to prepare Compound I. Certain useful technologies including synthetic methods, reagents, intermediates, conditions and characterization technologies are described in WO 2024 / 050078 and WO 2024 / 220843.

[0171] As an example, a preparation of Compound I is described below.

[0172] 3-[4-[2-[4-[(3R,5R)-5-[(5-bromo-l-methyl-6-oxo-pyridazin-4-yl)amino]-l-methyl-3-piperidyl]benzoyl]-2,7-diazaspiro[4.4]nonan-7-yl]phenyl]piperidine-2, 6-dione (Compound I)Step-1: tert-butyl 9-(4-bromophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate34 of 6213326598v1Attorney Docket No.: 2013405-0090HN X N-BOCPd2(dba)3, xanthphos, / =\ Cs2CO3, 1,4-dioxane / \ / \ / =\ Br — C n — I - ► Boc— N X N — n — Br

[0173] To a stirred solution of 1 -bromo-4-iodo-benzene (2.00 g, 7.09 mmol) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (2.00 g, 8.00 mmol) in 1,4-dioxane (35 mL), CS2CO3 (6.3 g, 19.38 mmol) was added at RT. The reaction mixture was purged with argon for 30 min. To the resulting reaction mixture, Pd2(dba)3 (0.64 g, 0.70 mmol) and xantphos-Pd (0.80 g, 1.40 mmol) were added and the reaction mixture was again purged with argon for 20 min. The reaction mixture was stirred in a sealed tube at 110 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through Celite®. The filtrate was diluted with cold water and extracted with ethyl acetate. Combined organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (7% EtOAc / hexane) to afford tert-butyl 9-(4-bromophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (0.90 g, 32%) as an off white solid. LC-MS: m / z 410.85 [M+H]+.Step-2: tert-butyl 9-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]-3,9-diazaspiro[5.5]undecane-3-carboxylateOHOBn

[0174] To a stirred solution of tert-butyl 9-(4-bromophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (1.0 g, 2.45 mmol, from step 1) and 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (1.24 g, 3.71 mmol) in 1,4-dioxane (40 mL), Na-CCL (0.52 g, 4.95 mmol) was added dissolved in H2O (10 mL) at RT. The reaction mixture was purged with argon for 30 min. To the resulting reaction mixture, PdCL(dppf) (0.20 g, 0.02 mmol) was added and the reaction mixture was again purged with argon for 20 min. The reaction mixture was stirred in a sealed tube at 110 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through Celite®. The filtrate was diluted with cold water and extracted with ethyl acetate. Combined organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (10% EtOAc / hexane) to afford pure tert-butyl 9-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (0.6 g, 40%) as colorless liquid. LC-MS: m / z 620.79 [M+H]+.35 of 6213326598v1Attorney Docket No.: 2013405-0090Step-3: tert-butyl 7-[4-(2,6-dioxo-3-piperidyl)phenyl]-2,7-diazaspiro[4.4]nonane-2 carboxylateOBn

[0175] To a stirred solution of tert-butyl 9-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (0.60 g, 0.96 mmol, from step 2) in EtOAc (6.6 inf) and EtOH (6.6 niL), Pd / C (0.49 g) and triethyl silane (1.20 g, 0.96 mmol) were added at RT. The reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (2% MeOH / DCM) to afford tertbutyl 9-[4-(2,6-dioxo-3-piperidyl)phenyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (0.32 g, 73%) as an off white solid. LC-MS: m / z 442.08 [M+H]+.Step-4: 3-[4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl]piperidine-2, 6-dione

[0176] A mixture of tert-butyl 9-[4-(2,6-dioxo-3-piperidyl)phenyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (0.40 g, 0.90 mmol, from step 3) in DCM (10 mL) and 30% TFA in DCM (0.6 mL) was stirred at 0 °C for 5 min followed by at RT for 2 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure to afford 3-[4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl]piperidine-2, 6-dione (0.35 g, TFA salt) as white solid which was used as such for the next reaction. LC-MS: m / z 342.05 [M+H]+.Step-5: 3-[4-[3-[4-[(3R,5R)-5-[(5-bromo-l-methyl-6-oxo-pyridazin-4-yl)amino]-l-methyl-3-piperidyl]benzoyl]-3,9-diazaspiro[5.5]undecan-9-yl]phenyl]piperidine-2, 6-dione

[0177] To a stirred solution of 3-[4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl]piperidine-2, 6-dione (0.08 g, 0.23 mmol, from step 4) in DMF (1.5 mL), 4-[(3R,5R)-5-[(5-bromo-l-methyl-6-oxo-pyridazin-4-yl)amino]-l-methyl-3-piperidyl]benzoic acid (0.09 g, 0.23 mmol, intermediate 1) was added followed by 36 of 6213326598v1Attorney Docket No.: 2013405-0090N-methyl imidazole (0.09 g, 1.7 mmol) and the reaction mixture was stirred at RT for 10 min. To the resulting reaction mixture, N, N, N', N'-tetramethylchloroformamidinium hexafluorophosphate (0.09 g, 0.35 mmol) was added and stirred at 85 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with ice cold water. The precipitated solid was filtered to yield crude compound which was purified by prep HPLC (Method E) to afford 3-[4-[3-[4- [(3R,5R)-5-[(5-bromo-l-methyl-6-oxo-pyridazin-4-yl)amino]-l-methyl-3-piperidyl]benzoyl]-3,9- diazaspiro[5.5]undecan-9-yl]phenyl]piperidine-2, 6-dione (0.06 g, 35%) as an off white solid.!H NMR (400 MHz, DMSO-ds) 8 = 10.76 (s, 1H), 7.87 (s, 1H), 7.33 (s, 4H), 7.03 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 5.81 (d, J = 9.0 Hz, 1H), 4.00 - 3.91 (m, 1H), 3.71 (dd, J = 5.0, 10.9 Hz, 1H), 3.59 (s, 5H), 3.13 (brs, 4H), 3.03 - 2.87 (m, 4H), 2.64 - 2.59 (m, 2H), 2.43 (d, J = 4.6 Hz, 1H), 2.25 (s, 3H), 2.15 - 1.98 (m, 5H), 1.72 (d, J = 11.6 Hz, 1H), 1.60 (brs, 4H), 1.54 - 1.44 (m, 4H); LC-MS: m / z 744 and 746 [M+H]+.

[0178] Stereoisomers, (R)-3-(4-(9-(4-((3R,5R)-5-((5-bromo-l-methyl-6-oxo-l,6-dihydropyridazin-4- yl)amino)-l-methylpiperidin-3-yl)benzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2, 6-dione and (S)-3-(4-(9-(4-((3R,5R)-5-((5-bromo-l-methyl-6-oxo-l,6-dihydropyridazin-4-yl)amino)-l- methylpiperidin-3-yl)benzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2, 6-dione (Compounds 239 and 240), can also be prepared, e.g., using chiral prep-SFC using CHIRAL PAKIG (30 mm x 250 mm x 5 pm) column and DCM: MeOH (1:1).

[0179] In some embodiments, as those skilled in the art reading the present disclosure appreciate, the glutaramide chiral center can interconvert from one isomer to the other.Example 2. Preparation of Tablets Comprising Compound I.

[0180] Many technologies can be utilized to prepare a tablet comprising Compound 1.

[0181] As an example, a preparation of tablet comprising Compound I is described below.

[0182] Preparation of a uniform blend followed a geometric mixing approach. Components for the blends are detailed in Table 1.Table 1: Materials in Formulation of CompositionsMaterial Name Material GradeCompound 1 API37 of 6213326598v1Attorney Docket No.: 2013405-0090Microcrystalline cellulose (MCC) Avicel pH 102Lactose Anhydrous SuperTab 14SD or 2 IANMilled lactose Monohydrate Pharma Tose 200MHydroxypropoyl cellulose (HPC) Klucel ® EXFCroscamellose Ac-Di-SolSodium starch glycolate Primojel ®Colloidal silicon dioxide HDK-N20 PharamMagnesium Stearate Ligamed ®

[0183] All the materials except Magnesium Stearate were sieved through a 500 pm mesh sieve. Compound 1 was mixed with an approximately equal amount of Microcrystalline Cellulose PH 102 in a 250 ml Turbula blender using a Turbula T2F mixer for 2 mins at 48 rpm. Approximately equal amount of Microcrystalline Cellulose PH 102 was added to the above blend and blended for 2 mins. Approximately equal amount of Pharmatose 200M were added to the above blend and blended for 2 mins. Approximately equal amount of Microcrystalline Cellulose PH 102 and equal amount of Pharmatose 200M were added to the above blend and blended for 5 mins. The above materials (approximately 120 g, 40 % (w / w)) was transferred from a 250 ml container to a 2 Litres turbula blender shell. Colloidal Silicon Dioxide co-sieved with Microcrystalline Cellulose PH 102 using a 500 pm mesh sieve and added to the blender shell. All the remaining materials were mixed with the above blend and mixed for 15 mins at 48 rpm. Magnesium stearate was sieved through a 250 pm mesh sieve and was added to the rest of the materials and mixed for another 2 min. The obtained final blend was ready for compression and was compressed into tablets.

[0184] Moreover, many technologies can be utilized to prepare a coat for a tablet provided herein.

[0185] As an example, a preparation of coated tablet comprising Compound I is described below.

[0186] In some preparations, the 0.5 mg and the 10 mg strength tablets were coated with Opadry II pink and yellow coating systems, respectively, and the 3 mg strength tablets (150 mg tablet weight) were white (e.g., coated with Opadry II white coating system).

[0187] A useful coating procedure is detailed below:• The coating suspension was prepared with 15% solids in purified water at least 45 mins prior to coating as per Colorcon Opadry reconstitution procedures.• At least 30 tablets were weighed and added to the coating pan.• Tablet cores were coated with aqueous PVA-based film coat (OPADRY II, Pink for the 0.5 mg dose strength, and Yellow for the 10 mg dose strength) to achieve 3% weight gain.38 of 6213326598v1Attorney Docket No.: 2013405-0090• Coating was carried out using the Caleva Mini Coater Dryer fluid bed coater on tablet cores.Filmcoated tablets were characterized for appearance and weight gain

[0188] In some embodiments, the present disclosure provides Compound I as 0.5 mg, 3.0 mg, and 10 mg immediate release, film-coated tablets for oral administration.Example 3. Clinical Studies of Compound I.

[0189] Among other things, the present disclosure provides technologies for assessing Compound I for administration or delivery to human subjects, e.g., for treating conditions, diseases or disorders. Applicant has conducted extensive in vitro studies of Compound I, and in vivo studies in various animals, including pharmacokinetics, pharmacodynamics, toxicology, etc. to facilitate designs of clinical studies of Compound I.

[0190] Among other things, various effects of Compound I is assessed in clinical trials. A useful clinical study protocol is presented below as an example. In some embodiments, a clinical trial is or comprises one or more conditions, protocols, methods, criteria, out measures, designs, objectives, endpoints, etc. of the study described below. In some embodiments, a clinical trial is conducted according to a study described below. Those skilled in the art appreciate that a study may be adjusted. In some embodiments, a study is or comprises a study identified witfi ClinicalTrials.gov ID NCT06846606.A Phase 1 Study of Compound I in Participants with Relap sed / Refractory Acute Myeloid Leukemia andMyelodysplastic Syndromes

[0191] In some embodiments, a study is or comprises a phase 1 study of Compound I in Relapsed / Refractory AML and MDS. In some embodiments, a study is or comprises a Phase 1, multicenter, openlabel, dose escalation and dose optimization study designed to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of Compound I administered orally in subjects with advanced hematologic malignancies. In some embodiments, a study assesses one or more of safety and tolerability of Compound I in participants with relapsed or refractory (“R / R”) AML and MDS, including pharmacokinetics (PK), pharmacodynamic (PD), and clinical activity profile of Compound I, any treatment emergent adverse events (AEs), etc. In some embodiments, a study has 2 pails: Part A (Dose Escalation) to determine the maximum tolerated dose (MTD) and / or recommended Phase 2 dose (RP2D), and Part B (Dose Optimization) to further evaluate safety, PK, PD and efficacy at selected dosages. In some embodiments, in Part A, participants are assigned sequentially to escalating dosages of Compound I to determine the maximum tolerated dose (MTD) and / or the recommended Phase 2 dose (RP2D). In Part B, participants are randomly assigned to receive one of two dosages of Compound I for safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity.39 of 6213326598v1Attorney Docket No.: 2013405-0090

[0192] In some embodiments, an objective is or comprises to evaluate safety and tolerability of Compound I. In some embodiments, endpoints are or comprise incidence and severity of AEs, DLTs, SAEs, and / or AEs leading to treatment discontinuation. In some embodiments, an objective is or comprises evaluation to identify the RP2D(s) of Compound I. In some embodiments, endpoints are or comprise evaluation of the totality of the safety, tolerability, PK, PD, and / or clinical activity data. In some embodiments, an objective is or comprises PK of Compound I. In some embodiments, endpoints are or comprise plasma PK parameters including, but not limited to: AUCinf, AUChst, Clli;: S. Tmax, Vd / F, CL / F, and / or t / 2of Compound I. In some embodiments, an objective is or comprises PD of Compound I. In some embodiments, endpoints are or comprise measurement of KAT2A and / or KAT2B levels in peripheral blood and / or bone marrow. In some embodiments, an objective is or comprises preliminary evidence of clinical activity associated with Compound I. In some embodiments, endpoints are or comprise clinical activity -for AML: CR rate, CR + CRh rate, duration of CR, duration of CR+CRh, ORR, DoR, TI, EFS, OS; and / or for MDS: CR rate, PR rate, CR+PR rate, duration of CR, duration of PR, duration of CR+PR, TI, EFS, OS. In some embodiments, an objective is or comprises the PK of the diastereomers of Compound I. In some embodiments, endpoints are or comprise plasma PK parameters including, but not limited to: AUCinf, AUCiast, Cmax, Tmax, Vd / F, CL / F, and / or ti / 2of the diastereomers of Compound I. In some embodiments, an objective is or comprise PD measures of immunophenotypic, genomic, transcriptomic, metabolic, and proteomic features in bone marrow and blood. In some embodiments, endpoints are or comprise (i) measurement of H3K9ac levels as well as other target related genes and proteins in peripheral blood and bone marrow, (ii) measurement of cell state signature in peripheral blood and / or bone marrow, and / or (iii) measurement of efficacy biomarkers (i.e., markers of differentiation in peripheral blood and bone marrow). In some embodiments, an objective is or comprise dose- and exposure response relationships of Compound I. In some embodiments, endpoints are or comprise assessment of relationships between PK exposure / dose and clinical activity, safety and / or PD biomarkers.

[0193] Part A can be guided by the Bayesian optimal interval (BOIN) design to estimate the maximum-tolerated dose (MTD) of Compound I. Successive cohorts of participants receive Compound I at increasing dosages until the MTD or presumptive recommended Phase 2 dose (s) (RP2D[s]) is / are reached. Additional participants may be added to select dosages to further explore the safety, PK, PD, and preliminary activity of Compound I.

[0194] The presumptive RP2D(s) can be determined by the Clinical Study Team (CST) and are the dosages identified for continued study based on observed safety, tolerability, PK, PD, and clinical activity data. The identification of presumptive RP2D(s) may or may not include the identification of the MTD (defined as the dosage with a dose-limiting toxicity [DLT] probability that is closest to the target toxicity40 of 6213326598v1Attorney Docket No.: 2013405-0090rate); a presumptive RP2D and MTD may be equivalent. In the absence of observing an MTD, Compound I will be escalated to allow for the estimation of the optimal safe and biologically effective dosage based on the target toxicity rate and an assessment of preliminary clinical activity, PD, and exploratory efficacy biomarkers.

[0195] Following selection of the presumptive RP2D(s) from Part A, dose optimization of Compound I is initiated. In some cases, 2 dosages of Compound I are further evaluated in Part B to further characterize safety and tolerability, PK, PD, and clinical activity.

[0196] Screening Procedures.

[0197] Participants undergo screening procedures within 28 days prior to the first dose of study treatment to determine eligibility for the study.

[0198] Treatment Period.

[0199] Participants who satisfy all inclusion and exclusion criteria receive study treatment according to their assigned dose and schedule (dosage). Dosing with Compound I begin on Cycle 1 Day 1 and treatment cycles are 28-days in length.

[0200] End of Treatment.

[0201] Participants continue treatment with Compound I until disease progression, treatment failure, unacceptable toxicity, withdrawal of consent, introduction of other therapy for R / R AML or R / R MDS, or until the criteria for participant withdrawal or for study termination are met.

[0202] An end-of-treatment (EOT) visit occur within 5 days following the date on which it is decided that study treatment be discontinued (this date is not required to be equivalent to the date of the last Compound I dose).

[0203] Safety Follow-Up.

[0204] A safety follow-up visit occur approximately 28 (±7) days following the EOT Visit. If a participant’s Compound I dose is interrupted for 28 days and the participant then discontinues Compound I without restarting treatment, the EOT visit can serve as the Safety Follow-Up visit.

[0205] Long-Term Follow-Up.

[0206] After participants have discontinued Compound I, unless consent to participate is withdrawn, they are contacted every 3 months (±14 days) for long-term follow-up. Long-term follow-up continue until 1 year after the Safety Follow-Up Visit or until the participant has died, withdrawn consent, or is lost to follow-up, whichever occurs first.

[0207] End of Study41 of 6213326598v1Attorney Docket No.: 2013405-0090

[0208] End of Study (EOS) is defined as the time point at which all participants have discontinued study treatment and have been followed for survival and disease status assessment for at least 1 year, or have died, been lost to follow-up, or withdrawn consent.

[0209] Useful participant eligibility criteria are presented below:

[0210] Participant Eligibility Criteria

[0211] Key Inclusion Criteria1. Participant must be > 18 years of age.2. Participant must have confirmed diagnosis as follows: R / R AML and has not achieved adequate response to, cannot tolerate, or refused all approved therapies known to be active for treatment of their disease OR R / R MDS with over 10% blasts in tire bone marrow and has not achieved an adequate response to at least 4 cycles of a hypomethylating agent (HMA)- containing regimen or other treatment known to be active for their disease OR R / R AML or R / R MDS that has relapsed after a hematopoietic stem cell transplant (HSCT).3. Participant must be willing and able to comply with scheduled study visits and treatment plans.4. Participant must be willing to undergo all study procedures unless contraindicated due to medical risk.5. Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of <2.6. Participant must have adequate hepatic function.7. Participant must have adequate renal function.8. Participant must have adequate cardiovascular function.9. Participant must have a white blood cell (WBC) count < 20 x 109 / L (with stable hydroxyurea use allowed).10. Participant must meet timing requirements with respect to prior therapy and surgery.11. Participant must agree to use effective contraception during the study and for the required posttreatment period: Males: Use condoms (even if vasectomized) during the study and for 90 days post-treatment. Females of childbearing potential: Use a combination of 1 highly effective and 1 effective method of contraception during the study and for 180 days post-treatment.

[0212] Key Exclusion Criteria1. Participant is unable to provide informed consent and / or to follow protocol requirements.2. Participant has undergone chimeric antigen receptor T cell therapy or HSCT within 60 days of the first dose of study treatment or has active clinically significant graft- versus-host disease (GVHD).42 of 6213326598v1Attorney Docket No.: 2013405-00903. Participant has another malignancy that may interfere with diagnosis and treatment of R / R AML or R / R MDS.4. Participant has an active severe infection that requires anti -infective therapy or has an unexplained temperature of >38.5 °C during screening visits or on their first day of study treatment.5. Participant has a known sensitivity to Compound I or any of its components.6. Participant is taking systemic strong CYP3A4 inhibitors or inducers within 14 days of the first dose of study treatment.7. Participant who are taking proton pump inhibitors should be switched to another acid-reducing agent such as an antacid or H2 blocker (e.g., at least 3 days prior to the first dose of Compound I).8. Participant is taking P-gp and breast cancer resistance protein (BCRP) inhibitors or inducers within 14 days or 5 half-lives / whichever is shorter) of first dose of study treatment. Mild P-gp inhibitors (e.g., isavuconazonium sulfate / isavuconazole) are permitted.9. Participant has active hepatitis B virus (HBV) or hepatitis C virus (HCV) infections with detectable viral load.10. Participant has experienced AIDS related illness within the past 6 months or have detectable HIV viral load.11. Participant has an uncontrolled intercurrent illness.12. Participant has active Class III or IV cardiovascular disease within 6 months prior to the start of study treatment.13. Participant is unable to tolerate the administration of oral medication or has CsI dysfunction that would preclude adequate absorption, distribution, metabolism, or excretion of an oral medication.14. Participant is pregnant or breastfeeding or is planning to become pregnant within 1 year of the start of study treatment.Table 2: Certain Strong Inhibitors and Inducers of CYP3A4Category Name*Strong Inhibitor - CYP3A4 adagrasib, boceprevir, certinib, clarithromycin, cobicistat, danoprevir and ritonavir, elvitegravir and ritonavir, idelalisib, idinavir alone and with ritonavir, itraconazole, josamycin, ketoconazole, LCL161, lonafarnib, lopinavir alone and with and ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir alone and with ritonavir, paritaprevir and ritonavir and (ombitasvir and / or dasbuvir),43 of 6213326598v1Attorney Docket No.: 2013405-0090Category Name*posaconazole, ribociclib, ritonavir, saquinavir alone and with ritonavir, telaprevir, telithromycin, tipranavir alone and with ritonavir, troleandomycin, tucatinib, vroiconazoleStrong Inducer - CYP3A4 apaluamide, avasimibe, carbamazepine, enzalutamide, ivosidenib, lumacaftor and ivacaftor, mitotane, phenytoin, rifampin, rifapentine, St. John’s wortAbbreviations: CYP3A4 = cytoc irome P4503A4.* Merely exemplary not an exha jstive list. For an updated list, see: fda.gov / drugs / drug-interactions-labeling / drug-development-and-< irug-interactions-table-substrates-inhibitors-and-inducers.Table 3: Certain Proton Pump In libitorsCategory Name*Proton Pump Inhibitors dexlansoprazole, esomeprazole alone and with naproxen, lansoprazole, omeprazole alone and with sodium bicarbonate, pantoprazole, rabeprazole* Merely exemplary not an exhaustive list. For an updated list, see: fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers.Table 4: Certain P-gp and BCRP Inhibitors and InducersCategory Name*Inhibitor - P-gp amiodarone, clarithromycin, cobicistat, cyclosporine, dronedarone, erythromycin, itraconazole, ketoconazole, lapatinib, lopinavir and ritonavir, propafenone, quinidine, ranolazine, saquinavir and ritonavir, sofosbuvir and velpatasvir and voxilaprevir, verapamilInhibitor - BCRP curcumin, cyclosporine, darolutamide, eltrombopag, febuxostat,fostamatinib, rolapitantl7, sofosbuvir and velpatasvir and voxilaprevir, teriflunomideInducer - P-gpaapalutamide, avasimibe, carbamazepine, curcumin, dan-shen (Salvia miltiorrhiza), efavirenz, genistein, green tea, lorlatinib, phenytoin, quercetin, rifabutin, rifampin, ritonavir, St. John's wort (Hypericum perforatum), tivantinib44 of 6213326598v1Attorney Docket No.: 2013405-0090Category Name*Inducer - BCRP No known BCRP inducersAbbreviations: BCRP = breast cancer resistance protein; P-gp = P-glycoprotein.Certara Drug Interaction Database, October 2024.* Merely exemplary not an exhaustive list. For an updated list, see: fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers.Table 5: Certain P-gp SubstratesCategory Name*P-gp Substrates dabigatran, digoxin, edoxaban, fexofenadineAbbreviations: P-gp = P-glycoprotein.* Merely exemplary not an exhaustive list. For an updated list, see: fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers.

[0213] In some embodiments, a subject is recommended to avoid direct sun exposure or exposure to ultraviolet lights. In some embodiments, factor 30 or higher sunscreen is applied to exposed areas and / or protective clothing and / or sunglasses are worn, e.g., when a subject is anticipated for longer than 15 minutes.

[0214] In some embodiments, concomitant use of foods or drinks that have CYP3A4 inhibition potential (e.g., grapefruit, grapefruit juice, Seville orange juice, pomelos, starfruits) is restricted.

[0215] Study Treatment Administration

[0216] Starting Dose Selection

[0217] The FIH starting dosage of Compound I is 5 mg taken orally twice weekly (BIW).

[0218] Dose Escalation Methodology and Guidelines

[0219] A Dose Escalation Phase is designed to determine the safety and tolerability of Compound I. Dose escalation decisions are conducted according to set criteria and rules including a target toxicity rate for the MTD and escalation / de-escalation boundaries.

[0220] Successive cohorts of participants receive Compound I at increasing dosages until the presumptive RP2D(s) is / are reached. Certain Compound I dose levels that can be evaluated are presented in Table 6 and Table 7as an example.45 of 6213326598v1Attorney Docket No.: 2013405-0090Table 6: Certain Compound I Dose LevelsDose Level Proposed Compound I DoseDose -1 3 mgStarting Dose 5 mgDose 2 10 mgDose 3 16 mgDose 4 24 mgDose 5 33 mgDose 6 43 mgTable 7: Certain Compound I Dose LevelsDose Level Proposed Compound I DoseDose -1 2 mgDose - 2 1 mgStarting Dose 5 mgDose 2 10 mgDose 3 16 mgDose 4 24 mgDose 5 33 mgDose 6 43 mg

[0221] Intra-participant dose escalation may be permitted. For example, participants who are receiving a dosage of Compound I that has been cleared for escalation may be escalated to a higher dosage that has been cleared for escalation by the CST under certain circumstances.

[0222] Concomitant Therapies

[0223] All concomitant medications including over-the-counter or prescription medicines, vitamins, and / or supplements taken and procedures conducted within 28 days prior to the first dose of study treatment and through 28 days after the last dose of study treatment during the study may be considered, including reason for use, dose information, and dates of administration. In addition, all prior treatments for the underlying malignancy may be considered.

[0224] In some embodiments, in a study or in a provided method, certain concomitant therapies are prohibited, certain concomitant therapies are monitored, and certain concomitant therapies are allowed.

[0225] In some embodiments, systemic strong CYP3A4 inhibitors and strong CYP3A4 inducers (see, e.g., Table 2) are prohibited. In some embodiments, subjects who are taking a triazole antifungal that is 46 of 6213326598v1Attorney Docket No.: 2013405-0090considered a strong C YP3 A4 inhibitor may be switched to alternative antifungal regimen that is not a strong CYP3A4 inhibitor. In some embodiments, use of P-gp and BCRP inhibitors and inducers are prohibited.

[0226] In some embodiments, proton pump inhibitors are prohibited. In some embodiments, subjects who are taking a proton pump inhibitor are switched to another acid-reducing agent such as an antacid or H2 blocker.

[0227] In some embodiments, use of antacids and H2 blockers is permitted according to the following guidelines:• Antacids: Compound I administered at least 4 hours before or at least 4 hours after administration of antacids.• H2 blockers: Compound I administered at least 4 hours before or at least 10 hours after administration of H2 blockers.

[0228] In some embodiments, use of P-gp and BCRP inhibitors is permitted according to the following guidelines:• Compound I administered at least 4 hours before or at least 4 hours after administration of the P-gp and / or BCRP inhibitor.

[0229] In some embodiments, use of sensitive P-gp substrates is permitted according to the following guidelines:• Compound I administered at least 4 hours before or at least 4 hours after administration of the sensitive P-gp substrate.

[0230] In some embodiments, hydroxyurea is administered prior to enrollment or start of Compound I. In some embodiments, hydroxyurea is adminstered after the start of Compound I for the control of peripheral leukemic blasts.

[0231] In some embodiments, a study has the following arms and interventions:Participant Group / Arm Intervention / Treatment Experimental: Dose Escalation - Part A Drug: Compound I Participants will receive escalating dosages of Compound I orally Compound I administered orally in tablet form once, twice or three times weekly to determine themaximum tolerated dose (MTD) and / or recommended Phase 2dose (RP2D).Experimental: Dose Optimization - Part B, Dosage 1 Drug: Compound I Participants will receive Compound I at the first selected dosage Compound I administered orally determined from Part A, administered orally in tablet form either47 of 6213326598v1Attorney Docket No.: 2013405-0090once, twice or three times weekly to further evaluate safety,pharmacokinetics (PK), pharmacodynamics (PD), andpreliminary clinical activity at this specified dose.Experimental: Dose Optimization - Part B, Dosage 2 Drug: Compound I Participants will receive Compound I at the second selected Compound I administered orally dosage determined from Part A. administered orally in tablet formeither once, twice or three times weekly to further evaluate safety,pharmacokinetics (PK), pharmacodynamics (PD), andpreliminary clinical activity at this specified dose.

[0232] In some embodiments, a study comprises one or more of the following assessments:Incidence of Adverse Events (AEs), Dose-Limiting Toxicities (DLTs), and Serious Adverse Events (SAEs), To Identify the Recommended Phase 2 Dose (RP2D) of Compound I, Peak Plasma Concentration (Cmax), Time to Maximum Concentration (Tmax), Area Under the Plasma Concentration-Time Curve from Time Zero to Infinity (AUCinf), Area Under the Plasma Concentration-Time Curve to the Last Measurable Concentration (AUClast), Elimination Half-Life (t½), Apparent Clearance (CL / F), Apparent Volume of Distribution (Vd / F), To characterize the PD of Compound 1, AML: Complete remission (CR) rate, AML: CR + CRh rate, AML: Duration of CR, AML: Duration of CR + CRh, Objective response rate (ORR), AML: Duration of response (DOR), AML: Transfusion independence (TI) rate, AML: Event free survival (EFS), AML: Overall survival (OS), MDS: Complete remission (CR) rate, MDS: PR rate, MDS: CR+PR rate, MDS: Duration of CR, MDS: Duration of PR, MDS: Duration of CR+PR, MDS: Event free survival (EFS), and MDS: Overall survival (OS). In some embodiments, KAT2A and / or KAT2B levels in peripheral blood and bone marrow are assessed. In some embodiments, KAT2A and / or KAT2B polypeptide levels in peripheral blood and bone marrow are assessed. In some embodiments, KAT2A and / or KAT2B transcript levels in peripheral blood and bone marrow are assessed. In some embodiments, changes in KAT2A and KAT2B levels in peripheral blood and bone marrow are utilized markers of pharmacodynamic response. In some embodiments, one or more bone marrow aspirates are performed.

[0233] In some embodiments, a study comprises one or more of the following assessments performed according to the below:Outcome Measure Measure Description Time Frame Incidence of Adverse Events To assess the safety and From the first dose through 28 (AEs), Dose-Limiting Toxicities tolerability of Compound I by days after the last dose of study48 of 6213326598v1Attorney Docket No.: 2013405-0090(DLTs), and Serious Adverse evaluating the incidence and drug.Events (SAEs) severity of AEs, DLTs, SAEs,and AEs leading to treatmentdiscontinuation.To Identify the Recommended To determine the RP2D of From the first dose through 28 Phase 2 Dose (RP2D) of Compound I based on safety, days after the last dose of study Compound I tolerability, pharmacokinetics drug.(PK), pharmacodynamics (PD),and preliminary clinical activitydata.Peak Plasma Concentration From the first dose through the (Cmax) first treatment cycle (28 days) Time to Maximum From the first dose through the Concentration (Tmax) first treatment cycle (28 days) Area Under the Plasma From the first dose through the Concentration-Time Curve from first treatment cycle (28 days) Time Zero to Infinity (AUCinf)Area Under the Plasma From the first dose through the Concentration-Time Curve to the first treatment cycle (28 days) Last Measurable Concentration(AUClast)Elimination Half-Life (t1 / 2) From the first dose through the first treatment cycle (28 days) Apparent Clearance (CL / F) From the first dose through the first treatment cycle (28 days) Apparent Volume of Distribution From the first dose through the (Vd / F) first treatment cycle (28 days) To characterize the PD of To evaluate changes in KAT2A From the first dose through 28 Compound I and KAT2B levels in peripheral days after the last dose of study blood and bone marrow as drugmarkers of pharmacodynamicresponse49 of 6213326598v1Attorney Docket No.: 2013405-0090AML: Complete remission (CR) Up to 18 months rateAML: CR + CRh rate Up to 18 months AML: Duration of CR Up to 18 months AML: Duration of CR + CRh Up to 18 months Objective response rate (ORR) Up to 24 months AML: Duration of response Up to 18 months (DOR)AML: Transfusion independence Up to 18 months (TI) rateAML: Event free survival (EFS) Up to 24 months AML: Overall survival (OS) Up to 24 months MDS: Complete remission (CR) Up to 18 months rateMDS: PR rate Up to 18 months MDS: CR+PR rate Up to 18 months MDS: Duration of CR Up to 18 months MDS: Duration of PR Up to 18 months MDS: Duration of CR+PR Up to 18 months MDS: Event free survival (EFS) Up to 24 months MDS: Overall survival (OS) Up to 24 months50 of 6213326598v1

Claims

Attorney Docket No.: 2013405-0090CLAIMS1. A method, comprising administering to a subject suffering from a condition, disease or disorder a dose of a compound having the structure of formula I (“Compound I”);Iwherein the amount of Compound I in the dose is about 1 mg or more (e.g., about Img, 2 mg, 3 mg, 5 mg, 10 mg, 16 mg, 24 mg, 33 mg, 43 mg or more) in free base form.

2. The method of any one of the preceding claims, wherein the condition, disease or disorder is or comprises an advanced hematologic malignancy.

3. The method of any one of the preceding claims, wherein the condition, disease or disorder is or comprises acute myeloid leukemia (AML).

4. The method of any one of the preceding claims, wherein the AML is relapsed AML.

5. The method of any one of the preceding claims, wherein the AML is refractory AML.

6. The method of any one of the preceding claims, wherein the subject has not achieved an adequate response to, cannot tolerate, and / or refused all approved therapies known to be active for treatment of AML.

7. The method of any one of the preceding claims, wherein the condition, disease or disorder is relapsed or refractory AML that has relapsed after the subject received hematopoietic stem cell transplantation (HSCT).

8. The method of any one of the preceding claims, wherein the condition, disease or disorder is or comprises myelodysplastic syndromes (MDS).

9. The method of claim 8, wherein the MDS is relapsed MDS.

10. The method of claim 8 or 9, wherein the MDS is refractory MDS.

11. The method of any one of claims 8-10, wherein the subject has at least 10% blasts in bone marrow.

12. The method of any one of claims 8-11, wherein the subject has not achieved an adequate response to at least about 4 cycles of a hypomethylating agent (HM A) -containing regimen or other treatment known to be active for their disease.51 of 6213326598v1Attorney Docket No.: 2013405-009013. The method of any one of claims 8-12, wherein the MDS has relapsed after a hematopoietic stem cell transplant (HSCT).

14. The method of any one of the preceding claims, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of no more than about 2.

15. The method of any one of the preceding claims, wherein the subject has adequate hepatic function.

16. The method of any one of the preceding claims, wherein the subject has adequate renal function.

17. The method of any one of the preceding claims, wherein the subject has adequate cardiovascular function.

18. The method of any one of the preceding claims, wherein the subject has a white blood cell count of no more than about 20 x 109cells / L.

19. The method of any one of the preceding claims, wherein the subject has received another anticancer therapy, and at least 2 weeks, or at least 5 half-lives, have elapsed prior to administration of the first dose of Compound I.

20. The method of any one of the preceding claims, wherein the subject has received prior hydroxyurea treatment.

21. The method of any one of the preceding claims, wherein the subject is on hydroxyurea treatment.

22. The method of any one of the preceding claims, wherein the subject has received radiotherapy, and at least about 2 weeks have elapsed since the last radiotherapy.

23. The method of any one of the preceding claims, wherein the subject has recovered from any clinically relevant effects of any prior surgery.

24. The method of any one of the preceding claims, wherein the subject has not received chimeric antigen receptor T cell therapy within about 60 days of an initial dose of Compound I.

25. The method of any one of the preceding claims, wherein the subject has not received HSCT within about 60 days of an initial dose of Compound I.

26. The method of any one of the preceding claims, wherein the subject does not have an active clinically significant graft-versus-host disease (GVHD).

27. The method of any one of the preceding claims, wherein the subject does not have another malignancy that may interfere with diagnosis and treatment of the condition, disease or disorder.

28. The method of any one of the preceding claims, wherein the subject does not have an active severe infection that requires anti-infective therapy.

29. The method of any one of the preceding claims, wherein the subject is not taking systemic strong CYP3A4 inhibitors or inducers within 14 days of the first dose of Compound I.52 of 6213326598v1Attorney Docket No.: 2013405-009030. The method of any one of the preceding claims, wherein the subject is not taking proton pump inhibitor.

31. The method of any one of the preceding claims, wherein the subject is on an acid-reducing agent which is not a proton pump inhibitor.

32. The method of any one of the preceding claims, wherein the subject is on an antacid or H2 blocker.

33. The method of any one of the preceding claims, wherein the subject is not taking a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitor or inducer within about 14 days of the first dose of Compound I.

34. The method of any one of the preceding claims, wherein the subject is not taking a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitor or inducer within about 5 half-lives of the first dose of Compound I.

35. The method of any one of claims 1-33, wherein the subject is taking a mild P-gp inhibitor (e.g., isavuconazonium sulfate, isavuconazole, etc.)36. The method of any one of the preceding claims, wherein the subject does not have active hepatitis B virus (HBV) or hepatitis C virus (HCV) infections with detectable viral load.

37. The method of any one of the preceding claims, wherein the subject has not experienced AIDS-related illness within the past 6 months or does not have detectable HIV viral load.

38. The method of any one of the preceding claims, wherein the subject does not have an uncontrolled intercurrent illness.

39. The method of any one of the preceding claims, wherein the subject does not have active Class III or IV cardiovascular disease within 6 months prior to the first dose of Compound I.

40. The method of any one of the preceding claims, wherein the subject is able to tolerate the administration of oral medication.

41. The method of any one of the preceding claims, wherein the subject does not have a GI dysfunction that would preclude adequate absorption, distribution, metabolism, or excretion of an oral medication.

42. The method of any one of the preceding claims, wherein the subject is not pregnant.

43. The method of any one of the preceding claims, wherein the subject is not breastfeeding.

44. The method of any one of the preceding claims, wherein Compound I is or comprises a structure as depicted in formula IA (“Structure IA”):53 of 6213326598v1Attorney Docket No.: 2013405-009045. The method of any one of the preceding claims, wherein Compound I is or comprises a free base form of Structure IA.

46. The method of any one of the preceding claims, wherein Compound I is or comprises a salt form of Structure IA.

47. The method of any one of the preceding claims, wherein Compound I is or comprises a solvate form of Structure IA.

48. The method of any one of the preceding claims, wherein Compound I is or comprises a solvate form of a salt form of Structure IA.

49. The method of any one of the preceding claims, wherein Compound I is or comprises a hydrate form of Structure IA.

50. The method of any one of the preceding claims, wherein Compound I is or comprises a hydrate form of a salt form of Structure IA.

51. The method of any one of the preceding claims, wherein Compound I is or comprises a structure as depicted in formula IB (“Structure IB”):

52. The method of any one of the preceding claims, wherein Compound I is or comprises a free base form of Structure IB.

53. The method of any one of the preceding claims, wherein Compound I is or comprises a salt form of Structure IB.

54. The method of any one of the preceding claims, wherein Compound I is or comprises a solvate form of Structure IB.54 of 6213326598v1Attorney Docket No.: 2013405-009055. The method of any one of the preceding claims, wherein Compound I is or comprises a solvate form of a salt form of Structure IB.

56. The method of any one of the preceding claims, wherein Compound I is or comprises a hydrate form of Structure IB.

57. The method of any one of the preceding claims, wherein Compound I is or comprises a hydrate form of a salt form of Structure IB.

58. The method of any one of the preceding claims, wherein the molar ratio of all forms of Structure IA and all forms of Structure IB in the dose is about 1:1.

59. The method of any one of the preceding claims, wherein the total amount of Structure IA free base form and Structure IB free base form in a dose is about the amount of Compound I in the dose in free base form.

60. The method of any one of the preceding claims, wherein Compound 1 in a dose exist in the form of Structure IA free base form or Structure IB free base form.

61. The method of any one of the preceding claims, wherein two or more doses are administered.

62. The method of any one of the preceding claims, wherein a dose is administered orally.

63. The method of any one of the preceding claims, wherein each dose is administered orally.

64. The method of any one of claims 1-59, wherein a dose is administered intravenously.

65. The method of any one of claims 1-60, wherein each dose is administered intravenously.

66. The method of any one of the preceding claims, comprising administering doses of Compound I about weekly.

67. The method of any one of the preceding claims, comprising administering doses of Compound I about weekly for about or at least about 4 weeks.

68. The method of any one of the preceding claims, comprising administering doses of Compound I about twice weekly.

69. The method of any one of the preceding claims, comprising administering doses of Compound I about twice weekly for about or at least about 4 weeks.

70. The method of any one of the preceding claims, comprising administering doses of Compound I about three times weekly.

71. The method of any one of the preceding claims, comprising administering doses of Compound I about three times weekly for about or at least about 4 weeks.

72. The method of any one of the preceding claims, wherein the subject is administered 4 or more doses every 28 days.55 of 6213326598v1Attorney Docket No.: 2013405-009073. The method of any one of the preceding claims, wherein doses are administered in one or more cycles each of which is independently about 28 days.

74. The method of any one of the preceding claims, wherein the amount of Compound I in a dose is about 1 mg in free base form.

75. The method of any one of the preceding claims, wherein the amount of Compound I in a dose is about 2 mg in free base form.

76. The method of any one of the preceding claims, wherein the amount of Compound I in a dose is about 3 mg in free base form.

77. The method of any one of the preceding claims, wherein the amount of Compound I in a dose is about 5 mg in free base form.

78. The method of any one of the preceding claims, wherein the amount of Compound I in a dose is about 10 mg in free base form.

79. The method of any one of the preceding claims, wherein the amount of Compound I in a dose is about 16 mg in free base form.

80. The method of any one of the preceding claims, wherein the amount of Compound I in a dose is about 24 mg in free base form.

81. The method of any one of the preceding claims, wherein the amount of Compound I in a dose is about 33 mg in free base form.

82. The method of any one of the preceding claims, wherein the amount of Compound I in a dose is about 43 mg in free base form.

83. The method of any one of claims 1-73, wherein the amount of Compound I in each dose is independently about 1 mg or more in free base form.

84. The method of any one of claims 1-73, wherein the amount of Compound I in each dose is independently about 2 mg or more in free base form.

85. The method of any one of claims 1 -73, wherein the amount of Compound 1 in each dose is independently about 3 mg or more in free base form.

86. The method of any one of claims 1-73, wherein the amount of Compound I in each dose is independently about 5 mg or more in free base form.

87. The method of any one of claims 1-73, wherein the amount of Compound I in each dose is independently about 5 mg in free base form.

88. The method of any one of claims 1-65, comprising administering Compound I about weekly, wherein the amount of Compound I in each dose is independently about 1 mg in free base form.56 of 6213326598v1Attorney Docket No.: 2013405-009089. The method of any one of claims 1-65, comprising administering Compound I about twice weekly, wherein the amount of Compound I in each dose is independently about 1 mg in free base form.

90. The method of any one of claims 1-65, comprising administering Compound I about three times weekly, wherein the amount of Compound I in each dose is independently about 1 mg in free base form.

91. The method of any one of claims 1-65, comprising administering Compound I about weekly, wherein the amount of Compound I in each dose is independently about 2 mg in free base form.

92. The method of any one of claims 1-65, comprising administering Compound I about twice weekly, wherein the amount of Compound I in each dose is independently about 2 mg in free base form.

93. The method of any one of claims 1-65, comprising administering Compound I about three times weekly, wherein the amount of Compound I in each dose is independently about 2 mg in free base form.

94. The method of any one of claims 1-65, comprising administering Compound I about weekly, wherein the amount of Compound 1 in each dose is independently about 5 mg in free base form.

95. The method of any one of claims 1-65, comprising administering Compound I about twice weekly, wherein the amount of Compound I in each dose is independently about 5 mg in free base form.

96. The method of any one of claims 1-65, comprising administering Compound I about three times weekly, wherein the amount of Compound I in each dose is independently about 5 mg in free base form.

97. The method of any one of claims 1-65, comprising administering Compound I about weekly, wherein the amount of Compound 1 in each dose is independently about 10 mg in free base form.

98. The method of any one of claims 1-65, comprising administering Compound I about twice weekly, wherein the amount of Compound I in each dose is independently about 10 mg in free base form.

99. The method of any one of claims 1-65, comprising administering Compound I about three times weekly, wherein the amount of Compound I in each dose is independently about 10 mg in free base form.

100. The method of any one of the preceding claims, wherein in each dose Compound I exists in the same forms.

101. The method of any one of the preceding claims, wherein the polypeptide level of lysine acetyltransferase 2A (KAT2A) and / or lysine acetyltransferase 2B (KAT2B) is assessed.

102. The method of claim 101, wherein the polypeptide level of lysine acetyltransferase 2A (KAT2A) and / or lysine acetyltransferase 2B (KAT2B) is reduced.

103. The method of any one of the preceding claims, wherein a level of H3K9 acetylation is assessed.

104. The method of claim 103, wherein the level of H3K9 acetylation is reduced.

105. The method of any one of the preceding claims, wherein one or more cell state signatures are assessed.57 of 6213326598v1Attorney Docket No.: 2013405-0090106. The method of any one of the preceding claims, wherein one or more markers of differentiation are assessed.

107. The method of any one of the preceding claims, wherein one or more morphologic changes are assessed.

108. The method of any one of claims 101-107, wherein assessment is performed for a population of the subjects.

109. The method of claim 108, wherein the subjects in the population receive the same dosing regimen.

110. The method of claim 108, wherein the subjects in the population receive different dosing regimen.

111. The method of any one of claims 1-110, wherein one or more peripheral blood and / or bone marrow samples are assessed.

112. The method of any one of claims 1-111, wherein one or more peripheral blood samples are assessed.

113. The method of any one of claims 1-112, wherein one or more bone marrow samples are assessed.

114. The method of any one of claims 1-113, wherein an assessment is performed:(i) about 4 hours, about 8 hours, about 12 hours, about 16 hours, about 20 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, or more days, or (ii) about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, or more weeks, or(ii) or about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, or more months;after administration of a dose and before a next dose, if any, is administered.

115. The method of any one of claims 1-114, wherein an assessment is performed once the subject achieves a complete remission (CR), CR with partial hematologic recovery (CRh), or CR with incomplete hematologic recovery (CRi).58 of 6213326598v1Attorney Docket No.: 2013405-0090116. The method of claim 115, wherein the assessment is performed at least about every 3 months.

117. The method of claim 115, wherein the assessment is performed until a relapse and / or suspected relapse.

118. The method of any one of the preceding claims, wherein Compound I is administered in a pharmaceutical composition.

119. The method of claim 118, wherein the pharmaceutical composition is a tablet.

120. A tablet, comprising:a compound having the structure of formula I (“Compound I”):Ia pharmaceutically acceptable excipient.

121. The tablet of claim 120, comprising a filler, a disintegrant, a binder, a lubricant, or a glidant.

122. The tablet of claim 120, comprising a filler, a disintegrant, a binder, a lubricant, and a glidant.

123. The tablet of claim 120, comprising:colloidal silicon dioxide;croscarmellose sodium;hydroxypropylcellulose;lactose monohydrate;magnesium stearate; andmicrocrystalline cellulose.

124. The tablet of any one of the preceding claims, wherein Compound I is or comprises a structure as depicted in formula IA (“Structure 1A”):59 of 6213326598v1Attorney Docket No.: 2013405-0090125. The tablet of any one of the preceding claims, wherein Compound I is or comprises a free base form of Structure IA.

126. The tablet of any one of the preceding claims, wherein Compound I is or comprises a salt form of Structure IA.

127. The tablet of any one of the preceding claims, wherein Compound I is or comprises a solvate form of Structure IA.

128. The tablet of any one of the preceding claims, wherein Compound I is or comprises a solvate form of a salt form of Structure IA.

129. The tablet of any one of the preceding claims, wherein Compound I is or comprises a hydrate form of Structure IA.

130. The tablet of any one of the preceding claims, wherein Compound I is or comprises a hydrate form of a salt form of Structure IA.

131. The tablet of any one of the preceding claims, wherein Compound I is or comprises a structure as depicted in formula IB (“Structure IB”):

132. The tablet of any one of the preceding claims, wherein Compound I is or comprises a free base form of Structure IB.

133. The tablet of any one of the preceding claims, wherein Compound I is or comprises a salt form of Structure IB.

134. The tablet of any one of the preceding claims, wherein Compound I is or comprises a solvate form of Structure IB.

135. The tablet of any one of the preceding claims, wherein Compound I is or comprises a solvate form of a salt form of Structure IB.

136. The tablet of any one of the preceding claims, wherein Compound I is or comprises a hydrate form of Structure IB.

137. The tablet of any one of the preceding claims, wherein Compound I is or comprises a hydrate form of a salt form of Structure IB.60 of 6213326598v1Attorney Docket No.: 2013405-0090138. The tablet of any one of the preceding claims, wherein the molar ratio of all forms of Structure IA and all forms of Structure IB in the composition is about 1:1.

139. The tablet of any one of the preceding claims, wherein the total amount of Compound I in the tablet is about 0.5 mg in free base form.

140. The tablet of any one of the preceding claims, wherein the total amount of Compound I in the tablet is about 3 mg in free base form.

141. The tablet of any one of the preceding claims, wherein the total amount of Compound I in the tablet is about 5 mg in free base form.

142. The tablet of any one of the preceding claims, wherein the total amount of Compound I in the tablet is about 10 mg in free base form.

143. The tablet of claim 139, wherein the total amount of Structure IA free base form and Structure IB free base form in the dose is about 0.5 mg.

144. The tablet of claim 140, wherein the total amount of Structure IA free base form and Structure IB free base form in the dose is about 3 mg.

145. The tablet of claim 141, wherein the total amount of Structure IA free base form and Structure IB free base form in the dose is about 5 mg.

146. The tablet of claim 142, wherein the total amount of Structure IA free base form and Structure IB free base form in the dose is about 10 mg.

147. The tablet of any one of the preceding claims, wherein the tablet is an immediate release tablet.

148. The tablet of any one of the preceding claims, wherein the tablet is film-coated.

149. The tablet of any one of the preceding claims, wherein the tablet is coated with a water-based color film coating.

150. The tablet of any one of the preceding claims, wherein the tablet is coated with a water-based Opadry II color film coating.

151. The tablet of any one of claims 120-147, wherein the tablet is uncoated.

152. The tablet of any one of the preceding claims, wherein the tablet is for oral administration.

153. The method of any one of the preceding claims, wherein the dose is administered as one or more tablets, each of which is independently a tablet of any one of claims 120-152.61 of 6213326598v1

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