VCP / p97 inhibitors for cancer treatment

Abstract

Described herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, or a pharma- ceutically acceptable salt thereof, whereby the subject experiences a therapeutic response.

Description

[Technical field]

[0001] Cross-reference of related payments This application claims the benefit of U.S. Provisional Patent Application No. 63 / 277,725, filed November 10, 2021, which is incorporated by reference herein in its entirety. [Background technology]

[0002] The valosin-containing protein VCP / p97 and its function are essential for continued cell viability. Summary of the Invention [Means for solving the problem]

[0003] 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide is a VCP / p97 inhibitor. In one aspect, described herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to 1500 mg, whereby the subject experiences a therapeutic response. In some embodiments, the pharmaceutical composition comprises the tosylate salt of 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide. In some embodiments, the dosage administered over a 24 hour period is about 450 mg to about 1250 mg, about 450 mg to about 1000 mg, about 450 mg to about 900 mg, about 450 mg to about 850 mg, about 450 mg to about 800 mg, about 450 mg to about 750 mg, about 450 mg to about 700 mg, about 450 mg to about 65 ... about 600 mg, about 600 mg to about 1250 mg, about 600 mg to about 1000 mg, about 600 mg to about 900 mg, about 600 mg to about 850 mg, about 600 mg to about 800 mg, about 600 mg to about 750 mg, about 600 mg to about 700 mg, about 900 mg to about 950 mg, about 900 mg to about 1000 mg, about 900 mg to about 1250 mg. In some embodiments, the dosage administered over a 24 hour period is about 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, or 1250 mg.In some embodiments, the dosage administered over a 24 hour period is about 450 mg to about 1250 mg, about 450 mg to about 1000 mg, about 450 mg to about 900 mg, about 450 mg to about 850 mg, about 450 mg to about 800 mg, about 450 mg to about 750 mg, about 450 mg to about 700 mg, about 450 mg to about 650 mg, about 450 mg to about 600 mg, about 600 mg to about 1250 mg, about 60 In some embodiments, the dosage administered over a 24 hour period is about 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1250 mg, or 1500 mg.

[0004] In some embodiments, the doses administered over a 24 hour period are administered as a single dose per day on the day of administration.

[0005] In some embodiments, the dose over a 24 hour period is administered as a twice daily dose on the day of administration, such that the total dose is divided into two smaller doses. In some embodiments, the dose over a 24 hour period is administered as a twice daily dose on the day of administration, such that the total dose is divided into two smaller doses, each of the two smaller doses comprising the same dose. In some embodiments, the dose over a 24 hour period is administered as a twice daily dose on the day of administration, such that the total dose is divided into two smaller doses, each of the two smaller doses comprising a different dose. In some embodiments, the dose over a 24 hour period is administered as a twice daily dose on the day of administration, such that the total dose is divided into two smaller doses, and the time interval between administration of the first daily dose and administration of the second daily dose is 8 to 12 hours.

[0006] In some embodiments, the cancer is selected from the group consisting of solid tumors, metastatic forms of solid tumors, progressive metastatic solid tumors, lymphomas, and aggressive lymphomas. In some embodiments, the cancer is a hematological cancer. In some embodiments, the cancer is acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), myelodysplastic / myeloproliferative overlap neoplasms (MDS / MPN), CMML (chronic myelomonocytic leukemia), atypical CML (chronic myelogenous leukemia), multiple myeloma, myeloma, amyloidosis, Waldenstrom's macroglobulinemia (also known as lymphoplasmacytic lymphoma), acute lymphoblastic leukemia (ALL), B-lymphoblastic leukemia, T-lymphoblastic leukemia, lymphoma, B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, B-cell acute lymphoblastic lymphoma, T ... The cancer is selected from the group consisting of follicular acute lymphoblastic lymphoma, Burkitt's leukemia / lymphoma, non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), B-cell NHL, follicular lymphoma, marginal zone lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma (DLBCL), double / triple hit B-cell lymphoma, myeloproliferative neoplasms (MPN), essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis, primary myelofibrosis, post-PV myelofibrosis, post-ET myelofibrosis, chronic myelogenous leukemia (CML), blastic plasmacytoid dendritic cell neoplasm (BPDCN), M3 AML, and APL (acute promyelocytic leukemia). In some embodiments, the cancer is acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). In some embodiments, the AML is relapsed AML, recurrent AML, refractory AML, or any combination thereof. In some embodiments, the AML is primary AML, secondary AML, including therapy-related AML and AML with myelodysplasia-related changes (AML with MRC), biphenotypic acute leukemia (also called acute leukemia of unknown lineage), or AML with recurrent abnormalities. In some embodiments, the AML is AML with actionable mutations. In some embodiments, the AML is AML without actionable mutations. In some embodiments, the MDS is relapsed or refractory MDS.In some embodiments, the MDS is classified as low-risk, intermediate-risk, high-risk, or very high-risk MDS by the International Prognostic Scoring System-Revised (IPSS-R). In some embodiments, the MDS is selected from the group consisting of MDS with single lineage dysplasia (MDS-SLD), MDS with multilineage dysplasia (MDS-MLD), MDS with ringed sideroblasts (MDS-RS), MDS with ringed sideroblasts with single lineage dysplasia (MDS-RS-SLD), MDS with ringed sideroblasts (MDS-RS), MDS with ringed sideroblasts with multilineage dysplasia (MDS-RS-MLD), MDS with excess blasts 1 and / or excess blasts 2 (MDS-EB-1, MDS-EB-2), unclassified MDS (MDS-U), and MDS with isolated del(5q).

[0007] In some embodiments, a subject is treated regardless of the subject's mutation or cytogenetic status.

[0008] In some embodiments, therapeutic response includes complete remission, complete remission with minimal residual disease, complete remission with incomplete hematologic recovery, morphologic leukemia-free status or partial remission, hematologic improvement, complete cytogenetic response, transfusion independence, red blood cell transfusion independence or platelet transfusion independence, or eligibility for stem cell transplantation.

[0009] In some embodiments, the therapeutic response comprises an increase in overall survival, an increase in recurrence-free survival, an increase in event-free survival, an increase in duration of response, or a decrease in the cumulative incidence of recurrence.

[0010] In some embodiments, the pharmaceutical composition is administered in a regimen that includes (a) administering the agent to the subject for 4 consecutive days followed by 3 consecutive days without administration, (b) administering the agent to the subject for 5 consecutive days followed by 2 consecutive days without administration, (c) administering once a week, or (d) administering twice a week. In some embodiments, the administration regimen is repeated. In some embodiments, the pharmaceutical composition is administered in 28-day cycles that include administration on days 1-4, 8-11, 15-18, and 22-25 of each cycle. In some embodiments, the 28-day cycle is repeated at least once. In some embodiments, the 28-day cycle is repeated until relapse.

[0011] In some embodiments, the pharmaceutical composition is administered orally.

[0012] In some embodiments, the pharmaceutical composition is administered as a tablet or capsule.

[0013] In some embodiments, the cancer is AML and the subject is diagnosed with ABL1, ASXL1, BCOR, BCORL1, BCR, BRAF, CALR, CBFB, CBL, CBLB, CDKN2A, CEBPA, CSF3R, CUX1, DEK, DNMT3A, ETV6, EZH2, FBXW7, FLT3, GATA1, GATA2, GNAS, HRAS, IDH1, IDH2, IKZF1, JAK2, JAK3, KDM6A, KIT , KMT2A, MECOM(EVI1), MLL, MLLT3, MPL, MYD88, MYH11, NOTCH1, NPM1, NUP214, NRAS, PDGFRA, PHF6, PTEN, PTPN11, RAD21, RUNX1, SF3B1, SRSF2, SMC1A, SMC3, STAG2, TET2, TP53, U2AF1, WT1, and ZRSR2.

[0014] In some embodiments, the treatment further comprises administration of a second therapeutic agent. In some embodiments, the second therapeutic agent is a DNA damaging agent, a methylation inhibitor, an agent that disrupts DNA synthesis, or an agent that disrupts DNA replication. In some embodiments, the second therapeutic agent is decitabine, azacytidine, or cytarabine. In some embodiments, the second therapeutic agent is cytarabine administered in a 7+3 regimen with an anthracycline antibiotic. In some embodiments, the 7+3 comprises 7 days of cytarabine and 3 days of an anthracycline antibiotic selected from daunorubicin, doxorubicin, idarubicin, and mitoxantrone. In some embodiments, the second therapeutic agent is a tyrosine kinase inhibitor. In some embodiments, the second therapeutic agent is a DNA damage repair inhibitor. In some embodiments, the second therapeutic agent is an inhibitor of ATM, ATR, PARP, or Chk1. In some embodiments, the second therapeutic agent is a proteasome inhibitor. In some embodiments, the second therapeutic agent is Velcade (bortezomib), Kyprolis (carfilzomib), or Ninlaro (ixazomib). In some embodiments, the second therapeutic agent is lenalidomide, pomalidomide, dexamethasone, or a combination of two of them, one agent being dexamethasone. In some embodiments, the second therapeutic agent is an inhibitor of FLT3, IDH1, or IDH2. In some embodiments, the second therapeutic agent is an immuno-oncology agent or an immunomodulatory agent. In some embodiments, the second therapeutic agent is Circlisa (isatuximab) or other CD38-targeted monoclonal antibody. In some embodiments, the anti-CD38 antibody is Circlisa (isatuximab). In some embodiments, the anti-CD38 antibody is daratumumab. In some embodiments, the second therapeutic agent comprises a menin inhibitor. In some embodiments, the second therapeutic agent comprises SNDX-5613. In some embodiments, the second therapeutic agent comprises KO-539. In some embodiments, the second therapeutic agent comprises a selective inhibitor of nuclear export. In some embodiments, the second therapeutic agent comprises selinexor.In some embodiments, the cancer is selected from the group consisting of solid tumors, metastatic forms of solid tumors, advanced metastatic solid tumors, lymphomas, and advanced lymphomas. In some embodiments, the subject has received at least one prior therapy. In some embodiments, the second therapeutic agent comprises gilteritinib, midostaurin, quizartinib, or an analog thereof. In some embodiments, the second therapeutic agent comprises gilteritinib or an analog thereof. In some embodiments, the second therapeutic agent comprises midostaurin or an analog thereof. In some embodiments, the second therapeutic agent comprises quizartinib or an analog thereof. In some embodiments, the cancer comprises a FLT3 mutation. In some embodiments, the second therapeutic agent inhibits poly ADP ribose polymerase (PARP). In some embodiments, the second therapeutic agent comprises talazoparib, olaparib, niraparib, or an analog thereof. In some embodiments, the cancer comprises a BRCA-2 mutation. In some embodiments, the cancer is MSI high. In some embodiments, the cancer comprises a mutation that inhibits homologous recombination. In some embodiments, the second therapeutic agent inhibits Bcl-2. In some embodiments, the second therapeutic agent comprises a BH3 mimetic. In some embodiments, the BH3 mimetic comprises venetoclax or an analog thereof. In some embodiments, the cancer is a bcr-abl negative myeloid tumor. In some embodiments, the administration does not result in visual impairment in the subject. In some embodiments, the second therapeutic agent is administered prior to administration of the pharmaceutical composition. In some embodiments, the second therapeutic agent is administered about 24 hours or 1 day prior to administration of the pharmaceutical composition. Incorporation by Reference

[0015] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference, to the extent applicable and relevant, and to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. [Brief description of the drawings]

[0016] [Figure 1] Plasma concentration-time plots for doses of 25 mg, 50 mg, 100 mg, 175 mg, 275 mg, 350 mg, and 450 mg of Compound 1 on Day 1 in Cohorts 1-7. [Diagram 2] Plasma concentration-time plots for doses of 25 mg, 50 mg, 100 mg, 175 mg, 275 mg, 350 mg, and 450 mg of Compound 1 on Day 4 in Cohorts 1-7. [Figure 3A] Graphs of AUC0-t versus dose on days 1 and 4 (Figures 3A and 3C), and Cmax versus dose on days 1 and 4 (Figures 3B and 3D). [Figure 3B] Graphs of AUC0-t versus dose on days 1 and 4 (Figures 3A and 3C), and Cmax versus dose on days 1 and 4 (Figures 3B and 3D). [Figure 3C] Graphs of AUC0-t versus dose on days 1 and 4 (Figures 3A and 3C), and Cmax versus dose on days 1 and 4 (Figures 3B and 3D). [Figure 3D] Graphs of AUC0-t versus dose on days 1 and 4 (Figures 3A and 3C), and Cmax versus dose on days 1 and 4 (Figures 3B and 3D). [Figure 4] 1 is a comparison of plasma concentration-time plots for Compound 1 and CB-5083. [Diagram 5] FIG. 1 is the structure of 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide (CB-5339, also referred to herein as Compound 1). [Figure 6]Clinical objectives and endpoints for administration of 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide are presented. Abbreviations used in Figure 6: AML = acute myeloid leukemia, AUC∞ = area under the plasma concentration-time curve from time 0 to 24 hours, AUC0-t = area under the concentration-time curve from time 0 to the last quantifiable time point, Cmax = maximum observed plasma concentration, CR = complete remission, CRi = complete remission within complete hematologic recovery, DoCR = duration of complete remission / complete remission with incomplete hematologic recovery, DoR = duration of remission, ELN = European LeukemiaNet, IWG = International Working Group, MTD = maximum tolerated dose, MDS = myelodysplastic syndromes, MPN = myeloproliferative neoplasms, PD = pharmacodynamics, PK = pharmacokinetics, PR = partial remission, RP2D = recommended phase 2 dose, RR = relapsed / refractory, to = half-life, tmax = time to reach maximum concentration. [Figure 7A] 1 is a graph of AUC0-t versus dose on Day 1. [Figure 7B] 4 is a graph of AUC0-t versus dose on day 4. [Figure 8A] 1 is a graph of Cmax vs. dose on Day 1. [Figure 8B] 4 is a graph of Cmax versus dose on day 4. [Figure 9] FIG. 1 is a comparison of plasma concentration-time plots of Compound 1 administered QD and BID on day 1. [Figure 10] FIG. 11 is a comparison of plasma concentration-time plots of Compound 1 administered QD and BID on day 4. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] Despite the considerable heterogeneity of tumors, malignant transformation endows cancer cells with common features, so-called "hallmarks of cancer", including replicative immortality, resistance to negative growth signals and apoptosis, and the ability to induce angiogenesis. While these properties confer a survival advantage to cancer cells, they also expose them to stress conditions that normal cells do not normally experience, forcing them to rely on intracellular pathways that are essentially non-oncogenic, but nevertheless essential for survival (i.e., "non-oncogenic dependent"). Based on this observation, mechanisms of stress overload that interact with cancer cells in a synthetic lethal manner are considered viable options for therapeutic intervention.

[0018] Two major stresses that cancer cells face are proteotoxic stress and genomic stress. Proteotoxic stress, i.e., the inappropriate overproduction of intracellular and extracellular proteins, including normal proteins, mutated cancer-associated proteins, and novel cancer-associated fusion proteins, leads to a dependency on proteostasis pathways and the misfolded protein response. The high levels of proteotoxic stress in cancer cells suggest that therapeutic strategies targeting proteostasis should show significant anticancer activity by inducing apoptosis in cancer cells that are overly dependent on proteostasis mechanisms. Although proteostasis and degradation pathways are not unique to cancer cells, their overdependence on these systems may lead to increased sensitivity to certain inhibitors of proteostasis, resulting in anticancer effects that are less toxic to normal cells. Genomic stress in cancer cells arises from initial mutations in genes involved in genome integrity that enable neoplastic transformation, their rapid proliferation potential, and the DNA replication errors that accompany their proliferation, and may be amplified by the number of mutations that cancer cells harbor in the mechanisms responsible for replication fidelity and proper repair of DNA damage that occurs during these processes.

[0019] There are two major intracellular degradation pathways that control protein homeostasis: the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal system (ALS). The valosin-containing protein VCP / p97 has a well-described role in the UPS, where it extracts misfolded proteins from the endoplasmic reticulum in a process called endoplasmic reticulum-associated degradation (ERAD) and directs a subset of proteins to the proteasome for degradation. VCP / p97 also plays an important role in regulating chromatin-associated events such as DNA damage response and repair. VCP / p97 is known to be overproduced in multiple cancers. Thus, pharmacological interference with VCP / p97 function is expected to have significant antitumor effects by generating irresolvable endoplasmic reticulum (ER) stress and / or irresolvable genotoxic stress. Thus, inhibitors of VCP / p97 function could provide a mechanism to exploit cancer cells' dependency on protein homeostasis and DNA damage repair pathways.

[0020] There is a need for inhibitors of VCP / p97 that are useful cancer therapeutic agents. One such inhibitor is 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide (Compound 1). Provided herein are methods of treating cancer with Compound 1, including dosages of Compound 1 and dosing regimens to achieve a therapeutic response, such as in difficult-to-treat cancer types and subtypes. Methods herein include methods for increasing efficacy and / or reducing or mitigating potential side effects. Also provided are methods for increasing efficacy or therapeutic response and / or expanding the range of cancers that can be treated by combining Compound 1 with additional therapeutic agents.

[0021] definition In this specification and the appended claims, unless otherwise stated, the following terms have the meanings indicated below.

[0022] The singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "an agent" includes a plurality of such agents, and a reference to "the cell" includes a reference to one or more cells (or cells) and their equivalents. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of the ranges and specific embodiments therein are intended to be included. The term "about" when referring to a numerical value or numerical range means that the referenced numerical value or numerical range is an approximation within experimental variation (or within statistical experimental error), and thus the numerical value or numerical range varies from 1% to 15% of the stated numerical value or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude other specific embodiments, such as those that "consist of" or "consist essentially of" the described features, such as any compositions, compositions, methods, uses, or processes of matter described herein.

[0023] "Optionally" or "optionally" means that the event or circumstance described thereafter may or may not occur, and that the description includes both cases where the event or circumstance occurs and cases where it does not occur.

[0024] As used herein, "treatment" or "treating" or "alleviating" or "ameliorating" are used interchangeably herein. These terms refer to an approach to obtain a beneficial or desired outcome, including but not limited to therapeutic benefit and / or preventive benefit. "Therapeutic benefit" refers to eradication or amelioration of the underlying disease being treated. Also, the therapeutic effect is achieved by eradicating or ameliorating one or more physiological symptoms associated with the underlying disease, so that an improvement in the patient's condition is observed even though the patient still suffers from the underlying disease. For preventive effect, the composition is administered to a patient at risk of developing a particular disease or a patient who reports one or more physiological symptoms of the disease, even though the patient has not been diagnosed with the disease.

[0025] Dosage amounts and dosage ranges of Compound 1 described herein refer to dosages of the free base of Compound 1 or dosages of a pharma- ceutically acceptable salt form of Compound 1.

[0026] In some embodiments, "participant," "subject," and "patient" are used interchangeably. In some embodiments, "subject" refers to a healthy individual. In other embodiments, "subject" refers to a patient in need of treatment. In some embodiments, "subject" refers to a human or animal, particularly a mammal. In some embodiments, "subject" refers to a human. In some embodiments, "subject" refers to a non-human mammal.

[0027] 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide (Compound 1) is a VCP / p97 inhibitor. 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide (Compound 1) is CB-5339. "Compound 1", "CB-5339", or "1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide" refers to a compound having the structure:

[0028] [ka]

[0029] In some embodiments, compound 1 is in the form of a pharma- ceutically acceptable salt. In some embodiments, compound 1 is in the form of a pharma- ceutically acceptable salt selected from hydrochloride, hydrobromide, sulfate, methanesulfonate, benzenesulfonate, toluenesulfonate, phosphate, citrate, tartrate, gentisate, acetate, adipate, benzoate, glutamate, glycolate, lactate, malate, malonate, and succinate. In some embodiments, compound 1 is in the form of a toluenesulfonate. In some embodiments, compound 1 is in the form of a sulfate. In some embodiments, compound 1 is in the form of a hydrochloride. In some embodiments, compound 1 is a free base. Furthermore, compound 1 can exist in a nonsolvated form as well as in a solvated form with a pharma- ceutically acceptable solvent. In some embodiments, compound 1 is solvated. In some embodiments, compound 1 is nonsolvated.

[0030] As used herein, "pharmacologically acceptable" refers to a substance, such as a carrier or diluent, that does not interfere with the biological activity or properties of the compound and is relatively non-toxic, i.e., that the substance may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0031] The term "pharmaceutical acceptable salt" refers to a form of a therapeutically active agent that consists of the cationic form of the therapeutically active agent combined with a suitable anion, or in an alternative embodiment, the anionic form of the therapeutically active agent combined with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. SM Berge, LD Bighley, DC Monkhouse, J.Pharm.Sci. 1977, 66, 1-19. PH Stahl and CG Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. Pharmaceutical salts are useful in solid dosage forms because they are generally more soluble in gastric and intestinal fluids and dissolve more rapidly than non-ionic species. Furthermore, the solubility of pharmaceutical salts is often a function of pH, allowing selective dissolution in certain parts of the gastrointestinal tract, a feature that can be manipulated as an aspect of delayed- and sustained-release behavior. Salt-forming molecules can also be in equilibrium with neutral forms, allowing for tailored passage across biological membranes.

[0032] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent and are formed during the product formation or isolation process using pharma- ceutically acceptable solvents such as water, ethanol, methanol, tert-butyl methyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptane, toluene, anisole, acetonitrile, and the like. In some embodiments, the solvates are formed using, but are not limited to, Class 3 solvent(s). In some embodiments, the solvates are formed using, but are not limited to, Class 2 solvent(s). Solvent categories are defined, for example, in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), “Impurities: Guidelines for Residual Solvents Q3C(R6),” (October 2016). Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol.

[0033] In some embodiments, Compound 1 is prepared in various forms, including, but not limited to, amorphous phase, crystalline form, milled form, and nanoparticulate form.

[0034] method Disclosed herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharmaceutically acceptable salt thereof at a dose of about 450 mg to about 1500 mg, whereby the subject experiences a therapeutic response. In some embodiments, the method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable salt of 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide at a dose of about 450 mg to about 1500 mg. In some embodiments, the method of treating cancer in a subject in need of such treatment comprises administering to the subject a pharmaceutical composition comprising the toluenesulfonate salt of 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide at a dosage of about 450 mg to about 1500 mg. In some embodiments, the method of treating cancer in a subject in need of such treatment comprises administering to the subject a pharmaceutical composition comprising the sulfate salt of 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide at a dosage of about 450 mg to about 1500 mg. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising the hydrochloride salt of 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide in a dosage of about 450 mg to about 1500 mg.

[0035] In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide free base at a dosage of about 450 mg to about 1500 mg, whereby the subject experiences a therapeutic response.

[0036] In some embodiments, a therapeutic response includes achievement of one or more response criteria as measured by medical standards established or proposed, such as by a nationally or internationally recognized medical consortium. Exemplary criteria include the 2017 European LeukemiaNet (ELN) response criteria for AML (Dohner et al. (2017), Blood Vol. 129 (4) 424-427), the 2006 revised International Working Group (IWG) response criteria for MDS (Cheson et al. (2006), Blood Vol. 108 (2), 419-25), and the International Consortium's proposal for uniform response criteria for adult myelodysplastic / myeloproliferative neoplasms (MDS / MPN) (Savona et al. Blood (2015), Vol. 125 (12), 1857-65); see also Tefferi et al. Blood (2013), Vol. 122 (8), 1395-98.

[0037] In some embodiments, a method of treating cancer in a subject in need thereof includes administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutical acceptable salt thereof, wherein the dosage administered over a 24 hour period is from about 450 mg to about 1250 mg, from about 450 mg to about 1000 mg, from about 450 mg to about 900 mg, from about 450 mg to about 850 mg, from about 450 mg to about 900 mg, from about 450 mg to about 1000 mg, from about 450 mg to about 1250 mg, from about 450 mg to about 1000 mg, from about 450 mg to about 1500 mg, from about 450 mg to about 1600 mg, from about 450 mg to about 1800 mg, from about 450 mg to about 2000 mg, from about 450 mg to about 2000 mg, from about 450 mg to about 3000 mg, from about 450 mg to about 500 mg, from about 450 mg to about 600 mg, from about 450 mg to about 700 mg, from about 450 mg to about 800 mg, from about 450 mg to about 900 mg, from about 450 mg to about 1000 mg, from about 450 mg to about 2000 mg, from about 450 mg to about 3000 mg, from about 450 mg to about 500 mg, from about 450 mg to about 600 mg, from about 450 mg to about 700 mg, from about 450 mg to about 80 50 mg to about 800 mg, about 450 mg to about 750 mg, about 450 mg to about 700 mg, about 450 mg to about 650 mg, about 450 mg to about 600 mg, about 600 mg to about 1250 mg, about 600 mg to about 1000 mg, about 600 mg to about 900 mg, about 600 mg to about 850 mg, about 600 mg to about 800 mg, about 600 mg to about 750 mg, about 600 mg to about 700 mg, about 900 mg to about 950 mg, about 900 mg to about 1000 mg, about 900 mg to about 1250 mg, whereby the subject experiences a therapeutic response. In some embodiments, a method of treating cancer in a subject in need thereof includes administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutical acceptable salt thereof, wherein the dosage administered over a 24 hour period is about 450 mg to about 1250 mg, about 450 mg to about 1000 mg, about 450 mg to about 900 mg, about 450 mg to about 850 mg, about 450 mg to about 800 mg, about 450 mg to about 1000 mg, about 450 mg to about 15 ... mg to about 750 mg, about 450 mg to about 700 mg, about 450 mg to about 650 mg, about 450 mg to about 600 mg, about 600 mg to about 1250 mg, about 600 mg to about 1000 mg, about 600 mg to about 900 mg, about 600 mg to about 850 mg, about 600 mg to about 800 mg, about 600 mg to about 750 mg, about 600 mg to about 700 mg, about 900 mg to about 950 mg, about 900 mg to about 1000 mg, about 900 mg to about 1250 mg, about 1000 mg to about 1250 mg, about 1000 mg to about 1500 mg, or about 1250 mg to about 1500 mg.In some embodiments, a method of treating cancer in a subject in need of such treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period. In some embodiments, a method of treating cancer in a subject in need of such treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1250 mg administered over a 24 hour period. In some embodiments, a method of treating cancer in a subject in need of such treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1000 mg administered over a 24 hour period. In some embodiments, a method of treating cancer in a subject in need of such treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 900 mg administered over a 24 hour period. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof, at a dosage of about 450 mg to about 850 mg administered over a 24 hour period.In some embodiments, a method of treating cancer in a subject in need of such treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharmaceutically acceptable salt thereof at a dosage of about 450 mg to about 800 mg administered over a 24 hour period. In some embodiments, a method of treating cancer in a subject in need of such treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharmaceutically acceptable salt thereof at a dosage of about 450 mg to about 750 mg administered over a 24 hour period. In some embodiments, a method of treating cancer in a subject in need of such treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharmaceutically acceptable salt thereof at a dosage of about 450 mg to about 700 mg administered over a 24 hour period. In some embodiments, a method of treating cancer in a subject in need of such treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharmaceutically acceptable salt thereof at a dosage of about 450 mg to about 650 mg administered over a 24 hour period. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutical acceptable salt thereof, at a dosage of about 450 mg to about 600 mg administered over a 24 hour period.In some embodiments, a method of treating cancer in a subject in need of such treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharmaceutically acceptable salt thereof at a dosage of about 600 mg to about 1500 mg administered over a 24 hour period. In some embodiments, a method of treating cancer in a subject in need of such treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharmaceutically acceptable salt thereof at a dosage of about 600 mg to about 1250 mg administered over a 24 hour period. In some embodiments, a method of treating cancer in a subject in need of such treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharmaceutically acceptable salt thereof at a dosage of about 600 mg to about 1000 mg administered over a 24 hour period. In some embodiments, a method of treating cancer in a subject in need of such treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharmaceutically acceptable salt thereof at a dosage of about 600 mg to about 900 mg administered over a 24 hour period. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, or a pharma- ceutically acceptable salt thereof, at a dosage of about 600 mg to about 850 mg administered over a 24 hour period.In some embodiments, a method of treating cancer in a subject in need of such treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 600 mg to about 800 mg administered over a 24 hour period. In some embodiments, a method of treating cancer in a subject in need of such treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 600 mg to about 750 mg administered over a 24 hour period. In some embodiments, a method of treating cancer in a subject in need of such treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 600 mg to about 700 mg administered over a 24 hour period. In some embodiments, a method of treating cancer in a subject in need of such treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 600 mg to about 650 mg administered over a 24 hour period. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof, at a dosage of about 900 mg to about 1250 mg administered over a 24 hour period.In some embodiments, a method of treating cancer in a subject in need of cancer treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharmaceutically acceptable salt thereof at a dosage of about 900 mg to about 1000 mg administered over a 24 hour period. In some embodiments, a method of treating cancer in a subject in need of cancer treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharmaceutically acceptable salt thereof at a dosage of about 1000 mg to about 15 ... The method of treating cancer in a subject includes administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutical acceptable salt thereof at a dosage of about 1250 mg to about 1500 mg administered over a 24 hour period. In some embodiments, the dose administered over a 24 hour period is administered BID (twice a day), such that a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutical acceptable salt thereof is administered in a total dose over a 24 hour period of about 450 mg to about 1250 mg, about 450 mg to about 1000 mg, about 450 mg to about 900 mg, about 450 mg to about 850 mg, or about 500 mg to about 600 mg. 0 mg, about 450 mg to about 800 mg, about 450 mg to about 750 mg, about 450 mg to about 700 mg, about 450 mg to about 650 mg, about 450 mg to about 600 mg, about 600 mg to about 1250 mg, about 600 mg to about 1000 mg, about 600 mg to about 900 mg, about 600 mg to about 850 mg, about 600 mg to about 800 mg, about 600 mg to about 750 mg, about 600 mg to about 700 mg, about 900 mg to about 950 mg, about 900 mg to about 1000 mg, and about 900 mg to about 1250 mg.In some embodiments, the dose administered over a 24 hour period is administered BID (twice a day) such that a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutical acceptable salt thereof is administered in a total dose over a 24 hour period of about 450 mg to about 1250 mg, about 450 mg to about 1000 mg, about 450 mg to about 900 mg, about 450 mg to about 850 mg, about 450 mg to about 800 mg, about 450 mg to about 750mg, about 450mg to about 700mg, about 450mg to about 650mg, about 450mg to about 600mg, about 600mg to about 1250mg, about 600mg to about 1000mg, about 600mg to about 900mg, about 600mg to about 850mg, about 600mg to about 800mg, about 600mg to about 750mg, about 600mg to about 700mg, about 900mg to about 950mg, about 900mg to about 1000mg, about 900mg to about 1250mg, about 1000mg to about 1250mg, about 1000mg to about 1500mg, or about 1250mg to about 1500mg. In some embodiments, the pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof administered BID is administered at about 225 mg, 250 mg, 275 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, or 600 mg per dose. In some embodiments, each dose of the BID dosing schedule is administered at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 hours apart. In some embodiments, each dose of the BID dosing schedule is administered at least 4, 5, 6, 7, or 8 hours apart. In some embodiments, each dose of the BID dosing schedule is administered at least 9, 10, 11, 12, 13, or 14 hours apart. In some embodiments, each dose of the BID dosing schedule is administered at least 4, 6, 8, 10, 12, 14, or 16 hours apart.In some embodiments, each dose in the BID dosing schedule is administered 4-16, 4-12, 6-16, 6-14, 6-12, 6-10, 8-14, 8-12, 8-10, 9-10, 9-11, 9-12, 9-13, 9-14, 10-11, 10-12, 10-13, 10-14, 11-12, 11-13, 11-14, 12-13, 12-14, 13-14, or 14-16 hours apart. In some embodiments, each dose of the BID dosing schedule is administered 9-10, 9-11, 9-12, 9-13, 9-14, 10-11, 10-12, 10-13, 10-14, 11-12, 11-13, 11-14, 12-13, 12-14, or 13-14 hours apart. In some embodiments, each dose of the BID dosing schedule is administered 4-16, 4-12, 6-16, 6-14, 6-12, 6-10, 8-14, 8-12, 8-10, or 14-16 hours apart.

[0038] In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, or 1250 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response. In some embodiments, the dose administered over a 24 hour period is administered BID (twice a day) such that a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof is administered at a total dose of about 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, or 1250 mg over a 24 hour period. In some embodiments, the dose administered over a 24 hour period is administered BID (twice a day) such that a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof is administered in a total dose of about 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1250 mg, or 1500 mg over a 24 hour period. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof, at a dosage of about 450 mg administered over a 24 hour period.In some embodiments, the 450 mg dose is comprised of two doses administered over a 24 hour period, such as two doses of 225 mg each. In some embodiments, the 450 mg dose is comprised of a single dose administered over a 24 hour period. In some embodiments, a method of treating cancer in a subject in need of such treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dose administered over a 24 hour period of about 500 mg. In some embodiments, the 500 mg dose is comprised of two doses administered over a 24 hour period, such as two doses of 250 mg each. In some embodiments, the 500 mg dose is comprised of a single dose administered over a 24 hour period. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof in a dose administered over a 24 hour period of about 600 mg. In some embodiments, the 600 mg dose consists of two doses administered over a 24 hour period, such as two doses of 300 mg each. In some embodiments, the 600 mg dose consists of a single dose administered over a 24 hour period. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof in a dose administered over a 24 hour period of about 700 mg. In some embodiments, the 700 mg dose is made up of two doses administered over a 24 hour period, such as two doses of 350 mg each.In some embodiments, the 700 mg dose is comprised of a single dose administered over a 24 hour period. In some embodiments, a method of treating cancer in a subject in need of cancer treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dose administered over a 24 hour period of about 800 mg. In some embodiments, the 800 mg dose is comprised of two doses administered over a 24 hour period, such as two doses of 400 mg each. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof in a dose administered over a 24 hour period of about 900 mg. In some embodiments, the 900 mg dose consists of two doses administered over a 24 hour period, such as two doses of 450 mg each. In some embodiments, the 900 mg dose consists of a single dose administered over a 24 hour period. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof in a dose administered over a 24 hour period of about 1000 mg. In some embodiments, the 1000 mg dose consists of two doses administered over a 24 hour period, such as two doses of 500 mg each. In some embodiments, the 1000 mg dose consists of a single dose administered over a 24 hour period.

[0039] In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the cancer is selected from the group consisting of a solid tumor, a metastatic form of a solid tumor, an aggressive metastatic solid tumor, lymphoma, and aggressive lymphoma, whereby the subject experiences a therapeutic response. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the cancer is a solid tumor. In some such embodiments, the dosage is administered as a single dose or in two divided doses BID. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the cancer is a metastatic form of a solid tumor. In some such embodiments, the dosage is administered as a single dose or BID in two divided doses. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the cancer is a progressive metastatic solid tumor.In some such embodiments, the dose is administered as a single dose or in two divided doses BID. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dose of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the cancer is lymphoma. In some such embodiments, the dose is administered as a single dose or in two divided doses BID. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the cancer is aggressive lymphoma. In some such embodiments, the dosage is administered as a single dose or is administered BID in two divided doses.

[0040] In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response. In some such embodiments, the dosage is administered as a single dose or BID in two divided doses. In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is a bcr-abl negative myeloid tumor. In some such embodiments, the dosage is administered as a single dose or BID in two divided doses.In some embodiments, the method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharmaceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is acute myeloid leukemia, acute myeloma, or acute myeloma. Myelodysplastic / myeloproliferative overlap neoplasms (MDS / MPN) such as myelodysplastic syndromes (MDS), MDS / MPN-RS-T, unclassified MDS / MPN, CMML (chronic myelomonocytic leukemia) such as CMML-1 and CMML-2, aCML (atypical chronic myelogenous leukemia), multiple myeloma, myeloma, amyloidosis, Waldenstrom's macroglobulinemia (also known as lymphoplasmacytic lymphoma), acute lymphoblastic leukemia, Allergic rheumatoid arthritis (ALL), B-lymphoblastic leukemia, T-lymphoblastic leukemia, lymphoma, B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, B-cell acute lymphoblastic lymphoma, T-cell acute lymphoblastic lymphoma, Burkitt's leukemia / lymphoma, Non-Hodgkin's lymphoma (NHL), Chronic lymphocytic leukemia (CLL), Small lymphocytic lymphoma (SLL), B-cell NHL, Follicular lymphoma, Marginal zone lymphoma, Mantle cell lymphoma, Diffuse large B-cell lymphoma In some such embodiments, the tumor is selected from the group consisting of: lymphoma (DLBCL), double / triple hit B-cell lymphoma, myeloproliferative neoplasms (MPN) including CES-NOS and unclassifiable MPN, essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis, primary myelofibrosis, post-PV myelofibrosis, post-ET myelofibrosis, post-PV / ET myelofibrosis, myelofibrosis secondary to PV and ET prognostic model [MYSEC-PM], chronic myeloid leukemia (CML), blastic plasmacytoid dendritic cell neoplasm (BPDCN), M3 AML, and APL (acute promyelocytic leukemia). In some such embodiments, the dose is administered as a single dose or BID in two divided doses.In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is acute myeloid leukemia (AML). In some such embodiments, the dosage is administered as a single dose or BID in two divided doses. In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is myelodysplastic syndrome (MDS). In some such embodiments, the dosage is administered as a single dose or BID in two divided doses. In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is myelodysplastic / myeloproliferative overlap neoplasm (MDS / MPN). In some aspects, the MDS / MPN is MDS / MPN-RS-T or unclassifiable MDS / MPN. In some such embodiments, the dosage is administered as a single dose or BID in two divided doses.In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is CMML (chronic myelomonocytic leukemia). In some aspects, the CMML is CMML-1 or CMML-2. In some such embodiments, the dosage is administered as a single dose or BID in two divided doses. In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is atypical chronic myeloid leukemia (aCML). In some such embodiments, the dosage is administered as a single dose or BID in two divided doses. In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is multiple myeloma. In some such embodiments, the dosage is administered as a single dose or BID in two divided doses.In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is myeloma. In some such embodiments, the dosage is administered as a single dose or is administered BID in two divided doses. In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is amyloidosis. In some such embodiments, the dosage is administered as a single dose or is administered BID in two divided doses. In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is Waldenstrom's macroglobulinemia (also known as lymphoplasmacytic lymphoma). In some such embodiments, the dosage is administered as a single dose or BID in two divided doses.In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is acute lymphoblastic leukemia (ALL). In some such embodiments, the dosage is administered as a single dose or BID in two divided doses. In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is B-lymphoblastic leukemia. In some such embodiments, the dosage is administered as a single dose or is administered BID in two divided doses. In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is T-lymphoblastic leukemia. In some such embodiments, the dosage is administered as a single dose or BID in two divided doses.In some embodiments, the method of treating a hematological cancer in a subject in need of treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutical acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is lymphoma. In some such embodiments, the dosage is administered as a single dose or administered BID in two divided doses. ... The method includes administering to a subject a pharmaceutical composition comprising 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutical acceptable salt thereof, in a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is B-cell acute lymphoblastic leukemia. In some such embodiments, the dosage is administered as a single dose or in two divided doses BID. In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is T-cell acute lymphoblastic leukemia. In some such embodiments, the dosage is administered as a single dose or BID in two divided doses. In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutical acceptable salt thereof at a dosage of about 450 mg to about 1500 mg, wherein the hematological cancer is B-cell acute lymphoblastic lymphoma. In some such embodiments, the dosage is administered as a single dose or BID in two divided doses. In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharmaceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is T-cell acute lymphoblastic lymphoma.In some such embodiments, the dosage is administered as a single dose or in two divided doses BID. In some embodiments, a method of treating hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is Burkitt's leukemia / lymphoma. In some such embodiments, the dosage is administered as a single dose or in two divided doses BID. In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is non-Hodgkin's lymphoma (NHL). In some such embodiments, the dosage is administered as a single dose or BID in two divided doses. In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is chronic lymphocytic leukemia (CLL). In some such embodiments, the dosage is administered as a single dose or BID in two divided doses.In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutical acceptable salt thereof at a dosage of about 450 mg to about 1500 mg, wherein the hematological cancer is small lymphocytic lymphoma (SLL). In some such embodiments, the dosage is administered as a single dose or BID in two divided doses. In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is B-cell NHL. In some such embodiments, the dosage is administered as a single dose or is administered BID in two divided doses. In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is follicular lymphoma. In some such embodiments, the dosage is administered as a single dose or is administered BID in two divided doses. In some embodiments, the method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharmaceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is marginal zone lymphoma.In some such embodiments, the dosage is administered as a single dose or in two divided doses BID. In some embodiments, a method of treating hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is mantle cell lymphoma. In some such embodiments, the dosage is administered as a single dose or in two divided doses BID. In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutical acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is diffuse large B-cell lymphoma (DLBCL). In some such embodiments, the dosage is administered as a single dose or BID in two divided doses. In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutical acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is double-hit / triple-hit B-cell lymphoma. In some such embodiments, the dosage is administered as a single dose or is administered BID in two divided doses.In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is a myeloproliferative neoplasm (MPN). In some aspects, the MPN is a CES-NOS or unclassifiable MPN. In some such embodiments, the dosage is administered as a single dose or BID in two divided doses. In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is essential thrombocythemia (ET). In some such embodiments, the dosage is administered as a single dose or is administered BID in two divided doses. In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is polycythemia vera (PV). In some such embodiments, the dosage is administered as a single dose or is administered BID in two divided doses.

[0041] In some embodiments of the methods described herein, the dose is administered as a single dose. In some embodiments of the methods described herein, the dose is administered BID in two divided doses. In some embodiments of the methods described herein, the dose is administered BID in two divided doses, each of the two divided doses comprising the same dose. In some embodiments of the methods described herein, the dose is administered BID in two divided doses, each of the two divided doses comprising a different dose. In some embodiments of the methods described herein, the dose is administered BID in two divided doses, and the time interval between administration of the first dose and administration of the second dose is 4-16 hours. In some embodiments of the methods described herein, the dose is administered BID in two divided doses, and the time interval between administration of the first dose and administration of the second dose is 6-16 hours. In some embodiments of the methods described herein, the dose is administered BID in two divided doses, and the time interval between administration of the first dose and administration of the second dose is 4-14 hours. In some embodiments of the methods described herein, the dose is administered BID in two divided doses and the time interval between administration of the first dose and administration of the second dose is 6-14 hours. In some embodiments of the methods described herein, the dose is administered BID in two divided doses and the time interval between administration of the first dose and administration of the second dose is 4-12 hours. In some embodiments of the methods described herein, the dose is administered BID in two divided doses and the time interval between administration of the first dose and administration of the second dose is 6-12 hours. In some embodiments of the methods described herein, the dose is administered BID in two divided doses and the time interval between administration of the first dose and administration of the second dose is 8-12 hours. In some embodiments of the methods described herein, the dose is administered BID in two divided doses and the time interval between administration of the first dose and administration of the second dose is 6-8 hours. In some embodiments of the methods described herein, the dose is administered BID in two divided doses, and the time interval between administration of the first dose and administration of the second dose is 8-10 hours.In some embodiments of the methods described herein, the dose is administered BID in two divided doses, and the time interval between administration of the first dose and administration of the second dose is 10-12 hours. In some embodiments of the methods described herein, the dose is administered BID in two divided doses, and the time interval between administration of the first dose and administration of the second dose is 4 hours. In some embodiments of the methods described herein, the dose is administered BID in two divided doses, and the time interval between administration of the first dose and administration of the second dose is 5 hours. In some embodiments of the methods described herein, the dose is administered BID in two divided doses, and the time interval between administration of the first dose and administration of the second dose is 6 hours. In some embodiments of the methods described herein, the dose is administered BID in two divided doses, and the time interval between administration of the first dose and administration of the second dose is 7 hours. In some embodiments of the methods described herein, the dose is administered BID in two divided doses, and the time interval between administration of the first dose and administration of the second dose is 8 hours. In some embodiments of the methods described herein, the dose is administered BID in two divided doses, and the time interval between administration of the first dose and administration of the second dose is 9 hours. In some embodiments of the methods described herein, the dose is administered BID in two divided doses, and the time interval between administration of the first dose and administration of the second dose is 10 hours. In some embodiments of the methods described herein, the dose is administered BID in two divided doses, and the time interval between administration of the first dose and administration of the second dose is 11 hours. In some embodiments of the methods described herein, the dose is administered BID in two divided doses, and the time interval between administration of the first dose and administration of the second dose is 12 hours. In some embodiments of the methods described herein, the dose is administered BID in two divided doses and the time interval between administration of the first dose and administration of the second dose is 13 hours. In some embodiments of the methods described herein, the dose is administered BID in two divided doses and the time interval between administration of the first dose and administration of the second dose is 14 hours.In some embodiments of the methods described herein, the dose is administered BID in two divided doses and the time interval between administration of the first dose and administration of the second dose is 15 hours. In some embodiments of the methods described herein, the dose is administered BID in two divided doses and the time interval between administration of the first dose and administration of the second dose is 16 hours.

[0042] In some embodiments, a method of treating a hematological cancer in a subject in need of treatment includes administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharmaceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg, wherein the hematological cancer is myelofibrosis. In some embodiments, a method of treating a hematological cancer in a subject in need of treatment includes administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharmaceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is primary myelofibrosis. In some embodiments, the method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharmaceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg, wherein the hematological cancer is primary myelofibrosis. In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is post-PV myelofibrosis or post-ET myelofibrosis. In some aspects, the myelofibrosis is post-PV / ET myelofibrosis or myelofibrosis secondary to PV and ET prognostic model [MYSEC-PM].In some embodiments, the method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutical acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is chronic myeloid leukemia (CML). In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharmaceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is chronic neutrophilic leukemia (CNL). In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharmaceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is blastic plasmacytoid dendritic cell neoplasm (BPDCN). In some embodiments, the method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharmaceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is M3 AML.In some embodiments, a method of treating a hematological cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutical acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the hematological cancer is APL (acute promyelocytic leukemia).

[0043] In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response. In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need of treatment thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the AML is relapsed AML, recurrent AML, refractory AML, or any combination thereof. In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need of treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the AML is relapsed AML. In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need of treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the AML is recurrent AML.In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need of treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the AML is refractory AML. In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need of treatment thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the AML is any combination of relapsed AML, recurrent AML, and refractory AML.

[0044] In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response. In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the AML is de novo AML, secondary AML, including therapy-related AML and AML with myelodysplasia-related change (AML with MRC), biphenotypic acute leukemia (also referred to as acute leukemia of unknown lineage), or AML with recurrent abnormalities. In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need of treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the AML is newly developed AML.In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need of treatment thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the AML is secondary AML, including therapy-related AML and AML with myelodysplasia-related change (AML with MRC). In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need of treatment thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the AML is AML with myelodysplasia-related change (AML with MRC). In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need of treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein AML is a biphenotypic acute leukemia (also referred to as acute leukemia of unknown lineage). In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need of treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the AML is AML with recurrent abnormalities.In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need of treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the AML is AML with an actionable mutation. In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need of treatment thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the AML is AML that does not have an actionable mutation.

[0045] In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response. In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need of treatment thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the MDS is relapsed or refractory MDS. In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need of treatment thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutical acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the MDS is classified as low-risk MDS by the International Prognostic Scoring System-Revised (IPSS-R). In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need of treatment thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the MDS is classified as intermediate-risk MDS by the International Prognostic Scoring System-Revised (IPSS-R).In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need of treatment thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the MDS is classified as high-risk MDS according to the International Prognostic Scoring System-Revised (IPSS-R). In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need of treatment thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the MDS is classified as very high risk MDS by the International Prognostic Scoring System-Revised (IPSS-R). In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need of treatment thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, or a pharma- ceutical acceptable salt thereof, at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the MDS is selected from the group consisting of MDS with single lineage dysplasia (MDS). MDS-SLD), MDS with multilineage dysplasia (MDS-MLD), MDS with ringed sideroblasts (MDS-RS), MDS with ringed sideroblasts with single lineage dysplasia (MDS-RS-SLD), MDS with ringed sideroblasts (MDS-RS), MDS with ringed sideroblasts with multilineage dysplasia (MDS-RS-MLD), MDS with excess blasts 1 and / or excess blasts 2 (MDS-EB-1, MDS-EB-2), unclassified MDS (MDS-U), and MDS with isolated del(5q).In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need of treatment thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the MDS is MDS with single lineage dysplasia (MDS-SLD). In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need of treatment thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, or a pharma- ceutically acceptable salt thereof, at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the MDS is MDS with multilineage dysplasia (MDS-MLD). In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need of treatment thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the MDS is MDS with ringed sideroblasts (MDS-RS). In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need of treatment thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the MDS is MDS with ringed sideroblasts with single lineage dysplasia (MDS-RS-SLD).In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need of treatment thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the MDS is MDS with ringed sideroblasts (MDS-RS). In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need of treatment thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the MDS is MDS with ringed sideroblasts with multilineage dysplasia (MDS-RS-MLD). In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need of treatment thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the MDS is MDS with excess blasts 1 and / or excess blasts 2 (MDS-EB-1, MDS-EB-2). In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need of treatment thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the MDS is unclassifiable MDS (MDS-U).In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need of treatment thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, wherein the MDS is MDS with isolated del(5q).

[0046] In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the subject is treated regardless of the subject's mutation or cytogenetic status.

[0047] In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, the therapeutic response comprising complete remission, complete remission with minimal residual disease, complete remission with incomplete hematologic recovery, morphologic leukemia free or partial remission, hematologic improvement, complete cytogenetic response, transfusion independence, red blood cell transfusion independence or platelet transfusion independence, or eligibility for stem cell transplantation. In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need of treatment thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, the therapeutic response comprising a complete remission. In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need of treatment thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, or a pharma- ceutically acceptable salt thereof, at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, the therapeutic response comprising a partial remission.In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need of treatment thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, the therapeutic response comprising hematological improvement. In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, wherein the therapeutic response comprises a complete cytogenetic response. In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need of treatment thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, or a pharma- ceutically acceptable salt thereof, at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, wherein the therapeutic response comprises transfusion independence. In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, the therapeutic response comprising red blood cell transfusion independence or platelet transfusion independence.In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the therapeutic response comprises eligibility for stem cell transplantation.

[0048] In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, the therapeutic response comprising increased overall survival, increased recurrence-free survival, increased event-free survival, increased duration of response, or decreased cumulative incidence of recurrence. In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, the therapeutic response comprising an increase in overall survival. In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg, whereby the subject experiences a therapeutic response, the therapeutic response comprising an increase in recurrence-free survival.In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, the therapeutic response comprising an increase in event-free survival. In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, or a pharma- ceutically acceptable salt thereof, at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, wherein the therapeutic response comprises an increase in duration of response. In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, the therapeutic response comprising a reduction in the cumulative incidence of relapse.

[0049] In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, or a pharma- ceutical acceptable salt thereof, at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, thereby and the subject experiences a therapeutic response, and the pharmaceutical composition is administered in a regimen that includes: (a) administering the agent to the subject for 4 consecutive days followed by 3 consecutive days without administering the agent; (b) administering the agent to the subject for 5 consecutive days followed by 2 consecutive days without administering the agent; (c) administering once weekly; or (d) administering twice weekly, and for each of (a)-(d), the dosage is administered as a single dosage on the administration day(s) or as two dosages on the administration day(s), e.g., with 10-12 hours between doses. In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, wherein the pharmaceutical composition is administered in a regimen comprising administering to the subject the agent for four consecutive days followed by three consecutive days without administration, wherein the dosage is administered as a single dosage on the administration day(s) or as two dosages on the administration day(s), such as with 10-12 hours between doses.In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, or a pharma- ceutically acceptable salt thereof, at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, wherein the pharmaceutical composition is administered in a regimen that comprises administering the agent to the subject for 5 consecutive days followed by 2 consecutive days without administration, wherein the dosage is administered as a single dosage on the day of administration or as two dosages on the day of administration, such as with 10-12 hours between doses. In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, or a pharma- ceutically acceptable salt thereof, at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, wherein the pharmaceutical composition is administered in a regimen comprising weekly dosing, and wherein the dosage is administered as a single dosage on the day of administration or as two dosages on the day of administration, such as with 10-12 hours between the doses. In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, wherein the pharmaceutical composition is administered in a regimen comprising twice weekly administration, wherein the dosage is administered as a single dosage on the day of administration or as two dosages on the day of administration, such as with 10-12 hours between the dosages.In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, or a pharma- ceutically acceptable salt thereof, at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the dosing regimen is repeated. In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, wherein the pharmaceutical composition is administered in a 28 day cycle comprising administration on days 1-4, 8-11, 15-18, and 22-25 of each cycle, wherein the dosage is administered as a single dosage on the day of administration or as two dosages on the day of administration, such as with 10-12 hours between doses. In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, wherein the pharmaceutical composition is administered in a 28 day cycle comprising administration on days 1-4, 8-11, 15-18, and 22-25 of each cycle, the 28 day cycle being repeated at least once, and wherein the dosage is administered as a single dosage on the day of administration or as two dosages on the day of administration, such as with 10-12 hours between doses.In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, wherein the pharmaceutical composition is administered in 28 day cycles comprising administration on days 1-4, 8-11, 15-18, and 22-25 of each cycle, the 28 day cycles being repeated until relapse, and wherein the dosage is administered as a single dosage on the day of administration or as two dosages on the day of administration, such as with 10-12 hours between doses.

[0050] In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, or a pharma- ceutically acceptable salt thereof, at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and wherein the pharmaceutical composition is administered once daily on the day of administration. In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, or a pharma- ceutically acceptable salt thereof, at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and wherein the pharmaceutical composition is administered twice daily on the day of administration.

[0051] In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need of treatment thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, or a pharma- ceutically acceptable salt thereof, at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and wherein the pharmaceutical composition is administered orally.

[0052] In some embodiments, a method of treating myelodysplastic syndrome (MDS) in a subject in need of treatment thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the pharmaceutical composition is administered as one or more tablets or capsules.

[0053] In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need of treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, the therapeutic response comprising increased overall survival, increased relapse-free survival, increased event-free survival, increased duration of response, or decreased cumulative incidence of relapse. In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need of treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, the therapeutic response comprising an increase in overall survival. In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need of treatment includes administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg, whereby the subject experiences a therapeutic response, the therapeutic response comprising an increase in recurrence-free survival.In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need of treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, the therapeutic response comprising an increase in event-free survival. In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need of treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, wherein the therapeutic response comprises an increase in duration of response. In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need of treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, the therapeutic response comprising a reduction in the cumulative incidence of relapse.

[0054] In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need of such treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, or a pharma- ceutical acceptable salt thereof, at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, thereby and the subject experiences a therapeutic response, and the pharmaceutical composition is administered in a regimen that includes: (a) administering the agent to the subject for 4 consecutive days followed by 3 consecutive days without administering the agent; (b) administering the agent to the subject for 5 consecutive days followed by 2 consecutive days without administering the agent; (c) administering once weekly; or (d) administering twice weekly, and for each of (a)-(d), the dosage is administered as a single dosage on the administration day(s) or as two dosages on the administration day(s), e.g., with 10-12 hours between doses. In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, wherein the pharmaceutical composition is administered in a regimen comprising administering to the subject the agent for four consecutive days followed by three consecutive days without administration, wherein the dosage is administered as a single dosage on the administration day(s) or as two dosages on the administration day(s), such as with 10-12 hours between doses.In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, wherein the pharmaceutical composition is administered in a regimen that comprises administering the agent to the subject for 5 consecutive days followed by 2 consecutive days without administration, wherein the dosage is administered as a single dosage on the administration day(s) or as two dosages on the administration day(s), such as with 10-12 hours between doses. In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, wherein the pharmaceutical composition is administered in a regimen comprising weekly dosing, and wherein the dosage is administered as a single dosage on the day of administration or as two dosages on the day of administration, such as with 10-12 hours between the doses. In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, wherein the pharmaceutical composition is administered in a regimen comprising twice weekly administration, wherein the dosage is administered as a single dosage on the day of administration or as two dosages on the day of administration, such as with 10-12 hours between the dosages.In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, or a pharma- ceutically acceptable salt thereof, at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the dosing regimen is repeated. In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, wherein the pharmaceutical composition is administered in a 28 day cycle comprising administration on days 1-4, 8-11, 15-18, and 22-25 of each cycle, wherein the dosage is administered as a single dosage on the day of administration or as two dosages on the day of administration, such as with 10-12 hours between doses. In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, wherein the pharmaceutical composition is administered in a 28 day cycle comprising administration on days 1-4, 8-11, 15-18, and 22-25 of each cycle, the 28 day cycle being repeated at least once, and wherein the dosage is administered as a single dosage on the day of administration or as two dosages on the day of administration, such as with 10-12 hours between doses.In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, wherein the pharmaceutical composition is administered in 28 day cycles comprising administration on days 1-4, 8-11, 15-18, and 22-25 of each cycle, the 28 day cycles being repeated until relapse, and wherein the dosage is administered as a single dosage on the day of administration or as two dosages on the day of administration, such as with 10-12 hours between doses.

[0055] In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need of treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, or a pharma- ceutically acceptable salt thereof, at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and wherein the pharmaceutical composition is administered once daily on the day of administration. In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need of treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, or a pharma- ceutically acceptable salt thereof, at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and wherein the pharmaceutical composition is administered twice daily on the day of administration.

[0056] In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need of treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, or a pharma- ceutically acceptable salt thereof, at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the pharmaceutical composition is administered orally.

[0057] In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need of treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the pharmaceutical composition is administered as one or more tablets or capsules.

[0058] In some embodiments, a method of treating acute myeloid leukemia (AML) in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the subject exhibits a therapeutic response to a marker of ABL1, ASXL1, BCOR, BCORL1, BCR, BRAF, CALR, CBFB, CBL, CBLB, CDKN2A, CEBP1, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-38, IL-39, IL-40, IL-41, IL-42, IL-43, IL-44, IL-45, IL-46, IL-47, IL-48, IL-49, IL-50, IL-51, IL-52, IL-53, IL-54, IL-55, IL-55, IL-55, IL-55, IL-56, IL-57, IL-58, IL-59, IL- A, carrying one or more mutations in a locus selected from the group consisting of CSF3R, CUX1, DEK, DNMT3A, ETV6, EZH2, FBXW7, FLT3, GATA1, GATA2, GNAS, HRAS, IDH1, IDH2, IKZF1, JAK2, JAK3, KDM6A, KIT, KMT2A, MECOM(EVI1), MLL, MLLT3, MPL, MYD88, MYH11, NOTCH1, NPM1, NUP214, NRAS, PDGFRA, PHF6, PTEN, PTPN11, RAD21, RUNX1, SF3B1, SRSF2, SMC1A, SMC3, STAG2, TET2, TP53, U2AF1, WT1, and ZRSR2.In some embodiments, the subject is a candidate for the following markers: ABL1, ASXL1, BCOR, BCORL1, BCR, BRAF, CALR, CBFB, CBL, CBLB, CDKN2A, CEBPA, CSF3R, CUX1, DEK, DNMT3A, ETV6, EZH2, FBXW7, FLT3, GATA1, GATA2, GNAS, HRAS, IDH1, IDH2, IKZF1, JAK2, JAK3, KDM6A, KIT, KMT2A, MECOM(EVI1), MLL, MLLT3, MP L, MYD88, MYH11, NOTCH1, NPM1, NUP214, NRAS, PDGFRA, PHF6, PTEN, PTPN11, RAD21, RUNX1, SF3B1, SRSF2, SMC1A, SMC3, STAG2, TET2, TP53, U2AF1, WT1, and ZRSR2.

[0059] Treatment response The methods described herein include administering a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide (Compound 1), or a pharma- ceutically acceptable salt thereof, to produce a therapeutic response in a treated subject. The therapeutic response may depend on the type of cancer being treated, as well as the treated subject, the stage of the cancer, the subject's previous treatment, and other health factors. In some embodiments herein, the cancer being treated includes a hematological cancer, such as AML or MDS, and the therapeutic response is one or more of complete remission, complete remission with minimal residual disease, complete remission with incomplete hematological recovery, complete remission without platelet recovery, combined complete remission, morphological leukemia-free or partial remission, hematological improvement, complete cytogenetic response, transfusion independence, red blood cell transfusion independence, platelet transfusion independence, or eligibility for stem cell transplantation. In some embodiments, the therapeutic response also includes or is one or more of: increased overall survival, increased relapse-free survival, increased event-free survival, increased duration of response, or decreased cumulative incidence of relapse. In some embodiments, the therapeutic response of a subject treated for multiple myeloma includes or is one or more of: sustained MRD negativity, flow MRD negativity, sequencing MRD negativity, imaging+MRD negativity, stringent complete response, complete response, very good partial response, partial response, minimal response, or stable disease, such as by the criteria set forth in the NCCN Guidelines Version 3.2021 Multiple Myeloma or the criteria set forth in the International Myeloma Working Group Response Criteria (https: / / radiopaedia.org / articles / international-myeloma-working-group-response-criteria?lang=us).

[0060] In some embodiments, the subject's therapeutic response to treatment with a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide (Compound 1), or a pharma- ceutically acceptable salt thereof, is based on a physical examination. In some embodiments, the subject's therapeutic response to treatment with a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide (Compound 1), or a pharma- ceutical acceptable salt thereof, is evaluated according to the ELN (Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424-47) criteria for AML and the IWG (Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006;108(2):419-25), IWG-MRT and ELN response criteria for PV and ET (Barosi G, Mesa R, et al. Revised response criteria for polycythemia vera and essential thrombocythemia:and ELN and IWG-MRT consensus project. Blood. 2013;121(23):4778-4781), IWG-MRT and ELN response criteria for MF (Tefferi A, Cervantes F, Mesa R, et al.Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasm Research and Treatment(IWG-MRT)and European LeukemiaNet(ELN)consensus report.Blood.2013;122(8):1395-1398.) or for AML, MDS, bcr-abl negative MPN, or MDS / MPN, the MDS / MPN response criteria (Savona MR,Malcovati L,Komrokji R,et al.An international consortium proposal of uniform response criteria for myelodysplastic / myeloproliferative neoplasms(MDS / MPN)in adults.Blood.2015;125(12):1857-1865), respectively. In some embodiments, a subject's therapeutic response to treatment with a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide (Compound 1), or a pharma- ceutically acceptable salt thereof, is assessed based on one or more of the criteria set forth in FIG. 6.

[0061] Combination therapy Provided herein is a method of treating cancer in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof, wherein the treatment further comprises administration of a second therapeutic agent, whereby the subject experiences a therapeutic response from the combination that is greater than the response from either agent alone.

[0062] As used herein, a method of treating cancer in a subject in need thereof includes administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, wherein the treatment further includes administration of a second therapeutic agent, whereby the subject experiences a therapeutic response from the combination that is greater than the response from either agent alone. In some embodiments, the therapeutic response from the combination is additive to the response from either agent alone. In some embodiments, the therapeutic response from the combination is greater than the additive response from either agent alone. In some embodiments, the therapeutic response from the combination is synergistic compared to the response from either agent alone. Synergism and additive effects may be assessed by models available in the art. Representative models for assessing synergy and additivity include the Bliss independence model and the Loewe additivity model (see Greco, W., Unkelbach, HD, Poch, G., Suhnel, J., Kundi, M., & Bodeker, W. (1992). Consensus on concepts and terminology for combined-action assessment: the Saariselka agreement. Arch Complex Environ Stud, 4(3), 65-9).

[0063] Exemplary second therapeutic agents used in combination with 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide include one or more of chemotherapeutic agents, such as nucleic acid analogs and nucleic acid synthesis inhibitors, tyrosine kinase inhibitors, DNA damage repair inhibitors, inhibitors of ATM, inhibitors of ATR, inhibitors of PARP, inhibitors of Chk1, proteasome inhibitors, inhibitors of FLT3, inhibitors of IDH1, inhibitors of IDH2, immuno-oncology or immunomodulatory agents, p53 targeting agents, BCl-2 inhibitors, BH3 mimetics, DNA-PK inhibitors, and NEDD-8, inhibitors.

[0064] In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is a DNA damaging agent, a methylation inhibitor, an agent that interferes with DNA synthesis, or an agent that interferes with DNA replication. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is a DNA damaging agent. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and wherein the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is a methylation inhibitor.In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and wherein the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is an agent that disrupts DNA synthesis. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and wherein the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is an agent that interferes with DNA replication.

[0065] In some embodiments, the method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is decitabine, azacitidine, or cytarabine. In some embodiments, the method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is decitabine. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and wherein the treatment further comprises administration of a second therapeutic agent, and the second therapeutic agent is azacitidine.In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is cytarabine.

[0066] In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, the second therapeutic agent being cytarabine administered in a 7+3 regimen comprising 7 days of cytarabine and 3 days of an anthracycline antibiotic selected from daunorubicin, doxorubicin, idarubicin, and mitoxantrone. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, the second therapeutic agent being cytarabine administered in a 7+3 regimen comprising 7 days of cytarabine and 3 days of an anthracycline antibiotic. In some embodiments, the method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, the second therapeutic agent being cytarabine administered in a 7+3 regimen comprising 7 days of cytarabine and 3 days of daunorubicin.In some embodiments, the method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, the second therapeutic agent being cytarabine administered in a 7+3 regimen comprising 7 days of cytarabine and 3 days of doxorubicin. In some embodiments, the method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, the second therapeutic agent being cytarabine administered in a 7+3 regimen comprising 7 days of cytarabine and 3 days of idarubicin. In some embodiments, the method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, the second therapeutic agent being cytarabine administered in a 7+3 regimen comprising 7 days of cytarabine and 3 days of mitoxantrone.

[0067] In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and wherein the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is a tyrosine kinase inhibitor.

[0068] In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and wherein the treatment further comprises administering a second therapeutic agent, wherein the second therapeutic agent is a DNA damage repair inhibitor.

[0069] In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is an inhibitor of ATM, ATR, PARP, or Chk1. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and wherein the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is an inhibitor of ATM, such as AZD6738. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and wherein the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is an inhibitor of ATR, such as AZDO156.

[0070] In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is an inhibitor of poly ADP ribose polymerase (PARP). In some embodiments, a method of treating cancer in a subject in need of such treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is an inhibitor of PARP selected from the group consisting of talazoparib, niraparib, and olaparib. In some embodiments of the method, the PARP inhibitor comprises talazoparib or an analog thereof. In some embodiments of the method, the PARP inhibitor comprises niraparib or an analog thereof. In some embodiments of the method, the PARP inhibitor comprises olaparib or an analog thereof.

[0071] In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is an inhibitor of Chk1.

[0072] In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and wherein the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is a proteasome inhibitor. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is Velcade (bortezomib). In some embodiments, a method of treating cancer in a subject in need of such treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is Kyprolis (carfilzomib).In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is NINLARO (ixazomib). In some embodiments, the method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is an inhibitor of NEDD-8. In some embodiments, the inhibitor of NEDD-8 is pevonedistat.

[0073] In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is lenalidomide, dexamethasone, pomalidomide, or a combination thereof, e.g., one of the agents in the combination is dexamethasone. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is lenalidomide. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is pomalidomide.In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is dexamethasone. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is a combination of one or more of lenalidomide, pomalidomide, and dexamethasone.

[0074] In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is selected from a FLT3 inhibitor, an IDH1 inhibitor, an IDH2 inhibitor, a hedgehog pathway inhibitor, an anti-CD33 antibody, a purine analog, and a Bcl-2 inhibitor. In some embodiments, the method of treating cancer in a subject in need of such treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, the second therapeutic agent being an inhibitor of FLT3. In some embodiments of the method, the FLT3 inhibitor comprises gilteritinib, midostaurin, or an analog thereof. In some embodiments of the method, the FLT3 inhibitor comprises gilteritinib or an analog thereof. In some embodiments of the method, the FLT3 inhibitor comprises midostaurin or an analog thereof. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is an inhibitor of IDH1.In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and wherein the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is an inhibitor of IDH2. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and wherein the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is an inhibitor of a Hedgehog pathway inhibitor. In some embodiments, the method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is an inhibitor of a hedgehog pathway inhibitor, and the hedgehog pathway inhibitor is glasdegib.In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and wherein the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is an anti-CD33 antibody. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is an anti-CD33 antibody, and the anti-CD33 antibody is gemtuzumab ozogamicin. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is Circlisa (isatuximab) or a CD38-targeted monoclonal antibody. In some embodiments, the anti-CD38 antibody is Circlisa (isatuximab). In some embodiments, the anti-CD38 antibody is daratumumab.

[0075] In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and wherein the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is a menin inhibitor. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is the menin inhibitor SNDX-5613. In some embodiments, the method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is the menin inhibitor KO-539.In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is a selective inhibitor of nuclear export. In some embodiments, the method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is a selective inhibitor of nuclear export selinexol.

[0076] In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is a purine analog. In some embodiments, the method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is a purine analog, and the purine analog is fludarabine. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is an inhibitor of Bcl-2. In some embodiments of the method, the Bcl-2 inhibitor is a BH3 mimetic.In some embodiments, the method of treating cancer in a subject in need of such treatment comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is a Bcl-2 inhibitor, and the Bcl-2 inhibitor is venetoclax. In some embodiments, the method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is a DNA protein kinase inhibitor. In some such embodiments, the DNA protein kinase inhibitor is nedisertib. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and wherein the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent acts on p53 or a mutated form of p53. In some such embodiments, the second therapeutic agent is APR-246.

[0077] In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and wherein the treatment further comprises administration of a second therapeutic agent, wherein the second therapeutic agent is an immuno-oncology agent.

[0078] In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharma- ceutically acceptable salt thereof at a dosage of about 25 mg to about 2000 mg or about 450 mg to about 1500 mg administered over a 24 hour period, whereby the subject experiences a therapeutic response, and wherein the treatment further comprises administration of a second therapeutic agent, and the second therapeutic agent is an immunomodulatory agent.

[0079] Dosage In some embodiments of the methods disclosed herein, the dosage of Compound 1 (1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide), or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof over a 24 hour period, whereby the subject experiences a therapeutic response, is about 450 mg, about 455 mg, about 460 mg, about 465 mg, about 470 mg, about 475 mg, about 480 mg, about 485 mg, about 490 mg, about 495 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1010 mg, about 1020 mg, about 1030 mg, about g, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1125 mg, about 1150 mg, about 1175 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, or about 1500 mg, including increments therein.

[0080] In some embodiments of the methods disclosed herein, the dosage of compound 1 (1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide), or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof, such that the subject experiences a therapeutic response, is administered in a unit dosage, such as a tablet or capsule, and each tablet or capsule contains 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, The unit dosage of 2-yl)-2-methyl-1H-indole-4-carboxamide is about 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg or 1000 mg.

[0081] In some embodiments of the methods disclosed herein, the dosage of compound 1 (1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide), or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof over a 24 hour period, such that the subject experiences a therapeutic response, is about 450 mg to about 1500 mg administered in one or two doses. In some embodiments of the methods disclosed herein, the dosage of compound 1, or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof over a 24 hour period, such that the subject experiences a therapeutic response, is about 450 mg to about 1000 mg administered in one or two doses. In some embodiments of the methods disclosed herein, the dosage of Compound 1, or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof over a 24 hour period, such that the subject experiences a therapeutic response, is about 450 mg to about 900 mg administered in one or two doses. In some embodiments of the methods disclosed herein, the dosage of Compound 1, or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof over a 24 hour period, such that the subject experiences a therapeutic response, is about 450 mg to about 750 mg administered in one or two doses. In some embodiments of the methods disclosed herein, the dosage of Compound 1, or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof over a 24 hour period, such that the subject experiences a therapeutic response, is about 450 mg to about 600 mg administered in one or two doses. In some embodiments of the methods disclosed herein, the dosage of Compound 1, or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof over a 24 hour period such that the subject experiences a therapeutic response, is about 450 mg to about 525 mg administered in one or two doses. In some embodiments of the methods disclosed herein, the dosage of Compound 1, or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof over a 24 hour period such that the subject experiences a therapeutic response, is about 600 mg to about 1000 mg administered in one or two doses.In some embodiments of the methods disclosed herein, the dosage of Compound 1, or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof over a 24 hour period, such that the subject experiences a therapeutic response, is about 600 mg to about 900 mg administered in one or two doses. In some embodiments of the methods disclosed herein, the dosage of Compound 1, or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof over a 24 hour period, such that the subject experiences a therapeutic response, is about 600 mg to about 750 mg administered in one or two doses. In some embodiments of the methods disclosed herein, the dosage of Compound 1, or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof over a 24 hour period, such that the subject experiences a therapeutic response, is about 600 mg to about 700 mg administered in one or two doses. In some embodiments of the methods disclosed herein, the dosage of Compound 1, or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof over a 24 hour period, whereby the subject experiences a therapeutic response, is about 900 mg to about 1500 mg administered in one or two doses. In some embodiments of the methods disclosed herein, the dosage of Compound 1, or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof over a 24 hour period, whereby the subject experiences a therapeutic response, is about 900 mg to about 1250 mg administered in one or two doses. In some embodiments of the methods disclosed herein, the dosage of Compound 1, or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof over a 24 hour period, whereby the subject experiences a therapeutic response, is about 900 mg to about 1000 mg administered in one or two doses. In some embodiments of the methods disclosed herein, the dosage of Compound 1, or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof over a 24 hour period such that the subject experiences a therapeutic response is about 1000 mg to about 1500 mg administered in one or two doses.In some embodiments of the methods disclosed herein, the dosage of Compound 1, or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof over a 24 hour period such that the subject experiences a therapeutic response is from about 1000 mg to about 1250 mg administered in one or two doses.

[0082] In some embodiments of the methods disclosed herein, a dosage of compound 1 (1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide), or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof, whereby the subject experiences a therapeutic response, is administered orally. In some embodiments of the methods disclosed herein, a dosage of compound 1, or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof, whereby the subject experiences a therapeutic response, is administered with food. In some embodiments of the methods disclosed herein, a dosage of compound 1, or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof, whereby the subject experiences a therapeutic response, is administered without food.

[0083] In some embodiments of the methods disclosed herein, a dosage of compound 1 (1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide), or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof, whereby the subject experiences a therapeutic response, is administered once daily. In some embodiments of the methods disclosed herein, a dosage of compound 1, or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof, whereby the subject experiences a therapeutic response, is administered twice daily. In some embodiments of the methods disclosed herein, a dosage of compound 1, or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof, whereby the subject experiences a therapeutic response, is administered three times daily. In some embodiments of the methods disclosed herein, a dosage of compound 1, or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof, whereby the subject experiences a therapeutic response, is administered four times daily.

[0084] In some embodiments, a dose of Compound 1 (1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide), or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof such that the subject experiences a therapeutic response, is administered with a treatment "day off" of several days between successive doses. For example, a dose of Compound 1 is administered for 1-7 days ("on" days), followed by a period of 1-7 days during which a dose of Compound 1 is not administered to the subject ("off" days). In some embodiments, a dose of Compound 1, or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof such that the subject experiences a therapeutic response, is administered as 4 days on / 3 days off, 5 days on / 3 days off, 5 days on / 2 days off, or 4 days on / 2 days off. In some embodiments, the cycle of on / off administration is repeated such that a dose of Compound 1 is administered on an on / off schedule for 2, 3, 4, 5, or 6 or more cycles.

[0085] In some embodiments of the methods disclosed herein, a dosage of compound 1 (1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide), or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof, whereby the subject experiences a therapeutic response, is administered once every two days. In some embodiments of the methods disclosed herein, a dosage of compound 1, or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof, whereby the subject experiences a therapeutic response, is administered once every three days. In some embodiments of the methods disclosed herein, a dosage of compound 1, or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof, whereby the subject experiences a therapeutic response, is administered once every four days. In some embodiments of the methods disclosed herein, a dosage of Compound 1, or a pharma- ceutically acceptable salt thereof, which is administered to a subject in need thereof, such that the subject experiences a therapeutic response, is administered once every 5 days. In some embodiments of the methods disclosed herein, a dosage of Compound 1, or a pharma- ceutically acceptable salt thereof, which is administered to a subject in need thereof, such that the subject experiences a therapeutic response, is administered once every 6 days. In some embodiments of the methods disclosed herein, a dosage of Compound 1, or a pharma- ceutically acceptable salt thereof, which is administered to a subject in need thereof, such that the subject experiences a therapeutic response, is administered once a week.

[0086] In some embodiments of the methods disclosed herein, a dosage of compound 1 (1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide), or a pharma- ceutically acceptable salt thereof, administered to a subject in need thereof such that the subject experiences a therapeutic response, is administered four days on and three days off.

[0087] In some embodiments of the methods disclosed herein, a dosage of compound 1 (1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide), or a pharma- ceutically acceptable salt thereof, is administered to a subject in need thereof, and the subject has undergone at least one prior treatment.

[0088] Pharmaceutical Compositions In some embodiments, the 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide pharmaceutical composition described herein comprises 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient. In some embodiments, the pharmaceutical composition described herein comprises 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient in a solid dosage form. In some embodiments, the pharmaceutical compositions described herein comprise crystalline 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient in a solid dosage form. In some embodiments, the pharmaceutical compositions described herein comprise 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient in a solid dosage form selected from powders, tablets, chewable tablets, caplets, capsules, gelcaps, effervescent powders, fast disintegrating tablets, abuse-resistant tablets, modified release tablets, modified release caplets, modified release capsules, and aqueous suspensions made from the powders. In some embodiments, the pharmaceutical compositions described herein comprise 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient in a solid dosage form, wherein the solid dosage form is a capsule.In some embodiments, the pharmaceutical compositions described herein comprise 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient in a solid dosage form, wherein the solid dosage form is a tablet.

[0089] Excipients Suitable optional excipients for use in the 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide pharmaceutical compositions described herein include any excipient commonly used in pharmacology and are selected based on compatibility with the active pharmaceutical agent and release profile characteristics of the desired dosage form. Excipients include, but are not limited to, binders, fillers, flow aids, disintegrants, lubricants, glidants, polymeric carriers, plasticizers, stabilizers, surfactants, and the like. Summary summaries of the excipients described herein can be found in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999), which are incorporated by reference herein in their entireties.

[0090] Fillers or diluents increase the bulk in pharmaceutical compositions. Such compounds include, for example, lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose such as Avicel®, silicic acid treated microcrystalline cellulose such as ProSolv® HD90, dibasic calcium phosphate, dicalcium phosphate dihydrate, tricalcium phosphate, calcium phosphate, anhydrous lactose, spray-dried lactose, pregelatinized starch, compressible sugar such as Di-Pac® (Amstar), hydroxypropyl methylcellulose, sucrose-based diluents, powdered sugar, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate, dextrates, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, glycine, kaolin, sodium chloride, inositol, bentonite, etc. In some embodiments, the pharmaceutical compositions described herein include two fillers. In some embodiments of the pharmaceutical compositions described herein, the first filler and the second filler are selected from lactose, mannitol, dicalcium phosphate, microcrystalline cellulose, silicic acid treated microcrystalline cellulose, starch, and pregelatinized starch (Starch 1500). In some embodiments of the pharmaceutical compositions described herein, the first filler and the second filler are independently selected from lactose, mannitol, microcrystalline cellulose, and silicic acid treated microcrystalline cellulose.

[0091] Binders impart cohesiveness to solid oral dosage form compositions. In powder-filled capsule formulations, binders aid in the formation of a plug that can be filled into soft or hard shell capsules, and in tablet formulations, binders help ensure that the tablet remains intact after compression and ensure blend uniformity prior to the compression or filling step. Materials suitable for use as binders in the solid dosage forms described herein include carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropyl methylcellulose (e.g., Hypromellose UPS Pharmacoat-603), hydroxypropyl methylcellulose acetate stearate (Aqoate®), and hydroxypropyl methylcellulose acetate stearate (Aqoate®). HS-LF and HS), hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., Klucel®), ethyl cellulose (e.g., Ethocel®), microcrystalline cellulose (e.g., Avicel®), silicic acid-treated microcrystalline cellulose such as ProSolv® HD90, microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acid, bentonite, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, sucrose (e.g., Dipac®), glycerol, ... Examples of suitable binders include, but are not limited to, sugars such as glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), lactose, natural or synthetic gums such as acacia, tragacanth, ghatti gum, isapol shell mucilage, starch, polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone® XL-10, and Povidone® K-12), larch arabogalactan, Veegum®, polyethylene glycol, wax, sodium alginate, and the like. In some embodiments, the binder is hypromellose, hydroxypropyl cellulose, or ethyl cellulose.

[0092] Glidants improve the flow properties of powder mixtures. Such compounds include, for example, colloidal silicon dioxide, such as Cab-o-sil®, tribasic calcium phosphate, talc, cornstarch, DL-leucine, sodium lauryl sulfate, magnesium stearate, calcium stearate, sodium stearate, kaolin, and micronized amorphous silicon dioxide (Syloid®). In some embodiments of the pharmaceutical compositions described herein, the glidant is colloidal silicon dioxide or talc. In some embodiments, the glidant is talc. In some embodiments, the glidant is colloidal silicon dioxide.

[0093] A lubricant is a compound that prevents, reduces, or inhibits adhesion or friction of materials. Exemplary lubricants include, for example, stearic acid, calcium hydroxide, talc, paraffin, hydrocarbons such as mineral oils, or hydrogenated vegetable oils such as hydrogenated soybean oil (Sterotex®), Lubritab®, Cutina®, higher fatty acids and their alkali metal and alkaline earth metal salts such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearate, calcium stearate, magnesium stearate, glycerol, talc, wax, Stearowet®, boric acid, sodium acetate, leucine, polyethylene glycol or methoxypolyethylene glycol such as Carbowax™, sodium oleate, colloidal silica such as glyceryl behenate (Compitrol888®), glyceryl palmitostearate (Precirol®), Syloid™, Carb-O-Sil®, starch such as corn starch, silicone oil, surfactants, and the like. Hydrophilic lubricants include, for example, sodium stearyl fumarate (currently sold under the trade name PRUV®), polyethylene glycol (PEG), magnesium lauryl sulfate, sodium lauryl sulfate (SLS), sodium benzoate, sodium chloride, and the like. In some embodiments of the pharmaceutical compositions described herein, the lubricant is magnesium stearate, stearic acid, or sodium stearyl fumarate. In some embodiments, the lubricant is stearic acid. In some embodiments, the lubricant is sodium stearyl fumarate. In some embodiments, the lubricant is magnesium stearate.

[0094] Disintegrants facilitate the breakup or disintegration of pharmaceutical formulations after administration. Examples of disintegrants include starches, such as natural starches such as corn starch or potato starch, pregelatinized starches such as National1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, wood products, microcrystalline cellulose, such as Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Examples of disintegrants include celluloses such as Tia®, Solka-Floc®, methylcellulose, croscarmellose, or crosslinked celluloses such as crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose, crosslinked starches such as sodium starch glycolate, crosslinked polymers such as crospovidone, crosslinked polyvinylpyrrolidone, alginates such as alginic acid or salts of alginic acid such as sodium alginate, clays such as Veegum® HV (magnesium aluminum silicate), gums such as agar, guar, carob, karaya, pectin, tragacanth, sodium starch glycolate, resins such as bentonite, natural sponge, cation exchange resins, citrus pulp, sodium lauryl sulfate, starch compounded with sodium lauryl sulfate, etc. In some embodiments of the pharmaceutical compositions described herein, the disintegrant is selected from povidone, crospovidone, hypromellose, croscarmellose sodium, hydroxypropylcellulose, and polyvinyl alcohol. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the disintegrant is polyvinyl alcohol. In some embodiments, the disintegrant is hydroxypropyl cellulose. In some embodiments, the disintegrant is hypromellose. In some embodiments, the disintegrant is povidone. In some embodiments, the disintegrant is crospovidone.

[0095] In some embodiments, the pharmaceutical compositions described herein include one or more pH adjusting or buffering agents. In some embodiments, the pharmaceutical formulation includes a buffer selected from acetate, carbonate, phosphate, citrate, and glutamate. In some embodiments, the buffer is selected from potassium dihydrogen phosphate, sodium bicarbonate, magnesium carbonate, sodium citrate, sodium dihydrogen phosphate, dipotassium monohydrogen phosphate, and disodium monohydrogen phosphate. In some embodiments, the buffer is included in an amount necessary to maintain the pH of the pharmaceutical formulation within an acceptable range.

[0096] In some embodiments, a film coating is applied around the pharmaceutical composition. In some embodiments, the coating of 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, or a pharma- ceutically acceptable salt thereof, is an immediate release coating. In some embodiments, the immediate release coating comprises hydroxypropyl methylcellulose (HPMC) with or without a plasticizer, and with or without a surfactant and an antifoaming agent (clear or colored or dyed). In some embodiments, the coating of 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, or a pharma-ceutically acceptable salt thereof, is an immediate release coating with a moisture barrier. In some embodiments, the film coating is Opadry AMB II Beige. In some embodiments, the immediate release coating with moisture barrier comprises polyvinyl alcohol (PVA) with or without a plasticizer, with or without a surfactant and an antifoaming agent (clear or colored or dyed). In some embodiments, the composition is formulated into particles (e.g., for administration by capsules) and some or all of the particles are coated. In some embodiments, the composition is formulated into particles (e.g., for administration by capsules) and some or all of the particles are microencapsulated. In some embodiments, the composition is formulated into particles (e.g., for administration by capsules) and some or all of the particles are not microencapsulated and are not coated.

[0097] In some embodiments, the compositions described herein are delivered using a pulsatile dosage form. Pulsatile dosage forms can provide one or more immediate release pulses at a predetermined time point after a controlled lag time or at a specific site. Many other types of controlled release systems are known to those skilled in the art and are suitable for use with the compositions described herein. Examples of such delivery systems include polymer-based systems such as polylactic and polyglycolic acids, polyanhydrides and polycaprolactones, non-polymer-based systems such as porous matrices, lipids including sterols such as cholesterol, cholesterol esters and fatty acids, or neutral fats such as monoglycerides, diglycerides and triglycerides, hydrogel release systems, silastic systems, peptide-based systems, wax coatings, bioerodible dosage forms, compressed tablets using conventional binders, and the like. See, for example, LIBERMAN et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214 (1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2 nd Ed., pp. 751-753 (2002), U.S. Patent Nos. 4,327,725, 4, 624,848, 4,968,509, 5,461,140, ​​5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410, 5,977,175, 6,465,014, and 6,932,983, each of which is specifically incorporated by reference.

[0098] Stabilizers include compounds such as butylated hydroxytoluene (BHT), sodium ascorbate, and any antioxidants, buffers, acids, and the like, such as tocopherol.

[0099] Surfactants include compounds such as polysorbates, poloxamers, bile salts, glyceryl monostearate, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, copolymers of ethylene oxide and propylene oxide, and d-α-tocopheryl polyethylene glycol succinate (vitamin E TPGS). In some embodiments, the surfactant is selected from Soluplus, PEG4000, PEG6000, Poloxamer6200, and Kolliphor P407 micro. In some embodiments, the surfactant is a poloxamer. In some embodiments, the surfactant is Kolliphor P407 micro.

[0100] The above excipients are for illustrative purposes only and are not intended to be exhaustive of all possible options. Other suitable excipient classes include colorants, granulating agents, preservatives, antifoaming agents, plasticizers, etc. Additionally, many excipients may have more than one role or function or may be classified into more than one group, and the classification is for illustrative purposes only and does not limit the use of a particular excipient. Kits / Products

[0101] Also described herein are kits and articles of manufacture for use in the methods described herein.Such kits include carriers, packages, or containers that are compartmentalized to accommodate one or more containers, such as vials, tubes, and each of the containers (several) includes one of the individual elements used in the methods described herein.Suitable containers include, for example, bottles, vials, syringes, and test tubes.In one embodiment, the containers are formed from various materials, such as glass or plastic.

[0102] The manufactured article provided herein includes packaging material.Packaging material for use in packaging pharmaceutical products includes, for example, US Patent No. 5,323,907.Examples of pharmaceutical packaging material include, but are not limited to, blister packs, bottles, tubes, bags, containers, bottles, and any packaging material suitable for selected formulation and intended administration and treatment.

[0103] In some embodiments, the pharmaceutical composition of Compound 1 described herein is provided in a package or dispenser device that may contain one or more unit dosage forms containing the active ingredient. The pharmaceutical composition of Compound 1 described herein is packaged alone or with another compound or another ingredient or excipient. In some embodiments, the package includes one or more containers filled with one or more ingredients of the pharmaceutical composition. In some embodiments, the package includes a metal or plastic foil, such as a blister pack. In some embodiments, the package or dispenser includes a notice attached to the container in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects that the form of the drug has been approved by the government agency for human or veterinary administration. In some embodiments, such notice is, for example, a label approved by the U.S. Food and Drug Administration for prescription drugs, or an approved product insert.

[0104] A kit typically includes a label describing the contents and / or instructions for use, and a package insert containing instructions for use. A set of instructions will also typically be included.

[0105] In one embodiment, the label is on or attached to the container. In one embodiment, the label is on the container when the letters, numbers, or other symbols that make up the label are attached, molded, or etched into the container itself, and the label is attached to the container when it is in a receptacle or carrier that holds the container, for example, as a package insert. In one embodiment, the label is used to indicate that the contents are to be used for a particular therapeutic application. The label also indicates instructions for using the contents, such as in the methods described herein. EXAMPLES

[0106] List of Abbreviations The following abbreviations used throughout the description of the present invention shall be understood to have the following meanings, unless otherwise specified: AML = acute myeloid leukemia, AUC = acute myeloid leukemia, ∞ = area under the plasma concentration time curve from time zero to 24 hours, AUC 0-t = area under the concentration-time curve from time zero to the last quantifiable time point, C max = maximum observed plasma concentration, CR = complete remission, CRi = complete remission with incomplete hematologic recovery, DoCR = duration of complete remission / complete remission with incomplete hematologic recovery, DoR = duration of remission, ELN = European Leukemia Net, IWG = International Working Group, MTD = maximum tolerated dose, MDS = myelodysplastic syndromes, PD = pharmacodynamics, PK = pharmacokinetics, PR = partial remission, RP2D = recommended phase 2 dose, RR = relapsed / refractory, t 1 / 2 = half-life, t max = time to reach maximum concentration. Example 1: Preparation of Compound 1

[0107] The preparation of compound 1 is disclosed in US Pat. No. 9,828,363, the contents of which are incorporated by reference in their entirety. Example 2: A Phase I Study Evaluating the Safety and Pharmacokinetic Profile of Compound 1 in Patients with Relapsed / Refractory Acute Myeloid Leukemia or Relapsed / Refractory Intermediate- or High-Risk Myelodysplastic Syndrome

[0108] A first-in-human (FIH) study was designed and conducted to evaluate the safety, pharmacokinetic (PK), preliminary efficacy and pharmacodynamic (PD) profile of ascending doses of compound 1 monotherapy in adult participants with R / R AML or R / R intermediate-to-poor-risk MDS and to identify a recommended phase 2 dose (RP2D) and dosing schedule. Study design

[0109] The study was designed as a multicenter, open-label, Phase 1 study of oral administration of compound 1 in patients with R / R AML or R / R intermediate-high risk MDS. The study will include two parts: 1) a dose-escalation phase for participants with R / R AML or R / R intermediate-high risk MDS, and 2) a dose-expansion phase for participants with R / R AML for whom no standard treatment is available that could lead to disease remission. Additional cohorts for R / R intermediate-high risk MDS patients following hypomethylation therapy, or other AML cohorts, may be added at a later date.

[0110] In the first part, compound 1 was administered orally QD on a 4 / 3 schedule in consecutive 28-day cycles until progressive disease or intolerable toxicity. Similar doses may be used in the dose expansion portion of the study. Depending on the initial PK assessment, BID administration may also be tested. Participants were evaluated periodically for safety assessments, including physical and laboratory tests. Bone marrow aspirates and / or biopsies will be performed periodically, including evaluation of tumor response according to the 2017 European LeukemiaNet (ELN) response criteria for AML or the 2006 revised International Working Group (IWG) response criteria for MDS. Peripheral blood samples will be collected at cycle 1 for intensive PK studies and PD biomarker evaluation. Additional intensive PK studies will be collected for any participants undergoing intrapatient dose escalation. Dose Escalation Phase

[0111] The study began with a dose escalation phase using an accelerated titration design to define the maximum tolerated dose (MTD) and / or RP2D of compound 1 monotherapy in participants with R / R AML or R / R intermediate-to-poor risk MDS. During this portion of the study, eligible participants who provided consent were enrolled in successive cohorts of increasing doses of compound 1. The starting dose of compound 1 was 25 mg administered orally QD using a weekly 4 / 3 dosing schedule. One cycle consisted of 28 days, with the first cycle including a DLT observation period. Dose cohorts are shown in Table 1.

[0112] [Table 1]

[0113] A single participant cohort was used for the initial dose escalation during the acceleration phase. If a non-hematological adverse event > grade 2 was observed for the first time at any dose level (during the first cycle), the acceleration phase will be terminated and dose escalation will be changed to a 3+3 design. In all of the above situations, references to non-hematological AEs include any AEs considered potentially related to the study intervention.

[0114] If a 3+3 design is utilized, a minimum of three participants will be enrolled in a dose cohort (unless two DLTs occur within the first two participants). If no DLTs are observed after the last participant in the cohort completes the 28-day DLT observation period (i.e., cycle 1), the cohort will proceed to the next cohort with dose escalation following safety review. If one of the three participants experiences a DLT during the first cycle, three more participants will be enrolled in the cohort. If none of the additional three participants experience a DLT, dose escalation may continue to the next cohort following safety review. If two or more participants in a cohort experience a DLT during the first cycle, dose escalation will be stopped and the next lower dose level will be declared the MTD. Alternatively, an intermediate dose level between the dose level above the MTD and the previous dose level may be considered and declared the MTD if fewer than two of six participants experience a DLT at that dose. If the MTD cohort contains only 3 participants, an additional 3 participants will be enrolled at that dose level to ensure that fewer than 2 of 6 participants experienced a DLT at that dose.

[0115] If there are additional participants in the screening process at the time the last participant in a dose cohort begins treatment, the additional participants may be enrolled in the cohort as long as they can begin treatment within 1 week of the last enrolled participant and approval has been received from the clinical trial monitor.

[0116] After each cohort completes the DLT window, safety data and any available PK data will be evaluated to determine whether dose escalation is possible, whether additional participants need to be enrolled into dose cohorts, whether interim doses need to be evaluated, or whether BID dosing needs to be tested (Table 2).

[0117] At the completion of the 900 mg QD cohort, subjects were enrolled into a BID dosing cohort starting at 300 mg BID.

[0118] [Table 2]

[0119] To optimize the number of participants treated at potentially clinically relevant doses, intra-participant dose escalation will be permitted after Cycle 1 if the participant is tolerating the current dose and with the approval of the study monitor. Dose escalation will be permitted to any previously approved dose level. There is no limit to the number of dose escalations that may be performed on a participant.

[0120] After the MTD and / or RP2D of the 4 / 3 dosing schedule have been identified, alternative dosing schedules (e.g., once weekly or twice weekly dosing) may also be evaluated. Evaluation of alternative schedules may begin earlier, prior to identifying the MTD or RP2D with the 4 / 3 dosing schedule, if indicated by the pharmacokinetic profile or if clinically significant toxicity occurs with the 4 / 3 dosing schedule (e.g., withholding / discontinuation of study treatment due to multiple grade 2 AEs or intolerance). Alternative dosing schedules will be identified based on available cumulative safety and PK data and will be clarified in a formal protocol amendment.

[0121] Study procedures for these additional participant(s) / cohort(s) will be identical to those described for the other study participants / cohorts. Selecting RP2D

[0122] Upon completion of the dose escalation phase of the study, the following data will be available to determine the RP2D for the expansion phase of the study: The MTD is defined as the dose at which DLT rates are ≤17% in at least 6 participants during the first cycle. Delayed DLT (DLT occurring after the first cycle) Dose-limiting toxicities dominate Overall safety profile Pharmacokinetics of each cohort Number of participants who needed to discontinue or reduce the dose of the study drug Expansion Phase

[0123] Once the RP2D is identified, a cohort of approximately 38 additional participants with R / R AML will be treated with the RP2D (and schedule) to further confirm safety and evaluate preliminary activity in the participants. Depending on new data emerging from within this trial or other nonclinical or external data, the sponsor may choose to add another cohort of participants with specific subtypes of R / R intermediate-to-poor risk MDS or AML, which may increase the sample size for the expansion phase.

[0124] After a total of 20 R / R AML patients have been enrolled in the cohort on the RP2D and schedule and have received at least two cycles of treatment, the sponsor will evaluate the preliminary efficacy and safety data and benefit / risk profile to determine whether to discontinue the study for the development of compound 1 as a monotherapy for AML. If ORR or other parameters suggestive of activity are observed despite meeting the futility threshold for compound 1 monotherapy, dose escalation and dose expansion cohorts in combination with approved therapies may be included by formal protocol amendment. Study intervention period

[0125] Compound 1 will be administered orally QD on a 4 / 3 schedule weekly for one 28-day cycle. Participants will be evaluated for safety and tolerability, and tumor status will be evaluated after completion of the first cycle. Participants who do not suffer unacceptable toxicity from study treatment will be permitted to receive a second study treatment cycle, after which they will be reevaluated for safety, tolerability, and efficacy. Participants who do not suffer unacceptable toxicity at the end of cycle 2 and who are deemed by the investigator to be benefiting from study treatment (e.g., no evidence of disease progression for MDS participants, or at least PR for AML participants) will be permitted to continue study treatment until disease progression, unacceptable toxicity, completion of treatment, or any other discontinuation criterion, whichever occurs first. Participants will return to the study site for an end-of-treatment (EoT) visit 30 days (± 5 days) after the last 28-day treatment cycle.

[0126] After completion of treatment, participants will continue to receive long-term survival follow-up every 3 months (± 2 weeks) unless they withdraw consent for further follow-up.

[0127] participants A total of approximately 50-60 participants will be enrolled and treated in the dose escalation and dose expansion phases, including approximately 38 R / R AML participants planned to be enrolled and treated in the dose expansion phase.

[0128] Administration Compound 1 will be administered orally once daily on a 4 / 3 dosing schedule (4 days on, 3 days off) for 28-day cycles until progressive disease or unacceptable toxicity occurs. Depending on initial PK evaluation, BID dosing may also be tested. standard:

[0129] Selection criteria: ●Male or female? Be 18 years of age at the time of signing the consent form. One of the following advanced hematologic malignancies: Dose Escalation and Expansion: ●Patients with relapsed or refractory AML as defined by the 2016 WHO criteria (Arber et al. 2016) who are not candidates for curative therapy, such as allogeneic hematopoietic cell transplantation, or for whom standard treatments that, in the investigator's judgment, could lead to disease remission, are unavailable. Dose Escalation Only: High-to-very high risk MDS according to the Revised International Scoring System for Assessing the Prognosis of Myelodysplastic Syndromes, which is recurrent or refractory, or if the participant is unable to tolerate established therapies known to provide clinical benefit for their condition (e.g., relapsed after treatment with hypomethylating agents or no response after more than four cycles), as determined by the treating physician. Potential participants who meet the intermediate-risk criteria may be considered, with the approval of the clinical trial monitor, if the participant exhibits severe cytopenia(s) and / or elevated bone marrow blast counts. Adequate organ function is defined as: Serum creatinine ≦ 1.5mg / dL or estimated glomerular filtration rate calculated using the Cockcroft-Gault glomerular filtration rate formula ≧ 60mL / min Total bilirubin ≤ 1.5 x upper limit of normal (ULN) unless thought to be due to Gilbert's disease or leukemia. Aspartate aminotransferase (AST) ≤ 3 x ULN, alanine aminotransferase (ALT) ≤ 3 x ULN. For participants with known leukemic involvement of the liver, after consultation with the study monitor, AST and / or ALT levels ≤ 5 times the ULN may be acceptable. ●Eastern Cooperative Oncology Group (ECOG) performance status ≦2. Use of contraception by men or women must comply with local regulations regarding contraception for people participating in clinical trials. If of childbearing potential, agree to use effective contraception (e.g., latex condoms, diaphragms, cervical cap) to avoid pregnancy during the study and for 90 days after the last dose of Compound 1. Female participants of childbearing potential must have a negative serum or urine pregnancy test within 7 days of study enrollment. Non-childbearing status is defined as postmenopausal for 1 year or more or surgically sterilized. Be able to provide signed informed consent as described in Appendix 1. Informed consent includes compliance with the requirements and restrictions stated in the Informed Consent Form (ICF) and this protocol.

[0130] Exclusion criteria: • Acute promyelocytic leukemia with t(15;17)(q22;q12) or aberrant promyelocytic leukemia / retinoic acid receptor alpha (PML-RARA). Participants with active central nervous system (CNS) leukemia or clinical symptoms suggestive of known CNS leukemia. Cerebrospinal fluid evaluation is only required if there is clinical suspicion of CNS involvement by leukemia during screening. Participants with severe immediately life-threatening complications of leukemia, such as uncontrolled bleeding, pneumonia with hypoxia or shock, and / or disseminated intravascular coagulation. • Concurrent malignancies requiring aggressive treatment, except basal or squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, or localized prostate cancer. o Adjuvant treatment of breast or prostate cancer is permitted. ● Active, uncontrolled systemic infection or severe local infection during screening or before Day 1 of Cycle 1 (C1D1, unless determined by the investigator to be due to tumor). Participants receiving prophylactic anti-infectives can participate in the study. • Known human immunodeficiency virus (HIV) infection with a CD4+ T-cell count less than 350 cells / μL, initiation of antiretroviral therapy within 4 weeks prior to C1D1, or acquired immunodeficiency syndrome (AIDS)-related infection within 12 months prior to C1D1. - Hepatitis B virus (HBV) infection or hepatitis C virus (HCV) infection with a viral load above the limit of quantification. ●Major cardiac abnormalities defined as (but not limited to): uncontrolled angina or life-threatening unstable arrhythmia, history of myocardial infarction within 12 weeks prior to baseline, New York Heart Association (NYHA) congestive heart failure class 3 or greater, or left ventricular ejection fraction (LVEF) <45% measured by echocardiogram (ECHO) within 28 days of C1D1. Sustained prolongation (three consecutive electrocardiograms performed at least five minutes apart) of the Fredericia corrected QT interval (QTcF) of more than 480 milliseconds. Gastrointestinal conditions that may interfere with the absorption of orally administered medications, including but not limited to short bowel syndrome, gastroparesis, inflammatory bowel disease, and acute pancreatitis. Example 3: Human Dosage and Pharmacokinetic Data for Compound 1

[0131] Subjects were treated with Compound 1 QD as described in Example 2. Plasma concentrations of Compound 1 were measured on day 1 pre-dose and 0.5, 1, 2, 4, 6, 8, 12, 24 hours post-dose, and on day 4 pre-dose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48 hours post-dose. Linear and semi-logarithmic plots of plasma concentration-time plots are shown in Figures 1 and 2 and are expressed in ng / mL concentration units and μM concentration units for plasma concentrations administered at 25 mg to 450 mg QD on days 1 (Figure 1) and 4 (Figure 2). No adverse events were observed in any cohort. No symptoms of visual impairment were observed in the low-dose cohort. Two patients in cohort X experienced mild visual symptoms on the day of dosing, but the symptoms did not persist. Table 3 shows exemplary pharmacokinetic measurement analysis including Cmax, Cmax / dose, AUC (area under the curve), tmax, and half-life (t1 / 2) for two patients dosed in Cohort 1.

[0132] [Table 3]

[0133] The results show that the half-life of compound 1 is approximately 3-4 hours. No accumulation of compound 1 was observed between days 1 and 4. Surprisingly, compound 1 showed significantly higher plasma exposure than CB-5083 (1-[7,8-dihydro-4-[(phenylmethyl)amino]-5H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxamide), a compound previously tested in subjects. In comparison, 25 mg QD of compound 1 resulted in significantly higher plasma exposure than 40 mg QD of CB-5083. Compound 1 exposure was greater than doses of CB-5083 over 200 mg. See Figure 4. Also, unlike CB-5083, at comparable plasma exposure, compound 1 did not show symptoms of visual impairment or other visual adverse events as seen with lower doses of CB-5083, nor did it show persistent symptoms at the highest dose. As shown in Figures 1 and 2, exposure data from treatment of patients receiving 25 mg, 50 mg, 100 mg, 175 mg, 275 mg, 350 mg, and 450 mg according to the study design of Example 2 showed that the increase in exposure levels between doses was roughly proportional and linear. AUC on Days 1 and 4 0-t The dose versus dose is shown in Figures 3A and 3C. max The versus dose is shown in Figures 3B and 3D for days 1 and 4, respectively.

[0134] Two biomarkers were evaluated in patients from cohorts 4 and 5. The K48-Ub (ubiquitin) and activated caspase-3 biomarkers were analyzed in blood samples from five patients. Two of the patients showed changes in the K48-Ub (ubiquitin) biomarker after treatment (maximum change of approximately 3.5-fold). One of these patients also showed a nine-fold increase in activated caspase-3. Example 4: Combination of Compound 1 with an additional therapeutic agent

[0135] Compound 1 was tested with additional therapeutic agents according to the same protocol as in Example 3. Each combination was tested in three cell lines: MOML-13 (human acute myeloid leukemia cell line, Addex Bio), MV-4-11 (human B myelomonocytic leukemia cell line, ATCC), and OCI-AML-3 (human acute myeloid leukemia cell line). The genotypes of these cell lines for p53, FLT3-IDT, BRCA1 and BRCA2 are shown in Table 4.

[0136] [Table 4]

[0137] To test combinations of compound 1 with other therapeutic agents, the concentration ranges of the dose responses were all set to span evenly from one log higher to one log lower than the IC50 of that agent obtained when each agent was used alone. Within this range, 20 dose levels were tested for each combination, and each response was determined twice. For each agent-cell line combination evaluated, the dose response of each individual agent was compared to the dose response of three combinations of the two agents mixed in three fixed ratios (1:1, 1:2, or 2:1) across the dose response, with compound 1 always defined as the first agent in the ratio. The actual drug concentrations within the ratio were determined from the IC50 values ​​obtained for each individual agent. For example, if compound 1 has an IC50 of 1 uM and an additional agent has an IC50 of 10 uM, the actual ratio of agents in a 1:1 IC50 ratio would be 1:10.

[0138] Raw data were analyzed using Graph Pad Prism, a four-parameter logistic fit, and Chou-Talalay drug combination analysis. Chou-Talalay analysis requires data to be normalized and defined as a fractional effect, a number required to be between 0 and 1, with 0 representing no effect (CTG signal in the absence of drug) and 1 representing maximal effect (CTG signal in the absence of cells). In practice, many data points slightly exceeded these limits at the lower or upper limits of the dose range. For data points with fractional effects greater than 1, Fe was set to 0.999. For data points with Fe<0, the fractional effect was set to 0.001. Because the Chou-Talalay analysis applies equal weights across the range of effects to fit the data to the logarithm of the fractional effect, data points with Fe>0.99 or <0.01 were excluded from the Chou-Talalay analysis. As a result, very small changes in effects, both at the upper and lower limits of the dose-response, and within experimental error, would erroneously skew the results of the model fit.

[0139] Combination index (CI) versus fractional effect plots showing the actual combination index plotted against the fractional effect value were plotted for each combination dose. In this analysis, CI=1 represents additive activity, CI>1 represents less than additive activity (often called antagonism), and CI<1 represents synergistic activity (better than additive activity). CI scores across all three ratios were averaged and compared to compound 1 alone. The results are shown in Table 5.

[0140] [Table 5]

[0141] Scores between 0.200 and 0.800 indicate synergy between the combinations, scores between 0.800 and over 1.200 indicate additive effects of the combinations, and scores over 1.200 indicate antagonism of the combinations. Many combinations demonstrated synergy. The PARP inhibitor talazoparib demonstrated strong synergy in combination with compound 1, especially in the BRCA2 mutant cell line MOML-13. The FLT-3 agent gilteritinib demonstrated synergy in the homozygous mutant line MV-4-11 and additive effects in FLT3 wild-type and heterozygous AML lines. The combination of compound 1 with venetoclax demonstrated synergy in the MOML-13 line and strong additive effects (near synergistic effects) in the other two AML lines.

[0142] Some agents, such as the chemotherapy agent cytarabine, produced additive effects across cell lines. Other agents, such as the proteasome inhibitor ixazomib, showed striking antagonism when combined with Compound 1. Combination index data across the ED50, ED75, and ED90 for cytarabine, gilteritinib, talazoparib, and venetoclax are shown below in Tables 6-9.

[0143] [Table 6]

[0144] [Table 7]

[0145] [Table 8]

[0146] [Table 9]

[0147] Example 5: Additional Combinations of Compound 1 with Therapeutic Agents Compound 1 was tested in combination with additional therapeutic agents in the cell lines MOML-13, and MV-4-11 (see Example 4), as well as HL-60 (human acute promyelocytic leukemia, ATCC). The additional therapeutic agents for this example were azacitidine (Cayman Chemical Cat No. 11164), decitabine (Sigma Cat No. A3656), and venetoclax (InvivoChem Cat. No. V0001).

[0148] Cell Culture: Three human acute myeloid leukemia tumor cell lines, HL60, MV4;11, and MOLM-13, were used in this study. HL60 and MV4;11 were cultured in IMDM basal medium containing 20% ​​FBS and 10% FBS, respectively. MOLM-13 was cultured in RPMI 1640 basal medium containing 20% ​​FBS. All culture media contained 2 mM glutamine, 100 units / mL penicillin G sodium salt, 25 jtg / mL gentamicin, and 100 jtg / mL streptomycin sulfate. Tumor cells were cultured in tissue culture flasks in a humidified incubator at 37°C under an atmosphere of 5% CO2 and 95% air. Assay: Tumor cells were seeded in duplicate into 96-well microculture plates in a medium volume of 100 jtL / well at an initial density low enough to allow multiple population doublings (usually 3-5) during the designated incubation period. After 24 h of incubation, test agents were added to each well. Test articles were cultured for 72 h before cell viability was determined using the Cell Titer-Glo® (Promega G7571) assay. Briefly, Cell Titer-Glo® (Promega G7571) reagent was equilibrated at room temperature for 30 min and 100 jtL was added per well at the endpoint (72 h). Plates were gently shaken for 2 min, followed by a 10 min incubation at room temperature before luminescence was read on a BMG Clariostar Plus microplate reader.

[0149] IC for each cell line for each drug alone 50IC values ​​were then determined for varying concentrations of Compound 1 in a 20-point 1:1.5 dose-response curve starting at 5 jtM and including a vehicle control (labeled "fixed no drug"). 20 and I.C. 90 A second set of combinations was used to select fixed drug concentrations around the IC 20 It consisted of a fixed concentration of nearby compound 1 combined with varying concentrations of the second drug using a 20-point dose response of two-fold serial dilutions starting from 50jtM for compound 1, 40jtM for azacitidine and decitabine, and 10jtM venetoclax.

[0150] The results are shown in Tables 10 to 12. IC for each combination 50 Ratios were calculated from the ratio of the IC50 of the combination compared to the applicable fixed drug-free (vehicle) control. Drugs with enhanced activity in combination have a ratio less than 1. For example, in MOML-13 cells, the combination of azacitidine and compound 1 showed a ratio of 0.39 at both low and high doses of azacitidine combined with compound 1 (used as a variable dose agent), and a ratio of 0.28 when compound 1 was provided as a fixed dose and azacitidine was provided at various doses. The combination of compound 1 with decitabine and the combination of venetoclax + azacitidine also showed improved activity compared to monotherapy. Similar enhanced activity from these combinations was also confirmed in MV4;11 cells. These effects were less pronounced in HL60 cells.

[0151] [Table 10]

[0152] [Table 11]

[0153] [Table 12]

[0154] Compound 1 was tested in combination with three PARP inhibitors in various cancer cell lines. The PARP inhibitors used for this study were talazoparib, olaparib, and niraparib. Cisplatin was used as a reference control.

[0155] The cell lines used in the study are shown in Table 13.

[0156] [Table 13]

[0157] The cell lines were cultured in medium supplemented with 10-15% FBS at 37°C, 5% CO2 and 95% humidity. Compounds and combinations were assayed on the cell lines using the Cell Titer-Glo® (Promega G7571) assay according to the protocol in Example 10.

[0158] IC for each drug alone in each cell line 50 The IC50 values ​​were determined and are shown in Table 14.

[0159] [Table 14]

[0160] The interaction of the combination of compound 1 with each PARP inhibitor was evaluated as follows: each cell line was analyzed in a 72-h cell titer glow viability assay with compound 1 alone and in matrix dose combinations with one of the three PARP inhibitors. Cisplatin and culture medium were used as positive and negative controls, respectively. The activity of the combinations was evaluated using CrownSyn software, and synergy scores were determined by the Bliss independence method and the Loewe additivity method. Synergy scores of individual dose combinations >5 were synergistic by these methods, and the average synergy value gives an overview of synergy across all doses tested.

[0161] Synergy scores calculated by both the Bliss independence model and the Loewe additivity model (see Greco, W., Unkelbach, HD, Poch, G., Suhnel, J., Kundi, M., & Bodeker, W. (1992). Consensus on concepts and terminology for combined-action assessment: the Saariselka agreement. Arch Complex Environ Stud, 4(3), 65-9). Without being bound by theory, the Bliss independence model is often applied to evaluate the synergy of non-interacting drugs that independently cause a response, for example, by targeting separate pathways, whereas the Loewe additivity model may be more applicable when both drugs have a similar mode of action on the same target or pathway. In these models, a score higher than 5 indicates synergy and a score lower than -5 indicates an antagonistic effect.

[0162] Table 15 shows the average 6×6 matrix Bliss scores for each PARP inhibitor-Compound 1 combination tested across cell lines, and the number of drug concentration combinations within each matrix that had a Bliss score above 5. The results showed that the PARP inhibitor-Compound 1 combinations were synergistic at the specified dose concentrations in all cell lines tested for two PARP inhibitors, and in all but two cell lines for the remaining PARP inhibitor.

[0163] [Table 15]

[0164] Example 6: Pharmacokinetic analysis Subjects were treated with Compound 1 administered QD or BID as described in Example 2, and blood samples were collected from the subjects and analyzed as described in Example 3. Tables 16 and 17 show the pharmacokinetic analysis for the 100 mg, 175 mg, 275 mg, 350 mg, 400 mg, and 900 mg cohorts administered QD, and the 300 mg and 350 mg cohorts administered BID. Abbreviations for Tables 16 and 17: AR = AUC on Day 4 0-24 / AUC on day 1 0-24 , NR = not reported, NA = not applicable. Plots of total daily dose vs. AUC for QD and BID dosing are shown in Figures 7A and 7B for days 1 and 4, respectively, and plots of total daily dose vs. Cmax for QD and BID dosing are shown in Figures 8A and 8B for days 1 and 4, respectively. Figures 9 and 10 show the AUC for days 1 and 4 for 350-900 mg QD compared to 350 mg BID. Surprisingly, the 350 mg dose BID gave higher exposure levels on day 1 than those obtained with 600, 750, and 900 mg QD dosing. The significantly increased exposure with BID dosing offers the advantage of being able to maintain high plasma levels for extended periods of time without an excessively high Cmax (thus potentially avoiding toxicity due to Cmax).

[0165]

Table 16

[0166]

Table 17

Claims

1. 1. Use of a pharmaceutical composition comprising 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer in a subject in need thereof, the use comprising administering to a subject in need thereof a medicament for a period of 24 hours containing 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2-yl)-2-methyl-1H-indole-4-carboxamide or a pharmaceutically acceptable salt thereof. 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide is administered in twice daily (BID) doses of about 450 mg to about 1500 mg over a 24 hour period such that a total dose of 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide is administered at a dose of about 450 mg to about 1500 mg, whereby said subject experiences a therapeutic response.

2. The use of claim 1, wherein the BID dose maintains high plasma levels for a longer period of time without elevating Cmax to excessively high levels.

3. The use of claim 1, wherein the total dose of 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide over the 24-hour period is 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, or 1500 mg.

4. The use described in claim 1, wherein the cancer is a blood cancer.

5. The cancer is acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myelodysplastic / myeloproliferative overlap neoplasm (MDS / MPN), CMML (chronic myelomonocytic leukemia), atypical chronic myeloid leukemia (aCML), myeloma, amyloidosis, acute lymphoblastic leukemia (ALL), B-lymphoblastic leukemia, T-lymphoblastic leukemia, lymphoma, B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia (CLL), myeloproliferative neoplasm (MPN), essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis, primary myelofibrosis, post-PV myelofibrosis, post-ET myelofibrosis, chronic myeloid leukemia (CML), blastic plasmacytoid dendritic cell neoplasm (BPDCN), M3 2. The use according to claim 1, wherein the cancer is selected from the group consisting of AML and APL (acute promyelocytic leukemia).

6. The use described in claim 1, wherein the cancer is acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

7. The use according to claim 6, wherein the MDS is selected from the group consisting of MDS with unilineage dysplasia (MDS-SLD), MDS with ringed sideroblasts (MDS-RS), MDS with excess blasts 1 and / or excess blasts 2 (MDS-EB-1, MDS-EB-2), unclassifiable MDS (MDS-U), and MDS with isolated del(5q).

8. The use of claim 1, wherein the therapeutic response includes complete remission, freedom from morphologic leukemia or partial remission, hematological improvement, complete cytogenetic response, transfusion independence, or eligibility for stem cell transplantation.

9. The use of claim 1, wherein the pharmaceutical composition is administered in a regimen comprising: (a) administering the drug to the subject for four consecutive days followed by three consecutive days without administering the drug; (b) administering the drug to the subject for five consecutive days followed by two consecutive days without administering the drug; (c) administering the drug once weekly; or (d) administering the drug twice weekly.

10. The use of claim 9, wherein the regimen of administration is repeated.

11. The use of claim 9, wherein the pharmaceutical composition is administered in a 28-day cycle, including administration on days 1 to 4, days 8 to 11, days 15 to 18, and days 22 to 25 of each cycle.

12. The use of claim 11, wherein the 28-day cycle is repeated at least once.

13. The use of claim 1, wherein the pharmaceutical composition is administered orally.

14. The use of claim 1, wherein the pharmaceutical composition is administered as a tablet or capsule.

15. The use of claim 1, wherein the medicament further comprises administration of a second therapeutic agent or is administered in combination with a second therapeutic agent.

16. The use described in claim 5, wherein the myeloma is multiple myeloma.

17. The use of claim 5, wherein the lymphoma is Waldenstrom's macroglobulinemia (also known as lymphoplasmacytic lymphoma), B-cell acute lymphoblastic lymphoma, T-cell acute lymphoblastic lymphoma, Burkitt's leukemia / lymphoma, non-Hodgkin's lymphoma (NHL), small lymphocytic lymphoma (SLL), B-cell NHL, follicular lymphoma, marginal zone lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma (DLBCL), or double / triple hit B-cell lymphoma.

18. The use of claim 6, wherein the MDS is selected from the group consisting of MDS with multilineage dysplasia (MDS-MLD), MDS with ring sideroblasts with unilineage dysplasia (MDS-RS-SLD), or MDS with ring sideroblasts with multilineage dysplasia (MDS-RS-MLD).

19. The use of claim 1, wherein the therapeutic response includes complete remission with minimal residual disease, complete remission with incomplete hematologic recovery, or red blood cell transfusion independence or platelet transfusion independence.

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