VCP / p97 inhibitors for cancer treatment

Abstract

Described herein are methods 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, whereby the subject experiences a therapeutic response.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 023,120, filed May 11, 2020, and U.S. Provisional Patent Application No. 63 / 114,435, filed November 16, 2020, both of which are incorporated herein by reference in their entirety. Background Art

[0003] The valosin-containing protein VCP / p97 and its function are essential for sustained cell viability. Summary of the Invention

[0004] 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, whereby the subject

[0005] 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 is from about 25 mg to about 1000 mg, about 25 mg to about 750 mg, about 25 mg to about 500 mg, 25 mg to about 350 mg, about 25 mg to about 175 mg, about 50 mg to about 1000 mg, about 50 mg to about 750 mg, about 50 mg to about 500 mg, 50 mg to about 350 mg, about 50 mg to about 175 mg, 75 mg to about 1000 mg, about 75 mg to about 750 mg, about 75 mg to about 500 mg, 75 mg to about 350 mg, about 75 mg to about 175 mg, 100 mg to about 1000 mg, about 100 mg to about 750 mg, about 100 mg to about 500 mg, 100 mg to about 350 mg, or about 100 mg to about 175 mg. In some embodiments, the dosage is about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 275 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg. In some embodiments, the cancer is selected from the group consisting of a solid tumor, a metastatic form of a solid tumor, an advanced metastatic solid tumor, a lymphoma, and an advanced lymphoma. In some embodiments, the cancer is a hematological cancer.In some embodiments, the cancer is selected from the group consisting of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myelodysplastic / myeloproliferative overlap neoplasm (MDS / MPN), CMML (chronic myelomonocytic leukemia), atypical CML (chronic myeloid 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-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 (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 myeloid 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, AML is relapsed AML, recurrent AML, refractory AML, or any combination thereof. In some embodiments, AML is primary AML, secondary AML including treatment-related AML and AML with myelodysplasia-related changes (AML with MRC), biphenotypic acute leukemia (also referred to as acute leukemia of unknown lineage), or AML with recurrent abnormalities. In some embodiments, AML is AML with actionable mutations. In some embodiments, AML is AML without actionable mutations. In some embodiments, MDS is relapsed or refractory MDS. In some embodiments, MDS is classified as low-risk MDS, intermediate-risk MDS, high-risk MDS, or very high-risk MDS by the revised International Prognostic Scoring System (IPSS-R).In some embodiments, MDS is selected from the group consisting of: MDS with single lineage dysplasia (MDS-SLD), MDS with multilineage dysplasia (MDS-MLD), MDS with ring sideroblasts (MDS-RS), MDS with ring sideroblasts and single lineage dysplasia (MDS-RS-SLD), MDS with ring sideroblasts (MDS-RS), MDS with ring sideroblasts and multilineage dysplasia (MDS-RS-MLD), MDS with excess blasts 1 and / or 2 (MDS-EB-1, MDS-EB-2), unclassified MDS (MDS-U), and MDS with isolated del(5q).

[0006] In some embodiments, a subject is treated regardless of the subject's mutation or cytogenetic status.

[0007] In some embodiments, treatment responses include complete remission, complete remission without minimal residual disease, complete remission with incomplete hematologic recovery, morphologic aleukemic 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.

[0008] In some embodiments, a therapeutic response includes: an increase in overall survival, an increase in relapse-free survival, an increase in event-free survival, an increase in duration of response, or a decrease in the cumulative incidence of relapse.

[0009] In some embodiments, the pharmaceutical composition is administered in a regimen comprising: (a) administering the drug to the subject for 4 consecutive days, followed by 3 consecutive days of no administration; (b) administering the drug to the subject for 5 consecutive days, followed by 2 consecutive days of no administration; (c) a dose once per week; or (d) a dose twice per week. In some embodiments, the administration regimen is repeated. In some embodiments, the pharmaceutical composition is administered in a 28-day cycle, including 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.

[0010] In some embodiments, the pharmaceutical composition is administered once daily on the administration day.

[0011] In some embodiments, the pharmaceutical composition is administered twice daily on the administration day.

[0012] In some embodiments, the pharmaceutical composition is administered orally.

[0013] In some embodiments, the pharmaceutical composition is administered as a tablet or capsule.

[0014] In some embodiments, the cancer is AML and the subject carries a mutation in one or more loci selected from the group consisting of: 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, IKZ F1, 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.

[0015] In some embodiments, treatment further comprises administering a second therapeutic agent. In some embodiments, the second therapeutic agent is a DNA damaging agent, a hypomethylating agent, an agent that interferes with DNA synthesis, or an agent that interferes with DNA replication. In some embodiments, the second therapeutic agent is decitabine, azacytidine, or cytarabine. In some embodiments, the second therapeutic agent is cytarabine, which is administered in a 7+3 regimen together with an anthracycline. In some embodiments, 7+3 includes 7 days of cytarabine and 3 days of anthracycline 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) or Kyprolis (carfilzomib). In some embodiments, the second therapeutic agent is lenalidomide, dexamethasone, or a combination thereof. 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 immunomodulator. In some embodiments, the second therapeutic agent is an immuno-oncology agent or an immunomodulator. In some embodiments, the cancer is selected from: solid tumors, metastatic forms of solid tumors, advanced metastatic solid tumors, lymphomas and advanced lymphomas. In some embodiments, the subject has undergone at least one previous therapy. In some embodiments, the second therapeutic agent includes gilteritinib or its analogs. In some embodiments, the cancer includes a FLT3 mutation. In some embodiments, the second therapeutic agent inhibits poly ADP ribose polymerase (PARP). In some embodiments, the second therapeutic agent includes talazoparib or its analogs. In some embodiments, the cancer includes a BRCA-2 mutation. In some embodiments, the cancer includes a mutation that impairs homologous recombination. In some embodiments, the second therapeutic agent inhibits Bcl-2. In some embodiments, the second therapeutic agent includes a BH3 peptidomimetic. In some embodiments, the BH3 peptidomimetic comprises venetoclax or an analog thereof. In some embodiments, the cancer is a bcr-abl negative myeloid neoplasm. In some embodiments, 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.

[0016] Incorporation by reference

[0017] 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

[0018] Figure 1 .Describe the efficacy of various dosing regimens of Compound 1 on A549 lung adenocarcinoma xenograft tumors.

[0019] Figure 2 .Describe the effect of compound 1 on circulating MLL-AF9 cells in the MLL-AF9 disseminated mouse model of acute myeloid leukemia.

[0020] Figure 3 .Describe the effect of compound 1 on animal survival in the MLL-AF9 disseminated mouse model of acute myeloid leukemia.

[0021] Figure 4 .Describe the effect of the combination of Compound 1 and cytarabine / doxorubicin on circulating MLL-AF9 cells in the MLL-AF9 disseminated mouse model of acute myeloid leukemia.

[0022] Figure 5 .Describe the effect of the combination of Compound 1 and cytarabine / doxorubicin on animal survival in the MLL-AF9 disseminated mouse model of acute myeloid leukemia.

[0023] Figure 6 . Illustrate the plasma concentration-time profiles of Compound 1 in two human subjects dosed at 25 mg QD. Figure 6 A illustrates the plasma concentration-time profile on day 1 following administration of Compound 1, expressed as μM concentration (left panel) and ng / mL (right panel) over time. Figure 6 B illustrates the plasma concentration-time profile on day 4 following administration of Compound 1, expressed as μM concentration (left panel) and ng / mL (right panel) over time.

[0024] Figure 7 . Illustrate the comparison of the plasma concentration-time curves of Compound 1 and CB5083.

[0025] Figure 8 . Illustrate a comparison of the plasma concentration-time profiles of Compound 1 at 25, 50, 100 and 175 mg QD.

[0026] Figure 9The structure of 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, which is CB-5339 and also referred to herein as Compound 1, is described. DETAILED DESCRIPTION

[0027] Despite the considerable heterogeneity of tumors, malignant transformation confers common features to cancer cells, the so-called "hallmark of cancer," which include replicative immortality, resistance to negative growth signals and apoptosis, and the ability to induce angiogenesis. While these properties provide cancer cells with a survival advantage, they also expose them to stress conditions that normal cells do not typically experience and force them to rely on intracellular pathways that are non-oncogenic in themselves but critical for their survival (i.e., "non-oncogenic addiction"). Based on this observation, mechanisms of stress overload that interact with cancer cells in a synthetically lethal manner are considered viable options for therapeutic intervention.

[0028] The two main stresses faced by cancer cells are proteotoxic stress and genomic stress. Proteotoxic stress or the improper overproduction of intracellular and extracellular proteins (including normal proteins, mutant cancer-related proteins and novel cancer-related fusion proteins) leads to dependence on protein homeostasis pathways and unfolded protein response. High levels of proteotoxic stress in cancer cells indicate that therapeutic strategies for protein homeostasis should have significant anticancer activity by inducing apoptosis of those cancer cells that are overly dependent on their protein homeostasis mechanisms. Although protein homeostasis and degradation pathways are not unique to cancer cells, the overreliance of cancer cells on these systems may make them sensitive to specific inhibitors of protein homeostasis and result in anticancer activity with little toxicity to normal cells. Genomic stress is generated in cancer cells, from initial mutations to genes involved in genomic integrity, thereby making neoplastic transformation possible, and from their rapid growth potential and the DNA replication errors that accompany that growth, it is possible to amplify the many mutations that may be possessed by cancer cells during these processes as they are generated in the mechanisms responsible for the correct repair of replication fidelity and DNA damage.

[0029] There are two major intracellular degradation pathways that control protein homeostasis, the ubiquitin-proteasome system (UPS) and the autophagy-lysosome system (ALS). The role of the valosin-containing protein VCP / p97 in the UPS has been well described. In the UPS, it extracts misfolded proteins from the endoplasmic reticulum in a process called endoplasmic reticulum-associated degradation (ERAD) and chaperones a small portion of the protein to the proteasome for degradation. VCP / p97 also plays a key role in the regulation of chromatin-related events such as DNA damage response and repair. VCP / p97 is known to be overproduced in a variety of cancers. Therefore, by generating unresolvable endoplasmic reticulum (ER) stress and / or unresolvable genotoxic stress, pharmacological interference with VCP / p97 function is expected to have a significant anti-tumor effect. Therefore, inhibitors of VCP / p97 function can provide a mechanism that exploits the addiction of cancer cells to protein homeostasis and DNA damage repair pathways.

[0030] There is a need for inhibitors of VCP / p97 that are useful cancer therapeutics. 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 is a method of treating cancer with Compound 1, comprising administering Compound 1 and an administration regimen to achieve a therapeutic response, such as for difficult-to-treat cancer types and subtypes. The methods herein include methods for enhancing efficacy and / or reducing or mitigating potential side effects. Also provided are methods for enhancing efficacy or therapeutic response and / or increasing the range of cancers to be treated with a combination of Compound 1 and an additional therapeutic agent.

[0031] definition

[0032] As used in the specification and appended claims, the following terms have the meanings indicated below unless otherwise specified.

[0033] Unless the context clearly indicates otherwise, the singular forms "a," "an," and "the" include plural referents. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "a cell" includes reference to one or more cells (or cells) and equivalents thereof. When ranges are used herein for a physical property (such as a molecular weight) or a chemical property (such as a chemical formula), all combinations and subcombinations of ranges and specific embodiments thereof are intended to be included. When referring to a number or a numerical range, the term "about" means that the number or numerical range referred to is an approximation within experimental variation (or within statistical experimental error), and therefore, the number or numerical range will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in certain other embodiments, for example, embodiments of any composition of matter, composition, method, use, or process, etc. described herein may "consist of" or "consist essentially of" the features.

[0034] "Optional" or "optionally" means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0035] As used herein, "treatment" or "treating" or "palliating" or "ameliorating" are used interchangeably herein. These terms refer to an approach for obtaining a beneficial or desired result, including but not limited to a therapeutic benefit and / or a prophylactic benefit. "Therapeutic benefit" means eradication or amelioration of the underlying condition being treated. Additionally, a therapeutic benefit is achieved by eradicating or ameliorating one or more physiological symptoms associated with the underlying condition, such that an improvement is observed in the patient, even though the patient is still suffering from the underlying condition. For prophylactic benefit, the composition can be administered to a patient at risk for developing a particular disease or to a patient reporting one or more physiological symptoms of a disease, even though a diagnosis of the disease may not have been made.

[0036] The dosage amounts and ranges of Compound 1 described herein refer to the dosage of the free base of Compound 1 or the dosage of a pharmaceutically acceptable salt form of Compound 1.

[0037] In some embodiments, "participant," "subject," and "patient" are used interchangeably. In some embodiments, a "subject" refers to a healthy individual. In other embodiments, a "subject" refers to a patient in need of treatment. In some embodiments, a "subject" refers to a human or an animal, particularly a mammal. In some embodiments, a "subject" refers to a human. In some embodiments, a "subject" refers to a non-human mammal.

[0038] 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 the compound with the following structure:

[0039] In some embodiments, compound 1 is in the form of a pharmaceutically acceptable salt. In some embodiments, compound 1 is in the form of a pharmaceutically acceptable salt selected from the group consisting of 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 salt. In some embodiments, compound 1 is in the form of a sulfate salt. In some embodiments, compound 1 is in the form of a hydrochloride salt. In some embodiments, compound 1 is a free base. In addition, compound 1 may exist in an unsolvated form as well as a form solvated with a pharmaceutically acceptable solvent. In some embodiments, compound 1 is solvated. In some embodiments, compound 1 is unsolvated.

[0040] As used herein, "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively nontoxic, i.e., the material can be administered to a subject without causing undesirable biological effects or interacting in a deleterious manner with any component of the composition in which it is contained.

[0041] The term "pharmaceutically acceptable salt" refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination 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 Bigley, DC Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. PHStahl and CGWermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zürich: Wiley-VCH / VHCA, 2002. Pharmaceutically acceptable salts are generally more soluble and dissolve faster in gastric and intestinal fluids than non-ionic substances and can therefore be used in solid dosage forms. Furthermore, because their solubility often varies with pH, ​​selective solubility in one or another part of the digestive tract is possible, and this ability can be manipulated as an aspect of delayed and sustained release behavior. Furthermore, because salt-forming molecules can be in equilibrium with the neutral form, passage through biological membranes can be modulated.

[0042] Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are formed during the process of product formation or separation from a pharmaceutically acceptable solvent, 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, solvates are formed using, but not limited to, Class 3 solvents. In some embodiments, solvates are formed using, but not limited to, Class 2 solvents. For example, 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) defines the classes of solvents. When the solvent is water, a hydrate is formed, or when the solvent is alcohol, an alcoholate is formed.

[0043] In some embodiments, Compound 1 is prepared in various forms, including but not limited to an amorphous phase, a crystalline form, a milled form, and a nanoparticulate form.

[0044] method

[0045] Disclosed herein are methods 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response. In some embodiments, a method of treating cancer in a subject in need thereof, comprising 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 25 mg to about 2000 mg. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising a tosylate 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 25 mg to about 2000 mg. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising a 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 dose of about 25 mg to about 2000 mg. In some embodiments is a method of treating cancer in a subject in need thereof, comprising 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 at a dose of about 25 mg to about 2000 mg.

[0046] In some embodiments 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 free base at a dose of about 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response.

[0047] In some embodiments, a therapeutic response includes achieving one or more response criteria, as measured by medical criteria such as those established or proposed by nationally or internationally recognized medical associations. Exemplary criteria include: the 2017 European LeukemiaNet (ELN) response criteria for AML ( 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); the International Alliance's proposal for unified response criteria for myelodysplasia / myeloproliferative neoplasms (MDS / MPN) in adults (Savona et al. Blood (2015), Vol. 125(12), 1857-65), see also Tefferi et al. Blood (2013), Vol. 122(8), 1395-98.

[0048] In some embodiments 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 25 mg to about 1000 mg, about 25 mg to about 750 mg, about 25 mg to about 500 mg, about 25 mg to about 350 mg, about 25 mg to about 300 mg, about 25 mg to about 200 mg, about 25 mg to about 175 mg, about 50 mg to about 1000 mg, about 50 mg to about 750 mg, about 50 mg to about 500 mg, about 50 mg to about 350 mg, about 50 mg to about 175 mg. In some embodiments, the subject experiences a therapeutic response in the range of about 100 mg to about 300 mg, about 50 mg to about 200 mg, about 75 mg to about 1000 mg, about 75 mg to about 750 mg, about 75 mg to about 500 mg, about 75 mg to about 350 mg, about 75 mg to about 175 mg, about 75 mg to about 300 mg, about 75 mg to about 200 mg, about 100 mg to about 1000 mg, about 100 mg to about 750 mg, about 100 mg to about 500 mg, about 100 mg to about 350 mg, or about 100 mg to about 175 mg, about 100 mg to about 300 mg, about 100 mg to about 200 mg, about 300 mg to about 1000 mg, about 300 mg to about 750 mg, about 300 mg to about 500 mg, 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 pharmaceutically acceptable salt thereof, at a dose of about 25 mg to about 1000 mg. 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 pharmaceutically acceptable salt thereof, at a dose of about 25 mg to about 750 mg. In some embodiments 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 25 mg to about 500 mg.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 pharmaceutically acceptable salt thereof, at a dose of about 25 mg to about 350 mg. 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 pharmaceutically acceptable salt thereof, at a dose of about 25 mg to about 175 mg. 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 pharmaceutically acceptable salt thereof, at a dose of about 50 mg to about 1000 mg. 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 pharmaceutically acceptable salt thereof, at a dose of about 50 mg to about 750 mg. 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 pharmaceutically acceptable salt thereof, at a dose of about 50 mg to about 500 mg. 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 pharmaceutically acceptable salt thereof, at a dose of about 50 mg to about 350 mg. In some embodiments 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, in a dose of about 50 mg to about 175 mg.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 pharmaceutically acceptable salt thereof, at a dose of about 75 mg to about 1000 mg. 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 pharmaceutically acceptable salt thereof, at a dose of about 75 mg to about 750 mg. 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 pharmaceutically acceptable salt thereof, at a dose of about 75 mg to about 500 mg. 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 pharmaceutically acceptable salt thereof, at a dose of about 75 mg to about 350 mg. 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 pharmaceutically acceptable salt thereof, at a dose of about 75 mg to about 175 mg. 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 pharmaceutically acceptable salt thereof, at a dose of about 100 mg to about 1000 mg. In some embodiments 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 100 mg to about 750 mg.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 pharmaceutically acceptable salt thereof, at a dose of about 100 mg to about 500 mg. 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 pharmaceutically acceptable salt thereof, at a dose of about 100 mg to about 350 mg. In some embodiments 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 100 mg to about 175 mg.

[0049] In some embodiments 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 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 275 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg, 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 pharmaceutically acceptable salt thereof, at a dose of about 25 mg. 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 pharmaceutically acceptable salt thereof, at a dose of about 50 mg. 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 pharmaceutically acceptable salt thereof, at a dose of about 75 mg. 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 pharmaceutically acceptable salt thereof, at a dose of about 100 mg. In some embodiments 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 125 mg.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 pharmaceutically acceptable salt thereof, at a dose of about 150 mg. 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 pharmaceutically acceptable salt thereof, at a dose of about 175 mg. 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 pharmaceutically acceptable salt thereof, at a dose of about 200 mg. 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 pharmaceutically acceptable salt thereof, at a dose of about 250 mg. 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 pharmaceutically acceptable salt thereof, at a dose of about 275 mg. 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 pharmaceutically acceptable salt thereof, at a dose of about 300 mg. In some embodiments 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 350 mg.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 pharmaceutically acceptable salt thereof, at a dose of about 400 mg. 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 pharmaceutically acceptable salt thereof, at a dose of about 450 mg. 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 pharmaceutically acceptable salt thereof, at a dose of about 500 mg. 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 pharmaceutically acceptable salt thereof, at a dose of about 600 mg. 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 pharmaceutically acceptable salt thereof, at a dose of about 700 mg. 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 pharmaceutically acceptable salt thereof, at a dose of about 800 mg. In some embodiments 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 900 mg.In some embodiments 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 1000 mg.

[0050] 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, wherein the cancer is selected from a solid tumor, a metastatic form of a solid tumor, an advanced metastatic solid tumor, a lymphoma, and an advanced 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, wherein the cancer is a solid tumor. 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, wherein the cancer is a metastatic form of a solid tumor. 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, wherein the cancer is an advanced metastatic solid tumor. 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, wherein the cancer is lymphoma. 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, wherein the cancer is advanced lymphoma.

[0051] 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 dose of about 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response. 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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is a bcr-abl negative myeloid neoplasm.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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is selected from the group consisting of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative Dysfunctional / myeloproliferative overlap neoplasms (MDS / MPN) (such as MDS / MPN-RS-T, unclassified MDS / MPN), CMML (chronic myelomonocytic leukemia) (such as CMML-1 and CMML-2), aCML (atypical chronic myeloid 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-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 (DLBCL), double / triple hit B-cell lymphoma, myeloproliferative neoplasms Myelofibrosis (MPN) (including CES-NOS and unclassified MPN), essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis, chronic neutrophilic leukemia (CNL), primary myelofibrosis, post-PV myelofibrosis, post-ET myelofibrosis, post-PV / ET myelofibrosis, myelofibrosis secondary to the 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 embodiments is a method of treating a hematological 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 25 mg to about 2000 mg, wherein the hematological cancer is acute myeloid leukemia (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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, wherein the hematological cancer is myelodysplastic syndrome (MDS). 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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is myelodysplastic / myeloproliferative overlap neoplasm (MDS / MPN). In some aspects, the MDS / MPN is MDS / MPN-RS-T or unclassified MDS / MPN. 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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is CMML (chronic myelomonocytic leukemia). In some aspects, the CMML is CMML-1 or CMML-2. 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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is atypical chronic myeloid leukemia (aCML). 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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is multiple myeloma.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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is myeloma. 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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is amyloidosis. 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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is Waldenstrom's macroglobulinemia (also known as lymphoplasmacytic lymphoma). 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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is acute lymphoblastic leukemia (ALL). 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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is B lymphoblastic leukemia. 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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is T lymphoblastic leukemia.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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is lymphoma. 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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is B-cell acute lymphoblastic leukemia. 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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is T-cell acute lymphoblastic leukemia. 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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is B-cell acute lymphoblastic lymphoma. 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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is T-cell acute lymphoblastic lymphoma. 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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is Burkitt's leukemia / lymphoma.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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is non-Hodgkin's lymphoma (NHL). 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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is chronic lymphocytic leukemia (CLL). 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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is small lymphocytic lymphoma (SLL). 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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is B-cell NHL. 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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is follicular lymphoma. 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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is marginal zone lymphoma.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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is mantle cell lymphoma. 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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is diffuse large B-cell lymphoma (DLBCL). 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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is double / triple hit B-cell lymphoma. 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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is a myeloproliferative neoplasm (MPN). In certain aspects, the MPN is CES-NOS or unclassified MPN. 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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is essential thrombocythaemia (ET). In some embodiments is a method of treating a hematological 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 25 mg to about 2000 mg, wherein the hematological cancer is polycythemia vera (PV).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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, 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 the PV and ET prognostic model [MYSEC-PM]. 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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is chronic myeloid leukemia (CML). In some embodiments is a method of treating a hematological 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 25 mg to about 2000 mg, 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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is blastic plasmacytoid dendritic cell neoplasm (BPDCN). 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 dose of about 25 mg to about 2000 mg, wherein the hematological cancer is M3 AML. In some embodiments is a method of treating a hematological 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 25 mg to about 2000 mg, wherein the hematological cancer is APL (acute promyelocytic leukemia).

[0052] 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, wherein the AML is relapsed AML, relapsed AML, refractory AML, or any combination thereof. 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, wherein the AML is relapsed AML. 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, wherein the AML is relapsed AML. 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, wherein the AML is refractory AML. 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, wherein the AML is any combination of relapsed AML, recurrent AML, and refractory AML.

[0053] In some embodiments is a method of treating acute myeloid leukemia (AML) 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response. In some embodiments is a method of treating acute myeloid leukemia (AML) 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 25 mg to about 2000 mg, wherein the AML is de novo AML, secondary AML including therapy-related AML and AML with myelodysplasia-related changes (AML with MRC), biphenotypic acute leukemia (also known as acute leukemia of unknown lineage), or AML with a recurrent abnormality. 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, wherein the AML is de novo AML. 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, wherein the AML is secondary AML including therapy-related AML and AML with myelodysplasia-related changes (AML with MRC). In some embodiments is a method of treating acute myeloid leukemia (AML) 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 25 mg to about 2000 mg, wherein the AML is AML with myelodysplasia-related changes (AML with MRC).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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, wherein AML is biphenotypic acute leukemia (also known as acute leukemia of unknown lineage). 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, wherein AML is AML with recurrent abnormality. 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, 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 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 dose of about 25 mg to about 2000 mg, wherein the AML is AML without an actionable mutation.

[0054] 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, whereby the subject experiences a therapeutic 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, wherein the MDS is relapsed or refractory MDS. In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, wherein the MDS is classified as low-risk MDS by the Revised International Prognostic Scoring System (IPSS-R). In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, wherein the MDS is classified as intermediate-risk MDS by the Revised International Prognostic Scoring System (IPSS-R). In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, wherein the MDS is classified as high-risk MDS by the Revised International Prognostic Scoring System (IPSS-R).In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, wherein the MDS is classified as very high risk MDS by the Revised International Prognostic Scoring System (IPSS-R). 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, wherein the MDS is selected from the group consisting of: MDS with monophyletic dysplasia (MDS-SLD), MDS with multiphyletic dysplasia (MDS-SLD), MDS with ring sideroblasts (MDS-RS), MDS with ring sideroblasts and monolineage dysplasia (MDS-RS-SLD), MDS with ring sideroblasts (MDS-RS), MDS with ring sideroblasts and multilineage dysplasia (MDS-RS-MLD), MDS with excess blasts 1 and / or 2 (MDS-EB-1, MDS-EB-2), unclassified MDS (MDS-U), and MDS with isolated del(5q). In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, wherein the MDS is MDS with monophyletic dysplasia (MDS-SLD). In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, wherein the MDS is MDS with multilineage dysplasia (MDS-MLD).In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, wherein the MDS is MDS with ring sideroblasts (MDS-RS). In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, wherein the MDS is MDS with ring sideroblasts and monolineageal dysplasia (MDS-RS-SLD). In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, wherein the MDS is MDS with ring sideroblasts (MDS-RS). In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, wherein the MDS is MDS with ring sideroblasts and multilineage dysplasia (MDS-RS-MLD). In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, wherein the MDS is MDS with excess blasts 1 and / or 2 (MDS-EB-1, MDS-EB-2).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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, wherein the MDS is unclassified MDS (MDS-U). 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, wherein the MDS is MDS with isolated del(5q).

[0055] In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the subject is treated regardless of the subject's mutation or cytogenetic status.

[0056] In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the therapeutic response comprises complete remission, complete remission without minimal residual disease, complete remission with incomplete hematologic recovery, morphologic aleukemic 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 transplant. In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the therapeutic response comprises a complete remission. In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the therapeutic response comprises a partial remission. 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 pharmaceutically acceptable salt thereof, at a dose of about 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the therapeutic response comprises 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 pharmaceutically acceptable salt thereof, at a dose of about 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the therapeutic response comprises a complete cytogenetic response.In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the therapeutic response includes infusion independence. In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the therapeutic response comprises red blood cell transfusion independence or platelet transfusion independence. In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the therapeutic response includes eligibility for stem cell transplantation.

[0057] In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the therapeutic response comprises: an increase in overall survival, an increase in relapse-free survival, an increase in event-free survival, an increase in duration of response, or a decrease in the cumulative incidence of relapse. In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the therapeutic response includes an increase in overall survival. In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the therapeutic response includes an increase in relapse-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 pharmaceutically acceptable salt thereof, at a dose of about 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the therapeutic response comprises 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 pharmaceutically acceptable salt thereof, at a dose of about 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the therapeutic response comprises an increase in the duration of the response.In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the therapeutic response comprises a reduction in the cumulative incidence of relapse.

[0058] In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the pharmaceutical composition is administered on a regimen comprising: (a) administering the drug to the subject for 4 consecutive days, followed by 3 consecutive days without administration; (b) administering the drug to the subject for 5 consecutive days, followed by 2 consecutive days without administration; (c) dosing once weekly; or (d) dosing twice weekly. In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the pharmaceutical composition is administered on a regimen comprising (a) administering the drug to the subject for 4 consecutive days followed by 3 consecutive days without administration of the drug. In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the pharmaceutical composition is administered on a regimen that comprises administering the drug to the subject for 5 consecutive days followed by 2 consecutive days without administration of the drug. In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the pharmaceutical composition is administered on a regimen comprising a once weekly dosing. In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the pharmaceutical composition is administered on a regimen comprising twice weekly dosing.In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the administration regimen is repeated. In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the pharmaceutical composition is administered in 28-day cycles, including administration on days 1-4, 8-11, 15-18, and 22-25 of each cycle. In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the pharmaceutical composition is administered in a 28-day cycle, including administration on days 1-4, 8-11, 15-18, and 22-25 of each cycle, and the 28-day cycle is repeated at least once.

[0059] 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the pharmaceutical composition is administered once daily on the administration day. 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the pharmaceutical composition is administered twice daily on the administration day.

[0060] In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the pharmaceutical composition is administered orally.

[0061] In some embodiments is a method of treating myelodysplastic syndrome (MDS) 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the pharmaceutical composition is administered as a tablet or capsule.

[0062] 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, and the subject carries a mutation in one or more loci selected from the group consisting of: ABL1, ASXL1, BCOR, BCORL1, BCR, BRAF, CALR, CBFB, CBL, CBLB, CDKN2A, CEBPA, CSF3R, CUX 1. DEK, DNMT3A, ETV6, EZH2, FBXW7, FLT3, GATA1, GATA2, GNAS, HRAS, IDH1, IDH2, IKZF1, JAK2, JAK3, KDM6A, KIT, KMT2A, MECOM(EVI1), MLL, MLLT3, MPL, M YD88, 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 carries a mutation at 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more loci selected from: ABL1, ASXL1, BCOR, BCORL1, BCR, BRAF, CALR, CBFB, CBL, CBLB, CDKN2A, CEBPA, CSF3R, CUX1, DEK, DNMT3A, ETV6, EZH2, FBXW7, FLT3, GATA1, GATA2, GN AS, HRAS, IDH1, IDH2, IKZF1, JAK2, JAK3, KDM6A, KIT, KMT2A, MECOM(EVI1), MLL, MLLT3, MPL, MYD88, MYH11, NOTCH1, NPM1, N UP214, NRAS, PDGFRA, PHF6, PTEN, PTPN11, RAD21, RUNX1, SF3B1, SRSF2, SMC1A, SMC3, STAG2, TET2, TP53, U2AF1, WT1 and ZRSR2.

[0063] Treatment response

[0064] The methods 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 pharmaceutically acceptable salt thereof to provide a therapeutic response in the treated subject. The therapeutic response may depend on the type of cancer being treated, as well as the subject being treated, the stage of the cancer, the subject's previous treatments, 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 without minimal residual disease, complete remission with incomplete hematological recovery, morphologically aleukemic state 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 further includes or is one or more of: an increase in overall survival, an increase in relapse-free survival, an increase in event-free survival, an increase in duration of response, or a decrease in the cumulative incidence of relapse.

[0065] Combination therapy

[0066] In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent. In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is a DNA damaging agent, a hypomethylating agent, 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 pharmaceutically acceptable salt thereof, at a dose of about 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and 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 pharmaceutically acceptable salt thereof, at a dose of about 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is a hypomethylating agent. In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is an agent that interferes with DNA synthesis.In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is an agent that interferes with DNA replication.

[0067] In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is decitabine, azacytidine, or cytarabine. In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is decitabine. In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is azacytidine. In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is cytarabine.

[0068] In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is cytarabine administered in a 7+3 regimen comprising 7 days of cytarabine and 3 days of an anthracycline selected from daunorubicin, doxorubicin, idarubicin, and mitoxantrone. In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is cytarabine administered in a 7+3 regimen comprising 7 days of cytarabine and 3 days of an anthracycline antibiotic. In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is cytarabine administered in a 7+3 regimen comprising 7 days of cytarabine and 3 days of daunorubicin. In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is cytarabine administered in a 7+3 regimen comprising 7 days of cytarabine and 3 days of doxorubicin.In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is cytarabine administered in a 7+3 regimen comprising 7 days of cytarabine and 3 days of idarubicin. In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is cytarabine administered in a 7+3 regimen comprising 7 days of cytarabine and 3 days of mitoxantrone.

[0069] In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is a tyrosine kinase inhibitor.

[0070] In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is a DNA damage repair inhibitor.

[0071] In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and 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 pharmaceutically acceptable salt thereof, at a dose of about 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is an inhibitor of ATM. 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 pharmaceutically acceptable salt thereof, at a dose of about 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is an inhibitor of ATR. 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is an inhibitor of poly ADP ribose polymerase (PARP). In some embodiments of the method, the PARP inhibitor comprises talazoparib or an analog thereof. In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and 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 pharmaceutically acceptable salt thereof, at a dose of about 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and 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 pharmaceutically acceptable salt thereof, at a dose of about 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is Velcade (bortezomib). In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is Kyprolis (carfilzomib).

[0073] In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is lenalidomide, dexamethasone, or a combination 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 pharmaceutically acceptable salt thereof, at a dose of about 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and 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 pharmaceutically acceptable salt thereof, at a dose of about 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is dexamethasone. In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is a combination of lenalidomide and dexamethasone.

[0074] In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is selected from the group consisting of: 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, 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is an inhibitor of FLT3. In some embodiments of the method, the FLT3 inhibitor comprises gilteritinib 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 pharmaceutically acceptable salt thereof, at a dose of about 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and 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 pharmaceutically acceptable salt thereof, at a dose of about 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is an inhibitor of IDH2. In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is an inhibitor of hedgehog pathway inhibition.In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is an inhibitor of a hedgehog pathway inhibitor, wherein the hedgehog pathway inhibitor is gradib. In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is an anti-CD33 antibody. In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is an anti-CD33 antibody, wherein the anti-CD33 antibody is tocilizumab ozogamicin. In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is a purine analog. In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is a purine analog, wherein 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 pharmaceutically acceptable salt thereof at a dose of about 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and 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 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is a Bcl-2 inhibitor, wherein the Bcl-2 inhibitor is venetoclax.

[0075] In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is an immuno-oncology agent.

[0076] In some embodiments 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 25 mg to about 2000 mg, whereby the subject experiences a therapeutic response, wherein the treatment further comprises administering a second therapeutic agent, and the second therapeutic agent is an immunomodulatory agent.

[0077] dose

[0078] In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 1 25mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg , about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325mg, about 330mg, about 335mg, about 340mg, about 345mg, about 350mg, about 355mg, about 360mg, about 365mg, about 370mg, about 375mg, about 38 0 mg, about 385 mg, about 390 mg, about 395 mg, about 400 mg, about 405 mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg, about 430 mg, about 435 mg, about 440 mg, about 445 mg, 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 or about 500 mg, including increments therein. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, or about 750 mg, including increments therein.

[0079] In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 25 mg to about 1500 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 25 mg to about 1000 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 25 mg to about 750 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 25 mg to about 500 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 25 mg to about 450 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 25 mg to about 400 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 25 mg to about 375 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 25 mg to about 350 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 25 mg to about 325 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 25 mg to about 300 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 25 mg to about 275 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 25 mg to about 250 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 25 mg to about 225 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 25 mg to about 200 mg.In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 25 mg to about 175 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 25 mg to about 150 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 25 mg to about 125 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 25 mg to about 100 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 25 mg to about 75 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 25 mg to about 50 mg.

[0080] In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 50 mg to about 1000 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 50 mg to about 750 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 50 mg to about 500 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 50 mg to about 450 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 50 mg to about 400 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 50 mg to about 350 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 50 mg to about 300 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 50 mg to about 250 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 50 mg to about 200 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 50 mg to about 150 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 50 mg to about 125 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 50 mg to about 100 mg. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is from about 50 mg to about 75 mg.

[0081] In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically 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, the dose of Compound 1, or a pharmaceutically 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, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is not administered with food.

[0082] In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically 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, the dose of Compound 1, or a pharmaceutically 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, the dose of Compound 1, or a pharmaceutically 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, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is administered four times daily.

[0083] In some embodiments, the dose of Compound 1 or a pharmaceutically acceptable salt thereof administered to a subject in need (whereby the subject experiences a therapeutic response) is administered together with a treatment "holiday," which is a period of several days between consecutive doses. For example, the dose of Compound 1 is administered for 1-7 days ("dosing" days), and then the 1-7 day period is a "holiday," during which no dose of Compound 1 is administered to the subject ("off" days). In some embodiments, the dose of Compound 1 or a pharmaceutically acceptable salt thereof administered to a subject in need (whereby the subject experiences a therapeutic response) is administered on a 4-day dosing / 3-day off-dose schedule, a 5-day dosing / 3-day off-dose schedule, a 5-day dosing / 2-day off-dose schedule, or a 4-day dosing / 2-day off-dose schedule. In some embodiments, the dosing / off-dose dosage cycle is repeated so that the dose of Compound 1 is administered on 2, 3, 4, 5, or more than 5 dosing / off-dose schedule cycles.

[0084] In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically 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, the dose of Compound 1, or a pharmaceutically 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, the dose of Compound 1, or a pharmaceutically 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, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is administered once every five days. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is administered once every six days. In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is administered once every week.

[0085] In some embodiments of the methods disclosed herein, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof (whereby the subject experiences a therapeutic response) is administered for four days on and three days off.

[0086] In some embodiments of the methods disclosed herein, the subject has been undergoing at least one prior therapy.

[0087] Pharmaceutical composition

[0088] 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 pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. 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 pharmaceutically acceptable salt thereof and at least one pharmaceutically 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 pharmaceutically acceptable salt thereof, and at least one pharmaceutically 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 pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient in a solid dosage form selected from the group consisting of powders, tablets, bite-disintegrating tablets, chewable tablets, caplets, capsules, gelcaps, effervescent powders, rapidly disintegrating tablets, abuse-deterrent tablets, modified-release tablets, modified-release caplets, modified-release capsules, and aqueous suspensions derived from 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 pharmaceutically acceptable salt thereof, and at least one pharmaceutically 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 pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient in a solid dosage form, wherein the solid dosage form is a tablet.

[0089] excipient

[0090] Optional excipients suitable for use in the pharmaceutical compositions of 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide described herein include any excipient commonly used in pharmaceuticals and are selected based on compatibility with the active agent and the release profile characteristics of the desired dosage form. Excipients include, but are not limited to, binders, fillers, glidants, disintegrants, lubricants, glidants, polymer carriers, plasticizers, stabilizers, surfactants, and the like. A summary of the excipients described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th 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, 7th ed. (Lippincott Williams & Wilkins, 1999), which are incorporated herein by reference in their entireties.

[0091] Fillers or diluents increase the bulk of a pharmaceutical composition. Such compounds include, for example, lactose; starch; mannitol; sorbitol; dextrose; microcrystalline cellulose, such as Silicified microcrystalline cellulose, such as HD90; dibasic calcium phosphate; dicalcium phosphate dihydrate; tricalcium phosphate; calcium phosphate; anhydrous lactose; spray-dried lactose; pregelatinized starch; compressible sugars, such as (Amstar); hydroxypropyl methylcellulose; sucrose-based diluents; sugars for confectioners; calcium dihydrogen sulfate monohydrate; calcium sulfate dihydrate; calcium lactate trihydrate; dextrate; cereal hydrolyzed solids; amylose; powdered cellulose; calcium carbonate; glycine; kaolin; sodium chloride; inositol; bentonite; etc. In some embodiments, the pharmaceutical compositions described herein comprise 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, silicified 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 silicified microcrystalline cellulose.

[0092] Binders impart cohesiveness to solid oral dosage form compositions: for powder-filled capsule formulations, they aid in plunger formation that can be filled into soft or hard shell capsules, and for tablet formulations, they ensure that the tablet remains intact after compression and help ensure blending uniformity prior to the compression or filling step. Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to: carboxymethyl cellulose, methyl cellulose (e.g., ), hydroxypropyl methylcellulose (e.g., Hydroxypropyl methylcellulose USP Pharmacoat-603), hydroxypropyl methylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., ), ethyl cellulose (e.g., ), microcrystalline cellulose (e.g., ), siliconized unrefined cellulose (such as HD90), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonite, gelatin, polyvinyl pyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth gum, dextrin, sugars such as sucrose (e.g., ), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., ), lactose, natural or synthetic gums such as gum arabic, gum tragacanth, ghatti gum, mucilage of isapol husks, starch, polyvinyl pyrrolidone (e.g., CL, CL, XL-10 and K-12), larch arabinogalactan, Polyethylene glycol, wax, sodium alginate, etc. In some embodiments, the binder is hypromellose, hydroxypropyl cellulose, or ethyl cellulose.

[0093] Glidants improve the flow characteristics of a powder mixture. Such compounds include, for example, colloidal silicon dioxide, such as Tricalcium phosphate, talc, corn starch, DL-leucine, sodium lauryl sulfate, magnesium stearate, calcium stearate, sodium stearate, kaolin, and micronized amorphous silica Etc. 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.

[0094] Lubricants are compounds that prevent, reduce or inhibit adhesion or friction of materials. Exemplary lubricants include, for example, stearic acid; calcium hydroxide, talc; paraffin; hydrocarbons such as mineral oil or hydrogenated vegetable oils such as hydrogenated soybean oil. Higher fatty acids and alkali metal and alkaline earth metal salts thereof, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearate, calcium stearate, magnesium stearate, glycerol, talc, wax, Boric acid, sodium acetate, leucine, polyethylene glycol or methoxypolyethylene glycol such as Carbowax TM , sodium oleate, glyceryl behenate (Compitrol ), Glyceryl Palmitostearate Colloidal silica such as Syloid TM 、 Starch such as corn starch, silicone oil, surfactants, etc. Hydrophilic lubricants include, for example, sodium stearyl fumarate (currently sold under the trade name (available in Japan), 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.

[0095] Disintegrants aid in the breakdown or disintegration of a pharmaceutical formulation after administration. Examples of disintegrants include starches, for example, natural starches (such as corn starch or potato starch), pregelatinized starches (such as National 1551 or ) or sodium starch glycolate (such as or ); cellulose, such as wood products, microcrystalline cellulose (e.g., PH101, PH102, PH105, P100, and ), methylcellulose, cross-linked carboxymethylcellulose, or cross-linked cellulose (such as cross-linked carboxymethylcellulose sodium cross-linked carboxymethyl cellulose or cross-linked croscarmellose); cross-linked starch, such as sodium starch glycolate; cross-linked polymers, such as crospovidone; cross-linked polyvinyl pyrrolidone; alginates, such as alginic acid or alginates, such as sodium alginate; clays, such as HV (magnesium aluminum silicate); gums such as agar, guar, locust bean gum, karaya gum, pectin, or tragacanth; sodium starch glycolate; bentonite; natural sponge; resins such as cation exchange resins; citrus pulp; sodium lauryl sulfate; a combination of sodium lauryl sulfate and starch; and the like. In some embodiments of the pharmaceutical compositions described herein, the disintegrant is selected from povidone, crospovidone, hypromellose, cross-linked sodium carboxymethyl cellulose, hydroxypropyl cellulose, and polyvinyl alcohol. In some embodiments, the disintegrant is cross-linked sodium carboxymethyl cellulose. 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.

[0096] In some embodiments, the pharmaceutical compositions described herein comprise one or more pH adjusting agents or buffers. In some embodiments, the pharmaceutical formulation comprises 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 hydrogen phosphate, and disodium hydrogen phosphate. In some embodiments, the buffer is included in an amount required to maintain the pH of the pharmaceutical formulation within an acceptable range.

[0097] In some embodiments, a film coating is provided 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 pharmaceutically 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 a defoamer (transparent, pigmented, 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 pharmaceutically 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 instant release coating with a moisture barrier comprises polyvinyl alcohol (PVA), with or without a plasticizer, with or without a surfactant and a defoamer (transparent, or colored, or dyed). In some embodiments, the composition is formulated into particles (e.g., to be administered by capsule) and some or all of the particles are coated. In some embodiments, the composition is formulated into particles (e.g., to be administered by capsule) and some or all of the particles are microencapsulated. In some embodiments, the composition is formulated into particles (e.g., to be administered by capsule) and some or all of the particles are not microencapsulated and are not coated.

[0098] In some embodiments, the compositions described herein are delivered using a pulsatile dosage form. A pulsatile dosage form is capable of providing one or more immediate release pulses at a predetermined time point or at a specific site after a controlled lag time. Many other types of controlled release systems known to those of ordinary skill in the art are suitable for use with the compositions described herein. Examples of such delivery systems include, for example, polymer-based systems such as polylactic and polyglycolic acids, polyanhydrides, and polycaprolactones; porous matrices, non-polymer-based systems that are lipids, including sterols such as cholesterol, cholesterol esters, and fatty acids, or neutral fats such as monoglycerides, diglycerides, and triglycerides; hydrogel release systems; silicone rubber systems; peptide-based systems; wax coatings, bioerodible dosage forms, compressed tablets using conventional adhesives, and the like. See, e.g., Liberman et al., Pharmaceutical Dosage Forms, 2nd Edition, Vol. 1, pp. 209-214 (1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Edition, pp. 751-753 (2002); U.S. Pat. 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 expressly incorporated by reference.

[0099] Stabilizers include compounds such as any antioxidants, for example, butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol; buffers, acids, and the like.

[0100] 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, poloxamer 6200, and Kolliphor P407 micro. In some embodiments, the surfactant is a poloxamer. In some embodiments, the surfactant is Kolliphor P407 micro.

[0101] The above excipients are given as examples only and are not meant to be inclusive of all possible options. Other suitable excipient categories include colorants, granulating agents, preservatives, defoaming agents, plasticizers, and the like. In addition, many excipients may have more than one effect or function, or may be classified into more than one group; the categories are merely descriptive and are not intended to limit any use of a particular excipient.

[0102] Medicine boxes / products

[0103] For use in the methods described herein, kits and articles are also described herein. Such kits include carriers, packages, or containers that are separated to accommodate one or more containers, such as vials, tubes, etc., each container containing one of the individual elements to be used for the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In one embodiment, the container is formed from a variety of materials, such as glass or plastic.

[0104] The articles provided herein contain packaging materials. Packaging materials for packaging pharmaceutical products include, for example, U.S. Patent No. 5,323,907. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, bags, containers, bottles, and any packaging material suitable for the selected formulation and intended mode of administration and treatment.

[0105] In some embodiments, the pharmaceutical composition of compound 1 described herein is present in a package or dispenser device that may contain one or more unit dosage forms containing an active ingredient. The pharmaceutical composition of compound 1 described herein is packaged alone or packaged together with another compound or another ingredient or additive. In some embodiments, the packaging includes one or more containers filled with one or more ingredients of the pharmaceutical composition. In some embodiments, the packaging includes metal or plastic foil, such as a blister pack. In some embodiments, the packaging or dispenser is accompanied by a notice associated with the container in a form specified by a government agency for the manufacture, use or sale of a prescribed pharmaceutical preparation, the notice embodying the form of the drug approved by the agency for human or veterinary administration. In some embodiments, for example, such a notice can be a label approved for prescription drugs by the US Food and Drug Administration or an approved product insert.

[0106] The kit typically includes a label listing the contents and / or instructions for use, and a package insert containing instructions for use. A set of instructions is also typically included.

[0107] In one embodiment, the label is on or associated with the container. In one embodiment, the label is on the container when the letters, numbers, or other characters forming the label are affixed, molded, or etched into the container itself; the label is associated with the container when the label is present within a vessel or carrier that also holds the container, such as a package insert. In one embodiment, the label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates directions for use of the contents, such as in the methods described herein.

[0108] Example

[0109] List of abbreviations

[0110] As used throughout the description of the present invention, unless otherwise indicated, the following abbreviations shall be understood to have the following meanings:

[0111] AML = acute myeloid leukemia; AUC ∞ = 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 Network; IWG = International Working Group; MTD = maximum tolerated dose; MDS = myelodysplastic syndrome; PD = pharmacodynamics; PK = pharmacokinetic; PR = partial recovery; RP2D = recommended phase 2 dose; RR = relapsed / refractory; t 1 / 2 = half-life; t max = time to reach maximum concentration.

[0112] I. Chemical Synthesis

[0113] Example 1: Preparation of Compound 1

[0114] 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.

[0115] II. Biological Data

[0116] Example 2: p97 inhibition assay

[0117] The p97 assay is used to determine the inhibitory activity of compounds against the p97 complex. Inhibition of the activity of the p97 proteosome complex can induce apoptosis and lead to the elimination of tumor cells (cancer cells). The assay follows the method of Christianson (Nat. Cell Biol., (2011) 14:93). The reagents used in the p97 assay include assay buffer, which is a mixture of 50 mM TRIS pH 7.5, 20 mM MgCl₄, 0.02% TX-100, 1 mM DTT, and 0.2% (v / v) glycerol. The well plate is a Corning 3674 384w plate. The identification kit is the ADP glo kit (Promega): stop buffer and detection reagent.

[0118] The assay was performed as follows:

[0119] - Compounds were serially diluted in DMSO in a 1:3.33 fold 10-point serial dilution.

[0120] - Add the following reagents to each well of the 384w plate:

[0121] 0.5 μL of serially diluted compound in DMSO (final concentration 10%)

[0122] 2 μL ATP (final concentration = 20 μM, diluted in assay buffer)

[0123] 2.5 μL p97 (final concentration = 20 nM, diluted in assay buffer).

[0124] - Incubate at 37°C for 15 min.

[0125] - Add 5 μL of stop buffer and incubate at room temperature for 40 minutes.

[0126] -Add 10 μL of detection reagent and incubate at room temperature for 30 minutes.

[0127] - Luminescence was read on an Envision plate reader.

[0128] After obtaining data from the luminescence readout, the data can be analyzed as follows:

[0129] - Luminescence data were normalized using no enzyme (full inhibition) and no compound (no inhibition) controls.

[0130] - Normalized luminescence data were plotted against log-transformed concentration values ​​and sigmoidal curves were fitted to determine IC50 values ​​(performed in Collaborative Drug Discovery software).

[0131] When tested in the above assay, compound 1 demonstrated the ability to inhibit p97, p97IC 50 <30nM.

[0132] Example 3: In vitro evaluation of Compound 1 in 30 passage 1 (P1) human acute myeloid leukemia models

[0133] Acute myeloid leukemia (AML) is the most common acute leukemia in adults. As a hematological cancer, the disease is highly heterogeneous with multiple subtypes. Approximately 30% of AML cases have FLT3 / ITD mutations, which make the disease highly proliferative and more aggressive, with a high risk of relapse. Many FLT3 inhibitors have been successfully used to target AML with FLT3 / ITD mutations, but due to the rapid development of drug resistance, the duration of clinical response is generally short. The purpose of this study was to evaluate the cytotoxicity of compound 1 as a single agent or in combination with 500nM decitabine, 22nM cytarabine, 8nM gilteritinib or 8nM venetola in 30 first generation (P1) human acute myeloid leukemia models by CellTiter Glo.

[0134] Compound 1 in a single dose was tested in duplicate at 5 concentrations. Also tested were the combination of compound 1 at 5 concentrations (5000, 1667, 556, 185, 62, 0 nM) and a constant concentration of decitabine (500 nM), cytarabine (22 nM), gilteritinib (8 nM) or venetola (8 nM). Three wells with only culture medium and two wells with vehicle (0.2% DMSO) were used as negative controls. Three wells with cytarabine (5 μM) were used as positive controls for assay. In order to measure proliferation, untreated cells were assessed at day 0 and day 6 via Cell Titer Glo.

[0135] plan:

[0136] 1. Thaw AML cells and resuspend them in StemSpan TM Serum-free expansion medium (SFEM), 2% heat-inactivated FBS, StemSpan TM The cells were cultured in an enriched medium consisting of CC110 and recombinant human IL-3.

[0137] 2. On study day 0, plate 20,000 cells / well in a volume of 100 μL.

[0138] 3. Add 100 μL of Compound 1 (2x solution), decitabine, cytarabine, gilteritinib, or venetola (2x solution) to the corresponding single-dose wells for each dose. Add 50 μL of Compound 1 (4x solution) and 50 μL of decitabine, cytarabine, gilteritinib, or venetola (4x solution) to the corresponding combination wells.

[0139] 4. Incubate the cells in the presence of drugs for 6 days.

[0140] 5. On day 6, remove the plate from the incubator and equilibrate to room temperature for 20 minutes. Add 100 μL / well Cell TiterGlo to each well and incubate for 10 minutes before reading the plate.

[0141] 6. Luminescence was recorded using a Tecan Infinite M Plex plate reader.

[0142] IC of Compound 1 as a single agent and in combination with standard of care 50 The gene mutations in 30 AML models are shown in Table 1. Compound 1 as a single agent showed broad efficacy in these models, with IC 50 The range is about 200-800 nM. IC of the combination of Compound 1 with decitabine (500 nM), cytarabine (22 nM), gilteritinib (8 nM) or venetolac (8 nM) 50 Generally similar to Compound 1 as a single agent, except that the combination with cytarabine (22 nM) resulted in an IC of 0.04 in CTG-2227, CTG-2701, and CTG-2704 compared to Compound 1 alone. 50 The combination of compound 1 and gilteritinib (8 nM) also resulted in an IC 50 In the MV-411 cell line, the combination of Compound 1 with decitabine (500 nM), gilteritinib (8 nM), or venetolazepam (8 nM) also resulted in a significant decrease in IC 50 A meaningful reduction.

[0143] Table 1

[0144]

[0145]

[0146]

[0147] Table 2

[0148]

[0149]

[0150]

[0151]

[0152] Example 4: Effect of Compound 1 on Tumor Growth of Human Lung Adenocarcinoma A549 Xenograft Tumor Leukemia

[0153] The antitumor efficacy of compound 1 was investigated in female SCID beige mice bearing human A549 lung adenocarcinoma xenograft tumors ( Figure 1 ). Specifically, the efficacy of three different dosing regimens of Compound 1 was evaluated over an 18-day period. Group 1 received vehicle in a PO 4-day dosing and 3-day rest (QD4 / 3 rest) pattern. Group 2 received 100 mg / kg Compound 1 in a QD4 / 3 rest pattern. Group 3 received 150 mg / kg Compound 1 in a biweekly (BIW) pattern. Group 4 received 225 mg / kg Compound 1 in a weekly (I / W) pattern.

[0154] Following BIW administration of 150 mg / kg Compound 1, mild antitumor activity of 20% tumor growth inhibition (TGI) and nominal body weight loss of -1.5 and -3.9% was observed on days 2 and 3, respectively. No deaths were observed in the BIW study cohort. Weekly administration of 225 mg / kg Compound 1 demonstrated a 31% TGI and a nominal body weight loss of -8.1% on day 4. One drug-related death was observed in the 1 / W cohort.

[0155] The strongest antitumor activity was observed with 100 mg / kg compound 1 administered QD4 / 3 with withdrawal, resulting in a 61% TGI. This dosing regimen was generally tolerated throughout the study, with a mean body weight loss of -7.0% on day 2 and one drug-related death within the study group. Finally, 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) administered QD4 / 3 with withdrawal resulted in a 33% TGI. This dosing regimen was tolerated, with a mean body weight loss of -7.6% on day 2 and no drug-related deaths observed within the study group.

[0156] In the vehicle group, some weight loss was observed during the first day of dosing, resulting in a mean body weight change (BWC) of -5.4% on the second day. Of the eight animals, four that were housed exclusively in the same cage experienced >8% BWC. This effect was determined to be caused by the water bottle, and the animals recovered once the diet gel was reintroduced to provide them with water. These observed weight losses had no apparent effect on tumor growth, and the control group was used as planned during the experiment.

[0157] Example 5: Effect of Compound 1 on an Allogeneic Disseminated Mouse Model of Acute Myeloid Leukemia

[0158] Compound 1 was tested in the MLL-AF9 allogeneic disseminated mouse model of AML. 200,000 MLL-AF9 cells were injected into 6-week-old C57BL / 6 male mice (The Jackson Laboratory) via the tail vein. Starting on day 8 after cell injection, mice were treated with compound 1 (90 mg / kg) or vehicle (0.5% methylcellulose) delivered by oral gavage for 2 complete cycles (a total of 4 doses / 3 off for two weeks) according to a 4-day "dose" (administered on each of the 4 consecutive days) followed by a 3-day "off" (no administration on each of the 3 consecutive days).

[0159] 12 days after the injection of MLL-AF9 cells, the proportion of MLL-AF9 cells in peripheral blood was measured using flow cytometry (n=6 mice / group). Mouse peripheral blood, bone marrow and spleen were collected from each organ, washed with PBS-0.1% BSA-2mM EDTA and lysed with red blood cell lysis buffer (Sigma) for 10 minutes. After two washing steps with PBS-0.1% BSA-2mM EDTA, bone marrow cells were stained with the corresponding cell surface antibody for CD45 (CD45 antibody-alkaline phosphatase conjugate, Invitrogen) at 4°C for 30 minutes. The cells were then washed twice with PBS-0.1% BSA-2mM EDTA, and 10,000 cells gated for CD45+ (high) were analyzed with BD FACSCanto II (BD Biosciences) to separate AML primitive cell populations. Statistical significance compared to the vehicle was determined using the Mann-Whitney test. The results are shown in Figure 2 Middle. Error bars represent mean ± SEM.

[0160] The Kaplan-Meier curve showing the overall survival rate of mice is shown in Figure 3 Statistical significance was determined by the log-rank (Mantel-Cox) test. *p < 0.05, compared to vehicle. Animals treated with Compound 1 had reduced circulating blast counts and improved overall survival of diseased mice compared to vehicle controls ( Figure 3 ).

[0161] Example 6: Effect of the combination of compound 1 and SOC on the allogeneic disseminated mouse model of acute myeloid leukemia Influence

[0162] The combination of compound 1 and standard of care chemotherapy ("SOC" or "Chemo") was tested in the MLL-AF9 allogeneic disseminated mouse model of AML. MLL-AF9 cells were injected into mice as described in Example 5. Treatment was started on day 9 after cell injection, with 0.5% methylcellulose (vehicle group) or 50 mg / kg compound 1 (compound 1 group) for 4 days of treatment / 3 days of rest; or with doxorubicin and cytarabine administered intraperitoneally, 0.5 mg / kg for 3 days and 75 mg / kg for 5 days (Chemo group); or a combination of compound 1 plus Chemo. As described in Example 5, the proportion of MLL-AF9 cells in peripheral blood was determined 11 days after injection of MLL-AF9 cells (n=3 mice / group) and plotted.

[0163] The results are shown in Figure 4 The Kaplan-Meier curve showing the overall survival rate of mice (n=5 / group) is shown in Figure 5 *p<0.05, compared with vehicle. #p<0.05, compared with compound 1 or Chemo group. Compound 1 plus Chemo treatment reduced circulating blast counts ( Figure 4 ) and improved the overall survival of diseased mice ( Figure 5 The combination was well tolerated and did not result in changes in body weight.

[0164] Example 7: Evaluation of Compound 1 in patients with relapsed / refractory acute myeloid leukemia or relapsed / refractory A Phase I Study of the Safety and Pharmacokinetic Profile of Glucocorticoids in Participants with or High-Risk Myelodysplastic Syndrome

[0165] The objectives of this first-in-human (FIH) study are to evaluate the safety, pharmacokinetics (PK), preliminary efficacy, and pharmacodynamic (PD) profiles of escalating doses of Compound 1 monotherapy in adult participants with R / R A L or R / R intermediate-to-high-risk MDS and to determine the recommended Phase 2 dose (RP2D) and dosing schedule.

[0166] Study Design

[0167] This is a multicenter, open-label, Phase 1 study of orally administered Compound 1 in participants with R / R AML or R / R intermediate- to high-risk MDS. The study will include two parts: 1) a dose-escalation phase in participants with R / R AML or R / R intermediate- to high-risk MDS and 2) a dose-expansion phase in participants with R / R AML who have no available standard of care that could result in disease remission. Additional cohorts for participants with R / R intermediate- to high-risk MDS after receiving a hypomethylating agent or other AML cohorts may be added later.

[0168] During the two study periods, compound 1 will be orally administered according to the 4 / 3 schedule QD in a continuous 28-day cycle until progressive disease or intolerable toxicity is produced. BID administration can also be tested according to the initial PK assessment. Participants will be regularly assessed for safety assessment, including physical examination and laboratory tests. Bone marrow aspiration and / or biopsy will be performed at regular intervals, including for assessing tumor response according to the response criteria of the European Leukemia Network (ELN) for AML or the international working group (IWG) revised in 2006 for the response criteria of MDS. Peripheral blood samples will be collected in the 1st cycle for intensive PK testing and PD biomarker assessment. Additional intensive PK testing will be collected for any participant who performs intra-patient dose escalation.

[0169] Dose escalation phase

[0170] This study will use an accelerated titration design starting with a dose escalation phase to define the maximum tolerated dose (MTD) and / or RP2D of compound 1 in participants with R / R AML or R / R intermediate to high-risk MDS. During this part of the study, eligible participants who agree will be enrolled in a cohort of consecutive increasing doses of compound 1. The starting dose of compound 1 will be 25 mg, administered orally QD, using a 4 / 3 weekly dosing schedule, with 6 planned dosing cohorts (Table 3). One cycle consists of 28 days, and the first cycle will include a DLT observation period.

[0171] Table 3

[0172] Dosage levels Dose cohorts (once-daily [QD] dosing) 1 25mg 2 50mg (2x) 3 100mg (2x) 4 175mg (1.75x) 5 275mg (1.57x) 6 350mg (1.27x)

[0173] During the accelerated phase, single-participant cohorts will be used for initial dose escalation. When the first instance of a grade ≥2 non-hematologic adverse event is observed at any dose level (during the first cycle), the accelerated phase will end and dose escalation will change to a 3+3 design. In all of the above cases, references to non-hematologic AEs include all AEs that are considered possibly related to the study intervention.

[0174] When using a 3+3 design, at least 3 participants will be enrolled in the dose cohort (unless 2 DLTs occur in the first 2 participants). If no DLT is observed after the last participant in the cohort completes the 28-day DLT observation period (i.e., cycle 1), the study is continued to the next cohort with dose escalation after a safety review. If 1 of the 3 participants experiences a DLT during the first cycle, 3 additional participants will be enrolled in the cohort. If none of the additional 3 participants experience a DLT, then after a safety review, dose escalation may continue to the next cohort. If 2 or more participants in the cohort experience a DLT during the first cycle, dose escalation will be stopped, and the next lower dose level will be announced as MTD. Alternatively, the intermediate dose level between the dose level exceeding the MTD and the previous dose level can be investigated and announced as MTD, when <2 of the 6 participants have experienced a DLT at this dose. If the MTD cohort includes only 3 participants, 3 additional participants will be enrolled at the dose level to confirm that <2 of the 6 participants have experienced a DLT at the dose.

[0175] If additional participants are available during screening when the last participant in a dose cohort starts treatment, additional participants may be enrolled in the cohort as long as the participant can start treatment within 1 week of the last enrolled participant and has received approval from the medical supervisor.

[0176] After each cohort has completed the DLT window, safety data and any available PK data will be evaluated to determine whether dose escalation can occur, whether additional participants should be enrolled in the dose cohort, whether an intermediate dose should be assessed, or whether BID dosing should be tested (Table 4). If an intermediate dose is assessed, a modified Fibonacci schedule should be considered for further dose escalation, adjusted based on the availability of 25 mg and 75 mg capsule strengths. Increases of >100% are not allowed. If BID dosing is adopted, the first BID dosing cohort should not exceed the total dose of the last QD dosing cohort assessed.

[0177] Table 4

[0178]

[0179] To optimize the number of participants treated at a potentially clinically relevant dose, intra-participant dose escalation will be allowed after Cycle 1, provided the participant tolerates the current dose and has the approval of the medical supervisor. Dose escalation to any previously cleared dose level will be allowed. There is no limit to the number of dose escalations that can occur for a participant.

[0180] Alternatively, the dosing schedule (for example, once a week or twice a week administration) can also be assessed after the MTD and / or RP2D of a 4 / 3 dosing schedule has been defined. If indicated by a pharmacokinetic overview or if before the MTD or RP2D defined with a 4 / 3 dosing schedule, clinically significant toxicity (for example, a large amount of Grade 2 AEs or due to intolerance and research treatment stopping / withdrawal) occurs with a 4 / 3 dosing schedule, then the assessment of the alternative schedule can be initiated earlier. Alternative dosing schedules will be defined based on available cumulative safety and PK data, and will be summarized in the formal revision of the scheme.

[0181] Study procedures for these additional participants / cohorts will be the same as described for the other study participants / cohorts.

[0182] RP2D selection

[0183] Upon completion of the dose escalation phase of the study, the following data will be used to determine the RP2D for the expansion phase of the study:

[0184] The MTD, defined as the dose at which the DLT rate is ≤17% in at least six participants during cycle 1

[0185] ●Delayed DLT (DLT that occurs after the first cycle)

[0186] Major dose-limiting toxicity

[0187] Overall safety profile

[0188] Pharmacokinetics of each cohort

[0189] Number of participants who required interruption or dose reduction of study drug

[0190] Extension period

[0191] Once the RP2D is determined, an additional cohort of approximately 38 participants with R / R AML will be treated at the RP2D (and schedule) to further confirm safety and assess preliminary activity in participants. Based on updated data from this study or other nonclinical or external data, the sponsor may decide to add separate cohorts for participants with R / R intermediate- to high-risk MDS or specific AML subtypes, which may increase the sample size of the expansion phase.

[0192] After a total of 20 participants with R / R AML have been enrolled in the cohort at the RP2D and schedule and treated for at least 2 cycles, the sponsor will assess the primary efficacy and safety data and the benefit / risk profile to determine whether to stop the study to develop Compound 1 as a monotherapy in AML. If an ORR or other parameter indicating activity is observed despite meeting the futility threshold for Compound 1 monotherapy, a formal protocol amendment may include dose escalation and dose expansion cohorts in combination with approved therapies.

[0193] Duration of study intervention

[0194] Compound 1 will be orally administered QD according to a weekly 4 / 3 schedule for one 28-day cycle. Participants will be assessed for safety and tolerability, and their tumor status will be assessed after the completion of the first cycle. Participants who have not produced unacceptable toxicity due to study treatment will be allowed to receive the second cycle of study therapy, after which they will be reassessed for safety, tolerability, and efficacy. Participants who do not have unacceptable toxicity at the end of the second cycle and are determined by the investigator to benefit from study therapy (e.g., there is no evidence of disease progression for MDS participants or at least PR for participants with AML) will be allowed to continue receiving study therapy until disease progression, unacceptable toxicity, completion of treatment, or other exit criteria are met, whichever occurs first. 30 days (± 5 days) after the last 28-day treatment cycle, participants will return to the clinical site for an end-of-treatment (EoT) visit.

[0195] After treatment discontinuation, participants will remain on study for long-term survival follow-up every 3 months (± 2 weeks) unless they withdraw consent for further follow-up.

[0196] Participants

[0197] A total of approximately 50-60 participants will be enrolled and treated in the dose-escalation and dose-expansion phases, including approximately 38 participants with R / R AML who are planned to be enrolled and treated in the dose-expansion phase.

[0198] Drug administration

[0199] Compound 1 will be administered orally QD in consecutive 28-day cycles according to a 4 / 3 dosing schedule (4 days on, 3 days off) until progressive disease or unacceptable toxicity occurs. BID dosing may also be tested based on initial PK assessments.

[0200] standard:

[0201] Inclusion criteria:

[0202] Male or female, ≥18 years of age at the time of signing the consent form

[0203] One of the following advanced hematologic malignancies, including:

[0204] ○ Dose escalation and expansion:

[0205] Relapsed or refractory AML as defined by the 2016 WHO criteria (Arber et al., 2016) and who are not candidates for curative therapy (such as allogeneic hematopoietic cell transplantation) or for whom there is no standard of care available that could result in disease remission according to the investigators

[0206] ○ Dose escalation only:

[0207] High-very high risk for MDS according to the Revised International Scoring System for Assessing Prognosis in Relapsed or Relapsing Myelodysplastic Syndromes, or, according to the treating physician, the participant is intolerant to established therapies known to provide clinical benefit for the condition (e.g., relapse after treatment with a hypomethylating agent or no response after ≥4 cycles). If a potential participant who meets the intermediate-risk criteria has severe cytopenias and / or elevated bone marrow blast counts, the participant may be considered with approval of the medical supervisor.

[0208] Adequate organ function, defined as follows:

[0209] Serum creatinine ≤1.5 mg / dL or estimated glomerular filtration rate ≥60 mL / min as calculated by the Cockcroft-Gault glomerular filtration rate equation

[0210] Total bilirubin ≤ 1.5 × upper limit of normal (ULN), unless thought to be due to Gilbert's disease or leukemia

[0211] ○ Aspartate aminotransferase (AST) ≤ 3× ULN; alanine aminotransferase (ALT) ≤ 3× ULN. After discussion with the study medical monitor, AST and / or ALT levels ≤ 5× ULN are acceptable for participants with known leukemic liver involvement

[0212] Eastern Cooperative Oncology Group (ECOG) performance status ≤2.

[0213] ● Male or female contraceptive use should comply with local regulations on contraceptive methods for clinical study participants. If of childbearing potential, agree to use effective barrier contraception (i.e., latex condoms, diaphragms, cervical caps, etc.) to avoid pregnancy during the study and 90 days after the last dose of Compound 1. Female participants of childbearing potential need to have a negative serum or urine pregnancy test within 7 days of study enrollment. Infertility is defined as ≥1 year postmenopausal or surgically sterilized.

[0214] ● Be able to provide signed informed consent as described in Appendix 1, including compliance with the requirements and restrictions outlined in the Informed Consent Form (ICF) and this protocol.

[0215] Exclusion criteria:

[0216] Acute promyelocytic leukemia, t(15;17)(q22;q12); or promyelocytic leukemia / retinoic acid receptor alpha (PML-RARA) abnormality.

[0217] ● Participants have clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. CSF evaluation is only required if there is clinical suspicion of leukemia involving the CNS during screening.

[0218] ● Participants have severe, immediately life-threatening complications of leukemia, such as uncontrolled bleeding, pneumonia with hypoxia or shock, and / or disseminated intravascular coagulation.

[0219] ● Associated malignancies that require aggressive treatment, except for basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, or localized prostate cancer.

[0220] ○ Adjuvant therapy for breast or prostate cancer is allowed.

[0221] Active, uncontrolled systemic infection or severe localized infection during the screening period or before Cycle 1 Day 1 (C1D1; unless considered by the investigator to be due to tumor).

[0222] ○ Participants receiving prophylactic anti-infective medications were allowed to participate in the study.

[0223] ●Known human immunodeficiency virus (HIV) infection, CD4+ T-cell count <350 cells / microL, initiation of antiretroviral therapy within four weeks before C1D1, or acquired immunodeficiency syndrome (AIDS)-related infection within 12 months before C1D1.

[0224] Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection with a viral load above the limit of quantification

[0225] Major cardiac abnormality, as defined by but not limited to the following: uncontrolled angina or unstable life-threatening arrhythmia; history of myocardial infarction within 12 weeks prior to baseline; New York Heart Association (NYHA) class 3 or higher congestive heart failure; or left ventricular ejection fraction (LVEF) <45% as measured by echocardiography (ECHO) within 28 days of C1D1

[0226] Sustained prolongation of the QT interval (three consecutive ECGs performed ≥5 minutes apart) to >480 msec by the corrected QT interval (QTcF) method

[0227] • Gastrointestinal conditions that may interfere with the absorption of orally administered drugs, including but not limited to short bowel syndrome, gastroparesis, inflammatory bowel disease, or acute pancreatitis.

[0228] Example 8: Evaluation of the safety and pharmacokinetics of Compound 1 in participants with advanced solid tumors and lymphomas Phase I study of mechanical profiles

[0229] The objectives of this study are to determine the safety, tolerability, and recommended Phase 2 dose (RP2D) of Compound 1 administered orally on a once-daily schedule of 4 days of dosing and 3 days of rest in patients with advanced solid tumors and lymphomas.

[0230] Study Design

[0231] This is a first-in-human, open-label Phase I trial of oral Compound 1 in adult patients with advanced metastatic solid tumors and lymphoid malignancies. The study will be conducted in two parts: an initial dose-escalation phase, followed by a dose-expansion phase at the recommended Phase 2 dose (RP2D) in the same patient population. Additional expansion cohorts may be considered to investigate pharmacodynamic endpoints at lower dose levels (protocol amendments will be submitted to address these changes in the trial design).

[0232] Patient assessments will be conducted throughout the study as described below. A baseline medical history, physical examination, laboratory evaluations, and ECG must be performed within 8 days prior to the start of protocol therapy. If protocol therapy is initiated within 8 days of the eligibility screening evaluation, the results of these screening evaluations may be used as baseline measurements. If >8 days have passed since the screening evaluation, the medical history, physical examination, laboratory evaluations, and ECG must be repeated prior to the start of protocol therapy.

[0233] Baseline tumor imaging must be performed within 28 days prior to the start of protocol therapy. If protocol therapy is initiated within 28 days of an eligible screening tumor imaging, the screening assessment imaging result can be used as the baseline measurement; if >28 days have passed since the screening assessment tumor imaging, the imaging must be repeated prior to the start of protocol therapy.

[0234] A medical history and physical examination will be performed at baseline (within 8 days of starting protocol therapy), on Week 1 during Weeks 1, 2, 3, and 4, and at the start of each cycle thereafter (within 3 days prior to treatment).

[0235] A CBC with laboratory differential (serum chemistries, platelets) will be performed at baseline (within 8 days of starting protocol therapy), during Weeks 1, 2, 3, and 4 of Cycle 1, and at the start of each cycle thereafter (+ / - 1 day mid-cycle and up to 3 days prior to starting a new cycle) and during Week 1 thereof.

[0236] An ECG will be performed at baseline (within 8 days of starting regimen therapy) and may be performed on Day 1 (pre-dose) of each additional subsequent cycle (ie, Cycles 3, 5, 7, etc.) and as clinically indicated.

[0237] Blood and urine samples will be collected from all patients for relevant PD and PK studies.

[0238] In the expansion cohort, paired tumor biopsies will be collected at baseline and then 4-6 hours after receiving the first dose; optional biopsies may be collected at the time of disease progression or "pre-progression" (defined as a 10-19% increase in tumor volume as shown on a restaging scan). Investigators will perform an ophthalmologic examination on all patients during screening at baseline, including optical coherence tomography (OCT), color vision testing, and a questionnaire. The questionnaire will be repeated after treatment on Day 1 or 2 of Cycle 1; the questionnaire and eye examination may be repeated by the NEI as clinically indicated. Details regarding the questionnaire and eye examination, as well as the threshold for pre-existing visual impairment, can be found in Appendix B.

[0239] Compound 1 (Table 5) will be administered orally once daily on a 4-day dosing and 3-day rest schedule (28-day cycle). Dose escalation will continue until the RP2D (MTD) is determined. Intra-patient dose escalation will be allowed.

[0240] Table 5

[0241]

[0242] Once the RP2D is reached, an additional 15 patients will be treated at this dose to further investigate pharmacodynamic endpoints and obtain additional pharmacokinetic data. For the expansion cohort, patients will continue to be monitored for the occurrence of DLTs. Once pharmacodynamic data are obtained at the RP2D, additional expansion cohorts may be considered to investigate pharmacodynamic endpoints at lower dose levels (submit a protocol amendment to the trial design for these changes).

[0243] Before compound 1 is administered on day 1, then within the first 24 hours of cycle 1 (15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h after administration for all patients), and for only the first 3 study patients on day 4 of cycle 1 (before administration and 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h after administration), blood and urine samples will be collected for pharmacokinetic analysis. Peripheral blood mononuclear cells (PBMCs) will be collected before compound 1 is administered on day 1 and 4-6 hours after receiving compound 1 on day 1. Blood samples can be collected before compound 1 is administered on day 1, then at the beginning of each cycle, to obtain circulating tumor DNA (ctDNA). During the expansion cohort only, before compound 1 is administered, and 4-6 hours after receiving the first dose, tumor biopsy will be mandatory; optional biopsy can be collected at / near disease progression.

[0244] Drug administration

[0245] Compound 1 was administered once daily for 4 days on and 3 days off in a 28-day cycle. Compound 1 capsules should be taken on an empty stomach 1 hour before or 2 hours after a meal.

[0246] standard:

[0247] Eligibility criteria:

[0248] Patients with histologically documented metastatic or localized advanced (not amenable to surgery) solid tumors whose disease has progressed after at least one standard therapy

[0249] ●Sufficient prior therapy must have been completed ≥4 weeks (6 weeks for nitrosoureas and mitomycin C) or, if known, ≥5 half-lives of the prior agent (whichever is shorter) prior to protocol enrollment (minimum 1 week between prior therapy and study enrollment), and the participant must have recovered from prior cytotoxicity to qualifying levels. Prior definitive radiation should have been completed ≥4 weeks prior to study enrollment, or palliative radiation should have been completed ≥2 weeks prior to study enrollment, with all relevant toxicities recovered to qualifying levels (at the discretion of the PI, patients in the study may be eligible for palliative radiation therapy to non-targeted lesions after 2 cycles of treatment). At the discretion of the PI, patients must have been ≥2 weeks past any investigational agent administered as part of the Phase 0 study (when subtherapeutic doses of the drug were administered), and patients should have recovered from any toxicity to Grade 1 or baseline.

[0250] ● Patients who have received prior monoclonal antibody therapy must have completed that therapy for ≥6 weeks (or 3 antibody half-lives, whichever is shorter) prior to enrollment in the protocol (at least 1 week between prior therapy and study enrollment). The use of contraceptives by males or females should comply with local regulations on contraceptive methods for participants in clinical studies. If of childbearing potential, agree to use effective barrier contraceptive methods (i.e., latex condoms, diaphragms, cervical caps, etc.) to avoid pregnancy during the study and 90 days after the last dose of Compound 1. Female participants of childbearing potential need to have a negative serum or urine pregnancy test within 7 days of study enrollment. Infertility is defined as ≥1 year postmenopausal or surgical sterilization.

[0251] Age ≥ 18 years. Because there are currently no data on dosing or adverse events with Compound 1 in patients < 18 years of age, children were excluded from this study but will be eligible for further pediatric trials.

[0252] Eastern Cooperative Oncology Group performance status ≤2 (Karnofsky ≥60%, see Appendix A) and life expectancy >3 months.

[0253] ●Patients must have adequate organ and bone marrow function as defined by:

[0254] -Absolute neutrophil count ≥1,500 / mcL

[0255] - Platelets ≥100,000 / mcL (in patients with solid tumors)

[0256] ≥75,000 / mcL (lymphoma patients)

[0257] -Total bilirubin ≤ 1.5 x the upper limit of standard deviation (ULN)

[0258] -AST (SGOT) / ALT (SGPT) ≤ 3 × conventional ULN

[0259] Creatinine ≤ 1.5 x the conventional ULN, or 60 mL / min / 1.73 m for patients with creatinine levels greater than 1.5 x the conventional ULN 2

[0260] The effects of Compound 1 on the developing human fetus are unknown. For this reason, and because p97 inhibitors may be teratogenic, females and males of childbearing potential must agree to use adequate contraception (hormonal or barrier methods; abstinence) before entry into the study, during participation in the study, and for 4 months thereafter. If a female becomes pregnant or suspects pregnancy while she or her partner is participating in this study, she should promptly notify her treating physician. Males treated or enrolled in this protocol must also agree to use adequate contraception before entry into the study, during participation in the study, and for 4 months after completion of Compound 1 administration.

[0261] ●Able to understand and willing to sign written informed consent.

[0262] - Subjects in the expansion cohort must also be willing to undergo two core biopsy procedures and have lesions suitable for biopsy.

[0263] On entry, left ventricular ejection fraction ≥ the lower limit of normal based on echocardiography.

[0264] Mean QT interval (QTc) corrected for heart rate is <470 ms using Frederica's correction.

[0265] Exclusion criteria:

[0266] ●Patients who have received chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas and mitomycin C) before entering the study.

[0267] ●Patients who have not recovered from an adverse event due to previous anticancer therapy (ie, residual toxicity > Grade 1), except for alopecia.

[0268] ●Patients who are currently receiving any other investigational agents.

[0269] ● Patients with clinically significant illness that would affect study participation, including but not limited to active or uncontrolled infection, immunodeficiency, hepatitis B, hepatitis C, active tuberculosis, uncontrolled asthma, symptomatic congestive heart failure, unstable angina, uncontrolled arrhythmia, myocardial infarction within the past 6 months, cerebrovascular accident / stroke within the past 6 months, or psychiatric illness / social conditions that would limit compliance with study requirements.

[0270] Patients with human immunodeficiency virus (HIV) infection who have received effective antiretroviral therapy for 6 months and have an undetectable viral load are eligible for this trial.

[0271] o For patients with evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy, if indicated.

[0272] ●This clinical trial excluded patients with known brain metastases or carcinomatous meningitis, except for those whose brain metastases remained stable for ≥4 weeks after treatment of their brain metastases. Patients receiving antiepileptic medications were eligible for enrollment at the discretion of the principal investigator, provided they were taking or switching to non-enzyme-inducing antiepileptic drugs.

[0273] Pregnant women were excluded from this study because Compound 1 may have teratogenic or abortifacient effects. Breastfeeding should be discontinued if the mother is treated with Compound 1 because there is an unknown but potential risk of adverse events in the nursing infant secondary to maternal treatment with this agent.

[0274] • Current or previous history of vision-threatening retinal disease, including but not limited to proliferative diabetic retinopathy, severe retinal vascular disease, and advanced age-related macular degeneration.

[0275] ●Patients with a history of QT prolongation or torsade de pointes (TdP) or taking QT-prolonging medications are not eligible.

[0276] Example 9: Human Dosing and Pharmacokinetic Data of Compound 1

[0277] Two subjects were treated QD with 25 mg of Compound 1 as described in Example 7. Plasma concentrations of Compound 1 were analyzed before and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after dosing on Day 1 and before and 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours after dosing on Day 4. Linear and semi-logarithmic plots of plasma concentration-time profiles are shown in Figure 1. Figure 6 Plasma concentrations are expressed as ng / mL and μM concentration units. Analysis of pharmacokinetic measurements, including Cmax, Cmax / dose, AUC (area under the curve), tmax, and half-life (t1 / 2), are shown in Table 6. No adverse events or symptoms of visual impairment were observed in either subject.

[0278] Table 6

[0279]

[0280] The results for the two subjects showed almost identical profiles. The results indicate that the half-life of Compound 1 is about 3-4 hours. No accumulation of Compound 1 was found between Day 1 and Day 4. Surprisingly, the plasma exposure exhibited by Compound 1 was significantly higher than that of the compound CB-5083 (1-[7,8-dihydro-4-[(phenylmethyl)amino]-5H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxamide) previously tested in subjects. In comparison, the plasma exposure produced by Compound 1 at 25 mg QD was significantly higher than that of CB-5083 administered at 40 mg QD. The exposure of Compound 1 was greater than that of CB-5083 administered at greater than 200 mg. See Figure 7 Also unlike CB-5083, at equivalent plasma exposures, Compound 1 did not produce symptoms of visual impairment or other visual adverse events as seen with CB-5083.

[0281] Additional patients were treated in a dose escalation study following the protocol of Example 7. Figure 8 Shown are exposure data from a total of 9 patients who were administered compound 1 at 25 mg QD (2 patients), 50 mg QD (1 patient), 100 mg QD (3 patients) and 175 mg QD (3 patients). The increase in exposure levels between doses was proportional and linear. Two of the three subjects administered at the 100 mg level were also taking proton pump inhibitors (PPi), and this may have resulted in lower exposure due to the effect on the solubility of compound 1. The exposure of compound 1 was greater than that of CB-5083. No symptoms of visual impairment or other visual events were seen at any dose level of compound 1, including the highest level (275 mg QD) administered to date.

[0282] Example 10: Combination of Compound 1 and Additional Therapeutic Agents

[0283] Compound 1 was tested with additional therapeutic agents according to a similar protocol to 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 granulocyte monocytic 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 7.

[0284] Table 7

[0285] MOML-13 MV-4-11 OCI-AML-3 p53 WT WT WT FLT3-IDT HET IDT WT BRCA1 WT WT WT BRCA-2 MUT WT WT

[0286] In order to test the combination of compound 1 and other therapeutic agents, the concentration range of dose response is all set to evenly span the region of 1 log to low 1 log compared with the IC50 of the agent obtained when using each agent singly. Within this range, each combination has tested 20 dosage levels, and each reaction is determined in duplicate. For each agent-cell line combination evaluated, the dose response of each individual drug is compared with the dose response of the combination of 3 two agents, and each combination is mixed with three fixed ratios within the entire dose response: 1: 1, 1: 2 or 2: 1, wherein compound 1 is always defined as the first agent of the ratio. The actual drug concentration in the ratio is determined by the IC50 value obtained for each individual drug. For example, if the IC50 of compound 1 is 1uM, and the IC50 of additional agent is 10uM, the actual drug ratio of 1: 1IC50 ratio is 1: 10.

[0287] Raw data were analyzed using Graph Pad Prism, four-parameter logistic fitting, and Chou-Talalay drug combination analysis. Chou-Talalay analysis requires data normalization and definition as fractional effect, which is a number that needs to be between 0 and 1, where 0 represents no effect (CTG signal in the absence of drug), and 1 represents the maximum possible effect (CTG signal in the absence of cells). In fact, many data points slightly exceed these limits at the low or high end of the dose range. For data points with fractional effect>1, Fe is set to 0.999. For data points with Fe<0, fractional effect is set to 0.001. Data points with Fe>0.99 or <0.01 were omitted in the Chou-Talalay analysis because the Chou-Talalay analysis fits the data to the logarithm of the fractional effect, applying equal weights within the effect range so that the high and low end reactions of the dose, and very small effect changes within the experimental error range, can erroneously distort the results of the model fitting.

[0288] A combination index (CI) relative to the fractional effect curve showing the drawn agent combination index relative to the fractional effect value was drawn for each combined dose. In this analysis, CI=1 represents additive activity, CI>1 represents less than additive activity (commonly referred to as antagonism) and CI<1=synergistic activity (better than additive activity). The CI scores of all 3 ratios were averaged and compared with individual compound 1. The results are shown in Table 8.

[0289] Table 8: Combination Index Values ​​for Compound 1 and Additional Therapeutic Agents Tested in Three Cell Lines

[0290]

[0291] Scores of 0.200 to 0.800 demonstrate synergy between the combinations; scores above 0.800 to 1.200 demonstrate additive effects, and scores above 1.200 demonstrate antagonistic effects of the combinations. Many combinations demonstrate synergistic effects. The PARP inhibitor talazoparib demonstrates a strong synergistic effect in combination with compound 1, particularly in the BRCA2 mutant cell line MOML-13. The FLT-3 agent gilteritinib has a synergistic effect in the homozygous mutant line MV-4-11 and an additive effect in the FLT3 wild-type and heterozygous AML lines. The combination of compound 1 and venetolazepam demonstrates a synergistic effect in the MOML-13 line and a strong additive effect (close to a synergistic effect) in the other two AML lines.

[0292] Some agents, such as the chemotherapeutic agent cytarabine, produced additive effects in the cell lines. Other agents, such as the proteasome inhibitor ixazomib, had surprisingly antagonistic effects when combined with Compound 1. The combination index data for cytarabine, gilteritinib, talazoparib, and venetola at ED50, ED75, and ED90 are shown in Tables 9-12 below.

[0293] Table 9: Combination Index Data of Compound 1 + Cytarabine

[0294]

[0295] Table 10: Combination Index Data of Compound 1 + Gilteritinib

[0296]

[0297]

[0298] Table 11: Combination Index Data of Compound 1 + Talazoparib

[0299]

[0300] Table 12: Combination Index Data of Compound 1 + Venetola

[0301]

[0302] Example 11: Additional Combinations of Compound 1 and Therapeutic Agents

[0303] Compound 1 was tested in combination with additional therapeutic agents in the cell lines MOML-13 and MV-4-11 (see Examples 3 and 10) and HL-60 (human acute promyelocytic leukemia; ATCC). The additional therapeutic agents for this example were azacytidine (Cayman Chemical catalog number 11164), decitabine (Sigma catalog number A3656), and venetolac (InvivoChem catalog number V0001).

[0304] Cell Culture: Three human myeloid leukemia cell lines were used in this study: HL60, MV411, and MOLM-13. HL60 and MV411 were grown in IMDM basal medium with 20% and 10% FBS, respectively. MOLM-13 was grown in RPMI 1640 basal medium with 20% FBS. All media contained 2 mM glutamine, 100 units / mL penicillin G sodium, 25 μg / mL gentamicin, and 100 μg / mL streptomycin sulfate. Tumor cells were cultured in tissue culture flasks in a humidified incubator at 37°C in an atmosphere of 5% CO2 and 95% air.

[0305] Assay: Tumor cells were seeded in duplicate in a volume of 100 μL / well medium into 96-well microplates at an initial density low enough to allow several population doublings (usually three to five) during the indicated incubation period. After 24 hours of incubation, the test agent was added to each well. After 72 hours of incubation with the test article, the cells were plated using Cell Titer- Cell viability was determined using the Promega G7571 assay. (Promega G7571) reagent was equilibrated at room temperature for 30 minutes; 100 μL was added to each well at the end point (72 hours). The plate was gently shaken for two minutes and then incubated at room temperature for ten minutes before reading fluorescence on a BMG Clariostar Plus microplate reader.

[0306] For each agent alone, determine the IC in each cell line. 50 value, which is then used to select the proximity IC 20 and IC 90 The second group of combinations consisted of compounds close to their IC in each cell line. 20 A twenty-point dose-response consisting of a fixed concentration of Compound 1 or vehicle control and varying concentrations of the second dose was used using a two-fold serial dilution starting with 50 μM Compound 1, 40 μM azacytidine and decitabine, and 10 μM venetola.

[0307] The results are shown in Tables 13-15. The IC50 for each combination was calculated from the ratio of the combined IC50 to the no-fixative (vehicle) control used. 50Ratio. The ratio of agents that showed enhanced activity in combination was less than 1. For example, in MOML-13 cells, the combination of azacytidine and compound 1 showed a ratio of 0.39 for the combination of low and high doses of azacytidine and compound 1 (used as a variable dose agent), and a ratio of 0.28 when compound 1 was provided as a fixed dose and azacytidine was provided over a range of doses. The combination of compound 1 with decitabine and with venetolazepine + azacytidine also resulted in enhanced activity compared to monotherapy. Similar enhanced activity of these combinations was also observed in MV4;11 cells. These effects were less pronounced in HL60 cells.

[0308] Table 13: Evaluation of combination therapy in the MOML-13 cell line

[0309]

[0310] Table 14: Evaluation of combination therapy in HL-60 cell line

[0311]

[0312] Table 15: Evaluation of combination therapy in MV4;11 cell line

[0313]

[0314]

Claims

1. Use of a pharmaceutical composition for the preparation of a medicament for treating chronic myelomonocytic leukemia (CMML) in a subject in need thereof, wherein the pharmaceutical composition comprises 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 25 mg to 2000 mg in combination with a second therapeutic agent selected from gilteritinib, talazoparib, and venetola, whereby the subject experiences a therapeutic response; or Use of a pharmaceutical composition for the preparation of a medicament for treating acute myeloid leukemia (AML) in a subject in need thereof, wherein the pharmaceutical composition comprises 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 25 mg to 2000 mg in combination with a second therapeutic agent selected from talazoparib and venetola, whereby the subject experiences a therapeutic response.

2. The use according to claim 1, wherein 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.

3. The use of claim 1, wherein the dosage is 25 mg to 1000 mg, 25 mg to 750 mg, 25 mg to 500 mg, 25 mg to 350 mg, 25 mg to 175 mg, 50 mg to 1000 mg, 50 mg to 750 mg, 50 mg to 500 mg, 50 mg to 350 mg, 50 mg to 175 mg, 75 mg to 1000 mg, 75 mg to 750 mg, 75 mg to 500 mg, 75 mg to 350 mg, 75 mg to 175 mg, 100 mg to 1000 mg, 100 mg to 750 mg, 100 mg to 500 mg, 100 mg to 350 mg, or 100 mg to 175 mg.

4. The use according to claim 1, wherein the dosage is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 275 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg.

5. The use according to claim 1, wherein the AML is relapsed AML, recurrent AML, refractory AML or any combination thereof.

6. The method according to claim 1, wherein the AML is de novo AML, secondary AML including therapy-related AML and AML with myelodysplasia-related changes, biphenotypic acute leukemia or AML with recurrent abnormalities.

7. The use according to claim 1, wherein the AML is AML with actionable mutations.

8. The use according to claim 1, wherein the AML is AML without actionable mutations.

9. The use according to any one of claims 1 to 8, wherein the subject is treated regardless of the subject's mutation or cytogenetic status.

10. The use according to any one of claims 1 to 8, wherein the therapeutic response comprises: Complete remission, complete remission without minimal residual disease, complete remission with incomplete hematologic recovery, morphologic aleukemic 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.

11. The use according to any one of claims 1 to 8, wherein the therapeutic response comprises: Increased overall survival, increased relapse-free survival, increased event-free survival, increased duration of response, or decreased cumulative incidence of relapse.

12. The use of any one of claims 1-8, wherein the pharmaceutical composition is administered in a regimen comprising: (a) administering the drug to the subject for 4 consecutive days, followed by 3 consecutive days of no administration; (b) administering the drug to the subject for 5 consecutive days, followed by 2 consecutive days of no administration; (c) once-weekly dosing; or (d) twice-weekly dosing.

13. Use according to claim 12, wherein the administration regimen is repeated.

14. The use according to claim 12, 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.

15. The use according to claim 14, wherein the 28-day cycle is repeated at least once.

16. The use according to any one of claims 1 to 8, wherein the pharmaceutical composition is administered once a day on the administration day.

17. The use according to claim 9, wherein the pharmaceutical composition is administered once a day on the administration day.

18. The use according to claim 10, wherein the pharmaceutical composition is administered once a day on the administration day.

19. The use according to claim 11, wherein the pharmaceutical composition is administered once a day on the administration day.

20. The use according to any one of claims 1 to 8, wherein the pharmaceutical composition is administered twice a day on the administration day.

21. The use according to claim 9, wherein the pharmaceutical composition is administered twice a day on the administration day.

22. The use according to claim 10, wherein the pharmaceutical composition is administered twice a day on the administration day.

23. The use according to claim 11, wherein the pharmaceutical composition is administered twice a day on the administration day.

24. The use according to any one of claims 1-8, 13-15, 17-19 and 21-23, wherein the pharmaceutical composition is administered orally.

25. The use according to claim 9, wherein the pharmaceutical composition is administered orally.

26. The use according to claim 10, wherein the pharmaceutical composition is administered orally.

27. The use according to claim 11, wherein the pharmaceutical composition is administered orally.

28. The use according to claim 12, wherein the pharmaceutical composition is administered orally.

29. The use according to claim 16, wherein the pharmaceutical composition is administered orally.

30. The use according to claim 20, wherein the pharmaceutical composition is administered orally.

31. The use according to any one of claims 1-8, 13-15, 17-19, 21-23 and 25-30, wherein the pharmaceutical composition is administered as a tablet or a capsule.

32. The use according to claim 9, wherein the pharmaceutical composition is administered as a tablet or a capsule.

33. The use according to claim 10, wherein the pharmaceutical composition is administered as a tablet or a capsule.

34. The use according to claim 11, wherein the pharmaceutical composition is administered as a tablet or a capsule.

35. The use according to claim 12, wherein the pharmaceutical composition is administered as a tablet or a capsule.

36. The use according to claim 16, wherein the pharmaceutical composition is administered as a tablet or a capsule.

37. The use according to claim 20, wherein the pharmaceutical composition is administered as a tablet or a capsule.

38. The use according to claim 24, wherein the pharmaceutical composition is administered as a tablet or a capsule.

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