Use of BET inhibitors as a treatment for myelofibrosis

Abstract

The present disclosure provides methods, pharmaceutical compositions, and kits for treating cancer in a patient in need of treatment. The methods comprise administering to a patient in need thereof a BET (bromodomain and extraterminal protein) inhibitor, or a pharma- ceutically acceptable salt thereof, alone or in combination with one or more JAK inhibitors. Medicaments for use in treating cancer are also provided.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to European Application No. 21382163.0, filed February 25, 2021, U.S. Provisional Application No. 63 / 232,866, filed August 13, 2021, and U.S. Provisional Application No. 63 / 297,098, filed January 6, 2022, each of which is incorporated by reference in its entirety herein.

[0002] Field The present disclosure relates to methods of treating myeloproliferative neoplasms. In particular, the present disclosure provides methods of treating various myeloproliferative neoplasms by administering a BET inhibitor alone or in combination with one or more Janus-associated kinase (JAK) inhibitors. [Background technology]

[0003] Myeloproliferative neoplasms (MPNs) are a closely related group of rare but potentially life-threatening clonal hematopoietic disorders caused by excessive proliferation of bone marrow stem cells. MPNs represent a group of chronic diseases, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The main molecular lesion in these diseases is the JAK2 V617F mutation, which occurs in more than 90% of PVs and more than 50% of ETs and PMFs.

[0004] Myelofibrosis (MF) is a MPN characterized by proliferation of mature myeloid elements and progressive bone marrow (BM) fibrosis. Patients with MF have a poor prognosis, with a median time from diagnosis to death of 2.3 years, and most patients die from acute leukemia transformation, BM failure, congestive heart failure, and other disease outcomes.

[0005] Treatment options are limited and are often associated with significant morbidity and mortality. Constitutive activation of the Janus-associated kinase (JAK) / signal transducer and activator of transcription (STAT) pathway is a hallmark of MF pathogenesis and is driven by mutations in the JAK2, calreticulin (CALR), or myeloproliferative leukemia virus (MPL) genes in approximately 90% of MF cases. This results in downstream increased gene transcription and expression of genes important for cell cycle control, apoptosis, and proteasomal degradation. However, JAK inhibition alone is insufficient for long-term remission and has only modest, if any, disease-modifying effect.

[0006] Fedratinib is an oral kinase inhibitor with activity against wild-type and mutationally activated JAK2 and FMS-like tyrosine kinase 3 (FLT3). Fedratinib is a selective inhibitor of JAK2 with greater inhibitory activity against JAK2 than its family members JAK1, JAK3, and TYK2. Aberrant activation of JAK2 is associated with MPNs such as MF and PV. In cell models expressing mutationally activated JAK2V617F or FLT3ITD, fedratinib reduced phosphorylation of STAT3 and STAT5 proteins, inhibited cell proliferation, and induced apoptotic cell death. In a mouse model of JAK2V617F-driven myeloproliferative disorders, fedratinib blocked phosphorylation of STAT3 / 5 and improved survival, WBC count, hematocrit, splenomegaly, and fibrosis.

[0007] In recent years, BET proteins have emerged as a group of epigenetic transcriptional coregulators. They belong to a family of chromatin readers (BRD2, BRD3, BRD4 and BRDT) that recognize acetylated lysines in histones and other proteins. Each protein has two highly conserved bromodomains. Their main function is to recruit members of the pTEF-b complex to promoters to assist transcriptional elongation, and their functional importance is highlighted by their association with cancer when they are dysregulated. Small molecule inhibitors of BET proteins have shown activity in preclinical models of leukemia driven by mixed lineage leukemia (MLL) fusion proteins and are under investigation for other malignancies.

[0008] Inhibition of both the BET protein-mediated cellular pathway and the JAK-STAT pathway may reduce inflammation and reverse or reduce fibrosis associated with myelofibrosis, providing a more effective treatment for the disease than either agent alone. Summary of the Invention

[0009] In a first aspect, the present disclosure provides a method of treating a hematopoietic malignancy in a subject in need of treatment, the method comprising administering to the subject Compounds of formula (I): [ka] or a pharma- ceutically acceptable salt thereof; and Compounds of formula (II): [ka] or a pharma- ceutically acceptable salt and / or solvate thereof. The method comprises administering

[0010] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, and the compound of formula (II), or a pharma- ceutically acceptable salt and / or solvate thereof, are administered simultaneously.

[0011] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, and the compound of formula (II), or a pharma- ceutically acceptable salt and / or solvate thereof, are administered sequentially.

[0012] In some embodiments, administration of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and a compound of formula (II), or a pharma- ceutically acceptable salt and / or solvate thereof, results in a synergistic effect.

[0013] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, and the compound of formula (II), or a pharma- ceutically acceptable salt and / or solvate thereof, are each administered orally.

[0014] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered in a dose of about 0.1 mg to about 10 mg.

[0015] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered in a dose of about 0.25 mg to about 4.5 mg.

[0016] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered in a dose of 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.25 mg, 1.5 mg, or 2.0 mg.

[0017] In some embodiments, the compound of formula (II), or a pharma- ceutically acceptable salt and / or solvate thereof, is administered in an amount of about 50 mg to about 500 mg.

[0018] In some embodiments, the compound of formula (II), or a pharma- ceutically acceptable salt and / or solvate thereof, is administered in an amount of about 400 mg.

[0019] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered once daily.

[0020] In some embodiments, the compound of formula (II), or a pharma- ceutically acceptable salt thereof, is administered once daily.

[0021] In some embodiments, a compound of formula (II) or a pharma- ceutically acceptable salt and / or hydrate thereof is administered.

[0022] In some embodiments, the dihydrochloride monohydrate salt of the compound of formula (II) is administered.

[0023] In some aspects, the present disclosure provides a method of treating a hematopoietic malignancy in a subject in need thereof, the method comprising administering to the subject Compounds of formula (I): [ka] or a pharma- ceutically acceptable salt thereof; and Compounds of formula (III): [ka] or a pharma- ceutically acceptable salt thereof The method comprises administering

[0024] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, and the compound of formula (III), or a pharma- ceutically acceptable salt thereof, are administered simultaneously.

[0025] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, and the compound of formula (III), or a pharma- ceutically acceptable salt thereof, are administered sequentially.

[0026] In some embodiments, the administration of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and a compound of formula (III), or a pharma- ceutically acceptable salt thereof, results in a synergistic effect.

[0027] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, and the compound of formula (III), or a pharma- ceutically acceptable salt thereof, are each administered orally.

[0028] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered in a dose of about 0.1 mg to about 10 mg.

[0029] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered in a dose of about 0.25 mg to about 4.5 mg.

[0030] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered in a dose of 1.25 mg, 2.0 mg, 3.0 mg, 4.0 mg, or 4.5 mg.

[0031] In some embodiments, the compound of formula (III), or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 5 mg to about 50 mg.

[0032] In some embodiments, the compound of formula (III), or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 15 mg.

[0033] In some embodiments, the dose of the compound of Formula (III), or a pharma- ceutically acceptable salt thereof, is administered twice daily.

[0034] In some embodiments, the dose of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered twice daily.

[0035] In some embodiments, the dose of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered twice daily.

[0036] In some embodiments, a phosphate salt of the compound of formula (III) is administered.

[0037] In some aspects, the present disclosure provides a method of treating a hematopoietic malignancy in a subject in need thereof, the method comprising administering to the subject Compounds of formula (I): [ka] or a pharma- ceutically acceptable salt thereof The method comprises administering

[0038] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered at a dose of about 0.1 mg to about 10 mg; preferably at a dose of about 0.25 mg to about 4.5 mg; more preferably at a dose of 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.25 mg, 1.5 mg, or 2.0 mg.

[0039] In some embodiments, the hematopoietic neoplasm is a myeloproliferative neoplasm.

[0040] In some embodiments, the myeloproliferative neoplasm is myelofibrosis.

[0041] In some embodiments, the myelofibrosis is relapsed / refractory myelofibrosis.

[0042] In some embodiments, the subject is treatment naive.

[0043] In some embodiments, the subject has previously been treated with ruxolitinib.

[0044] In some embodiments, the myelofibrosis is primary myelofibrosis.

[0045] In some embodiments, the primary myelofibrosis is selected from intermediate-risk primary myelofibrosis and high-risk primary myelofibrosis.

[0046] In some embodiments, the myelofibrosis is secondary myelofibrosis.

[0047] In some embodiments, the myelofibrosis is post-essential thrombocythemia myelofibrosis.

[0048] In some embodiments, the myelofibrosis is post-polycythemia vera myelofibrosis.

[0049] In some embodiments, the myeloproliferative neoplasm is polycythemia vera.

[0050] In some embodiments, the myeloproliferative neoplasm is essential thrombocythemia.

[0051] In some embodiments, the hematopoietic malignancy is acute myeloid leukemia (AML).

[0052] In some embodiments, the present disclosure provides a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof; and Compounds of formula (II): [ka] or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate) The present invention provides a composition comprising:

[0053] In some embodiments, the present disclosure provides a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof; and [ka] or a pharma- ceutically acceptable salt thereof The present invention provides a composition comprising:

[0054] In some embodiments, the composition is used to manufacture a medicament for the treatment of hematopoietic malignancies.

[0055] In some embodiments, the composition further comprises a pharma- ceutically acceptable carrier.

[0056] In some embodiments, the composition is used to treat a hematopoietic malignancy. [Brief description of the drawings]

[0057] [Figure 1A] FIG. 1A shows a plot of Compound (I) viability dose-response curve with ruxolitinib (Rux) in HEL92.1.7 cells along with IC50 values. [Figure 1B] FIG. 1B shows a plot of the viability IC50 values ​​of the dose-response curve of Compound (I) in HEL92.1.7 cells at each concentration of ruxolitinib. [Figure 2A] Figure 2A shows a combination matrix plot of Compound (I) viability dose-response curves with Ruxolitinib (Rux) in HEL92.1.7 cells, describing the additive effect along with the HSA additivity score in the HSA model. Positive numbers indicate relative synergy and negative numbers indicate relative antagonism. [Figure 2B] Figure 2B shows a combination matrix plot of Compound (I) dose-response curves with ruxolitinib in HEL92.1.7 cells, describing antiproliferative synergy with the Bliss synergy score in the Bliss model. Positive numbers indicate relative synergy and negative numbers indicate relative antagonism. [Figure 3A] FIG. 3A shows a plot of Compound (I) viability dose-response curve with ruxolitinib (Rux) in SET-2 cells with IC50 values. [Figure 3B] FIG. 3B shows a plot of the viability IC50 values ​​of the compound (I) dose-response curve in SET-2 cells at each concentration of ruxolitinib (Rux). [Figure 4A]Figure 4A shows a combination matrix plot of Compound (I) viability dose-response curves with ruxolitinib in SET-2 cells, describing the additive effect along with the HSA additivity score in the HSA model. Positive numbers indicate relative synergy and negative numbers indicate relative antagonism. [Figure 4B] Figure 4B shows a combination matrix plot of Compound (I) dose-response curves with ruxolitinib in SET-2 cells, describing antiproliferative synergy with the Bliss synergy score in the Bliss model. Positive numbers indicate relative synergy and negative numbers indicate relative antagonism. [Figure 5A] FIG. 5A shows a plot of Compound (I) viability dose-response curve with ruxolitinib (Rux) in HEL92.1.7 cells. [Figure 5B] FIG. 5B shows a plot of Compound (I) viability dose-response curve with ruxolitinib (Rux) in SET-2 cells. [Figure 5C] FIG. 5C shows a plot of Compound (I) viability dose-response curve with ruxolitinib (Rux) in WI-38 cells. [Figure 6A] FIG. 6A shows a plot of Compound (I) viability dose-response curve with fedratinib (Fed) in HEL92.1.7 cells with IC50 values. [Figure 6B] FIG. 6B shows a plot of IC50 values ​​of Compound (I) viability dose-response curves in HEL92.1.7 cells at each concentration of fedratinib. [Figure 7A] Figure 7A shows a combination matrix plot of Compound (I) viability dose-response curves with Fedratinib in HEL92.1.7 cells, describing the additive effect along with the HSA additivity score in the HSA model. Positive numbers indicate relative synergy and negative numbers indicate relative antagonism. [Figure 7B]Figure 7B shows a combination matrix plot of Compound (I) dose-response curves with fedratinib in HEL92.1.7 cells, describing antiproliferative synergy with the Bliss synergy score in the Bliss model. Positive numbers indicate relative synergy and negative numbers indicate relative antagonism. [Figure 8A] FIG. 8A shows a plot of Compound (I) viability dose-response curve with fedratinib (Fed) in SET-2 cells with IC50 values. [Figure 8B] FIG. 8B shows a plot of IC50 values ​​of Compound (I) viability dose-response curve in SET-2 cells at each concentration of fedratinib (Fed). [Figure 9A] Figure 9A shows a combination matrix plot of Compound (I) viability dose-response curves with fedratinib in SET-2 cells, describing the additive effect along with the HSA additivity score in the HSA model. Positive numbers indicate relative synergy and negative numbers indicate relative antagonism. [Figure 9B] Figure 9B shows a combination matrix plot of Compound (I) dose-response curves with fedratinib in SET-2 cells, describing antiproliferative synergy with the Bliss synergy score in the Bliss model. Positive numbers indicate relative synergy and negative numbers indicate relative antagonism. [Figure 10A] FIG. 10A shows a plot of Compound (I) viability dose-response curve with Fedratinib (Fed) in HEL92.1.7 cells. [Figure 10B] FIG. 10B shows a plot of Compound (I) viability dose-response curve with Fedratinib (Fed) in SET-2 cells. [Figure 10C] FIG. 10C shows a plot of Compound (I) viability dose-response curve with Fedratinib (Fed) in WI-38 cells. [Figure 11] FIG. 11 shows the effect of Compound (I) on colony formation in primary human samples from myelofibrosis patients. [Figure 12A]FIG. 12A shows the inhibition of granulocyte macrophage progenitor cells (CFU-GM, granulocyte / macrophage colony forming cells) from two different healthy donors treated with compound (I). [Figure 12B] FIG. 12B shows the inhibition of erythroid progenitor cells (BFU-E, erythroid / macrophage burst forming cells) from two different healthy donors treated with compound (I). [Figure 13A] Figure 13A shows plots of the relative colony numbers formed by bone marrow CD34+ cells from two healthy donors treated for 14 days with compound (I) (light blue curve), fedratinib (gray curve), and a combination of 100 nM fedratinib and compound (I) (medium blue curve) or 300 nM fedratinib and compound (I) (dark blue curve). Data shows donor mean values ​​and effect on CFU-GM. [Figure 13B] Figure 13B shows plots of the relative colony numbers formed by bone marrow CD34+ cells from two healthy donors treated for 14 days with Compound (I) (light blue curve), ruxolitinib (gray curve), and a combination of 30 nM ruxolitinib and Compound (I) (medium blue curve) or 100 nM ruxolitinib and Compound (I) (dark blue curve). Data shows donor mean values ​​and effect on CFU-GM. [Figure 14A] FIG. 14A shows a plot of the relative colony numbers formed by cells from a myelofibrosis patient (Patient A) treated for 14 days with Compound (I) (light blue curve), Fedratinib (gray curve), and combinations of 100 nM Fedratinib and Compound (I) (medium blue curve) or 300 nM Fedratinib and Compound (I) (dark blue curve). [Figure 14B]FIG. 14B shows a plot of the relative colony numbers formed by cells from a myelofibrosis patient (Patient B) treated for 14 days with Compound (I) (light blue curve), ruxolitinib (gray curve), and a combination of 30 nM ruxolitinib with Compound (I) (medium blue curve) or 100 nM ruxolitinib with Compound (I) (dark blue curve). [Figure 15A] 15A and 15B show a schematic of the Phase IB / 2 study design described in Example 3. [Figure 15B] 15A and 15B show a schematic of the Phase IB / 2 study design described in Example 3. [Figure 16] FIG. 16 shows activation of caspase-3 over time in HEL cells upon treatment with compound (I) (green triangles), fedratinib (yellow circles and red squares), ruxolitinib (gray circles and gold symbols), a combination of compound (I) and fedratinib (black circles and black triangles), or a combination of compound (I) and ruxolitinib (pink triangles or lavender circles). [Figure 17] FIG. 17 shows activation of caspase-3 over time in SET-2 cells upon treatment with compound (I) (green triangles), fedratinib (yellow circles and red squares), ruxolitinib (gray circles and gold symbols), a combination of compound (I) and fedratinib (black circles and black triangles), or a combination of compound (I) and ruxolitinib (pink triangles or lavender circles). [Figure 18] Figure 18A shows activation of caspase-3 in HEL92.1.7 cells at 120 hours when treated with compound (I), fedratinib, ruxolitinib, a combination of compound (I) and fedratinib, or a combination of compound (I) and ruxolitinib. Figure 18B shows activation of caspase-3 in SET-2 cells at 120 hours when treated with compound (I), fedratinib, ruxolitinib, a combination of compound (I) and fedratinib, or a combination of compound (I) and ruxolitinib. [Figure 19A] FIG. 19A shows a plot of Compound (I) and CPI-0610 viability in HEL92.1.7 cells at day 3. [Figure 19B] FIG. 19B shows a plot of Compound (I) and CPI-0610 viability in SET-2 cells at day 3. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0058] Detailed Description Methods and compositions therefor are provided for the use of bromodomain and extraterminal motif (BET) protein inhibitors alone and in combination with Janus-associated kinase (JAK) inhibitors for the treatment of disease in a subject, where the JAK inhibitor is selected from fedratinib and ruxolitinib. The disclosed combinations are useful for the inhibition of BET and / or JAK proteins, and for the treatment of diseases, disorders, or conditions, such as cancer, particularly hematological tumors that are responsive to the inhibition of BET and / or JAK proteins.

[0059] Advantageously, the combination of a BET inhibitor and a JAK inhibitor produces a synergistic effect.

[0060] In some embodiments, the BET inhibitor and the JAK inhibitor are administered in a therapeutically effective amount sufficient to produce a therapeutic effect.The therapeutic effect of the combination therapy includes but is not limited to the delay, reduction, or prevention of hematopoietic tumor re-growth, spleen volume response, increase in hemoglobin, and transfusion independence.

[0061] definition In order that this specification may be more readily understood, certain terms are first defined. Further definitions are set forth throughout the detailed description.

[0062] It should be noted that the term "a" or "an" entity refers to one or more of that entity; for example, "a nucleotide sequence" is understood to represent one or more nucleotide sequences. Thus, the terms "a" (or "an"), "one or more," and "at least one" may be used interchangeably herein.

[0063] As used herein, the word "or" is used in its inclusive sense of "and / or" rather than its exclusive sense of "either / or," unless otherwise indicated.

[0064] Furthermore, "and / or" as used herein should be taken as specifically disclosing each of the two specified features or components with or without the other. Thus, the term "and / or" as used in phrases such as "A and / or B" herein is intended to include "A and B," "A or B," "A" (single), and "B" (single). Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (single); B (single); and C (single).

[0065] The term "effective amount" or "therapeutically effective amount" as used herein refers to an amount of a compound, or a combination of one or more compounds, that when administered (sequentially or simultaneously) causes a desired biological or pharmaceutical response, e.g., destruction of target cancer cells, slowing or stopping the progression of cancer in a patient, or otherwise reducing the severity of disease symptoms. The therapeutically effective amount may vary depending on the intended use (in vitro or in vivo), or the patient and condition being treated, e.g., the patient's weight and age, the severity of the condition, the method of administration, and the like, and may be readily determined by one of ordinary skill in the art. The term also applies to a dose that causes a particular response in a target cell, e.g., a decrease in cell proliferation and / or cell migration. For example, in some embodiments, a "therapeutically effective amount" as used herein refers to an amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and an amount of a JAK inhibitor that, when administered separately or in combination, produces a beneficial effect. In some embodiments, the combined effect is additive. In some embodiments, the combined effect is synergistic. Furthermore, it will be appreciated by those of skill in the art that in combination therapy, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, and / or the amount of the JAK inhibitor may be used in "sub-therapeutic amounts," i.e., amounts that are less than the therapeutically effective amount of each compound when used alone.

[0066] The term "about" refers to approximately, in the regions of, roughly, or around. When the term "about" is used in conjunction with a number or numerical range, it means that the stated number or numerical range is approximate within experimental variation (or within statistical experimental error), and therefore the number or numerical range may vary, for example, by between 1% and 15% of the stated number or numerical range. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of ±10%.

[0067] As used herein, a "patient" generally refers to a mammal (e.g., a human) who has been diagnosed with, is exhibiting symptoms of, or is otherwise believed to be afflicted by a disease, disorder, or condition (e.g., a malignant tumor, etc.). In some embodiments, the patient is an adult patient (e.g., an adult).

[0068] The term "malignant tumor" refers to hematopoietic tumors and cancers. Hematopoietic tumors are cancers of the cells of the blood / hematopoietic system. Cancers are generally non-hematopoietic / non-hematopoietic cancers, such as solid tumors.

[0069] The terms "co-administration," "administered in combination," and "administering a combination" refer to the administration of two or more active active ingredients, including, but not limited to, a compound of formula (I) disclosed herein, or a pharma- ceutically acceptable salt thereof, and a Janus-associated kinase inhibitor, to a patient. Co-administration can refer to simultaneous or sequential administration of a compound of formula (I) disclosed herein, or a pharma- ceutically acceptable salt thereof, and a Janus-associated kinase inhibitor.

[0070] The terms "concurrent" and "simultaneously" refer to administration of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and a Janus-associated kinase inhibitor to a patient at the same time or at two different times separated by no more than two hours. The simultaneous administration of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and a Janus-associated kinase inhibitor can be in a single dosage form or in separate dosage forms.

[0071] The terms "continuous" and "sequentially" refer to the administration of a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, and a Janus associated kinase inhibitor to a patient at two different time points separated by more than two hours, e.g., about 3 hours, about 4 hours, about 5 hours, about 8 hours, about 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days or even longer.

[0072] The term "intermittent period" refers to a period following administration of one or more particular active ingredients to a patient in an intermittent regimen. Intermittent period refers to a rest period during which a particular active ingredient is not administered for at least one day.

[0073] The term "synergy" refers to a situation in which the combination of two or more agents produces an effect that is greater than the sum of the effects of each agent individually. This term encompasses not only the alleviation of symptoms of the disorder being treated, but also improved side effect profile, increased tolerability, improved patient compliance, improved efficacy, or any other improvement in clinical outcome.

[0074] The determination of synergistic interaction between BET inhibitors and JAK inhibitors may be based on the results obtained from the assays described herein. For example, the combination effect may be evaluated using the Bliss independence model. The Bliss score quantifies the degree of synergy with single agents, and a Bliss score >0 indicates greater than simple additivity. In some embodiments, a Bliss score of greater than 10 indicates strong synergy. In other embodiments, a score of 6 or greater indicates synergy. In some embodiments, the Bliss score is about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, or about 25.

[0075] As used herein, the exemplary terms "include," "such as," "for example," and the like (and variations thereof, e.g., "includes," "including," "examples") are intended to be open-ended unless otherwise specified. That is, unless expressly stated otherwise, such terms are intended to mean "but not limited to," e.g., "including" means that "includes, but is not limited to."

[0076] Unless otherwise stated, structures depicted herein are also meant to include chemical entities that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of a hydrogen atom by deuterium or tritium, or 13 C or 14 Chemical substances having the present structure except for the replacement of carbon atoms with C-enriched carbons are within the scope of this disclosure.

[0077] Unless stereochemical configuration is indicated, the structures depicted herein are intended to include all stereochemical forms of the structure, i.e., R and S configurations for each asymmetric center.Thus, unless otherwise indicated, single stereochemical isomers as well as enantiomeric, racemic and diastereomeric mixtures of the chemical are within the scope of this disclosure.When stereochemical configuration is indicated for a compound, the diastereomeric or enantiomeric excess of the compound is at least 99.0%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9%.

[0078] As used herein, the description of a numerical range of a variable is intended to convey that the disclosure can be practiced with the variable equal to any of the values ​​within that range. Thus, for a variable that is discrete in nature, the variable can be equal to any integer value within the numerical range, including the end points. Similarly, for a variable that is continuous in nature, the variable can be equal to any real value within the numerical range, including the end points. By way of example and not of limitation, a variable described as having a value between 0 and 2 can take on values ​​of 0, 1, or 2 if the variable is discrete in nature, and can take on 0.0, 0.1, 0.01, 0.001, or any other real value greater than 0 and less than 2 if the variable is continuous in nature.

[0079] All references cited herein are incorporated by reference in their entirety.

[0080] BET inhibitors The present disclosure provides combination treatments for patients with malignancies, including hematopoietic malignancies, that include, inter alia, administration of a therapeutically effective amount of at least one BET inhibitor to a patient in need of treatment.

[0081] Bromodomain and extraterminal domain protein (BET) inhibitors In some embodiments, the BET inhibitor is a compound of formula (I) (also referred to as compound (I)): [ka] Or its pharmaceutically acceptable salt. Compounds of formula (I) can be prepared as described in U.S. Patent No. 9,458,156, which is incorporated by reference in its entirety. In some embodiments, the BET inhibitor is CPI-0610.

[0082] Janus-associated kinase (JAK) inhibitors In some embodiments, the disclosure provides combination treatments that include, inter alia, administration of a therapeutically effective amount of at least one Janus-associated kinase (JAK) inhibitor (e.g., ruxolitinib, fedratinib, tofacitinib, oclacitinib, baricitinib, peficitinib, or upadacitinib) to a subject in need of treatment.

[0083] In some embodiments, the JAK inhibitor is a JAK1 / 2 inhibitor. In some embodiments, the JAK1 / 2 inhibitor is ruxolitinib, which is [ka] and is described in U.S. Patents Nos. 7,598,257; 8,415,362; 8,722,693; 8,822,481; 8,829,013; 9,079,912; 9,814,722; and 10,016,429. Ruxolitinib phosphate is a kinase inhibitor with the chemical name (R)-3-(4-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate.

[0084] In some embodiments, the JAK inhibitor is a JAK2 specific inhibitor. In some embodiments, the JAK2 inhibitor is fedratinib, which is [ka] and has the chemical structure shown in, e.g., U.S. Pat. Nos. 7,528,143; 7,825,246; 8,138,199; and 10,391,094; and PCT Publication Nos. WO2020 / 167845 and WO2020 / 068755, each of which is incorporated herein by reference in its entirety.

[0085] Cancer Treatment Methods In some embodiments, the present disclosure relates to methods of treating a malignant tumor in a patient by administering to a patient in need of treatment a combination of a BET inhibitor, or a pharma- ceutically acceptable salt thereof, alone or in combination with a JAK inhibitor, or a pharma- ceutically acceptable salt and / or solvate (e.g., hydrate) thereof.

[0086] In some embodiments, the present disclosure relates to the use of a BET inhibitor, or a pharma- ceutically acceptable salt thereof, in combination with a JAK inhibitor, or a pharma- ceutically acceptable salt and / or solvate (e.g., a hydrate) thereof, for the treatment of a malignant tumor in a patient.

[0087] In some embodiments, the present disclosure relates to a composition comprising a BET inhibitor for use in treating a malignant tumor in a patient, wherein the patient is also treated with a JAK inhibitor. In some embodiments, the present disclosure relates to a composition comprising a BET inhibitor for use in treating cancer in a patient, wherein the BET inhibitor is combined with a JAK inhibitor. In some embodiments, the BET inhibitor can be administered simultaneously or sequentially with the JAK inhibitor.

[0088] In some embodiments, the present disclosure relates to a method of treating a malignant tumor, the method comprising administering to a patient in need of such treatment a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and a JAK inhibitor, or a pharma- ceutically acceptable salt thereof, in a combined or separate formulation, wherein the administration of the formulations is simultaneous, sequential, or alternating.

[0089] In some embodiments, the present disclosure relates to a method of treating cancer, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a combination of BET inhibitors, alone or in combination with a JAK inhibitor. In some embodiments, the combination of the present disclosure is less toxic than a BET inhibitor alone. In some embodiments, the combination of the present disclosure is less toxic than a JAK inhibitor alone.

[0090] In some embodiments, the disclosure relates to methods of treating cancer by administering to a patient a combination of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and a JAK inhibitor, or a pharma- ceutically acceptable salt thereof.

[0091] In another aspect, the present disclosure relates to the use of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, in combination with a JAK inhibitor, or a pharma- ceutically acceptable salt thereof, for the treatment of cancer.

[0092] In some embodiments, the JAK inhibitor is co-administered with thiamine.

[0093] In some embodiments, the disclosure relates to a method of treating a disorder, wherein the disorder is a hematopoietic neoplasm. In some embodiments, the hematopoietic neoplasm is acute myeloid leukemia (AML). In some embodiments, the hematopoietic neoplasm is a myeloproliferative neoplasm. In some embodiments, the myeloproliferative neoplasm is myelofibrosis. In some embodiments, the myelofibrosis is primary myelofibrosis. In some embodiments, the primary myelofibrosis is selected from intermediate-risk primary myelofibrosis and high-risk primary myelofibrosis. In some embodiments, the myelofibrosis is secondary myelofibrosis. In some embodiments, the myelofibrosis is post-essential thrombocythemia myelofibrosis. In some embodiments, the myelofibrosis is post-polycythemia vera myelofibrosis.

[0094] In some embodiments, the myeloproliferative neoplasm is polycythemia vera. In some embodiments, the myeloproliferative neoplasm is polycythemia vera in adults who have responded inadequately to or are intolerant of hydroxyurea. In some embodiments, the myeloproliferative neoplasm is intermediate-risk or high-risk myelofibrosis, such as primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis in adults. In some embodiments, the myeloproliferative neoplasm is intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF) in adult patients. In some embodiments, the myeloproliferative neoplasm is essential thrombocythemia.

[0095] Other non-limiting examples of hematological malignancies include chronic myeloid leukemia (CML), such as accelerated phase CML and CML blast crisis phase (CML-BP); acute lymphoblastic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin lymphoma (HL), such as classical Hodgkin lymphoma; B-cell lymphoma, T-cell lymphoma, follicular lymphoma (FL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DCL), and idiopathic leukemia (IDL). Non-Hodgkin's lymphoma (NHL), such as primary mediastinal large B-cell lymphoma, and Burkitt's lymphoma; multiple myeloma (MM); amyloidosis; Waldenstrom's macroglobulinemia; myelodysplastic syndrome (MDS), such as refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), and RAEB in transition (RAEB-T); and myeloproliferative syndrome. In some embodiments, the cancer is chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, or non-Hodgkin's lymphoma, such as follicular lymphoma (FL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and Burkitt's lymphoma.

[0096] In some embodiments, the hematopoietic malignancy is one that has relapsed. In some embodiments, a recurrent hematopoietic malignancy is a malignancy that has relapsed after a period of time in which the hematopoietic malignancy was undetectable.

[0097] In some embodiments, the hematopoietic malignancies are refractory. In some embodiments, refractory hematopoietic malignancies do not respond to treatment, also known as resistant hematopoietic malignancies. In some embodiments, the malignancies are resistant to ruxolitinib.

[0098] In some embodiments, the malignant tumor is a hematopoietic tumor and has not been previously treated.

[0099] In some embodiments, the patient has an advanced hematopoietic malignancy that has failed at least one prior treatment regimen.

[0100] Drugs In some embodiments, the present disclosure relates to a drug for use in the treatment of cancer in a patient in need of treatment.In some embodiments, the drug comprises a BET inhibitor.In some embodiments, the drug comprises a BET inhibitor and a JAK inhibitor, in a single dosage form or in separate dosage forms.

[0101] In some embodiments, the medicaments described herein may include a combination of a BET inhibitor, a JAK inhibitor, and optionally one or more additional therapeutic agents.

[0102] In some embodiments, the present disclosure relates to the use of a BET inhibitor in the manufacture of a medicament for treating cancer, wherein the BET inhibitor is administered alone or in combination with a JAK inhibitor. In some embodiments, when the BET inhibitor is administered in combination with a JAK inhibitor, the medicaments are in a single dosage form or in separate dosage forms.

[0103] In some embodiments, the disclosure relates to the use of a BET inhibitor for the manufacture of a medicament in the treatment of cancer in a patient, wherein the patient is also treated with a JAK inhibitor. In some embodiments, the BET inhibitor can be administered simultaneously or sequentially with the JAK inhibitor. In some embodiments, the disclosure relates to the use of a BET inhibitor for the manufacture of a medicament in the treatment of cancer in a patient, wherein the BET inhibitor is combined with a JAK inhibitor. In some embodiments, the BET inhibitor is in the same composition as the JAK inhibitor. In some embodiments, the BET inhibitor is in a separate composition from the JAK inhibitor. In some embodiments, the BET inhibitor is in the same composition as the JAK inhibitor. In some embodiments, the BET inhibitor is in a separate composition from the JAK inhibitor.

[0104] In some embodiments, the disclosure relates to the use of a compound of formula (I), designated Compound of Formula (I), or a pharma- ceutically acceptable salt thereof, in combination with a JAK inhibitor in the manufacture of a medicament for use in the treatment of cancer.In some embodiments, the disclosure relates to the use of a compound of formula (I), designated Compound of Formula (I), or a pharma- ceutically acceptable salt thereof, in combination with a JAK inhibitor in the manufacture of a medicament for use in the treatment of cancer.

[0105] In another aspect, the present disclosure relates to the use of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer, wherein the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered alone or in combination with a JAK inhibitor.

[0106] In another aspect, the present disclosure relates to a compound of formula (I), or a pharma- ceutically acceptable salt thereof, for use as a combination medicament with a JAK inhibitor, wherein the compound of formula (I) and said JAK inhibitor may be administered simultaneously or sequentially.

[0107] In another embodiment, the present disclosure relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a JAK inhibitor in the manufacture of a medicament for the treatment of cancer in a subject.In some embodiments, the present disclosure relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a JAK inhibitor in the manufacture of a medicament for the treatment of cancer in a subject, wherein the compound of formula (I) is formulated to be administered to the subject simultaneously or sequentially.In some embodiments, the present disclosure relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a JAK inhibitor in the manufacture of a medicament for the treatment of cancer in a subject, wherein the compound of formula (I) and the JAK inhibitor are formulated to be administered to the subject simultaneously or sequentially.

[0108] In some embodiments, the JAK inhibitor is fedratinib or ruxolitinib.

[0109] Combined pharmaceutical composition The combinations of the present disclosure may be administered to a mammal in the form of raw chemicals free of any other components, or the combinations of the present disclosure may also be administered to a mammal as part of a pharmaceutical composition containing the compounds combined with a suitable pharma- ceutically acceptable carrier (see, e.g., Gennaro, Remington: The Science and Practice of Pharmacy with Facts and Comparisons: Drugfacts Plus, 20th ed. (2003); Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed., Lippencott Williams and Wilkins (2004); Kibbe et al., Handbook of Pharmaceutical Excipients, 3rd ed., Pharmaceutical Press (2000)). Such carriers may be selected from pharma- ceutically acceptable additives and auxiliaries. The term "pharma- ceutically acceptable carrier" or "pharma- ceutically acceptable vehicle" encompasses any of the standard pharmaceutical carriers, solvents, surfactants, or vehicles. Standard pharmaceutical carriers and their formulations are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995.

[0110] The combination pharmaceutical compositions of the present disclosure may be prepared as a liquid suspension or solution using a liquid, such as an oil, water, an alcohol, or combinations thereof.

[0111] Combination pharmaceutical compositions to be used for in vivo administration can be sterile, which is readily accomplished, for example, by filtration through sterile filtration membranes.

[0112] Combination pharmaceutical compositions within the scope of the present disclosure include all compositions in which the BET inhibitors and JAK inhibitors of the present disclosure are combined with one or more pharma- ceutically acceptable carriers. In one embodiment, the BET inhibitors and JAK inhibitors of the present disclosure are present in the composition in an amount sufficient to achieve the intended therapeutic purpose.

[0113] The combined pharmaceutical composition of the present disclosure may be administered to any patient who may experience the beneficial effects of the combination of the present disclosure. Most important among such patients are mammals, such as humans and companion animals, although the present disclosure is not intended to be so limited. In one embodiment, the patient is a human. In one embodiment, the human is an adult. In another embodiment, the combined pharmaceutical composition of the present disclosure may be administered to a patient with JAK inhibitor-resistant or refractory cancer. In another embodiment, the combined pharmaceutical composition of the present disclosure may be administered to a patient with JAK inhibitor-resistant or refractory cancer.

[0114] In another embodiment, the present disclosure provides a kit comprising the combination of the present disclosure packaged in a manner that facilitates its use to practice the method of the present disclosure. In one embodiment, the kit includes the BET inhibitor and JAK inhibitor of the present disclosure packaged in a container, such as a sealed bottle or vessel, and a label describing the use of the compound to practice the method of the present disclosure is affixed to the container or included with the kit. In one embodiment, the combination composition is packaged in a unit dosage form. The kit may further include a device suitable for administering the combination composition JAK to the intended route of administration. In some embodiments, the present disclosure provides a kit comprising the BET inhibitor and JAK inhibitor of the present disclosure, or a pharma- ceutically acceptable salt or solvate thereof, and instructions for administering the compound, or a pharma- ceutically acceptable salt thereof, to a patient with cancer.

[0115] In some embodiments, the present disclosure provides a combination pharmaceutical composition comprising a BET inhibitor and a JAK inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0116] In some embodiments, the disclosure provides a combination pharmaceutical composition comprising a BET inhibitor and a JAK inhibitor of the disclosure, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, wherein the combination binds to a protein encoded by a BET gene and / or a JAK gene.

[0117] In some embodiments, the present disclosure provides a combination pharmaceutical composition comprising a BET inhibitor and a JAK inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, wherein the pharmaceutical composition is for use in the treatment of cancer.

[0118] In some embodiments, the present disclosure provides a combination pharmaceutical composition comprising a BET inhibitor and a JAK inhibitor of the present disclosure, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, wherein said pharmaceutical composition is for the manufacture of a medicament for the treatment of cancer.

[0119] Combination Administration The compound of formula (I), or a pharma- ceutically acceptable salt thereof, in combination with the JAK inhibitor may be administered in a single dosage form or as separate dosage forms. In some embodiments, when administered as separate dosage forms, the JAK inhibitor may be administered before, simultaneously with, or after administration of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, when administered as separate dosage forms, one or more doses of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, may be administered before the JAK inhibitor. In some embodiments, the JAK inhibitor is administered before administration of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. As used herein, administration of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, in "combination" with the JAK inhibitor refers to administration of the agents during a single treatment cycle, as well as simultaneous or sequential administration of the agents, as will be understood by those skilled in the art. When the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered in combination with the JAK inhibitor, a therapeutically effective amount of the combination is administered.

[0120] The BET inhibitor can be administered by any method known to those skilled in the art.For example, in some embodiments, the BET inhibitor can be administered in the form of a pharmaceutical composition of the BET inhibitor and a pharma- ceutically acceptable carrier (such as those described herein).In some embodiments, the pharmaceutical composition is suitable for oral administration.In some embodiments, the pharmaceutical composition is a tablet suitable for oral administration.

[0121] In some embodiments, the pharmaceutical composition comprising the BET inhibitor is formulated as a capsule suitable for oral administration. In some embodiments, the capsule is a hard gelatin capsule. In some embodiments, the pharmaceutical composition comprises polyethylene glycol. In some embodiments, the pharmaceutical composition comprises PEG 1450. In some embodiments, the concentration of the BET inhibitor in the PEG 1450 is about 1 mg / mL to about 10 mg / mL. In some embodiments, the concentration of the BET inhibitor in the PEG 1450 is about 1 mg / mL to about 6 mg / mL. In some embodiments, the concentration of the BET inhibitor in the PEG 1450 is about 1.25 mg / mL. In some embodiments, the concentration of the BET inhibitor in the PEG 1450 is about 6 mg / mL.

[0122] In some other embodiments, the pharmaceutical composition is in a liquid dosage form suitable for oral administration. In some embodiments, the pharmaceutical composition is suitable for parenteral administration. In some embodiments, the pharmaceutical composition is suitable for intravenous administration. In some embodiments, the pharmaceutical composition is suitable for intravenous infusion. In some embodiments, the pharmaceutical composition is suitable for injection. In some embodiments, the pharmaceutical composition is suitable for intravenous injection. In some embodiments, the pharmaceutical composition is suitable for subcutaneous injection. In some embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

[0123] The JAK inhibitor may be administered by any method known to those skilled in the art. In some embodiments, the JAK inhibitor is administered intravenously (iv). In some embodiments, the JAK inhibitor is administered subcutaneously (sc). In some embodiments, the JAK inhibitor is administered orally. For example, the JAK inhibitor may be administered in the form of a second composition, in some embodiments, in the form of a pharmaceutical composition of the JAK inhibitor and a pharma- ceutically acceptable carrier (such as, for example, as described herein). In some embodiments, the pharmaceutical composition is suitable for oral administration. In some embodiments, the pharmaceutical composition is a tablet or capsule suitable for oral administration. In some other embodiments, the pharmaceutical composition is a liquid dosage form suitable for oral administration. In some embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

[0124] In some embodiments, the JAK inhibitors may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, or by implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intraperitoneal, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In some embodiments, the JAK inhibitors are administered orally, intravenously, or subcutaneously. In some embodiments, the JAK inhibitors are administered orally. In some embodiments, the JAK inhibitors are administered intravenously. In some embodiments, the intravenous administration can be intravenous infusion or intravenous injection. In some embodiments, the JAK inhibitors are administered by intravenous infusion. In some embodiments, the JAK inhibitors are administered by intravenous injection. In some embodiments, the JAK inhibitors are administered by subcutaneous injection. In some embodiments, the JAK inhibitors are administered by intravenous infusion followed by subcutaneous injection. These administration methods may be designed to be short-acting, fast-releasing, or long-acting. Additionally, the JAK inhibitor may be administered in a local rather than systemic manner, such as administration at the tumor site (eg, by injection).

[0125] In some embodiments, each therapeutic agent in the combination disclosed herein (e.g., a compound of formula (I) and a JAK inhibitor) can be administered by the same route or different routes. For example, a first therapeutic agent of the combination can be administered by intravenous injection, while the other therapeutic agent of the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally and all therapeutic agents can be administered by intravenous injection. The therapeutic agents can also be administered alternately.

[0126] In some embodiments, the JAK inhibitor may be administered by nasal aerosol or inhalation. The JAK inhibitor may be prepared according to techniques well known in the art and may be prepared as a solution in saline, utilizing benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0127] The amount or suitable dose of the disclosed method varies depending on several factors, such as the nature of the severity of the condition to be treated, the specific inhibitor, the route of administration, and the age, weight, overall health, and response of each patient.In some embodiments, the suitable dose level is the dose level that achieves a therapeutic response measured by tumor regression or other standard measures of disease progression, progression-free survival, or overall survival.In some embodiments, the suitable dose level is the dose level that achieves this therapeutic response and also minimizes any side effects associated with the administration of the therapeutic agent.The suitable dose level may be the dose level that prolongs the therapeutic response and / or extends lifespan.

[0128] It is understood that the appropriate dose of the BET inhibitor, the JAK inhibitor, and optionally one or more additional therapeutic agents can be taken at any time of the day or night. In some embodiments, the appropriate dose of each agent is taken in the morning. In some other embodiments, the appropriate dose of each agent is taken in the evening. In some embodiments, the appropriate dose of each agent is taken both in the morning and in the evening. It is understood that the appropriate dose of each agent can be taken with or without food. In some embodiments, the appropriate dose of each agent is taken with food. In some embodiments, the appropriate dose of each agent is taken on an empty stomach.

[0129] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered on a daily schedule. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered twice a day. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered three times a day. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered four times a day. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered five times a day.

[0130] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered every other day. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered once every three days. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered on a twice-weekly schedule. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered on a three-times-weekly schedule. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered on a weekly schedule. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered on a biweekly schedule.

[0131] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered at least three times on alternate days within a seven-day cycle. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered on days 1 and 4 of a seven-day cycle. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered on consecutive days during a seven-day cycle, followed by an intermission period. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered for two consecutive days for at least one seven-day cycle, followed by an intermission period of five consecutive days. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered for three consecutive days for at least one seven-day cycle, followed by an intermission period of four consecutive days. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered for four consecutive days for at least one seven-day cycle, followed by an intermission period of three consecutive days. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered for 5 consecutive days, followed by a 2 consecutive day rest period, for at least one 7 day cycle. In some embodiments, there is a rest period between one or more of the 7 day treatment cycles. In some embodiments, there is a 7 day rest period between one or more of the 7 day treatment cycles.

[0132] The present disclosure contemplates administration of a BET inhibitor during one or more treatment cycles, e.g., 1, 2, 3, 4, 5, 6, or more treatment cycles. In some embodiments, the treatment cycle is about 7 days to about 56 days, or more. In some embodiments, the treatment cycle is 7 days, 14 days, 21 days, 28 days, 35 days, 42 days, 49 days, or 56 days. In some embodiments, the treatment cycle is 21 days or 28 days. In some embodiments, there is a rest period during or between one or more of the treatment cycles. For example, in some embodiments, there is a rest period at the end of a treatment cycle. In some embodiments, there is a rest period between the second and third treatment cycles, but not between the first and second treatment cycles. In another embodiment, there may be a rest period between the first and second treatment cycles, but not between the second and third treatment cycles. Dosing schedules include, for example, administering the BET inhibitor once during a treatment cycle (e.g., day 1 of a 21 day cycle), administering twice during a treatment cycle (e.g., days 1 and 15 of a 21 day cycle or days 1 and 15 of a 28 day cycle), administering three times during a treatment cycle (e.g., days 1, 8, and 15 of a 21 day cycle or days 1, 8, and 15 of a 28 day cycle), and administering four times during a treatment cycle (e.g., days 1, 4, 8, and 11 of a 21 day cycle or days 1, 4, 8, and 11 of a 28 day cycle). Other dosing regimens are encompassed by the present disclosure.

[0133] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered in a 21-day cycle. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered at least twice within a 21-day cycle. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered at least four times within a 21-day cycle. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered on day 1 of a 21-day cycle. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered on day 4 of a 21-day cycle. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered on day 8 of a 21-day cycle. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered on day 11 of a 21-day cycle. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered on days 1, 4, 8, and 11 of a 21 day cycle.

[0134] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered for a period of one year or less. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered for a period of one year or more. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered for a period of 24 months or less. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered for a period of 24 months or more.

[0135] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered once a week. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered once a week for two weeks. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered once a week for two weeks in a 21-day cycle.

[0136] In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 0.1 mg to about 20 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 0.1 mg to about 15 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 0.1 mg to about 10 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 0.1 mg to about 8 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 0.1 mg to about 5 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 0.2 mg to about 5 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is from about 0.25 mg to about 5 mg.

[0137] In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 0.1 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 0.2 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 0.25 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 0.3 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 0.4 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 0.5 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 0.6 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 0.7 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 0.8 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 0.9 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 1 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 1.1 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 1.2 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 1.3 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 1.4 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 1.5 mg.In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 1.6 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 1.7 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 1.8 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 1.9 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 2 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 2.1 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 2.2 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 2.3 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 2.4 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 2.5 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 2.6 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 2.7 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 2.8 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 2.9 mg. In some embodiments, the amount of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, administered on each day of administration is about 3 mg.

[0138] In some embodiments, the method features administering to the subject a daily dose of about 0.25 mg to about 6 mg, or about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 237 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5.0 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, or 6 mg of a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0139] All dosage amounts refer to the amount of a compound of formula (I) that is administered and do not include the weight of any pharma- ceutically acceptable salts.

[0140] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered at a dose of about 0.25 mg to about 4.5 mg. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered for 5 consecutive days in a 28-day cycle, followed by a 2-day rest period. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered for 14 consecutive days in a 21-day cycle, followed by a 7-day rest period. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered for 7 consecutive days in a 21-day cycle, followed by a 14-day rest period.

[0141] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered as an intravenous (IV) infusion. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered as a 60±10 minute IV infusion. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered as an IV infusion of 300 minutes or less. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered as an IV infusion of 60 minutes to 300 minutes.

[0142] In some embodiments, the JAK inhibitor is administered on a daily schedule. In some embodiments, the JAK inhibitor is administered every other day. In some embodiments, the JAK inhibitor is administered once every 3 days. In some embodiments, the JAK inhibitor is administered on a twice-weekly schedule. In some embodiments, the JAK inhibitor is administered on a three-times-weekly schedule. In some embodiments, the JAK inhibitor is administered on a weekly schedule. In some embodiments, the JAK inhibitor is administered on a once-every-2-week schedule. In some embodiments, the JAK inhibitor is administered on a once-every-3-week schedule. In some embodiments, the JAK inhibitor is administered on a once-every-4-week schedule. In some embodiments, the JAK inhibitor is administered on a once-every-8-week schedule. In some embodiments, the JAK inhibitor is administered on a once-every-12-week schedule.

[0143] In some embodiments, the JAK inhibitor is administered at least three times every other day within a seven day cycle. In some embodiments, the JAK inhibitor is administered on day 1 of the treatment cycle. In some embodiments, the JAK inhibitor is administered on days 1 and 4 of the seven day cycle. In some embodiments, the JAK inhibitor is administered on consecutive days during the seven day cycle, followed by an intermission. In some embodiments, the JAK inhibitor is administered for two consecutive days for at least one seven day cycle, followed by an intermission of five consecutive days. In some embodiments, the JAK inhibitor is administered for three consecutive days for at least one seven day cycle, followed by an intermission of four consecutive days. In some embodiments, the JAK inhibitor is administered for four consecutive days for at least one seven day cycle, followed by an intermission of three consecutive days. In some embodiments, the JAK inhibitor is administered for five consecutive days for at least one seven day cycle, followed by an intermission of two consecutive days.

[0144] The present disclosure contemplates administration of the JAK inhibitor during one or more treatment cycles, e.g., 1, 2, 3, 4, 5, 6, or more treatment cycles. In some embodiments, the treatment cycle is about 7 days to about 84 days, or more. In some embodiments, the treatment cycle is 7 days, 14 days, 21 days, 28 days, 35 days, 42 days, 49 days, 56 days, or 84 days. In some embodiments, the treatment cycle is 21 days or 28 days. In some embodiments, there is a rest period during or between one or more of the treatment cycles. For example, in some embodiments, there is a rest period at the end of a treatment cycle. In some embodiments, there is a rest period between the second and third treatment cycles, but not between the first and second treatment cycles. In another embodiment, there may be a rest period between the first and second treatment cycles, but not between the second and third treatment cycles. Dosing schedules include, for example, administering the JAK inhibitor once during a treatment cycle (e.g., day 1 of a 21 day cycle), twice during a treatment cycle (e.g., days 1 and 15 of a 21 day cycle or days 1 and 15 of a 28 day cycle), three times during a treatment cycle (e.g., days 1, 8, and 15 of a 21 day cycle or days 1, 8, and 15 of a 28 day cycle), and four times during a treatment cycle (e.g., days 1, 4, 8, and 11 of a 21 day cycle or days 1, 4, 8, and 11 of a 28 day cycle). Other dosing regimens are encompassed by the present disclosure.

[0145] In some embodiments, the JAK inhibitor is administered on a 21 day cycle. In some embodiments, the JAK inhibitor is administered on day 1 of the 21 day cycle.

[0146] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered on the same day as the JAK inhibitor. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered prior to the JAK inhibitor when both are administered on the same day. In some embodiments, the JAK inhibitor is administered prior to the compound of formula (I), or a pharma- ceutically acceptable salt thereof, when both are administered on the same day.

[0147] In some embodiments, administration of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is delayed by 1-3 days within a 21 day cycle. In some embodiments, administration of the JAK inhibitor is delayed by 1-3 days within a 21 day cycle. In some embodiments, administration of both the compound of formula (I), or a pharma- ceutically acceptable salt thereof, and the JAK inhibitor is delayed by 1-3 days within a 21 day cycle.

[0148] In some embodiments, the JAK inhibitor is administered by subcutaneous injection. In some embodiments, the JAK inhibitor is administered by intravenous infusion, followed by one or more subcutaneous injections. In some embodiments, the intravenous infusion and then one or more subcutaneous injections are administered according to the dosing schedule and method disclosed herein.

[0149] In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 5 mg to about 200 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 5 mg to about 190 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 5 mg to about 180 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 5 mg to about 170 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 5 mg to about 160 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 5 mg to about 150 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 5 mg to about 140 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 5 mg to about 130 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 5 mg to about 120 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 5 mg to about 110 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 5 mg to about 100 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 5 mg to about 90 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 5 mg to about 80 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 5 mg to about 70 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 5 mg to about 60 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 5 mg to about 50 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 5 mg to about 40 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 5 mg to about 30 mg.

[0150] In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 50 mg to about 500 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 55 mg to about 500 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 60 mg to about 500 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 70 mg to about 500 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 80 mg to about 500 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 90 mg to about 500 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 100 mg to about 500 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 120 mg to about 500 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 130 mg to about 500 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 140 mg to about 500 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 150 mg to about 500 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 160 mg to about 500 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 170 mg to about 500 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 180 mg to about 500 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 190 mg to about 500 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 200 mg to about 500 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 210 mg to about 500 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 220 mg to about 500 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 230 mg to about 500 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 240 mg to about 500 mg.In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 250 mg to about 500 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 260 mg to about 500 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 270 mg to about 500 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 280 mg to about 500 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 290 mg to about 500 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 300 mg to about 500 mg.

[0151] In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 50 mg to about 400 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 55 mg to about 400 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 60 mg to about 400 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 70 mg to about 400 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 80 mg to about 400 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 90 mg to about 400 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 100 mg to about 400 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 120 mg to about 400 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 130 mg to about 400 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 140 mg to about 400 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 150 mg to about 400 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 160 mg to about 400 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 170 mg to about 400 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 180 mg to about 400 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 190 mg to about 400 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 200 mg to about 400 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 210 mg to about 400 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 220 mg to about 400 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 230 mg to about 400 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 240 mg to about 400 mg.In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 250 mg to about 400 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 260 mg to about 400 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 270 mg to about 500 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 280 mg to about 400 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 290 mg to about 400 mg. In some embodiments, the amount of the JAK inhibitor administered on each day of administration is about 300 mg to about 400 mg.

[0152] In some embodiments, the JAK inhibitor is fedratinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is ruxolitinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is tofacitinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is oclacitinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is baricitinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is peficitinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is upadacitinib, or a pharmaceutically acceptable salt thereof.

[0153] In some embodiments, the method features administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and fedratinib, or a pharma- ceutically acceptable salt thereof, or ruxolitinib, or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (I) is administered in an amount of about 0.25 mg to about 6 mg, or about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 ...1 mg, about 3.2 mg, about 3.4 mg, about 3.5 mg, about

[0046] In some embodiments, the compound is administered in a daily dose of about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 237 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5.0 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, or 6 mg.

[0154] In some embodiments, the method features administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and fedratinib, or a pharma- ceutically acceptable salt thereof, wherein fedratinib is administered at a dose of about 25 mg to about 600 mg, or at a dose of about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about

[0036] In some embodiments, the compound is administered in a daily dose of about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, or about 600 mg.

[0155] In some embodiments, fedratinib, or a pharma- ceutically acceptable salt thereof, is administered with the compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a daily dose of 50 mg, 100 mg, 200 mg, 300, or 400 mg.

[0156] In some embodiments, the method features administering to the subject a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, and ruxolitinib, or a pharma- ceutically acceptable salt thereof, wherein ruxolitinib is administered at a dose of about 5 mg to about 100 mg, or about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 15 mg, about 16 mg, about 18 mg, about 20 mg, about 22 mg, about 24 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 34 mg, about 36 mg, or about 40 mg. g, about 38 mg, about 40 mg, about 42 mg, about 44 mg, about 46 mg, about 48 mg, about 50 mg, about 52 mg, about 54 mg, about 56 mg, about 58 mg, about 60 mg, about 62 mg, about 64 mg, about 66 mg, about 68 mg, about 70 mg, about 72 mg, about 74 mg, about 76 mg, about 78 mg, about 80 mg, about 82 mg, about 84 mg, about 86 mg, about 88 mg, about 90 mg, about 92 mg, about 94 mg, about 96 mg, about 98 mg or about 100 mg.

[0157] In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt thereof, is administered with a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a daily dose of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg or 60 mg.

[0158] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 0.25 mg, and fedratinib, or a pharma- ceutically acceptable salt and / or solvate (e.g., a hydrate) thereof, at a dose of 200 mg, 300 mg, or 400 mg.

[0159] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 0.25 mg, and fedratinib, or a pharma- ceutically acceptable salt and / or solvate (e.g., a hydrate) thereof, at a starting dose of 400 mg.

[0160] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 0.25 mg, and fedratinib, or a pharma- ceutically acceptable salt and / or solvate (e.g., a hydrate) thereof, at a dose of 400 mg.

[0161] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 0.5 mg, and fedratinib, or a pharma- ceutically acceptable salt and / or solvate (e.g., a hydrate) thereof, at a dose of 200 mg, 300 mg, or 400 mg.

[0162] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 0.5 mg, and fedratinib, or a pharma- ceutically acceptable salt and / or solvate (e.g., a hydrate) thereof, at a dose of 400 mg.

[0163] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 0.75 mg, and fedratinib, or a pharma- ceutically acceptable salt and / or solvate (e.g., a hydrate) thereof, at a dose of 200 mg, 300 mg, or 400 mg.

[0164] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 0.75 mg, and fedratinib, or a pharma- ceutically acceptable salt and / or solvate (e.g., a hydrate) thereof, at a dose of 400 mg.

[0165] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 1.0 mg, and fedratinib, or a pharma- ceutically acceptable salt and / or solvate (e.g., a hydrate) thereof, at a dose of 200 mg, 300 mg, or 400 mg.

[0166] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 1.0 mg, and fedratinib, or a pharma- ceutically acceptable salt and / or solvate (e.g., a hydrate) thereof, at a dose of 400 mg.

[0167] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 1.25 mg, and fedratinib, or a pharma- ceutically acceptable salt and / or solvate (e.g., a hydrate) thereof, at a dose of 200 mg, 300 mg, or 400 mg.

[0168] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 1.25 mg, and fedratinib, or a pharma- ceutically acceptable salt and / or solvate (e.g., a hydrate) thereof, at a dose of 400 mg.

[0169] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 1.5 mg, and fedratinib, or a pharma- ceutically acceptable salt and / or solvate (e.g., a hydrate) thereof, at a dose of 200 mg, 300 mg, or 400 mg.

[0170] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 1.5 mg, and fedratinib, or a pharma- ceutically acceptable salt and / or solvate (e.g., a hydrate) thereof, at a dose of 400 mg.

[0171] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 2.0 mg, and fedratinib, or a pharma- ceutically acceptable salt and / or solvate (e.g., a hydrate) thereof, at a dose of 200 mg, 300 mg, or 400 mg.

[0172] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 2.0 mg, and fedratinib, or a pharma- ceutically acceptable salt and / or solvate (e.g., a hydrate) thereof, at a dose of 400 mg.

[0173] In some embodiments, the subject being treated with a dose of 0.25 mg of a compound of formula (I), or a pharma- ceutically acceptable salt thereof; and a dose of 200 mg, 300 mg, or 400 mg of fedratinib, or a pharma- ceutically acceptable salt and / or solvate (e.g., hydrate) thereof, has relapsed or refractory disease or is intolerant to ruxolitinib.

[0174] In some embodiments, the subject being treated with a dose of 0.25 mg of a compound of formula (I), or a pharma- ceutically acceptable salt thereof; and a dose of 400 mg of fedratinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate) has relapsed or refractory disease or is intolerant to ruxolitinib.

[0175] In some embodiments, the subject being treated with a dose of 0.5 mg of a compound of formula (I), or a pharma- ceutically acceptable salt thereof; and a dose of 200 mg, 300 mg, or 400 mg of fedratinib, or a pharma- ceutically acceptable salt and / or solvate (e.g., hydrate) thereof, has relapsed or refractory disease or is intolerant to ruxolitinib.

[0176] In some embodiments, the subject being treated with a dose of 0.5 mg of a compound of formula (I), or a pharma- ceutically acceptable salt thereof; and a dose of 400 mg of fedratinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate) has relapsed or refractory disease or is intolerant to ruxolitinib.

[0177] In some embodiments, the subject being treated with a dose of 0.75 mg of a compound of formula (I), or a pharma- ceutically acceptable salt thereof; and a dose of 200 mg, 300 mg, or 400 mg of fedratinib, or a pharma- ceutically acceptable salt and / or solvate (e.g., hydrate) thereof, has relapsed or refractory disease or is intolerant to ruxolitinib.

[0178] In some embodiments, the subject being treated with a dose of 0.75 mg of a compound of formula (I), or a pharma- ceutically acceptable salt thereof; and a dose of 400 mg of fedratinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate) has relapsed or refractory disease or is intolerant to ruxolitinib.

[0179] In some embodiments, the subject being treated with a dose of 1.0 mg of a compound of formula (I), or a pharma- ceutically acceptable salt thereof; and a dose of 200 mg, 300 mg, or 400 mg of fedratinib, or a pharma- ceutically acceptable salt and / or solvate (e.g., hydrate) thereof, has relapsed or refractory disease or is intolerant to ruxolitinib.

[0180] In some embodiments, the subject being treated with a dose of 1.0 mg of a compound of formula (I), or a pharma- ceutically acceptable salt thereof; and a dose of 400 mg of fedratinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate) has relapsed or refractory disease or is intolerant to ruxolitinib.

[0181] In some embodiments, the subject being treated with a dose of 1.25 mg of a compound of formula (I), or a pharma- ceutically acceptable salt thereof; and a dose of 200 mg, 300 mg, or 400 mg of fedratinib, or a pharma- ceutically acceptable salt and / or solvate (e.g., hydrate) thereof, has relapsed or refractory disease or is intolerant to ruxolitinib.

[0182] In some embodiments, the subject being treated with a dose of 1.25 mg of a compound of formula (I), or a pharma- ceutically acceptable salt thereof; and a dose of 400 mg of fedratinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate) has relapsed or refractory disease or is intolerant to ruxolitinib.

[0183] In some embodiments, the subject being treated with a dose of 1.5 mg of a compound of formula (I), or a pharma- ceutically acceptable salt thereof; and a dose of 200 mg, 300 mg, or 400 mg of fedratinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate) has relapsed or refractory disease or is intolerant to ruxolitinib.

[0184] In some embodiments, the subject being treated with a dose of 1.5 mg of a compound of formula (I), or a pharma- ceutically acceptable salt thereof; and a dose of 400 mg of fedratinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate) has relapsed or refractory disease or is intolerant to ruxolitinib.

[0185] In some embodiments, the subject being treated with a dose of 2.0 mg of a compound of formula (I), or a pharma- ceutically acceptable salt thereof; and a dose of 200 mg, 300 mg, or 400 mg of fedratinib, or a pharma- ceutically acceptable salt and / or solvate (e.g., hydrate) thereof, has relapsed or refractory disease or is intolerant to ruxolitinib.

[0186] In some embodiments, the subject being treated with a dose of 2.0 mg of a compound of formula (I), or a pharma- ceutically acceptable salt thereof; and a dose of 400 mg of fedratinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate) has relapsed or refractory disease or is intolerant to ruxolitinib.

[0187] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 0.75 mg, and ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), at a dose of 5 mg, 10 mg, 15 mg, or 20 mg. In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), is administered twice daily.

[0188] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 0.75 mg, and ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate), at a starting dose of 15 mg. In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate), is administered twice daily.

[0189] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 0.75 mg, and ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), at a dose of 15 mg. In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), is administered twice daily.

[0190] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 1.0 mg, and ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), at a dose of 5 mg, 10 mg, 15 mg, or 20 mg. In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), is administered twice daily.

[0191] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 1.0 mg, and ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate), at a starting dose of 15 mg. In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate), is administered twice daily.

[0192] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 1.0 mg, and ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), at a dose of 15 mg. In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), is administered twice daily.

[0193] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 1.25 mg, and ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), at a dose of 5 mg, 10 mg, 15 mg, or 20 mg. In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), is administered twice daily.

[0194] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 1.25 mg, and ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate), at a starting dose of 15 mg. In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate), is administered twice daily.

[0195] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 1.25 mg, and ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), at a dose of 15 mg. In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), is administered twice daily.

[0196] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 1.5 mg, and ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), at a dose of 5 mg, 10 mg, 15 mg, or 20 mg. In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), is administered twice daily.

[0197] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 1.5 mg, and ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate), at a starting dose of 15 mg. In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate), is administered twice daily.

[0198] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 1.5 mg, and ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), at a dose of 15 mg. In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), is administered twice daily.

[0199] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 2.0 mg, and ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), at a dose of 5 mg, 10 mg, 15 mg, or 20 mg. In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), is administered twice daily.

[0200] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 2.0 mg, and ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate), at a starting dose of 15 mg. In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate), is administered twice daily.

[0201] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 2.0 mg, and ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), at a dose of 15 mg. In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), is administered twice daily.

[0202] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 3.0 mg, and ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), at a dose of 5 mg, 10 mg, 15 mg, or 20 mg. In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), is administered twice daily.

[0203] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 3.0 mg, and ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate), at a starting dose of 15 mg. In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate), is administered twice daily.

[0204] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 3.0 mg, and ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), at a dose of 15 mg. In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), is administered twice daily.

[0205] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 4.0 mg, and ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), at a dose of 5 mg, 10 mg, 15 mg, or 20 mg. In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), is administered twice daily.

[0206] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 4.0 mg, and ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate), at a starting dose of 15 mg. In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate), is administered twice daily.

[0207] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 4.0 mg, and ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), at a dose of 15 mg. In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), is administered twice daily.

[0208] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 4.5 mg, and ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), at a dose of 5 mg, 10 mg, 15 mg, or 20 mg. In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), is administered twice daily.

[0209] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 4.5 mg, and ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate), at a starting dose of 15 mg. In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate), is administered twice daily.

[0210] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 4.5 mg, and ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), at a dose of 15 mg. In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), is administered twice daily.

[0211] In some embodiments, the method comprises administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, at a dose of 2.0 mg, and ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), at a dose of 30 mg. In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., a hydrate), is administered twice daily.

[0212] In some embodiments, the subject treated with a compound of formula (I) or a pharmaceutically acceptable salt thereof at a dose of 0.75 mg; and ruxolitinib or a pharmaceutically acceptable salt and / or solvate thereof (e.g., hydrate) at a dose of 5 mg, 10 mg, 15 mg, or 20 mg is ruxolitinib-naive and other JAK inhibitor-naive. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt and / or solvate thereof (e.g., hydrate) is administered twice a day.

[0213] In some embodiments, the subject treated with a dose of 0.75 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof; and a starting dose of 15 mg of ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is ruxolitinib-naïve and naïve to other JAK inhibitors. In some embodiments, ruxolitinib, or a pharma-ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is administered twice daily.

[0214] In some embodiments, the subject treated with a dose of 0.75 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof; and a dose of 15 mg of ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is ruxolitinib-naïve and naïve to other JAK inhibitors. In some embodiments, ruxolitinib, or a pharma-ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is administered twice a day.

[0215] In some embodiments, the subject treated with a compound of formula (I) or a pharma- ceutically acceptable salt thereof at a dose of 1.0 mg; and ruxolitinib or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate) at a dose of 5 mg, 10 mg, 15 mg, or 20 mg is ruxolitinib-naïve and naïve to other JAK inhibitors. In some embodiments, ruxolitinib or a pharma-ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is administered twice daily.

[0216] In some embodiments, the subject treated with a dose of 1.0 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof; and a starting dose of 15 mg of ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is ruxolitinib-naïve and naïve to other JAK inhibitors. In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is administered twice daily.

[0217] In some embodiments, the subject treated with a dose of 1.0 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof; and a dose of 15 mg of ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is ruxolitinib-naïve and naïve to other JAK inhibitors. In some embodiments, ruxolitinib, or a pharma-ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is administered twice a day.

[0218] In some embodiments, the subject treated with a compound of formula (I) or a pharma- ceutically acceptable salt thereof at a dose of 1.25 mg; and ruxolitinib or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate) at a dose of 5 mg, 10 mg, 15 mg, or 20 mg is ruxolitinib-naïve and naïve to other JAK inhibitors. In some embodiments, ruxolitinib or a pharma-ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is administered twice a day.

[0219] In some embodiments, the subject treated with a dose of 1.25 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof; and a starting dose of 15 mg of ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is ruxolitinib-naïve and naïve to other JAK inhibitors. In some embodiments, ruxolitinib, or a pharma-ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is administered twice daily.

[0220] In some embodiments, the subject treated with a compound of formula (I) or a pharmaceutically acceptable salt thereof at a dose of 1.25 mg; and ruxolitinib or a pharmaceutically acceptable salt and / or solvate thereof (e.g., hydrate) at a dose of 15 mg is ruxolitinib-naive and other JAK inhibitor-naive. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt and / or solvate thereof (e.g., hydrate) is administered twice a day.

[0221] In some embodiments, the subject treated with a compound of formula (I) or a pharma- ceutically acceptable salt thereof at a dose of 1.5 mg; and ruxolitinib or a pharma-ceutically acceptable salt and / or solvate thereof (e.g., hydrate) at a dose of 5 mg, 10 mg, 15 mg, or 20 mg is ruxolitinib-naïve and naïve to other JAK inhibitors. In some embodiments, ruxolitinib or a pharma-ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is administered twice a day.

[0222] In some embodiments, the subject treated with a dose of 1.5 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof; and a starting dose of 15 mg of ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is ruxolitinib-naïve and naïve to other JAK inhibitors. In some embodiments, ruxolitinib, or a pharma-ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is administered twice daily.

[0223] In some embodiments, the subject treated with a dose of 1.5 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof; and a dose of 15 mg of ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is ruxolitinib-naïve and naïve to other JAK inhibitors. In some embodiments, ruxolitinib, or a pharma-ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is administered twice a day.

[0224] In some embodiments, the subject treated with a compound of formula (I) or a pharmaceutically acceptable salt thereof at a dose of 2.0 mg; and ruxolitinib or a pharmaceutically acceptable salt and / or solvate thereof (e.g., hydrate) at a dose of 5 mg, 10 mg, 15 mg, or 20 mg is ruxolitinib-naive and other JAK inhibitor-naive. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt and / or solvate thereof (e.g., hydrate) is administered twice a day.

[0225] In some embodiments, the subject treated with a dose of 2.0 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof; and a starting dose of 15 mg of ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is ruxolitinib-naïve and naïve to other JAK inhibitors. In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is administered twice daily.

[0226] In some embodiments, the subject treated with a dose of 2.0 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof; and a dose of 15 mg of ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is ruxolitinib-naïve and naïve to other JAK inhibitors. In some embodiments, ruxolitinib, or a pharma-ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is administered twice a day.

[0227] In some embodiments, the subject treated with a compound of formula (I) or a pharmaceutically acceptable salt thereof at a dose of 3.0 mg; and ruxolitinib or a pharmaceutically acceptable salt and / or solvate thereof (e.g., hydrate) at a dose of 5 mg, 10 mg, 15 mg, or 20 mg is ruxolitinib-naive and other JAK inhibitor-naive. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt and / or solvate thereof (e.g., hydrate) is administered twice a day.

[0228] In some embodiments, the subject treated with a dose of 3.0 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof; and a starting dose of 15 mg of ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is ruxolitinib-naïve and naïve to other JAK inhibitors. In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is administered twice daily.

[0229] In some embodiments, the subject treated with a 3.0 mg dose of the compound of formula (I), or a pharma- ceutically acceptable salt thereof; and a 15 mg dose of ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is ruxolitinib-naïve and other JAK inhibitor-naïve. In some embodiments, ruxolitinib, or a pharma-ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is administered twice daily.

[0230] In some embodiments, the subject treated with a compound of formula (I) or a pharma- ceutically acceptable salt thereof at a dose of 4.0 mg; and ruxolitinib or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate) at a dose of 5 mg, 10 mg, 15 mg, or 20 mg is ruxolitinib-naïve and naïve to other JAK inhibitors. In some embodiments, ruxolitinib or a pharma-ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is administered twice daily.

[0231] In some embodiments, the subject treated with a dose of 4.0 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof; and a starting dose of 15 mg of ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is ruxolitinib-naïve and naïve to other JAK inhibitors. In some embodiments, ruxolitinib, or a pharma-ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is administered twice daily.

[0232] In some embodiments, the subject treated with a compound of formula (I) or a pharma- ceutically acceptable salt thereof at a dose of 4.0 mg; and ruxolitinib or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate) at a dose of 15 mg is ruxolitinib-naïve and is naïve to other JAK inhibitors. In some embodiments, ruxolitinib or a pharma-ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is administered twice a day.

[0233] In some embodiments, the subject treated with a compound of formula (I) or a pharmaceutically acceptable salt thereof at a dose of 4.5 mg; and ruxolitinib or a pharmaceutically acceptable salt and / or solvate thereof (e.g., hydrate) at a dose of 5 mg, 10 mg, 15 mg, or 20 mg is ruxolitinib-naive and other JAK inhibitor-naive. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt and / or solvate thereof (e.g., hydrate) is administered twice a day.

[0234] In some embodiments, the subject treated with a dose of 4.5 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof; and a starting dose of 15 mg of ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is ruxolitinib-naïve and naïve to other JAK inhibitors. In some embodiments, ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is administered twice daily.

[0235] In some embodiments, the subject treated with a compound of formula (I) or a pharmaceutically acceptable salt thereof at a dose of 4.5 mg; and ruxolitinib or a pharmaceutically acceptable salt and / or solvate thereof (e.g., hydrate) at a dose of 15 mg is ruxolitinib-naive and is naive to other JAK inhibitors. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt and / or solvate thereof (e.g., hydrate) is administered twice a day.

[0236] In some embodiments, the subject treated with a dose of 2.0 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof; and a dose of 30 mg of ruxolitinib, or a pharma- ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is ruxolitinib-naïve and other JAK inhibitor-naïve. In some embodiments, ruxolitinib, or a pharma-ceutically acceptable salt and / or solvate thereof (e.g., hydrate) is administered twice a day.

[0237] Pharmaceutical Compositions The BET inhibitors and JAK inhibitors used in the methods and kits described herein can be formulated into pharmaceutical compositions suitable for administration. Pharmaceutical compositions may contain pharmaceutically acceptable additives. As used herein, pharmaceutically acceptable additives include, but are not limited to, any and all solvents, dispersion media, or other liquid vehicles, dispersion or suspension aids, diluents, granulating and / or dispersing agents, surfactants, isotonicity agents, thickening or emulsifying agents, preservatives, binders, lubricants or oils, coloring agents, sweeteners or flavoring agents, stabilizers, antioxidants, antibacterial or antifungal agents, osmotic pressure adjusting agents, pH adjusting agents, buffers, chelants, cryoprotectants, and / or bulking agents, as appropriate for the particular dosage form desired. Various excipients for formulating pharmaceutical compositions and techniques for preparing compositions are known in the art (see Remington: The Science and Practice of Pharmacy, 21st Ed., AR Gennaro (Lippincott, Williams & Wilkins, Baltimore, MD), 2006; incorporated by reference in its entirety).

[0238] Any of the therapeutic agents described herein can be in the form of pharmaceutically acceptable salt.The examples of pharmaceutically acceptable salt include, but are not limited to, mineral acid or organic acid salt of basic group (such as amine); and alkali or organic salt of acidic group (such as carboxylic acid).Pharmaceutically acceptable salt includes conventional non-toxic salt or, for example, quaternary ammonium salt of parent compound formed from non-toxic inorganic or organic acid. For example, such conventional non-toxic salts include those prepared from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; and from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isethionic acid.

[0239] The pharma- ceutically acceptable salts of the present invention can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Usually, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Usually, non-aqueous solvents such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of suitable salts can be found in Remington: The Science and Practice of Pharmacy, 22nd Edition, Allen, LV Jr., Ed.; Pharmaceutical Press, London, UK (2012), the disclosure of which is incorporated herein by reference.

[0240] The pharmaceutical composition may include a pharma- ceutically acceptable carrier. As used herein, "pharma-ceutically acceptable carrier" refers to a substance that is compatible with the recipient (human) and is suitable for delivering the active agent to the target site without terminating the activity of the agent. Any toxicity or adverse effects associated with the carrier are preferably commensurate with a reasonable risk / benefit ratio for the intended use of the active agent.

[0241] Pharmaceutically acceptable carriers which may be used in these compositions include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates or carbonates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene polyoxypropylene block polymers, polyethylene glycol and wool fat.

[0242] Pharmaceutical compositions for use in the methods of the present disclosure may be prepared by methods well known in the art, such as, inter alia, conventional granulation, mixing, dissolving, encapsulation, lyophilization, or emulsification processes. The compositions may be made in various forms, such as granules, precipitates, or particulates, powders (such as freeze-dried, rotary dried, or spray-dried powders), amorphous powders, tablets, capsules, syrups, suppositories, injectables, emulsions, elixirs, suspensions, or solutions. The formulations may include stabilizers, pH adjusters, surfactants, solubilizers, bioavailability modifiers, and combinations thereof. These pharmaceutical compositions are formulated for pharmaceutical administration to humans. Such compositions may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccal, vaginally, or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intraperitoneal, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In some embodiments, the composition is administered orally, intravenously or subcutaneously. In some embodiments, the composition is administered orally. In some embodiments, the composition is administered intravenously. In some embodiments, the intravenous administration can be intravenous infusion or intravenous injection. In some embodiments, the composition is administered by intravenous infusion. In some embodiments, the composition is administered by intravenous injection. In some embodiments, the composition is administered by subcutaneous injection. In some embodiments, the composition is administered by intravenous infusion followed by subcutaneous injection. These formulations can be designed to be short-acting, fast-releasing, or long-acting. Additionally, the composition can be administered in a local rather than systemic manner, such as administration (e.g., by injection) at the tumor site.

[0243] Pharmaceutical preparations can be prepared as liquid suspensions or solutions using liquids such as oil, water, alcohol, and combinations thereof. Solubilizers such as cyclodextrin can be included. Pharmaceutically suitable surfactants, suspending agents, or emulsifying agents can be added for oral or parenteral administration. Suspensions can include oils such as peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil. Suspension preparations can also include esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides. Suspension preparations can include alcohols such as ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol, and propylene glycol; ethers such as poly(ethylene glycol); petroleum hydrocarbons such as mineral oil and petrolatum; and water.

[0244] Sterile injectable forms of these pharmaceutical compositions may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents (e.g., as a solution in 1,3 butanediol). Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic saline. In addition, sterile fixed oils are conventionally used as solvents or suspending agents. For this purpose, any bland fixed oil may be used, such as synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharma- ceutical acceptable oils such as olive oil or castor oil, especially their polyoxyethylated versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants that are commonly used in the formulation of pharma- ceutically acceptable dosage forms, such as emulsions and suspensions. Other commonly used surfactants, such as sorbitan alkyl esters (e.g., Tween or Span), and other emulsifiers or bioavailability enhancers that are commonly used in the manufacture of pharma-ceutically acceptable solid, liquid, or other dosage forms, may also be used for the formulation. The compounds may be formulated for parenteral administration by injection, such as by bolus injection or continuous infusion. The unit dosage form for injection may be in ampoules or in multi-dose containers.

[0245] These pharmaceutical compositions can be orally administered in any orally acceptable dosage form, such as capsules, tablets, aqueous suspensions or solutions. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If necessary, certain sweeteners, flavorings or colorings may also be added. For oral administration in capsules, useful diluents include lactose and dried cornstarch. For tablets for oral use, commonly used carriers include lactose and cornstarch. Lubricants such as magnesium stearate are also usually added. Coatings can be used for various purposes, such as masking taste, affecting the site of dissolution or absorption, or prolonging the drug action. Coatings can be applied to tablets or to granular particles for use in capsules.

[0246] Alternatively, these pharmaceutical compositions can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating additive that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum and releases the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0247] These pharmaceutical compositions may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, such as diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0248] Topical application to the lower intestinal tract may be in a rectal suppository formulation (see above) or a suitable enema formulation. A topical transdermal patch may also be used. For topical application, the pharmaceutical composition may be formulated into a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present disclosure include mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition may be formulated into a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharma- ceutically acceptable carriers. Suitable carriers include mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol, and water.

[0249] For ophthalmic use, the pharmaceutical composition may be formulated as a micronized suspension in isotonic pH-adjusted sterile saline or, preferably, as a solution in isotonic pH-adjusted sterile saline, with or without a preservative, such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated in an ointment, such as petrolatum.

[0250] Pharmaceutical compositions may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, utilizing benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0251] In some embodiments, the compound of formula (I) can be formulated as a solution for intravenous infusion. In some embodiments, the compound of formula (I) is formulated in a solution with a buffer or pH adjuster and a cyclodextrin, such as beta cyclodextrin. In some embodiments, the solution comprises phosphoric acid and Captisol (betadex sulfobutyl ether sodium) in water. In some embodiments, the solution for intravenous infusion comprises the compound of formula (I) at 10 mg / mL.

[0252] In some embodiments, the compound of formula (I) is formulated as a pharmaceutical product, wherein said pharmaceutical product comprises the compound of formula (I) in an aqueous solution of phosphoric acid and Captisol (betadex sulfobutyl ether sodium). In some embodiments, the pharmaceutical product is packaged with a 10 mL volume of a sterile solution of the compound of formula (I).

[0253] In some embodiments, the JAK inhibitor is formulated as a solution for injection.

[0254] In some embodiments, the present disclosure relates to a pharmaceutical composition comprising a compound of (I), or a pharma- ceutically acceptable salt thereof, and a JAK inhibitor for treating or preventing cancer in a subject in need of such treatment or prevention. In some embodiments, the present disclosure relates to a pharmaceutical composition comprising a compound of (I), or a pharma- ceutically acceptable salt thereof, and a JAK inhibitor for treating or preventing cancer in a subject in need of such treatment or prevention. In some embodiments, the pharmaceutical composition is formulated for simultaneous or sequential administration of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, and the JAK inhibitor. In some embodiments, the pharmaceutical composition is formulated for simultaneous or sequential administration of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, and the JAK inhibitor.

[0255] kit In some embodiments, the BET inhibitors or JAK inhibitors described herein can be manufactured for inclusion in a kit. A "kit" is any article of manufacture (e.g., package or container) that contains at least one reagent or chemotherapeutic agent. A kit for use in the methods described herein may include a BET inhibitor, such as a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the kit may further include a JAK inhibitor. In some embodiments, the kit may include a compound of formula (I), or a pharmaceutically acceptable salt thereof, a JAK inhibitor. In some embodiments, the kit may include one or more BET inhibitors, or a pharmaceutically acceptable salt thereof. In some embodiments, the kit may include one or more JAK inhibitors.

[0256] In some embodiments, the present disclosure relates to a kit comprising a drug for treating cancer in a patient who needs such treatment.The kit comprises a drug comprising a BET inhibitor, and instructions for administering a BET inhibitor and a JAK inhibitor; or the kit comprises a drug comprising a JAK inhibitor, and instructions for administering a JAK inhibitor and a BET inhibitor.The kit may comprise a drug comprising a BET inhibitor and a JAK inhibitor, and instructions for administering a BET inhibitor and a JAK inhibitor. EXAMPLES

[0257] Example 1 - Antiproliferative Effects of Compound (I) and JAK Inhibitors in Myelofibrosis Cell Lines HEL92.1.792.1.7 and SET-2 are post-MPN secondary acute myeloid leukemia (sAML) cell lines that harbor the JAK2 V617F mutation and serve as cell line models of the malignant clone that drives disease in MPNs.

[0258] HEL92.1.792.1.7 (post-MPN sAML), homozygous mutant (V617F), SET-2 (post-MPN sAML), and heterozygous mutant (V617F) were cultured in Roswell Park Memorial Institute (RPMI) 1640 medium (ATCC) supplemented with 10% or 20% fetal bovine serum (FBS) (Corning), 2 mM L-glutamine (L-glu) (Gibco), and non-essential amino acids 1X (NEAA) cell culture supplement (Gibco) for HEL92.1.792.17 or SET-2, respectively. WI-38 Primary lung fibroblasts WI-38 were cultured in Eagle's Minimum Essential Medium (EMEM) (ATCC) with 10% FBS, 2 mM L-glu, and 1X NEAA. Cells were treated with compound (I) as a single agent and in combination with ruxolitinib (Rux) or fedratinib (Fed) to examine antiproliferative activity and cytotoxicity.

[0259] Cell proliferation was quantified in duplicate in the three cell types using CellTiter-Glo® (CTG), a fluorescent dye that measures adenosine-5'-triphosphate (ATP). Compound (I) was pre-spotted in 384-well plates (diluted in dimethylsulfoxide [DMSO] at a final concentration of 0.1% in an assay volume of 50 μL). A 10-point dose response was tested for each cell line, starting at 1 μM, with 4-fold dilutions, one point for DMSO, and nine points for drug. For each Compound (I) 10-point dose response curve (DRC), JAK inhibitors (JAKi) Rux and Fed were also pre-spotted at concentrations of 0, 0.03, 0.1, 0.3, and 0.6 μM, and HEL92.1.7 at a fixed concentration, generating five Compound of Formula (I) DRCs for each JAKi in each cell line.

[0260] A volume of 50 μL of cell suspension at each seeding density was added to 384-well plates containing compound (I) + JAKi. After 3 days of incubation, the effect of compound (I) alone or in combination with JAKi on cell proliferation / viability was evaluated. 25 microliters of CTG per well was then dispensed into the cell suspension and after 30 minutes of incubation, ATP released by live cells was measured as light units (RLU) using an EnVision plate reader (PerkinElmer, Covina, CA). Cytotoxicity was indicated by lower ATP levels in the culture medium after 3 days of drug treatment compared to ATP levels at day 0. Day 0 CTG was read for HEL92.1. and SET-2 suspension cell lines, but day 0 CTG could not be read for WI-38 since it is an adherent cell line.

[0261] Proliferation rates (% proliferation) were calculated by the equation [% proliferation = (RLU on day 5-RLU on day 0) / (RLU on day 0)], and percent DMSO (% DMSO) was calculated by the equation [% DMSO = (treatment RLU / DMSO RLU) x 100]. All data were analyzed with an XY analysis nonlinear regression curve fit in GraphPad Prism 7 using the parameters "log(inhibitor) vs. response - Variable slope (four parameters)". Cytotoxicity was called when any fraction of the DRC CTG signal fell below the day 0 CTG reading, and cytostatic effects were indicated by the DRC CTG signal remaining above the day 0 line.

[0262] Combination analyses were performed with the software Combenefit version 2.021. Combination matrix plots describing additive effects were generated with the Highest Single-Agent (HSA) model, and combination matrix plots describing synergistic effects were generated with the Bliss model, and HSA and Bliss scores for each combination matrix plot were tabulated. Arbitrary cutoff values ​​of 10 were used for HSA and Bliss scores to reflect significant additive and synergistic effects, respectively.

[0263] Finally, the compound (I) dose-response curves (DRC) plus the relative 50% inhibitory concentration (IC50) values ​​of Rux or Fed were plotted to account for any changes in potency that may support the calculated additive / synergistic scores. The additive and synergistic scores reported did not take into account the value of antagonism.

[0264] Compound (I) exhibited a single agent IC50 of 6.2 nM in HEL92.1.7 with cytotoxic effects and the addition of a fixed concentration of Rux resulted in a change in potency (Figures 1A, 1B).

[0265] Compound (I) dose-response curves with Rux in HEL92.1.7 showed additive effects with an HSA additivity score of 15.8 (FIG. 2A) and a Bliss synergy score of 7.6 (FIG. 2B), with an optimal dose of 4 nM compound of formula (I)+600 nM Rux.

[0266] Compound (I) exhibited a single agent IC50 of 1.9 nM in SET-2 with cytotoxic effects, and addition of a fixed concentration of Rux resulted in potency changes (Figures 3A, 3B).

[0267] Compound (I) dose-response curves with Rux in SET-2 showed additive effects with an HSA additivity score of 20.5 (Figure 4A) and a Bliss synergy score of 5.8 (Figure 4B), with the optimal dose being 1 nM compound (I) + 30 nM Rux.

[0268] Comparison of compound (I) dose-response curves with Rux in JAK2 mutant post-MPN sAML lines (HEL92.1.792.1.7 and SET-2) and the JAK2 wild-type, adherent WI-38 fibroblast cell line suggested a potential therapeutic window for compound (I)- / +Rux (Figures 5A, 5B, and 5C).

[0269] In a second series of experiments, compound (I) exhibited a single agent IC50 of 5.6 nM in HEL92.1.792.1.7 with no cytotoxic effects, and the addition of a fixed concentration of fedratinib (Fed) resulted in no change in potency (Figures 6A, 6B).

[0270] Compound (I) dose-response curves with Fed in HEL92.1.7 showed additive effects with an HSA additivity score of 13.9 (FIG. 7A) and a Bliss synergy score of 5.4 (FIG. 7B), with an optimal dose of 16 nM compound (I)+600 nM.

[0271] In SET-2 cells, compound (I) exhibited a single-agent IC50 of 1.9 nM with no cytotoxic effects, and addition of a fixed concentration of Fed resulted in little change in potency (Figures 8A, 8B).

[0272] The dose-response curve of Compound (I) with Fed in SET-2 showed synergy with an HSA additivity score of 28.9 (Figure 9A) and a Bliss synergy score of 16.9 (Figure 9B), with the optimal dose being 1 nM Compound (I) + 600 nM Fed.

[0273] Comparison of compound (I) dose-response curves with Fed in the JAK2 mutant MPN post-sAML lines, HEL92.1.792.1.7 and SET-2, and the JAK2 wild-type, adherent WI-38 fibroblast cell line suggested a potential therapeutic window for compound (I)- / +Fed (Figures 10A, 10B, and 10C).

[0274] These results demonstrated that Compound (I) was active as a single agent and in combination with Rux and Fed in the post-MPN sAML cell lines, HEL92.1.7 and SET-2.

[0275] Example 2 - Evaluation of the efficacy of Compound (I) as a single agent or in combination with fedratinib (Fed) or ruxolitinib (Rux) in primary myelofibrosis (MF) samples Bone marrow or peripheral blood mononuclear cells from myelofibrosis (MF) patients were seeded directly into semi-solid Methocult medium (H3404) containing compound (I) alone (at concentrations of 1.25-10 nM) or together with Fed (at 100 and 300 nM) or Rux (at 30 and 100 nM). Treatments were added initially and maintained throughout the 14-day incubation period without compound washout.

[0276] To test the effect of compound (I) on the functionality of normal hematopoietic progenitor cells, colony formation assays were performed on bone marrow CD34 cells from healthy volunteers using the same treatment conditions as described for MF samples. + This was also done in cells.

[0277] Colony forming unit (CFU) data collection and automated colony counting were performed using a STEMvision device and software (StemCell Technologies, Vancouver, Canada). Correction of counts according to standard criteria was performed manually by trained users. GraphPad Prism 7 was used for data plotting and analysis.

[0278] Differential sensitivity to compound (I) was observed among the 10 primary human myelofibrosis samples (Figure 11). IC50 values ​​for inhibition of colonies ranged from 1.25 to 4.46 nM (Figure 11).

[0279] Evaluation of the effect of compound (I) on normal progenitor cells using colony formation assays showed a decrease in the functionality of both granulocyte macrophage CFU (CFU-GM) and burst forming cell erythroid (BFU-E). Results showed IC50 values ​​for inhibition of CFU-GM and BFU-E that were comparable in magnitude between donors and within the range of 3 and 2.3 nM (Figures 12A and 12B).

[0280] To analyze the beneficial effects of compound (I) on MF cells versus normal bone marrow progenitor cells, a score called the therapeutic index (TI) was calculated based on the IC50 in each MF sample versus normal bone marrow CD34 cells. + The therapeutic index values ​​were calculated as the ratio of the mean IC50 in MF cells to the mean IC50 in MF cells. As shown in Table 1, the therapeutic index values ​​were greater than 1-fold in 7 of the 10 MF samples tested, and sensitivity to compound (I) was not clearly associated with JAK2 mutation status. [Table 1]

[0281] To further explore the therapeutic potential of compound (I) in MF, the compound was also tested in combination with Fed or Rux using colony formation assays in primary cells from both MF patients and healthy donors.

[0282] The number of normal progenitor cells was reduced by the combination of Compound (I) and both JAK2 inhibitors (Figures 13A and 13B).

[0283] An enhanced effect of the combination of Compound (I) and Fed on colony formation of cells from myelofibrosis patients was observed (FIG. 14A).

[0284] As shown in Table 2, moderate synergistic / additive effects of the combination of Compound (I) and Fed were observed in 8 out of 10 samples, but these effects were not accompanied by improved TI. Samples that showed no effect when Compound (I) and Fed were combined were resistant to Fed (bold). [Table 2]

[0285] Combination with Rux enhanced the activity of compound (I) in 6 of 10 MF samples. However, when comparing the effect to that in normal progenitor cells, the improvement in TI provided by this combination was observed in only one sample (Figure 14B, MF22). Samples that showed no effect when compound (I) and Rux were combined were highly resistant to Rux (bold; Table 3). [Table 3]

[0286] Example 3 - Phase IB / 2 Study of Compound (I) (also known as Compound (1)) Alone or in Combination with Ruxolitinib or Fedratinib in Participants with Intermediate or High Risk Myelofibrosis Objectives and Endpoints: [Table 4]

[0287] Overall Design: The study is a multicenter, open-label, phase 1b / 2 dose-escalation and expansion study in participants with intermediate- or high-risk PMF, post-polycythemia vera MF, or post-essential thrombocythemia MF.

[0288] The study consisted of three periods:

[0289] Screening Period of Up to 28 Days: The screening period begins when the informed consent form is signed and continues for up to 28 days (+3 days) prior to administration of study treatment 1.

[0290] Treatment duration: Part 1: Dose escalation Part 1A - Ruxolitinib combination cohort (Compound (I) + ruxolitinib) and Part 1B - Fedratinib combination cohort (Compound (I) + Fedratinib), followed by Part 2: Dose expansion Part 2A1-ruxolitinib combination cohort (Compound (I) + ruxolitinib) Part 2A2 - Add-on to ruxolitinib cohort (Compound (I) + ruxolitinib) and Randomized Part 2B1 - Fedratinib combination arm (Compound (I) + Fedratinib) vs. Part 2B2 - Compound (I) monotherapy arm (Compound (I) alone) Safety Follow-Up: The first visit will be 28 days after the last dose of Compound (I), with subsequent visits scheduled every 30 days (± 7 days) up to 90 days after the last dose of Compound (I). Survival follow-up period: 2 years for all cohorts / arms. Participants will be followed every 3 months (± 2 weeks) thereafter for survival follow-up for up to 2 years or until death, withdrawal of consent, loss to follow-up, or end of the study, whichever occurs first.

[0291] A schematic of the study design is shown in Figures 15A and 15B.

[0292] Example 4 - Caspase 3 / 7 Incucyte Live Cell Assay For single and combination drug experiments, cells were seeded in 96-well plates at 5,000 cells per well in 100 μL of 1:1000 caspase 3 / 7 green dye (Essen Bioscience, Ann Arbor, MI, USA) culture medium containing either 0.1% DMSO, various concentrations of drugs, or a combination of BET and JAK inhibitors for 5 days.

[0293] Cells were placed in an Incucyte Zoom System (Essen Bioscience, Ann Arbor, MI, USA) and programmed to capture images every 4 hours for 5 days (120 hours), after which cells were analyzed using Incucyte Zoom 2018A Software.

[0294] The results of the CellTiter-Glo® (CTG) assay (Promega Corporation, Madison, WI, USA) are expressed as the mean proliferation rate ± SD in triplicates. IC50 sigmoid curves were calculated from active compounds using the nonlinear regression (three parameters) statistical software package GraphPad Prism 8 (GraphPad Software, La Jolla, CA, USA). The graph shows the sigmoid curve for IC50 calculation of a representative experiment.

[0295] Caspase 3 / 7 Incucyte live cell imaging results are expressed as the mean caspase 3 / 7 counts (1 / image) ± SD from duplicates of a representative experiment.

[0296] As shown in Figures 16 and 17, the combination of Compound (I) and Fedratinib or Compound (I) and Ruxolitinib activated caspase-3 at a greater rate than Fedratinib or Ruxolitinib alone, indicating that the combination efficiently induces cell death / apoptosis. Figures 18A and 18B quantitate the data from Figures 16 and 17 at 120 hours.

[0297] Example 5 - Cell viability assay Cells were seeded in 96-well plates at 10,000 cells per well in 100 μL of culture medium containing either 0.1% DMSO or various concentrations of drugs. Cell viability was determined after 3 and 5 days with the CellTiter GloLuminescent Cell Viability Assay from Promega (Madison, WI) according to the manufacturer's protocol. Specifically, 50 μL of reagent was added to each well, and the plate was incubated in the dark for 10 min to stabilize the luminescent signal. Luminescence was then detected using a chemiluminescence detection system (EnVision Multimode Microplate Reader; PerkinElmer).

[0298] Compound (I) exhibited a single agent IC50 of 15 nM and 19 nM on days 3 and 5 in HEL92.1.7, respectively (Figures 19A and 19B).

[0299] Compound (I) exhibited a single agent IC50 of 2.8 nM and 2.4 nM on days 3 and 5 in SET-2, respectively (Figures 20A and 20B).

[0300] A comparison of compound (I) with the known BET inhibitor CPI-0610 in HEL92.1.7 and SET-2 cells is shown in Figures 19A and 19B, respectively. As shown in these figures, compound (I) showed superior activity against both cell lines compared to CPI-0610.

[0301] Example 6 - PK Study - Compound (I) Compound (I) was studied in first-in-human trials in certain advanced and hematological malignancies. PK data were available from 65 subjects across five doses and three schedules. Intensive samples were collected on day 1 of cycle 1 and days 5, 7, or 14 of cycle 2 based on the dosing schedule (5 days on / 2 days off, 7 days on / 14 days off, and 14 days on / 7 days off). PK data for the days on / 2 days off schedule are shown in Table 4. The terminal half-life of a single dose of Compound (I) during this dosing schedule was found to be approximately 64 hours. [Table 5]

[0302] In contrast, clinical trials in which CPI-0610 was administered at 125 mg QD demonstrated a Cmax of 4 micromolar and a T of 16 hours. 1 / 2 showed.

[0303] It is understood that the Detailed Description section, and not the Summary and Abstract sections, are intended to be used to interpret the claims. The Summary and Abstract sections may set forth one or more, but not all, representative aspects of the disclosure as contemplated by the inventors, and are therefore not intended to limit the scope of the disclosure and the appended claims in any way.

[0304] The present disclosure has been described above with functional components that illustrate the implementation of the specified functions and their relationships. The boundaries of these functional components have been arbitrarily defined herein for the convenience of description. Alternative boundaries may be defined so long as the specified functions and their relationships are appropriately implemented.

[0305] The description of the specific embodiments set forth above sufficiently reveals the overall nature of the disclosure so that others may, by applying knowledge within the skill of the art, easily modify and / or adapt such specific embodiments for various applications without undue experimentation and without departing from the overall concept of the disclosure. Thus, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed embodiments based on the teaching and guidance presented herein. It is to be understood that the language or terminology herein is intended to be descriptive rather than limiting, as it should be interpreted by those skilled in the art in light of the teaching and guidance.

[0306] The breadth and scope of the present disclosure should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

Claims

1. 1. A medicament for treating a hematopoietic malignancy in a subject, the medicament comprising: Compounds of formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof; The compound of formula (I) or a pharma- ceutically acceptable salt thereof Compound of formula (II): 【Chemistry 2】 or a pharma- ceutically acceptable salt and / or solvate thereof A pharmaceutical agent characterized in that it is used to be administered in combination with

2. The method according to claim 1, characterized in that the compound of formula (I), or a pharma- ceutically acceptable salt thereof, and the compound of formula (II), or a pharma- ceutically acceptable salt and / or solvate thereof, are used for simultaneous administration.

3. The method according to claim 1, characterized in that the compound of formula (I), or a pharma- ceutically acceptable salt thereof, and the compound of formula (II), or a pharma- ceutically acceptable salt and / or solvate thereof, are used for sequential administration.

4. The method according to any one of claims 1 to 3, wherein the administration of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and a compound of formula (II), or a pharma- ceutically acceptable salt and / or solvate thereof, results in a synergistic effect.

5. The pharmaceutical agent according to any one of claims 1 to 4, characterized in that the compound of formula (I), or a pharma- ceutically acceptable salt thereof, and the compound of formula (II), or a pharma- ceutically acceptable salt and / or solvate thereof, are each used for oral administration.

6. The method according to any one of claims 1 to 5, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered at a dose of about 0.1 mg to about 10 mg.

7. The method according to any one of claims 1 to 6, characterized in that the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is used to be administered at a dose of about 0.25 mg to about 4.5 mg.

8. The method according to any one of claims 1 to 7, characterized in that the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is used to be administered in a dose of 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.25 mg, 1.5 mg, or 2.0 mg.

9. The method according to any one of claims 1 to 8, characterized in that the compound of formula (II) or its pharma- ceutically acceptable salt and / or solvate is used to be administered in an amount of about 50 mg to about 500 mg.

10. The method according to any one of claims 1 to 9, characterized in that the compound of formula (II) or its pharma- ceutically acceptable salts and / or solvates is used to be administered in an amount of about 400 mg.

11. The method according to any one of claims 1 to 10, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered once a day.

12. The method according to any one of claims 1 to 11, characterized in that the compound of formula (II) or its pharma- ceutically acceptable salt and / or solvate is used to be administered once a day.

13. The pharmaceutical agent according to any one of claims 1 to 12, characterized in that it is used for administering a compound of formula (II) or a pharma- ceutically acceptable salt and / or hydrate thereof.

14. The method according to any one of claims 1 to 13, characterized in that the dihydrochloride monohydrate of the compound of formula (II) is administered.

15. The drug according to any one of claims 1 to 14, wherein the hematopoietic tumor is a myeloproliferative tumor.

16. The method of claim 15, wherein the myeloproliferative neoplasm is myelofibrosis.

17. The method of claim 16, wherein the myelofibrosis is relapsed / refractory myelofibrosis.

18. The method of any one of claims 1 to 17, wherein the subject is treatment naive.

19. The method of any one of claims 1 to 17, wherein the subject has previously been treated with ruxolitinib.

20. The method of claim 16, wherein the myelofibrosis is primary myelofibrosis.

21. The method of claim 20, wherein the primary myelofibrosis is selected from intermediate-risk primary myelofibrosis and high-risk primary myelofibrosis.

22. The method of claim 16, wherein the myelofibrosis is secondary myelofibrosis.

23. The method of claim 16, wherein the myelofibrosis is post-essential thrombocythemia myelofibrosis.

24. The method of claim 16, wherein the myelofibrosis is post-polycythemia vera myelofibrosis.

25. The method of claim 15, wherein the myeloproliferative neoplasm is polycythemia vera.

26. The method of claim 15, wherein the myeloproliferative neoplasm is essential thrombocythemia.

27. The drug according to any one of claims 1 to 14, wherein the hematopoietic tumor is acute myeloid leukemia (AML).

28. Compounds of formula (I): 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof; and Compound of formula (II): 【Chemistry 4】 or a pharma- ceutically acceptable salt and / or solvate thereof A composition comprising:

29. 30. Use of the composition according to claim 28 for the manufacture of a medicament for the treatment of hematopoietic tumors.

30. 30. A pharmaceutical composition comprising the composition of claim 28 and a pharma- ceutically acceptable carrier.

31. 31. The pharmaceutical composition of claim 30 for use in the treatment of hematopoietic malignancies.

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