EP4698182A1

EP4698182A1 - Combination of a menin-ll1 inhibitor, a dna intercalating agent and a pyrimidine analogue to treat a hematopoietic disorder

Info

Publication number: EP4698182A1
Application number: EP24720124.7A
Authority: EP
Inventors: Christina Diane GUTTKE; Laura BARREYRO; Lucille Angela FERRANTE; Kathryn Elizabeth Packman
Original assignee: Janssen Pharmaceutica NV
Current assignee: Janssen Pharmaceutica NV
Priority date: 2023-04-17
Filing date: 2024-04-16
Publication date: 2026-02-25
Also published as: IL323944A; MX2025012388A; CN120957725A; TW202448429A; AU2024258892A1; KR20250170131A; WO2024218072A1

Abstract

The present invention relates to combinations comprising a therapeutically effective amount of a menin-mixed-lineage leukemia 1 (menin-MLL) inhibitor; and a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog; as well as to methods for treating a subject diagnosed with cancer using such combinations.

Description

COMBINATION THERAPIES FIELD OF THE INVENTION The present invention relates to combinations comprising a therapeutically effective amount of a menin-mixed-lineage leukemia 1 (menin-MLL) inhibitor; and a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog; as well as to methods for treating a subject diagnosed with cancer using such combinations. BACKGROUND OF THE INVENTION Cancer is the leading cause of death worldwide. Of the 10 million cancer deaths recorded by GLOBOCAN in 2020, 7.1% are attributed to hematopoietic disorders. Accordingly, new treatment modalities are urgently needed for hematopoietic disorders, including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and acute lymphoblastic leukemia (ALL) as further detailed below. AML is a common hematological malignancy whose incidence rises from 3:100,000 in young adults to greater than 20:100,000 in older adults. For patients <60 years of age, overall survival (OS) is 40 to 50%, but is only 5% for patients >60 years of age. The majority of newly diagnosed patients with AML are over the age of 60. In this patient population, standard induction chemotherapy is often not an option due to increased treatment-related mortality as a result of age and co-morbidities. Standard of care for AML patients unfit for combination chemotherapy is treatment with hypomethylating agents (azacitidine or decitabine) or low dose cytarabine. Relapsed/refractory AML with a FMS-like tyrosine kinase 3 (FLT3) mutation is treated with a FLT3 kinase inhibitor (e.g., gilteritinib, midostaurin). Despite these frontline treatments, median OS is only about 10 months. In all types of AML, disease relapse is common despite an initial therapeutic response and is the most common reason for death. Standard chemotherapy and allogeneic stem cell transplant (when used) often fail to eradicate all tumor- propagating cells and select for chemotherapy-resistant leukemia-propagating subclones. Patients refractory to salvage therapy are treated palliatively, as current treatment options are extremely limited. These patients have a median survival of 2 months. In addition, patients with newly diagnosed intermediate or higher-risk MDS and those who relapse after standard care have a poor prognosis and high risk of progression to AML. Therefore, there is an urgent need for new treatment modalities for relapsed/refractory (R/R) AML and MDS patients, newly diagnosed AML patients ineligible for induction chemotherapy based on age and co- morbidities, and newly diagnosed intermediate/high/very high-risk MDS patients. ALL is a hematologic malignancy propagated by impaired differentiation, proliferation, and accumulation of lymphoid progenitor cells in the bone marrow and/or extramedullary sites. ALL represents 12% of all leukemia cases and is the most common childhood acute leukemia, with a worldwide incidence projected to be 1 to 4.75 per 100,000 people. ALL represents about 20% of adult leukemias. Despite high rates of complete remission (CR) (80% to 90%) with current therapies, the majority of adult patients with ALL relapse. The 5-year overall survival rate is approximately 30 to 40% in adults and elderly patients. Therefore, there is an urgent need for new treatment modalities for the treatment of cancer, in particular relapsed/refractory ALL, more particularly in adult and especially elderly patients. Compounds A, A1, A2, and A3 described herein are disclosed in PCT/CN2020/137266 (which published as WO 2021/121327 on June 24, 2021), which is incorporated by reference herein in its entirety, and which also discloses corresponding synthetic schemes and analytical characterizations. (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide besylate salt is published in WO 2022/262796, which is incorporated by reference herein in its entirety, and which also discloses corresponding synthetic schemes and analytical characterizations. BRIEF DESCRIPTION OF THE DRAWINGS FIG.1 is an X-ray powder diffraction (XRPD) pattern of Compound A4: a crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt hydrate. FIG.2A is a contour plot for maxR which illustrates the effect of Compound A4 in combination with idarubicin on proliferation of MOLM-13 cells in vitro. FIG.2B is a contour plot for maxR which illustrates the effect of Compound A4 in combination with idarubicin on proliferation of OCI-AML3 cells in vitro. FIG.2C is a contour plot for maxR which illustrates the effect of Compound A3 in combination with Cytarabine+Idarubicin on proliferation of MOLM-13 cells in vitro. FIG.2D is a contour plot for maxR which illustrates the effect of Compound A3 in combination with Cytarabine+Idarubicin on proliferation of OCI-AML3 cells in vitro. FIG.2E is a contour plot for maxR which illustrates the effect of Compound A3 in combination with Cytarabine+Daunorubicin on proliferation of MOLM-13 cells in vitro. FIG.2F is a contour plot for maxR which illustrates the effect of Compound A3 in combination with Cytarabine+Daunorubicin on proliferation of OCI-AML3 cells in vitro. DESCRIPTION OF THE INVENTION The present invention relates to combinations of a therapeutically effective amount of the menin-MLL inhibitor as described herein; and a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog (triple combinations). It will be clear for a skilled person that all combinations described herein are triple combinations of a menin-MLL inhibitor as described herein, a DNA intercalating agent and a pyrimidine analog. A menin-MLL inhibitor as described herein refers to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide, pharmaceutically acceptable salts and solvates thereof, or subgroups thereof. Embodiments of the present invention relate to combinations of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide (Compound A): Compound A or a pharmaceutically acceptable salt or solvate thereof; and a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In particular, Compound A or a pharmaceutically acceptable salt or solvate thereof, is any of the subgroups thereof as described herein in an embodiment. Embodiments of the present invention relate to combinations of Compound A1: Compound A1 and a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. Embodiments of the present invention relate to combinations of Compound A2: Compound A2 and a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. Embodiments of the present invention relate to combinations of Compound A3:

Compound A3 and a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. Embodiments of the present invention relate to combinations of Compound A4-a: Compound A4-a or a solvate thereof; and a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. A skilled person will understand that in this (and similar) embodiment(s) the ‘or a solvate thereof’ refers to the besylate salt of (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide. Embodiments of the present invention relate to combinations of Compound A4-a: Compound A4-a or a hydrate thereof; and a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. Embodiments of the present invention relate to combinations of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a solvate thereof; and a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. Embodiments of the present invention relate to combinations of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a hydrate thereof; and a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. Embodiments of the present invention relate to combinations of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 0.5-2.0 equivalents hydrate; and a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. Embodiments of the present invention relate to combinations of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 2.0 equivalents hydrate; and a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. Embodiments of the present invention relate to combinations of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt hydrate (Compound A4); and a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. Embodiments of the present invention relate to combinations of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt 0.5-2.0 equivalents hydrate; and a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. Embodiments of the present invention relate to combinations of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt 2.0 equivalents hydrate; and a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. According to embodiments, the DNA intercalating agent includes, but is not limited to, an anthracycline (e.g., daunorubicin, doxorubicin, idarubicin). According to embodiments, the DNA intercalating agent is an anthracycline. According to embodiments, the DNA intercalating agent is daunorubicin. According to embodiments, the DNA intercalating agent is doxorubicin. According to embodiments, the DNA intercalating agent is idarubicin. According to embodiments, the pyrimidine analog includes, but is not limited to, cytarabine (ARA-C). According to embodiments, the pyrimidine analog is cytarabine According to embodiments, the DNA intercalating agent is daunorubicin, and the pyrimidine analog is cytarabine. According to embodiments, the DNA intercalating agent is doxorubicin, and the pyrimidine analog is cytarabine. According to embodiments, the DNA intercalating agent is idarubicin, and the pyrimidine analog is cytarabine. Embodiments of the present invention relate to combinations of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide (Compound A):

Compound A or a pharmaceutically acceptable salt or solvate thereof; and a therapeutically effective amount of doxorubicin and cytarabine. Embodiments of the present invention relate to combinations of Compound A1: Compound A1 and a therapeutically effective amount of doxorubicin and cytarabine. Embodiments of the present invention relate to combinations of Compound A2: Compound A2 and a therapeutically effective amount of doxorubicin and cytarabine. Embodiments of the present invention relate to combinations of Compound A3: Compound A3 and a therapeutically effective amount of doxorubicin and cytarabine. Embodiments of the present invention relate to combinations of Compound A4-a: Compound A4-a or a solvate thereof; and a therapeutically effective amount of doxorubicin and cytarabine. Embodiments of the present invention relate to combinations of Compound A4-a: Compound A4-a or a hydrate thereof; and a therapeutically effective amount of doxorubicin and cytarabine. Embodiments of the present invention relate to combinations of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a solvate thereof; and a therapeutically effective amount of doxorubicin and cytarabine. Embodiments of the present invention relate to combinations of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a hydrate thereof; and a therapeutically effective amount of doxorubicin and cytarabine. Embodiments of the present invention relate to combinations of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 0.5-2.0 equivalents hydrate; and a therapeutically effective amount of doxorubicin and cytarabine. Embodiments of the present invention relate to combinations of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 2.0 equivalents hydrate; and a therapeutically effective amount of doxorubicin and cytarabine. Embodiments of the present invention relate to combinations of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt hydrate (Compound A4); and a therapeutically effective amount of doxorubicin and cytarabine. Embodiments of the present invention relate to combinations of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt 0.5-2.0 equivalents hydrate; and a therapeutically effective amount of doxorubicin and cytarabine. Embodiments of the present invention relate to combinations of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt 2.0 equivalents hydrate; and a therapeutically effective amount of doxorubicin and cytarabine. Embodiments of the present invention relate to combinations of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide (Compound A): Compound A or a pharmaceutically acceptable salt or solvate thereof; and a therapeutically effective amount of idarubicin and cytarabine. Embodiments of the present invention relate to combinations of Compound A1: Compound A1 and a therapeutically effective amount of idarubicin and cytarabine. Embodiments of the present invention relate to combinations of Compound A2:

Compound A2 and a therapeutically effective amount of idarubicin and cytarabine. Embodiments of the present invention relate to combinations of Compound A3: Compound A3 and a therapeutically effective amount of idarubicin and cytarabine. Embodiments of the present invention relate to combinations of Compound A4-a: Compound A4-a or a solvate thereof; and a therapeutically effective amount of idarubicin and cytarabine. Embodiments of the present invention relate to combinations of Compound A4-a: Compound A4-a or a hydrate thereof; and a therapeutically effective amount of idarubicin and cytarabine. Embodiments of the present invention relate to combinations of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a solvate thereof; and a therapeutically effective amount of idarubicin and cytarabine. Embodiments of the present invention relate to combinations of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a hydrate thereof; and a therapeutically effective amount of idarubicin and cytarabine. Embodiments of the present invention relate to combinations of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 0.5-2.0 equivalents hydrate; and a therapeutically effective amount of idarubicin and cytarabine. Embodiments of the present invention relate to combinations of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 2.0 equivalents hydrate; and a therapeutically effective amount of idarubicin and cytarabine. Embodiments of the present invention relate to combinations of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt hydrate (Compound A4); and a therapeutically effective amount of idarubicin and cytarabine. Embodiments of the present invention relate to combinations of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt 0.5-2.0 equivalents hydrate; and a therapeutically effective amount of idarubicin and cytarabine. Embodiments of the present invention relate to combinations of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt 2.0 equivalents hydrate; and a therapeutically effective amount of idarubicin and cytarabine. Embodiments of the present invention relate to combinations of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide (Compound A): Compound A or a pharmaceutically acceptable salt or solvate thereof; and a therapeutically effective amount of daunorubicin and cytarabine. Embodiments of the present invention relate to combinations of Compound A1:

Compound A1 and a therapeutically effective amount of daunorubicin and cytarabine. Embodiments of the present invention relate to combinations of Compound A2: Compound A2 and a therapeutically effective amount of daunorubicin and cytarabine. Embodiments of the present invention relate to combinations of Compound A3: Compound A3 and a therapeutically effective amount of daunorubicin and cytarabine. Embodiments of the present invention relate to combinations of Compound A4-a: Compound A4-a or a solvate thereof; and a therapeutically effective amount of daunorubicin and cytarabine. Embodiments of the present invention relate to combinations of Compound A4-a: Compound A4-a or a hydrate thereof; and a therapeutically effective amount of daunorubicin and cytarabine. Embodiments of the present invention relate to combinations of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a solvate thereof; and a therapeutically effective amount of daunorubicin and cytarabine. Embodiments of the present invention relate to combinations of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a hydrate thereof; and a therapeutically effective amount of daunorubicin and cytarabine. Embodiments of the present invention relate to combinations of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 0.5-2.0 equivalents hydrate; and a therapeutically effective amount of daunorubicin and cytarabine. Embodiments of the present invention relate to combinations of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 2.0 equivalents hydrate; and a therapeutically effective amount of daunorubicin and cytarabine. Embodiments of the present invention relate to combinations of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt hydrate (Compound A4); and a therapeutically effective amount of daunorubicin and cytarabine. Embodiments of the present invention relate to combinations of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt 0.5-2.0 equivalents hydrate; and a therapeutically effective amount of daunorubicin and cytarabine. Embodiments of the present invention relate to combinations of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt 2.0 equivalents hydrate; and a therapeutically effective amount of daunorubicin and cytarabine. In some embodiments, provided is a pharmaceutical composition comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of a combination as described in any of the other embodiments. Embodiments of the present invention relate to uses of such combinations for treating a subject who has been diagnosed with a hematopoietic disorder, including but not limited to, blood cancers. Embodiments of the present invention relate to uses of such combinations for treating a subject who has been diagnosed with a hematopoietic disorder, including but not limited to, hematopoietic cancers. Embodiments of the present invention relate to novel methods for treating a subject who has been diagnosed with a hematopoietic disorder using such combinations. Embodiments of the novel methods comprise administering to the subject a therapeutically effective amount of a menin-MLL inhibitor as described herein; and a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment, the subject is newly diagnosed in a chemotherapy eligible setting. In some embodiments, the present invention is directed to methods for treating a subject who has been diagnosed with a hematopoietic disorder, the methods comprising administering to the subject a therapeutically effective amount of a menin-MLL inhibitor; and a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. An additional embodiment of the invention relates to methods for treating a subject who has been diagnosed with cancer (e.g., wherein the cancer is a hematopoietic disorder, such as myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), a small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL)), wherein the method comprises administering to the subject: a therapeutically effective amount of (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide (Compound A): Compound A or a pharmaceutically acceptable salt or solvate thereof; and a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide (Compound A): Compound A or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide (Compound A): Compound A or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to Compound A or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a hematopoietic disorder in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a hematopoietic disorder in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to Compound A or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to Compound A or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to Compound A or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with daunorubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of daunorubicin and cytarabine. In an embodiment the invention relates to Compound A or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with doxorubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of doxorubicin and cytarabine. In an embodiment the invention relates to Compound A or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with idarubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of idarubicin and cytarabine. In an embodiment the invention relates to Compound A4-a: Compound A4-a or a solvate thereof, for use in the treatment of cancer in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of Compound A4- a: Compound A4-a or a solvate thereof, for use in the treatment of cancer in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to Compound A4-a or a solvate thereof, for use in the treatment of a hematopoietic disorder in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of Compound A4- a or a solvate thereof, for use in the treatment of a hematopoietic disorder in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to Compound A4-a or a solvate thereof, for use in the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of Compound A4-a or a solvate thereof, for use in the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to Compound A4-a or a solvate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of Compound A4-a or a solvate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to Compound A4-a or a solvate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with daunorubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of Compound A4- a or a solvate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of daunorubicin and cytarabine. In an embodiment the invention relates to Compound A4-a or a solvate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with doxorubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of Compound A4-a or a solvate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of doxorubicin and cytarabine. In an embodiment the invention relates to Compound A4-a or a solvate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with idarubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of Compound A4- a or a solvate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of idarubicin and cytarabine. In an embodiment the invention relates to Compound A4-a: Compound A4-a or a hydrate thereof, for use in the treatment of cancer in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of Compound A4- a: Compound A4-a or a hydrate thereof, for use in the treatment of cancer in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to Compound A4-a or a hydrate thereof, for use in the treatment of a hematopoietic disorder in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of Compound A4- a or a hydrate thereof, for use in the treatment of a hematopoietic disorder in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to Compound A4-a or a hydrate thereof, for use in the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of Compound A4-a or a hydrate thereof, for use in the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to Compound A4-a or a hydrate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of Compound A4-a or a hydrate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to Compound A4-a or a hydrate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with daunorubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of Compound A4- a or a hydrate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of daunorubicin and cytarabine. In an embodiment the invention relates to Compound A4-a or a hydrate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with doxorubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of Compound A4-a or a hydrate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of doxorubicin and cytarabine. In an embodiment the invention relates to Compound A4-a or a hydrate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with idarubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of Compound A4- a or a hydrate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of idarubicin and cytarabine. In an embodiment the invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a solvate thereof, for use in the treatment of cancer in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a solvate thereof, for use in the treatment of cancer in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a solvate thereof, for use in the treatment of a hematopoietic disorder in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a solvate thereof, for use in the treatment of a hematopoietic disorder in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a solvate thereof, for use in the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a solvate thereof, for use in the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a solvate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a solvate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a solvate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with daunorubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a solvate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of daunorubicin and cytarabine. In an embodiment the invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a solvate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with doxorubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a solvate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of doxorubicin and cytarabine. In an embodiment the invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a solvate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with idarubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a solvate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of idarubicin and cytarabine. In an embodiment the invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a hydrate thereof, for use in the treatment of cancer in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a hydrate thereof, for use in the treatment of cancer in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a hydrate thereof, for use in the treatment of a hematopoietic disorder in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a hydrate thereof, for use in the treatment of a hematopoietic disorder in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a hydrate thereof, for use in the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a hydrate thereof, for use in the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a hydrate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a hydrate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a hydrate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with daunorubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a hydrate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of daunorubicin and cytarabine. In an embodiment the invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a hydrate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with doxorubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a hydrate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of doxorubicin and cytarabine. In an embodiment the invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a hydrate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with idarubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a hydrate thereof, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of idarubicin and cytarabine. In an embodiment the invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 0.5-2.0 equivalents hydrate, for use in the treatment of cancer in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 0.5-2.0 equivalents hydrate, for use in the treatment of cancer in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 0.5-2.0 equivalents hydrate, for use in the treatment of a hematopoietic disorder in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 0.5-2.0 equivalents hydrate, for use in the treatment of a hematopoietic disorder in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 0.5-2.0 equivalents hydrate, for use in the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 0.5-2.0 equivalents hydrate, for use in the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 0.5-2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 0.5-2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 0.5-2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with daunorubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 0.5-2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of daunorubicin and cytarabine. In an embodiment the invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 0.5-2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with doxorubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 0.5-2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of doxorubicin and cytarabine. In an embodiment the invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 0.5-2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with idarubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 0.5-2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of idarubicin and cytarabine. In an embodiment the invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 2.0 equivalents hydrate, for use in the treatment of cancer in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 2.0 equivalents hydrate, for use in the treatment of cancer in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 2.0 equivalents hydrate, for use in the treatment of a hematopoietic disorder in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 2.0 equivalents hydrate, for use in the treatment of a hematopoietic disorder in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 2.0 equivalents hydrate, for use in the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 2.0 equivalents hydrate, for use in the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with daunorubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of daunorubicin and cytarabine. In an embodiment the invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with doxorubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of doxorubicin and cytarabine. In an embodiment the invention relates to (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with idarubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of idarubicin and cytarabine. In an embodiment the invention relates to crystalline form A of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt hydrate (Compound A4), for use in the treatment of cancer in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt hydrate (Compound A4), for use in the treatment of cancer in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to crystalline form A of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt hydrate (Compound A4), for use in the treatment of a hematopoietic disorder in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt hydrate (Compound A4), for use in the treatment of a hematopoietic disorder in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to crystalline form A of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt hydrate (Compound A4), for use in the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt hydrate (Compound A4), for use in the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to crystalline form A of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt hydrate (Compound A4), for use in the treatment of acute myeloid leukemia (AML) in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt hydrate (Compound A4), for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to crystalline form A of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt hydrate (Compound A4), for use in the treatment of acute myeloid leukemia (AML) in combination with daunorubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt hydrate (Compound A4), for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of daunorubicin and cytarabine. In an embodiment the invention relates to crystalline form A of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt hydrate (Compound A4), for use in the treatment of acute myeloid leukemia (AML) in combination with doxorubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt hydrate (Compound A4), for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of doxorubicin and cytarabine. In an embodiment the invention relates to crystalline form A of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt hydrate (Compound A4), for use in the treatment of acute myeloid leukemia (AML) in combination with idarubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt hydrate (Compound A4), for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of idarubicin and cytarabine. In an embodiment the invention relates to crystalline form A of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 0.5-2.0 equivalents hydrate, for use in the treatment of cancer in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt 0.5-2.0 equivalents hydrate, for use in the treatment of cancer in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to crystalline form A of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 0.5-2.0 equivalents hydrate, for use in the treatment of a hematopoietic disorder in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt 0.5-2.0 equivalents hydrate, for use in the treatment of a hematopoietic disorder in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to crystalline form A of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 0.5-2.0 equivalents hydrate, for use in the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt 0.5-2.0 equivalents hydrate, for use in the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to crystalline form A of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 0.5-2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt 0.5-2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to crystalline form A of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 0.5-2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with daunorubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt 0.5-2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of daunorubicin and cytarabine. In an embodiment the invention relates to crystalline form A of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 0.5-2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with doxorubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt 0.5-2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of doxorubicin and cytarabine. In an embodiment the invention relates to crystalline form A of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 0.5-2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with idarubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt 0.5-2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of idarubicin and cytarabine. In an embodiment the invention relates to crystalline form A of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 2.0 equivalents hydrate, for use in the treatment of cancer in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt 2.0 equivalents hydrate, for use in the treatment of cancer in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to crystalline form A of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 2.0 equivalents hydrate, for use in the treatment of a hematopoietic disorder in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt 2.0 equivalents hydrate, for use in the treatment of a hematopoietic disorder in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to crystalline form A of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 2.0 equivalents hydrate, for use in the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt 2.0 equivalents hydrate, for use in the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to crystalline form A of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to a therapeutically effective amount of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt 2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. In an embodiment the invention relates to crystalline form A of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with daunorubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt 2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of daunorubicin and cytarabine. In an embodiment the invention relates to crystalline form A of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with doxorubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt 2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of doxorubicin and cytarabine. In an embodiment the invention relates to crystalline form A of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt 2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with idarubicin and cytarabine. In an embodiment the invention relates to a therapeutically effective amount of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt 2.0 equivalents hydrate, for use in the treatment of acute myeloid leukemia (AML) in combination with a therapeutically effective amount of idarubicin and cytarabine. In particular, in any of the embodiments, the DNA intercalating agent is daunorubicin, and the pyrimidine analog is cytarabine. In particular, in any of the embodiments, the DNA intercalating agent is doxorubicin, and the pyrimidine analog is cytarabine. In particular, in any of the embodiments, the DNA intercalating agent is idarubicin, and the pyrimidine analog is cytarabine. A method for treating a subject who has been diagnosed with a hematopoietic disorder comprising administering to the subject a combination of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide (Compound A):

Compound A or a pharmaceutically acceptable salt or solvate thereof; and a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog. Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form with one or more equivalents of an appropriate base or acid, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g., in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin. The pharmaceutically acceptable salts as mentioned hereinabove or hereinafter are meant to comprise the therapeutically active non-toxic acid and base salt forms which (R)-N-ethyl- 5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide and solvates thereof, are able to form. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g., hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e., ethanedioic), malonic, succinic (i.e., butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p- aminosalicylic, pamoic and the like acids. Conversely said salt forms can be converted by treatment with an appropriate base into the free base form. (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide and solvates thereof containing an acidic proton may also be converted into their non-toxic metal or amine salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g., the lithium, sodium, potassium, cesium, magnesium, calcium salts and the like, salts with organic bases, e.g., primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di- n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; the benzathine, N-methyl- D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely the salt form can be converted by treatment with acid into the free acid form. All isotopes and isotopic mixtures of any particular atom or element as specified herein are contemplated within the scope of the invention, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br. Preferably, the isotope is selected from the group of ²H, ³H, ¹¹C, ¹³C and ¹⁸F. Preferably, the isotope is selected from the group of ²H, ³H, ¹¹C and ¹⁸F. More preferably, the isotope is ²H, ³H or ¹³C. More preferably, the isotope is ²H or ¹³C. More preferably, the isotope is ²H. In particular, deuterated compounds and ¹³C-enriched compounds are intended to be included within the scope of the present invention. In particular, deuterated compounds are intended to be included within the scope of the present invention. Certain isotopically-labeled compounds (e.g., those labeled with ³H and ¹⁴C) may be useful for example in substrate tissue distribution assays. Tritiated (³H) and carbon-l4 (¹⁴C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as ¹⁵O, ¹³N, ¹¹C and ¹⁸F are useful for positron emission tomography (PET) studies. PET imaging in cancer finds utility in helping locate and identify tumors, stage the disease and determine suitable treatment. Human cancer cells overexpress many receptors or proteins that are potential disease-specific molecular targets. Radiolabelled tracers that bind with high affinity and specificity to such receptors or proteins on tumor cells have great potential for diagnostic imaging and targeted radionuclide therapy (Charron, Carlie L. et al. Tetrahedron Lett. 2016, 57(37), 4119-4127). Additionally, target-specific PET radiotracers may be used as biomarkers to examine and evaluate pathology, by for example, measuring target expression and treatment response (Austin R. et al. Cancer Letters (2016), doi: 10.1016/j.canlet.2016.05.008). As used herein, the term “hematopoietic disorder” refers to any disorder associated with the production of the cellular components of blood and blood plasma, including but not limited to blood cancers. According to an embodiment, the invention provides combinations as described herein. According to an embodiment, the invention provides combinations as described herein for use as a medicament. According to an embodiment, the invention provides combinations as described herein for the manufacture of a medicament. According to an embodiment, the invention provides combinations as described herein for the manufacture of a medicament for the treatment or prevention of any one of the disease conditions mentioned herein. According to an embodiment, the invention provides combinations as described herein for use in the prevention or treatment, in particular treatment, of diseases as described herein. According to an embodiment, the invention provides combinations as described herein for use in the prevention or treatment, in particular treatment, of a hematopoietic disorder, including but not limited to blood cancers, including but not limited to lymphomas, myelomas and leukemias. According to an embodiment, the invention provides combinations as described herein for use in the prevention or treatment, in particular treatment, of a hematopoietic disorder. According to an embodiment, the hematopoietic disorder is selected from, but not limited to, lymphomas, myelomas, myelodysplasia and leukemias. According to an embodiment the hematopoietic disorder is a myelodysplasia including, but not limited to, myelodysplastic syndrome (MDS). According to an embodiment, the hematopoietic disorder is a leukemia. According to an embodiment, the hematopoietic disorder is a leukemia selected from acute leukemias and chronic leukemias. According to an embodiment, the leukemia is an acute leukemia. According to an embodiment, the leukemia is chronic leukemia. According to an embodiment, the hematopoietic disorder is a myeloid leukemia, myelogeneous leukemia, lymphoblastic leukemia, or lymphocytic leukemia, According to an embodiment, the hematopoietic disorder is a leukemia selected from, but not limited to, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), acute myeloid leukemia (AML), chronic idiopathic myelofibrosis (MF), chronic myelogenous leukemia (CML), T-cell prolymphocytic leukemia (T-PLL), B-cell prolymphocytic leukemia (B-PLL), chronic neutrophilic leukemia (CNL), Hairy cell leukemia (HCL), T-cell large granular lymphocyte leukemia (T-LGL) and aggressive NK-cell leukemia. According to an embodiment, the AML is acute megakaryoblastic leukemia (AMKL). According to an embodiment, the leukemia is MDS, CLL, SLL, ALL or AML. According to an embodiment, the leukemia is CLL, SLL or AML. According to an embodiment, the leukemia is CLL or SLL. In some embodiments, the CLL or SLL is a CD20 expressing cancer. According to an embodiment, the leukemia is ALL or AML. According to an embodiment, the leukemia is ALL. According to an embodiment, the leukemia is AML. According to an embodiment, the hematopoietic disorder is Waldenström macroglobulinemia. According to an embodiment, the hematopoietic disorder is a MLL-rearranged leukemia, MLL- partial tandem duplication (PTD) leukemia, MLL-amplified leukemia, MLL-positive leukemia, or leukemia exhibiting elevated HOX/MEIS1 gene expression signatures. According to an embodiment, the leukemia is a MLL-rearranged leukemia &/or a nucleophosmin 1 (NPM1)-mutated leukemia. According to an embodiment, the hematopoietic disorder is a MLL-rearranged leukemia. According to an embodiment, the hematopoietic disorder is a nucleophosmin 1 (NPM1)- mutated leukemia (e.g., NPM1c). According to an embodiment, the hematopoietic disorder is myelodysplastic syndrome (MDS) or a myeloproliferative neoplasm (MPN). According to an embodiment, the hematopoietic disorder is acute lymphocytic leukemia (ALL). According to an embodiment, the hematopoietic disorder is acute myeloid leukemia (AML). According to an embodiment, the hematopoietic disorder is a small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL). According to an embodiment, the hematopoietic disorder is a SLL or CLL where SLL or CLL is a CD20-expressing cancer. According to an embodiment, the hematopoietic disorder is myelodysplastic syndrome (MDS). According to an embodiment, the hematopoietic disorder is a myeloproliferative neoplasm (MPN). According to an embodiment, the hematopoietic disorder is a NPM1-mutated leukemia with a FLT3 mutation. According to an embodiment, the hematopoietic disorder is a FLT3-dependent leukemia. According to an embodiment, the hematopoietic disorder is a MEF2G-dependent leukemia. According to an embodiment, the hematopoietic disorder harbours one or more MLL1 (KMT2A) gene rearrangements or alterations (e.g., duplications or amplification) and/or NPM1 mutations. According to an embodiment, the hematopoietic disorder harbours (i) one or more MLL1 (KMT2A) gene rearrangements or alterations (e.g., duplications or amplification) and/or NPM1 mutations plus (ii) a FLT3 mutation. According to an embodiment, the hematopoietic disorder is an MLL-rearranged leukemia. According to an embodiment, the hematopoietic disorder is acute myeloid leukemia (AML). According to an embodiment, the hematopoietic disorder is a small lymphocytic lymphoma (SLL). According to an embodiment, the hematopoietic disorder is a chronic lymphocytic leukemia (CLL). According to an embodiment, the hematopoietic disorder is an acute leukemia, chronic leukemia, myeloid leukemia, myelogeneous leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myelogeneous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T cell prolymphocytic leukemias (T-PLL), large granular lymphocytic leukemia, Hairy cell leukemia (HCL), MLL- rearranged leukemia, MLL-PTD leukemia, MLL amplified leukemia, MLL-positive leukemia, or leukemia exhibiting elevated HOX/MEIS1 gene expression signatures. According to an embodiment, the hematopoietic disorder is AML, in particular nucleophosmin (NPM1)-mutated AML (i.e., NPM1^mut AML), more in particular abstract NPM1-mutated AML. According to an embodiment, the hematopoietic disorder is a MLL-rearranged leukemia, in particular MLL-rearranged AML or ALL. According to an embodiment, the hematopoietic disorder includes a MLL gene alteration, in particular the hematopoietic disorder is AML or ALL with MLL gene alteration(s). In certain embodiments, the MLL gene alteration is a duplication. In certain embodiments the MLL gene alteration is an amplification. According to an embodiment, the hematopoietic disorder includes a NPM1 gene mutation and/or MLL1 (also known as KMT2A) gene mutation. According to an embodiment, MLL1 gene mutations include, but are not limited to, MLL1 gene rearrangements, duplications or amplification. According to an embodiment, the hematopoietic disorder is a mixed-lineage leukemia (MLL), MLL-related leukemia, MLL-associated leukemia, MLL-positive leukemia, MLL-induced leukemia, leukemia associated with a MLL, acute leukemia, chronic leukemia, myelodysplastic syndrome (MDS), or myeloproliferative neoplasms (MPN). All embodiments described herein for methods for treating a disorder, are also applicable for use in treating said disorder. All embodiments described herein for use in treating a disorder, are also applicable for methods for treating said disorder. All embodiments described herein for use in the treatment of a disorder, are also applicable for methods for treating said disorder. All embodiments described herein for use in the treatment of a disorder, are also applicable for use in treating said disorder. All embodiments described herein for methods for treating a disorder, are also applicable for use in a method for treating said disorder. All embodiments described herein for use in a method for treating a disorder, are also applicable for methods for treating said disorder. The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medicinal doctor or other clinician, which includes alleviation or reversal of the symptoms of the disease or disorder being treated. All abbreviations used in the general schemes and examples for menin-MLL inhibitors described herein are as defined in Table 1. Variables are as defined in the scope or as specifically defined in the general Schemes. Examples Table 1- Abbreviations Abbreviation Meaning Ag(Phen)₂OTf silver triflate−bis(1,10-phenanthroline) complex 2-MeTHF 2-methyltetrahydrofuran ACN acetonitrile AcCl acetyl chloride AcOH acetic acid Ac2O acetic anhydride aq. aqueous Ar argon BBr₃ tribromoborane bn benzyl Boc tert-butyloxycarbonyl Boc₂O di-tert-butyl dicarbonate n-BuLi n-butyllithium Cbz benzyloxycarbonyl CD₃OD Methanol-d₄ CHCl3 chloroform Cs2CO3 cesium carbonate conc. concentrated DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCC dicyclohexylcarbodiimide DCE dichloroethane DCM dichloromethane DDQ 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile DEA diethylamine DIBAL-H diisobutylaluminum hydride DIEA or DIPEA N,N-diisopropylethylamine DMAP N,N-dimethylpyridin-4-amine DMF N,N-dimethylformamide DMP Dess-Martin periodinane DMSO dimethyl sulfoxide dppf 1,1′-ferrocenediyl-bis(diphenylphosphine) EDCI N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride EA or EtOAc ethyl acetate EtOH ethanol Abbreviation Meaning eq. equivalent(s) FA formic acid FCC flash column chromatography h hour(s) H₂ hydrogen HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b] pyridinium 3-oxid hexafluorophosphate H2O water HCl hydrochloric acid HOBt 1-Hydroxybenzotriazole HPLC high performance liquid chromatography ICH2Cl chloroiodomethane IPA isopropyl alcohol IPAc isopropyl acetate K2CO3 potassium carbonate KI potassium iodide K₂HPO₄ dipotassium phosphate K₃PO₄ tripotassium phosphate LiAlD4 lithium aluminum deuteride LAH lithium aluminum hydride LiBH₄ lithium borohydride LDA lithium diisopropylamide LiCl lithium chloride LG leaving group Me methyl MeOH methanol 2-MeTHF 2-methyltetrahydrofuran min minute(s) mL milliliters mmol millimoles mg milligram MgSO4 magnesium sulfate MSA methanesulfonic acid MsCl methanesulfonyl chloride MS molecular sieve MTBE methyl tert-butyl ether N2 nitrogen NA not available NaBH3CN sodium cyanoborohydride NaBH(OAc)3 sodium triacetoxyborohydride NaBD₃CN sodium cyanoborodeuteride Na2CO3 sodium carbonate NaH sodium hydride NaHCO₃ sodium bicarbonate NaI sodium iodide NaOAc sodium acetate NaOH sodium hydroxide Abbreviation Meaning Na2SO3 sodium sulfite Na₂SO₄ sodium sulfate NH4Cl ammonium chloride NMM 1-4-Methylmorpholine Pd₂dba₃ tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), 2 ^DCM complex with dichloromethane Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0) PE petroleum ether PG protecting group Phen phenanthroline psi pound per square inch p-TsOH p-toluenesulfonic acid p_{-TsOH ^H2O} p-toluenesulfonic acid monohydrate R_t retention time Rochelle’s salt potassium sodium tartrate tetrahydrate RT room temperature sat. saturated SFC supercritical fluid chromatography TBAF tetrabutylammonium fluoride TBDMS tert-butyldimethylsilyl TBDPS tert-butyldiphenylsilyl t-BuOK potassium tert-butoxide TEA triethylamine Tf trifluoromethanesulfonyl TFA trifluoroacetic acid THF tetrahydrofuran Ti(OiPr)₄ titanium(IV) isopropoxide TLC thin layer chromatography TMEDA N,N,N′,N′-tetramethylethylenediamine TMG 1,1,3,3-tetramethylguanidine TMSI iodotrimethylsilane Ts p-toluenesulfonyl TsCl p-toluenesulfonyl chloride v/v volume per volume vol. volume(s) wt weight Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene As understood by a person skilled in the art, compounds synthesized using the protocols as indicated may exist as a solvate e.g., hydrate, and/or contain residual solvent or minor impurities. Compounds or intermediates isolated as a salt form, may be integer stoichiometric i.e., mono- or di-salts, or of intermediate stoichiometry. When an intermediate or compound in the experimental part below is indicated as ‘HCl salt’ without indication of the number of equivalents of HCl, this means that the number of equivalents of HCl was not determined. The same principle will also apply to all other salt forms referred to in the experimental part, such A skilled person will realize that, even where not mentioned explicitly in the experimental protocols below, typically after a column chromatography purification, the desired fractions were collected and the solvent was evaporated. In case no stereochemistry is indicated, this means it is a mixture of stereoisomers, unless otherwise is indicated or is clear from the context. When a stereocenter is indicated with ‘RS’ this means that a racemic mixture was obtained at the indicated center, unless otherwise indicated. Example 1 – Synthesis of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl) (methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6- yl)oxy) benzamide (Compound A) – Preparation Method A Preparation of intermediate 1 - tert-butyl (5-methyl-4-oxohexyl)carbamate To a solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (5.0 g, 27 mmol) and TMEDA (5.0 mL, 33 mmol) in THF (60 mL) cooled at -70 °C was slowly added isopropylmagnesium bromide solution (19 mL, 55 mmol, 2.9 M in 2-methyltetrahydrofuran), the resulting mixture was slowly warmed to RT and stirred for 12 h. The mixture was poured into sat. aq. NH4Cl (50 mL) solution and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the crude product, which was further purified by FCC (PE/EtOAc = 1:0 to 100:1) to afford the title intermediate (3.7 g, 60% yield) as a yellow oil. Preparation of intermediate 13 - tert-butyl 6-(3,6-dichloro-1,2,4-triazin-5-yl)-2,6-diazaspiro [3.4]octane-2-carboxylate To the solution of 3,5,6-trichloro-1,2,4-triazine (10.0 g, 54.2 mmol) and TEA (15.2 mL, 109 mmol) in DCM (100 mL) cooled at 0 °C was added tert-butyl 2,6-diazaspiro[3.4]octane-2- carboxylate (9.21 g, 43.4 mmol), the mixture was warmed to RT and stirred for 1 h. The mixture was diluted with water (20 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product which was purified by FCC on silica gel (PE/EtOAc = 1:0 to 3:1) to afford the title intermediate (12.0 g, 58% yield) as a yellow solid. To the mixture of 5-fluoro-2-methoxybenzoic acid (8.00 g, 47.0 mmol) and N-ethylpropan-2- amine (8.19 g, 94.0 mmol) in dry DCM (150 mL) cooled at 0 °C, were slowly added HATU (21.5 g, 56.5 mmol) and DIEA (9.10 g, 70.4 mmol) in portions. The resulting mixture was slowly warmed to RT and stirred for 8 h. The organic layer was washed with water (20 mL x 3) and dried over anhydrous Na₂SO₄. After filtration, the solvent was removed under reduced pressure and the crude product was purified by FCC (EtOAc/PE = 0% to 20%) to afford the title intermediate (12.0 g, 96% yield) as a white solid. To the solution of N-ethyl-5-fluoro-N-isopropyl-2-methoxybenzamide (intermediate 27) (12.0 g, 50.1 mmol) in dry DCM (100 mL) cooled at -78 °C was slowly added BBr₃ (14.4 mL, 152 mmol), the resulting mixture was slowly warmed to RT and stirred for 8 h. The mixture was cooled to -78 °C again and MeOH (5 mL) was added dropwise to quench the reaction. The resulting mixture was slowly warmed to RT and the pH value was adjusted to about 8 by adding sat. aq. NaHCO₃ solution. The aqueous layer was extracted by DCM (50 mL x 3) and the combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give the crude product which was purified by FCC (EtOAc/PE = 0% to 20%) to afford the title intermediate (9.0 g, 78% yield) as a white solid.

Alternative preparation of intermediate 28 A mixture of 5-fluoro-2-hydroxy-benzoic acid (14.0 kg, 89.68mol, 1.0 equiv.) in THF (168 L, 12 volumes) was adjusted to between 15-25 °C, and 1,1-carbonyldiimidazole, (17.45kg, 107.62 mol, 1.2 equiv.) was added over a period of 1 hour. After addition, the mixture was stirred for 18 hours at 15-25 °C. After this time N-ethylpropan-2-amine (14.85kg, 170.39mol, 1.9 equiv.) was added to the mixture at 15-25 °C over a period of 2 hours. The resulting mixture was further aged for between 18-24 hours at 15-25 °C. The pH was the adjusted to between pH4-5 with aq. 10% H₂SO₄ (140kg, 10 volumes) and the layers were separated. The organic phase was concentrated to between 42-56L maintaining a temperature below 40°C, and then n-heptane (43kg, 4.5 volumes) was added to the mixture at 15-25°C over a period of 3 hours. The mixture was then cooled to 0-10 °C and stirred for an additional 6 hours. The resulting slurry was filtered and the cake was washed with a tert-butyl methyl ether (MTBE):n-heptane mixture (25 kg of a 2:3 volume/volume mixture of MTBE:n-heptane, 2.5 volumes). The cake wash was repeated a further two times and the resulting solid was dried in-vacuo at 50°C to afford intermediate 28 (16.5 kg, purity: 99.1%, yield: 80.4%). Preparation of intermediate 14 - tert-butyl 6-(3-chloro-6-(2-(ethyl(isopropyl)carbamoyl)-4- fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate The mixture of tert-butyl 6-(3,6-dichloro-1,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octane-2- carboxylate (intermediate 13) (12.0 g, 33.3 mmol), N-ethyl-5-fluoro-2-hydroxy-N- isopropylbenzamide (intermediate 28) (7.5 g, 33.3 mmol) and DBU (6.1 g, 40.1 mmol) in THF (120 mL) was stirred at 25 °C for 8 h. The mixture was diluted with water (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product which was purified by FCC (PE/EtOAc = 1:0 to 3:1) to afford the title intermediate (14.0 g, 73% yield) as green solid. Preparation of intermediate 2 - tert-butyl 6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluoro- phenoxy)-1,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate Synthesis method A for intermediate 2: To the mixture of tert-butyl 6-(3-chloro-6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)- 1,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (intermediate 14) (20 g, 36.4 mmol), NaBH₄ (2.48 g, 65.7 mmol) and TMEDA (8.54 g, 73.5 mmol) in THF (500 mL) was added Pd(dppf)Cl2 ^DCM (1.70 g, 2.08 mmol) under N2 atmosphere. After addition, the reaction mixture was stirred at 25 °C for 14 h. The reaction mixture was filtered and the filtrate was concentrated, the residue was purified by FCC on silica gel (EtOAc) to afford the title intermediate (15 g, 93% purity, 74% yield) as brown solid. Synthesis method B for intermediate 2: To the solution of tert-butyl 6-(3-chloro-6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)- 1,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (intermediate 14) (22.0 g, 40.1 mmol), TEA (15 mL) in MeOH (100 mL) was added Pd/C (wet, 5.0 g, 10%) The resulting mixture was stirred under H2 atmosphere (30 psi) at 25 °C for 8 h. The reaction mixture was filtered through a celite pad and the filtrate was concentrated in vacuo to afford the title intermediate (25.0 g, crude), which was used directly in next step without further purification. Preparation of intermediate 3 - 2-((5-(2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)- N-ethyl-5-fluoro-N-isopropylbenzamide To the solution of tert-butyl 6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4- triazin-5-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (intermediate 2) (300 mg, 0.583 mmol) in DCM (5 mL) was added TFA (0.5 mL, 6.4 mmol), the resulting mixture was stirred at RT for 3 h. Then 10% NaOH (5 mL) solution was slowly added into the mixture to adjust the pH value to about 12, the resulting mixture was extracted with DCM (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the title intermediate (220 mg, 90% yield) as a white solid. Preparation of Compound 61 - tert-butyl (4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4- The mixture 2-((5-(2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N- isopropylbenzamide (intermediate 3) (1.0 g, 2.4 mmol), tert-butyl (5-methyl-4- oxohexyl)carbamate (intermediate 1) (830 mg, 3.62 mmol) and ZnCl₂ (660 mg, 4.84 mmol) in MeOH (15 mL) was stirred at 80 °C for 0.5 h. Then NaBH₃CN (310 mg, 4.93 mmol) was added and the resulting mixture was stirred at 80 °C for 6 h. After cooled to RT, the mixture was concentrated under reduced pressure to give the crude product, which was further purified by preparative HPLC using a Waters Xbridge Prep OBD (column: C18150x40 mm 10 um; eluent: ACN/H2O (0.05% ammonia) from 45% to 75% v/v) to afford the title compound (700 mg, 46% yield) as colorless oil. Preparation of Compounds 62 and 63 - tert-butyl (R)-(4-(6-(6-(2-(ethyl(isopropyl) carbamoyl)- 4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)carbamate and tert-butyl (S)-(4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5- tert-butyl (4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,6- diazaspiro[3.4]octan-2-yl)-5-methylhexyl)carbamate (compound 61) (200 mg, 0.319 mmol) was purified by SFC over DAICEL CHIRALPAK IG (column: 250x30 mm 10 um; isocratic elution: EtOH (containing 0.1% of 25% ammonia): supercritical CO₂, 40% : 60% (v/v)) to afford the title compounds (compound 62) (85 mg, 42% yield) and (compound 63) (80 mg, 40% yield) both as light yellow oil. Compound 64 - (R)-2-((5-(2-(6-amino-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)- To the solution of tert-butyl (R)-(4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)- 1,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)carbamate (compound 62) (550 mg, 0.876 mmol) in DCM (4 mL) was slowly added TFA (4 mL), and the resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted in DCM (40 mL) and the pH value was adjusted to around 12 by aq. NaOH (2 M, 16 mL) solution. The aqueous layer was extracted with DCM (10 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to afford the title compound (460 mg, crude) as yellow solid, which was used directly in next step without further purification. Compound 11 - (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)amino)-2- The mixture of (R)-2-((5-(2-(6-amino-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)- 1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (compound 64) (120 mg, crude), 1-bromo-2-methoxyethane (32 mg, 0.23 mmol), Cs2CO3 (222 mg, 0.681 mmol), NaI (102 mg, 0.680 mmol) in DMF (1 mL) was stirred at 80 °C via microwave irradiation for 1 h. After cooling to RT, the mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with H2O (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product which was further purified by HPLC over a Phenomenex Gemini-NX (column: 150x30 mm 5 μm; eluent: ACN/H2O (10mM NH4HCO3) from 51% to 71% (v/v)) and further purified by SFC over DAICEL CHIRALCEL OD-H (column: 250x30 mm 5 um; eluent: supercritical CO₂ in EtOH (0.1% v/v ammonia) 25/25, v/v) to afford the title compound (5.13 mg, 96% purity) as yellow solid. LC-MS (ESI) (Method 1): Rt = 2.997 min, m/z found 586.3 [M+H]⁺. Compound A - (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl) (methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy) benzamide The mixture of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)amino)-2- methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide (compound 11) (40.0 mg, 0.068 mmol), formaldehyde (55.4 mg, 0.683 mol, 37% in water) and AcOH (8.2 mg, 0.137 mmol) in anhydrous MeOH (2 mL) was stirred at 45 °C for 1 h. Then, NaBH3CN (8.6 mg, 0.137 mmol) was added to the mixture and the resulting mixture was stirred at 45 °C for another 1 h. After cooling to RT, the reaction mixture was treated with sat. aq. NaHCO3 (40 mL) to adjust the pH value to about 8 and further extracted with DCM (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude which was purified by preparative HPLC over Boston Prime (column: C18 150x30mm 5um, Mobile Phase A: H2O (0.04% ammonia+10mM NH4HCO3), Mobile Phase B: ACN, Flow rate: 25 mL/min, gradient condition B/A from 50% to 80% (50%B to 80% B)) to afford the title compound (9.62 mg, 99.10% purity, 23.3% yield) as yellow oil. Example 2 – Synthesis of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl) (methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6- yl)oxy) benzamide (Compound A) – Preparation Method B Preparation of intermediate 7 - 4-((tert-butoxycarbonyl)(methyl)amino)butanoic acid To a solution of 4-(methylamino)butanoic acid hydrochloride (3.0 g, 19.5 mmol) and TEA (7.78 mL, 58.6 mmol) in MeOH (30 mL) was added Boc2O (4.69 g, 21.5 mmol) dropwise. The mixture was stirred at RT for 2 h. The mixture was concentrated under reduced pressure and the residue was diluted with EtOAc (100 mL), washed with cooled 0.1 N HCl (70 mL x 2), H₂O (50 mL x 2) and brine (50 mL), dried over Na2SO4, filtered and concentrated to afford the title intermediate (1.80 g, crude) as colorless oil. Preparation of intermediate 8 - tert-butyl (4-(methoxy(methyl)amino)-4-oxobutyl)(methyl) carbamate To a solution of 4-((tert-butoxycarbonyl)(methyl)amino)butanoic acid (intermediate 7) (1.80 g, crude) in CHCl3 (30 mL) was added N,O-dimethylhydroxylamine hydrochloride (960 mg, 9.84 mmol), HOBt (1.24 g, 9.18 mmol) and NMM (2.80 mL, 25.1 mmol). And, then EDCI (2.23 g, 11.6 mmol) was added and the reaction mixture was stirred at RT for 4 h. The reaction mixture was diluted with DCM (100 mL), washed with 1N HCl (30 mL x 3), sat. aq. NaHCO₃ (30 mL x 3) and brine (30 mL), dried over Na2SO4, filtered and concentrated under in vacuo to afford the title intermediate (1.70 g, crude) as colorless oil. To a solution of tert-butyl (4-(methoxy(methyl)amino)-4-oxobutyl)(methyl)carbamate (intermediate 8) (200 mg, crude) in THF (5 mL) cooled at -70°C under N2 atmosphere was added dropwise isopropyllithium (3.2 mL, 2.24 mmol, 0.7M in pentane). The resulting mixture was stirred at -70 °C for 2 h. The mixture was quenched with sat. aq. NH4Cl (15 mL), extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a crude product. The crude product was further purified by FCC (PE/EtOAc = 10:1) to afford the title intermediate (60 mg) as colorless oil. Preparation of Compound 60 - tert-butyl (4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4- fluorophenoxy)-1,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl) (methyl) carbamate To a solution of 2-((5-(2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro- N-isopropylbenzamide (intermediate 3) (600 mg, 1.45 mmol) and tert-butyl methyl(5-methyl- 4-oxohexyl)carbamate (intermediate 9) (330 mg, 1.37 mmol) in MeOH (50 mL) was added ZnCl₂ (789 mg, 5.79 mmol). The resulting mixture was stirred at 80 °C for 2 h. Then NaBH₃CN (729 mg, 11.6 mmol) was added and the reaction mixture was stirred at 80°C overnight. After cooling to RT, the mixture was concentrated under reduced pressure to give a crude residue, which was diluted with DCM (50 mL), quenched with sat. aq. NH4Cl (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a crude product which was further purified by FCC (DCM/MeOH = 10:1) to afford the title compound (400 mg, 42% yield) as white solid. Compound 67 - N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(2-methyl-6-(methylamino)hexan-3-yl)- To a solution of tert-butyl (4-(6-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4- triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-5-methylhexyl)(methyl)carbamate (compound 60) (1 g, 1.56 mmol) in DCM (10 mL) was added 4M HCl in dioxane (5 mL, 20 mmol), the resulting mixture was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo to afford the title compound (960 mg, crude, HCl salt) which was used directly in next step without further purification. Compound A - (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl) (methyl) amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy) benzamide To the mixture of N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(2-methyl-6-(methylamino) hexan-3- yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide hydrochloride (compound 67) (480 mg, crude), K₂CO₃ (700 mg, 5.07 mmol) and NaI (400 mg, 2.67 mmol) in DMF (5 mL) was added 1-bromo-2-methoxyethane (230 mg, 1.65 mmol). The resulting mixture was stirred at 50 ^oC overnight. After cooled to RT, the reaction mixture was quenched with H2O (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over Na₂SO₄, filtered and concentrated to give a crude residue. The residue was purified by FCC (DCM/MeOH = 10:1) to afford N-ethyl-5-fluoro-N-isopropyl-2- ((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6- yl)-1,2,4-triazin-6-yl)oxy)benzamide (compound 68) (250 mg, 48% yield) as yellow oil. The N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2- methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide (compound 68) (960 mg, combined from several batches obtained by Method B) was first separated by SFC using DAICEL CHIRALPAK IG (column: 250x30mm 10um; Mobile phase: A: Supercritical CO2, B: EtOH (0.1% ammonia), A:B=40:60 at 60 mL/min) and further purified by preparative HPLC using Boston Prime (column: 150x30mm 5um, Mobile Phase A: H₂O (10mM NH4HCO3), Mobile Phase B: ACN, Flow rate: 25 mL/min, gradient condition B/A from 55% to 85%) to afford the title compound (270 mg) as colorless oil. ¹H NMR (400 MHz, Methanol-d₄): δ = 8.40 (s, 1H), 7.47-7.32 (m, 1H), 7.30-7.10 (m, 2H), 4.24-4.01 (m, 2H), 3.89-3.60 (m, 3H), 3.48 (br s, 3H), 2.63-2.51 (m, 2H), 2.43-2.32 (m, 2H), 2.29-2.07 (m, 6H), 1.86-1.72 (m, 1H), 1.62-1.44 (m, 2H), 1.39-1.02 (m, 10H), 0.99-0.66 (m, 9H). Some protons were hidden by the solvent peak and are not reported. LCMS (ESI) (Method 2): R_t = 1.965 min, m/z found 600.3 [M+H]⁺. SFC (Method 11): Rt = 4.904 min. Example 3 – Synthesis of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl) (methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6- yl)oxy) benzamide (Compound A) – Preparation Method C Preparation of intermediate 227 - tert-butyl (R)-(1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-3- methylbutan-2-yl)carbamate Boc-L-valine (44.9 kg), 2,2-dimethyl-1,3-dioxane-4,6-dione (32.9 kg) and DMAP (35.5 kg) in DCM (607 kg) pre-cooled at -10 to 0°C were added to a solution of DCC (55.5 kg) in DCM (613 kg) over 3 h and aged for 16 h at -10 to 0°C. 10% citric acid aqueous solution (449 kg) was added whilst maintaining a temperature below 10°C. The resulting slurry was aged for 2 h at 0 to 10°C. then filtered. The filter cake was washed with DCM (91 kg). The filtrate was separated and the organic layer was washed with 10% citric acid aqueous solution (two times 450 kg) and 10% NaCl aqueous solution (449 kg). To organic phase (1200 kg), was added acetic acid (75.0 kg) whilst maintaining a temperature between -10 to 0°C. Sodium Borohydride (18.0 kg) was added in portions over 5 h whilst maintaining a temperature in the range -10 to 0°C and then resulting mixture was aged at -10 to 0°C for an additional 16 h. The mixture was warmed to 15 to 25°C, and aged for 2 h. The mixture was then washed with 14% NaCl aqueous solution (450 kg) followed by a second wash with 14% NaCl aqueous solution (432 kg) and a final water wash (444 kg). The organic phase was concentrated under reduced pressure to 2-4 vol. Iso-propanol (143 kg) was added to the residue and concentrated to 4-5 vol. under reduced pressure. After cooling to -10 to 0°C and aging for 8 h, the resulting slurry was filtered, washed with IPA (38 kg) and dried to afford the title intermediate (46.7 kg, 69% yield) as a white solid. Preparation of tert-butyl (R)-(1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-3-methylbutan-2-yl)carbamate (intermediate 227) (46.7 kg) in toluene (333 kg) was heated to reflux and aged for 4 h. The mixture was cooled to ambient temperature, filtered and washed with toluene (20 kg). The combined filtrates were concentrated to dryness at reduced pressure to afford the desired compound (31.05 kg, 96% yield) as an oil which was used directly without further purification. Preparation of intermediate 229 - tert-butyl (5R)-2-hydroxy-5-isopropylpyrrolidine-1- tert-butyl (R)-2-isopropyl-5-oxopyrrolidine-1-carboxylate (intermediate 228) (30.9 kg) in 2- MeTHF (26.7 kg) was cooled to -5 to 5°C. A solution of LiBH4 in 2-MeTHF (1M, 45.2 kg, 54.4 mol) was added over 3 h and the mixture was aged for 4 h. A cold aqueous solution of 5% NaHCO₃ (163 kg) was added at -5 to 5 °C over 3h and aged for an additional 2 h. The mixture was warmed to ambient temperature and aged for a further 2 h. The aqueous layer was separated and the organic layer was washed with 10% NaCl aqueous solution (170 kg) and water (155 kg). During the water wash, an emulsion formed and solid NaCl (3.1 kg) was added to affect the separation. After removal of the aqueous layer, the organic layer was concentrated under reduced pressure to dryness to afford the desired compound (28.5 kg, 91% yield) as an oil, which was used directly without further purification. Preparation of intermediate 230 - tert-butyl (R)-(6-((2-methoxyethyl)(methyl)amino)-2- methylhexan-3-yl)carbamate tert-butyl (5R)-2-hydroxy-5-isopropylpyrrolidine-1-carboxylate (intermediate 229) (28.55 kg) in DCM (344 kg), at 15 to 25°C was treated with 2-methoxy-N-methylethan-1-amine (12.3 kg, 138.0 mol) and the resulting mixture was aged for 1 h. Sodium triacetoxyborohydride (40.12 kg) was added in portions over 5h whilst maintaining a temperature between 15 to 25°C and the resulting mixture was aged for 48 h. The reaction mixture was quenched by the addition of 8% NaOH aqueous solution (184 kg) over 2 h whilst maintaining a temperature between 15 to 25°C and the mixture was aged for a further 2 h. The water layer was separated, and the organic layer was washed with water (169 kg). The organic layer was then concentrated under reduced pressure to dryness to afford the title intermediate (33.26 kg, 88% yield) as an oil which was used directly without further purification. Preparation of intermediate 231 - (R)-N¹-(2-methoxyethyl)-N¹,5-dimethylhexane-1,4-diamine, To 4 molar solution of HCl in iso-propanol (84.80 kg) at ambient temperature was added a solution of tert-butyl (R)-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)carbamate (intermediate 230) (32.38 kg) in iso-propanol (25.6 kg) over 3 h and the mixture was aged at ambient temperature for an additional 19 h. Methyl tert-butyl ether (95.25 kg) was then added over 1 h and the mixture was aged for 2.5 h. The resulting slurry was filtered and washed with MTBE (53 kg). The filter cake was dried to afford the title compound (23.92 kg, 81% yield) as a white solid. Preparation of intermediate 232 - ethyl 1-benzyl-3-(chloromethyl)pyrrolidine-3-carboxylate To a solution of DIPEA (952 g, 1.1 eq.) in THF (6 L) which was cooled to -35 to -25^oC was added n-BuLi (2.33 kg, 2.5 M in hexane, 1.0 eq.) whilst maintaining a temperature below - 25^oC. The resulting mixture was aged at -35 to -25^oC for an additional 30 min then cooled to between -78 to -60^oC. A solution of ethyl 1-benzylpyrrolidine-3-carboxylate (2 kg, 1.0 eq.) in THF (2 L) at -78 to -60^oC was added and stirred for an addition 30 min. Chloroiodomethane (1.81 kg, 1.2 eq.) was then charged at -78 to -60^oC. The reaction mixture was aged at -60 to - 40^oC for 2 h. To the reaction mixture was added to citric acid aqueous solution (660 g in 6 L H₂O) at a temperature between 0 to 10^oC and the resulting mixture was aged at 20 to 30^oC for an additional 20 min. After separating the layers, the aqueous layer was extracted with EtOAc (6 L) and the combined organic layers washed with brine (6 L) then warmed to 50 to 60^oC. Oxalic acid (2.22 kg) was charged at 50 to 60^oC. The resulting mixture was stirred at 50 to 60^oC for 3 h then cooled to 20 to 30^oC and aged overnight. The resulting solid was filtered and the cake was washed with ethyl acetate (2 L). The wet cake was added to toluene (4 L), H2O (8 L) and K₃PO₄ (1.5 eq.) and the resulting mixture was aged at 20 to 30^oC for 20 min. After separating the layers, the aqueous layer was extracted with toluene (2 L). The organic layers were combined and washed twice with water (2 L). The organic phase was concentrated under reduced pressure to afford 4.2 kg of the desired compound as a toluene solution (46 wt % by assay, giving an assay yield of 80%). Preparation of intermediate 233 - 1-benzyl-3-(chloromethyl)pyrrolidine-3-carbaldehyde Reaction conducted in a flow chemistry system: A solution of ethyl 1-benzyl-3- (chloromethyl)pyrrolidine-3-carboxylate (intermediate 232) (4.4 kg) in toluene (26 L) was pumped at 26.7 mL/min and cooled to -60^oC. After cooling, it was then mixed with a cooled solution of DIBAL-H (28.1 mol) in toluene at -60^oC (28 L) with a pumping rate of 32.1 mL/min. The mixture was passed through a Perfluoroalkoxy (PFA) coil tube reactor at ^60^oC (total flow rate of 58.8 mL/min with a residence time of 5 seconds). The resulting mixture was mixed with cooled MeOH (-60^oC) which was pumped at the rate of 15.2 mL/min. This mixed solution was pumped to another PFA coil tube reactor at ^60^oC (total flow rate of 74 mL/min with a residence time of 5 seconds). The resulting mixture was collected into a receiver which contained 20 wt % aq. solution Rochelle’s salt (20 V). The layers were separated, and the organic phase was twice washed with water (2 x 44 L). The organic phase was combined with another 3.0 kg batch prepared in an analogous manner and concentrated under reduced pressure to afford 20.8 kg of a toluene solution of the desired compound (25.5 wt % assay by HPLC, giving an assay yield of 85%) which was used directly without further purification. ¹H NMR (300 MHz, Chloroform-d): δ 9.62 (s, 1H), 7.39 - 7.20 (m, 5H), 3.83 - 3.57 (m, 4H), 2.96 (d, J = 10.2 Hz, 1H), 2.80 - 2.55 (m, 3H), 2.17 (ddd, J = 13.9, 7.9, 6.1 Hz, 1H), 1.83 (ddd, J = 13.4, 7.8, 5.5 Hz, 1H). Preparation of intermediate 234 - (R)-4-(6-benzyl-2,6-diazaspiro[3.4]octan-2-yl)-N-(2- To a solution of 1-benzyl-3-(chloromethyl)pyrrolidine-3-carbaldehyde (intermediate 233) in toluene (3.0 kg, 10 wt %) diluted with toluene (30 L) and (R)-N¹-(2-methoxyethyl)-N¹,5- dimethylhexane-1,4-diamine, dihydrochloride (intermediate 231) (3.47 kg) was added triethylamine (2.55 kg, 25.2 mol) at 20 to 30^oC. The resulting mixture was aged for 2 h at 20 to 30^oC. Then sodium triacetoxyborohydride (9.0 kg) was charged at 20 to 30^oC and the mixture was aged for 12 h. The reaction mixture was cooled to 5 to 15^oC and 25 wt % NaOH aqueous solution (25 L, ~16.75 eq.) was added maintaining a temperature below 35^oC. The resulting mixture was aged at 20 to 30^oC for 25 mins and the layers were separated. The organic layer was washed with 15 wt % aq. NaCl (10 L) and the layers were again separated and water (18 L) was charged to the organic phase. The pH of the aqueous phase was adjusted to 6~7 with 4M aq. HCl whilst maintaining an internal temperature below 35^oC. The organic phase was then discarded and the aqueous phase was separated and basified to pH 8~9 with K2HPO4. The resulting mixture was warmed to 50 to 55^oC and aged for 3 h. The reaction mixture was then cooled to ambient temperature and combined with other two batches (2.4 kg + 3.0 kg). The combined streams were washed with methyl tert-butyl ether three times (3 x 40 L). To the resulting aqueous layer was added additional methyl tert-butyl ether (83 L) and the aqueous phase was basified to pH 9~10 using 8 wt % aq. NaOH whilst maintaining a temperature between 15 to 35^oC. The aqueous layer was separated, and the organic layer was washed with three times water (3 x 30 L). The organic layer was then concentrated under reduced pressure to approximately 3 volumes and then flushed with methanol three times (3 x 30 L) and concentrated to dryness to afford the desired intermediate (12.4 kg, 90% isolated yield) as light- yellow oil, which was used directly without further purification. Preparation of intermediate 234a (citric acid salt of intermediate 234) EtOH (80 ml) and intermediate 234 (20 g) were added in a round bottom flask. Next, a 0.5 M solution of citric acid in EtOH (100 ml; 1 equivalent) was added to the mixture in the round bottom flask at room temperature. Subsequently, the mixture was evaporated till dryness (Rotavap, 40 °C). Acetonitrile (200 ml) was added to the residue and the mixture was evaporated till dryness (Rotavap, 40 °C). Acetonitrile (100 ml) was added to the residue and stirred overnight on a magnetic heating plate at room temperature. Finally, intermediate 234a was filtered off and dried at room temperature. Intermediate 234a (3.72 g) was added to acetonitrile (20 ml) at room temperature and the mixture was stirred. The mixture was heated to 60 °C until the reaction mixture became homogeneous (about 10 minutes). Next, the mixture was cooled to 50 °C at a rate of 0.5 °C/min. Next, seeds were added (19 mg of intermediate 234a; 0.5 w/w %) and the mixture was aged while stirring during 3 hours and 30 minutes. Next, the mixture was cooled non-linear to 20 °C over 8 hours with an exponent of 2,3. The obtained mixture was stirred overnight and the product was filtered off and dried (overnight at room temperature in hood). After isolation, intermediate 234b was obtained (2.75 g; yield 73.9%) as the crystalline form of the citric acid salt of intermediate 234. The obtained ratio of the intermediate/citric acid is 3/2 (NMR). The non-linear cooling referred to above was done according to the formula below: A new linear ramp is started every 30 seconds during the defined duration of the cooling. The ramp is calculated according to the following equation: Tset: Set value for each new ramp Tstart value: Measured mixture temperature at the start of the cooling trajectory T_{end value}: Defined end value of cooling trajectory t_action: Actual time from the start of the cooling Duration: Defined cooling duration n: Exponent ¹H NMR (400 MHz, MeOH-d₄) δ ppm 0.91 (3 H, d, J=6.88 Hz) 0.98 (3 H, d, J=6.88 Hz) 1.46 - 1.57 (2 H, m) 1.67 - 1.87 (2 H, m) 1.94 - 2.03 (1 H, m) 2.20 - 2.29 (2 H, m) 2.62 - 2.69 (2 H, m) 2.72 - 2.77 (4 H, m) 2.77 - 2.82 (2 H, m) 2.90 (2 H, t, J=7.32 Hz) 2.95 - 3.02 (2 H, m) 3.07 - 3.16 (2 H, m) 3.16 - 3.22 (2 H, m) 3.37 (3 H, s) 3.68 - 3.72 (2 H, m) 3.83 - 3.89 (2 H, m) 3.90 - 3.92 (2 H, m) 3.94 - 4.06 (2 H, m) 7.32 - 7.43 (5 H, m). Preparation of intermediate 224 - (R)-N-(2-methoxyethyl)-N,5-dimethyl-4-(2,6-diazaspiro To palladium hydroxide on carbon (1.2kg) in EtOH (1.47 kg) cooled to -5 to 5°C were added methanesulfonic acid (MSA) (11kg), (R)-4-(6-benzyl-2,6-diazaspiro[3.4]octan-2-yl- N-(2- methoxyethyl)-N,5-dimethylhexan-1-amine (intermediate 234) (10kg) and EtOH (250L). The mixture was warmed to 35-45°C and stirred under a hydrogen atmosphere (0.27 to 0.40 MPa) for 16-20h. The mixture was filtered over diatomite (20kg) and the pad was washed with EtOH (24L). The filtrate was concentrated under reduced pressure (<40°C) to 2~3 vol. and then flushed twice with 2-MeTHF (73kg and 47kg) to give a 2~3 vol. solution. After dilution with 2-MeTHF (65kg), 10% aq. sodium sulfate (30kg) was added and the mixture was cooled to 0 to 10°C, followed by the addition of 16% aq. NaOH (50kg) to adjust the pH to 13~14. The temperature was adjusted to 15 to 25°C and stirred for 30 to 60 min. The aqueous layer was separated and extracted twice with 2-MeTHF (47kg x 2). The combined organic layers were concentrated under reduced pressure (<40°C) to 3~4 vol. and 2-MeTHF (950g) was added. After concentration under reduced pressure (<40°C) to 3~4 vol., the resulting solution was diluted with 2-MeTHF (30kg), dried by passing through 4A molecular sieves (25kg) and washed with 2-MeTHF (30kg). The final solution was concentrated to afford the desired compound (6.7kg) as an oil with 90.1% assay purity in a 79% corrected yield. Preparation of intermediate 225 - (R)-4-(6-(3,6-dichloro-1,2,4-triazin-5-yl)-2,6-diazaspiro [3.4]octan-2-yl)-N-(2-methoxyethyl)-N,5-dimethylhexan-1-amine To (R)-N-(2-methoxyethyl)-N,5-dimethyl-4-(2,6-diazaspiro[3.4]octan-2-yl)hexan-1-amine (intermediate 224) (100 g) was added 2-MeTHF (430 g) and TEA (68 g) and the mixture was cooled to -50 to -40°C.3,5,6-trichloro-1,2,4-triazine (62 g) in 2-MeTHF (172 g) was added and the mixture was stirred for 1 to 3 h. The resulting mixture was warmed to -20 to -10°C and a 7% NaHCO₃ aqueous solution was added, the mixture was warmed to 20 to 30°C and stirred for 30 to 60 min. The aqueous layer was removed and the organic layer was washed with 10% Na2SO4 (500 g). The organic layer was dried by passing through 4Å molecular sieves (220 g) and washed with 2-MeTHF (180 g). The title intermediate was afforded in 90% assay yield as a solution 14.8 wt% in 2-MeTHF. Compound 393 - (R)-2-((3-chloro-5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3- yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropyl- benzamide Synthesis method A for Compound 393: The mixture of N-ethyl-5-fluoro-2-hydroxy-N-isopropylbenzamide (intermediate 28) (1.10 g, 4.88 mmol), (R)-4-(6-(3,6-dichloro-1,2,4-triazin-5-yl)-2,6-diazaspiro[3.4]octan-2-yl)-N-(2- methoxyethyl)-N,5-dimethylhexan-1-amine (intermediate 225) (1.70 g, 3.82 mmol) and DBU (750 mg, 4.93 mmol) in anhydrous THF (15 mL) was stirred at 40 °C for 8 h. After cooled to RT, the mixture was concentrated under reduced pressure, the resulting residue was diluted with DCM (60 mL) and washed with H2O (20 mL ^ 3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product which was purified FCC (MeOH/DCM = 0% to 10%) to afford a yellow oil (1.40 g), which was further separated by SFC over DAICEL CHIRALPAK AD (column: 250 ^50 mm,10 um; Mobile phase: A: Supercritical CO₂, B: EtOH (0.1% ammonia), A:B = 50:50 at 70 mL/min; Column Temp: 38 ^oC; Nozzle Pressure: 100Bar; Nozzle Temp: 60 ^oC; Evaporator Temp: 20 ^oC; Trimmer Temp: 25 ^oC; Wavelength: 220nm) to afford the title compound (1.0 g). To a 2-MeTHF solution of (R)-4-(6-(3,6-dichloro-1,2,4-triazin-5-yl)-2,6-diazospiro[3.4]octan- 2-yl)-N-(2-methoxyethyl)-N,5-dimethylhexan-1-amine (intermediate 225) (676g of a 14.8 wt% solution in 2-MeTHF, 100g corrected of intermediate 225) and N-ethyl-5-fluoro-2-hydroxy-N- isopropylbenzamide (intermediate 28) (50.6 g) in 2-MeTHF (40 g) at 20 to 30°C was added tetramethylguanidine (31 g) and the mixture was stirred for 40 to 48 h. A 7% NaHCO3 aqueous solution (500g) was added and the mixture was stirred for 30 to 60 min. The aqueous layer was removed and the organic layer was washed with twice with 4% NaOH aqueous solution (2 x 500 g) and once with 10% Na2SO4 aqueous solution (500 g). The organic layer was concentrated under reduced pressure (<40°C) to 2.2~3.0 vol. and flushed three times with MeOH (1 ^ 790g and 2 ^ 395g) until both 2-MeTHF and water content were both <1.0% to afford the desired compound in 86% assay yield as a 60.1 wt% solution in methanol. Compound A - (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl) (methyl) A methanol solution of (R)-2-((3-chloro-5-(2-(6-((2-methoxyethyl)(methyl)amino)-2- methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy-N-ethyl-5-fluoro-N- isopropylbenzamide (compound 393) (163.93g of a 60.1 wt % solution in MeOH, 100g corrected of compound 393), palladium on carbon (10 g) and MeOH (316 g) was stirred at 20 to 30°C under a hydrogen atmosphere (0.20 to 0.30 Mpa) for 18 h. The mixture was filtered over diatomite (75 g) and the cake was washed with MeOH (158 g). The filtrate was concentrated under reduced pressure (< 40°C) to ~3 vol., then flushed with isopropyl acetate (IPAc, 870 g) concentrating to ~3 vol. The mixture was then diluted with IPAc (696 g) and a 20% Na₂CO₃ aqueous solution was added (500 g). The mixture was stirred for 30 to 60 min. The aqueous layer was removed. The organic layer was washed with water (500 g) then concentrated under reduced pressure <45°C to ~3 vol. The title intermediate was afforded in approximately 90% assay yield as a 48.1 wt% solution in IPAc. Example 4 – Synthesis of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl) (methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6- yl)oxy) benzamide oxalate (Compound A3)

Compound A3 To a solution of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl) (methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy) benzamide (Compound A) (270 mg, 0.450 mmol) in 20 mL of ACN (20 mL) was added oxalic acid (81.0 mg, 0.900 mmol). After addition, the reaction mixture was stirred at RT for 1 h. Then the reaction mixture was concentrated, the residue was re-dissolved in ACN and deionized water, and lyophilized to afford the title compound (350 mg) as white solid. ¹H NMR (400 MHz, Methanol-d4): δ = 8.48 (s, 1H), 7.52-7.11 (m, 3H), 4.54-3.64 (m, 12H), 3.40-3.34 (m, 5H), 3.23-3.13 (m, 2H), 2.90 (s, 3H), 2.54-2.27 (m, 2H), 2.19-2.03 (m, 1H), 1.97- 1.77 (m, 2H), 1.75-1.50 (m, 2H), 1.35-0.65 (m, 17H). ¹H NMR (400 MHz, DMSO-d6): δ = 8.51 (s, 1H), 7.51-7.29 (m, 3H), 4.29-3.34 (m, 12H), 3.23-2.84 (m, 7H), 2.70 (s, 3H), 2.35-2.09 (m, 2H), 2.05-1.85 (m, 1H), 1.81-1.58 (m, 2H), 1.56- 1.33 (m, 2H), 1.18-0.60 (m, 17H). LCMS (ESI) (Method 2): Rt = 1.969 min, m/z found 600.4 [M+H]⁺. Example 5 – Synthesis of Compound A1 To a solution of Compound A (207.90 g of a 48 wt% solution in IPAc, 100g of active Compound A) in IPAc (360 g) was added EtOH (63 g) at 20 to 25°C. The solution was then treated with conc. HCl (32.9 g) in EtOH (49.5 g) over ~15 min. The mixture was seeded with crystalline Compound A1 seed (2 g, 2% seed load) then aged for 18 h. IPAc (870 g) was added slowly over 4 h at between 20 to 25°C and the slurry was stirred for an additional 18 h. After cooling to ~5°C, the product was filtered, washed with IPAc (522 g) and dried under vac at 20- 30 °C to afford the weakly crystalline Compound A1 as a white solid (91.0% yield, 115.4 g). (Note: A small amount of seed material used in the reaction was obtained via an analogous reaction protocol on small-scale.) Recrystallisation: A solution of weakly crystalline Compound A1 (100 g), EtOH (166 g), purified water (21.5 g) and IPAc (178 g) was stirred at 20 to 30°C for 0.5-2 h to get a clear solution. Extra IPAc (522 g) was added dropwise over 1~2 h, and then the mixture was seeded with crystalline Compound A1 seed (2 g, 2% seed load). Then the mixture was aged for 18 ~20 h, IPAc (348 g) was added slowly over 12 h at between 20 to 30°C, and the slurry was stirred for an additional 55~60 h. The product was filtered, washed with IPAc (158 g) and dried in vacuo at 20~30°C to afford Compound A1 as a white solid (85% yield, 85.0 g, net). ¹HNMR (DMSO-d6, 400MHz): δ = 11.60 (1H, brs), 10.8 (1H, brs), 8.52 (1H, s), 7.36 (3H, m), 3.97-4.20 (7H, m), 3.64-3.71 (4H, m), 3.47 (7H, m), 3.25 (2H, m), 3.05 (3H, m), 2.73 (3H, s), 2.10-2.45 (1H, m), 1.99 (1H, m), 1.78 (2H, m), 1.55 (2H, m), 0.83-1.12 (12H, m), 0.70 (2H, m). LCMS (Method 7): Rt = 0.669 min, m/z found 600.5 [M+H]⁺. Example 6 – Synthesis of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt hydrate (Compound A4) (equivalent water not determined) Compound A4 43.06 g benzenesulfonic acid (2 equivalents with respect to the free base Compound A) was added to 840 ml of an acetone/water 95/5 v/v mixture and dissolved.192.8 g of a solution of Compound A (containing 80 g API) in IPAc was added. The material was dissolved, resulting in a clear solution. A further 80 ml of IPAc is added and the temperature was adjusted to 25 °C. 2% of seeds were added and the mixture is stirred for an hour at 25 °C. Then 28.8 V (2312 ml) of IPAc was added over a period of 8 hours. Afterwards the suspension was stirred for 18 hours at 25 °C. The suspension was filtered and washed with 320 ml of a mixture of acetone/water/IPAc 23.75/1.75/75 v/v/v. 122.91 g of crystalline form A bis-besylate hydrate (equivalent water not determined) was obtained. A skilled person will understand that a small amount of initial seed material used in the reaction above can be obtained via an analogous reaction protocol on small-scale without addition of seeds and wait for spontaneous nucleation. Initial seeds of the besylate salt were also obtained during salt screening experiments. In these experiments 100 mg of the free base was weighed into 2mL vials, and then 200μL of ethyl acetate or acetone was added to dissolve the free base.1 eq counter-ions (benzenesulfonic acid) were added to the samples, and the samples were stirred at 25°C for 3 days. The suspension obtained was centrifuged and yielded initial seeds. An appropriate amount of crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt hydrate was dissolved in deuterated DMSO and the 1D ¹H NMR spectrum was recorded. A Bruker AVANCE NEO-600 MHz NMR spectrometer equipped with a Bruker 5 mm PA BBO 600S3 BB-H-D-05 Z-GRD high resolution probe and running TOPSPIN 4.0 software, was used to collect a 1-dimensional proton experiment at 300K on the sample in deuterated DMSO. ¹H NMR (600 MHz, DMSO-d₆) δ ppm 0.69 (br s, 2 H) 0.82 - 0.98 (m, 9 H) 1.07 (br s, 4 H) 1.31 - 1.46 (m, 1 H) 1.51 (br d, J=2.91 Hz, 1 H) 1.69 (br d, J=3.45 Hz, 2 H) 1.98 (br s, 1 H) 2.06 - 2.45 (m, 2 H) 2.77 (br s, 3 H) 2.87 - 3.19 (m, 3 H) 3.24 (br s, 1 H) 3.31 (s, 6 H) 3.64 (br s, 4 H) 3.71 - 4.59 (m, 7 H) 7.24 - 7.54 (m, 9 H) 7.61 (br d, J=7.27 Hz, 4 H) 8.45 - 8.60 (m, 1 H) 9.24 (br s, 1 H) 9.44 - 9.82 (m, 1 H). Example 7 – Alternative synthesis of crystalline form A of (R)-N-ethyl-5-fluoro- N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt hydrate (Compound A4) (equivalent water not determined) A mixture of isopropanol/water 95/5 (24 ml) was charged in a flask and heated to 40 °C. Benzenesulfonic acid (4.31 g; 98%) was added. Subsequently, 19.3 g of a solution of Compound A (containing 8 g of Compound A) in IPAc was added. Another 16 ml of IPAc was added.2% of seeds were added and the mixture was stirred for 1 hour at 40 °C. Then IPAc was added (115.2 ml) dropwise over a period of 8 hours. Next, the mixture was cooled to 0 °C for 15 hours. The suspension was filtered and the wet cake was washed with (IPA/H₂O 95/5)/IPAc 1/6 (32 ml). The wet cake was dried at 25 °C for 16 hours to obtain 11.44 g of crystalline form A bis-besylate hydrate (equivalent water not determined). Crystalline form A Crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt hydrate may be characterised by an X- ray powder diffraction pattern. X-ray powder diffraction (XRPD) analysis was carried out on a PANalytical Empyrean diffractometer. The instrument is equipped with a Cu-Kα X-ray tube using iCore and dCore tunable optics for the incident and the diffracted beam, respectively. The compound was loaded into the cavity of a 16mm sample holder using the back loading technique. Samples were run on XRPD using the method below: Tube: Cu: K-Alpha (λ=1.541874Ǻ) Generator: Voltage: 45 kV; Current: 40 mA Geometry: Bragg-Brentano Scan mode: Continuous Scan Scan Range: 3 to 35 deg. Step size: 0.0131 deg. Counting time: 30s Spinner revolution time: 1 sec Incident beam path (iCore) Program. divergence slit: automatic Irradiated length: 10 mm Soller slit: 0.03 rad Mask 1: 14 mm Mask 2: 6 mm Width: 7.7 mm Diffracted beam path (dCore) Anti scatter slit: automatic Irradiated length: 10 mm Soller slit: 0.04 rad Detector: PIXcel3D- Medipix31x1 One skilled in the art will recognize that diffraction patterns and peak positions are typically substantially independent of the diffractometer used and whether a specific calibration method is utilized. Typically, the peak positions may differ by about ± 0.2° two theta, or less. The intensities (and relative intensities) of each specific diffraction peak may also vary as a function of various factors, including, but not limited to particle size, orientation, sample purity, etc. The X-ray powder diffraction pattern comprises peaks at 5.4, 7.2, 11.1, 11.9 and 21.7 degrees two theta ± 0.2 degrees two theta. The X-ray powder diffraction pattern may further comprise at least one peak selected from 13.7, 14.5, 14.7, 15.0, 16.5, 17.8, 19.0, 19.4, 20.1 degrees two theta ± 0.2 degrees two theta. Form A may further be characterized by an X-ray powder diffraction pattern having four, five, six, seven, eight, nine or more peaks selected from those peaks identified in Table 2. Form A may further be characterized by an X-ray powder diffraction pattern comprising those peaks identified in Table 2, wherein the relative intensity of the peaks is greater than about 2%, preferably greater than about 5%, more preferably greater than about 10%, more preferably greater than about 15%. However, a skilled person will realize that the relative intensity of the peaks may vary between different samples and different measurements on the same sample. Form A may further be characterized by an X-ray powder diffraction pattern substantially as depicted in FIG.1. Table 2 provides peak listings and relative intensity for the XPRD of Crystalline form A of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis- besylate salt hydrate salt (FIG.1). Table 2 – Peak Listings and Relative Intensity for XRPD of Form A Pos. Rel. Int. [°2Th.] [%] 5.3965 16.30 7.1906 23.69 9.2513 8.14 9.4433 7.39 11.0719 11.34 11.9144 73.29 12.3921 29.17 12.5717 22.93 12.8791 8.93 13.6790 26.58 13.8694 15.67 14.4793 38.19 14.7398 55.26 14.9599 56.99 15.8715 20.66 16.4606 22.37 17.0459 20.43 17.4421 34.59 17.8203 46.78 18.2871 30.73 18.9573 43.91 19.4485 41.00 20.1190 35.53 20.7356 18.05 21.0535 30.09 21.6801 100.00 22.0236 18.06 22.7925 29.92 23.5044 41.92 23.9959 43.96 24.5555 31.47 25.1401 25.01 25.7588 59.24 26.0910 53.05 26.6137 39.47 27.5409 24.89 28.5493 22.44 29.1699 13.97 30.1441 21.01 31.2560 14.66 31.8783 16.47 32.7054 17.11 33.2797 24.40 33.9762 15.63 P^{HARMACOLOGICAL} P^ART In Vitro Proliferation - Menin-MLL Inhibitor (Compound A4) in Combination with DNA Intercalating Agent (Idarubicin) Cell lines AML cell lines MOLM-13, OCI-AML3 and MV4-11 were purchased from DSMZ. MOLM- 13 were grown in RPMI medium supplemented with 10% Fetal Bovine Serum (FBS) and 1% penicillin/streptomycin. MV4-11 cells were grown in IMDM medium supplemented with 10% FBS and 1% penicillin/streptomycin. OCI-AML3 cells were cultured in 80-90% alpha- MEM (with ribo- and deoxyribonucleosides) + 10-20% FBS. All cell lines were cultured at 37°C in 5% CO2 atmosphere. Cell Titer Glo assays AML cell lines (5 x 10³ cells/well) were seeded in 96-well plates and grown for 6 days in serum (10%)-containing medium in the presence or absence of inhibitors at the indicated concentrations. Proliferation was analyzed by means of a Cell Titer Glo assay using the CellTiter 96 Aqueous One Solution Cell Proliferation Assay (Promega, Madison, WI, USA), according to the manufacturer's instructions. Data are mean with standard deviation from two to four independent experiments in technical triplicates. Synergy calculations R-based Biochemically Intuitive Generalized Loewe (BIGL) model implemented with a highest single agent (HSA) null model. Specifically, the BIGL methodology was applied to calculate drug-drug interactions (Van der Borght, K., Tourny, A., Bagdziunas, R. et al. BIGL: Biochemically Intuitive Generalized Loewe null model for prediction of the expected combined effect compatible with partial agonism and antagonism. Sci Rep 7, 17935 (2017); Thas, O., Tourny, A., Verbist, B., Hawinkel, S., Nazarov, M., Mutambanengwe, K., & Bijnens, L. Statistical detection of synergy: New methods and a comparative study. Pharmaceutical Statistics (2021)). Synergy matrix results of the BIGL analysis of the cell line data with HSA as mean model calculated on the basis of the cellular metabolic activity using Cell Titer-Glo assay. Bootstrap confidence intervals are indicated. Effect sizes and their confidence intervals are shown. Notably, each data point based on the p-value and sign of the respective maxR statistic with the size of the dots reflecting the degree of synergy or antagonism corresponding to graded scale. No significant average effect if zero is included in the interval. Results Menin-MLL Inhibitor (Compound A4) in Combination with Idarubicin A pairwise matrix combination of idarubicin and Compound A4 was evaluated in MOLM-13 (KMT2A-AF9; FLT3-ITD) and OCI-AML3 (NPM1c AML) cells using a 6-day Cell Titer-Glo assay format. Notably, the combination of idarubicin and Compound A4 is not antagonistically cytotoxic in MOLM-13 (KMT2A-AF9; FLT3-ITD) cells as reflected in the contour plot (FIG. 2A) and detailed below in the Table 3A. Table 3A – Effect of Compound A4 in Combination with Idarubicin on MOLM-13 Cell Proliferation. Note that absence of any asterisk indicates an additive effect, antagonism is indicated by “ * ” and synergy is indicated by “ ** ”. Antagonistic and synergistic effects are derived from the significant calls based on the maxR test and numbers associated with same interpreted as antagonistic or synergistic, respectively. Likewise, the combination of idarubicin and Compound A4 is not antagonistically cytotoxic in OCI-AML3 (NPM1c AML) cells as reflected in the contour plot (FIG.2B) and detailed below in the Table 3B. Table 3B – Effect of Compound A4 in Combination with Idarubicin on OCI-AML3 Cell Proliferation.

Note that absence of any asterisk indicates an additive effect, antagonism is indicated by “ * ” and synergy is indicated by “ ** ”. Antagonistic and synergistic effects are derived from the significant calls based on the maxR test and numbers associated with same interpreted as antagonistic or synergistic, respectively. In Vitro Proliferation - Menin-MLL Inhibitor (Compound A3) in Combination with a Pyrimidine Analog (Cytarabine) and DNA Intercalating Agent (Idarubicin or Daunorubicin) Cell lines AML cell lines MOLM-13 and OCI-AML3 were purchased from DSMZ. MOLM-13 were grown in RPMI medium supplemented with 10% Fetal Bovine Serum (FBS) and 1% penicillin/streptomycin. OCI-AML3 cells were cultured in 80-90% alpha-MEM (without ribo- and deoxyribonucleosides) + 10-20% FBS. All cell lines were cultured at 37°C in 5% CO2 atmosphere. Cell Titer Glo assay AML cell lines (10 x 10³ cells/well) were seeded in 96-well plates and grown for 6 days in complete medium in the presence or absence of inhibitors at the indicated concentrations. Proliferation was analyzed by means of a Cell Titer Glo assay using the CellTiter 96 Aqueous One Solution Cell Proliferation Assay (Promega, Madison, WI, USA), according to the manufacturer's instructions. Data are mean with standard deviation from two to four independent experiments in technical triplicates. Synergy calculations R-based Biochemically Intuitive Generalized Loewe (BIGL) model implemented with a highest single agent (HSA) null model. Specifically, the BIGL methodology was applied to calculate drug-drug interactions (Van der Borght, K., Tourny, A., Bagdziunas, R. et al. BIGL: Biochemically Intuitive Generalized Loewe null model for prediction of the expected combined effect compatible with partial agonism and antagonism. Sci Rep 7, 17935 (2017); Thas, O., Tourny, A., Verbist, B., Hawinkel, S., Nazarov, M., Mutambanengwe, K., & Bijnens, L. Statistical detection of synergy: New methods and a comparative study. Pharmaceutical Statistics (2021)). Synergy matrix results of the BIGL analysis of the cell line data with HSA as mean model calculated on the basis of the cellular metabolic activity using Cell Titer-Glo assay. Bootstrap confidence intervals are indicated. Effect sizes and their confidence intervals are shown. Notably, each data point based on the p-value and sign of the respective maxR statistic with the size of the dots reflecting the degree of synergy or antagonism corresponding to graded scale. No significant average effect if zero is included in the interval. Results Menin-MLL Inhibitor (Compound A3) in Combination with Cytarabine + Idarubicin A pairwise matrix combination of Cytarabine+Idarubicin and Compound A3 was evaluated in MOLM-13 (KMT2A-AF9; FLT3-ITD) and OCI-AML3 (NPM1c AML) cells using a 6-day Cell Titer-Glo assay format. The triple combination of Cytrabine+Idarubicin and Compound A3 is synergistically cytotoxic in MOLM-13 (Fig.2C and Table 3C) and not antagonistically cytotoxic in OCI-AML3 cells as reflected below (Fig.2D and Table 3D). Table 3C – Effect of Compound A3 in Combination with Cytarabine+Idarubicin on MOLM-13 Cell Proliferation. Note that absence of any asterisk indicates an additive effect, antagonism is indicated by “ * ” and synergy is indicated by “ ** ”. Antagonistic and synergistic effects are derived from the significant calls based on the maxR test and numbers associated with same interpreted as antagonistic or synergistic, respectively. Table 3D – Effect of Compound A3 in Combination with Cytarabine+Idarubicin on OCI- AML3 Cell Proliferation. Note that absence of any asterisk indicates an additive effect, antagonism is indicated by “ * ” and synergy is indicated by “ ** ”. Antagonistic and synergistic effects are derived from the significant calls based on the maxR test and numbers associated with same interpreted as antagonistic or synergistic, respectively. Menin-MLL Inhibitor (Compound A3) in Combination with Cytarabine + Daunorubicin A pairwise matrix combination of Cytarabine+Daunorubicin and Compound A3 was evaluated in MOLM-13 (KMT2A-AF9; FLT3-ITD) and OCI-AML3 (NPM1c) cells using a 6-day Cell Titer-Glo assay format. The triple combination of Cytarabine+Daunorubicin and Compound A3 is synergistically cytotoxic in MOLM-13 (Fig.2E and Table 3E) and not antagonistically cytotoxic in OCI-AML3 cells as reflected below (Fig.2F and Table 3F). Table 3E – Effect of Compound A3 in Combination with Cytarabine+Daunorubicin on MOLM-13 Cell Proliferation.

Note that absence of any asterisk indicates an additive effect, antagonism is indicated by “ * ” and synergy is indicated by “ ** ”. Antagonistic and synergistic effects are derived from the significant calls based on the maxR test and numbers associated with same interpreted as antagonistic or synergistic, respectively. Table 3F – Effect of Compound A3 in Combination with Cytarabine+Daunorubicin on OCI-AML3 Cell Proliferation. Note that absence of any asterisk indicates an additive effect, antagonism is indicated by “ * ” and synergy is indicated by “ ** ”. Antagonistic and synergistic effects are derived from the significant calls based on the maxR test and numbers associated with same interpreted as antagonistic or synergistic, respectively. In Vitro Proliferation - Menin-MLL Inhibitor ((Compound A3) in Combination with DNA Intercalating Agent – (Daunorubicin), and Pyrimidine Analog (Cytarabine) in Primary NPM1c-positive AML Patient Samples Compound A3 was tested in combination with cytarabine and daunorubicin using primary NPM1c-positive AML patient samples (N=8). All samples were cultured in complete culture medium and seeded at 20,000 cells per well in 96-well plates then treated with doublet combination of cytarabine with daunorubicin (at an initial concentration of 10 μM cytarabine plus 5 μM daunorubicin, followed by a 6-point, 10-fold serial dilution), or triplet combination with Compound A3 and cytarabine plus daunorubicin (at an initial concentration of 10 μM Compound A3, 10 μM cytarabine plus 5 μM daunorubicin, followed by a 6-point, 10-fold serial dilution). Plates of cells with the aforementioned drug treatments as well as controls (wells with medium only (“medium control”) or medium including vehicle (“vehicle control”)) were incubated for 6 days at 37°C, 5% CO2; no further additions or changes to the medium were made over the duration of the experiment. ATP levels, as a surrogate marker of cell viability, were evaluated using the CELLTITER-GLO assay. Briefly, 96-well plates were removed from the incubator and allowed to equilibrate to room temperature for 30 minutes. CELLTITER- GLO was added to wells and mixed on a plate rocker for 2 minutes then incubated at room temperature for 10 minutes to stabilize the luminescent signal, prior to quantitation using a plate reader. Data, corrected for background signalling using medium control, normalized to vehicle control, and then log transformed, are reported as change in relative light units in response to treatment with different drug concentration and were directly proportional to cell viability. A variable slope model was applied to generate concentration-response curves; for each drug concentration (N=24 from N=8 patient samples evaluated in triplicate per drug concentration) data is indicated as mean ± standard deviation. The IC50 values were calculated by non-linear regression analysis. Overall, a lack of antagonism was observed in primary NPM1c-positive AML patient samples treated with the triplet combination of Compound A3, cytarabine plus daunorubicin as reflected below in Table 4. Table 4 – Effect of Cytarabine and Daunorubicin +/- Compound A3 on Cell Viability of Primary NPM1c-positive AML Patient Samples. Treatment Drug used to IC50 generate (nM) concentration- response curve for calculation of IC50 Triplet: Cytarabine and Daunorubicin + Compound A3 Compound A3 23 Triplet: Cytarabine and Daunorubicin + Compound A3 Cytarabine 23 Triplet: Cytarabine and Daunorubicin + Compound A3 Daunorubicin 11 Doublet: Cytarabine and Daunorubicin (- Compound A3) Cytarabine 30 Doublet: Cytarabine and Daunorubicin (- Compound A3) Daunorubicin 15

Claims

CLAIMS 1. A combination of a therapeutically effective amount of (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)- 2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide (Compound A): Compound A or a pharmaceutically acceptable salt or solvate thereof; and a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog (triple combination).

2. The combination according to claim 1 wherein Compound A or a pharmaceutically acceptable salt or solvate thereof, is a besylate salt (Compound A4-a) Compound A4-a or a solvate thereof.

3. The combination according to claim 2 wherein Compound A4-a or a solvate thereof is (R)-N-ethyl-5-fluoro-N-isopropyl- 2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt or a hydrate thereof.

4. The combination according to any one of claims 1-3 wherein the DNA intercalating agent is idarubicin, and the pyrimidine analog is cytarabine.

5. The combination according to any one of claims 1-3 wherein the DNA intercalating agent is daunorubicin, and the pyrimidine analog is cytarabine.

6. The combination according to any one of claims 1-3 wherein the DNA intercalating agent is doxorubicin, and the pyrimidine analog is cytarabine.

7. A pharmaceutical composition comprising a combination as claimed in any one of claims 1 to 6 and a pharmaceutically acceptable carrier.

8. A combination as claimed in any one of claims 1 to 6 or a pharmaceutical composition as claimed in claim 7 for use as a medicament.

9. A combination as claimed in any one of claims 1 to 6 or a pharmaceutical composition as claimed in claim 7 for use in the prevention or treatment, in particular treatment, of a hematopoietic disorder.

10. The combination or pharmaceutical composition for use according to claim 9 wherein the hematopoietic disorder harbours (i) one or more MLL1 (KMT2A) gene rearrangements or alterations (e.g., duplications or amplification) and/or NPM1 mutations plus (ii) a FLT3 mutation.

11. The combination or pharmaceutical composition for use according to claim 9 wherein the hematopoietic disorder harbours (i) one or more MLL1 (KMT2A) gene rearrangements plus (ii) a FLT3 mutation.

12. The combination or pharmaceutical composition for use according to claim 9, 10 or 11 wherein the hematopoietic disorder is acute myeloid leukemia (AML).

13. A method for treating a subject who has been diagnosed with a hematopoietic disorder comprising administering to the subject a combination of (R)-N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)- 2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide (Compound A): Compound A or a pharmaceutically acceptable salt or solvate thereof; and a therapeutically effective amount of a DNA intercalating agent and a pyrimidine analog (triple combination).