Inclusion Criteria:

• Aged ≥ 18 years old.
• Negative serum pregnancy (β-hCG) test in women of childbearing potential at screening
• Cytomorphology-confirmed diagnosis of R/R acute leukemia (including AML, ALL, and mixed lineage leukemia) according to the WHO criteria in 2022. R/R acute leukemia must meet at least one of the following conditions:
• Primary refractory disease, defined as non-response to 2 courses of standard induction therapy.
• R/R disease, defined as > 5% blasts on bone marrow aspirate (BMA) / bone marrow biopsy (BMB) after completing prior therapy.
• Relapse after allogeneic hematopoietic stem cell transplantation (HSCT), autologous HSCT, or immunotherapy such as chimeric antigen receptor T cell therapy (CAR-T) and T cell engager (TCE).
• Participants with secondary AML or AML transformed from myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), etc., can be included in the study, if they meet the above criteria after the disease has transformed into AML.
• Confirmation of KMT2At, NUP98t, or NPM1c mutation using next generation sequencing (NGS), fluorescence in situ hybridization (FISH), or polymerase chain reaction (PCR) based test in an accredited local or central lab within 28 days before start of treatment.
• Peripheral blood white blood cell (WBC) count ≤ 25 mm3 (hydroxyurea, steroids, or vincristine to reduce peripheral WBC count is permitted).
• Participants will be at least 2 weeks from prior therapy (except hydroxyurea, vincristine, or steroids and prespecified prephase therapy) and recovered from nadir to no worse than Grade 1 nonhematological toxicity from the prior treatment.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• Adequate electrolytes, liver, kidney, and cardiac function
• Sexually active male or female participants of childbearing potential must agree to use 2 medically accepted forms of effective contraception, e.g., oral, parenteral, or implanted contraceptives; intrauterine devices; and barrier methods with spermicides, during the study and for 3 or 6 months after the final administration of investigational medicinal product (IMP), in males and females respectively. Egg donation is not allowed during the study or within 6 months of the last dose of S243249.
• Male participants with women of childbearing potential (WOCBP) partners must use a condom during the study and for at least 3 months after the final administration of IMP.

Exclusion Criteria:

• Active central nervous system (CNS) leukemia (including imaging abnormalities and cerebrospinal fluid (CSF) smear or flow cytometry indicating leukemia cells)).
• Active disseminated intravascular coagulation (DIC).
• Active uncontrolled infection (prophylaxis because of absolute neutrophil count [ANC] is excepted).
• Diagnosis of acute promyelocytic leukemia (APL, M3).
• Corrected QT interval calculated by Fridericia (QTcF) > 450 msec on screening ECG.
• Participants with an increased pro-arrhythmic risk such as those with congenital long QT syndrome.
• Uncontrolled or severe cardiovascular disease, , within 12 months.
• Uncontrolled serious arrhythmias.
• Clinically significant pericardial disease.
• History of other malignancy within the past 5 years.
• Participants who receive autologous hematopoietic stem cell transplantation (ASCT) or CAR-T therapy within 60 days of the first dose of S243249 or have not yet recovered from toxicity related to ASCT or CAR-T therapy.
• Participants who receive allogeneic HSCT within 100 days of the first dose of S243249, still have active acute or chronic graft versus host disease (GVHD), or still require immune-modulating therapy.
• Have an active infection of hepatitis B or hepatitis C.
• Have advanced liver disease or cirrhosis.
• Uncontrolled human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome related illness.
• Pregnant and/or breast-feeding (lactating) women.
• Participant has received anti-leukemia treatment, including chemotherapy, radiation therapy, targeted small molecule agents, biologic agents, immunotherapy, or any other investigational therapy (excluding hydroxyurea, or vincristine for cytoreduction) within 2 weeks prior to the first dose of S243249.
• Previous treatment targeting menin, dose optimization phase only.
• Any concomitant participation in another therapeutic clinical trial is prohibited. Any participation in another nontherapeutic clinical trial could be approved by the medical monitor.
• Participants taking medications known to prolong the QT/QTc interval (with the exception of necessary azole antifungals).
• Ongoing toxicity from prior anti-leukemia therapy that has not resolved to Grade 1 7 days prior to the first dose of S243249 has to be approved by the medical monitor.
• Uncontrolled active infection
• Known allergy or hypersensitivity to menin inhibitors or any component of S243249.