Inclusion Criteria:  Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 to 2 Adequate organ function (bone marrow, hepatic, renal, cardiovascular) Left ventricular ejection fraction of ≥ 50% All patients must have recovered from the effects of any prior cancer related therapy, radiotherapy, or surgery (toxicity no greater than Grade 1). All patients on prior investigational agents must wait at least 5 half-lives of the agent in question, or 14 days, whichever is longer before enrollment into the trial, and until any toxicities of the prior investigational agent have resolved to Grade 1 or a baseline state Female patients of childbearing potential must have a negative pregnancy test within 7 days of the start of treatment and must agree to use a highly effective method of contraception during the trial  AML patients only: Pathologically confirmed diagnosis of AML as defined by the WHO Classification and patients with targeted mutations must have been treated with appropriate therapy for their disease  a. White blood cell count < 25 × 10^9/L. Hydroxyurea or leukapheresis are permitted to meet this criterion  CMML patients only: intermediate-2 or high risk per CMML-specific prognostic scoring system (CPSS) or clinical/molecular CPSS (CPSS-mol) criteria. Must have failed at least 4-6 cycles of prior therapy with a hypomethylating agent High Risk MDS - MDS/MPN Overlap Syndrome: intermediate, high, or very high risk by International Prognostic Scoring System-Revised [IPSS-R] criteria that is relapsed or refractory to approved therapies, including at least 4-6 cycles of a hypomethylating agent, or MDS/MPN Overlap Syndrome (displaying both fibrosis and dysplastic features)  Exclusion Criteria:  Known hypersensitivity to any of the components of PRT1419 Female patients who are pregnant or lactating Active inflammatory disorders of the gastrointestinal tract, or patients with GI malabsorption Mean QTcF interval of > 480 msec History of heart failure, additional risk factors for arrhythmias or requiring concomitant medications that prolong the QT/QTc interval Elevated cardiac troponin or evidence of recent cardiac injury HIV positive; known active hepatitis B or C Hematopoietic stem-cell transplantation within the last 90 days or have GVHD Grade > 1 at study entry Uncontrolled intercurrent illnesses Treatment with either OATP1B1, OATP1B3 substrates or strong inhibitors of CYP2C8 Prior exposure to an MCL1 inhibitor  History of another malignancy except for:  Malignancy treated with curative intent with no known active disease for > 2 years prior to study start Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease Adequately treated carcinoma in situ without evidence of disease Other concurrent low-grade malignancies (i.e., chronic lymphocytic leukemia (CLL) (Rai 0)) may be considered after consultation with Sponsor