Inclusion Criteria:

1. Males and females ≥18 years of age
2. Life expectancy of at least 3 months
3. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤1
4. Cytomorphology based confirmed diagnosis of MDS or AML with the following characteristics.

Phase 1 Dose Escalation (Monotherapy)

• AML (primary or secondary, including treatment-related) after failing at least 1 standard treatment (may include chemotherapy, re induction therapy or stem cell transplantation).

OR

• High-risk R/R MDS that are considered resistant/refractory following at least 2 to 3 cycles of hypermethylating agent (HMA) or evidence of early progression

Phase 1b (Combination Therapy) Doublet Arm: emavusertib + AZA

Patients:
* with International Prognostic Scoring System- revised (IPSS- R) High, high risk myelodysplastic syndrome (hrMDS)
* ineligible for intensive chemotherapy

Doublet Arm: emavusertib + Venetoclax

Patients with:

• R/R AML or hrMDS, after first line therapy

Phase 2a Dose Expansion (Monotherapy)

Patients with:
* R/R AMLwith FLT3 mutations, R/R including a FLT3 inhibitor
* R/R AML with spliceosome mutations of SF3B1 or U2AF1
* R/R hrMDS with spliceosome mutations of SF3B1 or U2AF1; bone marrow blast count \>/= 8%; ineligible for intensive chemotherapy
* Number of pretreatments: 1 or 2
5. Acceptable organ function at screening
6. Ability to swallow and retain oral medications
7. Negative serum pregnancy test in women of childbearing potential
8. Women of childbearing potential and men who partner with a woman of childbearing potential must agree to use highly effective contraceptive methods for the duration of the study and for 90 days after the last dose of emavusertib
9. Willing and able to provide written informed consent and comply with the requirements of the trial
10. Able to undergo serial bone marrow sampling and peripheral blood sampling

Exclusion Criteria:

1. Diagnosed with acute promyelocytic leukemia (APL, M3)
2. Has known active central nervous system (CNS) leukemia
3. Allogeneic hematopoietic stem cell transplant (Allo-HSCT) within 60 days of the first dose of emavusertib, or clinically significant graft-versus-host disease (GVHD) requiring ongoing up titration of immunosuppressive medications prior to start of emavusertib
4. Chronic myeloid leukemia (CML)
5. Any prior systemic anti-cancer treatment such as chemotherapy, immunomodulatory drug therapy, etc., received within 14 days prior to start of emavusertib. Localized radiation or surgical resection of skin cancers allowed.
6. Use of any investigational agent within 28 days or 5 half-lives, whichever is shorter, prior to start of emavusertib
7. Presence of an acute or chronic toxicity resulting from prior anti-cancer therapy, with the exception of alopecia that has not resolved to Grade ≤1 within 7 days prior to start of emavusertib
8. Known allergy or hypersensitivity to any component of the formulation of emavusertib
9. Major surgery, other than diagnostic surgery, \<28 days from the start of emavusertib; minor surgery \<14 days from the start of emavusertib
10. Known hypersensitivity to azacitidine or mannitol, as stated per label (Phase 1b only)
11. Patients with active advanced malignant solid tumors
12. Known to be human immunodeficiency virus (HIV) positive or have an acquired immunodeficiency syndrome-related illness
13. Hepatitis B virus (HBV) DNA positive or Hepatitis C virus (HCV) infection \<6 months prior to start of emavusertib unless viral load is undetectable, or HCV with cirrhosis
14. Uncontrolled or severe cardiovascular disease
15. Gastrointestinal disease or disorder that could interfere with the swallowing, oral absorption, or tolerance of emavusertib
16. History of other invasive malignancy, unless definitively treated with curative intent, provided it is deemed to be at low risk for recurrence by the treating physician
17. Pregnant or lactating
18. Systemic fungal, bacterial, viral, or other infection that is not controlled
19. Any other severe, acute, or chronic medical, psychiatric or social condition, or laboratory abnormality that may increase the risk of trial participation or emavusertib administration