-INCLUSION CRITERIA:

1. Participants must have histologically or cytologically confirmed MDS by the Laboratory of Pathology, NCI- according to 2016 WHO criteria AND:

-Cohort 1 (Phase 1) \& 2 (Phase 2): have HR-MDS (IPSS-R \> 3.5) with inadequate response to hypomethylating agent (HMA) therapy \[(received \>= 4 cycles of the standard dose (35 mg decitabine and 100 mg cedazuridine) without prior dose reductions, with failure to achieve at least a PR or experienced disease progression prior to completing 4 cycles)
2. Age \>=18 years
3. ECOG performance status \<= 2 (Karnofsky \>= 60%,)
4. Participants must have adequate organ and marrow function as defined below:

-total bilirubin \<= 1.5 X institutional upper limit of normal

OR

\<= 3 X institutional upper limit of normal in participants with Gilbert s syndrome (except for participants with increased bilirubin levels attributed to intramedullary hemolysis, which will be allowable)

-AST(SGOT)/ALT(SGPT) \<= 3 X institutional upper limit of normal

OR

\<= 5 X institutional upper limit of normal if related to MDS-specific cause
* creatinine clearance \>= 60 mL/min
* QTc(F) \<= 470 ms
5. Females of child-bearing potential (FOCP) must have a negative serum test at screening. FOCP is defined as the following:

* Has not undergone a hysterectomy, tubal ligation, or bilateral oophorectomy
* Has not been naturally postmenopausal for at least 24 consecutive months (i.e.,has had menses at any time in the preceding 24 consecutive months).
6. Females of childbearing potential (FOCP) and males of child-fathering potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) unless they have had a prior vasectomy, hysterectomy, or bilateral oophorectomy, prior to study entry, for the duration of study participation, and for at least 6 months after last dose of HMA.
7. Breastfeeding participants must be willing to discontinue breastfeeding from study treatment initiation through 30 days after the last administration of study drug
8. Any prior therapy must have been completed \>4 weeks or, if known, \>= 5 half-lives of the prior agent (whichever is shorter) prior to treatment (with a minimum of 1 week between prior therapy and study treatment). Note: This does not apply to prior HMA therapy if that therapy involves Inqovi
9. Ability to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

1. Participants with platelet transfusion-refractory thrombocytopenia, with inability to keep platelet threshold above 10K/mcL with transfusions or those with ongoing or uncontrolled hemorrhagic complications.
2. Participants with clinically significant neutropenia, defined as ANC \<100 cells/mcL with frequent hospitalizations for infection (average \> 1 hospitalization per month in the past 6 months).
3. Participants on treatment with a myeloid growth factor (e.g., G-CSF) within 14 days prior to initiation of study treatment.
4. History of allergic reactions attributed to compounds of similar chemical or biologic composition to HMAs or other agents used in study.
5. Uncontrolled intercurrent illness evaluated by history, physical exam, and chemistries or situations that would limit compliance with study requirements, interpretation of results or that could increase risk to the participant
6. Participants with the following cardiac conditions: symptomatic congestive heart failure, unstable angina pectoris, or uncontrolled cardiac arrhythmia as assessed by electrocardiogram (ECG).
7. Pregnancy (confirmed with Beta-HCG serum or urine pregnancy test performed in females of childbearing potential at screening)
8. Presence of any other malignancy (except basal and squamous cell carcinoma of the skin, or stable chronic cancers on hormone or targeted therapy) for which participant received systemic anticancer treatment (except maintenance therapy) within 24 months prior to treatment.
9. Participants with active/uncontrolled Hepatitis B
10. Participants with active/uncontrolled Hepatitis C
11. Participants with active/uncontrolled HIV infection or AIDS.
12. Participants currently taking contraindicated medications for HIV, Hepatitis B, or Hepatitis C disease control