Patients must meet all of the following inclusion criteria to be eligible: TP-3654 Monotherapy Arm:

• - Confirmed pathological diagnosis of primary myelofibrosis (PMF) or post-PV-MF/post-ET- MF as per WHO diagnostic criteria and intermediate or high-risk primary or secondary MF based on the Dynamic International Prognostic Scoring System (DIPSS) - Previously treated with JAK inhibitor(s) and is intolerant, resistant, refractory or has lost response to the JAK inhibitor(s) or is ineligible to be treated with JAK inhibitor.

• - Fulfill the following laboratory parameters: - Platelet count ≥ 25 X 10^9 /L, without the assistance of growth factors or platelet transfusions.

• - Absolute Neutrophil Count (ANC) ≥ 1 x 10^9/L without the assistance of granulocyte growth factors.

• - Peripheral blood blast count < 5% - Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.

• - Life expectancy ≥ 6 months.

• - Adequate renal function, as determined by clinical laboratory tests (serum creatinine ≤ 1.5 x upper limit of normal (ULN), or calculated creatinine clearance ≥ 30 mL/min) (Cockcroft-Gault) - Adequate hepatic function: ALT and AST ≤ 3 × ULN (ALT and AST ≤ 5 × ULN if liver involvement secondary to MF); direct bilirubin ≤ 2 × ULN.

• - Adequate coagulation function: PT and PTT ≤ 1.5 × ULN; INR ≤ 1.2 × ULN (INR < 2.5 x ULN permitted if on chronic anticoagulant therapy) - Splenomegaly defined as splenic length ≥ 5 cm below the costal margin by palpation or spleen volume of ≥ 450 cm3 by Magnetic Resonance Imaging (MRI) or Computerized Tomography (CT) scan, within 2 weeks prior to Cycle 1 Day 1.

• - Dose escalation: At least 2 symptoms measurable (score ≥ 1) using the MF-SAF, v4.0.

• - Dose expansion: At least 2 symptoms measureable with each score of ≥ 3 or a total average score of ≥ 10 per MFSAF, v4.0.

TP-3654 + Ruxolitinib Arm:

• - Confirmed pathological diagnosis of PMF or post-PV-MF/post ET- MF as per WHO diagnostic criteria, and intermediate or high-risk primary or secondary MF based on the DIPSS.

• - Has been on ruxolitinib treatment for ≥ 6 months, and on a stable dose of ruxolitinib (5 to 25 mg BID) for ≥ 8 weeks prior to the first dose of TP-3654, but has either lost response or had a suboptimal or plateau in response.

• - Fulfills the following laboratory parameters: - Platelet count ≥ 50 × 10^9/L (without the assistance of growth factors or platelet transfusions) - ANC ≥ 1 × 109/L without the assistance of granulocyte growth factors.

• - Peripheral blood blast count < 5% at screening.

• - Adequate renal function, as determined by clinical laboratory tests: serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance ≥ 30 mL/min (using Cockcroft-Gault formula) - Adequate hepatic function: ALT and AST ≤ 3 × ULN (ALT and AST ≤ 5 × ULN if liver involvement secondary to MF); direct bilirubin ≤ 2 × ULN.

• - Adequate coagulation function: PT and PTT ≤ 1.5 × ULN; INR ≤ 1.2 × ULN (INR < 2.5 x ULN permitted if on chronic anticoagulant therapy) - Splenomegaly, defined as splenic length ≥ 5 cm below the costal margin by palpation or spleen volume of ≥ 450 cm3 by MRI/CT scan, within 2 weeks prior to Cycle 1 Day 1.

• - At least 2 symptoms measurable with each score ≥ 3 or a total average score of ≥ 10 per MFSAF v4.0.

• - ECOG performance status ≤ 1.

• - Life expectancy ≥ 6 months.

TP-3654 + Momelotinib Arm.

• - Confirmed pathological diagnosis of PMF or post-PV-MF/post ET-MF as per WHO diagnostic criteria, and intermediate or high-risk primary or secondary MF based on the DIPSS.

• - Previously treated with an approved JAK inhibitor (except momelotinib) for PMF or Post-PV/ET MF for ≥ 12 weeks, or ≥ 4 weeks if JAK inhibitor therapy was complicated by a transfusion requirement of ≥ 4 units of red blood cells in 8 weeks, or Grade 3/4 AEs of thrombocytopenia, anemia, or hematoma.

• - Fulfills the following laboratory parameters: - Anemic, defined as Hb <10 g/dL or requiring RBC transfusion at baseline.

• - Platelet count ≥ 50 × 109/L (without the assistance of growth factors or platelet transfusions) - ANC ≥ 1 × 109/L without the assistance of granulocyte growth factors.

• - Peripheral blood blast count < 5% at screening.

• - Adequate renal function, as determined by clinical laboratory tests: serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance ≥ 30 mL/min (using Cockcroft-Gault formula) - Adequate hepatic function: ALT and AST ≤ 3 × ULN (ALT and AST ≤ 5 × ULN if there is liver involvement secondary to MF); direct bilirubin ≤ 2 × ULN.

• - Adequate coagulation function: PT and PTT ≤ 1.5 × ULN; INR ≤ 1.2 × ULN (INR < 2.5 × ULN permitted if on chronic anticoagulant therapy) - Splenomegaly, defined as splenic length ≥ 5 cm below the costal margin by palpation or spleen volume of ≥ 450 cm3 by MRI/CT scan within 2 weeks prior to Cycle 1 Day 1.

• - At least 2 symptoms measurable with each score of ≥ 3 or a total average score of ≥ 10 per MFSAF v4.0.

• - ECOG performance status ≤ 1.

• - Life expectancy ≥ 6 months.

Patients meeting any one of these exclusion criteria will be prohibited from participating in this study: TP-3654 Monotherapy Arm:

• - Received previous systemic antineoplastic therapy or any experimental therapy within 2 weeks or 5 half-lives, whichever is longer, prior to Cycle 1 Day 1.

• - Major surgery within 2 weeks before the first dose of either study drug.

• - Splenic irradiation within 6 months prior to Screening or prior splenectomy.

• - Prior allogeneic stem cell transplant within the last 6 months.

• - Eligible for allogeneic bone marrow or stem cell transplantation.

• - Unresolved Grade ≥ 2 non-hematological toxicity related to prior treatment.

• - History of symptomatic congestive heart failure, or myocardial infarction, or uncontrolled arrhythmia within 6 months prior to Cycle 1 Day 1; left ventricular ejection fraction (LVEF)< 45% by echocardiogram within 4 weeks prior to Cycle 1 Day 1.

• - Corrected QT interval (using Fridericia's correction formula) of > 480 msec.

• - Prior or concurrent malignancy whose natural history or treatment would have a significant potential to interfere with the safety or efficacy assessments of the investigational regime.

• - Known history of chronic liver disease, e.g. portal hypertension or any of its complications, cirrhosis, Child-Pugh C, auto-immune hepatitis, alpha-1 anti-trypsin deficiency, Wilson's disease, etc. - Experienced portal hypertension or any of its complications.

• - Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic antimicrobial within 1 week prior to Cycle 1 Day 1.

• - Chronic active or acute viral hepatitis A, B, or C infection (testing for hepatitis B and C are required) - Exhibited allergic reactions or sensitivity to TP-3654, or any structurally similar compound, biological agent, or to any component of the formulation.

• - Medical condition or gastrointestinal (GI) tract surgery that could impair absorption or result in short bowel syndrome with diarrhea.

• - Used hydroxyurea or anagrelide within 24 hours prior to the first dose.

• - Systemic steroid therapy (>10 mg daily prednisone or equivalent) within 1 week prior to the first dose of study treatment (note: topical, inhaled, nasal, and ophthalmic steroids are not prohibited).

TP-3654 + Ruxolitinib Arm:

• - Received previous systemic antineoplastic therapy (other than ruxolitinib) or any other experimental therapy within 2 weeks or 5 half-lives, whichever is longer, prior to Cycle 1 Day 1 (Note: Hydroxyurea or anagrelide are allowed up to 24 hours prior to Cycle 1 Day 1).

• - Received systemic steroid therapy (>10 mg daily prednisone or equivalent) within 1 week prior to Cycle 1 Day 1 (Note: Topical, inhaled, nasal, and ophthalmic steroids are not prohibited) - Currently receiving treatment with a prohibited medication that cannot be discontinued at least 1 week prior to Cycle 1 Day 1 (Section 6.9.

1)

• - Known allergic reactions or sensitivity to TP-3654, any structurally similar drug, or to any component of the formulation.

• - Splenic irradiation within 6 months prior to Screening or prior splenectomy.

• - Prior allogeneic stem cell transplant within the last 6 months (Note: Patients who have relapsed after 6 months post-transplant and do not have active GVHD are eligible).

• - Eligible for allogeneic bone marrow or stem cell transplantation (Note: Patients who are not willing to undergo transplantation or for whom a suitable donor is not available are considered as transplant ineligible.

_

• - Major surgery within 2 weeks prior to Cycle 1 Day 1.

• - Active, uncontrolled bacterial, viral, or fungal infections, requiring parenteral antimicrobial within 1 week prior to Cycle 1 Day 1.

• - Chronic active or acute viral hepatitis A, B, or C infection (testing for hepatitis B and C are required) - Known history of chronic liver disease (eg, portal hypertension or any of its complications, cirrhosis, Child-Pugh C, auto-immune hepatitis, alpha-1 anti-trypsin deficiency, Wilson's disease, etc) (Note: Abnormal liver morphology at baseline imaging may require additional testing, as needed).

• - Unresolved Grade ≥ 2 non-hematological adverse events related to prior treatment (stable Grade 2 conditions may be permitted in consultation with the Sponsor) - History of myocardial infarction or symptomatic congestive heart failure or uncontrolled arrhythmia within 6 months prior to Cycle 1 Day 1; LVEF < 45% by echocardiogram within 4 weeks prior to Cycle 1 Day 1.

• - Corrected QTcF of > 480 msec.

• - Prior or concurrent malignancy whose natural history or treatment has a significant potential to interfere with the safety or efficacy assessment of the study intervention.

• - History of a medical condition or GI tract surgery that could impair absorption or could result in short bowel syndrome with diarrhea.

• - Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or thalassemia, or severe GI bleeding.

TP-3654 + Momelotinib Arm:

• - Received previous systemic antineoplastic therapy or any experimental therapy within 2 weeks or 5 half-lives, whichever is longer, prior to Cycle 1 Day 1 (Notes: Prior treatment with momelotinib is not allowed, in patients with ongoing JAK inhibitor therapy, ie, ruxolitinib, at screening, JAK inhibitor therapy must be tapered over a period of at least 1 week.

Patients on a low dose of ruxolitinib (eg, 5 mg QD) may have a reduced taper period or no taper, hydroxyurea or anagrelide are allowed up to 24 hours prior to Cycle 1 Day 1).

• - Received systemic steroid therapy (>10 mg daily prednisone or equivalent) within 1 week prior to Cycle 1 Day 1 (Note: Topical, inhaled, nasal, and ophthalmic steroids are not prohibited).

• - Currently receiving treatment with a prohibited medication that cannot be discontinued at least 1 week prior to Cycle 1 Day 1.

• - Known allergic reactions or sensitivity to TP-3654, momelotinib, or any structurally similar drug, or to any component of the formulations of either study intervention.

• - Splenic irradiation within 6 months prior to screening or prior splenectomy.

• - Prior allogenic stem cell transplant within the last 6 months (Note: Patients who have relapsed after 6 months post-transplant and do not have active GVHD are eligible).

• - Eligible for allogeneic bone marrow or stem cell transplantation (Note: Patients who are not willing to undergo transplantation or for whom a suitable donor is not available are considered as transplant ineligible).

• - Major surgery within 2 weeks prior to Cycle 1 Day 1.

• - Active, uncontrolled bacterial, viral, or fungal infections, requiring parenteral antimicrobial within 1 week prior to Cycle 1 Day 1.

• - Chronic active or acute viral hepatitis A, B, or C infection (testing for hepatitis B and C are required) - Known history of chronic liver disease (eg, portal hypertension or any of its complications, cirrhosis, Child-Pugh C, auto-immune hepatitis, alpha-1 anti-trypsin deficiency, Wilson's disease, etc) (Note: Abnormal liver morphology at baseline imaging may require additional testing, as needed) - Unresolved Grade ≥ 2 non-hematological adverse events related to prior treatment (stable Grade 2 conditions may be permitted in consultation with the Sponsor) - Presence of Grade ≥ 2 peripheral neuropathy.

• - History of myocardial infarction or symptomatic congestive heart failure or uncontrolled arrhythmia within 6 months prior to Cycle 1 Day 1; LVEF < 45% by echocardiogram within 4 weeks prior to Cycle 1 Day 1.

• - Corrected QTcF of > 480 msec.

• - Prior or concurrent malignancy whose natural history or treatment has a significant potential to interfere with the safety or efficacy assessment of the study intervention.

• - History of a medical condition or GI tract surgery that could impair absorption or could result in short bowel syndrome with diarrhea.

- Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or thalassemia, or severe GI bleeding

Arm 1 will enroll patients who have been previously treated and failed on a JAK inhibitor or ineligible to receive ruxolitinib or fedratinib. Arm 2 will enroll patients who are on a stable dose of ruxolitinib, but who have either lost response or had a suboptimal or plateau in response. Arm 3 will enroll patients who have been previously treated on JAK inhibitor (except momelotinib) that was complicated by anemia, thrombocytopenia or hematoma.

Arms

Experimental: Arm 1: TP-3654

Experimental: Arm 2: TP-3654 added on to ruxolitinib

Experimental: Arm 3: TP-3654 in combination with momelotinib

Interventions

Drug: - TP-3654

Oral PIM Inhibitor

Drug: - Ruxolitinib

Oral JAK inhibitor

Drug: - Momelotinib

Oral JAK inhibitor