Therapeutic small molecules for treatment of pulmonary hypertension

A method of treating pulmonary hypertension in a subject in need thereof, the method comprising:

• administering a therapeutically effective amount of a pharmaceutical composition to the subject;
• wherein the pharmaceutical composition comprises piperlongumine analog BRD-K34222889 or a derivative thereof;
• and
• wherein the piperlongumine analog BRD-K34222889 or a derivative thereof has a structure according to Formula I:
• wherein
• A1 is C(O) or S(O)2;
• A2 is —C≡C— or —C(R′)═C (R″)—, wherein R′ and R″ are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, or C1-C6 haloalkyl;
• X is CH(R″), C(O), SO, SO2, or NR″′, wherein R″′ is hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, or C1-C6 haloalkyl;
• D is —C≡C— or —C(R′)═C (R″)—, wherein R′ and R″ are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, or C1-C6 haloalkyl;
• R1 is hydrogen, halogen, alkyl, haloalkyl, heteroalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, amine, alkylamine, amide, alkylamide, hydroxyl, cycloalkyl, heterocycloalkyl, cyano, or nitro, and wherein R1 is optionally substituted with one or more groups;
• R2, R3, and R4 are independently hydrogen, halogen, alkyl, haloalkyl, heteroalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, amine, alkylamine, amide, alkylamide, hydroxyl, cycloalkyl, heterocycloalkyl, cyano, nitro, carboxyl, ester, hydroxylamine, carbonyl substituted hydroxylamine, or thiol;
• R5, R6, R7, R8, and R9 are independently hydrogen, halogen, alkyl, haloalkyl, heteroalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, amine, alkylamine, amide, alkylamide, hydroxyl, cycloalkyl, heterocycloalkyl, cyano, nitro, carboxyl, ester, hydroxylamine, carbonyl substituted hydroxylamine, or thiol;
• n is 1 or 2;
• and
• ------- represents a bond that is present or absent;
• or a pharmaceutically acceptable salt, ester, or prodrug thereof.