Composition and methods for treating heritable pulmonary artery hypertension associated with nonsense mutations

A method for treating, preventing, or slowing the rate of development of a disease or condition mediated by a nonsense mutation in the bone morphogenetic protein receptor type II (Bmpr2) in a subject in need thereof, comprising administering to the subject a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof:

• wherein:
• X, Y, and Z are each independently O, S, or NR10;
• wherein R10 is hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, where each alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is independently optionally substituted;
• A is N or CR11;
• wherein R11 is alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein each alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is independently optionally substituted;
• B is Nor CR12:
• wherein R12 is hydrogen, halo, pseudohalo, alkyl, alkoxy, or thioalkoxy;
• D is N or CR13;
• wherein R13 is hydrogen, halo, pseudohalo, alkyl, alkoxy, or thioalkoxy;
• R1 is alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein each alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is independently optionally substituted;
• R2 is C1-3alkylene, C3-10cycloalkylene, or heterocyclylene of 3 to 10 atoms;
• R3 is hydroxy, alkoxy, —NR6R6a, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein each alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is independently optionally substituted;
• R4 is alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein each alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is independently optionally substituted;
• R5 is —NR5aR5b, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein each alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is independently optionally substituted;
• R5a is hydrogen or alkyl;
• R5b is alkyl, alkoxyalkyl, alkenyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl;
• wherein the aryl or heteroaryl, either alone or as part of arylalkyl and heteroarylalkyl, are optionally substituted with 1, 2, or 3 groups independently selected from alkyl, halo, haloalkyl, hydroxy, and alkoxy;
• R6 is hydrogen or alkyl;
• and
• R6a is —NHC(O)(arylalkyl), alkyl, hydroxyalkyl, cycloalkyl, heteroaryl, or aryl, wherein each aryl, arylalkyl, or heteroaryl are optionally substituted with 1, 2, or 3 groups selected from hydroxy, halo, haloalkyl, alkyl, alkoxy, carboxy, or alkoxycarbonyl.