Treprostinil derivative compounds and methods of using same

A compound represented by Formula II:

• wherein:
• R2 is selected from the group consisting of H and P2;
• R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, and R36 are independently selected from the group consisting of H and deuterium;
• L1 is selected from the group consisting of —O-alkylene-C(O)—, —O-alkylene-OC(O)—, and a bond;
• and
• P2 is selected from the group consisting of:
• wherein:
• m is 1, 2, 3, or 4;
• R14 and R15 are independently in each occurrence selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl;
• or
• R14 and R15 taken together with the atoms to which they attach optionally form a 5- to 7-membered ring which optionally incorporates one or two ring heteroatoms chosen from N, O, and S, and which is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy;
• R16 and R17 are independently H or alkyl;
• or
• R16 and R17 taken together with the atom to which they attach optionally form a 3- to 6-membered ring;
• and
• R18 and R19 are independently in each occurrence selected from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from the group consisting of halo, hydroxy, alkoxy, amino, thio, methylthio, —C(O)OH, —C(O)O-(alkyl), —CONH2, aryl, and heteroaryl, wherein the aryl or heteroaryl are is unsubstituted or substituted with a substituent selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, and haloalkoxy;
• or
• R14 and R18 taken together with the atoms to which they attach optionally form a 5- to 7-membered ring;
• or
• R14 and R19 taken together with the atoms to which they attach optionally form a 5- to 7-membered ring;
• or an enantiomer, a pharmaceutically acceptable salt or a polymorph thereof.

A compound of Formula II(AA):

• wherein:
• R2000 is selected from the group consisting of H, CONR9000R10000, and CR9000R10000OCOPR9000R10000, wherein R9000 and R10000 are selected from H, alkyl, and cycloalkyl and P is N or O;
• R3000, R4000, R5000, R6000, R7000 and R8000 are independently selected from the group consisting of H and deuterium;
• X is O, NR12000, or S, wherein R12000 is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl;
• and
• n is an integer from 1 to 7;
• or an enantiomer, a pharmaceutically acceptable salt or a polymorph thereof.

A compound represented by Formula IV:

• wherein:
• R1 is selected from the group consisting of H and P2;
• R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, and R36 are independently selected from the group consisting of H and deuterium;
• L1 is selected from the group consisting of —O-alkylene-C(O)—, —O-alkylene-OC(O)—, and a bond;
• P2 is selected from the group consisting of:
• wherein:
• m is 1, 2, 3, or 4;
• R14 and R15 are independently in each occurrence selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl;
• or
• R14 and R15 taken together with the atoms to which they attach optionally form a 5- to 7-membered ring which optionally incorporates one or two ring heteroatoms chosen from N, O, and S, and which is unsubstituted or substituted with 1, 2, or 3 substituents selected from the group consisting of halo, methyl, and methoxy;
• R16 and R17 are independently H or alkyl;
• or
• R16 and R17 taken together with the atom to which they attach optionally form a 3- to 6-membered ring;
• and
• R18 and R19 are independently in each occurrence selected from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from the group consisting of halo, hydroxy, alkoxy, amino, thio, methylthio, —C(O)OH, —C(O)O-(alkyl), —CONH2, aryl, and heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with a substituent selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, and haloalkoxy;
• or
• R14 and R18 taken together with the atoms to which they attach optionally form a 5- to 7-membered ring;
• or
• R14 and R19 taken together with the atoms to which they attach optionally form a 5- to 7-membered ring;
• or an enantiomer, a pharmaceutically acceptable salt or a polymorph thereof.