Treprostinil prodrug

Abstract

To provide a novel prodrug of treprostinil capable of being used in a treatment of pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH).SOLUTION: There is provided a compound represented by the following formula, or an enantiomer thereof or a pharmaceutically acceptable salt thereof. In the formula R20 to R36 are independently H or deuterium, Z is -OH, -OR11, -N(R11)R12, -SR11, R11 is alkyl which may be substituted, cycloalkyl which may be substituted, or the like, R12 is H, haloalkyl or the like. The compound is formulated and can applied percutaneously.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Description of Related Applications This application claims priority to U.S. Provisional Application No. 61 / 751,608, filed January 11, 2013, which is incorporated herein by reference in its entirety for all purposes. [Background technology]

[0002] background Pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH) is a potentially fatal disease characterized by increased pulmonary arterial pressure and pulmonary vascular resistance. There is a need for better compounds and methods for treating PH and PAH. See, e.g., U.S. Patent Application Publication No. 2013 / 0274261 (Patent Document 1). Many useful pharmacologically active compounds, including some compounds of interest for PH and PAH, cannot be effectively administered orally for various reasons and are generally administered via intravenous or intramuscular routes. These administration routes generally require intervention by a physician or other medical professional and can involve significant patient discomfort and potential local trauma. One example of such a compound is treprostinil and its derivatives, which have been used in the treatment of PH and PAH. See, e.g., WO 2005 / 007081 (Patent Document 2). The core chemical formula is the following (also referred to herein as Compound A): TIFF0007785053000001.tif37128, which formula includes pharmaceutically acceptable salts such as sodium salts.

[0003] Thus, there is a clinical need for improved formulations and methods for delivering treprostinil, e.g., orally or transdermally. More specifically, there is a need for safe and effective methods for increasing the systemic availability of treprostinil via administration of treprostinil or a treprostinil analog.

[0004] The application of transdermal drug delivery technology to the administration of a wide variety of drugs has been proposed, and various systems for achieving this have been disclosed in numerous technical journals and patents. U.S. Patent No. 3,598,122 (Patent Document 3), U.S. Patent No. 4,144,317 (Patent Document 4), U.S. Patent No. 4,201,211 (Patent Document 5), U.S. Patent No. 4,262,003 (Patent Document 6), and U.S. Patent No. 4,379,454 (Patent Document 7), all of which are incorporated herein by reference, are representative of various prior art transdermal drug delivery systems, which are capable of delivering controlled amounts of drug to patients over extended periods ranging from several hours to several days. Neither the above patents, nor any other prior art known to the inventors, describes a transdermal delivery system intended to deliver treprostinil or its derivatives, nor does it recognize data regarding skin permeability or therapeutic transdermal delivery rates sufficient to design such a system. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] U.S. Patent Application Publication No. 2013 / 0274261 [Patent Document 2] International Publication No. 2005 / 007081 [Patent Document 3] U.S. Patent No. 3,598,122 [Patent Document 4] U.S. Patent No. 4,144,317 [Patent Document 5] U.S. Patent No. 4,201,211 [Patent Document 6] U.S. Patent No. 4,262,003 [Patent Document 7] U.S. Patent No. 4,379,454 Summary of the Invention

[0006] overview Aspects described herein include compounds, compositions, and devices, as well as methods of making and using the same.

[0007] One embodiment is a compound of formula (I) providing a compound represented by TIFF0007785053000002.tif49128, In the formula, R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 are independently H or deuterium; Z is -OH, -OR 11 , -N(R 11 )R 12 , -SR 11 , or P1; R 11 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, or substituted alkylheteroaryl; R 12 is H, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl; P1 is TIFF0007785053000003.tif69128; where: m is 1, 2, 3, or 4; R 14 and R 15 is independently selected at each occurrence 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; R 14 and R 15 may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring which may incorporate 1 or 2 ring heteroatoms selected from N, O, or S, which are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy; R 18 and R 19 is independently selected at each occurrence from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with one substituent selected from the list 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 from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy; R 14 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 14 and R 19 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 15 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 15 and R 19 may form a 5- to 7-membered ring together with the atoms to which they are attached; and R1 and R2 are independently H or P2, and at least one of R1 and R2 is P2; P2 is TIFF0007785053000004.tif143128; where: m is 1, 2, 3, or 4; R 14 and R 15 is as defined above; R 14 and R 15 may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring which may incorporate 1 or 2 ring heteroatoms selected from N, O, or S, which are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the list consisting of halo, methyl, and methoxy; R 16 and R 17 is independently at each occurrence H or alkyl; R 16 and R 17 may form a 3- to 6-membered ring together with the atoms to which they are attached; R 18 and R 19 is as defined above; R 14 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 14 and R 19 may form a 5- to 7-membered ring together with the atoms to which they are attached; Formula I includes enantiomers, pharmaceutically acceptable salts, and polymorphs of compounds of Formula I.

[0008] In another embodiment, the parameters of Formula I are defined as follows: R 20 , R 21 , R 22 , R 23 , R 24 , R25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 are independently H or deuterium; Z is -OR 11 , -N(R 11 )R 12 , -SR 11 , or P1; R 11 is branched alkyl, haloalkyl, halocycloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, bicycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, substituted alkylheteroaryl; R 12 is H, branched alkyl, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl; P1 is TIFF0007785053000005.tif68128; where: m is 1, 2, 3, or 4; R 14 and R 15 is independently selected at each occurrence 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; R 14 and R 15may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring which may incorporate 1 or 2 ring heteroatoms selected from N, O, or S, which are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy; R 18 and R 19 is independently selected at each occurrence from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with one substituent selected from the list 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 from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy; R 14 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 14 and R 19 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 15 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 15 and R 19 may form a 5- to 7-membered ring together with the atoms to which they are attached; and R1 and R2 are independently H or P2; P2 is TIFF0007785053000006.tif143128; where: m is 1, 2, 3, or 4; R 14 and R 15 is as defined above; R 14 and R 15may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring which may incorporate 1 or 2 ring heteroatoms selected from N, O, or S, which are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the list consisting of halo, methyl, and methoxy; R 16 and R 17 is independently at each occurrence H or alkyl; R 16 and R 17 may form a 3- to 6-membered ring together with the atoms to which they are attached; R 18 and R 19 is as defined above; R 14 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 14 and R 19 may form a 5- to 7-membered ring together with the atoms to which they are attached; Formula I includes enantiomers, pharmaceutically acceptable salts, and polymorphs of compounds of Formula I.

[0009] In another embodiment, a compound of formula II A compound represented by TIFF0007785053000007.tif61128 is provided, During the ceremony, R2 is selected from the group consisting of H and P2; R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36are 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)-, or a bond; P2 is TIFF0007785053000008.tif143128; where: m is 1, 2, 3, or 4; R 14 and R 15 is as defined above; R 14 and R 15 may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring which may incorporate 1 or 2 ring heteroatoms selected from N, O, or S, which are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the list consisting of halo, methyl, and methoxy; R 16 and R 17 is independently at each occurrence H or alkyl; R 16 and R 17 may form a 3- to 6-membered ring together with the atoms to which they are attached; R 18 and R 19 is as defined above; R 14 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 14 and R 19 may form a 5- to 7-membered ring together with the atoms to which they are attached; Formula II includes enantiomers, pharmaceutically acceptable salts, and polymorphs of compounds of Formula II.

[0010] In another embodiment, the compound has formula III Represented by TIFF0007785053000009.tif58128, L2 is TIFF0007785053000010.tif41128; where: m is 1, 2, 3, or 4; X is NR 14 or O; R 14 is 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; R 16 and R 17 is independently at each occurrence H or alkyl; R 16 and R 17 may form a 3- to 6-membered ring together with the atoms to which they are attached; R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 are independently selected from the group consisting of H and deuterium; Z is -OH, -OR 11 , -N(R 11 )R 12 , -SR 11 , or P1; R 11is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, or substituted alkylheteroaryl; R 12 is H, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl; P1 is TIFF0007785053000011.tif68128; where: m is 1, 2, 3, or 4; R 14 and R 15 is independently selected at each occurrence 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; R 14 and R 15 may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring which may incorporate 1 or 2 ring heteroatoms selected from N, O, or S, which are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy; R 18 and R 19is independently selected at each occurrence from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with one substituent selected from the list 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 from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy; R 14 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 14 and R 19 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 15 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 15 and R 19 may form a 5- to 7-membered ring together with the atoms to which they are attached; Formula III includes enantiomers, pharmaceutically acceptable salts, and polymorphs of compounds of Formula III.

[0011] Another embodiment is a compound of formula IV providing a compound represented by TIFF0007785053000012.tif53128, R1 is selected from the group consisting of H and P2; R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , 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)-, or a bond; P2 is TIFF0007785053000013.tif143128; where: m is 1, 2, 3, or 4; R 14 and R 15 is independently selected at each occurrence 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; R 14 and R 15 may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring which may incorporate 1 or 2 ring heteroatoms selected from N, O, or S, which are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy; R 16 and R 17 is independently at each occurrence H or alkyl; R 16 and R 17 may form a 3- to 6-membered ring together with the atoms to which they are attached; R 18 and R 19is independently selected at each occurrence from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with one substituent selected from the list 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 from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy; R 14 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 14 and R 19 may form a 5- to 7-membered ring together with the atoms to which they are attached; Formula IV includes enantiomers, pharmaceutically acceptable salts, and polymorphs of compounds of Formula IV.

[0012] Also provided are compositions, including compositions comprising at least one compound according to formula I, II, III, and IV and at least one other ingredient. In one embodiment, the composition is formulated for transdermal delivery. In another embodiment, the composition is formulated for transdermal delivery by a patch. In one embodiment, the composition can further comprise at least one solvent. In one embodiment, the amount of the compound according to formula I, II, III, or IV is adapted to provide a delivery profile useful for human treatment. In one embodiment, the treatment is performed on a subject, such as a mammal, but the subject is not human.

[0013] At least one advantage of at least one embodiment includes the ability to tailor the chemical structure of the pharmaceutically useful motif to a particular application, including, for example, treatment and prevention of PH and PAH, e.g., drug delivery profiles can be tailored to a particular application.

[0014] At least one additional advantage of at least one embodiment includes the ability to use the compounds to provide greater bioavailability, including in transdermal drug delivery applications. [The present invention 1001] Formula (I) A compound represented by TIFF0007785053000014.tif49128, In the formula, R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 are independently H or deuterium; Z is -OH, -OR 11 , -N(R 11 )R 12 , -SR 11 , or P1; R 11 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, or substituted alkylheteroaryl; R 12 is H, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl; P1 is TIFF0007785053000015.tif68128; where: m is 1, 2, 3, or 4; R 14 and R 15 is independently selected at each occurrence 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; R 14 and R 15 may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring which may incorporate 1 or 2 ring heteroatoms selected from N, O, or S, which are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy; R 18 and R 19 is independently selected at each occurrence from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with one substituent selected from the list 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 from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy; R 14 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 14 and R 19 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 15 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 15 and R 19may form a 5- to 7-membered ring together with the atoms to which they are attached; and R1 and R2 are independently H or P2, and at least one of R1 and R2 is P2; P2 is TIFF0007785053000016.tif143128; where: m is 1, 2, 3, or 4; R 14 and R 15 is independently selected at each occurrence 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; R 14 and R 15 may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring which may incorporate 1 or 2 ring heteroatoms selected from N, O, or S, which are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy; R 16 and R 17 is independently at each occurrence H or alkyl; R 16 and R 17 may form a 3- to 6-membered ring together with the atoms to which they are attached; R 18 and R 19is independently selected at each occurrence from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with one substituent selected from the list 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 from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy; R 14 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 14 and R 19 may form a 5- to 7-membered ring together with the atoms to which they are attached; Formula I includes enantiomers, pharmaceutically acceptable salts, and polymorphs of compounds of Formula I. The compound. [The present invention 1002] 1001. The compound of the present invention, wherein R1 is P2 and R2 is H. [The present invention 1003] 1001. The compound of the present invention, wherein R1 is H and R2 is P2. [The present invention 1004] The compound of the present invention 1001, wherein R1 is P2 and R2 is P2. [The present invention 1005] P2 1001. A compound of the present invention selected from the group consisting of TIFF0007785053000017.tif123128. [The present invention 1006] P2 1001. A compound of the present invention selected from the group consisting of TIFF0007785053000018.tif67128. [The present invention 1007] P2 1001. A compound of the present invention selected from the group consisting of TIFF0007785053000019.tif50128. [The present invention 1008] P2 1001. A compound of the present invention selected from the group consisting of TIFF0007785053000020.tif19128. [The present invention 1009] P2 1001. A compound of the present invention selected from the group consisting of TIFF0007785053000021.tif50128. [The present invention 1010] P2 1001. A compound of the present invention selected from the group consisting of TIFF0007785053000022.tif50128. [The present invention 1011] P2 1001. A compound of the present invention selected from the group consisting of TIFF0007785053000023.tif34128. [The present invention 1012] P2 1001. A compound of the present invention selected from the group consisting of TIFF0007785053000024.tif12128. [The present invention 1013] P2 1001. A compound of the present invention selected from the group consisting of TIFF0007785053000025.tif17128. [The present invention 1014] P2 1001. A compound of the present invention selected from the group consisting of TIFF0007785053000026.tif16128. [The present invention 1015] P2 1001. A compound of the present invention selected from the group consisting of TIFF0007785053000027.tif12128. [The present invention 1016] R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29, R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 1001. The compound of the present invention, wherein is H. [The present invention 1017] R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 1001. The compound of the present invention, wherein at least one of the following is deuterium: [The present invention 1018] Z is -OR 11 , -N(R 11 )R 12 or P1. [The present invention 1019] 1001. A compound of the present invention wherein Z is P1. [The present invention 1020] Z is -OH, -OR 11 , -N(R 11 )R 12 or P1. [The present invention 1021] 1001. A compound of the present invention wherein Z is -OH. [The present invention 1022] Z is not -OH and R 11 is not unsubstituted or substituted benzyl. [The present invention 1023] Formula (IA) It is represented by TIFF0007785053000028.tif42128, During the ceremony, Z is -OH, -OR11 , or P1; R 11 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl; P1 is TIFF0007785053000029.tif43128; where: m is 1, 2, 3, or 4; R 14 and R 15 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl; R 14 and R 15 may form a 5- to 7-membered ring together with the atoms to which they are attached; and R1 and R2 are independently H or P2, and at least one of R1 and R2 is P2; P2 is TIFF0007785053000030.tif52128; where: R 14 is selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl; Formula IA includes enantiomers, pharmaceutically acceptable salts, and polymorphs of compounds of formula IA. 1001 compounds of the present invention. [The present invention 1024] Formula (I) A compound according to TIFF0007785053000031.tif49128, In the formula, R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 are independently H or deuterium; Z is -OR 11 , -N(R 11 )R 12 , -SR 11 , or P1; R 11 is branched alkyl, haloalkyl, halocycloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, bicycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl, alkylaryl, substituted alkylaryl, alkylheteroaryl, substituted alkylheteroaryl, heteroaryl, substituted heteroaryl; R 12 is H, branched alkyl, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl; P1 is TIFF0007785053000032.tif69128; where: m is 1, 2, 3, or 4; R 14 and R 15is independently selected at each occurrence 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; R 14 and R 15 may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring which may incorporate 1 or 2 ring heteroatoms selected from N, O, or S, which are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy; R 18 and R 19 is independently selected at each occurrence from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with one substituent selected from the list 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 from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy; R 14 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 14 and R 19 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 15 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 15 and R 19 may form a 5- to 7-membered ring together with the atoms to which they are attached; and R1 and R2 are independently H or P2; P2 is TIFF0007785053000033.tif142128; where: m is 1, 2, 3, or 4; R 14 and R 15 is independently selected at each occurrence 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; R 14 and R 15 may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring which may incorporate 1 or 2 ring heteroatoms selected from N, O, or S, which are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy; R 16 and R 17 is independently at each occurrence H or alkyl; R 16 and R 17 may form a 3- to 6-membered ring together with the atoms to which they are attached; R 18 and R 19 is independently selected at each occurrence from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with one substituent selected from the list 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 from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy; R 14 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 14and R 19 may form a 5- to 7-membered ring together with the atoms to which they are attached; Formula I includes enantiomers, pharmaceutically acceptable salts, and polymorphs of compounds of Formula I. The compound. [The present invention 1025] Z is -OR 11 The compound of the present invention 1024, [The present invention 1026] Z is -N(R 11 )R 12 The compound of the present invention 1024, [The present invention 1027] Z is -SR 11 The compound of the present invention 1024, [The present invention 1028] 1024. The compound of claim 1024, wherein Z is P1. [The present invention 1029] Z is OR 11 and R 11 1024. The compound of claim 1024, wherein is bicycloalkyl, alkylcycloalkyl, or alkylcycloheteroalkyl. [The present invention 1030] R 11 The compound of claim 1024, wherein is haloalkyl. [The present invention 1031] R 11 The compound of the present invention 1024, wherein is fluoroalkyl. [The present invention 1032] 1024. The compound of the present invention, wherein R1 is hydrogen and R2 is P2. [The present invention 1033] 1024. The compound of the present invention, wherein R1 is P2 and R2 is hydrogen. [The present invention 1034] The compound of the present invention 1024, wherein R1 is P2 and R2 is P2. [This invention 1035] 1024. The compound of the present invention, wherein R1 and R2 are each hydrogen. [The present invention 1036] R 20 , R21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 The compound of the present invention 1024, wherein is H. [This invention 1037] R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 The compound of the present invention 1024, wherein at least one of the groups is deuterium. [The present invention 1038] Formula (IAA) A compound according to TIFF0007785053000034.tif48128, During the ceremony, R 100 and R 200 are independently H, CONR 900 R 1000 , C.R. 900 R 1000 OCOP3R 900 R 1000 and R is selected from the group consisting of 900 and R 1000 is independently selected from H, alkyl, and cycloalkyl; R 300 , R 400 , R 500 , R 600 , R 700 , and R800 are independently selected from the group consisting of H and deuterium; X is O, NHR 1200 , or S, P3 is N or O, R 1100 is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, heteroaryl; R 1200 is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, heteroaryl; The compound. [This invention 1039] R 100 , R 200 The compound of the present invention 1038, wherein is H. [The present invention 1040] R 300 , R 400 , R 500 , R 600 , R 700 , and R 800 The compound of the present invention 1039, wherein is H. [The present invention 1041] 1040. The compound of claim 10, wherein X is O. [The present invention 1042] R 1100 but 1041. A compound of the present invention selected from TIFF0007785053000035.tif102128. [This invention 1043] X is NHR 1200 The compound of the present invention 1039, [This invention 1044] R 1100 but The compound of the present invention 1043 selected from TIFF0007785053000036.tif41128. [This invention 1045] The compound of the present invention 1038, wherein X is O. [The present invention 1046] R 300 , R400 , R 500 , R 600 , R 700 , and R 800 The compound of the present invention 1045, wherein is H. [This invention 1047] R 1100 The compound of the present invention 1046, wherein is alkyl. [This invention 1048] Formula II A compound represented by TIFF0007785053000037.tif61128, During the ceremony, R2 is selected from the group consisting of H and P2; R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 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)-, or a bond; P2 is TIFF0007785053000038.tif142128; where: m is 1, 2, 3, or 4; R 14 and R 15 is independently selected at each occurrence 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; R 14and R 15 may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring which may incorporate 1 or 2 ring heteroatoms selected from N, O, or S, which are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy; R 16 and R 17 is independently at each occurrence H or alkyl; R 16 and R 17 may form a 3- to 6-membered ring together with the atoms to which they are attached; R 18 and R 19 is independently selected at each occurrence from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with one substituent selected from the list 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 from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy; R 14 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 14 and R 19 may form a 5- to 7-membered ring together with the atoms to which they are attached; Formula II includes enantiomers, pharmaceutically acceptable salts, and polymorphs of compounds of Formula II. The compound. [This invention 1049] R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 The compound of the present invention 1048, wherein is H. [The present invention 1050] R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 The compound of claim 1048, wherein at least one of the groups is deuterium. [This invention 1051] 1048. The compound of the present invention, wherein L1 is -O-alkylene-C(O)-. [This invention 1052] 1048. The compound of the present invention, wherein L1 is -O-alkylene-OC(O)-. [This invention 1053] 1048. The compound of the present invention, wherein L1 is a bond. [This invention 1054] Compound 1048 of the present invention, wherein the alkylene group is a C1-C5 alkylene group. [This invention 1055] 1048. The compound of the present invention, wherein the alkylene group is a C1 alkylene group. [This invention 1056] Formula IIA A compound represented by TIFF0007785053000039.tif49128, wherein L1 and R2 are defined as in the present invention 1048. Compound 1048 of the present invention. [This invention 1057] Formula II(AA) TIFF0007785053000040.tif65128 and an enantiomer of a compound of formula II(AA): During the ceremony, R 2000 are independently H, CONR 9000 R 10000 , C.R. 9000 R 10000 OCOPR 9000 R 10000 and R is selected from the group consisting of 9000 and R 10000 is independently selected from H, alkyl, and cycloalkyl; R 3000 , R 4000 , R 5000 , R 6000 , R 7000 , and R 8000 are independently selected from the group consisting of H and deuterium; X is O, NR 12000 , S, P is N, O, R 12000 is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, heteroaryl; n is an integer from 1 to 7; and Formula II(AA) includes enantiomers of Formula II(AA), pharmaceutically acceptable salts of compounds of Formula II(a), and polymorphs of Formula II(AA). The compound and the enantiomer. [This invention 1058] Formula III A compound represented by TIFF0007785053000041.tif58128, In the formula, L2 is TIFF0007785053000042.tif41128; where: m is 1, 2, 3, or 4; X is NR 14 or O; R 14is 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; R 16 and R 17 is independently at each occurrence H or alkyl; R 16 and R 17 may form a 3- to 6-membered ring together with the atoms to which they are attached; and R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 are independently selected from the group consisting of H and deuterium; Z is -OH, -OR 11 , -N(R 11 )R 12 , -SR 11 , or P1; R 11 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, or substituted alkylheteroaryl; R 12is H, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl; P1 is TIFF0007785053000043.tif68128; where: m is 1, 2, 3, or 4; R 14 and R 15 is independently selected at each occurrence 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; R 14 and R 15 may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring which may incorporate 1 or 2 ring heteroatoms selected from N, O, or S, which are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy; R 18 and R 19 is independently selected at each occurrence from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with one substituent selected from the list 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 from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy; R 14 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 14 and R 19may form a 5- to 7-membered ring together with the atoms to which they are attached; R 15 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 15 and R 19 may form a 5- to 7-membered ring together with the atoms to which they are attached; Formula III includes enantiomers, pharmaceutically acceptable salts, and polymorphs of compounds of Formula III. The compound. [This invention 1059] L2 1058 compounds of the present invention selected from the group consisting of TIFF0007785053000044.tif40128. [The present invention 1060] R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 The compound of the present invention 1058, wherein is H. [This invention 1061] R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36The compound of claim 1058, wherein at least one of the groups is deuterium. [This invention 1062] Formula IIIA A compound represented by TIFF0007785053000045.tif49128, wherein Z and L2 are defined as in the present invention 1058. Compound 1058 of the present invention. [This invention 1063] Formula III(AA) TIFF0007785053000046.tif63128, and enantiomers of compounds of formula III(AA), and pharmaceutically acceptable salts of compounds of formula III(AA), and polymorphs of formula III(AA), During the ceremony, R 11 is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, heteroaryl; During the ceremony, R 03 , R 04 , R 05 , R 06 , R 07 , and R 08 are independently selected from the group consisting of H and deuterium; During the ceremony, X is O, NR 012 , S, R 012 is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, heteroaryl; Y is C=O, The compound, as well as the enantiomers, the pharmaceutically acceptable salts, and the polymorphs. [This invention 1064] Formula IV A compound represented by TIFF0007785053000047.tif53128, R1 is selected from the group consisting of H and P2; R 20 , R21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 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)-, or a bond; P2 is TIFF0007785053000048.tif142128; where: m is 1, 2, 3, or 4; R 14 and R 15 is independently selected at each occurrence 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; R 14 and R 15 may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring which may incorporate 1 or 2 ring heteroatoms selected from N, O, or S, which are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy; R 16 and R 17 is independently at each occurrence H or alkyl; R 16 and R 17 may form a 3- to 6-membered ring together with the atoms to which they are attached; R 18and R 19 is independently selected at each occurrence from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with one substituent selected from the list 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 from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy; R 14 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 14 and R 19 may form a 5- to 7-membered ring together with the atoms to which they are attached; Formula IV includes enantiomers, pharmaceutically acceptable salts, and polymorphs of compounds of Formula IV: The compound. [This invention 1065] formula IVA A compound represented by TIFF0007785053000049.tif50128, wherein L1 and R1 are defined as in the present invention 1064. Compound 1064 of the present invention. [The present invention 1066] A composition comprising at least one compound of the present invention 1001 to 1065 and at least one other component. [This invention 1067] The composition of the present invention 1066, which is formulated for transdermal delivery. [The present invention 1068] The composition of the present invention 1066, formulated for transdermal delivery via a patch. [The present invention 1069] The composition of claim 1066, further comprising at least one solvent. [The present invention 1070] A composition of claim 1063, wherein the amount of compound of claim 1001 to claim 1065 is adapted to provide a delivery profile useful for human treatment. DETAILED DESCRIPTION OF THE INVENTION

[0015] Detailed Description Introduction U.S. Provisional Priority Application No. 61 / 751,608, filed January 11, 2013, is incorporated herein by reference in its entirety for all purposes, including the formulae and claims, including Formula I, Formula II, and Formula III, as well as Schemes I-4, Examples, and the Table of Structures on pages 14-16.

[0016] Various prostacyclin analogs, including treprostinil, and methods for their use are known and can be used, for example, to promote vasodilation, inhibit platelet aggregation and thrombus formation, stimulate thrombolysis, inhibit cell proliferation (including vascular remodeling), provide cytoprotection, prevent atherogenesis, and induce angiogenesis. Through their prostacyclin-mimetic mechanisms, these compounds can be used in the treatment of pulmonary hypertension, ischemic diseases (e.g., peripheral vascular disease, Raynaud's phenomenon, scleroderma, myocardial ischemia, ischemic stroke, renal failure), heart failure (including congestive heart failure), conditions requiring anticoagulation (e.g., post-myocardial infarction, post-cardiac surgery), thrombotic microangiopathy, extracorporeal circulation, central retinal vein occlusion, atherosclerosis, inflammatory diseases (e.g., COPD, psoriasis), hypertension (e.g., preeclampsia), reproduction and childbirth, cancer or other uncontrolled cell proliferation conditions, cell / tissue preservation, and other emerging therapeutic areas where prostacyclin treatment appears to have a beneficial role. These compounds may also exhibit additive or synergistic benefits in combination with other cardiovascular agents (e.g., calcium channel blockers, phosphodiesterase inhibitors, endothelial antagonists, and antiplatelet agents).

[0017] Treprostinil is a chemically stable analog of prostacyclin. Although treprostinil sodium (Remodulin®) is approved by the U.S. Food and Drug Administration (FDA) for subcutaneous administration, treprostinil as the free acid exhibits an absolute oral bioavailability of less than 10% and a very short systemic half-life due to extensive metabolism.

[0018] definition Lists of chemical groups represented by multiple chemical formulas are provided herein (e.g., P1, P2, L1, and L2). As used herein, these lists of groups describe any combination of subgroups of the chemical formulas in the list of groups, as well as any single formula in the list of groups.

[0019] As used herein, the term "alkyl" refers to a monovalent saturated hydrocarbon group. C1-C8 alkyl refers to an alkyl having 1 to 8 carbon atoms, including, for example, C1-C3 alkyl, C1-C5 alkyl, and C1-C7 alkyl. Alkyl can be linear or branched. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0020] As used herein, the term "haloalkyl" refers to a monovalent saturated hydrocarbon group bonded to one or more halogens selected from Cl and F. Specific examples include 2-fluoroethyl, 2,2-difluoroethyl, 2-fluoropropyl, and 2,2-difluoropropyl.

[0021] As used herein, the term "heteroalkyl" refers to a monovalent saturated hydrocarbon group bonded to one or more heteroatoms selected from O, N, and S. C1-C8 heteroalkyl refers to an alkyl having 1 to 8 carbon atoms followed by a heteroatom selected from O, N, or S, and includes, for example, C1-C3-OH, C1-C5-SH, and C1-C7-NH2. Also included are C1-C2-O-C3-C4-OH and C1-C2-NH-C3-C4-OH.

[0022] As used herein, the term "cycloalkyl" refers to a monovalent monocyclic, bicyclic, or tricyclic saturated hydrocarbon ring system. 14 The term "cycloalkyl" means a cycloalkyl having 3 to 14 ring carbon atoms. 14 Examples of cycloalkyl are C3-C 10 Examples of cycloalkyl groups include cycloalkyl and C-C cycloalkyl. Bicyclic and tricyclic ring systems include fused, bridged, and spirocyclic ring systems. More specific examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cis- and trans-decalinyl, norbornyl, adamantyl, and spiro[4.5]decanyl.

[0023] As used herein, the term "cycloheteroalkyl" refers to a monovalent monocyclic, bicyclic, or tricyclic saturated ring system in which one to four ring atoms are heteroatoms independently selected from the group consisting of O, N, and S. The term "3- to 14-membered cycloheteroalkyl" refers to a cycloheteroalkyl having from 3 to 14 ring atoms. Examples of 3- to 14-membered cycloheteroalkyls include 3- to 10-membered cycloheteroalkyls and 3- to 6-membered cycloheteroalkyls. Bicyclic and tricyclic systems include fused, bridged, and spirocyclic systems. More specific examples of cycloheteroalkyl groups include azepanyl, azetidinyl, aziridinyl, imidazolidinyl, morpholinyl, oxazolidinyl, oxazolidinyl, piperazinyl, piperidinyl, pyrazolidinyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, thiomorpholinyl, and α-methyl-1,3-dioxol-2-onyl.

[0024] As used herein, the term "alkylcycloalkyl" refers to a monovalent monocyclic, bicyclic, or tricyclic saturated hydrocarbon ring system. 14 The term "cycloalkyl" means a cycloalkyl having 3 to 14 ring carbon atoms. 14 Examples of cycloalkyl are C3-C 10 Examples of such alkyl groups include cycloalkyl and C3-C6 cycloalkyl. Bicyclic and tricyclic ring systems include fused ring systems, bridged ring systems, and spirocyclic ring systems bonded to an alkyl group, which means a monovalent saturated hydrocarbon group. C1-C8 alkyl refers to an alkyl having 1 to 8 carbon atoms, such as C1-C3 alkyl, C1-C5 alkyl, and C1-C7 alkyl. Specific examples include cyclopropylmethyl, cyclopropylethyl, and cyclohexylethyl.

[0025] As used herein, the term "alkylheterocycloalkyl" refers to alkyl, a monovalent saturated hydrocarbon group. C1-C8 alkyl refers to alkyl having 1 to 8 carbon atoms, including C1-C3 alkyl, C1-C5 alkyl, and C1-C7 alkyl bonded to a cycloalkyl. Cycloalkyl refers to a monovalent monocyclic, bicyclic, or tricyclic saturated ring system in which 1 to 4 ring atoms are independently selected from the group consisting of O, N, and S. The term "3- to 14-membered heterocycloalkyl" refers to a heterocycloalkyl having 3 to 14 ring atoms. Examples of 3- to 14-membered heterocycloalkyl include 3- to 10-membered heterocycloalkyl and 3- to 6-membered heterocycloalkyl. Bicyclic and tricyclic ring systems include fused, bridged, and spirocyclic ring systems. Specific examples include N-ethylmorpholine, N-ethylpiperidine, 4-ethylpiperidine, 1-methyl-4-ethylpiperidine, and N-ethylpiperazine.

[0026] As used herein, the term "aryl" refers to a monovalent aromatic carbocyclic ring system which may be a monocyclic ring system, a fused bicyclic ring system, or a fused tricyclic ring system. 14 The term "aryl" means an aryl having 6 to 14 ring carbon atoms. 14 An example of an aryl is C6-C 10 More specific examples of aryl groups include phenyl, naphthyl, anthracyl, and phenanthryl.

[0027] As used herein, the term "heteroaryl" refers to an unsaturated aromatic heterocyclyl group. Examples of heteroaryl groups include unsaturated 3- to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, pyrrolinyl, imidazolyl, and tetrazolyl; unsaturated fused heterocyclyl groups containing 1 to 5 nitrogen atoms, such as indolyl, isoindolyl, benzimidazolyl, quinolyl, benzotriazolyl, and tetrazolopyridazinyl; unsaturated 3- to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl and oxadiazolyl; unsaturated fused heterocyclyl groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms; unsaturated 3- to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl and thiadiazolyl; and unsaturated fused heterocyclyl groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms.

[0028] As used herein, the term "alkylaryl" refers to aryl-substituted alkyl groups such as benzyl, diphenylmethyl, and phenylethyl.

[0029] As used herein, the term "alkylheteroaryl" refers to heteroaryl-substituted alkyl groups such as imidazoylmethyl, thiazoylmethyl, and pyridylethyl.

[0030] As used herein, terms described herein such as alkyl, haloalkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylheterocycloalkyl, aryl, heteroaryl, alkylaryl, and alkylheteroaryl will be understood to encompass several optional aspects in which they form a ring. For example, as further described herein, in some cases, R 14 , R 15 , R 16 , R 17 , R 18, and R 19 groups such as other groups R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 may form a ring with

[0031] The term "substituted" refers to the replacement of one or more hydrogen radicals in a given structure with a specific substituent group, including, but not limited to, halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkoxy, alkoxy, aryloxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, alkylhalo, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, hydroxyl, alkyloxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, carbonyl, carboxylic acid, sulfonic acid, phosphonic acid, aryl, heteroaryl, heterocyclic, and aliphatic. It will be understood that the substituent group may be further substituted within the normal limits of those skilled in the art. A moiety or group may be substituted, i.e., the group may or may not have one or more substituents.

[0032] The term "compound" as used herein is intended to include salts, solvates, and hydrates thereof. The specific mention of a "salt," "solvate," or "hydrate" in certain aspects of the invention described in this application is not to be construed as an intentional exclusion of these forms in other aspects of the invention where the term "compound" is used without mention of these other forms.

[0033] A salt of a compound of the present invention is formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group. In another preferred embodiment, the compound is a pharmaceutically acceptable acid addition salt.

[0034] As used herein, the term "pharmaceutically acceptable" means a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, etc., and is commensurate with a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt that is capable of directly or indirectly providing a compound of the invention or a prodrug of a compound upon administration to a recipient. A "pharmaceutically acceptable counterion" is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.

[0035] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, and related inorganic and organic acids. Accordingly, such pharmaceutically acceptable salts include sulfate, pyrosulfate, hydrogen sulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, and the like. Included are diacid salts, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, and the like. Preferred pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid.

[0036] As used herein, the term "hydrate" means a compound that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0037] As used herein, the term "solvate" means a compound that further includes a stoichiometric or non-stoichiometric amount of a solvent, such as water, acetone, ethanol, methanol, dichloromethane, 2-propanol, and the like, bound by non-covalent intermolecular forces.

[0038] Isotopes and isotopic abundances It should be recognized that depending on the origin of chemicals used in synthesis, some variation in natural isotope abundance will occur in synthesized compounds.Therefore, Treprostinil preparations inherently contain a small amount of deuterated isotopes.Despite this variation, the concentration of naturally abundant hydrogen and carbon stable isotopes is small and is not significant with respect to the degree of stable isotope substitution of the compounds of the present invention.See, for example, Wada E et al, Seikagaku 1994, 66:15; Ganes LZ et al, Comp Biochem Physiol Mol Integr Physiol 1998, 119:725.When a specific position in the compounds of the present invention is designated as having deuterium, it should be understood that the abundance of deuterium at that position is substantially greater than the natural deuterium abundance, which is 0.015%.Usually, a position designated as having deuterium has a minimum isotope enrichment factor of at least 3000 (45% deuterium incorporation) at each atom designated as deuterium in the compound.

[0039] As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0040] In some embodiments, compounds of the invention have an isotopic enrichment factor for each atom designated as deuterium of at least 3500 (52.5% deuterium incorporation at each atom designated as deuterium), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation), for each atom designated as deuterium.

[0041] In the compounds of the present invention, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen," the position will be understood to have hydrogen at its natural abundance isotopic composition.

[0042] In other embodiments, the compounds of the present invention contain less than 10%, preferably less than 6%, and more preferably less than 3%, of all other isotopologues, including deuterium-depleted forms. In certain aspects, the compounds contain less than "X"% of all other isotopologues, including deuterium-depleted forms, where X is any number between 0 and 10 (e.g., 1, 0.5, 0.001). Compositions containing more than 10% of all other isotopologues in total are referred to herein as "mixtures" and must meet the parameters set forth below. These limitations on isotopic composition, and all references herein to isotopic composition, refer only to the relative amounts of deuterium / hydrogen present in the active free base form of the compound of Formula I or II, and do not include the isotopic composition of hydrolyzable portions of prodrugs or the isotopic composition of counterions.

[0043] The term "isotopologue" refers to a species that differs from a specific compound of this invention only in the isotopic composition of a molecule or ion.

[0044] Core Structure I In one aspect, the present invention provides a compound of formula I The compound represented by TIFF0007785053000050.tif49128 is provided.

[0045] At least two subembodiments are provided to further define Formula I.

[0046] In a first subembodiment of Formula I, R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 are independently H or deuterium; Z is -OH, -OR 11 , -N(R 11 )R 12 , -SR 11 , or P1; R 11 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, or substituted alkylheteroaryl; R 12 is H, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl; P1 is TIFF0007785053000051.tif69128; where: m is 1, 2, 3, or 4; R 14 and R 15 is independently selected at each occurrence 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; R 14 and R 15 may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring which may incorporate 1 or 2 ring heteroatoms selected from N, O, or S, which are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy; R 18 and R 19 is independently selected at each occurrence from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with one substituent selected from the list 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 from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy; R 14 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 14 and R 19 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 15 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R15 and R 19 may form a 5- to 7-membered ring together with the atoms to which they are attached; and R1 and R2 are independently H or P2, and at least one of R1 and R2 is P2; P2 is TIFF0007785053000052.tif142128; where: m is 1, 2, 3, or 4; R 14 and R 15 is as defined above; R 14 and R 15 may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring which may incorporate 1 or 2 ring heteroatoms selected from N, O, or S, which are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the list consisting of halo, methyl, and methoxy; R 16 and R 17 is independently at each occurrence H or alkyl; R 16 and R 17 may form a 3- to 6-membered ring together with the atoms to which they are attached; R 18 and R 19 is as defined above; R 14 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 14 and R 19 may form a 5- to 7-membered ring together with the atoms to which they are attached; Formula I includes enantiomers, pharmaceutically acceptable salts, and polymorphs of the compound of Formula I. In this Formula I, in contrast to Formulas II, III, and IV described herein, the Z, R1, and R2 groups are not linked to each other.

[0047] In one embodiment, R1 is P2 and R2 is H. In another embodiment, R1 is H and R2 is P2. In another embodiment, R1 is P2 and R2 is P2.

[0048] The P2 group can be more specifically described. In one embodiment, P2 is TIFF0007785053000053.tif124128.

[0049] In another embodiment, P2 is TIFF0007785053000054.tif67128.

[0050] In another embodiment, P2 is TIFF0007785053000055.tif41128.

[0051] In another embodiment, P2 is TIFF0007785053000056.tif19128.

[0052] In another embodiment, P2 is TIFF0007785053000057.tif51128.

[0053] In another embodiment, P2 is TIFF0007785053000058.tif50128.

[0054] In another embodiment, P2 is TIFF0007785053000059.tif34128.

[0055] In another embodiment, P2 is TIFF0007785053000060.tif12128.

[0056] In another embodiment, P2 is TIFF0007785053000061.tif17128.

[0057] In another embodiment, P2 is TIFF0007785053000062.tif16128.

[0058] In another embodiment, P2 is TIFF0007785053000063.tif12128.

[0059] In one aspect, R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 is H.

[0060] In one embodiment, Z is -OR 11 , -N(R 11 )R 12 In another embodiment, Z is P1. In another embodiment, Z is -OH, -OR 11 , -N(R 11 )R 12 or P1. In another embodiment, Z is -OH.

[0061] In one embodiment, Z is not —OH and is R 11 is not unsubstituted or substituted benzyl.

[0062] In a second subembodiment of Formula I, R 20 , R 21 , R 22 , R 23 , R 24 , R25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 are independently H or deuterium; Z is -OR 11 , -N(R 11 )R 12 , -SR 11 , or P1; R 11 is branched alkyl, haloalkyl, halocycloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, bicycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, substituted alkylheteroaryl; R 12 is H, branched alkyl, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl; P1 is TIFF0007785053000064.tif69128; where: m is 1, 2, 3, or 4; R 14 and R 15 is independently selected at each occurrence 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; R 14 and R 15may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring which may incorporate 1 or 2 ring heteroatoms selected from N, O, or S, which are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy; R 18 and R 19 is independently selected at each occurrence from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with one substituent selected from the list 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 from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy; R 14 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 14 and R 19 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 15 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 15 and R 19 may form a 5- to 7-membered ring together with the atoms to which they are attached; and R1 and R2 are independently H or P2; P2 is TIFF0007785053000065.tif143157; where: m is 1, 2, 3, or 4; R 14 and R 15 is as defined above; R 14 and R 15may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring which may incorporate 1 or 2 ring heteroatoms selected from N, O, or S, which are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the list consisting of halo, methyl, and methoxy; R 16 and R 17 is independently at each occurrence H or alkyl; R 16 and R 17 may form a 3- to 6-membered ring together with the atoms to which they are attached; R 18 and R 19 is as defined above; R 14 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 14 and R 19 may form a 5- to 7-membered ring together with the atoms to which they are attached; Formula I includes enantiomers, pharmaceutically acceptable salts, and polymorphs of compounds of Formula I.

[0063] In one embodiment, Z is -OR 11 In one embodiment, Z is -N(R 11 )R 12 In one embodiment, Z is -SR 11 In one embodiment, Z is P1. In one embodiment, Z is OR 11 and R 11 is bicycloalkyl, alkylcycloalkyl, or alkylcycloheteroalkyl. In one embodiment, Z is P1.

[0064] In one aspect, R 11 is haloalkyl, or more specifically fluoroalkyl.

[0065] In one embodiment, R1 is hydrogen, or R2 is hydrogen. In one embodiment, R1 is hydrogen and R2 is P2. In one embodiment, R1 is P2 and R2 is hydrogen. In one embodiment, R1 and R2 are hydrogen. In one embodiment, R1 and R2 are P2.

[0066] In one aspect, R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 At least one of these is deuterium.

[0067] In one aspect, R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 is hydrogen.

[0068] Formula IA Another particular subembodiment of formula I is formula (IA): The compound represented by TIFF0007785053000066.tif42128 is During the ceremony, Z is -OH, -OR 11 , or P1; R 11is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl; P1 is TIFF0007785053000067.tif43128; where: m is 1, 2, 3, or 4; R 14 is selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl; and R1 and R2 are independently H or P2, and at least one of R1 and R2 is P2; P2 is TIFF0007785053000068.tif52128; where: R 14 and R 15 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl; R 14 and R 15 may form a 5- to 7-membered ring together with the atoms to which they are attached; Formula IA includes enantiomers, pharmaceutically acceptable salts, and polymorphs of compounds of formula IA.

[0069] Specific Compounds of Formula I The following are specific compounds of Formula I (Compound A, described above, is shown as a control and not a prodrug):

[0070] TIFF0007785053000069.tif40128 Compound 1 [2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid cyclopropylmethyl ester

[0071] TIFF0007785053000070.tif40128 Compound 2 N-Cyclopropylmethyl-2-[2-hydroxy-1-(3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetamide

[0072] TIFF0007785053000071.tif38128 Compound 3 [2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid 2-morpholin-4-yl-ethyl ester

[0073] TIFF0007785053000072.tif37128 Compound 4 [2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid 3-fluoro-propyl ester

[0074] TIFF0007785053000073.tif37128 Compound 5 [2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid tetrahydro-furan-3-yl ester

[0075] TIFF0007785053000074.tif42128 Compound 6 2-{2-[2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetoxy}-propionic acid methyl ester

[0076] TIFF0007785053000075.tif38128 Compound A [2-Hydroxy-1-(3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid

[0077] TIFF0007785053000076.tif40128 Compound 7 N-(2-hydroxyethyl)-2-[2-hydroxy-1-(3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetamide

[0078] TIFF0007785053000077.tif40128 Compound 8 N-(2-amino-ethyl)-2-[2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetamide

[0079] TIFF0007785053000078.tif38128 Compound 9 [2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid 2-hydroxy-ethyl ester

[0080] TIFF0007785053000079.tif38128 Compound 10 [2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid 2-methoxy-ethyl ester

[0081] TIFF0007785053000080.tif40128 Compound 11 2-[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-N-(3-hydroxy-propyl)-acetamide

[0082] TIFF0007785053000081.tif42128 Compound 12 {2-[2-Hydroxy-1-(3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetylamino}-acetic acid methyl ester

[0083] TIFF0007785053000082.tif42128 Compound 13 ({2-[2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetyl}-methyl-amino)-acetic acid methyl ester

[0084] TIFF0007785053000083.tif42128 Compound 14 2-[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-N-(2,2,2-trifluoro-ethyl)-acetamide

[0085] TIFF0007785053000084.tif37128 Compound 15 [2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid methyl ester

[0086] TIFF0007785053000085.tif41128 Compound 16 [2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid 2,2-dimethyl-propyl ester

[0087] TIFF0007785053000086.tif41128 Compound 17 [2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid 1,2-dimethyl-propyl ester

[0088] TIFF0007785053000087.tif41128 Compound 18 [2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid 1,2,2-trimethyl-propyl ester

[0089] TIFF0007785053000088.tif38128 Compound 19 [2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid bicyclo[2.2.1]hept-2-yl ester

[0090] TIFF0007785053000089.tif37128 Compound 20 [2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid isopropyl ester

[0091] TIFF0007785053000090.tif41128 Compound 21 2-[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-N-(2,2,3,3,3-pentafluoro-propyl)-acetamide

[0092] TIFF0007785053000091.tif37128 Compound 22 Pentanoic acid 1-(3-hydroxy-octyl)-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-yl ester

[0093] TIFF0007785053000092.tif37128 Compound 23 3-Methyl-butyric acid 1-(3-hydroxy-octyl)-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-yl ester

[0094] TIFF0007785053000093.tif37128 Compound 24 Cyclopropanecarboxylic acid 1-(3-hydroxy-octyl)-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-yl ester

[0095] TIFF0007785053000094.tif37128 Compound 25 [2-Ethoxycarbonyloxy-1-(3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid methyl ester

[0096] TIFF0007785053000095.tif37128 Compound 26 [2-Acetoxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid methyl ester

[0097] TIFF0007785053000096.tif38128 Compound 27 Succinic acid ethyl ester 1-(3-hydroxy-octyl)-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-yl ester

[0098] TIFF0007785053000097.tif41128 Compound 28 [2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid tert-butyl ester

[0099] TIFF0007785053000098.tif42128 Compound 29 3-{2-[2-hydroxy-1-(3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetyl}-oxazolidin-2-one

[0100] TIFF0007785053000099.tif49128 Compound 30 2-[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-N-(1H-tetrazol-5-yl)-acetamide

[0101] TIFF0007785053000100.tif42128 Compound 31 [2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid 2,2,2-trifluoro-1,1-dimethyl-ethyl ester

[0102] TIFF0007785053000101.tif41128 Compound 32 [2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid 1,2,2-trimethyl-propyl ester

[0103] TIFF0007785053000102.tif41128 Compound 33 [2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid 1,2,2-trimethyl-propyl ester

[0104] TIFF0007785053000103.tif45128 Compound 34 [2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid bicyclo[2.2.1]hept-2-yl ester

[0105] TIFF0007785053000104.tif45128 Compound 35 [2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid bicyclo[2.2.1]hept-2-yl ester

[0106] TIFF0007785053000105.tif45128 Compound 36 [2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid bicyclo[2.2.1]hept-2-yl ester

[0107] TIFF0007785053000106.tif45128 Compound 37 [2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid bicyclo[2.2.1]hept-2-yl ester

[0108] TIFF0007785053000107.tif50128 Compound 38 [2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid 2-isopropyl-5-methyl-cyclohexyl ester

[0109] TIFF0007785053000108.tif43128 Compound 39 [2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid 1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl ester

[0110] TIFF0007785053000109.tif38128 Compound 40 [2-(2-ethoxy-ethoxycarbonyloxy)-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid methyl ester

[0111] TIFF0007785053000110.tif38128 Compound 41 [2-(2-Dimethylamino-ethoxycarbonyloxy)-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid methyl ester

[0112] TIFF0007785053000111.tif37128 Compound 42 [1-(3-hydroxy-octyl)-2-(2,2,2-trifluoro-ethoxycarbonyloxy)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid methyl ester

[0113] TIFF0007785053000112.tif37128 Compound 43 3-Morpholin-4-yl-propionic acid 1-(3-hydroxy-octyl)-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-yl ester

[0114] TIFF0007785053000113.tif37128 Compound 44 [1-(3-Hydroxy-octyl)-2-(2-pyrrolidin-1-yl-acetoxy)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid methyl ester

[0115] TIFF0007785053000114.tif47128 Compound 45 Cyclopentanecarboxylic acid 1-[2-(2-hydroxy-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)-ethyl]-hexyl ester

[0116] TIFF0007785053000115.tif51128 Compound 46 1-Methyl-piperidine-2-carboxylic acid 1-[2-(2-hydroxy-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)-ethyl]-hexyl ester

[0117] TIFF0007785053000116.tif49128 Compound 47 4-Methyl-morpholine-2-carboxylic acid 1-[2-(2-hydroxy-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)-ethyl]-hexyl ester

[0118] TIFF0007785053000117.tif46128 Compound 48 Cyclopropanecarboxylic acid 1-[2-(2-hydroxy-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)-ethyl]-hexyl ester

[0119] TIFF0007785053000118.tif47128 Compound 49 2-Methyl-butyric acid 1-[2-(2-hydroxy-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)-ethyl]-hexyl ester

[0120] TIFF0007785053000119.tif47128 Compound 50 [1-(3-Cyclopentyloxycarbonyloxy-octyl)-2-hydroxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid methyl ester

[0121] TIFF0007785053000120.tif50128 Compound 51 {1-[3-(1-Aza-bicyclo[2.2.2]oct-3-yloxycarbonyloxy)-octyl]-2-hydroxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy}-acetic acid methyl ester

[0122] TIFF0007785053000121.tif44128 Compound 52 [2-Acetoxy-1-(3-acetoxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester

[0123] TIFF0007785053000122.tif37128 Compound 53 [2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester

[0124] TIFF0007785053000123.tif44128 Compound 54 Propionic acid 1-{2-[5-methoxycarbonylmethoxy-2-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyloxy)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl]-ethyl}-hexyl ester

[0125] TIFF0007785053000124.tif40128 Compound 55 [2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid 1,2-dimethyl-propyl ester

[0126] TIFF0007785053000125.tif41128 Compound 56 [2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid 1,2-dimethyl-propyl ester

[0127] Core Structures II and IIA In another aspect, the present invention provides a compound of formula II providing a compound represented by TIFF0007785053000126.tif61128, During the ceremony, R2 is selected from the group consisting of H and P2; R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 are independently selected from the group consisting of H, deuterium; L1 is selected from the group consisting of -O-alkylene-C(O)-, -O-alkylene-OC(O)-, or a bond; P2 is TIFF0007785053000127.tif143128; where: m is 1, 2, 3, or 4; R 14 and R 15 is as defined above; R 14 and R 15 may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring which may incorporate 1 or 2 ring heteroatoms selected from N, O, or S, which are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the list consisting of halo, methyl, and methoxy; R 16 and R 17 is independently at each occurrence H or alkyl; R 16 and R 17 may form a 3- to 6-membered ring together with the atoms to which they are attached; R 18 and R 19is as defined above; R 14 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 14 and R 19 may form a 5- to 7-membered ring together with the atoms to which they are attached; Formula II includes enantiomers, pharmaceutically acceptable salts, and polymorphs of compounds of Formula II.

[0128] In one aspect, R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 is H. In one aspect, R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 At least one of these is deuterium.

[0129] In one embodiment, L1 is selected from the group consisting of -O-alkyl-C(O)- and -O-alkyl-OC(O)-. In one embodiment, L1 is -O-alkylene-C(O)-. In one embodiment, L1 is -O-alkylene-OC(O)-. In one embodiment, the alkylene group of claim 41 is a C1 to C5 alkylene group. In one embodiment, the alkylene group of claim 41 is a C1 alkylene group.

[0130] In one subembodiment of Formula II, Formula IIA The compound of claim 41, represented by TIFF0007785053000128.tif50128, is provided, wherein L1 and R2 are defined as in Formula II.

[0131] Specific Compounds of Formula II The following represent specific compounds of formula II:

[0132] TIFF0007785053000129.tif33128 Compound 57 Treprostinil 2-hydroxylactone

[0133] TIFF0007785053000130.tif29128 Compound 58 [2-Hydroxy-1-(3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid carboxymethyl lactone

[0134] Core Structure III In another aspect, the present invention also provides a compound of formula III providing a compound represented by TIFF0007785053000131.tif58128, In the formula, L2 is TIFF0007785053000132.tif41128; where: m is 1, 2, 3, or 4; X is NR 14 or O; R14 is 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; R 16 and R 17 is independently at each occurrence H or alkyl; R 16 and R 17 may form a 3- to 6-membered ring together with the atoms to which they are attached; and R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 are independently selected from the group consisting of H, deuterium; Z is -OH, -OR 11 , -N(R 11 )R 12 , -SR 11 , or P1; R 11 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, or substituted alkylheteroaryl; R 12is H, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl; P1 is TIFF0007785053000133.tif69128; where: m is 1, 2, 3, or 4; R 14 and R 15 is independently selected at each occurrence 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; R 14 and R 15 may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring which may incorporate 1 or 2 ring heteroatoms selected from N, O, or S, which are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy; R 18 and R 19 is independently selected at each occurrence from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with one substituent selected from the list 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 from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy; R 14 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 14 and R 19may form a 5- to 7-membered ring together with the atoms to which they are attached; R 15 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 15 and R 19 may form a 5- to 7-membered ring together with the atoms to which they are attached; Formula III includes enantiomers, pharmaceutically acceptable salts, and polymorphs of compounds of Formula III.

[0135] In one embodiment, L2 is TIFF0007785053000134.tif41128.

[0136] In one aspect, R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 At least one of them is deuterium, or they are both hydrogen.

[0137] One particular subembodiment of formula III is formula IIIA The compound represented by TIFF0007785053000135.tif49128 is included. wherein Z and L2 are defined as in formula III.

[0138] Specific Examples of Compounds of Formula III The following compounds represent specific examples of compounds of formula III:

[0139] TIFF0007785053000136.tif43128 Compound 59 [2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid methyl ester 2,3-maleate

[0140] Core Structure of Compounds of Formula IV Another embodiment is a compound of formula IV TIFF0007785053000137.tif53128, wherein the L1 group is attached to R2 rather than R1, unlike in formula II; R1 is selected from the group consisting of H and P2; R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 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)-, or a bond; P2 is TIFF0007785053000138.tif142128; where: m is 1, 2, 3, or 4; R 14 and R 15is independently selected at each occurrence 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; R 14 and R 15 may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring which may incorporate 1 or 2 ring heteroatoms selected from N, O, or S, which are unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy; R 16 and R 17 is independently at each occurrence H or alkyl; R 16 and R 17 may form a 3- to 6-membered ring together with the atoms to which they are attached; R 18 and R 19 is independently selected at each occurrence from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with one substituent selected from the list 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 from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy; R 14 and R 18 may form a 5- to 7-membered ring together with the atoms to which they are attached; R 14 and R 19 may form a 5- to 7-membered ring together with the atoms to which they are attached; Formula IV includes enantiomers, pharmaceutically acceptable salts, and polymorphs of compounds of Formula IV.

[0141] In one aspect, R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 At least one of them is deuterium, or they are both hydrogen.

[0142] In certain embodiments of Formula IV, the compound has the formula IVA Represented by TIFF0007785053000139.tif50128, wherein L1 and R1 are defined as in formula IV.

[0143] A similar approach to compounds of formula II can be used to make and use compounds of formula IV.

[0144] Aspects of Priority Provisional Application No. 61 / 751,608 One embodiment of a priority provisional application is a compound of the formula (IAA) a compound described in TIFF0007785053000140.tif44128, During the ceremony, R 100 and R 200 are independently H, CONR 900 R 1000 , C.R. 900 R 1000 OCOP3R 900 R 1000 and R is selected from the group consisting of 900 and R 1000 is independently selected from H, alkyl, and cycloalkyl; R 300 , R 400 , R 500 , R 600 , R 700, and R 800 are independently selected from the group consisting of H and deuterium; X is O, NHR 1200 , or S, P3 is N or O, R 1100 is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, heteroaryl; R 1200 is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, heteroaryl.

[0145] In one aspect, R 100 , R 200 is H. In one aspect, R 300 , R 400 , R 500 , R 600 , R 700 , and R 800 is H. In one aspect, X is O. In one aspect, R 1100 teeth Selected from TIFF0007785053000141.tif103128.

[0146] In one embodiment, X is NHR 1200 is.

[0147] In one aspect, R 1100 teeth Selected from TIFF0007785053000142.tif41128.

[0148] In one aspect, X is O. In one aspect, R 300 , R 400 , R 500 , R 600 , R 700 , and R 800 is H. In one aspect, R 1100 is alkyl.

[0149] Another aspect of the priority provisional application is a compound of the formula: a compound of formula II(AA) represented by TIFF0007785053000143.tif65128, as well as enantiomers of formula II(AA), pharmaceutically acceptable salts of the compound of formula II(AA), and polymorphs of formula II(AA), During the ceremony, R 2000 are independently H, CONR 9000 R 10000 , C.R. 9000 R 10000 OCOPR 9000 R 10000 and R is selected from the group consisting of 9000 and R 10000 is independently selected from H, alkyl, and cycloalkyl; R 3000 , R 4000 , R 5000 , R 6000 , R 7000 , and R 8000 are independently selected from the group consisting of H and deuterium; X is O, NR 12000 , S, P is N, O, R 12000 is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, heteroaryl; n is an integer from 1 to 7.

[0150] Another aspect of the priority provisional application is a compound of formula III(AA): TIFF0007785053000144.tif63128, and enantiomers of the compound of formula III(AA); and pharmaceutically acceptable salts of the compound of formula III(AA), and polymorphs of formula III(AA), During the ceremony, R 11 is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, heteroaryl; In the formula, R 03 , R 04 , R 05 , R 06 , R07 , and R 08 are independently selected from the group consisting of H and deuterium; In the formula, X is O, NR 012 , S, R 012 is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, heteroaryl; Y is C=O.

[0151] Methods for Making Compounds of Formula I The compounds are prepared using organic synthesis, see, for example, March's Advanced Organic Chemistry, 6 th Ed., Wiley, 2007.

[0152] Compounds of Formula I where R1 = R2 = H can be prepared according to Scheme 1 where Z is OH, R1 is H, and R2 is the hydroxy group of Greene and Wuts Protective Groups in Organic Synthesis The carboxylic acid can be synthesized starting from a compound of Formula I, where PG represents a protecting group as described in the formula (I). The carboxylic acid is activated using coupling conditions that include the use of an activating agent, including, but not limited to, EDC, DCC, DIC, BOP, HATU, HBTU, CDI, thionyl chloride, or oxalyl chloride. The coupling conditions may or may not include an additive, including, but not limited to, DMF, HOSu, HOBT, or HOAT, and may or may not include one or more nucleophilic or non-nucleophilic bases or additives, including, but not limited to, DMAP, TEA, DIPEA, N-methylmorpholine, pyridine, and / or imidazole. The coupling conditions may be carried out in a suitable solvent or solvent mixture, including, but not limited to, DCM, THF, DMF, dioxane, ethyl acetate, or acetonitrile. The activated acid may be isolated and purified or treated directly with ZH. Alternatively, ZH may be present during the coupling conditions. Representative examples of coupling conditions, as well as definitions of activating agents, additives, and bases, are provided in the following table. Handbook of Reagents for Organic Synthesis: Activating Agents and Protecting Groups , John Wiley and Sons. The resulting compound of formula I, where Z is not OH, R1 is H, and R2 is PG, is deprotected using deprotection conditions appropriate for the type of protecting group represented by PG to yield a compound of formula I. Examples of suitable deprotection conditions can be found in Protective Groups in Organic Synthesis by Greene and Wuts.

[0153] Scheme 1 TIFF0007785053000145.tif83144

[0154] Compounds of Formula I where R1 = R2 or R1 is H can be synthesized according to Scheme 2, starting from compounds of Formula I where R1 = R2 = H, using acylation conditions and a reactive molecule ROH or RY where Y is a leaving group including, but not limited to, halogen, sulfonyl, phosphoryl, or acyl. When the reactive molecule ROH is used, the acylation conditions are the same as the coupling conditions described above. When the reactive molecule RY is used, the acylation conditions may or may not include one or more nucleophilic or non-nucleophilic bases or additives including, but not limited to, DMAP, TEA, DIPEA, N-methylmorpholine, pyridine, and / or imidazole, and may be carried out in a suitable solvent or solvent mixture including, but not limited to, DCM, THF, DMF, dioxane, ethyl acetate, and acetonitrile.

[0155] Scheme 2 TIFF0007785053000146.tif35143

[0156] Compounds of formula I where R2 is H can be synthesized according to Scheme 3, starting from compounds of formula I where R1 is H and R2 is PG as defined above, using acylation conditions using ROH or RY as defined above, followed by deprotection conditions as defined above.

[0157] Scheme 3 TIFF0007785053000147.tif84144

[0158] Methods for Making Compounds of Formula II Compounds of Scheme II can be synthesized according to Scheme 4, starting from compounds of Scheme I where Z is OH and R2 is PG as defined above, using lactonization conditions. Examples of lactonization conditions are Chemical Reviews (2007), 107, 239 and Beilstein Journal of Organic Chemistry (2012), 8, 1344, and include, but are not limited to, reactions using 2,4,6-trichlorobenzoic anhydride, TEA, and DMAP; 4-nitrobenzoic anhydride, TEA, and DMAP; 2-chloro-1-methylpyridinium iodide and tributylamine; 2,2'-dipyridyl disulfide and triphenylphosphine; and all of the above coupling and acylation conditions. The lactonization reaction may be carried out in a suitable solvent or solvent mixture, including, but not limited to, DCM, THF, DMF, dioxane, ethyl acetate, acetonitrile, and toluene.

[0159] Scheme 4 TIFF0007785053000148.tif82142

[0160] Methods for Making Compounds of Formula III Compounds of Formula III can be synthesized according to Scheme 5, starting from compounds of Formula 1 where R1 = R2 = H, by reacting with an activated carbonyl equivalent, including but not limited to, phosgene, carbonyldiimidazole, or 4-nitrophenyl chloroformate, in the presence or absence of one or more nucleophilic or non-nucleophilic bases or additives, including but not limited to, DMAP, TEA, DIPEA, N-methylmorpholine, pyridine, and / or imidazole, in a suitable solvent or solvent mixture, including but not limited to, DCM, THF, DMF, dioxane, ethyl acetate, acetonitrile, and toluene.

[0161] Scheme 5 TIFF0007785053000149.tif35144

[0162] composition The compounds described herein can be used alone or in combination with other components known in the art.In particular, multi-component formulations suitable for use in preventive and therapeutic treatments can be prepared.The composition can be in the form of, for example, a solid formulation, a liquid formulation, a semi-solid formulation, a solution, a suspension, or an emulsion.Water can be used as a formulating agent.Water can be in pure form or in combination with one or more excipients.

[0163] In one embodiment, the compound is formulated in a matrix form comprising a matrix material in which the drug is contained or dispersed. The matrix material further controls the release of the drug by controlling the dissolution and / or dispersion of the drug from the reservoir, and can increase the stability of the drug molecules while stored in the reservoir. In one embodiment, the drug is formulated with an excipient material useful for promoting release, such as a water-swellable material that can help push the drug from the reservoir through any tissue pockets above the reservoir. Examples include hydrogels and osmogens known in the art. In another embodiment, the drug is formulated with a penetration enhancer. The penetration enhancer further controls the release of the drug by facilitating transport of the drug through the skin to the site of topical administration or systemic delivery.

[0164] More specifically, to further control the release rate of the drug, the drug can be dispersed in a matrix material, which can be a "release system" as described in U.S. Patent No. 5,797,898, and whose degradability, elution, or dispersibility can provide a method for controlling the release rate of chemical molecules.

[0165] A release system can provide a timed release profile (e.g., pulsed release) when time-varying plasma levels are desired, for example, to enhance therapeutic efficacy, or a more continuous or consistent release profile when constant plasma levels are required. Pulsed release can be achieved from individual reservoirs, multiple reservoirs, or a combination thereof. For example, if each reservoir provides only a single pulse, multiple pulses (i.e., pulsed release) can be achieved by staggering the release of a single pulse from each of several reservoirs. Alternatively, multiple pulses can be achieved from a single reservoir by incorporating several layers of release systems and other materials into a single reservoir. Continuous release can be achieved by incorporating a release system through which molecules degrade, elute, or diffuse over an extended period of time. Furthermore, continuous release can be simulated by releasing several pulses of molecules in rapid succession ("digital" release). The active release systems described herein can be used alone or in combination with passive release systems, such as those described in U.S. Pat. No. 5,797,898.

[0166] The drug can be formulated with one or more pharmaceutically acceptable excipients. Representative examples include bulking agents, wetting agents, stabilizers, crystal growth inhibitors, antioxidants, antimicrobial agents, preservatives, buffers (e.g., acids, bases), surfactants, desiccants, dispersants, osmotic agents, binders (e.g., starch, gelatin), disintegrants (e.g., cellulose), glidants (e.g., talc), diluents (e.g., lactose, dicalcium phosphate), colorants, lubricants (e.g., magnesium stearate, hydrogenated vegetable oil), and combinations thereof. In some embodiments, the excipient is a wax or polymer. In one embodiment, the polymer comprises polyethylene glycol (PEG), such as those typically having a molecular weight of about 100 to 10,000 daltons (e.g., PEG 200, PEG 1450). In another embodiment, the polymer comprises polylactic acid (PLA), polyglycolic acid (PGA), its copolymers (PLGA), or ethyl-vinyl acetate (EVA) polymer. In yet another embodiment, the excipient material comprises a pharmaceutically acceptable oil (eg, sesame oil).

[0167] In one embodiment, the excipient material comprises a saturated drug solution. That is, the excipient material comprises a solution formed of the drug dissolved in a solvent for the drug. The solution is saturated so that the solvent does not dissolve the solid matrix form of the drug. The saturated solution acts as a non-solvent excipient material, substantially filling the pores and voids in the solid matrix.

[0168] In another embodiment, the excipient material comprises a pharmaceutically acceptable perhalohydrocarbon or unsubstituted saturated hydrocarbon. See, for example, U.S. Pat. No. 6,264,990 to Knepp et al., which describes anhydrous, aprotic, hydrophobic, nonpolar liquids such as biocompatible perhalohydrocarbons or unsubstituted saturated hydrocarbons, such as perfluorodecalin, perfluorobutylamine, perfluorotripropylamine, perfluoro-N-methyldecahydroquindine, perfluoro-octohydroquinolidine, perfluoro-N-cyclohexylpyrilidine, perfluoro-N,N-dimethylcyclohexylmethylamine, perfluoro-dimethyl-adamantane, perfluorotri-methylbicyclo(3.3.1)nonane, bis(perfluorohexyl)ethene, bis(perfluorobutyl)ethene, perfluoro-1-butyl-2-hexylethene, tetradecane, methoxyflurane, and mineral oil.

[0169] In one embodiment, the pharmaceutically acceptable excipient material comprises dimethyl sulfoxide (DMSO), glycerin, or ethanol.

[0170] Mixtures of compounds according to Formulas I, II, III, and IV can be used. [Example]

[0171] Further aspects are illustrated in the following non-limiting examples.

[0172] Four assays for the compounds were performed in the following manner, and the results are shown in Table I.

[0173] (Test 1) Human liver microsome stability assays were performed by incubating 0.5 μM test compound in 50 mM potassium phosphate buffer (pH 7.4) containing 0.5 mg of microsomal protein per mL and 50 μL of an NADPH-generating system (7.8 mg glucose 6-phosphate, 1.7 mg NADPH, and 6 U glucose 6-phosphate dehydrogenase) in 2% w / v sodium bicarbonate at 37°C for up to 45 minutes. Aliquots were taken at 0, 5, 15, 30, and 45 minutes and quenched with an internal standard containing stop solution. A cofactor-free control was also prepared at 45 minutes. After incubation, samples were analyzed by LC-MS / MS. The peak area ratio of the analyte to the internal standard was used to calculate intrinsic clearance. Intrinsic clearance (CLint) was determined by nonlinear regression from the first-order elimination rate constant. The formation of the active drug, Compound A, over time was also monitored by LC-MS / MS.

[0174] (Test 2) Human plasma stability assays were performed by incubating 0.5 μM test compound in heparinized human plasma at 37° C. for up to 120 minutes. Aliquots were taken at 0, 5, 15, 30, 60, and 120 minutes and quenched with an internal standard containing stop solution. After incubation, samples were analyzed by LC-MS / MS. The peak area ratio of the analyte to the internal standard was used to calculate half-life. The formation of the active drug, Compound A, over time was also monitored by LC-MS / MS.

[0175] (Test 3) Human skin homogenate stability assays were performed similarly to the human liver microsome stability assays by incubating 0.5 μM test compound in 50 mM potassium phosphate buffer (pH 7.4) containing 0.5 mg of human skin homogenate protein per mL and 50 μL of an NADPH-generating system (7.8 mg glucose 6-phosphate, 1.7 mg NADPH, and 6 U glucose 6-phosphate dehydrogenase) in 2% w / v sodium bicarbonate at 37°C for up to 45 minutes. Aliquots were taken at 0, 5, 15, 30, and 45 minutes and quenched with an internal standard containing stop solution. A cofactor-free control was also prepared at 45 minutes. After incubation, samples were analyzed by LC-MS / MS. Analyte-to-internal standard peak area ratios were used to calculate intrinsic clearance. Intrinsic clearance (CLint) was determined by nonlinear regression from the first-order elimination rate constant. The formation of the active drug, Compound A, over time was also monitored by LCMS / MS.

[0176] (Test 4) Human hepatocyte stability assays were performed by incubating 0.5 μM test compound at 37°C for up to 240 minutes. Cryopreserved human hepatocytes were obtained from Celsis IVT (Baltimore, MD). Cells were thawed according to the vendor's instructions and suspended in Williams' Medium E at 0.5 million cells / mL. The test compound was added to the cell suspension to initiate the reaction. Aliquots were taken at 0, 10, 30, 60, 120, and 240 minutes and quenched with an internal standard containing stop solution. After incubation, samples were analyzed by LC-MS / MS. The peak area ratio of the analyte to the internal standard was used to calculate intrinsic clearance. Intrinsic clearance (CLint) was determined by nonlinear regression from the first-order elimination rate constant. The formation of the active drug, Compound A, over time was also monitored by LC-MS / MS.

[0177] The assay results (half-life) are shown in Table I. In Table I, the assay test results are designated as follows: A = Less than 15 minutes B = 15~30 minutes C = 31~60 minutes D = more than 60 minutes

[0178] (Table I) TIFF0007785053000150.tif114128TIFF0007785053000151.tif241127

[0179] Synthesis Examples Additionally, the following representative syntheses are provided for compounds according to Formulas I, II, and III.

[0180] Example 1 Synthesis of 2-[2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-N-(2,2,2-trifluoro-ethyl)-acetamide A solution of {2-hydroxy-1-[3-(tetrahydro-pyran-2-yloxy)-octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy}-acetic acid (94 mg, 0.2 mmol), trifluoroethylamine (54 mg, 0.6 mmol), and DIPEA (104 μl, 0.6 mmol) in DMF (2 mL) was treated with HATU and stirred at room temperature for 24 hours. The reaction mixture was diluted with MTBE, washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography. The resulting material was dissolved in MeOH (4 mL), treated with Amberlite IR120H, and stirred for 24 hours. The reaction mixture was filtered and concentrated to give 2-[2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-N-(2,2,2-trifluoro-ethyl)-acetamide (46 mg) as an oil. TIFF0007785053000153.tif33140

[0181] Example 2 Synthesis of [2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid 1,2-dimethyl-propyl ester A solution of {2-hydroxy-1-[3-(tetrahydro-pyran-2-yloxy)-octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy}-acetic acid (47 mg, 0.1 mmol), 3-methyl-2-butanol (26 mg, 0.3 mmol), and DMAP (12 mg, 0.1 mmol) in DCM (1 mL) was treated with EDC (26 mg, 0.14 mmol) and stirred at room temperature for 24 hours. The reaction mixture was diluted with MTBE, washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography. The resulting material was dissolved in MeOH / THF (4 mL), treated with Amberlite IR120H, and stirred for 24 hours. The reaction mixture was filtered and concentrated to give [2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid 1,2-dimethyl-propyl ester (16 mg) as an oil. TIFF0007785053000155.tif40138

[0182] Example 3 Synthesis of Treprostinil 2-hydroxylactone A solution of {2-hydroxy-1-[3-(tetrahydro-pyran-2-yloxy)-octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy}-acetic acid (47 mg, 0.1 mmol) and DMAP (26 mg, 0.2 mmol) in DCM (1 mL) was treated with 2,4,6-trichlorobenzoyl chloride (27 mg, 0.11 mmol) and stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography. The resulting material was dissolved in MeOH / THF (4 mL), treated with Amberlite IR120H, and stirred for 24 hours. The reaction mixture was filtered and concentrated to give treprostinil 2-hydroxylactone (8 mg) as an oil. TIFF0007785053000157.tif27139

[0183] Example 4 Synthesis of cyclopropanecarboxylic acid 1-(3-hydroxy-octyl)-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-yl ester A solution of [2-hydroxy-1-(3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid methyl ester (32 mg, 0.06 mmol), DIPEA (31 μL, 0.18 mmol), and DMAP (1 crystal) in DCM (2 mL) was treated with cyclopropanecarbonyl chloride (8 μL, 0.08 mmol) and stirred under nitrogen at room temperature for 24 hours. The reaction mixture was diluted with MTBE, washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography. The resulting material was dissolved in MeOH / THF (4 mL), treated with Amberlite IR120H, and stirred for 24 hours. The reaction mixture was filtered and concentrated to give cyclopropanecarboxylic acid 1-(3-hydroxy-octyl)-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-yl ester (32 mg) as an oil. TIFF0007785053000159.tif27139

[0184] Example 5 Synthesis of Compounds of Formula III TIFF0007785053000160.tif47151 A solution of acrylic acid 1-[2-(2-acryloyloxy-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)-ethyl]-hexyl ester (51 mg, 0.1 mmol) in chloroform (20 mL) was treated with a solution of (PCy3)2Cl2Ru=CHPh (19 mg, 0.023 mmol) in chloroform (3 mL) and stirred at room temperature for 24 h. TEA (1 mL) was added, and the solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound.

[0185] A further synthetic scheme is shown below.

[0186] Example 6 (Compound of Formula I) TIFF0007785053000161.tif78144

[0187] Example 7 (Compound of Formula I) TIFF0007785053000162.tif79145

Claims

1. Formula (I) The compound according to During the ceremony, R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 are independently H or deuterium; Z is -OR 11 and R 11 is branched alkyl, haloalkyl, halocycloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, bicycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl, alkylheteroaryl, substituted alkylheteroaryl, heteroaryl, or substituted heteroaryl; wherein the heteroalkyl group is a hydroxy-substituted C 1 ~C 3 Alkyl, sulfhydryl-substituted C 1 ~C 5 Alkyl, amino substituted C 1 ~C 7 Alkyl, -CH 2 CH 2 OCH 2 CH 2 OH, or -CH 2 CH 2 NHCH 2 CH 2 OH, and wherein the substituted group is substituted with one or more substituents selected from the group consisting of halo, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl or heterocycle, thiol, alkylthio, arylthio, alkylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkoxy, aryloxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, hydroxyl, alkyloxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, and -CO2H; R 1 and R 2 are independently H or P 2 and P 2 teeth selected from the group consisting of where: m is 1, 2, 3, or 4; R 14 is independently selected at each occurrence 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; wherein heteroalkyl is a hydroxy-substituted C 1 ~C 3 Alkyl, sulfhydryl-substituted C 1 ~C 5 Alkyl, amino substituted C 1 ~C 7 Alkyl, CH 2 CH 2 OCH 2 CH 2 OH, or CH 2 CH 2 NHCH 2 CH 2 OH, and wherein the substituted group is substituted with one or more substituents selected from the group consisting of halo, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl or heterocycle, thiol, alkylthio, arylthio, alkylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkoxy, aryloxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, hydroxyl, alkyloxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, and -CO2H; The compound.

2. R 11 2. The compound of claim 1, wherein is bicycloalkyl, alkylcycloalkyl, or alkylcycloheteroalkyl.

3. R 11 10. The compound of claim 1, wherein is haloalkyl.

4. R 11 4. The compound of claim 3, wherein is fluoroalkyl.

5. R 1 is hydrogen and R 2 P 2 The compound according to any one of claims 1 to 4, wherein

6. R 1 P 2 and R 2 The compound of any one of claims 1 to 4, wherein is hydrogen.

7. R 1 P 2 and R 2 P 2 The compound according to any one of claims 1 to 4, wherein

8. R 1 and R 2 The compound of any one of claims 1 to 4, wherein each is hydrogen.

9. R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 The compound of any one of claims 1 to 8, wherein is H.

10. A composition comprising at least one compound according to claims 1 to 9 and at least one other ingredient.

11. 11. The composition of claim 10, formulated for transdermal delivery or for transdermal delivery via a patch.

12. 11. The composition of claim 10, further comprising at least one solvent.

13. A composition for use in the treatment of pulmonary hypertension, comprising a compound according to any one of claims 1 to 9.

14. 14. The composition of claim 13, wherein the pulmonary hypertension is pulmonary arterial hypertension.

15. 15. The composition of claim 13 or 14, formulated for transdermal delivery or for transdermal delivery via a patch.

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