JP7502381B2 - Treprostinil derivative compounds and methods of use thereof - Google Patents

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of U.S. Application No. 14/153,498, filed January 13, 2014, which claims priority to U.S. Provisional Application No. 61/751,608, filed January 11, 2013, each of which is incorporated by reference in its entirety for all purposes.

を有する。トレプロスチニルは塩（例えばナトリウム塩）として存在することができる。 2. 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, for example, U.S. Patent Application Publication No. 2013/0274261. Many useful pharmacologically active compounds, including some compounds of interest with respect to PH and PAH, cannot be effectively administered orally for a variety of reasons and are generally administered via intravenous or intramuscular routes. Generally, these routes of administration require intervention by a physician or other medical professional and may involve considerable discomfort and potential local trauma for the patient. One example of such a compound is treprostinil and its derivatives, which have been used in the treatment of PH and PAH. See, for example, WO 2005/007081. Treprostinil (also referred to herein as Compound A) has the following structure:

Treprostinil can exist as a salt, such as the sodium salt.

Therefore, there is a clinical need for improved formulations and methods of 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 its derivatives (including prodrugs) or analogs.

The application of transdermal drug delivery technology to the administration of a wide variety of drugs has been demonstrated, and various systems for accomplishing this have been disclosed in numerous technical journals and patents. U.S. Pat. No. 3,598,122 (Patent Document 3), U.S. Pat. No. 4,144,317 (Patent Document 4), U.S. Pat. No. 4,201,211 (Patent Document 5), U.S. Pat. No. 4,262,003 (Patent Document 6), and U.S. Pat. No. 4,379,454 (Patent Document 7), all of which are incorporated herein by reference, are representative of various transdermal drug delivery systems of the prior art, which are capable of delivering controlled amounts of drug to a patient over extended periods of time ranging from hours to days. None of the above patents describes a transdermal delivery system intended to deliver treprostinil or its derivatives.

US Patent Application Publication No. 2013/0274261 International Publication No. 2005/007081 U.S. Patent No. 3,598,122 U.S. Patent No. 4,144,317 U.S. Patent No. 4,201,211 U.S. Patent No. 4,262,003 U.S. Patent No. 4,379,454

SUMMARY Embodiments described herein include compounds, compositions, and devices, as well as methods of making and using the same.

で表される化合物を提供し、
式中、R₂₀、R₂₁、R₂₂、R₂₃、R₂₄、R₂₅、R₂₆、R₂₇、R₂₈、R₂₉、R₃₀、R₃₁、R₃₂、R₃₃、R₃₄、R₃₅、およびR₃₆は独立してHまたは重水素であり;
Zは-OH、-OR₁₁、-N(R₁₁)R₁₂、-SR₁₁、またはP₁であり;
R₁₁はアルキル、置換アルキル、シクロアルキル、置換シクロアルキル、ハロアルキル、ヘテロアルキル、置換ヘテロアルキル、シクロヘテロアルキル、置換シクロヘテロアルキル、アルキルシクロアルキル、置換アルキルシクロアルキル、アルキルシクロヘテロアルキル、置換アルキルシクロヘテロアルキル、アリール、置換アリール、アルキルアリール、置換アルキルアリール、ヘテロアリール、置換ヘテロアリール、アルキルヘテロアリール、または置換アルキルヘテロアリールであり;
R₁₂はH、ハロアルキル、ヘテロアルキル、シクロヘテロアルキル、アルキルシクロアルキル、アルキルシクロヘテロアルキル、アリール、またはヘテロアリールであり;
P₁は

からなる群より選択され、
ここで、
mは1、2、3、または4であり;
R₁₄およびR₁₅はそれぞれの場合で独立してH、アルキル、シクロアルキル、アルキルシクロアルキル、ハロアルキル、ヘテロアルキル、置換アルキル、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、置換アリール、置換ヘテロアリール、置換アリールアルキル、および置換ヘテロアリールアルキルからなる群より選択され;
R₁₄およびR₁₅は、それらが結合している原子と一緒になって、非置換であるかまたは独立してハロ、メチル、およびメトキシからなる群より選択される1個、2個、もしくは3個の置換基で置換されている、N、O、またはSより選択される1個または2個の環ヘテロ原子を組み入れていてもよい5員～7員環を形成してもよく;
R₁₈およびR₁₉はそれぞれの場合で独立して水素およびアルキルからなるリストより選択され、該アルキルは非置換であるかまたはハロ、ヒドロキシ、アルコキシ、アミノ、チオ、メチルチオ、-C(O)OH、-C(O)O-(アルキル)、-CONH₂、アリール、およびヘテロアリールからなるリストより選択される1個の置換基で置換されており、該アリールまたはヘテロアリールは非置換であるかまたはアルキル、ハロ、ハロアルキル、ヒドロキシ、アルコキシ、およびハロアルコキシからなるリストより置換されており;
R₁₄およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₄およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₅およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₅およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
かつ、R₁およびR₂は独立してHまたはP₂であり、R₁およびR₂のうち少なくとも一方はP₂であり、
P₂は

からなる群より選択され、
ここで、
mは1、2、3、または4であり;
R₁₄およびR₁₅は上記定義の通りであり;
R₁₄およびR₁₅は、それらが結合している原子と一緒になって、非置換であるかまたは独立してハロ、メチル、およびメトキシからなる群より選択される1個、2個、もしくは3個の置換基で置換されている、N、O、またはSより選択される1個または2個の環ヘテロ原子を組み入れていてもよい5員～7員環を形成してもよく;
R₁₆およびR₁₇はそれぞれの場合で独立してHまたはアルキルであり;
R₁₆およびR₁₇は、それらが結合している原子と一緒になって3員～6員環を形成してもよく;
R₁₈およびR₁₉は上記定義の通りであり;
R₁₄およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₄およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
式Iは、式Iの化合物の鏡像異性体、薬学的に許容される塩、溶媒和物、および多形体を含む。 One embodiment is a compound represented by formula (I):

and providing a compound represented by the formula:
wherein _R20 , _R21 , _R22 , _R23 , _R24 , R25, _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , _R33 , _R34 , _R35 , and _{R36 are} independently H or deuterium;
Z is -OH, -OR ₁₁ , -N(R ₁₁ )R ₁₂ , -SR ₁₁ , or P ₁ ;
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

is selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ , at each occurrence, are independently 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 ₁₄ and R ₁₅ together with the atom to which they are attached may 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 are each independently selected from the list consisting of hydrogen and alkyl, where 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), -CONH ₂ , aryl, and heteroaryl, where the aryl or heteroaryl is unsubstituted or substituted from the list consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, and haloalkoxy;
R ₁₄ and R ₁₈ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₅ and R ₁₈ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₅ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
and _R1 and _R2 are independently H or _P2 , and at least one of _R1 and _R2 is _P2 ;
_P2 is

is selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ are as defined above;
R ₁₄ and R ₁₅ together with the atom to which they are attached may 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 , at each occurrence, are independently H or alkyl;
R ₁₆ and R ₁₇ together with the atoms to which they are attached may form a 3- to 6-membered ring;
R ₁₈ and R ₁₉ are as defined above;
R ₁₄ and R ₁₈ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
Formula I includes the enantiomers, pharma- ceutically acceptable salts, solvates, and polymorphs of compounds of Formula I.

からなる群より選択され、
ここで、
mは1、2、3、または4であり;
R₁₄およびR₁₅はそれぞれの場合で独立してH、アルキル、シクロアルキル、アルキルシクロアルキル、ハロアルキル、ヘテロアルキル、置換アルキル、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、置換アリール、置換ヘテロアリール、置換アリールアルキル、および置換ヘテロアリールアルキルからなる群より選択され;
R₁₄およびR₁₅は、それらが結合している原子と一緒になって、非置換であるかまたは独立してハロ、メチル、およびメトキシからなる群より選択される1個、2個、もしくは3個の置換基で置換されている、N、O、またはSより選択される1個または2個の環ヘテロ原子を組み入れていてもよい5員～7員環を形成してもよく;
R₁₈およびR₁₉はそれぞれの場合で独立して水素およびアルキルからなるリストより選択され、該アルキルは非置換であるかまたはハロ、ヒドロキシ、アルコキシ、アミノ、チオ、メチルチオ、-C(O)OH、-C(O)O-(アルキル)、-CONH₂、アリール、およびヘテロアリールからなるリストより選択される1個の置換基で置換されており、該アリールまたはヘテロアリールは非置換であるかまたはアルキル、ハロ、ハロアルキル、ヒドロキシ、アルコキシ、およびハロアルコキシからなるリストより置換されており;
R₁₄およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₄およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₅およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₅およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
かつ、R₁およびR₂は独立してHまたはP₂であり、
P₂は

からなる群より選択され、
ここで、
mは1、2、3、または4であり;
R₁₄およびR₁₅は上記定義の通りであり;
R₁₄およびR₁₅は、それらが結合している原子と一緒になって、非置換であるかまたは独立してハロ、メチル、およびメトキシからなる群より選択される1個、2個、もしくは3個の置換基で置換されている、N、O、またはSより選択される1個または2個の環ヘテロ原子を組み入れていてもよい5員～7員環を形成してもよく;
R₁₆およびR₁₇はそれぞれの場合で独立してHまたはアルキルであり;
R₁₆およびR₁₇は、それらが結合している原子と一緒になって3員～6員環を形成してもよく;
R₁₈およびR₁₉は上記定義の通りであり;
R₁₄およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₄およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
式Iは、式Iの化合物の鏡像異性体、薬学的に許容される塩、溶媒和物、および多形体を含む。 In another embodiment, the parameters of formula I are defined as follows:
_R20 , _R21 , _R22 , _{R23 , R24, R25, R26, R27, R28, R29, R30, R31, R32 , R33 , R34 , R35 , and R36 are independently H} or deuterium;
Z is -OR ₁₁ , -N(R ₁₁ )R ₁₂ , -SR ₁₁ , or P ₁ ;
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, or substituted alkylheteroaryl;
R ₁₂ is H, branched alkyl, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl;
_P1 is

is selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ , at each occurrence, are independently 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 ₁₄ and R ₁₅ together with the atom to which they are attached may 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 are each independently selected from the list consisting of hydrogen and alkyl, where 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), -CONH ₂ , aryl, and heteroaryl, where the aryl or heteroaryl is unsubstituted or substituted from the list consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, and haloalkoxy;
R ₁₄ and R ₁₈ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₅ and R ₁₈ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₅ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
and _R1 and _R2 are independently H or _P2 ;
_P2 is

is selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ are as defined above;
R ₁₄ and R ₁₅ together with the atom to which they are attached may 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 , at each occurrence, are independently H or alkyl;
R ₁₆ and R ₁₇ together with the atoms to which they are attached may form a 3- to 6-membered ring;
R ₁₈ and R ₁₉ are as defined above;
R ₁₄ and R ₁₈ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
Formula I includes the enantiomers, pharma- ceutically acceptable salts, solvates, and polymorphs of compounds of Formula I.

で表される化合物が提供され、
式中、
R₂はHおよびP₂からなる群より選択され;
R₂₀、R₂₁、R₂₂、R₂₃、R₂₄、R₂₅、R₂₆、R₂₇、R₂₈、R₂₉、R₃₀、R₃₁、R₃₂、R₃₃、R₃₄、R₃₅、およびR₃₆は独立してHおよび重水素からなる群より選択され;
L₁は-O-アルキレン-C(O)-、-O-アルキレン-OC(O)-、または結合からなる群より選択され;
P₂は

からなる群より選択され、
ここで、
mは1、2、3、または4であり;
R₁₄およびR₁₅は上記定義の通りであり;
R₁₄およびR₁₅は、それらが結合している原子と一緒になって、非置換であるかまたは独立してハロ、メチル、およびメトキシからなる群より選択される1個、2個、もしくは3個の置換基で置換されている、N、O、またはSより選択される1個または2個の環ヘテロ原子を組み入れていてもよい5員～7員環を形成してもよく;
R₁₆およびR₁₇はそれぞれの場合で独立してHまたはアルキルであり;
R₁₆およびR₁₇は、それらが結合している原子と一緒になって3員～6員環を形成してもよく;
R₁₈およびR₁₉は上記定義の通りであり;
R₁₄およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₄およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
式IIは、式IIの化合物の鏡像異性体、薬学的に許容される塩、溶媒和物、および多形体を含む。 In another embodiment, the compound of formula II:

A compound represented by the formula:
In the formula,
_R2 is selected from the group consisting of H and _P2 ;
_R20 , _R21 , _R22 , _{R23 , R24, R25, R26, R27, R28, R29, R30, R31, R32 , R33 , R34 , R35 , and R36 are independently selected} from the group consisting of H and deuterium;
_L1 is selected from the group consisting of -O-alkylene-C(O)-, -O-alkylene-OC(O)-, or a bond;
_P2 is

is selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ are as defined above;
R ₁₄ and R ₁₅ together with the atom to which they are attached may 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 , at each occurrence, are independently H or alkyl;
R ₁₆ and R ₁₇ together with the atoms to which they are attached may form a 3- to 6-membered ring;
R ₁₈ and R ₁₉ are as defined above;
R ₁₄ and R ₁₈ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
Formula II includes enantiomers, pharma- ceutically acceptable salts, solvates, and polymorphs of compounds of Formula II.

で表され、
式中、L₂は、-CH₂-、-CHMe-、-C(Me)₂-、および

からなる群より選択され、
ここで、
mは1、2、3、または4であり;
XはNR₁₄またはOであり;
R₁₄はH、アルキル、シクロアルキル、アルキルシクロアルキル、ハロアルキル、ヘテロアルキル、置換アルキル、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、置換アリール、置換ヘテロアリール、置換アリールアルキル、および置換ヘテロアリールアルキルからなる群より選択され;
R₁₆およびR₁₇はそれぞれの場合で独立してHまたはアルキルであり;
R₁₆およびR₁₇は、それらが結合している原子と一緒になって3員～6員環を形成してもよく;
R₂₀、R₂₁、R₂₂、R₂₃、R₂₄、R₂₅、R₂₆、R₂₇、R₂₈、R₂₉、R₃₀、R₃₁、R₃₂、R₃₃、R₃₄、R₃₅、およびR₃₆は独立してHおよび重水素からなる群より選択され;
Zは-OH、-OR₁₁、-N(R₁₁)R₁₂、-SR₁₁、またはP₁であり;
R₁₁はアルキル、置換アルキル、シクロアルキル、置換シクロアルキル、ハロアルキル、ヘテロアルキル、置換ヘテロアルキル、シクロヘテロアルキル、置換シクロヘテロアルキル、アルキルシクロアルキル、置換アルキルシクロアルキル、アルキルシクロヘテロアルキル、置換アルキルシクロヘテロアルキル、アリール、置換アリール、アルキルアリール、置換アルキルアリール、ヘテロアリール、置換ヘテロアリール、アルキルヘテロアリール、または置換アルキルヘテロアリールであり;
R₁₂はH、ハロアルキル、ヘテロアルキル、シクロヘテロアルキル、アルキルシクロアルキル、アルキルシクロヘテロアルキル、アリール、またはヘテロアリールであり;
P₁は

からなる群より選択され、
ここで、
mは1、2、3、または4であり;
R₁₄およびR₁₅はそれぞれの場合で独立してH、アルキル、シクロアルキル、アルキルシクロアルキル、ハロアルキル、ヘテロアルキル、置換アルキル、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、置換アリール、置換ヘテロアリール、置換アリールアルキル、および置換ヘテロアリールアルキルからなる群より選択され;
R₁₄およびR₁₅は、それらが結合している原子と一緒になって、非置換であるかまたは独立してハロ、メチル、およびメトキシからなる群より選択される1個、2個、もしくは3個の置換基で置換されている、N、O、またはSより選択される1個または2個の環ヘテロ原子を組み入れていてもよい5員～7員環を形成してもよく;
R₁₈およびR₁₉はそれぞれの場合で独立して水素およびアルキルからなる群より選択され、該アルキルは非置換であるかまたはハロ、ヒドロキシ、アルコキシ、アミノ、チオ、メチルチオ、-C(O)OH、-C(O)O-(アルキル)、-CONH₂、アリール、およびヘテロアリールからなるリストより選択される1個の置換基で置換されており、該アリールまたはヘテロアリールは非置換であるかまたはアルキル、ハロ、ハロアルキル、ヒドロキシ、アルコキシ、およびハロアルコキシからなる群より置換されており;
R₁₄およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₄およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₅およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₅およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
式IIIは、式IIIの化合物の鏡像異性体、薬学的に許容される塩、溶媒和物、および多形体を含む。 In another embodiment, the compound has formula III:

It is expressed as
In the formula, _L2 is _-CH2- , -CHMe-, -C(Me) _2- , and

is selected from the group consisting of
here,
m is 1, 2, 3, or 4;
X is _NR14 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 , at each occurrence, are independently H or alkyl;
R ₁₆ and R ₁₇ together with the atoms to which they are attached may form a 3- to 6-membered ring;
_R20 , _R21 , _R22 , _{R23 , R24, R25, R26, R27, R28, R29, R30, R31, R32 , R33 , R34 , R35 , and R36 are independently selected} from the group consisting of H and deuterium;
Z is -OH, -OR ₁₁ , -N(R ₁₁ )R ₁₂ , -SR ₁₁ , or P ₁ ;
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

is selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ , at each occurrence, are independently 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 ₁₄ and R ₁₅ together with the atom to which they are attached may 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 are each independently selected 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), -CONH ₂ , aryl, and heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, and haloalkoxy;
R ₁₄ and R ₁₈ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₅ and R ₁₈ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₅ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
Formula III includes enantiomers, pharma- ceutically acceptable salts, solvates, and polymorphs of compounds of Formula III.

で表される化合物を提供し、
式中、R₁はHおよびP₂からなる群より選択され;
R₂₀、R₂₁、R₂₂、R₂₃、R₂₄、R₂₅、R₂₆、R₂₇、R₂₈、R₂₉、R₃₀、R₃₁、R₃₂、R₃₃、R₃₄、R₃₅、およびR₃₆は独立してHおよび重水素からなる群より選択され;
L₁は-O-アルキレン-C(O)-、-O-アルキレン-OC(O)-、または結合からなる群より選択され;
P₂は

からなる群より選択され、
ここで、
mは1、2、3、または4であり;
R₁₄およびR₁₅はそれぞれの場合で独立してH、アルキル、シクロアルキル、アルキルシクロアルキル、ハロアルキル、ヘテロアルキル、置換アルキル、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、置換アリール、置換ヘテロアリール、置換アリールアルキル、および置換ヘテロアリールアルキルからなる群より選択され;
R₁₄およびR₁₅は、それらが結合している原子と一緒になって、非置換であるかまたは独立してハロ、メチル、およびメトキシからなる群より選択される1個、2個、もしくは3個の置換基で置換されている、N、O、またはSより選択される1個または2個の環ヘテロ原子を組み入れていてもよい5員～7員環を形成してもよく;
R₁₆およびR₁₇はそれぞれの場合で独立してHまたはアルキルであり;
R₁₆およびR₁₇は、それらが結合している原子と一緒になって3員～6員環を形成してもよく;
R₁₈およびR₁₉はそれぞれの場合で独立して水素およびアルキルからなる群より選択され、該アルキルは非置換であるかまたはハロ、ヒドロキシ、アルコキシ、アミノ、チオ、メチルチオ、-C(O)OH、-C(O)O-(アルキル)、-CONH₂、アリール、およびヘテロアリールからなる群より選択される1個の置換基で置換されており、該アリールまたはヘテロアリールは非置換であるかまたはアルキル、ハロ、ハロアルキル、ヒドロキシ、アルコキシ、およびハロアルコキシからなるリストより置換されており;
R₁₄およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₄およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
式IVは、式IVの化合物の鏡像異性体、薬学的に許容される塩、溶媒和物、および多形体を含む。 Another embodiment is a compound of formula IV:

and providing a compound represented by the formula:
wherein R ₁ is selected from the group consisting of H and P ₂ ;
_R20 , _R21 , _R22 , _{R23 , R24, R25, R26, R27, R28, R29, R30, R31, R32 , R33 , R34 , R35 , and R36 are independently selected} from the group consisting of H and deuterium;
_L1 is selected from the group consisting of -O-alkylene-C(O)-, -O-alkylene-OC(O)-, or a bond;
_P2 is

is selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ , at each occurrence, are independently 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 ₁₄ and R ₁₅ together with the atom to which they are attached may 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 , at each occurrence, are independently H or alkyl;
R ₁₆ and R ₁₇ together with the atoms to which they are attached may form a 3- to 6-membered ring;
R ₁₈ and R ₁₉ , at each occurrence, are independently selected from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with one substituent selected from the group consisting of halo, hydroxy, alkoxy, amino, thio, methylthio, -C(O)OH, -C(O)O-(alkyl), -CONH ₂ , aryl, and heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted from the list consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, and haloalkoxy;
R ₁₄ and R ₁₈ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
Formula IV includes the enantiomers, pharma- ceutically acceptable salts, solvates, and polymorphs of compounds of Formula IV.

Also provided are compositions, including compositions comprising at least one compound according to Formula I, II, III, or 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.

At least one advantage of at least one embodiment includes the ability to tailor the chemical structure of the pharma- ceutically useful motif to a particular application, including, for example, therapeutic and prophylactic applications for PH and PAH. For example, the drug delivery profile can be tailored to the particular application.

で表される化合物であって、
式中、R₂₀、R₂₁、R₂₂、R₂₃、R₂₄、R₂₅、R₂₆、R₂₇、R₂₈、R₂₉、R₃₀、R₃₁、R₃₂、R₃₃、R₃₄、R₃₅、およびR₃₆は独立してHまたは重水素であり;
Zは-OH、-OR₁₁、-N(R₁₁)R₁₂、-SR₁₁、またはP₁であり;
R₁₁はアルキル、置換アルキル、シクロアルキル、置換シクロアルキル、ハロアルキル、ヘテロアルキル、置換ヘテロアルキル、シクロヘテロアルキル、置換シクロヘテロアルキル、アルキルシクロアルキル、置換アルキルシクロアルキル、アルキルシクロヘテロアルキル、置換アルキルシクロヘテロアルキル、アリール、置換アリール、アルキルアリール、置換アルキルアリール、ヘテロアリール、置換ヘテロアリール、アルキルヘテロアリール、または置換アルキルヘテロアリールであり;
R₁₂はH、ハロアルキル、ヘテロアルキル、シクロヘテロアルキル、アルキルシクロアルキル、アルキルシクロヘテロアルキル、アリール、またはヘテロアリールであり;
P₁は

からなる群より選択され、
ここで、
mは1、2、3、または4であり;
R₁₄およびR₁₅はそれぞれの場合で独立してH、アルキル、シクロアルキル、アルキルシクロアルキル、ハロアルキル、ヘテロアルキル、置換アルキル、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、置換アリール、置換ヘテロアリール、置換アリールアルキル、および置換ヘテロアリールアルキルからなる群より選択され;
R₁₄およびR₁₅は、それらが結合している原子と一緒になって、非置換であるかまたは独立してハロ、メチル、およびメトキシからなる群より選択される1個、2個、もしくは3個の置換基で置換されている、N、O、またはSより選択される1個または2個の環ヘテロ原子を組み入れていてもよい5員～7員環を形成してもよく;
R₁₈およびR₁₉はそれぞれの場合で独立して水素およびアルキルからなる群より選択され、該アルキルは非置換であるかまたはハロ、ヒドロキシ、アルコキシ、アミノ、チオ、メチルチオ、-C(O)OH、-C(O)O-(アルキル)、-CONH₂、アリール、およびヘテロアリールからなるリストより選択される1個の置換基で置換されており、該アリールまたはヘテロアリールは非置換であるかまたはアルキル、ハロ、ハロアルキル、ヒドロキシ、およびアルコキシ、ハロアルコキシからなるリストより置換されており;
R₁₄およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₄およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₅およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₅およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
かつ、R₁およびR₂は独立してHまたはP₂であり、R₁およびR₂のうち少なくとも一方はP₂であり、
P₂は

からなる群より選択され、
ここで、
mは1、2、3、または4であり;
R₁₄およびR₁₅はそれぞれの場合で独立してH、アルキル、シクロアルキル、アルキルシクロアルキル、ハロアルキル、ヘテロアルキル、置換アルキル、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、置換アリール、置換ヘテロアリール、置換アリールアルキル、および置換ヘテロアリールアルキルからなる群より選択され;
R₁₄およびR₁₅は、それらが結合している原子と一緒になって、非置換であるかまたは独立してハロ、メチル、およびメトキシからなる群より選択される1個、2個、もしくは3個の置換基で置換されている、N、O、またはSより選択される1個または2個の環ヘテロ原子を組み入れていてもよい5員～7員環を形成してもよく;
R₁₆およびR₁₇はそれぞれの場合で独立してHまたはアルキルであり;
R₁₆およびR₁₇は、それらが結合している原子と一緒になって3員～6員環を形成してもよく;
R₁₈およびR₁₉はそれぞれの場合で独立して水素およびアルキルからなる群より選択され、該アルキルは非置換であるかまたはハロ、ヒドロキシ、アルコキシ、アミノ、チオ、メチルチオ、-C(O)OH、-C(O)O-(アルキル)、-CONH₂、アリール、およびヘテロアリールからなるリストより選択される1個の置換基で置換されており、該アリールまたはヘテロアリールは非置換であるかまたはアルキル、ハロ、ハロアルキル、ヒドロキシ、およびアルコキシ、ハロアルコキシからなるリストより置換されており;
R₁₄およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₄およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
式Iが、式Iの化合物の鏡像異性体、薬学的に許容される塩、多形体、ならびに立体異性体（例えば、鏡像異性体およびジアステレオマー）を含む、
前記化合物。
[本発明1002]
R₁がP₂であり、かつR₂がHである、本発明1001の化合物。
[本発明1003]
R₁がHであり、かつR₂がP₂である、本発明1001の化合物。
[本発明1004]
R₁がP₂であり、かつR₂がP₂である、本発明1001の化合物。
[本発明1005]
P₂が

からなる群より選択される、本発明1001の化合物。
[本発明1006]
P₂が

からなる群より選択される、本発明1001の化合物。
[本発明1007]
P₂が

からなる群より選択される、本発明1001の化合物。
[本発明1008]
P₂が

からなる群より選択される、本発明1001の化合物。
[本発明1009]
P₂が

からなる群より選択される、本発明1001の化合物。
[本発明1010]
P₂が

からなる群より選択される、本発明1001の化合物。
[本発明1011]
P₂が

からなる群より選択される、本発明1001の化合物。
[本発明1012]
P₂が

からなる群より選択される、本発明1001の化合物。
[本発明1013]
P₂が

からなる群より選択される、本発明1001の化合物。
[本発明1014]
P₂が

からなる群より選択される、本発明1001の化合物。
[本発明1015]
P₂が

からなる群より選択される、本発明1001の化合物。
[本発明1016]
R₂₀、R₂₁、R₂₂、R₂₃、R₂₄、R₂₅、R₂₆、R₂₇、R₂₈、R₂₉、R₃₀、R₃₁、R₃₂、R₃₃、R₃₄、R₃₅、およびR₃₆がHである、本発明1001の化合物。
[本発明1017]
R₂₀、R₂₁、R₂₂、R₂₃、R₂₄、R₂₅、R₂₆、R₂₇、R₂₈、R₂₉、R₃₀、R₃₁、R₃₂、R₃₃、R₃₄、R₃₅、およびR₃₆のうち少なくとも1つが重水素である、本発明1001の化合物。
[本発明1018]
Zが-OR₁₁、-N(R₁₁)R₁₂、またはP₁である、本発明1001の化合物。
[本発明1019]
ZがP₁である、本発明1001の化合物。
[本発明1020]
Zが-OH、-OR₁₁、-N(R₁₁)R₁₂、またはP₁である、本発明1001の化合物。
[本発明1021]
Zが-OHである、本発明1001の化合物。
[本発明1022]
Zが-OHではなく、かつR₁₁が非置換または置換ベンジルではない、本発明1001の化合物。
[本発明1023]
式(IA)：

で表される化合物であって、
式中、
Zは-OH、-OR₁₁、またはP₁であり;
R₁₁はアルキル、置換アルキル、シクロアルキル、置換シクロアルキル、ハロアルキル、ヘテロアルキル、置換ヘテロアルキル、シクロヘテロアルキル、置換シクロヘテロアルキル、アルキルシクロアルキル、置換アルキルシクロアルキル、アルキルシクロヘテロアルキル、置換アルキルシクロヘテロアルキルであり;
P₁は

からなる群より選択され、
ここで、
mは1、2、3、または4であり;
R₁₄およびR₁₅はそれぞれの場合で独立してH、アルキル、シクロアルキル、アルキルシクロアルキル、ハロアルキル、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、置換アリール、置換ヘテロアリール、置換アリールアルキル、および置換ヘテロアリールアルキルからなる群より選択され;
R₁₄およびR₁₅は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
かつ、R₁およびR₂は独立してHまたはP₂であり、R₁およびR₂のうち少なくとも一方はP₂であり、
P₂は

からなる群より選択され、
ここで、
R₁₄はH、アルキル、シクロアルキル、アルキルシクロアルキル、ハロアルキル、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、置換アリール、置換ヘテロアリール、置換アリールアルキル、および置換ヘテロアリールアルキルからなる群より選択され;
式IAが、式IAの化合物の薬学的に許容される塩、多形体、ならびに立体異性体（例えば、鏡像異性体およびジアステレオマー）を含む、
本発明1001の化合物。
[本発明1024]
式(I)：

の化合物であって、
式中、R₂₀、R₂₁、R₂₂、R₂₃、R₂₄、R₂₅、R₂₆、R₂₇、R₂₈、R₂₉、R₃₀、R₃₁、R₃₂、R₃₃、R₃₄、R₃₅、およびR₃₆は独立してHまたは重水素であり;
Zは-OR₁₁、-N(R₁₁)R₁₂、-SR₁₁、またはP₁であり;
R₁₁は分岐アルキル、ハロアルキル、ハロシクロアルキル、ヘテロアルキル、置換ヘテロアルキル、シクロヘテロアルキル、置換シクロヘテロアルキル、ビシクロアルキル、アルキルシクロアルキル、置換アルキルシクロアルキル、アルキルシクロヘテロアルキル、置換アルキルシクロヘテロアルキル、アルキルアリール、置換アルキルアリール、アルキルヘテロアリール、置換アルキルヘテロアリール、ヘテロアリール、置換ヘテロアリールであり;
R₁₂はH、分岐アルキル、ハロアルキル、ヘテロアルキル、シクロヘテロアルキル、アルキルシクロアルキル、アルキルシクロヘテロアルキル、アリール、またはヘテロアリールであり;
P₁は

からなる群より選択され、
ここで、
mは1、2、3、または4であり;
R₁₄およびR₁₅はそれぞれの場合で独立してH、アルキル、シクロアルキル、アルキルシクロアルキル、ハロアルキル、ヘテロアルキル、置換アルキル、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、置換アリール、置換ヘテロアリール、置換アリールアルキル、および置換ヘテロアリールアルキルからなる群より選択され;
R₁₄およびR₁₅は、それらが結合している原子と一緒になって、非置換であるかまたは独立してハロ、メチル、およびメトキシからなる群より選択される1個、2個、もしくは3個の置換基で置換されている、N、O、またはSより選択される1個または2個の環ヘテロ原子を組み入れていてもよい5員～7員環を形成してもよく;
R₁₈およびR₁₉はそれぞれの場合で独立して水素およびアルキルからなる群より選択され、該アルキルは非置換であるかまたはハロ、ヒドロキシ、アルコキシ、アミノ、チオ、メチルチオ、-C(O)OH、-C(O)O-(アルキル)、-CONH₂、アリール、およびヘテロアリールからなるリストより選択される1個の置換基で置換されており、該アリールまたはヘテロアリールは非置換であるかまたはアルキル、ハロ、ハロアルキル、ヒドロキシ、およびアルコキシ、ハロアルコキシからなるリストより置換されており;
R₁₄およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₄およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₅およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₅およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
かつ、R₁およびR₂は独立してHまたはP₂であり、
P₂は

からなる群より選択され、
ここで、
mは1、2、3、または4であり;
R₁₄およびR₁₅はそれぞれの場合で独立してH、アルキル、シクロアルキル、アルキルシクロアルキル、ハロアルキル、ヘテロアルキル、置換アルキル、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、置換アリール、置換ヘテロアリール、置換アリールアルキル、および置換ヘテロアリールアルキルからなる群より選択され;
R₁₄およびR₁₅は、それらが結合している原子と一緒になって、非置換であるかまたは独立してハロ、メチル、およびメトキシからなる群より選択される1個、2個、もしくは3個の置換基で置換されている、N、O、またはSより選択される1個または2個の環ヘテロ原子を組み入れていてもよい5員～7員環を形成してもよく;
R₁₆およびR₁₇はそれぞれの場合で独立してHまたはアルキルであり;
R₁₆およびR₁₇は、それらが結合している原子と一緒になって3員～6員環を形成してもよく;
R₁₈およびR₁₉はそれぞれの場合で独立して水素およびアルキルからなる群より選択され、該アルキルは非置換であるかまたはハロ、ヒドロキシ、アルコキシ、アミノ、チオ、メチルチオ、-C(O)OH、-C(O)O-(アルキル)、-CONH₂、アリール、およびヘテロアリールからなるリストより選択される1個の置換基で置換されており、該アリールまたはヘテロアリールは非置換であるかまたはアルキル、ハロ、ハロアルキル、ヒドロキシ、およびアルコキシ、ハロアルコキシからなるリストより置換されており;
R₁₄およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₄およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
式Iが、式Iの化合物の鏡像異性体、薬学的に許容される塩、多形体、ならびに立体異性体（例えば、鏡像異性体およびジアステレオマー）を含む、
前記化合物。
[本発明1025]
Zが-OR₁₁である、本発明1024の化合物。
[本発明1026]
Zが-N(R₁₁)R₁₂である、本発明1024の化合物。
[本発明1027]
Zが-SR₁₁である、本発明1024の化合物。
[本発明1028]
ZがP₁である、本発明1024の化合物。
[本発明1029]
ZがOR₁₁であり、かつR₁₁がビシクロアルキル、アルキルシクロアルキル、またはアルキルシクロヘテロアルキルである、本発明1024の化合物。
[本発明1030]
R₁₁がハロアルキルである、本発明1024の化合物。
[本発明1031]
R₁₁がフルオロアルキルである、本発明1024の化合物。
[本発明1032]
R₁が水素であり、かつR₂がP₂である、本発明1024の化合物。
[本発明1033]
R₁がP₂であり、かつR₂が水素である、本発明1024の化合物。
[本発明1034]
R₁がP₂であり、かつR₂がP₂である、本発明1024の化合物。
[本発明1035]
R₁およびR₂がそれぞれ水素である、本発明1024の化合物。
[本発明1036]
R₂₀、R₂₁、R₂₂、R₂₃、R₂₄、R₂₅、R₂₆、R₂₇、R₂₈、R₂₉、R₃₀、R₃₁、R₃₂、R₃₃、R₃₄、R₃₅、およびR₃₆がHである、本発明1024の化合物。
[本発明1037]
R₂₀、R₂₁、R₂₂、R₂₃、R₂₄、R₂₅、R₂₆、R₂₇、R₂₈、R₂₉、R₃₀、R₃₁、R₃₂、R₃₃、R₃₄、R₃₅、およびR₃₆のうち少なくとも1つが重水素である、本発明1024の化合物。
[本発明1038]
式(IAA)：

の化合物であって、
式中、
R₁₀₀およびR₂₀₀は独立してH、CONR₉₀₀R₁₀₀₀、CR₉₀₀R₁₀₀₀OCOP₃R₉₀₀R₁₀₀₀からなる群より選択され、R₉₀₀およびR₁₀₀₀は独立してH、アルキル、およびシクロアルキルより選択され、
R₃₀₀、R₄₀₀、R₅₀₀、R₆₀₀、R₇₀₀、およびR₈₀₀は独立してHおよび重水素からなる群より選択され、
XはO、NHR₁₂₀₀、またはSであり、
P₃はNまたはOであり、
R₁₁₀₀はハロアルキル、ヘテロアルキル、シクロヘテロアルキル、アルキルシクロアルキル、アルキルシクロヘテロアルキル、アリール、ヘテロアリールであり;
R₁₂₀₀はハロアルキル、ヘテロアルキル、シクロヘテロアルキル、アルキルシクロアルキル、アルキルシクロヘテロアルキル、アリール、ヘテロアリールである、
前記化合物。
[本発明1039]
R₁₀₀、R₂₀₀がHである、本発明1038の化合物。
[本発明1040]
R₃₀₀、R₄₀₀、R₅₀₀、R₆₀₀、R₇₀₀、およびR₈₀₀がHである、本発明1039の化合物。
[本発明1041]
XがOである、本発明1040の化合物。
[本発明1042]
R₁₁₀₀が

より選択される、本発明1041の化合物。
[本発明1043]
XがNHR₁₂₀₀である、本発明1039の化合物。
[本発明1044]
R₁₁₀₀が

より選択される、本発明1043の化合物。
[本発明1045]
XがOである、本発明1038の化合物。
[本発明1046]
R₃₀₀、R₄₀₀、R₅₀₀、R₆₀₀、R₇₀₀、およびR₈₀₀がHである、本発明1045の化合物。
[本発明1047]
R₁₁₀₀がアルキルである、本発明1046の化合物。
[本発明1048]
式II：

で表される化合物であって、
式中、
R₂はHおよびP₂からなる群より選択され;
R₂₀、R₂₁、R₂₂、R₂₃、R₂₄、R₂₅、R₂₆、R₂₇、R₂₈、R₂₉、R₃₀、R₃₁、R₃₂、R₃₃、R₃₄、R₃₅、およびR₃₆は独立してHおよび重水素からなる群より選択され;
L₁は-O-アルキレン-C(O)-、-O-アルキレン-OC(O)-、または結合からなる群より選択され;
P₂は

からなる群より選択され、
ここで、
mは1、2、3、または4であり;
R₁₄およびR₁₅はそれぞれの場合で独立してH、アルキル、シクロアルキル、アルキルシクロアルキル、ハロアルキル、ヘテロアルキル、置換アルキル、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、置換アリール、置換ヘテロアリール、置換アリールアルキル、および置換ヘテロアリールアルキルからなる群より選択され;
R₁₄およびR₁₅は、それらが結合している原子と一緒になって、非置換であるかまたは独立してハロ、メチル、およびメトキシからなる群より選択される1個、2個、もしくは3個の置換基で置換されている、N、O、またはSより選択される1個または2個の環ヘテロ原子を組み入れていてもよい5員～7員環を形成してもよく;
R₁₆およびR₁₇はそれぞれの場合で独立してHまたはアルキルであり;
R₁₆およびR₁₇は、それらが結合している原子と一緒になって3員～6員環を形成してもよく;
R₁₈およびR₁₉はそれぞれの場合で独立して水素およびアルキルからなる群より選択され、該アルキルは非置換であるかまたはハロ、ヒドロキシ、アルコキシ、アミノ、チオ、メチルチオ、-C(O)OH、-C(O)O-(アルキル)、-CONH₂、アリール、およびヘテロアリールからなるリストより選択される1個の置換基で置換されており、該アリールまたはヘテロアリールは非置換であるかまたはアルキル、ハロ、ハロアルキル、ヒドロキシ、およびアルコキシ、ハロアルコキシからなるリストより置換されており;
R₁₄およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₄およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
式IIが、式IIの化合物の鏡像異性体、薬学的に許容される塩、多形体、ならびに立体異性体（例えば、鏡像異性体およびジアステレオマー）を含む、
前記化合物。
[本発明1049]
R₂₀、R₂₁、R₂₂、R₂₃、R₂₄、R₂₅、R₂₆、R₂₇、R₂₈、R₂₉、R₃₀、R₃₁、R₃₂、R₃₃、R₃₄、R₃₅、およびR₃₆がHである、本発明1048の化合物。
[本発明1050]
R₂₀、R₂₁、R₂₂、R₂₃、R₂₄、R₂₅、R₂₆、R₂₇、R₂₈、R₂₉、R₃₀、R₃₁、R₃₂、R₃₃、R₃₄、R₃₅、およびR₃₆のうち少なくとも1つが重水素である、本発明1048の化合物。
[本発明1051]
L₁が-O-アルキレン-C(O)-である、本発明1048の化合物。
[本発明1052]
L₁が-O-アルキレン-OC(O)-である、本発明1048の化合物。
[本発明1053]
L₁が結合である、本発明1048の化合物。
[本発明1054]
アルキレン基がC₁～C₅アルキレン基である、本発明1048の化合物。
[本発明1055]
アルキレン基がC₁アルキレン基である、本発明1048の化合物。
[本発明1056]
式IIA：

で表される化合物であって、
式中、L₁およびR₂が本発明1048で定義されたとおりである、
本発明1048の化合物。
[本発明1057]
式II(AA)

の化合物、および式II(AA)の化合物の鏡像異性体であって、
式中、
R₂₀₀₀は独立してH、CONR₉₀₀₀R₁₀₀₀₀、CR₉₀₀₀R₁₀₀₀₀OCOPR₉₀₀₀R₁₀₀₀₀からなる群より選択され、R₉₀₀₀およびR₁₀₀₀₀は独立してH、アルキル、シクロアルキルより選択され、
R₃₀₀₀、R₄₀₀₀、R₅₀₀₀、R₆₀₀₀、R₇₀₀₀、およびR₈₀₀₀は独立してH、重水素からなる群より選択され、
XはO、NR₁₂₀₀₀、Sであり、
PはN、Oであり、
R₁₂₀₀₀はハロアルキル、ヘテロアルキル、シクロヘテロアルキル、アルキルシクロアルキル、アルキルシクロヘテロアルキル、アリール、ヘテロアリールであり、
nは1～7の整数であり;
かつ式II(AA)が、式II(AA)の立体異性体（例えば、鏡像異性体およびジアステレオマー）、式II(a)の化合物の薬学的に許容される塩、および式II(AA)の多形体を含む、
前記化合物および前記鏡像異性体。
[本発明1058]
式III：

で表される化合物であって、
式中、L₂は

からなる群より選択され、
ここで、
mは1、2、3、または4であり;
XはNR₁₄またはOであり;
R₁₄はH、アルキル、シクロアルキル、アルキルシクロアルキル、ハロアルキル、ヘテロアルキル、置換アルキル、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、置換アリール、置換ヘテロアリール、置換アリールアルキル、置換ヘテロアリールアルキルからなる群より選択され;
R₁₆およびR₁₇はそれぞれの場合で独立してHまたはアルキルであり;
R₁₆およびR₁₇は、それらが結合している原子と一緒になって3員～6員環を形成してもよく; かつ
R₂₀、R₂₁、R₂₂、R₂₃、R₂₄、R₂₅、R₂₆、R₂₇、R₂₈、R₂₉、R₃₀、R₃₁、R₃₂、R₃₃、R₃₄、R₃₅、およびR₃₆は独立してHおよび重水素からなる群より選択され;
Zは-OH、-OR₁₁、-N(R₁₁)R₁₂、-SR₁₁、またはP₁であり;
R₁₁はアルキル、置換アルキル、シクロアルキル、置換シクロアルキル、ハロアルキル、ヘテロアルキル、置換ヘテロアルキル、シクロヘテロアルキル、置換シクロヘテロアルキル、アルキルシクロアルキル、置換アルキルシクロアルキル、アルキルシクロヘテロアルキル、置換アルキルシクロヘテロアルキル、アリール、置換アリール、アルキルアリール、置換アルキルアリール、ヘテロアリール、置換ヘテロアリール、アルキルヘテロアリール、または置換アルキルヘテロアリールであり;
R₁₂はH、ハロアルキル、ヘテロアルキル、シクロヘテロアルキル、アルキルシクロアルキル、アルキルシクロヘテロアルキル、アリール、またはヘテロアリールであり;
P₁は

からなる群より選択され、
ここで、
mは1、2、3、または4であり;
R₁₄およびR₁₅はそれぞれの場合で独立してH、アルキル、シクロアルキル、アルキルシクロアルキル、ハロアルキル、ヘテロアルキル、置換アルキル、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、置換アリール、置換ヘテロアリール、置換アリールアルキル、および置換ヘテロアリールアルキルからなる群より選択され;
R₁₄およびR₁₅は、それらが結合している原子と一緒になって、非置換であるかまたは独立してハロ、メチル、およびメトキシからなる群より選択される1個、2個、もしくは3個の置換基で置換されている、N、O、またはSより選択される1個または2個の環ヘテロ原子を組み入れていてもよい5員～7員環を形成してもよく;
R₁₈およびR₁₉はそれぞれの場合で独立して水素およびアルキルからなる群より選択され、該アルキルは非置換であるかまたはハロ、ヒドロキシ、アルコキシ、アミノ、チオ、メチルチオ、-C(O)OH、-C(O)O-(アルキル)、-CONH₂、アリール、およびヘテロアリールからなるリストより選択される1個の置換基で置換されており、該アリールまたはヘテロアリールは非置換であるかまたはアルキル、ハロ、ハロアルキル、ヒドロキシ、およびアルコキシ、ハロアルコキシからなるリストより置換されており;
R₁₄およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₄およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₅およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₅およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
式IIIが、式IIIの化合物の立体異性体（例えば、鏡像異性体およびジアステレオマー）、薬学的に許容される塩、および多形体を含む、
前記化合物。
[本発明1059]
L₂が

からなる群より選択される、本発明1058の化合物。
[本発明1060]
R₂₀、R₂₁、R₂₂、R₂₃、R₂₄、R₂₅、R₂₆、R₂₇、R₂₈、R₂₉、R₃₀、R₃₁、R₃₂、R₃₃、R₃₄、R₃₅、およびR₃₆がHである、本発明1058の化合物。
[本発明1061]
R₂₀、R₂₁、R₂₂、R₂₃、R₂₄、R₂₅、R₂₆、R₂₇、R₂₈、R₂₉、R₃₀、R₃₁、R₃₂、R₃₃、R₃₄、R₃₅、およびR₃₆のうち少なくとも1つが重水素である、本発明1058の化合物。
[本発明1062]
式IIIA：

で表される化合物であって、
式中、ZおよびL₂が本発明1058で定義されたとおりである、
本発明1058の化合物。
[本発明1063]
式III(AA)：

を有する化合物、ならびに式III(AA)の化合物の立体異性体（例えば、鏡像異性体およびジアステレオマー）、および式III(AA)の化合物の薬学的に許容される塩、および式III(AA)の多形体であって、
式中、
R₁₁はハロアルキル、ヘテロアルキル、シクロヘテロアルキル、アルキルシクロアルキル、アルキルシクロヘテロアルキル、アリール、ヘテロアリールであり、
R₀₃、R₀₄、R₀₅、R₀₆、R₀₇、およびR₀₈は独立してH、重水素からなる群より選択され、
XはO、NR₀₁₂、Sであり、
R₀₁₂はハロアルキル、ヘテロアルキル、シクロヘテロアルキル、アルキルシクロアルキル、アルキルシクロヘテロアルキル、アリール、ヘテロアリールであり、
YはC=Oである、
前記化合物、ならびに前記立体異性体、および前記薬学的に許容される塩、および前記多形体。
[本発明1064]
式IV：

で表される化合物であって、
R₁はHおよびP₂からなる群より選択され;
R₂₀、R₂₁、R₂₂、R₂₃、R₂₄、R₂₅、R₂₆、R₂₇、R₂₈、R₂₉、R₃₀、R₃₁、R₃₂、R₃₃、R₃₄、R₃₅、およびR₃₆は独立してHおよび重水素からなる群より選択され;
L₁は-O-アルキレン-C(O)-、-O-アルキレン-OC(O)-、または結合からなる群より選択され;
P₂は

からなる群より選択され、
ここで、
mは1、2、3、または4であり;
R₁₄およびR₁₅はそれぞれの場合で独立してH、アルキル、シクロアルキル、アルキルシクロアルキル、ハロアルキル、ヘテロアルキル、置換アルキル、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、置換アリール、置換ヘテロアリール、置換アリールアルキル、および置換ヘテロアリールアルキルからなる群より選択され;
R₁₄およびR₁₅は、それらが結合している原子と一緒になって、非置換であるかまたは独立してハロ、メチル、およびメトキシからなる群より選択される1個、2個、もしくは3個の置換基で置換されている、N、O、またはSより選択される1個または2個の環ヘテロ原子を組み入れていてもよい5員～7員環を形成してもよく;
R₁₆およびR₁₇はそれぞれの場合で独立してHまたはアルキルであり;
R₁₆およびR₁₇は、それらが結合している原子と一緒になって3員～6員環を形成してもよく;
R₁₈およびR₁₉はそれぞれの場合で独立して水素およびアルキルからなる群より選択され、該アルキルは非置換であるかまたはハロ、ヒドロキシ、アルコキシ、アミノ、チオ、メチルチオ、-C(O)OH、-C(O)O-(アルキル)、-CONH₂、アリール、およびヘテロアリールからなるリストより選択される1個の置換基で置換されており、該アリールまたはヘテロアリールは非置換であるかまたはアルキル、ハロ、ハロアルキル、ヒドロキシ、およびアルコキシ、ハロアルコキシからなるリストより置換されており;
R₁₄およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₄およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
式IVが、式IVの化合物の立体異性体（例えば、鏡像異性体およびジアステレオマー）、薬学的に許容される塩、および多形体を含む、
前記化合物。
[本発明1065]
式IVA：

で表される化合物であって、
式中、L₁およびR₁が本発明1064で定義されたとおりである、
本発明1064の化合物。
[本発明1066]
本発明1001～1065の少なくとも1つの化合物と、少なくとも1つの他の成分とを含む、組成物。
[本発明1067]
経皮送達用に製剤化されている、本発明1066の組成物。
[本発明1068]
パッチによる経皮送達用に製剤化されている、本発明1066の組成物。
[本発明1069]
少なくとも1つの溶媒をさらに含む、本発明1066の組成物。
[本発明1070]
本発明1001～1065の化合物の量が、ヒトの治療に有用な送達プロファイルを提供するように適合されている、本発明1063の組成物。
[本発明1071]
以下の群より選択される化合物、またはその薬学的に許容される塩、溶媒和物、クラスレート、多形体、もしくは立体異性体（例えば、鏡像異性体もしくはジアステレオマー）：

。
[本発明1072]
本発明1071の化合物と1つまたは複数の薬学的に許容される担体または賦形剤とを含む、組成物。
[本発明1073]
肺高血圧症を治療する方法であって、治療を必要とする対象に治療有効量のトレプロスチニル誘導体またはその薬学的に許容される塩、溶媒和物、クラスレート、もしくは多形体を投与する段階を含む、前記方法。
[本発明1074]
トレプロスチニル誘導体が本発明1001～1065のいずれかの化合物である、本発明1073の方法。
[本発明1075]
トレプロスチニル誘導体が本発明1071の化合物である、本発明1073の方法。
[本発明1076]
トレプロスチニル誘導体が経口投与、局所投与、または非経口投与される、本発明1073の方法。
[本発明1077]
トレプロスチニル誘導体が（例えば経皮パッチ剤によって）経皮投与される、本発明1076の方法。
[本発明1078]
肺高血圧症が肺動脈性肺高血圧症である、本発明1073の方法。
[本発明1079]
さらなる治療剤を投与する段階をさらに含む、本発明1073の方法。
[本発明1080]
さらなる治療剤が血管作用薬、利尿薬、および抗凝固薬からなる群より選択される、本発明1079の方法。
[本発明1081]
肺高血圧症が肺動脈性肺高血圧症であり；
トレプロスチニル誘導体が本発明1071の化合物であり；かつ
トレプロスチニル誘導体が局所投与（例えば経皮投与）される、
本発明1073の方法。 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 the formula:
wherein _R20 , _R21 , _R22 , _R23 , _R24 , R25, _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , _R33 , _R34 , _R35 , and _{R36 are} independently H or deuterium;
Z is -OH, -OR ₁₁ , -N(R ₁₁ )R ₁₂ , -SR ₁₁ , or P ₁ ;
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

is selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ , at each occurrence, are independently 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 ₁₄ and R ₁₅ together with the atom to which they are attached may 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 are each independently selected 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), -CONH ₂ , 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 together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₅ and R ₁₈ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₅ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
and _R1 and _R2 are independently H or _P2 , and at least one of _R1 and _R2 is _P2 ;
_P2 is

is selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ , at each occurrence, are independently 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 ₁₄ and R ₁₅ together with the atom to which they are attached may 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 , at each occurrence, are independently H or alkyl;
R ₁₆ and R ₁₇ together with the atoms to which they are attached may form a 3- to 6-membered ring;
R ₁₈ and R ₁₉ are each independently selected 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), -CONH ₂ , 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 together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
Formula I includes the enantiomers, pharma- ceutically acceptable salts, polymorphs, and stereoisomers (e.g., enantiomers and diastereomers) of the compounds of Formula I;
The compound.
[The present invention 1002]
The compound of the present invention, wherein R ₁ is P ₂ and R ₂ is H.
[The present invention 1003]
The compound of the present invention, wherein R ₁ is H and R ₂ is P ₂ .
[The present invention 1004]
The compound of the present invention, wherein R ₁ is P ₂ and R ₂ is P ₂ .
[The present invention 1005]
_P2

1001 A compound of the present invention selected from the group consisting of:
[The present invention 1006]
_P2

1001 A compound of the present invention selected from the group consisting of:
[The present invention 1007]
_P2

1001 A compound of the present invention selected from the group consisting of:
[The present invention 1008]
_P2

1001 A compound of the present invention selected from the group consisting of:
[The present invention 1009]
_P2

1001 A compound of the present invention selected from the group consisting of:
[The present invention 1010]
_P2

1001 A compound of the present invention selected from the group consisting of:
[The present invention 1011]
_P2

1001 A compound of the present invention selected from the group consisting of:
[The present invention 1012]
_P2

1001 A compound of the present invention selected from the group consisting of:
[The present invention 1013]
_P2

1001 A compound of the present invention selected from the group consisting of:
[The present invention 1014]
_P2

1001 A compound of the present invention selected from the group consisting of:
[The present invention 1015]
_P2

1001 A compound of the present invention selected from the group consisting of:
[The present invention 1016]
The compound of the present invention ₁₀₀₁ , wherein _R20 , _R21 , _R22 , _R23 , _R24 , R25, _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , _R33 , _R34 , _R35 , and _R36 are H.
[The present invention 1017]
A compound of the present invention ₁₀₀₁ , wherein at least one of _R20 , _R21 , _R22 , _R23 , R24, _R25 , _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , _R33 , _R34 , _R35 , and _R36 is deuterium.
[The present invention 1018]
1001. The compound of claim 1001, wherein Z is -OR ₁₁ , -N(R ₁₁ )R ₁₂ , or _P1 .
[The present invention 1019]
The compound of the present invention, wherein Z is _P1 .
[The present invention 1020]
1001. The compound of claim 1001, wherein Z is -OH, -OR ₁₁ , -N(R ₁₁ )R ₁₂ , or P ₁ .
[The present invention 1021]
1001. The compound of claim 10, wherein Z is -OH.
[The present invention 1022]
1001. A compound of the present invention, wherein Z is not -OH and R ₁₁ is not unsubstituted or substituted benzyl.
[The present invention 1023]
Formula (IA):

A compound represented by the formula:
In the formula,
Z is -OH, -OR ₁₁ , or P ₁ ;
R ₁₁ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl;
_P1 is

is selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ , at each occurrence, are independently selected 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 together with the atoms to which they are attached may form a 5- to 7-membered ring;
and _R1 and _R2 are independently H or _P2 , and at least one of _R1 and _R2 is _P2 ;
_P2 is

is selected from the group consisting of
here,
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 pharma- ceutically acceptable salts, polymorphs, and stereoisomers (e.g., enantiomers and diastereomers) of compounds of formula IA:
1001 compounds of the present invention.
[The present invention 1024]
Formula (I):

A compound of the formula:
wherein _R20 , _R21 , _R22 , _R23 , _R24 , R25, _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , _R33 , _R34 , _R35 , and _{R36 are} independently H or deuterium;
Z is -OR ₁₁ , -N(R ₁₁ )R ₁₂ , -SR ₁₁ , or P ₁ ;
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

is selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ , at each occurrence, are independently 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 ₁₄ and R ₁₅ together with the atom to which they are attached may 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 are each independently selected 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), -CONH ₂ , 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 together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₅ and R ₁₈ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₅ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
and _R1 and _R2 are independently H or _P2 ;
_P2 is

is selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ , at each occurrence, are independently 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 ₁₄ and R ₁₅ together with the atom to which they are attached may 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 , at each occurrence, are independently H or alkyl;
R ₁₆ and R ₁₇ together with the atoms to which they are attached may form a 3- to 6-membered ring;
R ₁₈ and R ₁₉ are each independently selected 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), -CONH ₂ , 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 together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
Formula I includes the enantiomers, pharma- ceutically acceptable salts, polymorphs, and stereoisomers (e.g., enantiomers and diastereomers) of the compounds of Formula I;
The compound.
[The present invention 1025]
The compound of the present invention 1024, wherein Z is -OR ₁₁ .
[The present invention 1026]
1024. The compound of the present invention, wherein Z is -N( _R11 ) _R12 .
[The present invention 1027]
The compound of the present invention 1024, wherein Z is -SR ₁₁ .
[The present invention 1028]
The compound of the present invention 1024, wherein Z is _P1 .
[The present invention 1029]
1024. The compound of the present invention, wherein Z is OR ₁₁ and R ₁₁ is bicycloalkyl, alkylcycloalkyl, or alkylcycloheteroalkyl.
[The present invention 1030]
1024. The compound of the present invention, wherein R ₁₁ is haloalkyl.
[The present invention 1031]
1024. The compound of the present invention, wherein R ₁₁ is fluoroalkyl.
[The present invention 1032]
The compound of the present invention 1024, wherein R ₁ is hydrogen and R ₂ is P ₂ .
[The present invention 1033]
The compound of the present invention 1024, wherein R ₁ is P ₂ and R ₂ is hydrogen.
[The present invention 1034]
The compound of the present invention 1024, wherein R ₁ is P ₂ and R ₂ is P ₂ .
[The present invention 1035]
The compound of the present invention 1024, wherein R ₁ and R ₂ are each hydrogen.
[The present invention 1036]
The compound of the present invention ₁₀₂₄ , wherein _R20 , _R21 , _R22 , _R23 , _R24 , R25, _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , _R33 , _R34 , _R35 , and _R36 are H.
[The present invention 1037]
The compound of the present invention ₁₀₂₄ , wherein at least one of _R20 , _R21 , _R22 , _R23 , R24, _R25 , _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , _R33 , _R34 , _R35 , and _R36 is deuterium.
[The present invention 1038]
Formula (IAA):

A compound of the formula:
In the formula,
R ₁₀₀ and R ₂₀₀ are independently selected from the group consisting of H, CONR ₉₀₀ R ₁₀₀₀ , CR ₉₀₀ R ₁₀₀₀ OCOP ₃ R ₉₀₀ R 1000 , R ₉₀₀ and _{R 1000 are} 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;
The compound.
[The present invention 1039]
1038. The compound of the present invention, wherein R ₁₀₀ and R ₂₀₀ are H.
[The present invention 1040]
1039. The compound of the present invention, wherein R ₃₀₀ , R ₄₀₀ , R ₅₀₀ , R ₆₀₀ , R ₇₀₀ , and R ₈₀₀ are H.
[The present invention 1041]
The compound of the present invention 1040, wherein X is O.
[The present invention 1042]
R ₁₁₀₀

The compound of the present invention 1041 selected from:
[The present invention 1043]
The compound of the present invention 1039, wherein X is NHR ₁₂₀₀ .
[The present invention 1044]
R ₁₁₀₀

The compound of the present invention 1043 selected from the group consisting of:
[The present invention 1045]
The compound of the present invention 1038, wherein X is O.
[The present invention 1046]
1045. The compound of the present invention, wherein R ₃₀₀ , R ₄₀₀ , R ₅₀₀ , R ₆₀₀ , R ₇₀₀ , and R ₈₀₀ are H.
[The present invention 1047]
1046. The compound of the present invention, wherein R ₁₁₀₀ is alkyl.
[The present invention 1048]
Formula II:

A compound represented by the formula:
In the formula,
_R2 is selected from the group consisting of H and _P2 ;
_R20 , _R21 , _R22 , _{R23 , R24, R25, R26, R27, R28, R29, R30, R31, R32 , R33 , R34 , R35 , and R36 are independently selected} from the group consisting of H and deuterium;
_L1 is selected from the group consisting of -O-alkylene-C(O)-, -O-alkylene-OC(O)-, or a bond;
_P2 is

is selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ , at each occurrence, are independently 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 ₁₄ and R ₁₅ together with the atom to which they are attached may 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 , at each occurrence, are independently H or alkyl;
R ₁₆ and R ₁₇ together with the atoms to which they are attached may form a 3- to 6-membered ring;
R ₁₈ and R ₁₉ are each independently selected 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), -CONH ₂ , 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 together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
Formula II includes enantiomers, pharma- ceutically acceptable salts, polymorphs, and stereoisomers (e.g., enantiomers and diastereomers) of compounds of Formula II;
The compound.
[The present invention 1049]
The compound of the present invention ₁₀₄₈ , wherein _R20 , _R21 , _R22 , _R23 , _R24 , R25, _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , _R33 , _R34 , _R35 , and _R36 are H.
[The present invention 1050]
A compound of the present invention ₁₀₄₈ , wherein at least one of _R20 , _R21 , _R22 , _R23 , R24, _R25 , _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , _R33 , _R34 , _R35 , and _R36 is deuterium.
[The present invention 1051]
1048. The compound of the present invention, wherein _L1 is -O-alkylene-C(O)-.
[The present invention 1052]
1048. The compound of the present invention, wherein _L1 is -O-alkylene-OC(O)-.
[The present invention 1053]
1048. The compound of the present invention, wherein L ₁ is a bond.
[The present invention 1054]
1048. The compound of the present invention, wherein the alkylene group is a _C1 - _C5 alkylene group.
[The present invention 1055]
1048. The compound of the present invention, wherein the alkylene group is a _C1 alkylene group.
[The present invention 1056]
Formula IIA:

A compound represented by the formula:
wherein L ₁ and R ₂ are as defined in the present invention 1048;
Compound 1048 of the present invention.
[The present invention 1057]
Formula II(AA)

and an enantiomer of a compound of formula II(AA):
In the formula,
_R2000 is _{independently} selected from the group consisting of H, _{CONR9000R10000} , _{CR9000R10000OCOPR9000R10000 , R9000} and _{R10000 are} 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, 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 stereoisomers (e.g., enantiomers and diastereomers) of Formula II(AA), pharma- ceutically acceptable salts of compounds of Formula II(a), and polymorphs of Formula II(AA).
The compound and the enantiomer.
[The present invention 1058]
Formula III:

A compound represented by the formula:
In the formula, _L2 is

is selected from the group consisting of
here,
m is 1, 2, 3, or 4;
X is _NR14 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, substituted heteroarylalkyl;
R ₁₆ and R ₁₇ , at each occurrence, are independently H or alkyl;
R ₁₆ and R ₁₇ together with the atoms to which they are attached may form a 3- to 6-membered ring; and
_R20 , _R21 , _R22 , _{R23 , R24, R25, R26, R27, R28, R29, R30, R31, R32 , R33 , R34 , R35 , and R36 are independently selected} from the group consisting of H and deuterium;
Z is -OH, -OR ₁₁ , -N(R ₁₁ )R ₁₂ , -SR ₁₁ , or P ₁ ;
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

is selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ , at each occurrence, are independently 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 ₁₄ and R ₁₅ together with the atom to which they are attached may 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 are each independently selected 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), -CONH ₂ , 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 together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₅ and R ₁₈ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₅ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
Formula III includes stereoisomers (e.g., enantiomers and diastereomers), pharma- ceutically acceptable salts, and polymorphs of compounds of formula III:
The compound.
[The present invention 1059]
_L2

The compound of the present invention 1058 selected from the group consisting of:
[The present invention 1060]
The compound of the present invention ₁₀₅₈ , wherein _R20 , _R21 , _R22 , _R23 , _R24 , R25, _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , _R33 , _R34 , _R35 , and _R36 are H.
[The present invention 1061]
The compound of claim ₁₀₅₈ , wherein at least one of _R20 , _R21 , _R22 , _R23 , R24, _R25 , _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , _R33 , _R34 , _R35 , and _R36 is deuterium.
[The present invention 1062]
Formula IIIA:

A compound represented by the formula:
wherein Z and _L2 are as defined in the present invention 1058;
Compound 1058 of the present invention.
[The present invention 1063]
Formula III(AA):

and stereoisomers (e.g., enantiomers and diastereomers) of compounds of formula III(AA), and pharma- ceutically acceptable salts of compounds of formula III(AA), and polymorphs of formula III(AA),
In the formula,
R ₁₁ is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl;
R ₀₃ , R ₀₄ , R ₀₅ , R ₀₆ , R ₀₇ , and R ₀₈ are independently selected from the group consisting of H, deuterium;
X is O, NR ₀₁₂ , S;
R ₀₁₂ is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl;
Y is C=O;
The compounds, as well as the stereoisomers, and the pharma- ceutically acceptable salts, and the polymorphs.
[The present invention 1064]
Formula IV:

A compound represented by the formula:
_R1 is selected from the group consisting of H and _P2 ;
_R20 , _R21 , _R22 , _{R23 , R24, R25, R26, R27, R28, R29, R30, R31, R32 , R33 , R34 , R35 , and R36 are independently selected} from the group consisting of H and deuterium;
_L1 is selected from the group consisting of -O-alkylene-C(O)-, -O-alkylene-OC(O)-, or a bond;
_P2 is

is selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ , at each occurrence, are independently 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 ₁₄ and R ₁₅ together with the atom to which they are attached may 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 , at each occurrence, are independently H or alkyl;
R ₁₆ and R ₁₇ together with the atoms to which they are attached may form a 3- to 6-membered ring;
R ₁₈ and R ₁₉ are each independently selected 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), -CONH ₂ , 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 together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
Formula IV includes stereoisomers (e.g., enantiomers and diastereomers), pharma- ceutically acceptable salts, and polymorphs of compounds of formula IV:
The compound.
[The present invention 1065]
Formula IVA:

A compound represented by the formula:
wherein L ₁ and R ₁ are as defined 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 1001-1065 and at least one other ingredient.
[The present 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, which is 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 according to claim 1063, wherein the amount of the compound according to claim 1001-1065 is adapted to provide a delivery profile useful for human treatment.
[The present invention 1071]
A compound selected from the group consisting of:

.
[The present invention 1072]
A composition comprising a compound of the present invention and one or more pharma- ceutically acceptable carriers or excipients.
[The present invention 1073]
1. A method for treating pulmonary hypertension, comprising administering to a subject in need of treatment a therapeutically effective amount of a treprostinil derivative or a pharma- ceutically acceptable salt, solvate, clathrate, or polymorph thereof.
[The present invention 1074]
The method of claim 1073, wherein the treprostinil derivative is any of the compounds of claims 1001 to 1065.
[The present invention 1075]
The method of claim 1073, wherein the treprostinil derivative is a compound of claim 1071.
[The present invention 1076]
The method of claim 1073, wherein the treprostinil derivative is administered orally, topically, or parenterally.
[The present invention 1077]
The method of claim 1076, wherein the treprostinil derivative is administered transdermally (eg, by a transdermal patch).
[The present invention 1078]
The method of claim 1073, wherein the pulmonary hypertension is pulmonary arterial hypertension.
[The present invention 1079]
The method of claim 1073, further comprising the step of administering an additional therapeutic agent.
[The present invention 1080]
The method of claim 1079, wherein the additional therapeutic agent is selected from the group consisting of vasoactive agents, diuretics, and anticoagulants.
[The present invention 1081]
The pulmonary hypertension is pulmonary arterial hypertension;
the treprostinil derivative is a compound of the present invention; and the treprostinil derivative is administered locally (e.g., transdermally),
The method of the present invention 1073.

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, the Examples, and the Table of Structures on pages 14-16.

Various prostacyclin analogs, including treprostinil, and methods of their use are known. For example, they can be used 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 these 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-MI, post-cardiac surgery), thrombotic microangiopathy, extracorporeal circulation, central retinal vein occlusion, atherosclerosis, inflammatory diseases (e.g., COPD, psoriasis), hypertension (e.g., preeclampsia), reproduction and parturition, cancer or other uncontrolled cell proliferation conditions, cell/tissue preservation, and other emerging therapeutic areas in which 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).

Treprostinil is a chemically stable analogue 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 less than 10% absolute oral bioavailability and a very short systemic half-life due to extensive metabolism.

DEFINITIONS In the present specification, lists of chemical groups are provided that are represented by multiple chemical formulas (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, and also any single formula in the list of groups.

The term "alkyl" means a monovalent saturated hydrocarbon group. _C1 - _C8 alkyl means an alkyl having from 1 to 8 carbon atoms, such as _C1 - _C3 alkyl, _C1 - _C5 alkyl, and _C1 - _C7 alkyl. Alkyl can be straight 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.

The term "haloalkyl" means a monovalent saturated hydrocarbon radical bonded to one or more halogen atoms selected from Cl and F. Specific examples include 2-fluoroethyl, 2,2-difluoroethyl, 2-fluoropropyl, and 2,2-difluoropropyl.

The term "heteroalkyl" means a monovalent saturated hydrocarbon group attached to one or more heteroatoms selected from O, N, and S. _C1 - _C8 heteroalkyl means an alkyl having from 1 to 8 carbon atoms and one or more heteroatoms selected from O, N, S, such as _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.

The term "cycloalkyl" means a monovalent monocyclic, bicyclic, or tricyclic saturated hydrocarbon ring system. The term " _C3 - _C14 cycloalkyl" means a cycloalkyl having from 3 to 14 ring carbon atoms. Examples of _C3 - _C14 cycloalkyl include _C3 - _C10 cycloalkyl and _C3 - _C6 cycloalkyl. Bicyclic and tricyclic systems include fused, bridged, and spiro 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.

The term "cycloheteroalkyl" or "heterocycloalkyl" 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 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, piperazinyl, piperidinyl, pyrazolidinyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, thiomorpholinyl, and α-methyl-1,3-dioxol-2-onyl.

The term "alkylcycloalkyl" means a monovalent monocyclic, bicyclic, or tricyclic saturated hydrocarbon ring system attached to an alkyl group. Specific examples include cyclopropylmethyl, cyclopropylethyl, and cyclohexylethyl.

The term "alkylheterocycloalkyl" or "alkylcycloheteroalkyl" refers to a cycloheteroalkyl group linked to an alkyl group. Examples include N-ethylmorpholine, N-ethylpiperidine, 4-ethylpiperidine, 1-methyl-4-ethylpiperidine, and N-ethylpiperazine.

The term "aryl" means a monovalent aromatic carbocyclic ring system which may be a monocyclic, fused bicyclic, or fused tricyclic ring system. The term " _C6 - _C14 aryl" means an aryl having from 6 to 14 ring carbon atoms. An example of a _C6 - _C14 aryl is a _C6 - _C10 aryl. More specific examples of aryl groups include phenyl, naphthyl, anthracyl, and phenanthryl.

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, tetrazolyl, etc.; unsaturated fused heterocyclyl groups containing 1 to 5 nitrogen atoms, such as indolyl, isoindolyl, benzimidazolyl, quinolyl, benzotriazolyl, tetrazolopyridazinyl, etc.; unsaturated 3- to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl, oxadiazolyl, etc.; 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, thiadiazolyl, etc.; and unsaturated fused heterocyclyl groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms.

The term "alkylaryl" refers to an aryl-substituted alkyl group such as benzyl, diphenylmethyl, or phenylethyl.

The term "alkylheteroaryl" refers to a heteroaryl-substituted alkyl group such as imidazolylmethyl, thiazolylmethyl, or pyridylethyl.

It will be understood that terms described herein such as alkyl, haloalkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylheterocycloalkyl, aryl, heteroaryl, alkylaryl, and alkylheteroaryl may also cover the embodiment in which they form a ring. For example, optionally, groups such as _R14 , _R15 , _R16 , _R17 , _R18 , and _R19 may form a ring with another _R14 group, _R15 group, _R16 group, _R17 group, _R18 group, and _R19 group.

The term "substituted" means that one or more hydrogen radicals in a given structure are replaced with a specified group of substituents, 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 substituents may be further substituted within the normal limits of one of ordinary skill in the art. A moiety or group may be substituted, i.e., the group may or may not have one or more substituents.

The term "compound" as used herein is intended to include its salts, solvates, hydrates, and polymorphs. The specific mention of a "salt," "solvate," "hydrate," or "polymorph" 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.

A salt of a compound of the 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 pharma- ceutically acceptable base or acid addition salt.

The term "pharmacologically 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 reaction, or the like, and is commensurate with a reasonable benefit/loss ratio. "Pharmaceutically acceptable salt" means any non-toxic salt that is capable of directly or indirectly imparting a compound of the invention or a prodrug of a compound upon administration to a recipient. "Pharmaceutically acceptable counterion" means an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.

Acids commonly used to form pharma- ceutically 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. Thus, pharma- ceutically acceptable salts include, but are not limited to, 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. Salts include 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 similar salts. Preferred pharma- ceutically 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.

As used herein, the term "hydrate" refers to a compound that further contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

As used herein, the term "solvate" refers to a compound that further contains a stoichiometric or nonstoichiometric amount of a solvent, such as water, acetone, ethanol, methanol, dichloromethane, 2-propanol, etc., bound by noncovalent intermolecular forces.

It will be recognized that some variation in natural isotopic abundance will occur in the synthesized compound depending on the origin of the chemicals used in isotope and isotopic abundance synthesis. Thus, formulations of Treprostinil inherently contain a small amount of deuterated isotopologues. Despite this variation, the concentrations of naturally abundant hydrogen and carbon stable isotopes are small and 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 particular position in the compounds of the present invention is designated as having deuterium, it will be understood that the abundance of deuterium at that position is substantially greater than the natural deuterium abundance, which is about 0.015%. Typically, a position designated as having deuterium has a minimum isotopic enrichment factor of at least about 3000 (about 45% deuterium incorporation) at each atom designated as deuterium in said compound.

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

In some embodiments, the compounds of the present 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).

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.

In other embodiments, the compounds of the invention contain less than 10%, preferably less than 6%, more preferably less than 3%, in total, of all other isotopologues, including forms lacking deuterium. In certain aspects, the compounds contain less than "X"% in total of all other isotopologues, including forms lacking deuterium, where X is any number between 0 and 10, e.g., 1, 0.5, 0.001. Compositions containing more than 10% in total of all other isotopologues 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, relate 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 the hydrolyzable portion of the prodrug, or the isotopic composition of the counterion.

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

Stereoisomers It will be understood that the present invention encompasses all possible stereoisomers, including all possible diastereomers and enantiomers, of the compounds described herein, and does not encompass only the specific stereoisomers shown in the depicted structures or nomenclature. Some aspects of the present invention relate to the specific stereoisomers shown in the depicted structures or nomenclature.

で表される化合物を提供する。 Core Structure I
In one aspect, the present invention provides a compound of formula I:

The present invention provides a compound represented by the formula:

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

からなる群より選択され、
ここで、
mは1、2、3、または4であり;
R₁₄およびR₁₅はそれぞれの場合で独立してH、アルキル、シクロアルキル、アルキルシクロアルキル、ハロアルキル、ヘテロアルキル、置換アルキル、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、置換アリール、置換ヘテロアリール、置換アリールアルキル、および置換ヘテロアリールアルキルからなる群より選択され;
R₁₄およびR₁₅は、それらが結合している原子と一緒になって、非置換であるかまたは独立してハロ、メチル、およびメトキシからなる群より選択される1個、2個、もしくは3個の置換基で置換されている、N、O、またはSより選択される1個または2個の環ヘテロ原子を組み入れていてもよい5員～7員環を形成してもよく;
R₁₈およびR₁₉はそれぞれの場合で独立して水素およびアルキルからなる群より選択され、該アルキルは非置換であるかまたはハロ、ヒドロキシ、アルコキシ、アミノ、チオ、メチルチオ、-C(O)OH、-C(O)O-(アルキル)、-CONH₂、アリール、およびヘテロアリールからなる群より選択される1個の置換基で置換されており、該アリールまたはヘテロアリールは非置換であるかまたはアルキル、ハロ、ハロアルキル、ヒドロキシ、アルコキシ、およびハロアルコキシからなるリストより置換されており;
R₁₄およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₄およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₅およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₅およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
かつ、R₁およびR₂は独立してHまたはP₂であり、R₁およびR₂のうち少なくとも一方はP₂であり、
P₂は

からなる群より選択され、
ここで、
mは1、2、3、または4であり;
R₁₄およびR₁₅は上記定義の通りであり;
R₁₄およびR₁₅は、それらが結合している原子と一緒になって、非置換であるかまたは独立してハロ、メチル、およびメトキシからなるリストより選択される1個、2個、もしくは3個の置換基で置換されている、N、O、またはSより選択される1個または2個の環ヘテロ原子を組み入れていてもよい5員～7員環を形成してもよく;
R₁₆およびR₁₇はそれぞれの場合で独立してHまたはアルキルであり;
R₁₆およびR₁₇は、それらが結合している原子と一緒になって3員～6員環を形成してもよく;
R₁₈およびR₁₉は上記定義の通りであり;
R₁₄およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₄およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
式Iは、式Iの化合物の鏡像異性体、薬学的に許容される塩、溶媒和物、および多形体を含む。この式Iでは、本明細書に記載の式II、III、およびIVとは対照的に、Z、R₁、およびR₂基は互いに結合していない。 In a first subembodiment of formula I, _R20 , _R21 , _R22 , R23, _R24 , _R25 , _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , _R33 , _R34 , _R35 , _{and R36} are independently H or deuterium;
Z is -OH, -OR ₁₁ , -N(R ₁₁ )R ₁₂ , -SR ₁₁ , or P ₁ ;
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

is selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ , at each occurrence, are independently 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 ₁₄ and R ₁₅ together with the atom to which they are attached may 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 , at each occurrence, are independently selected from the group consisting of hydrogen and alkyl, where the alkyl is unsubstituted or substituted with one substituent selected from the group consisting of halo, hydroxy, alkoxy, amino, thio, methylthio, -C(O)OH, -C(O)O-(alkyl), -CONH ₂ , aryl, and heteroaryl, where the aryl or heteroaryl is unsubstituted or substituted from the list consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, and haloalkoxy;
R ₁₄ and R ₁₈ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₅ and R ₁₈ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₅ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
and _R1 and _R2 are independently H or _P2 , and at least one of _R1 and _R2 is _P2 ;
_P2 is

is selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ are as defined above;
R ₁₄ and R ₁₅ together with the atom to which they are attached may form a 5- to 7-membered ring that 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 , at each occurrence, are independently H or alkyl;
R ₁₆ and R ₁₇ together with the atoms to which they are attached may form a 3- to 6-membered ring;
R ₁₈ and R ₁₉ are as defined above;
R ₁₄ and R ₁₈ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
Formula I includes the enantiomers, pharma- ceutically acceptable salts, solvates, and polymorphs of the compounds 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 bonded to each other.

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 .

からなる群より選択される。 The _P2 group can be more specifically described. In one embodiment, _P2 is

is selected from the group consisting of:

からなる群より選択される。 In another embodiment, _P2 is

is selected from the group consisting of:

からなる群より選択される。 In another embodiment, _P2 is

is selected from the group consisting of:

からなる群より選択される。 In another embodiment, _P2 is

is selected from the group consisting of:

からなる群より選択される。 In another embodiment, _P2 is

is selected from the group consisting of:

からなる群より選択される。 In another embodiment, _P2 is

is selected from the group consisting of:

からなる群より選択される。 In another embodiment, _P2 is

is selected from the group consisting of:

からなる群より選択される。 In another embodiment, _P2 is

is selected from the group consisting of:

からなる群より選択される。 In another embodiment, _P2 is

is selected from the group consisting of:

からなる群より選択される。 In another embodiment, _P2 is

is selected from the group consisting of:

からなる群より選択される。 In another embodiment, _P2 is

is selected from the group consisting of:

In one embodiment, _R20 , _R21 , _R22 , _R23 , R24, _R25 , _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , _R33 , _R34 , _R35 , _{and R36} are H.

In one embodiment, Z is -OR ₁₁ , -N(R ₁₁ )R ₁₂ , or P _1. In another embodiment, Z is P _1. In another embodiment, Z is -OH, -OR ₁₁ , -N(R ₁₁ )R ₁₂ , or P _1. In another embodiment, Z is -OH.

In one embodiment, Z is not -OH and R ₁₁ is not unsubstituted or substituted benzyl.

からなる群より選択され、
ここで、
mは1、2、3、または4であり;
R₁₄およびR₁₅はそれぞれの場合で独立してH、アルキル、シクロアルキル、アルキルシクロアルキル、ハロアルキル、ヘテロアルキル、置換アルキル、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、置換アリール、置換ヘテロアリール、置換アリールアルキル、および置換ヘテロアリールアルキルからなる群より選択され;
R₁₄およびR₁₅は、それらが結合している原子と一緒になって、非置換であるかまたは独立してハロ、メチル、およびメトキシからなる群より選択される1個、2個、もしくは3個の置換基で置換されている、N、O、またはSより選択される1個または2個の環ヘテロ原子を組み入れていてもよい5員～7員環を形成してもよく;
R₁₈およびR₁₉はそれぞれの場合で独立して水素およびアルキルからなる群より選択され、該アルキルは非置換であるかまたはハロ、ヒドロキシ、アルコキシ、アミノ、チオ、メチルチオ、-C(O)OH、-C(O)O-(アルキル)、-CONH₂、アリール、およびヘテロアリールからなるリストより選択される1個の置換基で置換されており、該アリールまたはヘテロアリールは非置換であるかまたはアルキル、ハロ、ハロアルキル、ヒドロキシ、アルコキシ、およびハロアルコキシからなる群より置換されており;
R₁₄およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₄およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₅およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₅およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
かつ、R₁およびR₂は独立してHまたはP₂であり、
P₂は

からなる群より選択され、
ここで、
mは1、2、3、または4であり;
R₁₄およびR₁₅は上記定義の通りであり;
R₁₄およびR₁₅は、それらが結合している原子と一緒になって、非置換であるかまたは独立してハロ、メチル、およびメトキシからなるリストより選択される1個、2個、もしくは3個の置換基で置換されている、N、O、またはSより選択される1個または2個の環ヘテロ原子を組み入れていてもよい5員～7員環を形成してもよく;
R₁₆およびR₁₇はそれぞれの場合で独立してHまたはアルキルであり;
R₁₆およびR₁₇は、それらが結合している原子と一緒になって3員～6員環を形成してもよく;
R₁₈およびR₁₉は上記定義の通りであり;
R₁₄およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₄およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
式Iは、式Iの化合物の鏡像異性体、薬学的に許容される塩、溶媒和物、および多形体を含む。 In a second subembodiment of formula I,
_R20 , _R21 , _R22 , _{R23 , R24, R25, R26, R27, R28, R29, R30, R31, R32 , R33 , R34 , R35 , and R36 are independently H} or deuterium;
Z is -OR ₁₁ , -N(R ₁₁ )R ₁₂ , -SR ₁₁ , or P ₁ ;
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, or substituted alkylheteroaryl;
R ₁₂ is H, branched alkyl, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl;
_P1 is

is selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ , at each occurrence, are independently 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 ₁₄ and R ₁₅ together with the atom to which they are attached may 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 , at each occurrence, are independently selected 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), -CONH ₂ , aryl, and heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, and haloalkoxy;
R ₁₄ and R ₁₈ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₅ and R ₁₈ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₅ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
and _R1 and _R2 are independently H or _P2 ;
_P2 is

is selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ are as defined above;
R ₁₄ and R ₁₅ together with the atom to which they are attached may form a 5- to 7-membered ring that 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 , at each occurrence, are independently H or alkyl;
R ₁₆ and R ₁₇ together with the atoms to which they are attached may form a 3- to 6-membered ring;
R ₁₈ and R ₁₉ are as defined above;
R ₁₄ and R ₁₈ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
Formula I includes the enantiomers, pharma- ceutically acceptable salts, solvates, and polymorphs of compounds of Formula I.

In one embodiment, Z is _-OR11 . In one embodiment, Z is -N( _R11 ) _R12 . In one embodiment, Z is _-SR11 . In one embodiment, Z is _P1 . In one embodiment, Z is _OR11 , where _R11 is bicycloalkyl, alkylcycloalkyl, or alkylcycloheteroalkyl. In one embodiment, Z is _P1 .

In one embodiment, R ₁₁ is haloalkyl, or, more specifically, fluoroalkyl.

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 .

In one embodiment, at least one of _R20 , _R21 , _R22 , _R23 , R24, _R25 , _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , _R33 , _R34 , _{R35 ,} and _R36 is deuterium.

In one embodiment, _R20 , _R21 , _R22 , _R23 , R24, _R25 , _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , _R33 , _R34 , _R35 , _{and R36} are hydrogen.

で表される化合物であり、
式中、
Zは-OH、-OR₁₁、またはP₁であり;
R₁₁はアルキル、置換アルキル、シクロアルキル、置換シクロアルキル、ハロアルキル、ヘテロアルキル、置換ヘテロアルキル、シクロヘテロアルキル、置換シクロヘテロアルキル、アルキルシクロアルキル、置換アルキルシクロアルキル、アルキルシクロヘテロアルキル、または置換アルキルシクロヘテロアルキルであり;
P₁は

からなる群より選択され、
ここで、
mは1、2、3、または4であり;
R₁₄はH、アルキル、シクロアルキル、アルキルシクロアルキル、ハロアルキル、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、置換アリール、置換ヘテロアリール、置換アリールアルキル、および置換ヘテロアリールアルキルからなる群より選択され;
かつ、R₁およびR₂は独立してHまたはP₂であり、R₁およびR₂のうち少なくとも一方はP₂であり、
P₂は

からなる群より選択され、
ここで、
R₁₄およびR₁₅はそれぞれの場合で独立してH、アルキル、シクロアルキル、アルキルシクロアルキル、ハロアルキル、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、置換アリール、置換ヘテロアリール、置換アリールアルキル、および置換ヘテロアリールアルキルからなる群より選択され;
R₁₄およびR₁₅は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
式IAは、式IAの化合物の鏡像異性体、薬学的に許容される塩、溶媒和物、および多形体を含む。 Formula IA
One subembodiment of formula I is formula (IA):

A compound represented by the formula:
In the formula,
Z is -OH, -OR ₁₁ , or P ₁ ;
R ₁₁ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, or substituted alkylcycloheteroalkyl;
_P1 is

is selected from the group consisting of
here,
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

is selected from the group consisting of
here,
R ₁₄ and R ₁₅ , at each occurrence, are independently selected 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 together with the atoms to which they are attached may form a 5- to 7-membered ring;
Formula IA includes enantiomers, pharma- ceutically acceptable salts, solvates, and polymorphs of compounds of formula IA.

[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸

[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸シクロプロピルメチルエステル(化合物1を含むすべてのありうる立体異性体)

N-シクロプロピルメチル-2-[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-アセトアミド(化合物2を含むすべてのありうる立体異性体)

[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸2-モルホリン-4-イル-エチルエステル(化合物3を含むすべてのありうる立体異性体)

[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸3-フルオロ-プロピルエステル(化合物4を含むすべてのありうる立体異性体)

[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸テトラヒドロ-フラン-3-イルエステル(化合物5を含むすべてのありうる立体異性体)

2-{2-[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-アセトキシ}-プロピオン酸メチルエステル(化合物6を含むすべてのありうる立体異性体)

N-(2-ヒドロキシ-エチル)-2-[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-アセトアミド(化合物7を含むすべてのありうる立体異性体)

N-(2-アミノ-エチル)-2-[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-アセトアミド(化合物8を含むすべてのありうる立体異性体)

[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸2-ヒドロキシ-エチルエステル(化合物9を含むすべてのありうる立体異性体)

[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸2-メトキシ-エチルエステル(化合物10を含むすべてのありうる立体異性体)

2-[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-N-(3-ヒドロキシ-プロピル)-アセトアミド(化合物11を含むすべてのありうる立体異性体)

{2-[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-アセチルアミノ}-酢酸メチルエステル(化合物12を含むすべてのありうる立体異性体)

({2-[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-アセチル}-メチル-アミノ)-酢酸メチルエステル(化合物13を含むすべてのありうる立体異性体)

2-[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-N-(2,2,2-トリフルオロ-エチル)-アセトアミド(化合物14を含むすべてのありうる立体異性体)

[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸メチルエステル(化合物15を含むすべてのありうる立体異性体)

[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸2,2-ジメチル-プロピルエステル(化合物16を含むすべてのありうる立体異性体)

[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸1,2-ジメチル-プロピルエステル(化合物17を含むすべてのありうる立体異性体)

[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸1,2,2-トリメチル-プロピルエステル(化合物18を含むすべてのありうる立体異性体)

[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸ビシクロ[2.2.1]ヘプタ-2-イルエステル(化合物19を含むすべてのありうる立体異性体)

[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸イソプロピルエステル(化合物20を含むすべてのありうる立体異性体)

2-[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-N-(2,2,3,3,3-ペンタフルオロ-プロピル)-アセトアミド(化合物21を含むすべてのありうる立体異性体)

ペンタン酸1-(3-ヒドロキシ-オクチル)-5-メトキシカルボニルメトキシ-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-2-イルエステル(化合物22を含むすべてのありうる立体異性体)

3-メチル-酪酸1-(3-ヒドロキシ-オクチル)-5-メトキシカルボニルメトキシ-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-2-イルエステル(化合物23を含むすべてのありうる立体異性体)

シクロプロパンカルボン酸1-(3-ヒドロキシ-オクチル)-5-メトキシカルボニルメトキシ-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-2-イルエステル(化合物24を含むすべてのありうる立体異性体)

[2-エトキシカルボニルオキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸メチルエステル(化合物25を含むすべてのありうる立体異性体)

[2-アセトキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸メチルエステル(化合物26を含むすべてのありうる立体異性体)

コハク酸エチルエステル1-(3-ヒドロキシ-オクチル)-5-メトキシカルボニルメトキシ-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-2-イルエステル(化合物27を含むすべてのありうる立体異性体)

[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸tert-ブチルエステル(化合物28を含むすべてのありうる立体異性体)

3-{2-[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-アセチル}-オキサゾリジン-2-オン(化合物29を含むすべてのありうる立体異性体)

2-[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-N-(1H-テトラゾール-5-イル)-アセトアミド(化合物30を含むすべてのありうる立体異性体)

[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸2,2,2-トリフルオロ-1,1-ジメチル-エチルエステル(化合物31を含むすべてのありうる立体異性体)

[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸1,2,2-トリメチル-プロピルエステル(化合物32を含むすべてのありうる立体異性体)

[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸1,2,2-トリメチル-プロピルエステル(化合物33を含むすべてのありうる立体異性体)

[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸ビシクロ[2.2.1]ヘプタ-2-イルエステル(化合物34を含むすべてのありうる立体異性体)

[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸ビシクロ[2.2.1]ヘプタ-2-イルエステル(化合物35を含むすべてのありうる立体異性体)

[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸ビシクロ[2.2.1]ヘプタ-2-イルエステル(化合物36を含むすべてのありうる立体異性体)

[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸ビシクロ[2.2.1]ヘプタ-2-イルエステル(化合物37を含むすべてのありうる立体異性体)

[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸2-イソプロピル-5-メチル-シクロヘキシルエステル(化合物38を含むすべてのありうる立体異性体)

[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸1,7,7-トリメチル-ビシクロ[2.2.1]ヘプタ-2-イルエステル(化合物39を含むすべてのありうる立体異性体)

[2-(2-エトキシ-エトキシカルボニルオキシ)-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸メチルエステル(化合物40を含むすべてのありうる立体異性体)

[2-(2-ジメチルアミノ-エトキシカルボニルオキシ)-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸メチルエステル(化合物41を含むすべてのありうる立体異性体)

[1-(3-ヒドロキシ-オクチル)-2-(2,2,2-トリフルオロ-エトキシカルボニルオキシ)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸メチルエステル(化合物42を含むすべてのありうる立体異性体)

3-モルホリン-4-イル-プロピオン酸1-(3-ヒドロキシ-オクチル)-5-メトキシカルボニルメトキシ-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-2-イルエステル(化合物43を含むすべてのありうる立体異性体)

[1-(3-ヒドロキシ-オクチル)-2-(2-ピロリジン-1-イル-アセトキシ)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸メチルエステル(化合物44を含むすべてのありうる立体異性体)

シクロペンタンカルボン酸1-[2-(2-ヒドロキシ-5-メトキシカルボニルメトキシ-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-1-イル)-エチル]-ヘキシルエステル(化合物45を含むすべてのありうる立体異性体)

1-メチル-ピペリジン-2-カルボン酸1-[2-(2-ヒドロキシ-5-メトキシカルボニルメトキシ-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-1-イル)-エチル]-ヘキシルエステル(化合物46を含むすべてのありうる立体異性体)

4-メチル-モルホリン-2-カルボン酸1-[2-(2-ヒドロキシ-5-メトキシカルボニルメトキシ-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-1-イル)-エチル]-ヘキシルエステル(化合物47を含むすべてのありうる立体異性体)

シクロプロパンカルボン酸1-[2-(2-ヒドロキシ-5-メトキシカルボニルメトキシ-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-1-イル)-エチル]-ヘキシルエステル(化合物48を含むすべてのありうる立体異性体)

2-メチル-酪酸1-[2-(2-ヒドロキシ-5-メトキシカルボニルメトキシ-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-1-イル)-エチル]-ヘキシルエステル(化合物49を含むすべてのありうる立体異性体)

[1-(3-シクロペンチルオキシカルボニルオキシ-オクチル)-2-ヒドロキシ-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸メチルエステル(化合物50を含むすべてのありうる立体異性体)

{1-[3-(1-アザ-ビシクロ[2.2.2]オクタ-3-イルオキシカルボニルオキシ)-オクチル]-2-ヒドロキシ-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ}-酢酸メチルエステル(化合物51を含むすべてのありうる立体異性体)

[2-アセトキシ-1-(3-アセトキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸1-アザ-ビシクロ[2.2.2]オクタ-3-イルエステル(化合物52を含むすべてのありうる立体異性体)

[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸1-アザ-ビシクロ[2.2.2]オクタ-3-イルエステル(化合物53を含むすべてのありうる立体異性体)

プロピオン酸1-{2-[5-メトキシカルボニルメトキシ-2-(5-メチル-2-オキソ-[1,3]ジオキソール-4-イルメトキシカルボニルオキシ)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-1-イル]-エチル}-ヘキシルエステル(化合物54を含むすべてのありうる立体異性体)

[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸1,2-ジメチル-プロピルエステル(化合物55を含むすべてのありうる立体異性体)

[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸1,2-ジメチル-プロピルエステル(化合物56を含むすべてのありうる立体異性体)

Examples of Compounds of Formula I The following are specific compounds of formula I (wherein compound A is treprostinil):

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid cyclopropyl methyl ester (all possible stereoisomers including compound 1)

N-Cyclopropylmethyl-2-[2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetamide (all possible stereoisomers including compound 2)

[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 (all possible stereoisomers including compound 3)

[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 (all possible stereoisomers including compound 4)

[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 (all possible stereoisomers including compound 5)

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 (all possible stereoisomers including compound 6)

N-(2-hydroxy-ethyl)-2-[2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetamide (all possible stereoisomers including compound 7)

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 (all possible stereoisomers including compound 8)

[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 (all possible stereoisomers including compound 9)

[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 (all possible stereoisomers including compound 10)

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 (all possible stereoisomers including compound 11)

{2-[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetylamino}-acetic acid methyl ester (all possible stereoisomers including compound 12)

({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 (all possible stereoisomers including compound 13)

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 (all possible stereoisomers, including compound 14)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid methyl ester (all possible stereoisomers including compound 15)

[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 (all possible stereoisomers including compound 16)

[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 (all possible stereoisomers including compound 17)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid 1,2,2-trimethyl-propyl ester (all possible stereoisomers including compound 18)

[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 (all possible stereoisomers including compound 19)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid isopropyl ester (all possible stereoisomers including compound 20)

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 (all possible stereoisomers including compound 21)

Pentanoic acid 1-(3-hydroxy-octyl)-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-yl ester (all possible stereoisomers including compound 22)

3-Methyl-butyric acid 1-(3-hydroxy-octyl)-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-yl ester (all possible stereoisomers including compound 23)

Cyclopropanecarboxylic acid 1-(3-hydroxy-octyl)-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-yl ester (all possible stereoisomers including compound 24)

[2-Ethoxycarbonyloxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid methyl ester (all possible stereoisomers including compound 25)

[2-Acetoxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid methyl ester (all possible stereoisomers including compound 26)

Succinic acid ethyl ester 1-(3-hydroxy-octyl)-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-yl ester (all possible stereoisomers including compound 27)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid tert-butyl ester (all possible stereoisomers including compound 28)

3-{2-[2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetyl}-oxazolidin-2-one (all possible stereoisomers, including compound 29)

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 (all possible stereoisomers including compound 30)

[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 (all possible stereoisomers including compound 31)

[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 (all possible stereoisomers including 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 (all possible stereoisomers including compound 33)

[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 (all possible stereoisomers, including 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 (all possible stereoisomers, including 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 (all possible stereoisomers including 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 (all possible stereoisomers including compound 37)

[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 (all possible stereoisomers including compound 38)

[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 (all possible stereoisomers including compound 39)

[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 (all possible stereoisomers including compound 40)

[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 (all possible stereoisomers including compound 41)

[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 (all possible stereoisomers including compound 42)

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 (all possible stereoisomers including compound 43)

[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 (all possible stereoisomers including compound 44)

Cyclopentanecarboxylic acid 1-[2-(2-hydroxy-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)-ethyl]-hexyl ester (all possible stereoisomers, including compound 45)

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 (all possible stereoisomers including compound 46)

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 (all possible stereoisomers including compound 47)

Cyclopropanecarboxylic acid 1-[2-(2-hydroxy-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)-ethyl]-hexyl ester (all possible stereoisomers including compound 48)

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 (all possible stereoisomers including compound 49)

[1-(3-Cyclopentyloxycarbonyloxy-octyl)-2-hydroxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid methyl ester (all possible stereoisomers including compound 50)

{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 (all possible stereoisomers including compound 51)

[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 (all possible stereoisomers including compound 52)

[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 (all possible stereoisomers including compound 53)

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 (all possible stereoisomers including compound 54)

[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 (all possible stereoisomers including 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 (all possible stereoisomers including compound 56)

で表される化合物を提供し、
式中、
R₂はHおよびP₂からなる群より選択され;
R₂₀、R₂₁、R₂₂、R₂₃、R₂₄、R₂₅、R₂₆、R₂₇、R₂₈、R₂₉、R₃₀、R₃₁、R₃₂、R₃₃、R₃₄、R₃₅、およびR₃₆は独立してHおよび重水素からなる群より選択され;
L₁は-O-アルキレン-C(O)-、-O-アルキレン-OC(O)-、または結合からなる群より選択され;
P₂は

からなる群より選択され、
ここで、
mは1、2、3、または4であり;
R₁₄およびR₁₅は上記定義の通りであり;
R₁₄およびR₁₅は、それらが結合している原子と一緒になって、非置換であるかまたは独立してハロ、メチル、およびメトキシからなる群より選択される1個、2個、もしくは3個の置換基で置換されている、N、O、およびSより選択される1個または2個の環ヘテロ原子を組み入れていてもよい5員～7員環を形成してもよく;
R₁₆およびR₁₇はそれぞれの場合で独立してHまたはアルキルであり;
R₁₆およびR₁₇は、それらが結合している原子と一緒になって3員～6員環を形成してもよく;
R₁₈およびR₁₉は上記定義の通りであり;
R₁₄およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₄およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
式IIは、式IIの化合物の鏡像異性体、薬学的に許容される塩、溶媒和物、および多形体を含む。 Core Structures II and IIA
In another aspect, the present invention provides a compound of formula II:

and providing a compound represented by the formula:
In the formula,
_R2 is selected from the group consisting of H and _P2 ;
_R20 , _R21 , _R22 , _{R23 , R24, R25, R26, R27, R28, R29, R30, R31, R32 , R33 , R34 , R35 , and R36 are independently selected} from the group consisting of H and deuterium;
_L1 is selected from the group consisting of -O-alkylene-C(O)-, -O-alkylene-OC(O)-, or a bond;
_P2 is

is selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ are as defined above;
R ₁₄ and R ₁₅ together with the atom to which they are attached may form a 5- to 7-membered ring that may incorporate 1 or 2 ring heteroatoms selected from N, O, and 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 , at each occurrence, are independently H or alkyl;
R ₁₆ and R ₁₇ together with the atoms to which they are attached may form a 3- to 6-membered ring;
R ₁₈ and R ₁₉ are as defined above;
R ₁₄ and R ₁₈ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
Formula II includes enantiomers, pharma- ceutically acceptable salts, solvates, and polymorphs of compounds of Formula II.

In one embodiment, _R20 , _R21 , _R22 , _R23 , R24, _R25 , _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , R33, R34, _R35 , and _R36 are H. In one embodiment, at least one of _R20 , _{R21 , R22} , _R23 , _R24 , _R25 , _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , _{R33 , R34} , _R35 , and _R36 is deuterium _.

In one aspect, _L1 is selected from the group consisting of -O-alkyl-C(O)-, -O-alkyl-OC(O)-. In one aspect, _L1 is -O-alkylene-C(O)-. In one aspect, _L1 is -O-alkylene-OC(O)-. In one aspect, the alkylene group of claim 41 is a _C1 to _C5 alkylene group. In one aspect, the alkylene group of claim 41 is a _C1 alkylene group.

で表される請求項41に記載の化合物が提供され、
式中、L₁およびR₂は式IIで定義されたとおりである。 In one subembodiment of formula II, formula IIA:

The compound according to claim 41 is provided,
wherein _L1 and _R2 are as defined in formula II.

トレプロスチニル2-ヒドロキシラクトン（化合物57を含む、可能性のある全ての立体異性体）

[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸カルボキシメチルラクトン（化合物58を含む、可能性のある全ての立体異性体） Examples of Compounds of Formula II The following represent specific compounds of Formula II.

Treprostinil 2-hydroxylactone (all possible stereoisomers, including compound 57)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid carboxymethyl lactone (all possible stereoisomers, including compound 58)

で表される化合物を提供し、
式中、L₂は、-CH₂-、-CHMe-、-C(Me)₂-、および

からなる群より選択され、
ここで、
mは1、2、3、または4であり;
XはNR₁₄またはOであり;
R₁₄はH、アルキル、シクロアルキル、アルキルシクロアルキル、ハロアルキル、ヘテロアルキル、置換アルキル、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、置換アリール、置換ヘテロアリール、置換アリールアルキル、および置換ヘテロアリールアルキルからなる群より選択され;
R₁₆およびR₁₇はそれぞれの場合で独立してHまたはアルキルであり;
R₁₆およびR₁₇は、それらが結合している原子と一緒になって3員～6員環を形成してもよく; かつ
R₂₀、R₂₁、R₂₂、R₂₃、R₂₄、R₂₅、R₂₆、R₂₇、R₂₈、R₂₉、R₃₀、R₃₁、R₃₂、R₃₃、R₃₄、R₃₅、およびR₃₆は独立してHおよび重水素からなる群より選択され;
Zは-OH、-OR₁₁、-N(R₁₁)R₁₂、-SR₁₁、またはP₁であり;
R₁₁はアルキル、置換アルキル、シクロアルキル、置換シクロアルキル、ハロアルキル、ヘテロアルキル、置換ヘテロアルキル、シクロヘテロアルキル、置換シクロヘテロアルキル、アルキルシクロアルキル、置換アルキルシクロアルキル、アルキルシクロヘテロアルキル、置換アルキルシクロヘテロアルキル、アリール、置換アリール、アルキルアリール、置換アルキルアリール、ヘテロアリール、置換ヘテロアリール、アルキルヘテロアリール、または置換アルキルヘテロアリールであり;
R₁₂はH、ハロアルキル、ヘテロアルキル、シクロヘテロアルキル、アルキルシクロアルキル、アルキルシクロヘテロアルキル、アリール、またはヘテロアリールであり;
P₁は

からなる群より選択され、
ここで、
mは1、2、3、または4であり;
R₁₄およびR₁₅はそれぞれの場合で独立してH、アルキル、シクロアルキル、アルキルシクロアルキル、ハロアルキル、ヘテロアルキル、置換アルキル、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、置換アリール、置換ヘテロアリール、置換アリールアルキル、および置換ヘテロアリールアルキルからなる群より選択され;
R₁₄およびR₁₅は、それらが結合している原子と一緒になって、非置換であるかまたは独立してハロ、メチル、およびメトキシからなる群より選択される1個、2個、もしくは3個の置換基で置換されている、N、O、およびSより選択される1個または2個の環ヘテロ原子を組み入れていてもよい5員～7員環を形成してもよく;
R₁₈およびR₁₉はそれぞれの場合で独立して水素およびアルキルからなる群より選択され、該アルキルは非置換であるかまたはハロ、ヒドロキシ、アルコキシ、アミノ、チオ、メチルチオ、-C(O)OH、-C(O)O-(アルキル)、-CONH₂、アリール、およびヘテロアリールからなるリストより選択される1個の置換基で置換されており、該アリールまたはヘテロアリールは非置換であるかまたはアルキル、ハロ、ハロアルキル、ヒドロキシ、アルコキシ、およびハロアルコキシからなるリストより置換されており;
R₁₄およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₄およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₅およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₅およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
式IIIは、式IIIの化合物の鏡像異性体、薬学的に許容される塩、溶媒和物、および多形体を含む。 Core Structure III
In one embodiment, the present invention provides a compound of formula III:

and providing a compound represented by the formula:
In the formula, _L2 is _-CH2- , -CHMe-, -C(Me) _2- , and

is selected from the group consisting of
here,
m is 1, 2, 3, or 4;
X is _NR14 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 , at each occurrence, are independently H or alkyl;
R ₁₆ and R ₁₇ together with the atoms to which they are attached may form a 3- to 6-membered ring; and
_R20 , _R21 , _R22 , _{R23 , R24, R25, R26, R27, R28, R29, R30, R31, R32 , R33 , R34 , R35 , and R36 are independently selected} from the group consisting of H and deuterium;
Z is -OH, -OR ₁₁ , -N(R ₁₁ )R ₁₂ , -SR ₁₁ , or P ₁ ;
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

is selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ , at each occurrence, are independently 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 ₁₄ and R ₁₅ together with the atom to which they are attached may form a 5- to 7-membered ring that may incorporate 1 or 2 ring heteroatoms selected from N, O, and 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 are each independently selected from the group consisting of hydrogen and alkyl, where 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), -CONH ₂ , aryl, and heteroaryl, where the aryl or heteroaryl is unsubstituted or substituted from the list consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, and haloalkoxy;
R ₁₄ and R ₁₈ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₅ and R ₁₈ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₅ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
Formula III includes enantiomers, pharma- ceutically acceptable salts, solvates, and polymorphs of compounds of Formula III.

からなる群より選択される。 In one embodiment, _L2 is

is selected from the group consisting of:

In one embodiment, at least one of _R20 , _R21 , _R22 , _R23 , _{R24 , R25} , _R26 , R27, _R28 , _R29 , _R30 , _R31 , _R32 , _R33 , _R34 , _R35 , and _R36 is deuterium or they are all hydrogen.

で表される化合物を含み、
式中、ZおよびL₂は式IIIで定義されたとおりである。 One particular subembodiment of formula III is formula IIIA:

The compound represented by the formula:
wherein Z and _L2 are as defined in formula III.

[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸メチルエステル2,3-マレイン酸塩（化合物59を含む、可能性のある全ての立体異性体） Examples of Compounds of Formula III The following compounds represent specific examples of compounds of formula III.

[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 (all possible stereoisomers, including compound 59)

で表される化合物であり、式中、L₁基は式IIとは異なって、R₁よりもむしろR₂に結合し、
R₁はHおよびP₂からなる群より選択され;
R₂₀、R₂₁、R₂₂、R₂₃、R₂₄、R₂₅、R₂₆、R₂₇、R₂₈、R₂₉、R₃₀、R₃₁、R₃₂、R₃₃、R₃₄、R₃₅、およびR₃₆は独立してHおよび重水素からなる群より選択され;
L₁は-O-アルキレン-C(O)-、-O-アルキレン-OC(O)-、および結合からなる群より選択され;
P₂は

からなる群より選択され、
ここで、
mは1、2、3、または4であり;
R₁₄およびR₁₅はそれぞれの場合で独立してH、アルキル、シクロアルキル、アルキルシクロアルキル、ハロアルキル、ヘテロアルキル、置換アルキル、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、置換アリール、置換ヘテロアリール、置換アリールアルキル、および置換ヘテロアリールアルキルからなる群より選択され;
R₁₄およびR₁₅は、それらが結合している原子と一緒になって、非置換であるかまたは独立してハロ、メチル、およびメトキシからなる群より選択される1個、2個、もしくは3個の置換基で置換されている、N、O、およびSより選択される1個または2個の環ヘテロ原子を組み入れていてもよい5員～7員環を形成してもよく;
R₁₆およびR₁₇はそれぞれの場合で独立してHまたはアルキルであり;
R₁₆およびR₁₇は、それらが結合している原子と一緒になって3員～6員環を形成してもよく;
R₁₈およびR₁₉はそれぞれの場合で独立して水素およびアルキルからなる群より選択され、該アルキルは非置換であるかまたはハロ、ヒドロキシ、アルコキシ、アミノ、チオ、メチルチオ、-C(O)OH、-C(O)O-(アルキル)、-CONH₂、アリール、およびヘテロアリールからなるリストより選択される1個の置換基で置換されており、該アリールまたはヘテロアリールは非置換であるかまたはアルキル、ハロ、ハロアルキル、ヒドロキシ、アルコキシ、およびハロアルコキシからなるリストより置換されており;
R₁₄およびR₁₈は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
R₁₄およびR₁₉は、それらが結合している原子と一緒になって5員～7員環を形成してもよく;
式IVは、式IVの化合物の鏡像異性体、薬学的に許容される塩、溶媒和物、および多形体を含む。 Core Structure IV
Another embodiment is a compound of formula IV:

wherein, unlike in formula II, the _L1 group is attached to _R2 rather than to _R1 ;
_R1 is selected from the group consisting of H and _P2 ;
_R20 , _R21 , _R22 , _{R23 , R24, R25, R26, R27, R28, R29, R30, R31, R32 , R33 , R34 , R35 , and R36 are independently selected} from the group consisting of H and deuterium;
_L1 is selected from the group consisting of -O-alkylene-C(O)-, -O-alkylene-OC(O)-, and a bond;
_P2 is

is selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ , at each occurrence, are independently 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 ₁₄ and R ₁₅ together with the atom to which they are attached may form a 5- to 7-membered ring that may incorporate 1 or 2 ring heteroatoms selected from N, O, and 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 , at each occurrence, are independently H or alkyl;
R ₁₆ and R ₁₇ together with the atoms to which they are attached may form a 3- to 6-membered ring;
R ₁₈ and R ₁₉ are each independently selected from the group consisting of hydrogen and alkyl, where 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), -CONH ₂ , aryl, and heteroaryl, where the aryl or heteroaryl is unsubstituted or substituted from the list consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, and haloalkoxy;
R ₁₄ and R ₁₈ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
Formula IV includes the enantiomers, pharma- ceutically acceptable salts, solvates, and polymorphs of compounds of Formula IV.

In one embodiment, at least one of _R20 , _R21 , _R22 , _R23 , _{R24 , R25} , _R26 , R27, _R28 , _R29 , _R30 , _R31 , _R32 , _R33 , _R34 , _R35 , and _R36 is deuterium or they are all hydrogen.

で表され、
式中、L₁およびR₁は式IVで定義されたとおりである。 In certain embodiments of formula IV, the compound has formula IVA:

It is expressed as
wherein _L1 and _R1 are as defined in formula IV.

Compounds of formula IV can be made and used using a similar approach to compounds of formula II.

に記載の化合物であり、
式中、
R₁₀₀およびR₂₀₀は独立してH、CONR₉₀₀R₁₀₀₀、CR₉₀₀R₁₀₀₀OCOP₃R₉₀₀R₁₀₀₀からなる群より選択され、R₉₀₀およびR₁₀₀₀は独立してH、アルキル、およびシクロアルキルより選択され、
R₃₀₀、R₄₀₀、R₅₀₀、R₆₀₀、R₇₀₀、およびR₈₀₀は独立してHおよび重水素からなる群より選択され、
XはO、NHR₁₂₀₀、またはSであり、
P₃はNまたはOであり、
R₁₁₀₀はハロアルキル、ヘテロアルキル、シクロヘテロアルキル、アルキルシクロアルキル、アルキルシクロヘテロアルキル、アリール、またはヘテロアリールであり;
R₁₂₀₀はハロアルキル、ヘテロアルキル、シクロヘテロアルキル、アルキルシクロアルキル、アルキルシクロヘテロアルキル、アリール、ヘテロアリールである。 Embodiments of Priority Provisional Application No. 61/751,608 One embodiment of the priority provisional application is a compound of the formula (IAA)

is a compound according to
In the formula,
R ₁₀₀ and R ₂₀₀ are independently selected from the group consisting of H, CONR ₉₀₀ R ₁₀₀₀ , CR ₉₀₀ R ₁₀₀₀ OCOP ₃ R ₉₀₀ R 1000 , R ₉₀₀ and _{R 1000 are} 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, or heteroaryl;
R ₁₂₀₀ is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl.

からなる群より選択される。 In one embodiment, R ₁₀₀ , R ₂₀₀ are H. In one embodiment, R ₃₀₀ , R ₄₀₀ , R ₅₀₀ , R ₆₀₀ , R ₇₀₀ , and R ₈₀₀ are H. In one embodiment, X is O. In one embodiment, R ₁₁₀₀ is

is selected from the group consisting of:

In one embodiment, X is NHR ₁₂₀₀ .

からなる群より選択される。 In one embodiment, R ₁₁₀₀ is

is selected from the group consisting of:

In one embodiment, X is O. In one embodiment, R ₃₀₀ , R ₄₀₀ , R ₅₀₀ , R ₆₀₀ , R ₇₀₀ , and R ₈₀₀ are H. In one embodiment, R ₁₁₀₀ is alkyl.

の化合物であり、
式中、
R₂₀₀₀は独立してH、CONR₉₀₀₀R₁₀₀₀₀、CR₉₀₀₀R₁₀₀₀₀OCOP₄R₉₀₀₀(R₁₀₀₀₀)からなる群より選択され、R₉₀₀₀およびR₁₀₀₀₀は独立してH、アルキル、およびシクロアルキルより選択され、
R₃₀₀₀、R₄₀₀₀、R₅₀₀₀、R₆₀₀₀、R₇₀₀₀、およびR₈₀₀₀は独立してHおよび重水素からなる群より選択され、
XはO、NR₁₂₀₀₀、またはSであり、
P₄はNまたはOであり、
R₁₂₀₀₀はハロアルキル、ヘテロアルキル、シクロヘテロアルキル、アルキルシクロアルキル、アルキルシクロヘテロアルキル、アリール、またはヘテロアリールであり、
nは1～7の整数であり、
ここで、式II(AA)の化合物には、式II(AA)の鏡像異性体、薬学的に許容される塩、溶媒和物、および多形体が含まれる。 Another embodiment of the priority provisional application is a compound of formula II(AA):

is a compound of
In the formula,
R ₂₀₀₀ is independently selected from the group consisting of H, CONR ₉₀₀₀ R ₁₀₀₀₀ , CR ₉₀₀₀ R ₁₀₀₀₀ OCOP ₄ R ₉₀₀₀ (R ₁₀₀₀₀ ), R ₉₀₀₀ and R ₁₀₀₀₀ are 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 , or S;
_P4 is N or O;
R ₁₂₀₀₀ is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl;
n is an integer from 1 to 7,
As used herein, compounds of formula II(AA) include enantiomers, pharma- ceutically acceptable salts, solvates, and polymorphs of formula II(AA).

を有する化合物であり、
式中、
R₁₁はハロアルキル、ヘテロアルキル、シクロヘテロアルキル、アルキルシクロアルキル、アルキルシクロヘテロアルキル、アリール、またはヘテロアリールであり、
式中、R₀₃、R₀₄、R₀₅、R₀₆、R₀₇、およびR₀₈は独立してHおよび重水素からなる群より選択され、
式中、XはO、-NR₀₁₂、またはSであり、
R₀₁₂はハロアルキル、ヘテロアルキル、シクロヘテロアルキル、アルキルシクロアルキル、アルキルシクロヘテロアルキル、アリール、またはヘテロアリールであり、
Yは、C=O、-CH₂-、-CHMe-、または-C(Me)₂-であり、
式III(AA)の化合物には、式III(AA)の鏡像異性体、薬学的に許容される塩、溶媒和物、および多形体が含まれる。 Another embodiment of the priority provisional application is a compound of formula III(AA):

is a compound having the formula
In the formula,
R ₁₁ is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl;
wherein R ₀₃ , R ₀₄ , R ₀₅ , R ₀₆ , R ₀₇ , and R ₀₈ are independently selected from the group consisting of H and deuterium;
wherein X is O, -NR ₀₁₂ , or S;
R ₀₁₂ is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl;
Y is C=O, _-CH2- , -CHMe-, or -C(Me) _2- ;
Compounds of formula III(AA) include enantiomers, pharma- ceutically acceptable salts, solvates, and polymorphs of formula III(AA).

Methods for Making Compounds of Formula I
Compounds of formula I, where _R1 and _R2 are H, can be synthesized according to scheme 1 starting from compounds of formula I, where Z is OH, _R1 is H, and _R2 is PG, which represents a protecting group as described in Protective Groups in Organic Synthesis by Greene and Wuts. 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 include or not include additives, including but not limited to DMF, HOSu, HOBT, or HOAT, and may include or 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, and/or acetonitrile. The activated acid may be isolated and purified or may be treated directly with the reagent 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, can be found in 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, R ₁ is H, and R ₂ is PG, is deprotected using deprotection conditions appropriate for the type of protecting group represented by PG to obtain the compound of formula I. Examples of suitable deprotection conditions can be found in Protective Groups in Organic Synthesis by Greene and Wuts.

Scheme 1

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 and _R2 are H using acylation conditions and reactive molecules ROH or RY where Y is a leaving group including but not limited to halogen, sulfonyl, phosphoryl, or acyl. When using reactive molecule ROH, the acylation conditions are similar to the coupling conditions described above. When using reactive molecule RY, the acylation conditions may be carried out in a suitable solvent or solvent mixture including but not limited to DCM, THF, DMF, dioxane, ethyl acetate, and/or acetonitrile with or without one or more nucleophilic or non-nucleophilic bases or additives including but not limited to DMAP, TEA, DIPEA, N-methylmorpholine, pyridine, and/or imidazole.

Scheme 2

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.

Scheme 3

Methods for Making Compounds of Formula II Compounds of formula II can be synthesized starting from compounds of formula I, where Z is OH and _R2 is PG as above, using lactonization conditions according to scheme 4. Examples of lactonization conditions can be found in Chemical Reviews (2007), 107, 239 and Beilstein Journal of Organic Chemistry (2012), 8, 1344, and include, but are not limited to, 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 reactions under 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/or toluene.

Scheme 4

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 and _R2 are H, by reacting with an activated carbonyl equivalent, including but not limited to, phosgene, carbonyldiimidazole, or 4-nitrophenyl chloroformate, in a suitable solvent or mixture of solvents, including but not limited to, DCM, THF, DMF, dioxane, ethyl acetate, acetonitrile, and/or toluene, 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.

Scheme 5

Pharmaceutical Compositions The compounds described herein can be used alone or in combination with other components known in the art. In particular, multi-component formulations can be prepared that are suitable for use in preventive and therapeutic treatments. 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.

In one embodiment, the compound is formulated in a matrix form that includes 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 molecule while stored in the reservoir. In one embodiment, the drug is formulated with an excipient material useful for enhancing the release, such as a water-swellable material that can help push the drug out of the reservoir and 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 into the site of topical administration or systemic delivery.

More specifically, to further control the release rate of the drug, the drug can be dispersed in a matrix material. This matrix material can be a "release system" as described in U.S. Pat. No. 5,797,898, and its degradability, dissolution, or dispersibility can provide a method for controlling the release rate of chemical molecules.

The release system can provide a timed release profile (e.g., pulsed release) when time variation in plasma levels is 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, from multiple reservoirs, or a combination thereof. For example, where 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 the single reservoir. Continuous release can be achieved by incorporating a release system through which molecules degrade, elute, or disperse over an extended period of time. Additionally, 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, for example, as described in U.S. Pat. No. 5,797,898.

The agent may be formulated with one or more pharma- ceutically 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 100-10,000 daltons (e.g., PEG 200, PEG 1450). In another embodiment, the polymer comprises polylactic acid (PLA), polyglycolic acid (PGA), copolymers thereof (PLGA), or ethyl-vinyl acetate (EVA) polymers. In yet another embodiment, the excipient material comprises a pharma- ceutically acceptable oil (e.g., sesame oil).

In one aspect, 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 such that the solvent does not dissolve the solid matrix form of the drug. The saturated solution acts as a non-solvent excipient material and substantially fills the pores and voids in the solid matrix.

In another embodiment, the excipient material comprises a pharma- ceutically acceptable perhalohydrocarbon or unsubstituted saturated hydrocarbon. See, for example, U.S. Patent No. 6,264,990 to Knepp et al., which describes anhydrous, aprotic, hydrophobic, non-polar 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.

In one embodiment, the pharma- ceutically acceptable excipient material includes dimethyl sulfoxide (DMSO), glycerin, or ethanol.

Mixtures of compounds described in formulas I, II, III, and IV may be used.

As described above, the pharmaceutical composition may include a treprostinil derivative or a pharma- ceutically acceptable salt, solvate, clathrate, or polymorph thereof and one or more pharma- ceutically acceptable carriers or excipients. The composition may also contain an additional therapeutic agent.

Pharmaceutically acceptable carriers and excipients include pharma- ceutically acceptable materials, vehicles, and substances. Non-limiting examples of excipients include liquid and solid fillers, diluents, binders, lubricants, glidants, surfactants, dispersants, disintegrants, emulsifiers, wetting agents, suspending agents, thickening agents, solvents, isotonicity agents, buffers, pH adjusters, absorption retarders, sweeteners, flavoring agents, coloring agents, stabilizers, preservatives, antioxidants, antibacterial agents, antibacterial agents, antifungal agents, adjuvants, encapsulating materials, and coating materials. The use of such excipients in pharmaceutical formulations is known in the art. Except where any conventional carrier or excipient is incompatible with the active ingredient, the present disclosure encompasses the use of conventional carriers and excipients in formulations containing treprostinil derivatives. See, e.g., Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (Philadelphia, Pennsylvania [2005]); Handbook of Pharmaceutical Excipients, 5th Ed., Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association (2005); Handbook of Pharmaceutical Additives, 3rd Ed., Ash and Ash, Eds., Gower Publishing Co. (2007); and Pharmaceutical Preformulation and Formulation, Gibson, Ed., CRC Press LLC (Boca Raton, Florida [2004]).

A suitable formulation may depend on a variety of factors, such as the route of administration selected. Potential routes of administration of pharmaceutical compositions containing treprostinil derivatives include, but are not limited to, oral, parenteral (including intramuscular, subcutaneous, intradermal, intravascular, intravenous, intraarterial, intramedullary, and intrathecal), intraperitoneal, and topical (including dermal/epidermal, transdermal, mucosal, transmucosal, intranasal (e.g., via nasal spray or nasal drops), intraocular (e.g., via eye drops), pulmonary (e.g., via inhalation), buccal, sublingual, rectal, and vaginal).

By way of example, formulations of the treprostinil derivative suitable for oral administration may be presented, for example, as capsules (including push-fit capsules and soft capsules), cachets, or tablets; as powders or granules; or as a bolus, lozenge, or paste. For example, push-fit capsules may contain a mixture of the treprostinil derivative with, for example, fillers (e.g., lactose), binders (e.g., starches), and lubricants (e.g., talc or magnesium stearate), and optionally, stabilizers. In soft capsules, the treprostinil derivative may be dissolved or suspended in a suitable liquid (e.g., fatty oils, liquid paraffin, or liquid polyethylene glycol), and stabilizers may be added.

Compositions for oral administration can also be formulated as solutions or suspensions in aqueous and/or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions. Dispersible powders or granules of the treprostinil derivative can be mixed with any suitable combination of aqueous liquids, organic solvents, and/or oils and any suitable excipients (e.g., any combination of dispersing agents, wetting agents, suspending agents, emulsifying agents, and/or preservatives) to form solutions, suspensions, or emulsions.

The treprostinil derivative may also be formulated for parenteral administration by injection or infusion. The formulation for injection or infusion may be in the form of a solution, suspension, or emulsion, for example, in an oily or aqueous medium, and may contain excipients such as suspending agents, dispersing agents, and/or stabilizers. For example, an aqueous or non-aqueous (e.g., oily) sterile injectable solution may contain the treprostinil derivative together with excipients such as antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the subject. An aqueous or non-aqueous sterile suspension may contain the treprostinil derivative together with excipients such as suspending and thickening agents, and optionally stabilizers, and agents that increase the solubility of the treprostinil derivative to allow the preparation of more concentrated solutions or suspensions. As another example, a sterile aqueous solution for injection or infusion (e.g., subcutaneous or intravenous) may contain the treprostinil derivative, sodium chloride, a buffer (e.g., sodium citrate), a preservative (e.g., m-cresol), and optionally a base (e.g., NaOH) and/or an acid (e.g., HCl) to adjust the pH.

For delayed or sustained release of the treprostinil derivative, the composition can be formulated as a depot that can be implanted or injected, for example, intramuscularly or subcutaneously, into the subject. The depot formulation can be designed to deliver the treprostinil derivative over a relatively long period of time, for example, at least about 1 week, 2 weeks, 3 weeks, 1 month, 1.5 months, 2 months, or more. For example, the treprostinil derivative can be formulated with polymeric materials, with hydrophobic materials (e.g., as an emulsion in oil), and/or with ion exchange resins, or as a poorly soluble derivative (e.g., a poorly soluble salt).

In some embodiments, the typical dosage form of the treprostinil derivative is formulated as a buccal or sublingual tablet or pill. Advantages of a buccal or sublingual tablet or pill include avoidance of first-pass metabolism and avoidance of gastrointestinal absorption. Also, the buccal or sublingual tablet or pill can be designed to provide a more rapid release of the treprostinil derivative for more rapid uptake of the treprostinil derivative into the systemic circulation. Buccal or sublingual tablets or pills may contain, in addition to a therapeutically effective amount of a treprostinil derivative, suitable excipients, including, but not limited to, any combination of fillers and diluents (e.g., mannitol and sorbitol), binders (e.g., sodium carbonate), humectants (e.g., sodium carbonate), disintegrants (e.g., crospovidone and croscarmellose sodium), lubricants (e.g., silicon dioxide [including colloidal silicon dioxide] and sodium stearyl fumarate), stabilizers (e.g., sodium bicarbonate), flavors (e.g., spearmint flavor), sweeteners (e.g., sucralose), and colors (e.g., yellow iron oxide).

Additionally, the treprostinil derivatives can be formulated for intranasal administration. Intranasal administration avoids first-pass metabolism and can introduce significant concentrations of the treprostinil derivative into the central nervous system, thereby reducing side effects. Intranasal formulations can include the treprostinil derivative along with excipients such as a solubility enhancer (e.g., propylene glycol), a humectant (e.g., mannitol or sorbitol), a buffer and water, and optionally a preservative (e.g., benzalkonium chloride), a mucoadhesive agent (e.g., hydroxyethylcellulose), and/or a penetration enhancer.

Additionally, the treprostinil derivatives can be formulated for administration by oral inhalation. Advantages of administration by inhalation include selective accumulation of the therapeutic agent in the lungs with relatively few systemic side effects. In certain embodiments, a sterile aqueous solution for oral inhalation contains the treprostinil derivative, sodium chloride, a buffer (e.g., sodium citrate), optionally a preservative (e.g., m-cresol), and optionally a base (e.g., NaOH) and/or an acid (e.g., HCl) to adjust pH.

The pharmaceutical compositions can be manufactured in any suitable manner known in the art, for example by conventional mixing, dissolving, suspending, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapment, or compressing processes.

The composition may be provided in a unit dosage form as a single dose. In the unit dosage form, all active and inactive ingredients are combined in a suitable system, and the ingredients do not need to be mixed to form a composition that is administered. The unit dosage form may contain an effective amount, or an appropriate fraction thereof, of the treprostinil derivative. Representative examples of unit dosage forms are tablets, capsules, or pills for oral ingestion. With respect to the contents of a pharmaceutical composition, the term "active ingredient" includes prodrugs.

Alternatively, the composition may be presented as a kit. In a kit, the active ingredient, excipients, and carrier (e.g., solvent) are provided in two or more separate containers (e.g., ampoules, vials, tubes, bottles, or syringes) that must be combined to form the composition to be administered. The kit may include instructions for preparing and administering the composition (e.g., a solution to be injected intravenously).

Topical Compositions Topical formulations applied to the skin or mucosa can be useful for transdermal or transmucosal administration of therapeutic agents into the blood for systemic distribution. Advantages of topical administration can include avoiding first-pass metabolism, avoiding gastrointestinal absorption, delivering a therapeutic agent with a relatively short biological half-life, providing a more controlled release of the therapeutic agent, effecting a more uniform plasma distribution of the therapeutic agent, and improving user compliance.

In general, and in addition to the disclosure regarding topical formulations elsewhere herein, compositions suitable for topical administration include, but are not limited to, liquid or semi-liquid formulations, such as sprays, gels, liniments, lotions, oil-in-water or water-in-oil emulsions, such as creams, foams, ointments, and pastes, and solutions or suspensions, such as drops (e.g., eye drops, nose drops, and ear drops). In some embodiments, the topical composition comprises a therapeutic agent dissolved, dispersed, or suspended in a carrier. The carrier can be in the form of, for example, a solution, suspension, emulsion, ointment, or gel base, and can contain, for example, petrolatum, lanolin, wax (e.g., beeswax), mineral oil, long chain alcohol, polyethylene glycol or polypropylene glycol, diluent (e.g., water and/or alcohol [e.g., ethanol or propylene glycol]), emulsifier, stabilizer, or thickener, or combinations thereof. The topical composition can include, or the topical formulation can be administered by, for example, a transdermal patch, a microneedle patch, or an iontophoretic device. A transdermal patch may, for example, include a microporous membrane made of suitable materials (e.g., cellulose nitrate or acetate, propylene, or polycarbonate), a skin adhesive, and a backing material. Topical compositions may deliver therapeutic agents transdermally (including transdermal and transmucosal delivery) by concentration gradients or activation mechanisms (e.g., ionospheres).

For illustrative purposes, representative types of topical compositions are described below.

Topical Compositions Comprising a Penetration Enhancer In some embodiments, the topical composition comprises a treprostinil derivative and a penetration enhancer. The composition may contain an additional therapeutic agent.

The penetration enhancer increases the permeability of the therapeutic agent through the skin or mucosa. In certain embodiments, the penetration enhancer is N-lauroyl sarcosine, sodium octyl sulfate, methyl laurate, isopropyl myristate, oleic acid, glyceryl oleate, or sodium lauryl sulfoacetate, or a combination thereof. In certain embodiments, the composition contains the penetration enhancer in an amount of about 1-20%, 1-15%, 1-10%, or 1-5% by weight/volume (w/v). To further enhance the ability of the therapeutic agent to penetrate the skin or mucosa, the composition may contain a surfactant, an azone-like compound, an alcohol, a fatty acid or fatty acid ester, or an aliphatic thiol.

The composition may further contain one or more additional excipients. Suitable excipients include, but are not limited to, solubilizers (e.g., _C2 - _C8 alcohols), humectants or humectants (e.g., glycerol [glycerin], propylene glycol, amino acids and their derivatives, polyamino acids and their derivatives, and pyrrolidone carboxylic acid and its salts and derivatives), surfactants (e.g., sodium laureth sulfate and sorbitan monolaurate), emulsifiers (e.g., cetyl alcohol and stearyl alcohol), thickeners (e.g., methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, and acrylic polymers), and formulation bases or carriers (e.g., polyethylene glycol as an ointment base). As non-limiting examples, the bases or carriers of the composition may include ethanol, propylene glycol, and polyethylene glycol (e.g., PEG 300), and optionally aqueous liquids (e.g., isotonic phosphate buffered saline).

Topical compositions may have any suitable form, such as solutions (e.g., eye, nose, or ear drops), suspensions, emulsions, creams, lotions, gels, ointments, pastes, jellies, foams, or sprays. In some embodiments, the compositions are applied to the skin or mucosa to cover a surface area of about 10-800 ^cm2 , 10-400 ^cm2 , or 10-200 ^cm2 . The compositions may be formulated, for example, as a transdermal or microneedle patch, for transdermal or transmucosal administration of a therapeutic agent to the systemic circulation.

Topical Composition Comprising a Penetration Enhancer and a Volatile Liquid In a further embodiment, the topical composition comprises a treprostinil derivative, a penetration enhancer, and a volatile liquid. The composition may contain an additional therapeutic agent.

The penetration enhancer increases the permeability of the therapeutic agent through the skin or mucosa. In some embodiments, the penetration enhancer is selected from the group consisting of _C8 - _C18 alkyl aminobenzoates (e.g., _C8 - _C18 alkyl p-aminobenzoates), _C8 - _C18 alkyl dimethylaminobenzoates (e.g., _C8 - _C18 alkyl p-dimethylaminobenzoates), C8- _{C18 alkyl} cinnamates, _C8 - _C18 alkyl methoxycinnamates (e.g., _C8 - _C18 alkyl p-methoxycinnamates), and _C8 - _C18 alkyl salicylates. In certain embodiments, the penetration enhancer is octyl salicylate, octyl p-dimethylaminobenzoate, or octyl p-methoxycinnamate, or a combination thereof.

The volatile liquid can be any volatile solvent that is skin or mucous membrane tolerant. In certain embodiments, the volatile liquid is a _C2 - _C5 alcohol or an aqueous solution thereof, such as ethanol or isopropanol or an aqueous solution thereof. Aerosol propellants (e.g., dimethyl ether) can be considered volatile liquids. In some embodiments, the volatile liquid functions as a carrier or vehicle for the composition.

The composition may contain a thickening agent. Non-limiting examples of thickening agents include cellulosic thickeners (e.g., ethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose), povidone, polyacrylic acid/polyacrylates (e.g., Carbopol® polymers), Sepigel® (polyacrylamide/isoparaffin/laureth-7), and the Gantrez® series of polymethylvinyl ether/maleic anhydride copolymers (e.g., butyl ester of PMV/MA copolymer Gantrez® A-425).

In some embodiments, the compositions contain about 0.1-5%, 0.5-5%, or 1-5% treprostinil derivative, about 1-20%, 1-15%, or 1-10% penetration enhancer, and about 40-98%, 45-95%, 50-90%, or 60-80% volatile liquid by weight. In further embodiments, the compositions may contain about 1-40%, 1-30%, 1-20%, or 5-20% water by weight, and/or about 0.1-15%, 0.5-10%, or 1-5% thickener.

By way of example, in certain embodiments, the topical spray composition contains about 0.1-5% w/v of a treprostinil derivative, about 2-10% w/v of octyl salicylate or octyl p-methoxycinnamate, and about 95% aqueous ethanol as a carrier. In further embodiments, the topical gel composition contains about 0.1-5% w/v of a treprostinil derivative, about 1-10% w/v of octyl salicylate or octyl p-methoxycinnamate, about 0.5-5% w/v of Carbopol® polyacrylic acid, and about 70% aqueous ethanol as a carrier, and optionally about 1-10% w/v of a basic solution (e.g., 0.1 N NaOH). In a further embodiment, the topical lotion composition contains about 0.1-5% w/v of the treprostinil derivative, about 1-10% w/v of octyl salicylate or octyl p-methoxycinnamate, about 1-5% w/v of ethylcellulose or hydroxypropylcellulose, and about 90% aqueous ethanol as a carrier.

The composition may further include other excipients such as a formulating agent (e.g., paraffin oil, silicone oil, vegetable oil, or fatty acid ester such as isopropyl myristate), a diluent, a cosolvent (e.g., acetone, or a glycol ether such as diethylene glycol monoethyl ether), an emulsifier, a surfactant (e.g., an ethoxylated fatty alcohol, glycerol monostearate, or a phosphate ester), a stabilizer, an antioxidant, or a preservative (e.g., a hydroxybenzoic acid ester), or a combination thereof. For example, a cosolvent and/or surfactant may be used to maintain a desired concentration of the therapeutic agent in the solution or suspension.

The topical composition may have any suitable form, such as a cream, lotion, gel, ointment, mousse, spray or aerosol, or any transdermal device (e.g., patch) that administers a drug by absorption through the skin or mucosa. In some embodiments, the topical composition is applied to the skin or mucosa to cover a surface area of about 10-800 ^cm2 , 10-400 ^cm2 , or 10-200 ^cm2 .

In yet another embodiment, the topical composition comprises a treprostinil derivative, a penetration enhancer, and at least one of a lipophilic solvent, a formulation base, and a thickener.In some embodiments, the composition comprises a lipophilic solvent and a formulation base, or the same substance can function as both a lipophilic solvent and a formulation base.In a further embodiment, the composition comprises a lipophilic solvent, a formulation base, and a thickener.The composition may comprise an additional therapeutic agent.

Penetration enhancers increase the permeability of therapeutic agents through the skin or mucosa. Non-limiting examples of penetration enhancers include dimethyl sulfoxide (DMSO), decyl methyl sulfoxide, laurocapram, pyrrolidones (e.g., 2-pyrrolidone and N-methyl-2-pyrrolidine), surfactants, alcohols (e.g., oleyl alcohol), polyethylene glycols (e.g., PEG 400), diethylene glycol monoethyl ether, oleic acid, and fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerol monooleate, and propylene glycol monooleate).

Non-limiting examples of lipophilic solvents include lipophilic alcohols (e.g., hexylene glycol, octyldodecanol, oleyl alcohol, and stearyl alcohol), polyethylene glycols (e.g., PEG 100, PEG 300, PEG 400, and PEG 3350), diethylene glycol monoethyl ether, polysorbates (e.g., Tween® 20-80), Labrasol®, fatty acid esters (e.g., isopropyl myristate and diisopropyl adipate), diethyl sebacate, propylene glycol monocaprylate, propylene glycol laurate, mono- and diglycerides (e.g., Capmul® MCM), medium chain triglycerides, caprylic/capric triglycerides, glyceryl monocaprylate, glyceryl mono-oleate, glyceryl mono-linoleate, glycerol oleate/propylene glycol, mineral oils, and vegetable oils.

Lipophilic solvents can also function as formulation bases or carriers. For example, polyethylene glycols (e.g., PEG 100 to PEG 3500, e.g., PEG 300, PEG 400, and PEG 3350) can function as lipophilic solvents and formulation bases.

The composition may also contain a hydrophilic solvent, such as a C ₁ -C ₅ alcohol (eg, ethanol, isopropanol, glycerin, propylene glycol, and 1,2-pentanediol) and/or water.

The composition may contain a thickening agent to increase the viscosity and/or physical stability of the composition. Examples of thickening agents include, but are not limited to, glycerin, stearyl alcohol, and polymers (e.g., polydimethylsiloxane [dimethicone] and Carbopol® polymers).

In some embodiments, the composition further comprises an antioxidant. Non-limiting examples of antioxidants include butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tocopherols (e.g., vitamin E and its esters), flavinoids, glutathione, ascorbic acid and its esters, DMSO, and chelating agents (e.g., EDTA and citric acid).

In certain embodiments, the topical composition comprises, in w/w ratios, about 0.1-5% or 0.5-5% of the treprostinil derivative, about 2-30% or 5-20% of a penetration enhancer, about 20-80% or 30-70% of a lipophilic solvent that may also function as a formulation base, about 0.1-10% or 1-7.5% of a thickener, and about 0.01-2% or 0.05-1% of an antioxidant. As a non-limiting example, the topical composition may contain the treprostinil derivative, PEG 400 and/or PEG 3350 as a lipophilic solvent and formulation base, diethylene glycol monoethyl ether, oleyl alcohol, and/or isopropyl myristate as a penetration enhancer, stearyl alcohol as a thickener, and BHT as an antioxidant.

Topical compositions may have any suitable formulation, such as a cream, lotion, gel, ointment, jelly, paste, or any transdermal device (e.g., patch) that administers a drug by absorption through the skin or mucosa.

Topical Composition Comprising a Penetration Enhancer and an Adhesive In a further embodiment, the topical composition comprises a treprostinil derivative, a penetration enhancer, and an adhesive. The composition may contain an additional therapeutic agent.

The penetration enhancer increases the permeability of the therapeutic agent through the skin or mucosa. For example, the penetration enhancer can be a fatty acid ester having a fatty acyl chain length of _C8 - _C20 or _C12 - _C18 and a _C1 - _C6 or _C2 - _C4 alcohol moiety (e.g., isopropanol). In certain embodiments, the penetration enhancer is isopropyl myristate or isopropyl palmitate. In some embodiments, the penetration enhancer is in an amount of about 0.1-20%, 0.5-15%, 1-15%, 2-12%, or 4-10% by weight of the composition or the skin contact layer of the transdermal patch.

The adhesive maintains contact of the topical composition with the skin or mucosa. Non-limiting examples of adhesives include acrylics/acrylates (e.g., polyacrylates, including polyalkyl acrylates and Duro-Tak® polyacrylates), polyvinyl acetates, ethylene vinyl acetate copolymers, polysiloxanes, polyurethanes, plasticized polyether block amide copolymers, natural and synthetic rubbers, plasticized styrene-butadiene rubber block copolymers (e.g., Duro-Tak® 87-6173), and mixtures thereof.

The topical composition may include one or more additional excipients. The additional excipients may be, for example, a diluent, an emollient, a plasticizer, or an agent that reduces irritation to the skin or mucous membranes, or a combination thereof.

In certain embodiments, the topical composition prior to application to the skin or mucous membranes is substantially free of water, tetraglycol (glycofurol), and/or hydrophilic organic solvents (eg, C ₁ -C ₅ alcohols).

The composition can administer a therapeutic agent transdermally (including transdermal and transmucosal administration) through a body surface or membrane, such as intact, unbroken skin or intact, unbroken mucosal tissue, into the systemic circulation.

In some embodiments, the topical composition is in the form of a transdermal patch that is applied to the skin or mucosa. The patch has a skin-contacting layer or mucosa-contacting layer (simply "skin-contacting layer") that is laminated or otherwise attached to a backing layer. The skin-contacting layer may be covered with a removable release liner before use to protect the skin-contacting surface and to keep it clean until the skin-contacting layer is applied to the skin or mucosa. The backing layer of the patch acts as a support for the skin-contacting layer and as a barrier to prevent loss of the therapeutic agent in the skin-contacting layer to the environment. The material of the backing layer is compatible with the therapeutic agent, the permeation enhancer, and the adhesive, and is minimally permeable to the components of the patch. The backing layer may be opaque to protect the components of the patch from degradation due to exposure to ultraviolet light. The backing layer is also capable of bonding to and supporting the adhesive layer, but is flexible enough to allow the patch to adapt to the movements of the subject. The material of the support layer can be, for example, a metal foil, a metal polyfoil, or a composite foil or film containing a polymer (e.g., polyester [such as polyester terephthalate] or aluminum vapor deposited polyester, polyethylene, polypropylene, polytetrafluoroethylene, polyethylene methyl methacrylate block copolymers, polyether block amide copolymers, polyurethane, polyvinylidene chloride, nylon, silicone elastomers, rubber-based polyisobutylene, styrene, or styrene-butadiene or styrene-isoprene copolymers). The release liner can be made of the same material as the support layer or can be a film coated with a suitable release surface.

Therapeutic Use of Treprostinil Derivatives In some embodiments, the compounds described herein are used to treat pulmonary hypertension.Accordingly, the present disclosure provides a method for treating pulmonary hypertension, comprising administering to a subject in need of treatment a therapeutically effective amount of a treprostinil derivative or its pharma-ceutically acceptable salt, solvate, clathrate, or polymorph.Treprostinil derivatives include prodrugs of treprostinil.An additional therapeutic agent may be administered to treat pulmonary hypertension.

Pulmonary hypertension is elevated blood pressure in the pulmonary vasculature, including the pulmonary arteries, veins, and capillaries. Thus, pulmonary hypertension includes pulmonary arterial hypertension (PAH) and pulmonary venous hypertension (PVH) (e.g., congestive heart failure). More broadly, pulmonary hypertension includes:
WHO Group I - Pulmonary arterial hypertension, including idiopathic PAH, hereditary PAH (e.g., BMPR2, ALK1, and endoglin [with or without hereditary hemorrhagic telangiectasia]), drug-induced and toxin-induced PAH, PAH associated with various conditions (e.g., connective tissue disease, HIV infection, portal hypertension, congenital heart disease, schistosomiasis, and chronic hemolytic anemia [e.g., sickle cell disease]), persistent pulmonary hypertension of the newborn, pulmonary veno-occlusive disease (PVOD), and pulmonary capillary hemangiomatosis (PCH);
WHO Class II - pulmonary hypertension due to left heart disease, including systolic dysfunction, diastolic dysfunction, and valvular heart disease;
WHO Group III - Pulmonary hypertension due to lung disease and/or hypoxia, including chronic obstructive pulmonary disease (COPD), interstitial lung disease, other lung diseases with mixed restrictive and obstructive disorders, sleep-disordered breathing, alveolar hypoventilation disorders, chronic exposure to high altitude, and developmental disorders;
WHO Group IV - Chronic Thromboembolic Pulmonary Hypertension (CTEPH); and
WHO Group V - Pulmonary hypertension with unknown multifactorial mechanisms including hematological disorders (e.g. myeloproliferative disorders and splenectomy), systemic diseases (e.g. sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, and vasculitis), metabolic disorders (e.g. glycogen storage disease, Gaucher disease, and thyroid disease), and other causes (e.g. tumor obstruction, fibrosing mediastinitis, and chronic renal failure in the dialysis phase).

The therapeutically effective amount and frequency of administration of a treprostinil derivative for treating pulmonary hypertension may depend on a variety of factors, including the type of pulmonary hypertension, the severity of the condition, the mode of administration, the subject's age, weight, general health, sex, and diet, and the subject's response to treatment, and can be determined by the treating physician. In certain embodiments, the effective amount of treprostinil derivative per day is about 0.1-100 mg, 0.1-50 mg, 0.5-50 mg, 0.5-25 mg, 0.5-10 mg, 1-10 mg, or 1-5 mg, or a dose deemed appropriate by the treating physician, which may be administered in single or divided doses. In further embodiments, the effective amount of treprostinil derivative per day is about 0.001-2 mg/kg body weight, 0.005-1 mg/kg body weight, 0.01-0.5 mg/kg body weight, or 0.01-0.1 mg/kg body weight, or a dose deemed appropriate by the treating physician.

In some embodiments, the treprostinil derivative is administered once or multiple times daily (including once, twice, three times, or more daily), every other day, every third day, twice a week, three times a week, weekly, every two weeks, every three weeks, monthly, every six weeks, every two months, or every three months, or as frequently as the treating physician deems appropriate. In further embodiments, the treprostinil derivative is administered under a chronic dosing regimen. In certain embodiments, a therapeutically effective amount of the treprostinil derivative is administered for at least 2 weeks, 3 weeks, 1 month, 1.5 months, 2 months, 3 months, 4 months, 5 months, 6 months, or more.

The treprostinil derivative may be administered by any suitable route. Potential routes of administration of the treprostinil derivative include, but are not limited to, oral, parenteral (including intramuscular, subcutaneous, intradermal, intravascular, intravenous, intraarterial, intramedullary, and intrathecal), intraperitoneal, and topical (including dermal/epidermal, transdermal, mucosal, transmucosal, intranasal (e.g., by nasal spray or nasal drops), intraocular (e.g., by eye drops), intrapulmonary (e.g., by inhalation), buccal, sublingual, rectal, and vaginal). In certain embodiments, the treprostinil derivative is administered orally. In other embodiments, the treprostinil derivative is administered topically (e.g., dermal, transdermal, mucosal, transmucosal, intranasal, intrapulmonary (e.g., by inhalation), or sublingual). In further embodiments, the treprostinil derivative is administered parenterally (e.g., subcutaneously or intravenously, including by injection or infusion).

In some embodiments, a treprostinil derivative is used to treat PAH. In further embodiments, an additional therapeutic agent is used to treat PAH in combination with the treprostinil derivative. The additional therapeutic agent may be administered simultaneously with or sequentially (before or after) administration of the treprostinil derivative. When administered simultaneously with the treprostinil derivative, the additional therapeutic agent may be included in the same composition as the treprostinil derivative or may be included in a separate composition.

In certain embodiments, the additional therapeutic agent for the treatment of PAH is selected from the group consisting of:
vasoactive agents, including, but not limited to, prostaglandins and prostanoids (e.g., prostacyclin [prostaglandin _I2 ] and beraprost), endothelin receptor (e.g., ET _A and/or ET _B ) antagonists (e.g., ambrisentan, bosentan, sitaxsentan, and Actelion-1), phosphodiesterase type 5 (PDE5) inhibitors (e.g., sildenafil and tadalafil), soluble guanylate cyclase activators (e.g., cinaciguat and riociguat), and analogs and derivatives thereof;
Diuretics, including but not limited to thiazide diuretics (e.g., bendroflumethiazide, chlorothiazide, epitizide, and hydrochlorothiazide), thiazide-like diuretics (e.g., chlorthalidone, indapamide, and metolazone), and analogs and derivatives thereof;
Anticoagulants, including, but not limited to, vitamin K antagonists (e.g., acenocoumarol, atromentin, coumarin, phenindione, phenprocoumon, and warfarin), direct thrombin inhibitors (e.g., argatroban, dabigatran, hirudin, lepirudin, and bivalirudin), direct factor Xa inhibitors (e.g., apixaban, betrixaban, darexaban, edoxaban, erivaxaban, retaxaban, and rivaroxaban), heparin and its derivatives (e.g., unfractionated heparin, low molecular weight heparin, fondaparinux, and idraparinux), etc. (e.g., antithrombin, batroxobin, and hementin), and analogs, derivatives, and fragments thereof; and other types of therapeutic agents, including, but not limited to, cardiac glycosides (e.g., digoxin, acetyldigoxin, and digoxigenin) and oxygen therapy.

Further aspects are illustrated in the non-limiting examples below.

Four assays for the compounds were performed as follows. The results are shown in Table I.

(Test 1) Human liver microsomal stability assays were performed by incubating 0.5 uM test compound in 50 mM potassium phosphate buffer (pH 7.4) containing 0.5 mg microsomal protein per mL and 50 μL 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 for up to 45 min at 37°C. Aliquots were taken at 0, 5, 15, 30, and 45 min and quenched with an internal standard containing stop solution. A no-cofactor control was also prepared at 45 min. After incubation, samples were analyzed by LC-MS/MS. Analyte to internal standard peak area ratios were used to calculate intrinsic clearance. Intrinsic clearance (CL _int ) 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.

(Study 2) Human plasma stability assays were performed by incubating 0.5 uM test compound in heparinized human plasma at 37°C for up to 120 min. Aliquots were taken at 0, 5, 15, 30, 60, and 120 and 240 min and quenched with an internal standard containing stop solution. After incubation, samples were analyzed by LC-MS/MS. Half-lives were calculated using peak area ratios of analyte to internal standard. Formation of the active drug, Compound A, over time was also monitored by LC-MS/MS.

(Test 3) Human skin homogenate stability assays were performed similarly to the human liver microsome stability assays by incubating 0.5 uM test compound in 50 mM potassium phosphate buffer (pH 7.4) containing 0.5 mg human skin homogenate protein per mL and 50 μL 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 for up to 45 minutes at 37°C. Aliquots were taken at 0, 5, 15, 30, and 45 minutes and quenched with internal standard containing stop solution. A no-cofactor 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 (CL _int ) 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.

(Test 4) Human hepatocyte stability assay was performed by incubating 0.5 uM test compound at 37°C for up to 240 min. Cryopreserved human hepatocytes were obtained from Celsis IVT (Baltimore, MD). Cells were thawed according to vendor's instructions and suspended in William's Medium E at 500,000 cells/mL. Test compound was added to the cell suspension to initiate the reaction. Aliquots were taken at 0, 10, 30, 60, 120, and 240 min and quenched with an internal standard containing stop solution. After incubation, samples were analyzed by LC-MS/MS. Analyte to internal standard peak area ratio was used to calculate intrinsic clearance. Intrinsic clearance (CLint) was determined by nonlinear regression from the first-order elimination rate constant. Formation of the active drug, Compound A, over time was also monitored by LC-MS/MS.

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 = >60 minutes

Table I

Compounds 60-64 have the structures shown below.

SYNTHESIS EXAMPLES OF TREPROSTINIL DERIVATIVES The following representative syntheses are provided for compounds according to Formulas I, II, and III.

{2-ヒドロキシ-1-[3-(テトラヒドロ-ピラン-2-イルオキシ)-オクチル]-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ}-酢酸(94mg、0.2mmol)、トリフルオロエチルアミン(54mg、0.6mmol)、およびDIPEA(104μl、0.6mmol)のDMF(2ml)溶液をHATUで処理し、室温で24時間攪拌した。反応混合物をMTBEで希釈し、飽和炭酸水素ナトリウム溶液およびブラインで洗浄し、硫酸ナトリウムで乾燥させ、減圧濃縮した。残渣をシリカゲルクロマトグラフィーで精製した。この得られた材料をMeOH(4ml)に溶解させ、Amberlite IR120Hで処理し、24時間攪拌した。反応混合物を濾過し、濃縮して2-[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-N-(2,2,2-トリフルオロ-エチル)-アセトアミド(46mg)を油状物として得た。

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. This 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.

{2-ヒドロキシ-1-[3-(テトラヒドロ-ピラン-2-イルオキシ)-オクチル]-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ}-酢酸(47mg、0.1mmol)、3-メチル-2-ブタノール(26mg、0.3mmol)、およびDMAP(12mg、0.1mmol)のDCM(1ml)溶液をEDC(26mg、0.14mmol)で処理し、室温で24時間攪拌した。反応混合物をMTBEで希釈し、飽和炭酸水素ナトリウム溶液およびブラインで洗浄し、硫酸ナトリウムで乾燥させ、減圧濃縮した。残渣をシリカゲルクロマトグラフィーで精製した。この得られた材料をMeOH/THF(4ml)に溶解させ、Amberlite IR120Hで処理し、24時間攪拌した。反応混合物を濾過し、濃縮して[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸1,2-ジメチル-プロピルエステル(16mg)を油状物として得た。

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. This 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.

{2-ヒドロキシ-1-[3-(テトラヒドロ-ピラン-2-イルオキシ)-オクチル]-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ}-酢酸(47mg、0.1mmol)およびDMAP(26mg、0.2mmol)のDCM(1ml)溶液を2,4,6-トリクロロベンゾイルクロリド(27mg、0.11mmol)で処理し、室温で24時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム溶液およびブラインで洗浄し、硫酸ナトリウムで乾燥させ、減圧濃縮した。残渣をシリカゲルクロマトグラフィーで精製した。この得られた材料をMeOH/THF(4ml)に溶解させ、Amberlite IR120Hで処理し、24時間攪拌した。反応混合物を濾過し、濃縮してトレプロスチニル2-ヒドロキシラクトン(8mg)を油状物として得た。

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. This 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.

[2-ヒドロキシ-1-(3-ヒドロキシ-オクチル)-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-5-イルオキシ]-酢酸メチルエステル(32mg、0.06mmol)、DIPEA(31μl、0.18mmol)およびDMAP(1結晶)のDCM(2ml)溶液をシクロプロパンカルボニルクロリド(8μl、0.08mmol)で処理し、窒素下、室温で24時間攪拌した。反応混合物をMTBEで希釈し、飽和炭酸水素ナトリウム溶液およびブラインで洗浄し、硫酸ナトリウムで乾燥させ、減圧濃縮した。残渣をシリカゲルクロマトグラフィーで精製した。この得られた材料をMeOH/THF(4ml)に溶解させ、Amberlite IR120Hで処理し、24時間攪拌した。反応混合物を濾過し、濃縮してシクロプロパンカルボン酸1-(3-ヒドロキシ-オクチル)-5-メトキシカルボニルメトキシ-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-2-イルエステル(32mg)を油状物として得た。

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-hydroxy-octyl)-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. This 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.

アクリル酸1-[2-(2-アクリロイルオキシ-5-メトキシカルボニルメトキシ-2,3,3a,4,9,9a-ヘキサヒドロ-1H-シクロペンタ[b]ナフタレン-1-イル)-エチル]-ヘキシルエステル(51mg、0.1mmol)のクロロホルム(20ml)溶液を(PCy3)2Cl2Ru=CHPh(19mg、0.023mmol)のクロロホルム(3ml)溶液で処理し、室温で24時間攪拌する。TEA(1ml)を加え、溶液を減圧濃縮する。残渣をシリカゲルクロマトグラフィーで精製して標記化合物を得る。 Example 5: Synthesis of Compounds of Formula III

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) is 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) is added and the solution is concentrated under reduced pressure. The residue is purified by silica gel chromatography to give the title compound.

Further synthesis scheme is shown below.

Example 6 (Compound of Formula I)

Example 7 (Compound of Formula I)

Claims (15)

A transdermal patch comprising a topical composition comprising:
(1) A compound represented by the following formula (I), or a stereoisomer or a pharma- ceutically acceptable salt thereof:

In the formula,
_R20 , _R21 , _R22 , _{R23 , R24} , R25, _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , _R33 , _R34 , _R35 and _R36 are independently H or deuterium;
Z is -OH, _-OR11 , -N( _R11 ) _R12 , _-SR11 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

is selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ , at each occurrence, are independently selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl;
or
R ₁₄ and R ₁₅ together with the atom to which they are attached may form a 5- to 7-membered ring incorporating two ring heteroatoms selected from N, O and 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 , at each occurrence, are independently hydrogen or alkyl, wherein the alkyl is unsubstituted or substituted with one substituent selected from the group consisting of halo, hydroxy, alkoxy, amino, thio, methylthio, -C(O)OH, -C(O)O-(alkyl), -CONH ₂ , aryl, and heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with a substituent selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, and haloalkoxy;
R ₁₄ and R ₁₈ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
R ₁₅ and R ₁₈ may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring; and
R ₁₅ and R ₁₉ together with the atoms to which they are attached may form a 5- to 7-membered ring;
and,
_R1 and _R2 are independently H or _P2 ;
wherein at least one of _R1 and R2 _is P2, and _{P2 is}

is selected from the group consisting of
here,
m is 1, 2, 3, or 4; and
R ₁₄ , at each occurrence, is independently 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;
However, P2 _is not the following group:

here,
R ₁₄ and R ₁₅ , at each occurrence, are independently H or alkyl;
R ₁₈ and R ₁₉ , at each occurrence, are independently H or alkyl, wherein the alkyl is unsubstituted or substituted with one substituent selected from the group consisting of hydroxy, amino, thio, methylthio, -C(O)OH, -C(O)NH ₂ , aryl, and heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with hydroxy; and
R ₁₄ and R ₁₈ or R ₁₉ may form a 5-membered ring together with the atoms to which they are attached;
here,
said substituted groups are substituted with one or more substituents selected from halo, alkyl, alkenyl, alkynyl, aliphatic, aryl, heteroaryl, heterocyclyl or heterocycle, thiol, alkylthio, arylthio, alkylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, 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 and phosphonic acid;
said heteroalkyl is C ₁ -C ₃ alkyl substituted with hydroxyl , C ₁ -C ₅ alkyl substituted with sulfhydryl, and C ₁ -C ₅ alkyl substituted with amino , -CH ₂ CH ₂ OCH ₃ , -CH ₂ CH ₂ OCH ₂ CH ₃ , -CH ₂ CH ₂ OCH ₂ CH 2 OH, -CH ₂ CH ₂ N(CH ₃ ) ₂ , or -CH ₂ CH ₂ NHCH ₂ CH ₂ OH _;
said cycloheteroalkyl is azepanyl, azetidinyl, aziridinyl, imidazolidinyl, morpholinyl, oxazolidinyl, piperazinyl, piperidinyl, pyrazolidinyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, thiomorpholinyl, or α-methyl-1,3-dioxol-2-onyl;
said heteroaryl is pyrrolyl, pyrrolinyl, imidazolyl, tetrazolyl, indolyl, isoindolyl, benzimidazolyl, quinolyl, benzotriazolyl, tetrazolopyridazinyl, oxazolyl, oxadiazolyl, thiazolyl, or thiadiazolyl;
(2) a penetration enhancer; and
(3) At least one of a lipophilic solvent, a formulation base, and a thickening agent. With respect to the compound of formula (I),
(a) R ₁ is P ₂ and R ₂ is H; or
(b) R ₁ is H and R ₂ is P ₂ , or
(c) R ₁ is P ₂ and R ₂ is P ₂ ;
2. The transdermal patch of claim 1. With respect to the compound of formula (I),
(a) _P2 is

or
(b) _P2

That is,
3. The transdermal patch of claim 1 or 2. With respect to the compound of formula (I),
(a) R ₂₀ to R ₃₆ are each hydrogen; or
(b) at least one of R ₂₀ to R ₃₆ is deuterium;
The transdermal patch according to any one of claims 1 to 3. With respect to the compound of formula (I),
(a) Z is -OH, or
(b) Z is -OR ₁₁ ; or
(c) Z is -N( _R11 ) _R12 , or
(d) Z is _P1 ;
The transdermal patch according to any one of claims 1 to 4. The transdermal patch according to any one of claims 1 to 5, wherein the compound represented by formula (I) is a compound represented by the following formula (IA) or a stereoisomer or a pharma- ceutically acceptable salt thereof:

In the formula,
Z is -OH, -OR ₁₁ , or P ₁ ;
R ₁₁ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, or substituted alkylcycloheteroalkyl;
_P1 is

is selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ are independently selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl; or
R ₁₄ and R ₁₅ together with the atoms to which they are attached may form a 5- to 7-membered ring;
and,
_R1 and _R2 are independently H or _P2 ;
wherein at least one of _R1 and _R2 is _P2 , and _P2 is

wherein:
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. The transdermal patch of any one of claims 1 to 6, wherein the penetration enhancer is selected from the group consisting of N-lauroyl sarcosine, sodium octyl sulfate, methyl laurate, sodium lauryl sulfoacetate, dimethyl sulfoxide, decyl methyl sulfoxide, laurocapram, pyrrolidone, surfactants, azone-like compounds, alcohols, polyethylene glycol, diethylene glycol monoethyl ether, aliphatic thiols, fatty acids and fatty acid esters, and combinations thereof. The transdermal patch according to any one of claims 1 to 7, wherein the lipophilic solvent is selected from the group consisting of lipophilic alcohols, polyethylene glycols, diethylene glycol monoethyl ether, polysorbates, Labrasol®, fatty acid esters, diethyl sebacate, propylene glycol monocaprylate, propylene glycol laurate, mono- and diglycerides, medium chain triglycerides, caprylic/capric triglycerides, glyceryl monocaprylate, glyceryl mono-oleate, glyceryl mono-linoleate, glycerol oleate/propylene glycol, mineral oils and vegetable oils, and combinations thereof. The transdermal patch of any one of claims 1 to 8, wherein the thickening agent is selected from the group consisting of glycerin, stearyl alcohol and polymers, and combinations thereof. The transdermal patch according to any one of claims 1 to 9, wherein the topical composition further comprises a hydrophilic solvent. The transdermal patch of any one of claims 1 to 10, wherein the topical composition further comprises a solubilizer or emulsifier. The transdermal patch of any one of claims 1 to 11, wherein the topical composition further comprises a microporous membrane, a skin adhesive and a backing material. A transdermal patch according to any one of claims 1 to 12 for use in the treatment of a disease or condition selected from the group consisting of hypertension, pulmonary hypertension, ischemic disease, heart failure, conditions requiring anticoagulation, thrombotic microangiopathy, central retinal vein occlusion, atherosclerosis, inflammatory diseases, and cancer and other uncontrolled cell proliferation conditions. A transdermal patch for use as described in claim 13 for the treatment of pulmonary arterial hypertension. 15. The transdermal patch of any one of claims 1 to 14, wherein the topical composition comprises a penetration enhancer in an amount of 1-5%, 1-10%, 1-15% or 1-20% by weight/volume (w/v).