JP7138685B2 - 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, claiming priority from U.S. Provisional Application No. 61/751,608, filed January 11, 2013. Applications, each of which is hereby 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。 BACKGROUND Pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH) is a potentially fatal disease characterized by increased pulmonary arterial pressure and pulmonary vascular resistance. A need exists for better compounds and methods for treating PH and PAH. See, for example, US 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 various reasons and are commonly administered via intravenous or intramuscular routes. . Generally, these routes of administration require intervention by a physician or other medical professional and can be associated with considerable patient discomfort and potential local trauma. One example of such a compound is treprostinil and its derivatives, which are used in the treatment of PH and PAH. See, for example, International Publication No. 2005/007081 (Patent Document 2). Treprostinil (also referred to herein as Compound A) has the following structure:

have Treprostinil can exist as a salt (eg sodium salt).

Therefore, there is a clinical need to provide treprostinil with improved formulations and methods, eg, orally or transdermally. More specifically, there is a need for safe and effective methods to increase the systemic availability of treprostinil through administration of treprostinil or its derivatives (including prodrugs) or analogues.

Application of transdermal drug delivery technology to the administration of a wide variety of drugs has been suggested, and numerous technical journals and patents disclose various systems for accomplishing this. U.S. Pat. No. 3,598,122, U.S. Pat. No. 4,144,317, U.S. Pat. No. 4,201,211, U.S. Pat. 6), and U.S. Pat. No. 4,379,454 (Patent Document 7) are representative of various transdermal drug delivery systems in the prior art, which deliver controlled amounts of drug to patients over several hours. It has the ability to deliver over an extended period of time ranging from to several days. None of the above patents describe a transdermal delivery system intended to deliver treprostinil or its derivatives.

U.S. Patent Application Publication No. 2013/0274261 WO 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

Overview 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 aspect is the formula (I):

providing a compound represented by
_In the formula, _R20 , _R21 , _R22 , _R23 , _R24 , _R25 , _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , R33, _R34 , _R35 , and R is 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 alkylcyclo heteroalkyl, 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

selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ are each independently 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 are 1, 2, or 3 unsubstituted or independently selected from the group consisting of halo, methyl, and methoxy; may form a 5- to 7-membered ring optionally incorporating 1 or 2 ring heteroatoms selected from N, O, or S, substituted with 1 substituent;
R ₁₈ and R ₁₉ are in each instance independently selected from the list consisting of hydrogen and alkyl, said alkyl being unsubstituted or 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 may, together with the atoms to which they are attached, form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ may be taken together with the atoms to which they are attached to 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;
R ₁₅ and R ₁₉ may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring;
and R ₁ and R ₂ are independently H or P ₂ , and at least one of R ₁ and R ₂ is P ₂ ,
_P2 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 are 1, 2, or 3 unsubstituted or independently selected from the group consisting of halo, methyl, and methoxy; may form a 5- to 7-membered ring optionally incorporating 1 or 2 ring heteroatoms selected from N, O, or S, substituted with 1 substituent;
R ₁₆ and R ₁₇ are independently H or alkyl at each occurrence;
R ₁₆ and R ₁₇ may, together with the atoms to which they are attached, form a 3- to 6-membered ring;
R ₁₈ and R ₁₉ are as defined above;
R ₁₄ and R ₁₈ may, together with the atoms to which they are attached, form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring;
Formula I includes enantiomers, pharmaceutically 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 aspect, 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} R ₃₆ is independently H or deuterium;
Z is _-OR11 , -N( _R11 ) _R12 , _-SR11 , or _P1 ;
R ₁₁ is branched alkyl, haloalkyl, halocycloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, bicycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl , alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, or substituted alkylheteroaryl;
R ₁₂ is H, branched alkyl, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl;
_P1 is

selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ are each independently 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 are 1, 2, or 3 unsubstituted or independently selected from the group consisting of halo, methyl, and methoxy; may form a 5- to 7-membered ring optionally incorporating 1 or 2 ring heteroatoms selected from N, O, or S, substituted with 1 substituent;
R ₁₈ and R ₁₉ are in each instance independently selected from the list consisting of hydrogen and alkyl, said alkyl being unsubstituted or 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 may, together with the atoms to which they are attached, form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ may be taken together with the atoms to which they are attached to 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;
R ₁₅ and R ₁₉ may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring;
and R ₁ and R ₂ are independently H or P ₂ ,
_P2 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 are 1, 2, or 3 unsubstituted or independently selected from the group consisting of halo, methyl, and methoxy; may form a 5- to 7-membered ring optionally incorporating 1 or 2 ring heteroatoms selected from N, O, or S, substituted with 1 substituent;
R ₁₆ and R ₁₇ are independently H or alkyl at each occurrence;
R ₁₆ and R ₁₇ may, together with the atoms to which they are attached, form a 3- to 6-membered ring;
R ₁₈ and R ₁₉ are as defined above;
R ₁₄ and R ₁₈ may, together with the atoms to which they are attached, form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring;
Formula I includes enantiomers, pharmaceutically 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 aspect, Formula II:

A compound represented by is provided,
During the ceremony,
_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} R ₃₆ is independently selected from the group consisting of H and deuterium;
L ₁ is selected from the group consisting of -O-alkylene-C(O)-, -O-alkylene-OC(O)-, or a bond;
_P2 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 are 1, 2, or 3 unsubstituted or independently selected from the group consisting of halo, methyl, and methoxy; may form a 5- to 7-membered ring optionally incorporating 1 or 2 ring heteroatoms selected from N, O, or S, substituted with 1 substituent;
R ₁₆ and R ₁₇ are independently H or alkyl at each occurrence;
R ₁₆ and R ₁₇ may, together with the atoms to which they are attached, form a 3- to 6-membered ring;
R ₁₈ and R ₁₉ are as defined above;
R ₁₄ and R ₁₈ may, together with the atoms to which they are attached, form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring;
Formula II includes enantiomers, pharmaceutically 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 aspect, the compound is of formula III:

is represented by
wherein L2 is _-CH2- , _{-CHMe-, -C(Me)2- ,} and

selected from the group consisting of
here,
m is 1, 2, 3, or 4;
X is NR ₁₄ or O;
R ₁₄ is H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl selected from the group consisting of;
R ₁₆ and R ₁₇ are independently H or alkyl at each occurrence;
R ₁₆ and R ₁₇ may, together with the atoms to which they are attached, form a 3- to 6-membered ring;
_R20 , _R21 , _R22 , _R23 , _R24 , _R25 , _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , _{R33, R34, R35 , and} R ₃₆ is independently selected from the group consisting of H and 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 alkylcyclo heteroalkyl, 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

selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ are each independently 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 are 1, 2, or 3 unsubstituted or independently selected from the group consisting of halo, methyl, and methoxy; may form a 5- to 7-membered ring optionally incorporating 1 or 2 ring heteroatoms selected from N, O, or S, substituted with 1 substituent;
R ₁₈ and R ₁₉ are in each instance independently selected from the group consisting of hydrogen and alkyl, said alkyl being unsubstituted or 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 may, together with the atoms to which they are attached, form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ may be taken together with the atoms to which they are attached to 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;
R ₁₅ and R ₁₉ may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring;
Formula III includes enantiomers, pharmaceutically 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 Formula IV:

providing a compound represented by
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} R ₃₆ is independently selected from the group consisting of H and deuterium;
L ₁ is selected from the group consisting of -O-alkylene-C(O)-, -O-alkylene-OC(O)-, or a bond;
_P2 is

selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ are each independently 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 are 1, 2, or 3 unsubstituted or independently selected from the group consisting of halo, methyl, and methoxy; may form a 5- to 7-membered ring optionally incorporating 1 or 2 ring heteroatoms selected from N, O, or S, substituted with 1 substituent;
R ₁₆ and R ₁₇ are independently H or alkyl at each occurrence;
R ₁₆ and R ₁₇ may, together with the atoms to which they are attached, form a 3- to 6-membered ring;
R ₁₈ and R ₁₉ are in each instance independently selected from the group consisting of hydrogen and alkyl, said alkyl being unsubstituted or 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 may, together with the atoms to which they are attached, form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring;
Formula IV includes enantiomers, pharmaceutically acceptable salts, solvates, and polymorphs of compounds of Formula IV.

Compositions are also provided, including compositions comprising at least one compound according to Formula I, II, III, or IV and at least one other ingredient. In one aspect, the composition is formulated for transdermal delivery. In another aspect, the composition is formulated for transdermal delivery via a patch. In one aspect, the composition may further comprise at least one solvent. In one aspect, the amount of compound according to Formula I, II, III, or IV is adapted to provide a delivery profile useful for human therapy. In one aspect, treatment is directed to 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 pharmaceutically useful motifs for specific uses, including therapeutic and prophylactic uses, eg, against PH and PAH. For example, drug delivery profiles may be tailored to specific uses.

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 use in transdermal drug delivery applications.
[Invention 1001]
Formula (I):

A compound represented by
_In the formula, _R20 , _R21 , _R22 , _R23 , _R24 , _R25 , _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , R33, _R34 , _R35 , and R is 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 alkylcyclo heteroalkyl, 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

selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ are each independently 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 are 1, 2, or 3 unsubstituted or independently selected from the group consisting of halo, methyl, and methoxy; may form a 5- to 7-membered ring optionally incorporating 1 or 2 ring heteroatoms selected from N, O, or S, substituted with 1 substituent;
R ₁₈ and R ₁₉ are in each instance independently selected from the group consisting of hydrogen and alkyl, said alkyl being unsubstituted or 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 may, together with the atoms to which they are attached, form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ may be taken together with the atoms to which they are attached to 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;
R ₁₅ and R ₁₉ may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring;
and R ₁ and R ₂ are independently H or P ₂ , and at least one of R ₁ and R ₂ is P ₂ ,
_P2 is

selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ are each independently 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 are 1, 2, or 3 unsubstituted or independently selected from the group consisting of halo, methyl, and methoxy; may form a 5- to 7-membered ring optionally incorporating 1 or 2 ring heteroatoms selected from N, O, or S, substituted with 1 substituent;
R ₁₆ and R ₁₇ are independently H or alkyl at each occurrence;
R ₁₆ and R ₁₇ may, together with the atoms to which they are attached, form a 3- to 6-membered ring;
R ₁₈ and R ₁₉ are in each instance independently selected from the group consisting of hydrogen and alkyl, said alkyl being unsubstituted or 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 may, together with the atoms to which they are attached, form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring;
Formula I includes enantiomers, pharmaceutically acceptable salts, polymorphs, and stereoisomers (e.g., enantiomers and diastereomers) of compounds of Formula I;
said compound.
[Invention 1002]
_A compound of the invention 1001 wherein _R1 is P2 and _R2 is H.
[Invention 1003]
_A compound of the invention 1001 wherein _R1 is H and _R2 is P2.
[Invention 1004]
_A compound of the invention 1001 wherein _R1 is _P2 and _R2 is P2.
[Invention 1005]
_P2 is

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

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

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

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

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

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

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

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

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

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

A compound of the present invention 1001 selected from the group consisting of:
[Invention 1016]
_R20 , _R21 , _R22 , _R23 , _R24 , _R25 , _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , _{R33, R34, R35 , and} R A compound of the invention 1001, wherein ₃₆ is H.
[Invention 1017]
_R20 , _R21 , _R22 , _R23 , _R24 , _R25 , _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , _{R33, R34, R35 , and} R Compounds of the invention 1001 wherein at least one of ₃₆ is deuterium.
[Invention 1018]
Compounds of Invention 1001 wherein Z is _-OR11 , _-N ( _R11 ) _R12 , or P1.
[Invention 1019]
Compounds of the invention ₁₀₀₁ , wherein Z is P1.
[Invention 1020]
Compounds of Invention 1001 wherein Z is _-OH , _-OR11 , -N( _R11 ) _R12 , or P1.
[Invention 1021]
Compounds of Invention 1001 wherein Z is -OH.
[Invention 1022]
A compound of invention 1001 wherein Z is not -OH and R ₁₁ is not unsubstituted or substituted benzyl.
[Invention 1023]
Formula (IA):

A compound represented by
During the ceremony,
Z is -OH, _-OR11 , or _P1 ;
R ₁₁ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkylcyclo is heteroalkyl;
_P1 is

selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ are each independently H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and selected from the group consisting of substituted heteroarylalkyl;
R ₁₄ and R ₁₅ may, together with the atoms to which they are attached, form a 5- to 7-membered ring;
and R ₁ and R ₂ are independently H or P ₂ , and at least one of R ₁ and R ₂ is P ₂ ,
_P2 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 pharmaceutically acceptable salts, polymorphs, and stereoisomers (e.g., enantiomers and diastereomers) of compounds of Formula IA;
A compound of the invention 1001.
[Invention 1024]
Formula (I):

is a compound of
_In the formula, _R20 , _R21 , _R22 , _R23 , _R24 , _R25 , _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , R33, _R34 , _R35 , and R is independently H or _deuterium ;
Z is _-OR11 , -N( _R11 ) _R12 , _-SR11 , or _P1 ;
R ₁₁ is branched alkyl, haloalkyl, halocycloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, bicycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl , alkylaryl, substituted alkylaryl, alkylheteroaryl, substituted alkylheteroaryl, heteroaryl, substituted heteroaryl;
R ₁₂ is H, branched alkyl, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl;
_P1 is

selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ are each independently 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 are 1, 2, or 3 unsubstituted or independently selected from the group consisting of halo, methyl, and methoxy; may form a 5- to 7-membered ring optionally incorporating 1 or 2 ring heteroatoms selected from N, O, or S, substituted with 1 substituent;
R ₁₈ and R ₁₉ are in each instance independently selected from the group consisting of hydrogen and alkyl, said alkyl being unsubstituted or 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 may, together with the atoms to which they are attached, form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ may be taken together with the atoms to which they are attached to 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;
R ₁₅ and R ₁₉ may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring;
and R ₁ and R ₂ are independently H or P ₂ ,
_P2 is

selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ are each independently 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 are 1, 2, or 3 unsubstituted or independently selected from the group consisting of halo, methyl, and methoxy; may form a 5- to 7-membered ring optionally incorporating 1 or 2 ring heteroatoms selected from N, O, or S, substituted with 1 substituent;
R ₁₆ and R ₁₇ are independently H or alkyl at each occurrence;
R ₁₆ and R ₁₇ may, together with the atoms to which they are attached, form a 3- to 6-membered ring;
R ₁₈ and R ₁₉ are in each instance independently selected from the group consisting of hydrogen and alkyl, said alkyl being unsubstituted or 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 may, together with the atoms to which they are attached, form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring;
Formula I includes enantiomers, pharmaceutically acceptable salts, polymorphs, and stereoisomers (e.g., enantiomers and diastereomers) of compounds of Formula I;
said compound.
[Invention 1025]
A compound of the invention 1024 wherein Z is _-OR11 .
[Invention 1026]
Compounds of Invention 1024 wherein Z is -N( _R11 ) _R12 .
[Invention 1027]
A compound of the invention 1024 wherein Z is -SR ₁₁ .
[Invention 1028]
_A compound of the invention 1024, wherein Z is P1.
[Invention 1029]
A compound of Invention 1024 wherein Z is OR ₁₁ and R ₁₁ is bicycloalkyl, alkylcycloalkyl, or alkylcycloheteroalkyl.
[Invention 1030]
A compound of Invention 1024 wherein R ₁₁ is haloalkyl.
[Invention 1031]
A compound of Invention 1024 wherein R ₁₁ is fluoroalkyl.
[Invention 1032]
_A compound of the invention 1024 wherein _R1 is hydrogen and _R2 is P2.
[Invention 1033]
_A compound of Invention 1024 wherein _R1 is P2 and _R2 is hydrogen.
[Invention 1034]
_A compound of Invention 1024 wherein _R1 is _P2 and _R2 is P2.
[Invention 1035]
A compound of Invention 1024 wherein R ₁ and R ₂ are each hydrogen.
[Invention 1036]
_R20 , _R21 , _R22 , _R23 , _R24 , _R25 , _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , _{R33, R34, R35 , and} R A compound of invention 1024 wherein ₃₆ is H.
[Invention 1037]
_R20 , _R21 , _R22 , _R23 , _R24 , _R25 , _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , _{R33, R34, R35 , and} R A compound of the invention 1024 wherein at least one of ₃₆ is deuterium.
[Invention 1038]
Formula (IAA):

is a compound of
During the ceremony,
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 and R ₉₀₀ and R ₁₀₀₀ are independently selected from H, alkyl and cycloalkyl. selected,
_R300 , _R400 , _R500 , _R600 , _R700 , and _R800 are independently selected from the group consisting of H and deuterium;
X is O, NHR ₁₂₀₀ , or S;
_P3 is N or O,
R ₁₁₀₀ is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, heteroaryl;
R ₁₂₀₀ is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, heteroaryl;
said compound.
[Invention 1039]
Compounds of Invention 1038 wherein R ₁₀₀ , R ₂₀₀ are H;
[Invention 1040]
Compounds of Invention 1039 wherein _R300 , _R400 , _R500 , _R600 , _R700 , and _R800 are H.
[Invention 1041]
A compound of invention 1040 wherein X is O.
[Invention 1042]
R ₁₁₀₀ is

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

A compound of the present invention 1043 selected from
[Invention 1045]
A compound of invention 1038 wherein X is O.
[Invention 1046]
Compounds of Invention 1045 wherein _R300 , _R400 , _R500 , _R600 , _R700 , and _R800 are H;
[Invention 1047]
Compounds of Invention 1046 wherein R ₁₁₀₀ is alkyl.
[Invention 1048]
Formula II:

A compound represented by
During the ceremony,
_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} R ₃₆ is independently selected from the group consisting of H and deuterium;
L ₁ is selected from the group consisting of -O-alkylene-C(O)-, -O-alkylene-OC(O)-, or a bond;
_P2 is

selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ are each independently 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 are 1, 2, or 3 unsubstituted or independently selected from the group consisting of halo, methyl, and methoxy; may form a 5- to 7-membered ring optionally incorporating 1 or 2 ring heteroatoms selected from N, O, or S, substituted with 1 substituent;
R ₁₆ and R ₁₇ are independently H or alkyl at each occurrence;
R ₁₆ and R ₁₇ may, together with the atoms to which they are attached, form a 3- to 6-membered ring;
R ₁₈ and R ₁₉ are in each instance independently selected from the group consisting of hydrogen and alkyl, said alkyl being unsubstituted or 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 may, together with the atoms to which they are attached, form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring;
Formula II includes enantiomers, pharmaceutically acceptable salts, polymorphs, and stereoisomers (e.g., enantiomers and diastereomers) of compounds of Formula II;
said compound.
[Invention 1049]
_R20 , _R21 , _R22 , _R23 , _R24 , _R25 , _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , _{R33, R34, R35 , and} R A compound of invention 1048 wherein ₃₆ is H.
[Invention 1050]
_R20 , _R21 , _R22 , _R23 , _R24 , _R25 , _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , _{R33, R34, R35 , and} R A compound of invention 1048 wherein at least one of ₃₆ is deuterium.
[Invention 1051]
A compound of Invention 1048 wherein L ₁ is -O-alkylene-C(O)-.
[Invention 1052]
A compound of Invention 1048 wherein L ₁ is -O-alkylene-OC(O)-.
[Invention 1053]
A compound of Invention 1048 wherein L ₁ is a bond.
[Invention 1054]
A compound of Invention 1048 wherein the alkylene group is a C ₁ -C ₅ alkylene group.
[Invention 1055]
A compound of Invention 1048 wherein the alkylene group is a C ₁ alkylene group.
[Invention 1056]
Formula IIA:

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

and an enantiomer of the compound of formula II(AA),
During the ceremony,
R ₂₀₀₀ is independently selected from the group consisting of H, CONR ₉₀₀₀ R ₁₀₀₀₀ , CR ₉₀₀₀ R ₁₀₀₀₀ OCOPR ₉₀₀₀ R ₁₀₀₀₀ , R ₉₀₀₀ and R ₁₀₀₀₀ are independently selected from H, alkyl, cycloalkyl;
_{R3000, R4000, R5000, R6000, R7000 , and R8000 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) is a stereoisomer (e.g., enantiomers and diastereomers) of Formula II(AA), a pharmaceutically acceptable salt of a compound of Formula II(a), and Formula II(AA ), including polymorphs of
Said compounds and said enantiomers.
[Invention 1058]
Formula III:

A compound represented by
where _L2 is

selected from the group consisting of
here,
m is 1, 2, 3, or 4;
X is NR ₁₄ or O;
R ₁₄ is from H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, substituted heteroarylalkyl selected from the group of;
R ₁₆ and R ₁₇ are independently H or alkyl at each occurrence;
R ₁₆ and R ₁₇ may be taken together with the atoms to which they are attached to 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} R ₃₆ is independently selected from the group consisting of H and 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 alkylcyclo heteroalkyl, 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

selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ are each independently 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 are 1, 2, or 3 unsubstituted or independently selected from the group consisting of halo, methyl, and methoxy; may form a 5- to 7-membered ring optionally incorporating 1 or 2 ring heteroatoms selected from N, O, or S, substituted with 1 substituent;
R ₁₈ and R ₁₉ are in each instance independently selected from the group consisting of hydrogen and alkyl, said alkyl being unsubstituted or 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 may, together with the atoms to which they are attached, form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ may be taken together with the atoms to which they are attached to 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;
R ₁₅ and R ₁₉ may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring;
Formula III includes stereoisomers (e.g., enantiomers and diastereomers), pharmaceutically acceptable salts, and polymorphs of compounds of Formula III;
said compound.
[Invention 1059]
_L2 is

A compound of the present invention 1058 selected from the group consisting of:
[Invention 1060]
_R20 , _R21 , _R22 , _R23 , _R24 , _R25 , _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , _{R33, R34, R35 , and} R A compound of invention 1058 wherein ₃₆ is H.
[Invention 1061]
_R20 , _R21 , _R22 , _R23 , _R24 , _R25 , _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , _{R33, R34, R35 , and} R A compound of invention 1058 wherein at least one of ₃₆ is deuterium.
[Invention 1062]
Formula IIIA:

A compound represented by
wherein Z and L2 _are as defined in Invention 1058;
A compound of the invention 1058.
[Invention 1063]
Formula III(AA):

and stereoisomers (e.g., enantiomers and diastereomers) of compounds of formula III(AA), and pharmaceutically acceptable salts of compounds of formula III(AA), and compounds of formula III(AA ), which is a polymorph of
During the ceremony,
R ₁₁ is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, heteroaryl;
_R03 , _R04 , _R05 , _R06 , _R07 , and _R08 are independently selected from the group consisting of H, deuterium;
X is O, _NR012 , S;
R ₀₁₂ is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, heteroaryl;
Y is C=O
Said compounds, and said stereoisomers, and said pharmaceutically acceptable salts, and said polymorphs.
[Invention 1064]
Formula IV:

A compound represented by
_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} R ₃₆ is independently selected from the group consisting of H and deuterium;
L ₁ is selected from the group consisting of -O-alkylene-C(O)-, -O-alkylene-OC(O)-, or a bond;
_P2 is

selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ are each independently 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 are 1, 2, or 3 unsubstituted or independently selected from the group consisting of halo, methyl, and methoxy; may form a 5- to 7-membered ring optionally incorporating 1 or 2 ring heteroatoms selected from N, O, or S, substituted with 1 substituent;
R ₁₆ and R ₁₇ are independently H or alkyl at each occurrence;
R ₁₆ and R ₁₇ may, together with the atoms to which they are attached, form a 3- to 6-membered ring;
R ₁₈ and R ₁₉ are in each instance independently selected from the group consisting of hydrogen and alkyl, said alkyl being unsubstituted or 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 may, together with the atoms to which they are attached, form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring;
Formula IV includes stereoisomers (e.g., enantiomers and diastereomers), pharmaceutically acceptable salts, and polymorphs of compounds of Formula IV;
said compound.
[Invention 1065]
Formula IVA:

A compound represented by
wherein L ₁ and R ₁ are as defined in the present invention 1064;
A compound of the invention 1064.
[Invention 1066]
A composition comprising at least one compound of the invention 1001-1065 and at least one other ingredient.
[Invention 1067]
A composition of the invention 1066 formulated for transdermal delivery.
[Invention 1068]
A composition of the invention 1066 formulated for transdermal delivery via a patch.
[Invention 1069]
A composition of the invention 1066 further comprising at least one solvent.
[Invention 1070]
A composition of invention 1063, wherein the amount of a compound of invention 1001-1065 is adapted to provide a delivery profile useful for human therapy.
[Invention 1071]
A compound selected from the group of, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or stereoisomer (e.g., enantiomer or diastereomer) thereof:

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

detailed description
Introduction
U.S. Priority Provisional Application No. 61/751,608, filed January 11, 2013, provides chemical formulas and claims, including Formulas I, II, and III, as well as Schemes I-4, Examples, and 14- The entirety of this document, including the structure table on page 16, is hereby incorporated by reference for all purposes.

Various prostacyclin analogues, including treprostinil, and methods of their use are known. For example, it promotes vasodilation, inhibits platelet aggregation and thrombus formation, stimulates thrombolysis, inhibits cell proliferation (including vascular remodeling), provides cytoprotection, prevents atherogenesis, and promotes angiogenesis. Can be used in guiding. Through their prostacyclin-mimetic mechanisms, these compounds can induce pulmonary hypertension, ischemic disease (e.g., peripheral vascular disease, Raynaud's phenomenon, scleroderma, myocardial ischemia, ischemic stroke, renal failure), and heart failure (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. pre-eclampsia), reproduction and delivery, cancer or other uncontrolled cell growth conditions, cell/tissue preservation, and other emerging therapeutic areas where prostacyclin treatment appears to have a beneficial role. It can be used in therapy. These compounds may also show additive or synergistic benefits in combination with other cardiovascular agents such as calcium channel blockers, phosphodiesterase inhibitors, endothelial antagonists, and antiplatelet agents.

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

Definitions Provided herein are lists of chemical groups represented by multiple formulas (eg, P ₁ , P ₂ , L ₁ , and L ₂ ). As used herein, these group listings also describe any combination of subgroups of chemical formulas in the group listing, as well as any single formula in the group listing.

The term "alkyl" means a monovalent saturated hydrocarbon radical. C ₁ -C ₈ alkyl refers to alkyl having 1 to 8 carbon atoms, including C ₁ -C ₃ alkyl, C ₁ -C ₅ alkyl, and C ₁ -C ₇ alkyl. Alkyl can be linear or branched. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

The term "haloalkyl" means a monovalent saturated hydrocarbon group attached 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. C ₁ -C ₈ heteroalkyl refers to alkyl having 1 to 8 carbon atoms and one or more heteroatoms selected from O, N, S, for example C ₁ -C ₃ -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 ring systems include fused ring systems, bridged ring systems, 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 ring in which 1-4 ring atoms are heteroatoms independently selected from the group consisting of O, N, and S. It means a formula, bicyclic, or tricyclic saturated ring system. The term "3- to 14-membered cycloheteroalkyl" means a cycloheteroalkyl having from 3 to 14 ring atoms. Examples of 3- to 14-membered cycloheteroalkyl include 3- to 10-membered cycloheteroalkyl and 3- to 6-membered cycloheteroalkyl. Bicyclic and tricyclic ring systems include fused ring systems, bridged ring systems, and spiro ring 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-dioxole- 2-onyl is mentioned.

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 terms "alkylheterocycloalkyl" or "alkylcycloheteroalkyl" refer to a cycloheteroalkyl group attached to an alkyl group. Specific 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 ₆ to ₁₄ ring carbon atoms. An example of C6 _{- C14} aryl is C6 _{- C10} aryl. More specific examples of aryl groups include phenyl, naphthyl, anthracyl, and phenanthryl.

The term "heteroaryl" means 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.; containing 1 to 5 nitrogen atoms. unsaturated fused heterocyclyl groups such as indolyl, isoindolyl, benzimidazolyl, quinolyl, benzotriazolyl, tetrazolopyridazinyl, etc.; unsaturated 3-membered containing 1-2 oxygen atoms and 1-3 nitrogen atoms; ~6-membered heteromonocyclic groups such as oxazolyl, oxadiazolyl, etc.; unsaturated fused heterocyclyl groups containing 1-2 oxygen atoms and 1-3 nitrogen atoms; 1-2 sulfur atoms and 1-3 unsaturated 3- to 6-membered heteromonocyclic groups containing 1 nitrogen atom, such as thiazolyl, thiadiazolyl, etc.; and unsaturated fused heterocyclyl groups containing 1-2 sulfur atoms and 1-3 nitrogen atoms. is mentioned.

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

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

Terms used herein such as alkyl, haloalkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylheterocycloalkyl, aryl, heteroaryl, alkylaryl, and alkylheteroaryl mean that they contain a ring. It will be appreciated that this may cover any form of formation. For example, optionally groups such as R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₁₈ , and R ₁₉ are combined with other R ₁₄ groups, R ₁₅ groups, R ₁₆ groups, R ₁₇ groups, R ₁₈ groups, and may form a ring with the R ₁₉ group.

The term "substituted" means that one or more hydrogen groups in a given structure are 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, arylamino Specific including but not limited to alkyl, hydroxyl, alkyloxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, carbonyl, carboxylic acid, sulfonic acid, phosphonic acid, aryl, heteroaryl, heterocyclic, and aliphatic is substituted with the substituent group of It will be appreciated that the substituents may be further substituted within the ordinary limits of those skilled in the art. A moiety or group may be substituted, ie, the group may or may not have one or more substituents.

The term "compound" as used herein is intended to also include salts, solvates, hydrates and polymorphs thereof. The specific descriptions of "salts," "solvates," "hydrates," or "polymorphs" in certain aspects of the invention described in this application mean that the term "compound" refers to these other forms. It shall not be construed as an intentional exclusion of these forms in other aspects of the invention to be used without recitation.

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. According to another preferred aspect, the compound is a pharmaceutically acceptable base or acid addition salt.

The term "pharmaceutically acceptable" means that, within the scope of sound medical judgment, the term "pharmaceutically acceptable" is used in contact with human and other mammalian tissues without undue toxicity, irritation, allergic reactions, etc. and commensurate with a reasonable profit/loss ratio. "Pharmaceutically acceptable salt" means any non-toxic salt that, upon administration to a recipient, is capable of directly or indirectly providing a compound of the invention or a prodrug of a compound. A "pharmaceutically acceptable counterion" is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.

Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and p-toluene. sulfonic acid, salicylic acid, tartaric acid, ditartaric 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 - organic acids such as bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, and related inorganic and organic acids. Thus, pharmaceutically acceptable salts include sulfates, pyrosulfates, hydrogen sulfates, sulfites, hydrogen sulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, 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, benzoic acid salt, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate acid, phenylbutyrate, citrate, lactate, beta-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene -2-sulfonates, mandelates, and similar salts. Preferred pharmaceutically acceptable acid addition salts include salts formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially salts formed with organic acids such as maleic acid.

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

The term "solvate" as used herein refers to stoichiometric or non-stoichiometric amounts of water, acetone, ethanol, methanol, dichloromethane, 2- It means a compound further comprising a solvent such as propanol.

Isotopes and Isotopic Abundances It will be recognized that some variation in natural isotopic abundance will occur in the synthesized compounds, depending on the origin of the chemicals used in the synthesis. Therefore, formulations of treprostinil inherently contain small amounts of deuterated isotopologues. Despite this variation, the concentrations of naturally-abundant stable isotopes of hydrogen and carbon are small and insignificant with respect to the degree of stable isotope substitution of the compounds of this invention. See, eg, Wada E et al, Seikagaku 1994, 66:15; Ganes LZ et al, Comp Biochem Physiol Mol Integr Physiol 1998, 119:725. In the compounds of this invention, when a particular position is designated as having deuterium, it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.015%. Yo. Generally, positions designated as having deuterium have a minimum isotopic enrichment factor of at least about 3000 (about 45% deuterium incorporation) at each atom designated as deuterium in the compound.

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

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

In the compounds of this invention any atom not specifically designated as a specific isotope is intended to represent any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", that position is 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% total of all other isotopologues, including deuterated forms. In certain aspects, the compound contains less than “X” % total of all other isotopologues, including forms that lack deuterium, where X is any number from 0 to 10 (e.g., 1, 0.5, 0.001). Compositions containing more than 10% total of all other isotopologues are referred to herein as "mixtures" and must comply with the parameters described below. These limitations regarding 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 compounds of Formula I or II, It does not include the isotopic composition of the hydrolyzable portion of the prodrug, or the isotopic composition of the counterion.

The term "isotopologue" refers to species that differ from specific compounds of the present invention only in the isotopic composition of their molecules or ions.

Stereoisomers The present invention encompasses all possible stereoisomers, including all possible diastereomers and enantiomers, of the compounds described herein, either by structures depicted or by nomenclature. It will be understood that it does not include only the specific stereoisomers shown. Some embodiments of the present invention pertain to specific stereoisomers as indicated in the structures depicted or by nomenclature.

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

to provide a compound represented by

At least two sub-embodiments 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 sub-embodiment of Formula I, _R20 , _R21 , _R22 , _R23 , _R24 , _R25 , R26, _R27 , _R28 , _R29 , _{R30, R31, R32 , R 33} , _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 alkylcyclo heteroalkyl, 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

selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ are each independently 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 are 1, 2, or 3 unsubstituted or independently selected from the group consisting of halo, methyl, and methoxy; may form a 5- to 7-membered ring optionally incorporating 1 or 2 ring heteroatoms selected from N, O, or S, substituted with 1 substituent;
R ₁₈ and R ₁₉ are in each instance independently selected from the group consisting of hydrogen and alkyl, said alkyl being unsubstituted or 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 may, together with the atoms to which they are attached, form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ may be taken together with the atoms to which they are attached to 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;
R ₁₅ and R ₁₉ may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring;
and R ₁ and R ₂ are independently H or P ₂ , and at least one of R ₁ and R ₂ is P ₂ ,
_P2 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, are 1, 2, or 3 unsubstituted or independently selected from the list consisting of halo, methyl, and methoxy; may form a 5- to 7-membered ring optionally incorporating 1 or 2 ring heteroatoms selected from N, O, or S, substituted with 1 substituent;
R ₁₆ and R ₁₇ are independently H or alkyl at each occurrence;
R ₁₆ and R ₁₇ may, together with the atoms to which they are attached, form a 3- to 6-membered ring;
R ₁₈ and R ₁₉ are as defined above;
R ₁₄ and R ₁₈ may, together with the atoms to which they are attached, form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring;
Formula I includes enantiomers, pharmaceutically acceptable salts, solvates, and polymorphs of compounds of Formula I. In this Formula I, in contrast to Formulas II, III, and IV described herein, the Z, R ₁ , and R ₂ groups are not attached to each other.

In one aspect, R ₁ is P ₂ and R ₂ 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 aspect, P2 is

selected from the group consisting of

からなる群より選択される。 _In another aspect, P2 is

selected from the group consisting of

からなる群より選択される。 _In another aspect, P2 is

selected from the group consisting of

からなる群より選択される。 _In another aspect, P2 is

selected from the group consisting of

からなる群より選択される。 _In another aspect, P2 is

selected from the group consisting of

からなる群より選択される。 _In another aspect, P2 is

selected from the group consisting of

からなる群より選択される。 _In another aspect, P2 is

selected from the group consisting of

からなる群より選択される。 _In another aspect, P2 is

selected from the group consisting of

からなる群より選択される。 _In another aspect, P2 is

selected from the group consisting of

からなる群より選択される。 _In another aspect, P2 is

selected from the group consisting of

からなる群より選択される。 _In another aspect, P2 is

selected from the group consisting of

_In one aspect, _R20 , _R21 , _R22 , _R23 , _R24 , _R25 , _R26 , _R27 , _R28 , _R29 , R30, _R31 , _{R32, R33, R34 , R 35} and R ₃₆ are H.

In one aspect, Z is -OR ₁₁ , -N(R ₁₁ )R ₁₂ , or P ₁ . In _another aspect, Z is P1. _{In another} aspect, Z is -OH, _-OR11 , -N(R11) _R12 , or P1. In another aspect, Z is -OH.

In one aspect 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 sub-embodiment of Formula I,
_R20 , _R21 , _R22 , _R23 , _R24 , _R25 , _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , _{R33, R34, R35 , and} R ₃₆ is independently H or deuterium;
Z is _-OR11 , -N( _R11 ) _R12 , _-SR11 , or _P1 ;
R ₁₁ is branched alkyl, haloalkyl, halocycloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, bicycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl alkyl, 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

selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ are each independently 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 are 1, 2, or 3 unsubstituted or independently selected from the group consisting of halo, methyl, and methoxy; may form a 5- to 7-membered ring optionally incorporating 1 or 2 ring heteroatoms selected from N, O, or S, substituted with 1 substituent;
R ₁₈ and R ₁₉ are in each instance independently selected from the group consisting of hydrogen and alkyl, said alkyl being unsubstituted or 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 may, together with the atoms to which they are attached, form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ may be taken together with the atoms to which they are attached to 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;
R ₁₅ and R ₁₉ may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring;
and R ₁ and R ₂ are independently H or P ₂ ,
_P2 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, are 1, 2, or 3 unsubstituted or independently selected from the list consisting of halo, methyl, and methoxy; may form a 5- to 7-membered ring optionally incorporating 1 or 2 ring heteroatoms selected from N, O, or S, substituted with 1 substituent;
R ₁₆ and R ₁₇ are independently H or alkyl at each occurrence;
R ₁₆ and R ₁₇ may, together with the atoms to which they are attached, form a 3- to 6-membered ring;
R ₁₈ and R ₁₉ are as defined above;
R ₁₄ and R ₁₈ may, together with the atoms to which they are attached, form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring;
Formula I includes enantiomers, pharmaceutically acceptable salts, solvates, and polymorphs of compounds of Formula I.

In one aspect, Z is _-OR11 . _In one aspect, Z is -N(R11) _R12 . In one aspect, Z is -SR ₁₁ . In _one aspect, Z is P1. In one aspect, Z is OR ₁₁ and R ₁₁ is bicycloalkyl, alkylcycloalkyl, or alkylcycloheteroalkyl. In _one aspect, Z is P1.

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

In one aspect, R ₁ is hydrogen or R ₂ is hydrogen. _In one aspect, _R1 is hydrogen and _R2 is P2. In one aspect, R ₁ is P ₂ and R ₂ is hydrogen. In one aspect, R ₁ and R ₂ are hydrogen. In one aspect, R ₁ and R ₂ are P ₂ .

_In one aspect, _R20 , _R21 , _R22 , _R23 , _R24 , _R25 , _R26 , _R27 , _R28 , _R29 , R30, _R31 , _{R32, R33, R34 , R 35} and at least one of R ₃₆ is deuterium.

_In one aspect, _R20 , _R21 , _R22 , _R23 , _R24 , _R25 , _R26 , _R27 , _R28 , _R29 , R30, _R31 , _{R32, R33, R34 , R 35} and R ₃₆ 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 sub-embodiment of Formula I is Formula (IA):

is a compound represented by
During the ceremony,
Z is -OH, _-OR11 , or _P1 ;
R ₁₁ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, or substituted alkyl is cycloheteroalkyl;
_P1 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 R ₁ and R ₂ are independently H or P ₂ , and at least one of R ₁ and R ₂ is P ₂ ,
_P2 is

selected from the group consisting of
here,
R ₁₄ and R ₁₅ are each independently H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and selected from the group consisting of substituted heteroarylalkyl;
R ₁₄ and R ₁₅ may, together with the atoms to which they are attached, form a 5- to 7-membered ring;
Formula IA includes enantiomers, pharmaceutically 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 (where 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 cyclopropylmethyl ester (Compound 1 all possible stereoisomers including

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-morpholin-4-yl [2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetate -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]-tetrahydro-furan-3-yl acetate 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]naphthalene-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]naphthalene-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 (including compound 15 all possible stereoisomers)

2,2-dimethyl-propyl [2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetate Ester (all possible stereoisomers including compound 16)

1,2-dimethyl-propyl [2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetate Ester (all possible stereoisomers, including compound 17)

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

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 compounds including compound 22) possible stereoisomers)

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

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

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

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

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

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

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-tetrazole -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-tri Fluoro-1,1-dimethyl-ethyl ester (all possible stereoisomers including compound 31)

1,2,2-trimethyl [2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid -propyl ester (all possible stereoisomers, including compound 32)

1,2,2-trimethyl [2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid -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]hepta -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]hepta -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]hepta -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]hepta -2-yl ester (all possible stereoisomers including compound 37)

2-Isopropyl-5-methyl [2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetate -cyclohexyl ester (all possible stereoisomers including compound 38)

1,7,7-trimethyl [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 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]naphthalene- 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]naphthalene-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]naphthalene-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]naphthalene-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)

1-[2-(2-Hydroxy-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)-ethyl] 2-methyl-butyric acid -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 (compound all possible stereoisomers including 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] octa-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] octa-3-yl ester (all possible stereoisomers, including compound 53)

1-{2-[5-Methoxycarbonylmethoxy-2-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyloxy)-2,3,3a,4,9, propionate 9a-Hexahydro-1H-cyclopenta[b]naphthalen-1-yl]-ethyl}-hexyl ester (all possible stereoisomers including compound 54)

1,2-dimethyl-propyl [2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetate Ester (all possible stereoisomers including compound 55)

1,2-dimethyl-propyl [2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetate 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 Structural Formulas II and IIA
In another aspect, the present invention provides a compound of formula II:

providing a compound represented by
During the ceremony,
_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} R ₃₆ is independently selected from the group consisting of H and deuterium;
L ₁ is selected from the group consisting of -O-alkylene-C(O)-, -O-alkylene-OC(O)-, or a bond;
_P2 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 are 1, 2, or 3 unsubstituted or independently selected from the group consisting of halo, methyl, and methoxy; may form a 5- to 7-membered ring optionally incorporating 1 or 2 ring heteroatoms selected from N, O, and S, substituted with 1 substituent;
R ₁₆ and R ₁₇ are independently H or alkyl at each occurrence;
R ₁₆ and R ₁₇ may, together with the atoms to which they are attached, form a 3- to 6-membered ring;
R ₁₈ and R ₁₉ are as defined above;
R ₁₄ and R ₁₈ may, together with the atoms to which they are attached, form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring;
Formula II includes enantiomers, pharmaceutically acceptable salts, solvates, and polymorphs of compounds of Formula II.

_In one aspect, _R20 , _R21 , _R22 , _R23 , _R24 , _R25 , _R26 , _R27 , _R28 , _R29 , R30, _R31 , _{R32, R33, R34 , R 35} and R ₃₆ are H. _In one aspect, _R20 , _R21 , _R22 , _R23 , _R24 , _R25 , _R26 , _R27 , _R28 , _R29 , R30, _R31 , _{R32, R33, R34 , R 35} and at least one of R ₃₆ is deuterium.

In one aspect, L ₁ is selected from the group consisting of -O-alkyl-C(O)-, -O-alkyl-OC(O)-. In one aspect, L ₁ is -O-alkylene-C(O)-. In one aspect, L ₁ is -O-alkylene-OC(O)-. In one aspect, the alkylene group of claim 41 is a C ₁ -C ₅ 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 sub-embodiment of Formula II, Formula IIA:

42. There is provided a compound of claim 41 represented by
wherein L ₁ and R ₂ 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 carboxymethyllactone (compound 58 all possible stereoisomers, including

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 structural formula III
In one aspect, the present invention provides a compound of formula III:

providing a compound represented by
wherein L2 is _-CH2- , _{-CHMe-, -C(Me)2- ,} and

selected from the group consisting of
here,
m is 1, 2, 3, or 4;
X is NR ₁₄ or O;
R ₁₄ is H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl selected from the group consisting of;
R ₁₆ and R ₁₇ are independently H or alkyl at each occurrence;
R ₁₆ and R ₁₇ may be taken together with the atoms to which they are attached to 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} R ₃₆ is independently selected from the group consisting of H and 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 alkylcyclo heteroalkyl, 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

selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ are each independently 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 are 1, 2, or 3 unsubstituted or independently selected from the group consisting of halo, methyl, and methoxy; may form a 5- to 7-membered ring optionally incorporating 1 or 2 ring heteroatoms selected from N, O, and S, substituted with 1 substituent;
R ₁₈ and R ₁₉ are in each instance independently selected from the group consisting of hydrogen and alkyl, said alkyl being unsubstituted or 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 may, together with the atoms to which they are attached, form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ may be taken together with the atoms to which they are attached to 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;
R ₁₅ and R ₁₉ may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring;
Formula III includes enantiomers, pharmaceutically acceptable salts, solvates, and polymorphs of compounds of Formula III.

からなる群より選択される。 _In one aspect, L2 is

selected from the group consisting of

_In one aspect, _R20 , _R21 , _R22 , _R23 , _R24 , _R25 , _R26 , _R27 , _R28 , _R29 , R30, _R31 , _{R32, R33, R34 , R 35} , and at least one of R ₃₆ is deuterium, or they are both 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 sub-embodiment of Formula III is Formula IIIA:

including a compound represented by
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-malein acid salt (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 structural formula IV
Another embodiment is Formula IV:

wherein the L1 group is attached to _R2 rather _{than R1} , unlike Formula II;
_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} R ₃₆ is independently selected from the group consisting of H and deuterium;
L ₁ is selected from the group consisting of -O-alkylene-C(O)-, -O-alkylene-OC(O)-, and a bond;
_P2 is

selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ are each independently 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 are 1, 2, or 3 unsubstituted or independently selected from the group consisting of halo, methyl, and methoxy; may form a 5- to 7-membered ring optionally incorporating 1 or 2 ring heteroatoms selected from N, O, and S, substituted with 1 substituent;
R ₁₆ and R ₁₇ are independently H or alkyl at each occurrence;
R ₁₆ and R ₁₇ may, together with the atoms to which they are attached, form a 3- to 6-membered ring;
R ₁₈ and R ₁₉ are in each instance independently selected from the group consisting of hydrogen and alkyl, said alkyl being unsubstituted or 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 may, together with the atoms to which they are attached, form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring;
Formula IV includes enantiomers, pharmaceutically acceptable salts, solvates, and polymorphs of compounds of Formula IV.

_In one aspect, _R20 , _R21 , _R22 , _R23 , _R24 , _R25 , _R26 , _R27 , _R28 , _R29 , R30, _R31 , _{R32, R33, R34 , R 35} , and at least one of R ₃₆ is deuterium, or they are both 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 is of Formula IVA:

is represented by
wherein L ₁ and R ₁ are as defined in Formula IV.

Compounds of Formula IV can be made and used using similar approaches 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。 Aspects of Priority Provisional Application No. 61/751,608 One aspect of the priority provisional application is the formula (IAA)

is a compound according to
During the ceremony,
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 and R ₉₀₀ and R ₁₀₀₀ are independently selected from H, alkyl and cycloalkyl. selected,
_R300 , _R400 , _R500 , _R600 , _R700 , and _R800 are independently selected from the group consisting of H and deuterium;
X is O, NHR ₁₂₀₀ , or S;
_P3 is N or O,
R ₁₁₀₀ is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl;
R ₁₂₀₀ is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, heteroaryl.

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

selected from the group consisting of

In one aspect, X is NHR ₁₂₀₀ .

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

selected from the group consisting of

In one aspect, X is O. In one aspect, R ₃₀₀ , R ₄₀₀ , R ₅₀₀ , R ₆₀₀ , R ₇₀₀ , and R ₈₀₀ are H. In one aspect, 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 aspect of the provisional priority application is Formula II(AA):

is a compound of
During the ceremony,
_R2000 is independently selected from the group _consisting of _H , _{CONR9000R10000} , _{CR9000R10000OCOP4R9000 ( R10000} ), _R9000 and _R10000 are independently _selected from H, alkyl, and cycloalkyl is,
_{R3000, R4000, R5000, R6000, R7000 , and R8000 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, pharmaceutically 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 aspect of the provisional priority application is formula III(AA):

is a compound having
During the ceremony,
R ₁₁ is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl;
wherein _R03 , _R04 , _R05 , _R06 , _R07 , and _R08 are independently selected from the group consisting of H and deuterium;
where 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, pharmaceutically acceptable salts, solvates, and polymorphs of Formula III(AA).

Methods of Making Compounds of Formula I
Compounds of Formula I wherein R ₁ and R ₂ are H are compounds of Formula I wherein Z is OH, R ₁ is H and R ₂ is a protecting group as described in Greene and Wuts, Protective Groups in Organic Synthesis , according to Scheme 1. It can be synthesized starting from a compound of formula I which is PG represented. The carboxylic acid is activated using coupling conditions that include the use of activating agents including, but not limited to, EDC, DCC, DIC, BOP, HATU, HBTU, CDI, thionyl chloride, or oxalyl chloride. Coupling conditions may or may not include additives including but not limited to DMF, HOSu, HOBT, or HOAT, including DMAP, TEA, DIPEA, N-methylmorpholine, pyridine, and/or imidazole. It may or may not include, but is not limited to, one or more nucleophilic or non-nucleophilic bases or additives. 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 treated directly with reagent ZH. Alternatively, ZH may be present during the coupling conditions. Representative examples of coupling conditions and definitions of activators, 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, wherein 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. A compound of formula I is obtained. Examples of suitable deprotection conditions can be found in Greene and Wuts, Protective Groups in Organic Synthesis.

scheme 1

Compounds of Formula I where R ₁ = R ₂ or R ₁ is H can be prepared according to Scheme 2 starting from compounds of Formula I where R ₁ and R ₂ are H, under the acylation conditions, and Y is Synthesis can be achieved using reactive molecules ROH or RY that are leaving groups including, but not limited to, halogen, sulfonyl, phosphoryl, or acyl. When using the reactive molecule ROH, the acylation conditions are similar to the coupling conditions described above. When using the reactive molecule RY, the acylation conditions are one or more nucleophilic or non-nucleophilic, including but not limited to DMAP, TEA, DIPEA, N-methylmorpholine, pyridine, and/or imidazole. may or may not contain a base or additive, and 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.

scheme 2

Compounds of Formula I wherein R ₂ is H can be prepared according to Scheme 3 starting from compounds of Formula I wherein R ₁ is H and R ₂ is PG above followed by acylation using ROH or RY above. It can be synthesized using the conditions followed by deprotection conditions described above.

Scheme 3

Methods of Making Compounds of Formula II Compounds of Formula II are synthesized according to Scheme 4, starting from compounds of Formula I wherein Z is OH and _R2 is PG as described above, using lactonization conditions. be able to. Examples of lactonization conditions can be found in Chemical Reviews (2007), 107, 239 and Beilstein Journal of Organic Chemistry (2012), 8, 1344, 2,4,6-trichlorobenzoic anhydride, TEA, and DMAP; 4-nitrobenzoic anhydride, TEA, and DMAP; 2-chloro-1-methylpyridinium iodide and tributylamine; 2,2'-dipyridyldisulfide and triphenylphosphine; and all of the above coupling and acylation conditions. Examples include, but are not limited to, reactions. 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 are prepared according to Scheme 5, starting from compounds of Formula 1 where R ₁ and R ₂ are H, DCM, THF, DMF, dioxane, ethyl acetate, acetonitrile, and/or or one or more nucleophilic or non-nucleophilic agents including but not limited to DMAP, TEA, DIPEA, N-methylmorpholine, pyridine, and/or imidazole in a suitable solvent or solvent mixture including but not limited to toluene. It can be synthesized by reaction with activated carbonyl equivalents including, but not limited to, phosgene, carbonyldiimidazole, or 4-nitrophenyl chloroformate, in the presence or absence of a nuclear base or additive. .

scheme 5

Pharmaceutical Compositions The compounds described herein can be used alone or in combination with other ingredients known in the art. In particular, multi-component formulations adapted for use in prophylactic and therapeutic treatments can be prepared. Compositions can be in the form of, for example, solid formulations, liquid formulations, semi-solid formulations, solutions, suspensions, or emulsions. Water can be used as a formulating agent. Water may be in pure form or in combination with one or more excipients.

In one aspect, the compound is formulated in a matrix form comprising a matrix material in which the drug is housed 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 enhance the stability of the drug molecule while stored in the reservoir. In one aspect, the drug is formulated with excipient materials useful for facilitating release, such as water-swellable materials that can help push the drug out of the reservoir and through any tissue sac on the reservoir. Examples include hydrogels and osmogens known in the art. In another aspect, the drug is formulated with a penetration enhancer. In addition, penetration enhancers control drug release by facilitating transport of the drug through the skin into the site of topical administration or systemic delivery.

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

The release system can provide a timed release profile (e.g. pulsatile release), e.g., where time-varying plasma levels are desired, e.g., to enhance therapeutic efficacy, or where constant plasma levels are required. can provide a more continuous or consistent release profile. Pulsed release can be achieved from individual reservoirs, multiple reservoirs, or a combination thereof. For example, where each reservoir provides only a single pulse, multiple pulses (ie, pulsed discharge) are achieved by staggering the discharge 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 system and other materials into a single reservoir. Continuous release can be achieved by incorporating a release system through which the molecule degrades, dissolves, or disperses over an extended period of time. Furthermore, releasing several pulses of molecules in quick succession (“digital” release) can mimic continuous release. The active release systems described herein can be used alone or in combination with passive release systems, such as described in US Pat. No. 5,797,898.

Agents can be formulated with one or more pharmaceutically acceptable excipients. Representative examples include bulking agents, wetting agents, stabilizers, crystal growth inhibitors, antioxidants, antibacterial agents, preservatives, buffering agents (e.g. acids, bases), surfactants, drying agents, dispersing agents, osmotic agents. , binders (e.g. starch, gelatin), disintegrants (e.g. cellulose), lubricants (e.g. talc), diluents (e.g. lactose, dicalcium phosphate), coloring agents, lubricants (e.g. magnesium stearate, hydrogenated vegetable oils), and combinations thereof. In some aspects, the excipient is a wax or polymer. In one aspect, the polymer comprises polyethylene glycol (PEG), typically having a molecular weight of about 100-10,000 Daltons (eg, 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 aspect, the excipient material comprises a pharmaceutically acceptable oil (eg sesame oil).

In one aspect, the excipient material comprises a saturated drug solution. That is, excipient materials include solutions formed of drug dissolved in a solvent for the drug. This solution is saturated so that the solvent does not dissolve the solid matrix form of the drug. A saturated solution acts as a non-solvent excipient material and substantially fills the pores and voids in the solid matrix.

In another aspect, the excipient material comprises a pharmaceutically acceptable perhalohydrocarbon or unsubstituted saturated hydrocarbon. For example anhydrous liquids, aprotic liquids, hydrophobic liquids, 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 minerals See Knepp et al. US Pat. No. 6,264,990 where oils are described.

In one aspect, pharmaceutically acceptable excipient materials include dimethylsulfoxide (DMSO), glycerin, or ethanol.

Mixtures of compounds described in Formulas I, II, III, and IV can be used.

As described above, the pharmaceutical composition comprises a treprostinil derivative or a pharmaceutically acceptable salt, solvate, clathrate, or polymorph thereof and one or more pharmaceutically acceptable carriers or excipients. agents. The composition may contain additional therapeutic agents.

Pharmaceutically acceptable carriers and excipients include pharmaceutically 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. agents, solvents, tonicity agents, buffers, pH adjusters, absorption delaying agents, sweeteners, flavoring agents, coloring agents, stabilizers, preservatives, antioxidants, antibacterial agents, antibacterial agents, antifungal agents, Adjuvants, encapsulating materials, and coating materials are included. The use of such excipients in pharmaceutical formulations is known in the art. Except to the extent that 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]).

Proper formulation can depend on various factors such as the route of administration chosen. Potential routes of administration for pharmaceutical compositions comprising treprostinil derivatives include oral, parenteral (including intramuscular, subcutaneous, intradermal, intravascular, intravenous, intraarterial, intramedullary, and intrathecal), Intraperitoneal as well as topical (cutaneous/on the skin, 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 intravaginal).

By way of example, formulations of treprostinil derivatives suitable for oral administration are, for example, as capsules (including push-fit and soft capsules), cachets, or tablets; as powders or granules; Alternatively, it can be presented as a paste. For example, push-fit capsules can contain a mixture of a treprostinil derivative and, for example, fillers such as lactose, binders such as starches, and lubricants such as talc or magnesium stearate, and, optionally, stabilizers. . In soft capsules, the treprostinil derivative can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols, and stabilizers can 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 a treprostinil derivative are combined with aqueous liquids, organic solvents, and/or oils and any suitable excipients such as dispersing agents, wetting agents, suspending agents, emulsifying agents, and/or preservatives. ) can be mixed with any suitable combination to form a solution, suspension, or emulsion.

Treprostinil derivatives may also be formulated for parenteral administration by injection or infusion. Formulations for injection or infusion can be, for example, in the form of solutions, suspensions, or emulsions in oily or aqueous vehicles, and contain excipients such as suspending, dispersing, and/or stabilizing agents. can contain. For example, aqueous or non-aqueous (e.g. oily) sterile injectable solutions contain a treprostinil derivative together with excipients such as antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the subject. I can. Aqueous or non-aqueous sterile suspensions contain a treprostinil derivative, a suspending agent and a thickening agent, and optionally a stabilizer, and treprostinil to allow for the preparation of more highly concentrated solutions or suspensions. It may be included with an excipient such as an agent that increases the solubility of the derivative. As another example, a sterile aqueous solution for injection or infusion (e.g. subcutaneous or intravenous) contains a treprostinil derivative, sodium chloride, a buffering agent (e.g. sodium citrate), a preservative (e.g. m-cresol), and optionally It may contain a base (eg NaOH) and/or an acid (eg 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, eg, intramuscularly or subcutaneously into the subject. Depot formulations can be designed to deliver the treprostinil derivative over a relatively long period of time, such as at least about 1 week, 2 weeks, 3 weeks, 1 month, 1.5 months, 2 months, or longer. For example, a treprostinil derivative can be formulated with a polymeric material, with a hydrophobic material (eg, as an emulsion in oil), and/or with an ion exchange resin, or as a sparingly soluble derivative (eg, a sparingly soluble salt).

In some embodiments, a typical dosage form of a treprostinil derivative is formulated as a buccal or sublingual tablet or pill. Advantages of buccal or sublingual tablets or pills include avoidance of first-pass metabolism and avoidance of gastrointestinal absorption. Also, buccal or sublingual tablets or pills can be designed to provide 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 contain, in addition to a therapeutically effective amount of a treprostinil derivative, fillers and diluents (eg mannitol and sorbitol), binders (eg sodium carbonate), wetting agents (eg 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 (eg, sucralose), and coloring agents (eg, iron yellow) in any combination.

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

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

Pharmaceutical compositions may be formulated in any suitable manner known in the art, such as by conventional mixing, dissolving, suspending, granulating, dragee-making, wet-milling, emulsifying, encapsulating, entrapping, or compressing processes. can be manufactured.

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

Alternatively, the composition may be presented as a kit. In kits, 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) to form the composition to be administered. They must be combined for Kits can include instructions for preparing and administering the compositions (eg, solutions for intravenous injection).

Topical Compositions Topical formulations applied to the skin or mucous membranes can be useful for transdermal or transmucosal administration of therapeutic agents into the blood for systemic distribution. Advantages of local administration include avoidance of first-pass metabolism, avoidance of gastrointestinal absorption, delivery of therapeutic agents with relatively short biological half-lives, more controlled release of therapeutic agents, more uniform plasma administration of therapeutic agents. and improved user adaptability.

In addition to the disclosure of topical formulations generally and elsewhere herein, compositions suitable for topical administration include sprays, gels, liniments, lotions, creams, foams, ointments. and oil-in-water or water-in-oil emulsions, such as pastes, and liquid or semi-liquid formulations, such as solutions or suspensions, such as drops (e.g., eye drops, nose drops, and ear drops). include but are not limited to. In some aspects, topical compositions comprise 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, such as petrolatum, lanolin, waxes (such as beeswax), mineral oil, long chain alcohols, polyethylene glycols or polypropylene. Glycols, diluents (eg, water and/or alcohols [eg, ethanol or propylene glycol]), emulsifiers, stabilizers, or thickeners, or combinations thereof may be included. Topical compositions can include, for example, transdermal patches, microneedle patches, or iontophoretic devices, or topical formulations can be administered thereby. Transdermal patches can, for example, include a microporous membrane made of suitable material (eg, nitric acid or cellulose acetate, propylene, or polycarbonate), a skin adhesive, and a backing material. Topical compositions can deliver therapeutic agents transdermally (including transdermal and transmucosal) via a concentration gradient or mechanism of action (eg, ionospheres).

For purposes of illustration, 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 additional therapeutic agents.

Penetration enhancers increase the permeability of a therapeutic agent through the skin or mucous membranes. 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 combinations thereof. In certain embodiments, the composition contains a penetration enhancer in an amount of about 1-20%, 1-15%, 1-10%, or 1-5% on a weight/volume (w/v) ratio. To further enhance the ability of the therapeutic agent to penetrate the skin or mucous membranes, the composition may contain surfactants, azone-like compounds, alcohols, fatty acids or fatty acid esters, or fatty thiols.

The composition may further contain one or more additional excipients. Suitable excipients include solubilizers (eg C ₂ -C ₈ alcohols), humectants or humectants (eg glycerol [glycerin], propylene glycol, amino acids and their derivatives, polyamino acids and their derivatives, and pyrrolidone carboxylic acid and salts and derivatives thereof), 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 (eg, polyethylene glycol for ointment bases). As non-limiting examples, the base or carrier of the composition can include ethanol, propylene glycol, and polyethylene glycol (eg, PEG 300), and optionally aqueous liquids (eg, isotonic phosphate-buffered saline). .

Topical compositions include solutions (such as eye drops, nose drops, or ear drops), suspensions, emulsions, creams, lotions, gels, ointments, pastes, jellies, foams, Or it can have any suitable dosage form such as a spray. In some embodiments, the composition is applied to skin or mucosa to cover a surface area of about 10-800 cm ² , 10-400 cm ² , or 10-200 cm ² . The compositions may be formulated for transdermal or transmucosal administration of therapeutic agents to the systemic circulation, eg, as transdermal or microneedle patches.

Topical Compositions Comprising a Penetration Enhancer and a Volatile Liquid In a further aspect, the topical composition comprises a treprostinil derivative, a penetration enhancer, and a volatile liquid. The composition may contain additional therapeutic agents.

Penetration enhancers increase the permeability of a therapeutic agent through the skin or mucous membranes. In some embodiments, the penetration enhancer is C ₈ -C ₁₈ alkyl aminobenzoate (eg, C _{8 -C 18 alkyl p-aminobenzoate), C 8 -C 18 alkyl dimethylaminobenzoate} (eg, p-dimethylamino). C8 _{- C18} alkyl benzoate), C8 _{- C18} alkyl cinnamate, C8 _{- C18} alkyl methoxycinnamate (e.g. C8 _{- C18} alkyl p-methoxycinnamate), and C8 _{- C18} salicylate. selected from the group consisting of alkyl; 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 mucosa-resistant. In certain embodiments, the volatile liquid is a _{C2 -} C5 alcohol or aqueous solution thereof, such as ethanol or isopropanol or aqueous solution thereof. Aerosol propellants (eg dimethyl ether) can be considered volatile liquids. In some aspects, a volatile liquid serves as a carrier or medium for the composition.

The composition may contain a thickening agent. Non-limiting examples of thickeners include cellulosic thickeners (e.g., ethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose), povidone, polyacrylic acid/polyacrylates (e.g., Carbopol® polymers), Sepigel ( (Polyacrylamide/Isoparaffin/Laureth-7), as well as the Gantrez® series of polymethyl vinyl ether/maleic anhydride copolymers (e.g. PMV/MA copolymer Gantrez® A-425 butyl ester).

In some embodiments, the composition comprises about 0.1-5%, 0.5-5%, or 1-5% treprostinil derivative and about 1-20%, 1-15%, or 1-10% by weight of a penetration enhancer. %, and about 40-98%, 45-95%, 50-90%, or 60-80% volatile liquids. In further embodiments, the composition contains about 1-40%, 1-30%, 1-20%, or 5-20% water and/or about 0.1-15%, 0.5-10% thickener by weight. , or 1 to 5%.

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

The composition may contain formulating agents (e.g. paraffin oil, silicone oil, vegetable oil, or fatty acid esters such as isopropyl myristate), diluents, co-solvents (e.g. acetone or glycol ethers such as diethylene glycol monoethyl ether), emulsifiers, interfacial Other excipients such as active agents (eg, ethoxylated fatty alcohols, glycerol monostearate, or phosphate esters), stabilizers, antioxidants, or preservatives (eg, hydroxybenzoic acid esters), or combinations thereof. can contain For example, co-solvents and/or surfactants can be used to maintain a desired concentration of therapeutic agent in solution or suspension.

Topical compositions include creams, lotions, gels, ointments, mousses, sprays or aerosols, or any transdermal device (e.g., patch) that administers a drug by absorption through the skin or mucous membranes. can have any suitable dosage form of In some embodiments, topical compositions are applied to skin or mucous membranes to cover a surface area of about 10-800 cm ² , 10-400 cm ² , or 10-200 cm ² .

Topical Compositions Comprising a Penetration Enhancer and Another Excipient In a still further aspect, the topical composition comprises a treprostinil derivative, a penetration enhancer, and at least one of a lipophilic solvent, a formulation base, and a thickening agent. including. In some embodiments, the composition contains a lipophilic solvent and a formulation base, or the same substance can function as both the lipophilic solvent and the formulation base. In a further aspect, the composition contains a lipophilic solvent, a formulation base, and a thickening agent. The composition may contain additional therapeutic agents.

Penetration enhancers increase the permeability of a therapeutic agent through the skin or mucous membranes. Non-limiting examples of penetration enhancers include dimethylsulfoxide (DMSO), decylmethylsulfoxide, laurocapram, pyrrolidones (such as 2-pyrrolidone and N-methyl-2-pyrrolidine), surfactants, alcohols (such as oleyl alcohol), Polyethylene glycol (eg PEG 400), diethylene glycol monoethyl ether, oleic acid, and fatty acid esters (eg isopropyl myristate, methyl laurate, glycerol monooleate, and propylene glycol monooleate).

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

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

The compositions may also contain hydrophilic solvents such as C ₁ -C ₅ alcohols (eg, ethanol, isopropanol, glycerin, propylene glycol, and 1,2-pentanediol) and/or water.

The composition may contain thickening agents 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 such as polydimethylsiloxane [dimethicone] and Carbopol® polymers.

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

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

A topical composition may be any cream, lotion, gel, ointment, jelly, paste, or any transdermal device (e.g., patch) that administers a drug by absorption through the skin or mucous membranes. It can have a suitable dosage form.

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

Penetration enhancers increase the permeability of a therapeutic agent through the skin or mucous membranes. For example, the penetration enhancer can be a fatty acid ester having a _{C8 - C20} or C12- _C18 fatty acyl chain length and a C1 _- C6 or _{C2 - C4} alcohol component (eg, isopropanol). . In certain aspects, the penetration enhancer is isopropyl myristate or isopropyl palmitate. In some embodiments, the penetration enhancer is about 0.1-20%, 0.5-15%, 1-15%, 2-12%, or The amount is between 4 and 10% by weight.

Adhesives maintain contact of the topical composition to the skin or mucous membranes. Non-limiting examples of adhesives include acrylics/acrylates (e.g. polyacrylates including polyalkylacrylates 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 (eg Duro-Tak® 87-6173), and mixtures thereof.

Topical compositions may contain one or more additional excipients. Additional excipients can be, for example, diluents, emollients, plasticizers, or agents that reduce irritation to skin or mucous membranes, or combinations thereof.

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

The compositions are intended for transdermal administration (including transdermal and transmucosal administration) of the therapeutic agent through body surfaces or membranes, such as intact, undamaged skin or intact, undamaged mucosal tissue, into the systemic circulation. can be done.

In some embodiments, topical compositions are in the form of transdermal patches that are applied to skin or mucous membranes. Patches have a skin-contacting layer or a mucosal-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 prior to use to protect the skin-contacting surface and 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 contact layer and as a barrier to prevent loss of therapeutic agent in the skin contact layer to the environment. The backing layer material is compatible with the therapeutic agent, penetration enhancer, and adhesive, and is minimally permeable to the components of the patch. The backing layer can 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 conform to movement of the subject. The material of the support layer may be, for example, metal foil, metal polyfoil, or a polymer (e.g. polyester [such as polyester terephthalate] or aluminized polyester, polyethylene, polypropylene, polytetrafluoroethylene, polyethylene methyl methacrylate block copolymer, polyether block amide copolymer). polymer, polyurethane, polyvinylidene chloride, nylon, silicone elastomer, rubber-based polyisobutylene, styrene, or styrene-butadiene or styrene-isoprene copolymer). The release liner may be made of the same material as the backing layer and may be a film coated with a suitable release surface.

Therapeutic Uses of Treprostinil Derivatives In some embodiments, the compounds described herein are used to treat pulmonary hypertension. Accordingly, the present disclosure provides a method of treating pulmonary hypertension comprising administering to a subject in need thereof a therapeutically effective amount of a treprostinil derivative or a pharmaceutically acceptable salt, solvate, clathrate, or polymorph thereof. is provided. Treprostinil derivatives include prodrugs of treprostinil. Additional therapeutic agents may be administered to treat pulmonary hypertension.

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

The therapeutically effective amount and frequency of administration of a treprostinil derivative for treating pulmonary hypertension will depend on the type of pulmonary hypertension, severity of condition, mode of administration, age, weight, general health status, sex, and diet of the subject, as well as the subject's response to treatment, which can be determined by the treating physician. In certain embodiments, the effective amount of the 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 as appropriate to the treating physician. and can be administered in single or divided doses. In further embodiments, the effective amount of the 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 Dosage considered appropriate.

In some embodiments, the treprostinil derivative is administered once or daily (including once, twice, three times, or more times daily), every two days, every three days, twice weekly. , three times weekly, weekly, every two weeks, every three weeks, monthly, every six weeks, every two months, or every three months, or as often as the treating physician deems appropriate. In a further aspect, the treprostinil derivative is administered under a chronic dosing regimen. In certain embodiments, a therapeutically effective amount of a 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 administered over

A treprostinil derivative may be administered by any suitable route. Potential routes of administration of treprostinil derivatives include oral, parenteral (including intramuscular, subcutaneous, intradermal, intravascular, intravenous, intraarterial, intramedullary, and intrathecal), intraperitoneal, and topical ( Cutaneous/on the skin, 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 intravaginal). In certain aspects, the treprostinil derivative is administered orally. In other embodiments, the treprostinil derivative is administered topically (eg, cutaneously, transdermally, mucosally, transmucosally, intranasally, intrapulmonarily [eg, by inhalation], or sublingually). In a further aspect, the treprostinil derivative is administered parenterally (including, for example, subcutaneously or intravenously, by injection or infusion).

In some embodiments, a treprostinil derivative is used to treat PAH. In further embodiments, additional therapeutic agents are used to treat PAH in combination with the treprostinil derivative. The additional therapeutic agent may be administered concurrently with (before or after) administration of the treprostinil derivative. When co-administered with a treprostinil derivative, the additional therapeutic agent may be in the same composition as the treprostinil derivative or in separate compositions.

In certain embodiments, the additional therapeutic agent for treating PAH is selected from the group consisting of:
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), Vasoactive agents, including, but not limited to, 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, epitidide, and hydrochlorothiazide), thiazide-like diuretics (e.g., chlorthalidone, indapamide, and metolazone), and analogs and derivatives thereof;
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), others (e.g., antithrombin, batroxobin, and hementin), and analogs, derivatives, and fragments thereof; Not other types of therapeutic agents.

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

Four assays for compounds were performed in the following manner. Results are shown in Table I.

(Test 1) A human liver microsomal stability assay was performed using 0.5 mg microsomal protein per mL and 50 μL NADPH producing system (glucose 6-phosphate 7.8 mg, NADPH 1.7 mg, and glucose 6-phosphate 1.7 mg) in 2% w/v sodium bicarbonate. Incubation of 0.5 uM test compound in 50 mM potassium phosphate buffer (pH 7.4) containing phosphate dehydrogenase (6 U) at 37° C. for up to 45 min. Aliquots were taken at 0, 5, 15, 30, and 45 minutes and quenched with an internal standard containing stop solution. A no cofactor control was also prepared at 45 minutes. After incubation, samples were analyzed by LC-MS/MS. Intrinsic clearance was calculated using the peak area ratio of analyte to internal standard. Intrinsic clearance (CL _int ) was determined by nonlinear regression from first-order elimination rate constants. Formation of active drug Compound A over time was also monitored by LC-MS/MS.

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

(Test 3) A human skin homogenate stability assay was performed similar to the human liver microsomal stability assay with 0.5 mg human skin homogenate protein per mL in 2% w/v sodium bicarbonate and 50 μL of NADPH-producing system (glucose 6- 0.5 uM test compound in 50 mM potassium phosphate buffer (pH 7.4) containing 7.8 mg phosphate, 1.7 mg NADPH, and 6 U glucose 6-phosphate dehydrogenase) at 37° C. for up to 45 minutes. rice field. Aliquots were taken at 0, 5, 15, 30, and 45 minutes and quenched with an internal standard containing stop solution. A no cofactor control was also prepared at 45 minutes. After incubation, samples were analyzed by LC-MS/MS. Intrinsic clearance was calculated using the peak area ratio of analyte to internal standard. Intrinsic clearance (CL _int ) was determined by nonlinear regression from first-order elimination rate constants. Formation of active drug Compound A over time was also monitored by LC-MS/MS.

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

Assay results (half-life) are shown in Table I. In Table I, the symbols for the assay test results are as follows.
A = less than 15 minutes
B = 15-30 minutes
C = 31-60 minutes
D = greater than 60 minutes

(Table I)

Compounds 60-64 have the structures shown below.

Synthesis of Treprostinil Derivatives Examples The following representative syntheses are provided for compounds described in 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: 2-[2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-N- Synthesis of (2,2,2-trifluoro-ethyl)-acetamide

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

{2-hydroxy-1-[3-(tetrahydro-pyran-2-yloxy)-octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy}- A solution of 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) at room temperature. Stirred 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) was obtained 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

{2-hydroxy-1-[3-(tetrahydro-pyran-2-yloxy)-octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy}- A solution of 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: Cyclopropanecarboxylic acid 1-(3-hydroxy-octyl)-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-yl ester Synthesis 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 at room temperature under nitrogen 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 1-(3-hydroxy-octyl)-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene cyclopropanecarboxylic acid. -2-yl ester (32 mg) was obtained 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

1-[2-(2-Acryloyloxy-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)-ethyl]-hexyl acrylate A solution of the 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 hours. 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.

Additional synthetic schemes are shown below.

Example 6 (Compound of Formula I)

Example 7 (Compound of Formula I)

Claims (18)

A compound represented by formula (I) below, or a stereoisomer or pharmaceutically acceptable salt thereof:

During the ceremony,
_R20 , _R21 , _R22 , _R23 , _R24 , _R25 , _R26 , _R27 , _R28 , _R29 , _R30 , _R31 , _R32 , _R33 , _R34 , _R35 and _R36 is 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 alkyl cycloheteroalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, or substituted alkylheteroaryl;
wherein substituted groups are 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 substituted with one or more substituents;
R ₁₂ is H, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl;
_P1 is

selected from the group consisting of
here,
m is 1, 2, 3, or 4;
R ₁₄ and R ₁₅ are each independently H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted hetero selected from the group consisting of aryl, substituted arylalkyl, and substituted heteroarylalkyl ;
wherein substituted groups are 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 substituted with one or more substituents;
or
R ₁₄ and R ₁₅ , together with the atoms to which they are attached, are unsubstituted or 1, 2 or 3 independently selected from the group consisting of halo, methyl and methoxy; may form a 5- to 7-membered ring incorporating two ring heteroatoms selected from N, O and S, substituted with substituents;
R ₁₈ and R ₁₉ are each independently hydrogen or alkyl, which alkyl is unsubstituted or halo, hydroxy, alkoxy, amino, thio, methylthio, -C(O)OH, - substituted with one substituent selected from the group consisting of C(O)O-(alkyl), _-CONH2 , aryl and heteroaryl, wherein said aryl or heteroaryl is unsubstituted or alkyl , halo, haloalkyl, hydroxy, alkoxy, and haloalkoxy substituted with a substituent selected from the group;
R ₁₄ and R ₁₈ may together with the atoms to which they are attached form a 5- to 7-membered ring;
R ₁₄ and R ₁₉ may together with the atoms to which they are attached form a 5- to 7-membered ring;
R ₁₅ and R ₁₈ may, together with the atoms to which they are attached, form a 5- to 7-membered ring; and
R ₁₅ and R ₁₉ may together with the atoms to which they are attached form a 5- to 7-membered ring;
And,
_R1 and _{R2 are} independently H or P2,
wherein at least one of R ₁ and R ₂ is P ₂ and P ₂ is -C(=O)R ₁₄ ;
wherein R ₁₄ is alkyl or halo, alkyl , alkenyl, alkynyl, aliphatic, aryl, heteroaryl, heterocyclyl or heterocycle, thiol, alkylthio, arylthio, alkylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkoxy, aryl oxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, alkylhalo, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, hydroxyl, alkyloxy alkyl substituted with one or more substituents selected from alkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, carbonyl, carboxylic acid, sulfonic acid and phosphonic acid ;
however,
alkyl for R ₁₄ for P ₂ is not methyl, and
_P2 is not the group:

here,
m is 1 or 2;
R ₁₄ and R ₁₅ are independently H or alkyl at each occurrence;
R ₁₈ and R ₁₉ are each independently H or alkyl, which is unsubstituted or hydroxy, amino, thio, methylthio, -C(O)OH, -C(O ) substituted with one substituent selected from the group consisting of _NH2 , aryl, and heteroaryl, wherein said aryl or heteroaryl is unsubstituted or substituted with hydroxy; and
R ₁₄ and R ₁₈ or R ₁₉ may, together with the atoms to which they are attached, form a 5-membered ring ;
here,
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 , -CH2CH2OCH2CH3 , _{-CH2CH2OCH2CH2OH} , -CH2CH2N ( CH3 ) ₂ , or -CH2CH2NHCH2CH2OH _{; _} _ _{_ _} _ _{_ _} _ _{_ _} _ _{_ _ _ _} _ _{_} _ _{_} _
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. The compound of claim 1, wherein _R1 is P2 and _R2 is H. _2. The compound of claim 1, wherein _R1 is H and _R2 is P2. _2. The compound of claim ₁ , wherein _R1 is P2 and _R2 is P2. _5. The compound of any one of claims 1-4, wherein R20- _R36 are each hydrogen. A compound according to any one of claims 1-4, wherein at least one of R ₂₀ -R ₃₆ is deuterium. A compound according to any one of claims 1 to 6, wherein Z is -OH. 7. The compound of any one of claims 1-6, wherein Z is _-OR11 . A compound according to any _one of claims 1 to 6, wherein Z is P1. A compound according to any one of claims 1 to 6, wherein Z is -N(R ₁₁ )R ₁₂ . The compound according to any one of claims 1 to 9, which is a compound represented by formula (IA) below, or a stereoisomer or pharmaceutically acceptable salt thereof:

During the ceremony,
Z is -OH, _-OR11 , or _P1 ;
R ₁₁ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, or substituted is alkylcycloheteroalkyl;
here,
heteroalkyl and cycloheteroalkyl are as defined in claim 1; and
substituted groups are substituted with one or more substituents selected from the substituents defined in claim 1;
_P1 is

selected from the group consisting of
here,
m is 1, 2, 3, or 4;
_R14 and _R15 are independently H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroaryl selected from the group consisting of alkyl;
here,
heteroaryl is as defined in claim 1; and
substituted groups are substituted with one or more substituents selected from the substituents defined in claim 1; or
R ₁₄ and R ₁₅ may, together with the atoms to which they are attached, 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 -C( ₌ O) _R14 , wherein
R ₁₄ is alkyl other than methyl. A composition comprising a compound according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, and at least one other ingredient. 13. The composition of claim 12, optionally formulated with a transdermal patch, for transdermal delivery. 14. The composition of claim 12 or 13, further comprising at least one solvent. A composition comprising a compound according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical. 16. A composition for use according to claim 15 for use in treating pulmonary hypertension. 17. The composition of Claim 16, wherein the pulmonary hypertension is pulmonary arterial hypertension. 15. The composition of claim 14, optionally formulated with a transdermal patch, for transdermal administration.