Triprostinil analogs and related methods of making and using

Abstract

Provided are novel treprostinil derivatives, including treprostinil prodrugs and treprostinil analogs, as well as methods of making and using these compounds.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 440,034, filed January 19, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure generally relates to prostacyclin, and more specifically to treprostrin, its prodrugs and analogs, and related methods of preparation and use. Summary of the Invention

[0004] One embodiment is a compound of formula (1), its enantiomer or a pharmaceutically acceptable salt thereof:

[0005]

[0006] Where R 1 Protected by H, C1-C3 alkyl, or acid groups, such as carboxylic acid protecting groups; R 2 It is an H or alcohol protecting group; and R 3 for Where Y 1 For -C≡C-; -CH=CH-; or -(CH2) m - m is an integer from 0 to 5; R 4 For H, OH, or =O; R 5 It is H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic, or substituted or unsubstituted carbocyclic; R 6 For substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, wherein, when R 1 and R 2 When each of them is H, R 3 Not for

[0007] Another embodiment is a compound having formula (2), its enantiomer, or a pharmaceutically acceptable salt thereof:

[0008]

[0009] Where X 1 For hydrogen, Where q is 1, 2, or 3, p1 is an integer from 1 to 20, and R 12 It is a phosphate ester group or COOH; X 2 and X 3 Each of them is independently hydrogen, Phosphate group or Where p2 is an integer from 1 to 20, R 11 It is a C1-C8 alkyl group, wherein one or more carbon atoms of the C1-C8 alkyl group may optionally be substituted with O, and one or more hydrogen atoms of the C1-C8 alkyl group may optionally be substituted with halogen; X 2 It is hydrogen, where X 1 X 2 and X 3 Not all of it is hydrogen; in X 1 It is hydrogen and X 2 and X 3 When one of them is a phosphate ester group, X 2 and X 3 The other one is neither a phosphate ester group nor a hydrogen; in X 1 It is hydrogen and X 2 and X 3 One of them is And R 11 In the case of unsubstituted C1-C8 alkyl groups, X 2 and X 3 The other one in X is not hydrogen and X 2 or X 3 They are not the same.

[0010] Another embodiment is a compound of formula (3): Where R 21 It is a phenolic protecting group or CH2COOR 24 ;R 22 It is an alcohol protecting group; R 23 It is a hydroxyl-terminated alkyl group, -C=CH2, -C≡CH or R 24 It is a carboxylic acid protecting group. Attached Figure Description

[0011] Figure 1A -B illustrates scheme 1, which can be used to synthesize an intermediate that can be further used to synthesize treprostrinil, its prodrug, and analogues.

[0012] Figure 2A -B illustrates scheme 2, which can be used to synthesize further intermediates from intermediates synthesized based on scheme 1. These further intermediates can be used to synthesize treprostrinil, its prodrug, and analogues.

[0013] Figure 3A -B illustrates scheme 3, which can be used to synthesize intermediates that can be further used to synthesize treprostrinil, its prodrugs, and analogues.

[0014] Figure 4A -B shows Scheme 4, which can be used to synthesize the pre-Lennier from intermediates synthesized based on Scheme 3.

[0015] Figure 5A -B illustrates scheme 5, which can be used to synthesize a triprostene analogue according to one implementation scheme from intermediates synthesized based on scheme 3.

[0016] Figure 6 An exemplary trigonelline analogue according to one embodiment is shown.

[0017] Figure 7A -B illustrates scheme 6, which can be used to synthesize a tripronil analogue according to one implementation scheme from intermediates synthesized based on scheme 1.

[0018] Figure 8A -B illustrates scheme 7, which can be used to synthesize a tripronil analogue according to one implementation scheme from intermediates synthesized based on scheme 1.

[0019] Figure 9A -B illustrates scheme 8, which can be used to synthesize a tripronil analogue according to one implementation scheme from an intermediate synthesized based on scheme 1.

[0020] Figure 10A -B illustrates scheme 9, which can be used to synthesize a tripronil analogue according to one implementation scheme from an intermediate synthesized based on scheme 1.

[0021] Figure 11A -B illustrates scheme 10, which can be used to synthesize a treprostinil analog according to one embodiment from treprostinil.

[0022] Figure 12A -B illustrates scheme 11, which can be used to synthesize a treprostinil analog according to one embodiment from treprostinil.

[0023] Figure 13 The chemical formulas of treprostene and selected treprostene analogues are shown.

[0024] Figure 14A -B indicates the selected treprostinil prodrug.

[0025] Figure 15 An exemplary fatty acid conjugate with treprolinil is shown. Detailed Implementation

[0026] As used herein and in the claims, unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” all include the plural referent. Throughout this specification, unless otherwise stated, “comprising,” “including,” and “containing” are inclusive rather than exclusive; therefore, a specified integer or group of integers may include one or more other unspecified integers or groups of integers. The term “or” is inclusive unless modified by, for example, “any.” Therefore, unless the context clearly indicates otherwise, the word “or” means any member of a particular list, including any combination of members in that list. Except as provided in the operational examples or otherwise, all figures used herein to indicate amounts of ingredients or reaction conditions should in all cases be understood to be modified by the term “about.”

[0027] The headings are provided for convenience only and should not be construed as limiting the invention in any way. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention, which is defined only by the claims. To facilitate understanding of this disclosure, certain terms are defined first. Other definitions will be set forth throughout the detailed description.

[0028] All numerical expressions, such as pH, temperature, time, concentration, and molecular weight, including ranges, are approximate values, varying in increments of 0.05%, 1%, 2%, 5%, 10%, or 20% (+) or (-). It should be understood that, although not always explicitly stated, all numerical names are preceded by the word "approximately." It should also be understood that, although not always explicitly stated, the reagents described herein are merely exemplary, and their equivalents are known in the art.

[0029] "Pharmaceutically acceptable salts" refers to salts of compounds suitable for pharmaceutical use and derived from a variety of organic and inorganic counterions known in the art, including (by way of example only) sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium when the compound contains acidic functional groups; and including salts of organic or inorganic acids, such as hydrochlorides, hydrobromic acids, tartrates, methanesulfonates, acetates, maleates, and oxalates, when the molecule contains basic functional groups. For a discussion of pharmaceutically acceptable salts, their selection, preparation, and use, see Stahl and Wermuth, eds., "Handbook of Pharmaceutically Acceptable Salts," (2002), Verlag Helvetica Chimica Acta, Zürich, Switzerland.

[0030] "Pulmonary hypertension" refers to all types of pulmonary hypertension, classified as Groups 1-5 by the World Health Organization (WHO). Pulmonary arterial hypertension, also known as PAH, refers to WHO Group 1 pulmonary hypertension. PAH includes idiopathic pulmonary hypertension, hereditary pulmonary hypertension, drug- or toxin-induced pulmonary hypertension, and persistent neonatal pulmonary hypertension (PPHN).

[0031] Generally, pharmaceutically acceptable salts are those that substantially retain one or more of the desired pharmacological activities of the parent compound and are suitable for in vivo administration. Pharmaceutically acceptable salts include acid addition salts formed with inorganic or organic acids. Inorganic acids suitable for forming pharmaceutically acceptable acid addition salts include, but are not limited to, hydrohalic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.), sulfuric acid, nitric acid, and phosphoric acid.

[0032] Pharmaceutically acceptable salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion) or an ammonium ion (e.g., an ammonium ion derived from an organic base, such as ethanolamine, diethanolamine, triethanolamine, morpholine, piperidine, dimethylamine, diethylamine, triethylamine, and ammonia).

[0033] Triprostene is (Trprostine) Injection, (treprostinil) inhalation solution and The active ingredient in treprostrin sustained-release tablets has been described in U.S. Patent No. 4,306,075. Methods for preparing treprostrin and other prostacyclin derivatives are described, for example, in Moriarty, et al., J. Org. Chem. 2004, 69, 1890-1902, Drug of the Future, 2001, 26(4), 364-374, and U.S. Patent Nos. 6,441,245, 6,528,688, 6,700,025, 6,809,223, 6,756,117, 8,461,393, 8,481,782, 8,242,305, 8,497,393, 8,940,930, 9,029,607, 9,156,786 and 9,388,154, 9,346. ,738; U.S. Patent Application Publications Nos. 2012-0197041, 2013-0331593, 2014-0024856, 2015-0299091, 2015-0376106, 2016-0107973, 2015-0315114, 2016-0152548 and 2016-0175319; PCT Publications Nos. WO2016 / 0055819 and WO2016 / 081658.

[0034] Various uses and / or forms of treprolinil are disclosed in, for example, U.S. Patent Nos. 5,153,222, 5,234,953, 6,521,212, 6,756,033, 6,803,386, 7,199,157, 6,054,486, 7,417,070, 7,384,978, 7,879,909, 8,563,614, 8,252,839, 8,536,363, 8,410,169, 8,232,316, 8,609,728, and 8,350. 079, 8,349,892, 7,999,007, 8,658,694, 8,653,137, 9,029,607, 8,765,813, 9,050,311, 9,199,908, 9,278,901, 8,747,897, 9,358,240, 9,339,507, 9,255,064, 9,278,902, 9,278,903, 9,758,465, 9,422,223, 9,878,972, 9,624,156 U.S. Patent Application Publication Nos. 2009-0036465, 2008-0200449, 2008-0280986, 2009-0124697, 2014-0275616, 2014-0275262, 2013-0184295, 2014-0323567, 2016-0030371, 2016-0051505, 2016-0030355, 2016-0143868, 2015-0328232, 2015-0148414, 2 Among them are 016-0045470, 2016-0129087, 2017-0095432, 2018-0153847, 2021-0121433, 2021-0054009, 2021-0330621, 2021-0378996; and PCT publication numbers WO00 / 57701, WO2016 / 0105538, WO2016 / 038532, WO2018 / 058124, WO2021 / 041320, and WO2022 / 132655.

[0035] Treprostaneil has the following chemical formula:

[0036]

[0037] The term "effective amount" can refer to the amount of a compound (e.g., treprostene analogue, treprostene prodrug, and / or treprostene conjugate) required to treat a disease or condition. In some embodiments, the effective amount of treprostene analogue, treprostene prodrug, and / or treprostene conjugate may be the same as or similar to the effective amount of treprostene for treating the same disease or condition. In some embodiments, the effective amount of treprostene analogue, treprostene prodrug, and / or treprostene conjugate may differ from the effective amount of treprostene for treating the same disease or condition. Those skilled in the art can determine the "effective amount" of treprostene analogue, treprostene prodrug, and / or treprostene conjugate based on, for example, the relevant disease or condition, the known amount of treprostene used to treat, improve, or prevent the disease or condition, and the rate at which the prodrug is converted to treprostene in vivo.

[0038] As used in this article, C is applied before the group. m -C n (e.g., C1-C) 12 When C1-C8 or C1-C6 is used, it refers to a group containing m to n carbon atoms.

[0039] "Optional substitution" refers to a group selected from the group and its substituted forms. Substituents may include any group as defined below. In one embodiment, the substituent is selected from C1-C1. 10 Or C1-C6 alkyl, substituted C1-C 10 Or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C6-C 10 Aryl, C3-C8 cycloalkyl, C2-C 10 Heterocyclic groups, C1-C 10 Heteroaryl, substituted C2-C6 alkenyl, substituted C2-C6 alkynyl, substituted C6-C 10 Aryl, substituted C3-C8 cycloalkyl, substituted C2-C 10 Heterocyclic groups, substituted C1-C 10 Heteroaryl, halogen, nitro, cyano, -CO2H or their C1-C6 alkyl esters.

[0040] "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 10, preferably 1 to 6, carbon atoms. This term includes, for example, straight-chain and branched hydrocarbon groups, such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), tert-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2), and neopentyl ((CH3)3CCH2-).

[0041] "Alkenyl" refers to a monovalent straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, or preferably 2 to 4 carbon atoms, and having at least 1, preferably 1 to 2 vinyl (>C=C<) unsaturated sites. Examples of such groups include vinyl, allyl, and but-3-en-1-yl. The term includes cis and trans isomers, or mixtures of these isomers.

[0042] "Alynyl" refers to a straight-chain or branched monovalent hydrocarbon group having 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, or preferably 2 to 3 carbon atoms, and having at least one, preferably one to two, alkynyl (-C≡C-) unsaturated sites. Examples of such alkynyl groups include ethynyl (-C≡CH) and propynyl (-CH2C≡CH).

[0043] "Substituted alkyl" refers to an alkyl group having 1 to 5, preferably 1 to 3, more preferably 1 to 2 substituents selected from the group consisting of: alkoxy, substituted alkoxy, acyl, amide, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidine, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkane Oxygen, substituted cycloalkoxy, cycloalkoxy, substituted cycloalkoxy, cycloalkenyl, substituted cycloalkenyl, cycloalkenoxy, substituted cycloalkenoxy, cycloalkenoxy, substituted cycloalkenoxy, guanidine, substituted guanidine, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroaryloxy, substituted heteroaryloxy, heteroaryloxy, substituted heteroaryloxy, heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclic, substituted heterocyclic, heterocyclic thio, substituted heterocyclic thio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkoxy, and substituted alkoxy, wherein the substituents are as defined herein.

[0044] "Heteroalkyl" refers to a group of one or more carbon atoms separated by -O-, -S-, SO2, the P-containing moiety provided in this document, or -NR. Q -、

[0045]

[0046] Partially substituted alkyl groups, wherein R Q It is an H or C1-C6 alkyl group. A substituted heteroalkyl group refers to a heteroalkyl group having 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of: alkoxy, substituted alkoxy, acyl, amide, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidine, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cyclo Alkoxy, substituted cycloalkoxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenoxy, substituted cycloalkenoxy, cycloalkenthio, substituted cycloalkenthio, guanidine, substituted guanidine, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclicoxy, substituted heterocyclicoxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkoxide and substituted alkoxide, wherein the substituents are as defined herein.

[0047] "Substituted alkenyl" refers to an alkenyl group having 1 to 3 substituents, preferably 1 to 2 substituents, wherein the substituents are selected from the group consisting of: alkoxy, substituted alkoxy, acyl, amide, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidine, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, cycloalkyl Thioyl, substituted cycloalkylthioyl, cycloalkenyl, substituted cycloalkenyl, cycloalkenoxyl, substituted cycloalkenoxyl, cycloalkenthiol, substituted cycloalkenthiol, guanidinyl, substituted guanidinyl, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxyl, substituted heteroaryloxyl, heteroarylthiol, substituted heteroarylthiol, heterocyclic, substituted heterocyclic, heterocyclicoxyl, substituted heterocyclicoxyl, heterocyclicthiol, substituted heterocyclicthiol, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxyl, thioacyl, thiol, alkylthiol and substituted alkylthiol, wherein the substituents are as defined herein, provided that any hydroxyl or thiol substituent is not attached to a vinyl (unsaturated) carbon atom.

[0048] "Heterene group" refers to one or more carbon atoms separated by -O-, -S-, SO2, the P-containing moiety provided in this article, or -NR. Q -、

[0049]

[0050] Partially substituted alkenyl groups, wherein R QIt is an H or C1-C6 alkyl group. A substituted heteroalkenyl group refers to a heteroalkenyl group having 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of: alkoxy, substituted alkoxy, acyl, amide, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidine, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cyclo Alkoxy, substituted cycloalkoxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenoxy, substituted cycloalkenoxy, cycloalkenthio, substituted cycloalkenthio, guanidine, substituted guanidine, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclicoxy, substituted heterocyclicoxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkoxide and substituted alkoxide, wherein the substituents are as defined herein.

[0051] "Substituted alkynyl" refers to an alkynyl group having 1 to 3 substituents, preferably 1 to 2 substituents, wherein the substituents are selected from the group consisting of: alkoxy, substituted alkoxy, acyl, amide, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidine, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy , cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenoxy, substituted cycloalkenoxy, cycloalkenthio, substituted cycloalkenthio, guanidine, substituted guanidine, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclicoxy, substituted heterocyclicoxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkoxide and substituted alkoxide, wherein the substituents are as defined herein, provided that any hydroxyl or thiol substituent is not attached to an alkyne carbon atom.

[0052] "Heterynyl group" refers to a group of one or more carbon atoms separated by -O-, -S-, SO2, the P-containing moiety provided in this article, or -NR. Q -、

[0053]

[0054] Partially substituted alkynyl groups, wherein R Q It is an H or C1-C6 alkyl group. A substituted heteroynyl group refers to a heteroynyl group having 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of: alkoxy, substituted alkoxy, acyl, amide, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidine, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cyclo Alkoxy, substituted cycloalkoxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenoxy, substituted cycloalkenoxy, cycloalkenthio, substituted cycloalkenthio, guanidine, substituted guanidine, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclicoxy, substituted heterocyclicoxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkoxide and substituted alkoxide, wherein the substituents are as defined herein.

[0055] "Alkylene" refers to a divalent saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 3 carbon atoms, which can be straight-chain or branched. Examples of this term include methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)- or -CH(CH3)CH2-), butylene (-CH2CH2CH2CH2-), isobutylene (-CH2CH(CH3-)CH2-), and tert-butylene (-CH2CH2(CH3-)CH2-). 3- (CH-) etc. Similarly, "alkenyl" and "ynylene" refer to alkylene moieties containing one or two carbon-carbon double or triple bonds, respectively.

[0056] "Substituted alkylene" refers to an alkylene in which one to three hydrogen atoms are substituted by substituents selected from the group consisting of: alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, amide, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl ester, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and oxo, wherein the substituents are defined as described herein. In some embodiments, the alkylene has one to two of the above groups, or has one to three carbon atoms substituted with -O-, -S-, or -NR. Q - Partial replacement, where R Q It is an H or C1-C6 alkyl group. It should be noted that when an alkylene group is substituted with an oxo group, the two hydrogen atoms attached to the same carbon atom in the alkylene group are replaced by "=O". "Substituted alkenylyl" and "substituted ynylyl" refer to the alkenylyl and ynylylyl moieties being substituted with substituents as described in the section on substituted alkylene groups.

[0057] "Immyneyl" refers to a straight-chain or branched divalent hydrocarbon group having 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, or preferably 2 to 3 carbon atoms, and having at least one, preferably one to two, alkynyl (-C≡C-) unsaturated sites. Examples of such imyneyl groups include C≡C- and CH2C≡C-.

[0058] "Substituted alkyneylyl group" refers to an alkyneylyl group having 1 to 3 substituents, preferably 1 to 2 substituents, wherein the substituents are selected from the group consisting of: alkoxy, substituted alkoxy, acyl, amide, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidine, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy The following groups are included: alkyl, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenoxy, substituted cycloalkenoxy, cycloalkenthio, substituted cycloalkenthio, guanidine, substituted guanidine, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclicoxy, substituted heterocyclicoxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are as defined herein, provided that any hydroxyl or thiol substitution is not attached to an alkyne carbon atom.

[0059] "Heteroalkylene" refers to a compound in which one or more carbon atoms are separated by -O-, -S-, SO2, the P-containing moiety provided herein, or -NR. Q -、

[0060]

[0061] Partially substituted alkylene groups, wherein R Q It is an H or C1-C6 alkyl group. "Substituted heteroalkylene" refers to a heteroalkynyl group having 1 to 3 substituents, preferably 1 to 2 substituents, said substituents being selected from the substituents disclosed with respect to substituted heteroalkylene.

[0062] "Heteroene group" refers to a group in which one or more carbon atoms are separated by -O-, -S-, SO2, the P-containing moiety provided in this article, or -NR. Q -、

[0063]

[0064] Partially substituted alkenyl groups, wherein R Q It is H or C1-C6 alkyl. "Substituted heteroeneyl" refers to a heteroeneyl group having 1 to 3 substituents, preferably 1 to 2 substituents, said substituents being selected from the substituents disclosed with respect to substituted heteroeneyl groups.

[0065] "Hetero-ynyl group" refers to a group in which one or more carbon atoms are bonded by -O-, -S-, SO2, the P-containing moiety provided in this article, or -NR. Q -、

[0066]

[0067] Partially substituted ynylene groups, wherein R Q It is an H or C1-C6 alkyl group. "Substituted heteroynyl" refers to a heteroynyl group having 1 to 3 substituents, preferably 1 to 2 substituents, said substituents being selected from the substituents disclosed with respect to substituted heteroynyl.

[0068] "Alkoxy" refers to an O-alkyl group, where alkyl is defined as defined herein. Alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, and n-pentoxy.

[0069] "Substituted alkoxy" refers to the group O (substituted alkyl), wherein the substituted alkyl is as defined herein.

[0070] "Acyl" refers to the following groups: HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl- -C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Acyl groups include the "acetyl" group CH3C(O)-.

[0071] "Acylamino" refers to -NR 47 C(O)alkyl, -NR 47 C(O) substituted alkyl groups, -NR 47 C(O)cycloalkyl, -NR 47 C(O) substituted cycloalkyl groups, -NR 47 C(O)cycloalkenyl, -NR 47 C(O)-substituted cycloalkenyl, -NR 47 C(O) alkenyl, -NR 47 C(O)-substituted alkenyl groups, -NR 47 C(O) ynyl group, -NR 47 C(O) substituted alkynyl groups, -NR 47 C(O)aryl, -NR 47 C(O)-substituted aryl, -NR 47 C(O) heteroaryl, -NR 47 C(O)-substituted heteroaryl, -NR 47 C(O) heterocyclic group and NR 47 C(O)-substituted heterocyclic groups, where R 47 It is hydrogen or alkyl, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic as defined herein.

[0072] "Acyloxy group" refers to alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O-, alkynyl-C(O)O-, substituted alkynyl-C(O)O-, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, cycloalkenyl-C(O)O-, and substituted cycloalkenyl-C(O)O-. (O)O-, heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocyclic-C(O)O- and substituted heterocyclic-C(O)O- groups, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic groups are as defined herein.

[0073] "Amino" refers to the NH2 group.

[0074] "Substituted amino" refers to the -NR group. 48 R 49 , where R 48 and R 49 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, ynyl, substituted ynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, SO2-alkyl, -SO2-substituted alkyl, -SO2-alkenyl, -SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl, -SO2-cycloalkenyl, -SO2-substituted cycloalkenyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocyclic and -SO2-substituted heterocyclic, wherein R 48 and R 49 Optionally linked to the nitrogen to which it is bonded to form a heterocyclic group or a substituted heterocyclic group, provided that R 48 and R 49 None of them are hydrogen. Alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. When R 48 It is hydrogen and R 49 When R is alkyl, the substituted amino group is sometimes referred to herein as an alkylamino group. 48 and R 49 When the amino group is alkyl, the substituted amino group is sometimes referred to as dialkylamino in this document. When referring to a monosubstituted amino group, it means R... 48 Or R 49It can be hydrogen, but not simultaneously hydrogen. When referring to a disubstituted amino group, it means R 48 and R 49 Neither of them are hydrogen.

[0075] "Amino carbonyl" refers to the group -C(O)NR 50 R 51 , where R 50 and R 51 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and wherein R 50 and R 51 Optionally linked to the nitrogen to which it is bonded to form a heterocyclic group or a substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic groups are as defined herein.

[0076] "Aminothiocarbonyl" refers to the group -C(S)NR 50 R 51 , where R 50 and R 51 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, wherein R 50 and R 51 Optionally linked to the nitrogen to which it is bonded to form a heterocyclic group or a substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic groups are as defined herein.

[0077] "Aminocarbonylamino" refers to the group -NR 47 C(O)NR 50 R 51 , where R 47 It is hydrogen or alkyl, and R 50 and R 51 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, wherein R50 and R 51 Optionally linked to the nitrogen to which it is bonded to form a heterocyclic group or a substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic groups are as defined herein.

[0078] "Aminothiocarbonylamino" refers to the group -NR 47 C(S)NR 50 R 51 , where R 47 It is hydrogen or alkyl, and R 50 and R 51 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, wherein R 50 and R 51 Optionally linked to the nitrogen to which it is bonded to form a heterocyclic group or a substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic groups are as defined herein.

[0079] "Aminocarbonyloxy group" refers to the group -OC(O)NR 50 R 51 , where R 50 and R 51 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, wherein R 50 and R 51 Optionally linked to the nitrogen to which it is bonded to form a heterocyclic group or a substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic groups are as defined herein.

[0080] "Aminosulfonyl" refers to the group -SO2NR 50 R 51 , where R 50 and R 51Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and wherein R 50 and R 51 Optionally linked to the nitrogen to which it is bonded to form a heterocyclic group or a substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic groups are as defined herein.

[0081] "Aminosulfonyloxy" refers to the group -O-SO2NR. 50 R 51 , where R 50 and R 51 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, wherein R 50 and R 51 Optionally linked to the nitrogen to which it is bonded to form a heterocyclic group or a substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic groups are as defined herein.

[0082] "Aminosulfonylamino" refers to the group -NR 47 SO2NR 50 R 51 , where R 47 It is hydrogen or alkyl, and R 50 and R 51 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, wherein R 50 and R 51 Optionally linked to the nitrogen to which it is bonded to form a heterocyclic group or a substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic groups are as defined herein.

[0083] "Amino group" refers to the group -C (=NR) 52 )NR 50 R 51 , where R 50 R 51 and R 52 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and wherein R 50 and R 51 Optionally linked to the nitrogen to which it is bonded to form a heterocyclic group or a substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic groups are as defined herein.

[0084] "Ar" or "Ar" refers to a monovalent aromatic carbocyclic group having 6 to 14 carbon atoms, consisting of a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthracene). The fused rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)one-7-yl, etc.), provided that their attachment sites are located on aromatic carbon atoms. Preferred aryl groups include phenyl and naphthyl.

[0085] "Substituted aryl" refers to an aryl group substituted by 1 to 5, preferably 1 to 3, more preferably 1 to 2, substituents selected from the group consisting of: alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, amide, acoxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidine, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano. Cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenoxy, substituted cycloalkenoxy, cycloalkenthio, substituted cycloalkenthio, guanidine, substituted guanidine, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclic, substituted heterocyclic, heterocyclic, substituted heterocyclic, heterocyclicthio, substituted heterocyclic, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkathio, and substituted alkathio, wherein the substituents are as defined herein.

[0086] "Arylidene" refers to a divalent aromatic carbocyclic group having a monocyclic or multiple fused rings with 6 to 14 carbon atoms. "Substituted arylidene" refers to an arylidene having 1 to 5, preferably 1 to 3, more preferably 1 to 2 substituents as defined with respect to aryl groups.

[0087] "Heteroarylene" refers to a divalent aromatic group containing 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. "Substituted heteroarylene" refers to a heteroarylene substituted with 1 to 5, preferably 1 to 3, more preferably 1 to 2 substituents selected from the same group of substituents as defined with respect to substituted aryl groups.

[0088] "Aryloxy group" refers to the -O-aryl group, where aryl groups are defined herein and include, for example, phenoxy and naphthoxy groups.

[0089] "Substituted aryl group" refers to the group -O- (substituted aryl group), where the substituted aryl group is as defined herein.

[0090] "Arylthio" refers to the group -S-aryl, where aryl is as defined in this article.

[0091] "Substituted arylthio" refers to the group S (substituted aryl), where the substituted aryl is as defined herein.

[0092] "Carbonyl" refers to the divalent group -C(O)-, which is equivalent to -C(=O)-.

[0093] The "carboxyl" group (or "carboxy") refers to COOH or its salt.

[0094] "Carboxyl ester" (or "carboxy ester") refers to a group consisting of the following subgroups: -C(O)(O)-alkyl, -C(O)(O)-substituted alkyl, -C(O)O-alkenyl, -C(O)(O)-substituted alkenyl, -C(O)(O)-ynyl, -C(O)(O)-substituted ynyl, -C(O)(O)-aryl, -C(O)(O)-substituted aryl, -C(O)(O)-cycloalkyl, -C(O)(O)-substituted cycloalkyl, -C(O)(O)-cycloalkenyl, - C(O)(O)-substituted cycloalkenyl, -C(O)(O)-heteroaryl, -C(O)(O)-substituted heteroaryl, -C(O)(O)-heterocyclic and -C(O)(O)-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0095] "(Carboxyl ester) amino refers to -NR" 47 C(O)(O)-alkyl, -NR 47 C(O)(O)-substituted alkyl group, -NR 47 C(O)O-alkenyl, -NR 47 C(O)(O)-substituted alkenyl, -NR 47 C(O)(O)-alkynyl group, -NR 47 C(O)(O)-substituted alkynyl groups, -NR 47 C(O)(O)-Aryl, -NR 47 C(O)(O)-substituted aryl, -NR 47 C(O)(O)-cycloalkyl, -NR 47 C(O)(O)-substituted cycloalkyl, -NR 47 C(O)(O)-cycloalkenyl, -NR 47 C(O)(O)-substituted cycloalkenyl, -NR 47 C(O)(O)-heteroaryl, -NR 47 C(O)(O)-substituted heteroaryl, -NR 47 C(O)(O)-heterocyclic group and -NR 47 C(O)(O)-substituted heterocyclic groups, where R 47 It is an alkyl or hydrogen, and wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0096] "(Carboxyl ester)oxy group" refers to the following groups: -OC(O)O-alkyl, -OC(O)O-substituted alkyl, -OC(O)O-alkenyl, -OC(O)O-substituted alkenyl, -OC(O)O-ynyl, -OC(O)(O)-substituted ynyl, -OC(O)O-aryl, -OC(O)O-substituted aryl, -OC(O)O-cycloalkyl, -OC(O)O-substituted cycloalkyl, -OC(O)O-cycloalkenyl, - OC(O)O-substituted cycloalkenyl, -OC(O)O-heteroaryl, -OC(O)O-substituted heteroaryl, -OC(O)O-heterocyclic and -OC(O)O-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0097] "Cyano" refers to the CN group.

[0098] "Cycloalkyl" refers to a cyclic alkyl group having a monocyclic or polycyclic structure with 3 to 10 carbon atoms, including fused rings, bridged rings, and spirocyclic systems. The fused ring can be an aromatic ring, provided that the non-aromatic portion is attached to the rest of the molecule. Suitable examples of cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.

[0099] "Cycloalkenyl" refers to a non-aromatic cyclic alkyl group having 3 to 10 carbon atoms, having a monocyclic or polycyclic structure, having at least one >C=C< ring unsaturation, and preferably having 1 to 2 >C=C< ring unsaturation sites.

[0100] "Substituted cycloalkyl" and "substituted cycloalkenyl" refer to cycloalkyl or cycloalkenyl groups having 1 to 5, or preferably 1 to 3, substituents selected from the group consisting of: oxo, thio, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, amide, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidine, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl) Ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenoxy, substituted cycloalkenoxy, cycloalkenthio, substituted cycloalkenthio, guanidine, substituted guanidine, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclic, substituted heterocyclic, heterocyclic, substituted heterocyclic, heterocyclicthio, substituted heterocyclic, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkathio, and substituted alkathio, wherein the substituents are as defined herein.

[0101] "Cyclopropyl" refers to:

[0102]

[0103] "Cyclobutane" refers to:

[0104]

[0105] “Cycloalkoxy” refers to -O-cycloalkyl.

[0106] "Substituted cycloalkoxy" refers to -O- (substituted cycloalkyl).

[0107] "Cyclothio" refers to -S-cycloalkyl.

[0108] "Substituted cycloalkanethio" refers to -S- (substituted cycloalkyl).

[0109] "Cycloalkenyl group" refers to -O-cycloalkenyl group.

[0110] "Substituted cycloalkenyl group" refers to -O- (substituted cycloalkenyl group).

[0111] "Cycloalenylthio" refers to -S-cycloalenyl.

[0112] "Substituted cycloalkenyl thio" refers to -S- (substituted cycloalkenyl).

[0113] "Guidinyl" refers to the group -NHC(=NH)NH2.

[0114] "Substituted guanidine group" refers to -NR 53 C(=NR 53 )N(R 53 )2, where each R 53 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic, and two R atoms attached to the same guanidine nitrogen atom. 53 The group may optionally be linked to the nitrogen to which it is bonded to form a heterocyclic group or a substituted heterocyclic group, provided that at least one R 53 It is not hydrogen, and the substituents therein are as defined herein.

[0115] "Halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0116] The "hydroxyl" (or "hydroxyl") refers to the -OH group.

[0117] "Heteroaryl" refers to an aromatic group having 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Such heteroaryl groups may have a monocyclic ring (e.g., pyridyl or furanyl) or multiple fused rings (e.g., indoleazinyl or benzothiopheneyl), wherein the fused rings may or may not be aromatic and / or contain heteroatoms, provided that the attachment point is through an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and / or sulfur ring atoms of the heteroaryl group may optionally be oxidized to form an N oxide (N→O), sulfinyl, or sulfonyl moiety. Certain non-limiting examples include pyridyl, pyrroleyl, indoleyl, thiopheneyl, oxazolyl, thiazolyl, and furanyl.

[0118] "Substituted heteroaryl" means a heteroaryl group substituted with 1 to 5, preferably 1 to 3, more preferably 1 to 2 substituents selected from the same group of substituents as defined with respect to substituted aryl.

[0119] "Heteroaryl group" refers to -O-heteroaryl group.

[0120] "Substituted heteroaryl group" refers to the group -O- (substituted heteroaryl group).

[0121] "Heteroaryl thioyl" refers to the -S-heteroaryl group.

[0122] "Substituted heteroaryl thiols" refers to the group -S- (substituted heteroaryl).

[0123] "Heterocyclic," "heterocyclic," "heterocyclic alkyl," or "heterocyclic group" refers to a saturated or partially saturated but non-aromatic group having 1 to 10 ring carbon atoms and 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen. Heterocycles encompass monocyclic or multiple fused rings, including fused bridged rings and spirocyclic systems. In fused ring systems, one or more rings can be cycloalkyl, aryl, or heteroaryl, provided that the attachment point is through a non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atoms of the heterocyclic group are optionally oxidized to form an N oxide, sulfinyl, or sulfonyl moiety.

[0124] "Substituted heterocycle" or "substituted heterocyclic alkyl" or "substituted heterocyclic group" refers to a heterocyclic group that is substituted by 1 to 5, or preferably 1 to 3, substituents that are the same as those defined with respect to substituted cycloalkyl.

[0125] "Heterocyclic group" refers to the -O-heterocyclic group.

[0126] "Substituted heterocyclic group" refers to the group -O- (substituted heterocyclic group).

[0127] "Heterocyclic thio group" refers to the -S-heterocyclic group.

[0128] "Substituted heterocyclic thio group" refers to the group -S- (substituted heterocyclic group).

[0129] Examples of heterocyclic and heteroaryl compounds include, but are not limited to, azacyclic butanes, pyrroles, furans, thiophenes, imidazoles, pyrazoles, pyridines, pyrazines, pyrimidines, pyridazines, indolizines, isoindole, indole, dihydroindole, indazoles, purines, quinazines, isoquinoline, quinoline, phthalazines, naphthylpyridine, quinoxaline, quinazoline, cyclophosphine, pteridine, carbazole, caroline, phenanthridine, acridine, phenanthrene-rhein, isothiazoles, phenazines. Isoxazole, phenoxazine, phenothiazine, imidazoline, imidazoline, piperidine, piperazine, dihydroindole, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazoline, thiophene, benzo[b]thiophene, morpholino, thiomorpholino (also known as thiozamorpholino), 1,1-dioxothiomorpholino, piperidinyl, pyrrolidinyl, and tetrahydrofuranyl.

[0130] "Nitro" refers to the group -NO2.

[0131] “Oxo” refers to an atom (=O).

[0132] Phenylidene refers to a divalent aromatic ring containing 6 carbon atoms.

[0133] A substituted phenylene refers to a phenylene substituted with 1 to 4, preferably 1 to 3, more preferably 1 to 2, substituents selected from the group consisting of: alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, amide, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidine, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano. Cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenoxy, substituted cycloalkenoxy, cycloalkenthio, substituted cycloalkenthio, guanidine, substituted guanidine, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclic, substituted heterocyclic, heterocyclic, substituted heterocyclic, heterocyclicthio, substituted heterocyclic, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkathio, and substituted alkathio, wherein the substituents are as defined herein.

[0134] "Spirocycloalkyl" and "spirocyclic system" refer to divalent cyclic groups having 3 to 10 carbon atoms and a spirocyclic linkage (a connection formed by a single atom that is the only common member of the ring), such as the following structures:

[0135]

[0136] "Sulfoyl" refers to the divalent group -S(O)2-.

[0137] "Substituted sulfonyl" refers to the groups -SO2-alkyl, -SO2-substituted alkyl, -SO2-alkenyl, -SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl, -SO2-cycloalkenyl, -SO2-substituted cycloalkenyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocyclic, and -SO2-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, ynyl, substituted ynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Substituted sulfonyl groups include groups such as methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-.

[0138] "Substituted sulfonyloxy" refers to the group -OSO2-alkyl, -OSO2-substituted alkyl, -OSO2-alkenyl, -OSO2-substituted alkenyl, -OSO2-cycloalkyl, -OSO2-substituted cycloalkyl, -OSO2-cycloalkenyl, -OSO2-substituted cycloalkenyl, -OSO2-aryl, -OSO2-substituted aryl, -OSO2-heteroaryl, -OSO2-substituted heteroaryl, -OSO2-heterocyclic, -OSO2-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0139] "Thioacyl" refers to the following groups: HC(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-, cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, cycloalkenyl-C(S)-, substituted cycloalkenyl-C(S)-, aryl-C(S)-. Substituted aryl-C(S)-, heteroaryl-C(S)-, substituted heteroaryl-C(S)-, heterocyclic-C(S)-, and substituted heterocyclic-C(S)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0140] "Thiol" refers to the SH group.

[0141] "Thiocarbonyl" refers to the divalent group -C(S)-, which is equivalent to -C(=S)-.

[0142] "Thio group" refers to an atom (=S).

[0143] "alkylthio" refers to the S-alkyl group, where the alkyl group is as defined herein.

[0144] "Substituted alkylthio" refers to the group -S- (substituted alkyl), wherein the substituted alkyl is as defined herein.

[0145] The substituted ring can be replaced by one or more fused rings and / or spirocyclic rings. Such fused rings include fused cycloalkyl groups, fused heterocyclic groups, fused aryl groups, and fused heteroaromatic rings, each ring may be unsubstituted or substituted. Such spirocyclic rings include fused cycloalkyl groups and fused heterocyclic groups, each ring may be unsubstituted or substituted.

[0146] It should be understood that the above definition is not intended to include unacceptable substitution patterns (e.g., methyl groups substituted with five fluorine groups). Such unacceptable substitution patterns are well known to those skilled in the art.

[0147] This application discloses various novel treprostrin analogs, treprostrin prodrugs, and / or treprostrin conjugates. This application also discloses novel methods for synthesizing treprostrin, its analogs, its prodrugs, and / or its conjugates. Furthermore, this application discloses novel intermediates that can be used in these methods.

[0148] One embodiment is a compound of formula (1), its enantiomer or a pharmaceutically acceptable salt thereof.

[0149] Where R 1 It can be H, a lower alkyl group such as C1-C3 alkyl, or an acid protecting group such as a carboxylic acid protecting group; R 2 It can be an H or alcohol protecting group; and R 3 It can be Where Y 1 It is -C≡C-; -CH=CH-; or -(CH2) m - m can be an integer from 0 to 5; R 4 It can be H, OH, or =O; R 5 It is H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic, or substituted or unsubstituted carbocyclic; R 6 It can be a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted cycloalkyl, wherein in R 1 and R 2 If each of them is H, then R 3 Not for It corresponds to the pre-Church Lenier.

[0150] In some implementation schemes, R 1 It can be H or a lower alkyl group, such as C1-C3 alkyl groups, such as methyl, ethyl, or propyl. For example, R 1 It can be H or methyl.

[0151] In some implementation schemes, R 2 It can be H.

[0152] In some implementation schemes, R 3 It can be Where R 7 It can be, for example, alkyl, alkenyl, or alkynyl; Z can be O, CH2, NH, or S; R 8 It can be a heterocyclic group; and R 4 It can be H, OH, or =O.

[0153] In some implementation schemes, R 3 It can be Each Z can be independently selected from CH, N, O, or S, n is 0 or 1, and R 9 It can be alkyl, aryl, electron-withdrawing group, electron-donating group, heterocyclic or carbocyclic; and R 4 It can be H, OH, or =O.

[0154] In some implementation schemes, R 3 for Where R 10 It is a cycloalkyl group having 3 to 8 carbon atoms, wherein one or more carbon atoms of the cycloalkyl group may optionally be substituted with heteroatoms selected from O, N and S; and R 4 It can be H, OH, or =O.

[0155] In some implementation schemes, R 3 Optional

[0156]

[0157] Another embodiment may be a compound having formula (2), its enantiomer, or a pharmaceutically acceptable salt thereof:

[0158]

[0159] Where X 1 It can be hydrogen. Where q can be 1, 2, or 3, p1 can be an integer from 1 to 20, and R 12 It can be a phosphate ester group or COOH; X 2 and X 3 Each of them can be independently hydrogen, Phosphate group or Where p2 can be an integer from 1 to 20, R 11 It is a C1-C8 alkyl group, wherein one or more carbon atoms of the C1-C8 alkyl group may optionally be substituted with O, and one or more hydrogen atoms of the C1-C8 alkyl group may optionally be substituted with halogen; X 2 It can be hydrogen, provided that (a)X 1 X 2 and X 3 (b) Not all of it is hydrogen; 1 It is hydrogen and X 2 and X 3 When one of them is a phosphate ester group, X 2 and X 3 The other one is neither a phosphate ester group nor a hydrogen; (c) in X 1 It is hydrogen and X 2 and X 3 One of them is And R 11 In the case of unsubstituted C1-C8 alkyl groups, X 2 and X 3 The other one in X is not hydrogen and X 2 or X 3 They are not the same.

[0160] In some implementation schemes, X 1 It can be

[0161] In some implementation schemes, X 2 and X 3 They can be the same group. For example, in some embodiments, X 2 and X 3 Each of them can be hydrogen. However, in some implementations, X... 2 and X 3 Each of them can be

[0162] In some implementation schemes, X 1 It could be hydrogen.

[0163] In some implementation schemes, X 2 and X 3 One of them is a phosphate ester group, while X 2 and X 3 Another one is

[0164] In some implementation schemes, X 2 and X 3 At least one of them is Where R 11It is a C1-C8 alkyl group, wherein one or more carbon atoms of the C1-C8 alkyl group are substituted with O or one or more hydrogen atoms are substituted with halogen.

[0165] In some implementation schemes, X 2 and X 3 At least one of them is Where R 11 It is a C1-C8 alkyl group, wherein one or more hydrogen atoms of the C1-C8 alkyl group are substituted with halogens. In some embodiments, X 2 and X 3 Each of them is Where R 11 It is a C1-C8 alkyl group, wherein one or more hydrogen atoms of the C1-C8 alkyl group are replaced by halogens.

[0166] In some implementation schemes, X 2 and X 3 same.

[0167] In some implementation schemes, X 2 and X 3 At least one of them is Where p2 is an integer from 12 to 16, or X 1 for Where p1 is an integer from 12 to 16.

[0168] In some implementation schemes, X 2 and X 3 Each of them is hydrogen and X 1 for (b)X 3 for X 2 for And X 1 (c)X is hydrogen; 3 for X 2 for And X 1 For hydrogen; (d)X 3 for X 2 for And X 1 It is hydrogen; (e)X 2 and X 3 Each of them is And X 1 for (f)X 2 and X 3 Each of them is And X 1 for (g)X1 and X 2 Each of them is hydrogen and X 3 for (h)X 3 for X 2 for And X 1 For hydrogen; (i)X 2 for X 3 for And X 1 For hydrogen; (j)X 1 and X 2 Each of them is hydrogen and X 3 for (k)X 1 and X 2 Each of them is hydrogen and X 3 for (l)X 2 and X 3 Each of them is And X 1 For hydrogen; (m)X 2 and X 3 Each of them is And X 1 For hydrogen; (n)X 1 and X 3 Each of them is hydrogen and X 3 for (o)X 1 It is hydrogen; X 2 for And X 3 for (p)X 1 It is hydrogen; X 2 for And X 3 for (q)X 2 and X 3 Each of them is hydrogen and X 1 for (r)X 1 and X 2 Each of them is hydrogen and X 3 for (s)X 1 and X 3 Each of them is hydrogen and X 2 for or (t)X 1 for And X 2 and X 3 Each of them is

[0169] Another embodiment is a compound of formula (3): Where R 21 It is a phenolic protecting group or CH2COOR 24 ;R 22 It is an alcohol protecting group; R 23 It is a hydroxyl-terminated alkyl group, -C=CH2, -C≡CH or R 24 It is an alcohol protecting group.

[0170] In some implementation schemes, R 23 It is a hydroxyl-terminated alkyl group, such as a hydroxyl-terminated C1-C8 alkyl group or a C1-C4 alkyl group.

[0171] In some embodiments, the compound of formula (3) can be a compound having formula (31):

[0172] In some embodiments, the compound of formula (3) can be a compound having formula (32):

[0173] In some embodiments, the compound of formula (3) can be a compound having formula (33):

[0174] In some implementation schemes, R 21 It is a C1-C4 alkyl group, a substituted or unsubstituted benzyl group, or CH2COOR. 24 , where R 24 It is a C1-C4 alkyl group or a substituted or unsubstituted benzyl group.

[0175] In some implementation schemes, R 22 It is an acetyl group or a silyl group.

[0176] Compounds of formula (3), such as compounds of formula (31), (32) or (33), can be used as intermediates for the synthesis of treprostil analogs, treprostil prodrugs and / or treprostil conjugates (such as compounds of formula (1) or (2) above).

[0177] Treprostrenil analogues, treprostrenil prodrugs, and / or treprostrenil conjugates can be used to treat any disease or condition that can be treated with treprostrenil or its pharmaceutical salts. Treprostrenil analogues, treprostrenil prodrugs, and / or treprostrenil conjugates can be formulated into suitable pharmaceutical compositions according to their intended use and route of administration (e.g., parenteral, oral, or inhalation). In some embodiments, the disease or condition is one or more selected from the group consisting of: pulmonary hypertension, congestive heart failure, peripheral vascular disease, Raynaud's phenomenon, scleroderma, renal insufficiency, peripheral neuropathy, finger (toe) ulcers, intermittent claudication, ischemic limb disease, peripheral ischemic lesions, pulmonary fibrosis, and asthma. In some embodiments, the disease is pulmonary hypertension. Pulmonary hypertension can be any form of pulmonary hypertension, such as pulmonary arterial hypertension (WHO Group 1 pulmonary hypertension).

[0178] Administration can be performed via the routes described above, or, for example, by oral, intravenous, intra-arterial, intramuscular, intranasal, rectal, vaginal, or subcutaneous administration. In some embodiments, the composition is administered by injection. In some embodiments, administration is performed orally. In some embodiments, administration is performed subcutaneously. In some embodiments, administration is performed intravenously.

[0179] The subjects of treatment can be humans, canines, felines, birds, non-human primates, bovines, or equines. In some implementations, the subjects are humans.

[0180] Compounds (e.g., treprostrenil analogs, treprostrenil prodrugs, and / or treprostrenil conjugates) may be provided as pharmaceutical compositions, which may also include pharmaceutically acceptable carriers, excipients, binders, diluents, etc. Such pharmaceutical compositions may be prepared by methods known in the art, such as granulation, mixing, dissolving, encapsulation, lyophilization, emulsification, or grinding processes. The compositions may be in the form of, for example, granules, powders, tablets, capsules, syrups, suppositories, injections, emulsions, elixirs, suspensions, and solutions. The compositions may be formulated for a variety of different routes of administration, such as oral administration, mucosal administration, rectal administration, transdermal or subcutaneous administration, and intrathecal, intravenous, intramuscular, intraperitoneal, intranasal, intraocular, or intraventricular injection. Compounds (e.g., treprostrenil analogs, treprostrenil prodrugs, and / or treprostrenil conjugates) may be administered via any of the above routes, for example, by local rather than systemic administration, including as injectable formulations or as sustained-release formulations.

[0181] In one embodiment, the pharmaceutical composition may comprise a compound (e.g., a treprostene analog, a treprostene prodrug, and / or a treprostene conjugate) and a carrier (e.g., sterile water). In some embodiments, the compound (e.g., a treprostene analog, a treprostene prodrug, and / or a treprostene conjugate) is formulated for subcutaneous administration, and such formulations may or may not contain m-cresol or other preservatives.

[0182] The treprostene analogues, treprostene prodrugs, and / or treprostene conjugates described herein may be used to treat pulmonary hypertension. In some embodiments, the compound (e.g., treprostene analogues, treprostene prodrugs, and / or treprostene conjugates) may be used to treat pulmonary arterial hypertension (PAH). In some embodiments, the compound (e.g., treprostene analogues, treprostene prodrugs, and / or treprostene conjugates) may be used to treat one or more of the WHO Groups 1-5 of pulmonary hypertension. Similarly, the treprostene analogues, treprostene prodrugs, and / or treprostene conjugates described herein may be used to treat any disease or condition to which treprostene is applicable or effective. Treprostene analogues, treprostene prodrugs, and / or treprostene conjugates may be administered as the sole therapeutic agent or in combination with other active agents, including treprostene.

[0183] For oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, soft capsules, and capsules are acceptable solid dosage forms. These dosage forms can be prepared, for example, by mixing one or more compounds (e.g., treprostene analogs, treprostene prodrugs, and / or treprostene conjugates or pharmaceutically acceptable salts thereof) with at least one additive or excipient (e.g., starch or other additives). Suitable additives or excipients may be sucrose, lactose, cellulose sugars, mannitol, maltitol, dextran, sorbitol, starch, agar, alginate, chitin, chitosan, pectin, tragacanth gum, gum arabic, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymers or glycerides, methylcellulose, hydroxypropyl methylcellulose, and / or polyvinylpyrrolidone. Optionally, oral dosage forms may contain other adjuvants such as inactive diluents, lubricants (e.g., magnesium stearate), preservatives (e.g., parabens or sorbic acid), antioxidants (e.g., ascorbic acid, tocopherol, or cysteine), disintegrants, binders, thickeners, buffers, sweeteners, flavorings, or aromatizers. Additionally, dyes or pigments may be added for identification. The tablets may also be further treated with suitable coating materials known in the art.

[0184] Liquid dosage forms for oral administration can be pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, pastes, and solutions, and may contain inactive diluents such as water. Pharmaceutical preparations can be prepared as liquid suspensions or solutions using sterile liquids (e.g., but not limited to oils, water, alcohols, and combinations thereof). Pharmaceutically suitable surfactants, suspending agents, and emulsifiers may be added for oral or parenteral administration.

[0185] As mentioned above, suspensions may contain oils. These oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil. Suspension formulations may also contain fatty acid esters, such as ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides. Suspension formulations may contain alcohols, such as, but not limited to, ethanol, isopropanol, cetyl alcohol, glycerol, and propylene glycol. Ethers, such as, but not limited to, polyethylene glycol, petroleum hydrocarbons (e.g., mineral oil and petrolatum); water may also be used in suspension formulations.

[0186] Injectable dosage forms typically include aqueous or oil-based suspensions, which can be prepared using suitable dispersants or wetting agents and suspending agents. Injectable dosage forms can be in solution or suspension form, the latter prepared with solvents or diluents. Acceptable solvents or carriers include sterile water, Ringer's solution, or isotonic saline solution. Alternatively, sterile oils can be used as solvents or suspending agents. Preferably, the oil or fatty acid is a non-volatile substance, including natural or synthetic oils, fatty acids, monoglycerides, diglycerides, or triglycerides.

[0187] For injection, the pharmaceutical formulation may be a powder suitable for reconstitution with the appropriate solutions described above. Examples of such powders include, but are not limited to, lyophilized, rotary-dried, or spray-dried powders, amorphous powders, granules, precipitates, or microparticles. For injections, the formulation may optionally contain stabilizers, pH adjusters, surfactants, bioavailability modifiers, and combinations thereof. The compound may be formulated for parenteral administration by injection, such as by bolus or continuous infusion. The unit dosage form for injection may be in ampoules or multi-dose containers. In addition to the representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known and can be used by those skilled in the art. Such excipients and carriers are described, for example, in “Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference.

[0188] Compounds (e.g., treprostrine analogs, treprostrine prodrugs, and / or treprostrine conjugates) can be formulated into preparations suitable for parenteral administration, comprising a sterile aqueous formulation of the compound or a pharmaceutically acceptable salt thereof, and isotonic with the blood of the intended recipient. These preparations can be administered subcutaneously, but may also be administered intravenously, intramuscularly, or intradermally. Such preparations can be conveniently prepared by mixing the compound with water or a glycine or citrate buffer and ensuring the resulting solution is sterile and isotonic with blood. Injectable preparations may contain 0.1% to 5% w / v of treprostrine based on the weight of the prodrug, analog, and / or conjugate, and may be administered at a rate of 0.1 ml / min / kg. Alternatively, the prodrug, analog, and / or conjugate may be administered at a rate of 0.625 to 50 ng / kg / min based on the weight of treprostrine in the prodrug. Alternatively, the prodrug, analogue, and / or conjugate may be administered at a rate of 10 to 15 ng / kg / min based on the weight of treprostol in the prodrug.

[0189] In some embodiments, the concentration of treprostil prodrug, treprostil analogues, and / or treprostil conjugates in formulations intended for parenteral administration (e.g., intravenous or subcutaneous infusion, including continuous subcutaneous infusion) may be from 0.0005 to 30 mg / mL, or from 0.0007 to 50 mg / mL, or from 0.001 to 15 mg / mL, or any value or subrange within these ranges. Exemplary concentrations may include 0.1 mg / mL, 1 mg / mL, 2.5 mg / mL, 5 mg / mL, or 10 mg / mL.

[0190] In some embodiments, formulations of treprostine prodrugs, treprostine analogs, and / or treprostine conjugates for parenteral administration (e.g., intravenous or subcutaneous infusion, including continuous subcutaneous infusion) can be prepared by mixing the prodrug with a carrier (e.g., a buffer solution). In some embodiments, the carrier may be a phosphate-containing carrier, i.e., at least one phosphate, such as a hydrogen phosphate (e.g., disodium hydrogen phosphate or dipotassium hydrogen phosphate), or a triphosphate (e.g., trisodium phosphate or tripotassium phosphate). In some embodiments, the carrier may also contain a halogen salt, such as a chloride salt, which may be, for example, sodium chloride or potassium chloride. The halogen salt (e.g., sodium chloride) may be used to adjust the osmotic pressure of the carrier. In some embodiments, it is preferred that the phosphate and the halogen salt have the same cation. For example, when the phosphate is sodium phosphate (e.g., trisodium phosphate or trisodium chloride), the halogen salt may be a sodium halide, such as sodium chloride. Similarly, when the phosphate is potassium phosphate (e.g., tripotassium phosphate or tripotassium chloride), the halogen salt may be a potassium halide, such as potassium chloride. The solvent in the carrier may contain water. In some embodiments, water may be the only solvent in the carrier. However, in some embodiments, the carrier may contain one or more other solvents besides water. In some embodiments, the other solvents may be preservatives, such as m-cresol.

[0191] Preferably, the carrier is isotonic with the blood of a patient (e.g., a human). The term "isotonic" can mean that the osmotic pressure and ion concentration of the carrier match those of the patient's (e.g., a human) blood. Non-limiting examples of carriers include phosphate-buffered saline, a water-based salt solution containing disodium hydrogen phosphate and sodium chloride, and in some formulations, potassium chloride and potassium dihydrogen phosphate. Other examples may include carriers containing 20 mM disodium hydrogen phosphate and 125 mM sodium chloride, and carriers containing 15 mM trisodium phosphate, 125 mM sodium chloride, and 0.3% w / w m-cresol.

[0192] Option 1

[0193] Figure 1A -B illustrates scheme 1, which can be used to synthesize intermediate 12, which can be further used to synthesize treprostrinil, its prodrug and analogues. Figure 1A The general process of scheme 1 is shown, while Figure 1B An exemplary condition for scheme 1 is shown. In the scheme, n is a non-zero integer, such as 0, 1, 2, 3, 4, 5. P 1 P 2 and P 3All are alcohol (hydroxyl) protecting groups. Various protecting groups, including but not limited to hydroxyl and phenolic protecting groups, are disclosed, for example, in Greene's Protective Groups in OrganicSynthesis 5th Edition, Wiley; 5th edition, 2014. Non-limiting examples of hydroxyl protecting groups include 2-tetrahydropyranyl (THP), acetyl (Ac), and silyl ether protecting groups, such as tert-butyldimethylsilyl ether (TBDMS / TBS), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldiphenylsilyl (TBDPS), and triisopropylsilyl (TIPS). X is a phenolic protecting group, such as an alkyl group (e.g., C1-C4 alkyl) or a substituted or unsubstituted benzyl group, or CH2COOR. 24 , where R 24 It is an alcohol protecting group, such as an alkyl group (e.g., C1-C4 alkyl) or a substituted or unsubstituted benzyl group. The substituted benzyl group in X may optionally be substituted by one or more substituents at one or more meta, ortho, or para positions, said substituents may be independently selected from the group consisting of: -NO2, -CN, halogens (e.g., -F, -Cl, -Br or -I), (C1-C3)alkyl, halo(C1-C3)alkyl, (C1-C3)alkoxy, and halo(C1-C3)alkoxy.

[0194] Scheme 1 involves the chiral addition of the protected alkyne compound 2 to the aldehyde compound 3 to yield a chiral alcohol 6. The length of the alkyne compound 2 can vary. In some embodiments, the chiral addition can be carried out in the presence of a chiral catalyst such as one or more of the following: (+)-N-methylephedrine, Zn(OTf)2 / Et3N, or (1S,2S)-3-(tert-butyldimethylsiloxy)-2-N,N-dimethylamino-L-(p-nitrophenyl)-prop-1-ol. However, in some embodiments, the chiral addition can be carried out via intermediate compounds 4 and 5.

[0195] Chiral alcohol 6 can react with alcohol (hydroxyl) group protecting agents to form protected alcohol compound 7. "Alcohol protecting agent" refers to an agent that converts the -OH group to -OP. 2 The reagent. In one embodiment, the alcohol protecting reagent is TBDMSCl.

[0196] In some embodiments, the reaction of chiral alcohol 6 with the alcohol (hydroxyl) group protecting agent can be carried out in the presence of a base. Suitable bases that can be used include, but are not limited to, alkali metal carbonates, alkali metal hydroxides, amines, and ammonium hydroxide. In some embodiments, the base may include an amine. In some embodiments, the base may include dimethylaminopyridine (DMAP).

[0197] In some embodiments, the reaction of chiral alcohol 6 with the alcohol (hydroxyl) group protecting agent can be carried out in a suitable solvent or mixture of solvents. For example, the reaction can be carried out in organic solvents such as ether solvents (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, and dimethoxyethane), aromatic solvents (e.g., benzene and toluene), chlorinated solvents (e.g., dichloromethane and 1,2-dichloroethane), dimethylformamide, dimethyl sulfoxide, acetonitrile, or any mixture of these solvents. In one embodiment, the solvent may include one or more of dimethylformamide (DMF) and dichloromethane (DCM).

[0198] The protected alcohol compound 7 can be converted into a tricyclic compound 8 via a cyclization reaction. This cyclization reaction can be carried out in the presence of a cyclization catalyst, which may be a cobalt-containing cyclization catalyst, such as CO2(CO)8.

[0199] In some embodiments, the cyclization reaction is carried out in an organic solvent or a mixture of organic solvents. Suitable organic solvents include, but are not limited to, ether solvents (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, and dimethoxyethane), aromatic solvents (e.g., benzene and toluene), chlorinated solvents (e.g., dichloromethane and 1,2-dichloroethane), dimethylformamide, dimethyl sulfoxide, acetonitrile, or mixtures of these solvents. In some embodiments, the cyclization reaction can be carried out in CH₂Cl₂, followed by removal of the solvent by distillation. The reaction can then be carried out in acetonitrile.

[0200] Tricyclic compound 8 can be hydrogenated with H2 to form compound 9. In some embodiments, the hydrogenation reaction is carried out in the presence of a hydrogenation catalyst (e.g., Pd, C, or a combination thereof). In some embodiments, the hydrogenation reaction is carried out in the presence of a Pd / C hydrogenation catalyst. In some embodiments, the hydrogenation reaction is carried out in the presence of a base (e.g., a basic carbonate (e.g., K2CO3)). In some embodiments, the hydrogenation reaction is carried out in the presence of a hydrogenation catalyst (e.g., Pd / C) and a base (e.g., a basic carbonate (e.g., K2CO3)).

[0201] The hydrogenation reaction can be carried out in organic solvents, such as ether solvents (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, and dimethoxyethane), aromatic solvents (e.g., benzene and toluene), chlorinated solvents (e.g., dichloromethane and 1,2-dichloroethane), alcohol solvents (e.g., methanol, ethanol, 2-propanol), dimethylformamide, or any combination of these solvents. In some embodiments, the hydrogenation reaction is carried out in EtOH.

[0202] Compound 9 reacts with a reducing agent to form compound 10. A "reducing agent" is a reagent capable of converting a carbonyl functional group into an alcohol (hydroxyl) functional group. Suitable reducing agents include, but are not limited to, NaBH4 and LiAlH4. In some embodiments, the reaction can be carried out in the presence of a base, such as an alkali metal hydroxide (e.g., NaOH). The reaction can be carried out in an organic solvent, such as the organic solvents discussed in the previous reactions above. In some embodiments, the reaction can be carried out in EtOH.

[0203] Compound 10 can react with an alcohol (or hydroxyl) protecting agent to form compound 11. This reaction is achieved by protecting group P with the alcohol (or hydroxyl) group in compound 11. 3 The hydrogen atom on the cyclopentyl hydroxyl group in compound 10 is replaced, thereby protecting the cyclopentyl hydroxyl group. In some embodiments, P 3 The protecting group can be acetyl (Ac) or a silyl ether hydroxyl group, such as tert-butyldimethylsilyl ether (TBDMS / TBS), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldiphenylsilyl (TBDPS), or triisopropylsilyl (TIPS). This protection reaction can be carried out in one or more of the organic solvents discussed in the previous reactions.

[0204] Compound 11 can be modified by replacing the alcohol protecting group P with hydrogen. 1 To deprotect and form compound 12. When P 1 When the substance is THP, the deprotection reaction can be carried out in the presence of MgBr2. The deprotection reaction can be carried out in an organic solvent, such as those discussed in the previous reactions described above. In some embodiments, the deprotection reaction can be carried out in diethyl ether.

[0205] Compound 12 can be used as an intermediate in the synthesis of treprostrinil, its analogues, its prodrugs and / or its conjugates.

[0206] Option 2

[0207] Figure 2A -B illustrates scheme 2, which shows how compound 12 can be used to synthesize treprostrinil, its analogues, its prodrugs, and / or its conjugates. Figure 2A The general process of Scheme 2 is shown. Figure 2B Exemplary conditions for scheme 2 are shown.

[0208] Compound 12 can be converted into tricyclic olefin 21, which can also be used as an intermediate in the synthesis of treprostrin, its analogues, its prodrugs, and / or its conjugates. In some embodiments, tricyclic olefin 21 can be directly converted into treprostrin, treprostrin analogues, or treprostrin prodrugs, such as compounds 25A or 25B, via, for example, metathesis reactions.

[0209] In some further embodiments, tricyclic olefin 21 can be converted into tricyclic aldehyde 22, which can also be used as an intermediate in the synthesis of treprostyl, its analogues, its prodrugs, and / or its conjugates. The synthesis of tricyclic olefin 21 and tricyclic aldehyde 22 is as follows: Figure 3A As shown in Scheme 3 of -B. In some embodiments, tricyclic olefin 21 can be converted to tricyclic aldehyde 22 in the presence of an oxidant (e.g., OsO4, NaIO4, O3, or any combination thereof). For example, the oxidant can be OsO4 / NaIO4 or O3.

[0210] In some implementations, tricyclic aldehyde 22 can be directly converted into treprostyl, treprostyl analogues, or treprostyl prodrugs, such as compounds 25A or 25B, for example, as in scheme 4 ( Figure 4A -B) or Option 5 Figure 5A -B) is shown. Such transformations may involve coupling reactions, such as the Horner-Wadsworth-Emmons (HWE) coupling reaction.

[0211] In some embodiments, tricyclic aldehyde 22 can be converted into tricyclic alkyne 24, which can also be used as an intermediate in the synthesis of treprostyl, its analogues, its prodrugs, and / or its conjugates. In some embodiments, tricyclic aldehyde 22 can be converted into tricyclic alkyne 24 via a Seyferth-Gilbert homologation reaction and / or a Corey-Fuchs reaction. Tricyclic alkyne 24 can be directly converted into treprostyl, treprostyl analogues, or treprostyl prodrugs, such as compounds 25A or 25B, for example, by reacting with compound 23. Treprostyl, treprostyl analogues, or treprostyl prodrugs, such as compounds 25A or 25B, can be further converted into treprostyl analogues or treprostyl prodrugs, such as compounds 26A or 26B. 3 R 4 R 5 Various combinations (as Figure 2A-2B In this regard, a variety of treprostil analogues and prodrugs can be obtained, such as compounds 25A, 25B, 26A and 26B.

[0212] Option 3

[0213] Figure 3A Scheme 3 in -B schematically illustrates an exemplary route for synthesizing tricyclic olefins (e.g., tricyclic olefin 21 in Scheme 2) and tricyclic aldehydes (e.g., tricyclic aldehyde 22 in Scheme 2). Figure 3A The general process of Scheme 3 is shown, while Figure 3B Exemplary conditions for Scheme 3 are shown. The initial reaction in Scheme 3 is similar to that in Scheme 1.

[0214] Scheme 3 involves the chiral addition of the protected alkyne compound 32 (compound 2 in Scheme 1, n=0) to the aldehyde compound 31 (compound 3 in Scheme 1) to obtain the chiral alcohol 33 (compound 6 in Scheme 1, where n=0).

[0215] Chiral alcohol 33 can react with an alcohol (hydroxyl) group protector to form protected alcohol compound 34 (compound 7 in scheme 1, where n = 0).

[0216] The protected alcohol compound 34 can be converted into a tricyclic compound 35 (compound 8 in scheme 1, where n = 0) through a cyclization reaction.

[0217] Tricyclic compound 35 can be hydrogenated with H2 to form compound 36. When X is Bn in the preceding compound of Scheme 1, compound 36 can be compound 9 of Scheme 1 (n = 0, X = H), or when X is CH3, compound 36 can be compound 9 of this scheme (n = 0 and X is CH3). During hydrogenolysis, the benzyl group of X will be cleaved and replaced by H; only CH3 will not be cleaved under hydrogenolysis conditions.

[0218] Compound 36 can react with a reducing agent to form compound 37 (compound 10 in scheme 1, where n = 0 and X = H).

[0219] Compound 37 is converted into compound 38 (compound 10 in scheme 1, where n = 0 and X = CH2COOP). 4 , where P 4 (The protecting group is a carboxylic acid, such as a C1-C4 alkyl group or a substituted or unsubstituted benzyl group).

[0220] Compound 38 can react with an alcohol (or hydroxyl) protecting agent to form compound 39 (compound 11 in scheme 1, where n = 0, X = CH2COOP). 4 ).

[0221] Compound 39 is protected by replacing the alcohol group P with hydrogen. 1 Deprotection is then performed to form compound 40 (compound 12 in scheme 1), where n = 0 and X = CH2COOP. 4 ).

[0222] Compound 40 can react with alcohol (hydroxyl) protecting agents, using alcohol protecting group P. 6 The terminal hydrogen is replaced by the alcohol protecting group P. 6 It can react with the alcohol protecting group P 1 The differences lead to the formation of compound 41. For example, in some embodiments, P 6The solvent may be a sulfonated alcohol, such as methanesulfonyl or toluenesulfonyl. The reaction with the sulfonated alcohol (e.g., methanesulfonyl chloride or toluenesulfonyl chloride) may be carried out in one or more of the solvents described above. In some embodiments, the solvent may include trimethylamine, dichloromethane, or a combination thereof.

[0223] Compound 41 can be modified by replacing OP with a halogen (e.g., Br or I). 6 (where P) 6 The sulfonated alcohol is converted to compound 42. This conversion can be achieved, for example, by reacting compound 41 with a halide salt of an alkali metal (e.g., Na or K). For example, compound 41 can react with NaI, NaBr, KI, or KBr. The reaction can be carried out in one or more of the above-mentioned solvents. In some embodiments, the reaction can be carried out in 2-butanone.

[0224] Compound 42 can be converted into tricyclic olefin compound 43 (compound 21 in scheme 2, wherein R 1 For P 3 R 2 CH2COOP 4 Such a transformation can be carried out, for example, by reacting compound 42 with a base (e.g., potassium tert-butoxide). This reaction can be carried out in one or more of the solvents described above. In some embodiments, the reaction can be carried out in DMF.

[0225] Compound 43 can be converted to compound 44. This conversion can be carried out, for example, by reacting compound 43 with an oxidizing agent, which may include, for example, 4-methylmorpholine 4-oxide (NMO), OsO4, or combinations thereof. The reaction can be carried out in one or more of the above-described solvents. In some embodiments, the reaction can be carried out in tetrahydrofuran (THF), water, or combinations thereof.

[0226] Compound 44 can be converted into tricyclic aldehyde compound 45 (compound 22 in scheme 2, wherein R 1 For P 3 R 2 CH2COOP 4 Such a conversion can be carried out, for example, by reacting compound 43 with an oxidizing agent, which may include, for example, OsO4, NaIO4, O3, or a combination of two or more thereof. The reaction can be carried out in one or more of the aforementioned solvents. In some embodiments, the reaction can be carried out in 1,2-dichloroethane (DCE), water, or a combination thereof.

[0227] although Figure 3A -B is not shown, but in some embodiments, tricyclic olefin compound 43 can be converted into tricyclic aldehyde compound 45 by ozone decomposition.

[0228] Tricyclic olefin compound 43 and tricyclic aldehyde compound 45 can be used to synthesize treprostil, treprostil analogs and treprostil prodrugs.

[0229] Option 4

[0230] Figure 4A Scheme 4 in -B schematically illustrates an exemplary route for the synthesis of triprostene from tricyclic aldehyde compound 45, which can be synthesized, for example, according to Scheme 3. Figure 4A The general process of Scheme 4 is shown, while Figure 4B Exemplary conditions for scheme 4 are shown.

[0231] Tricyclic aldehyde compound 45 can be converted into compound 47 via a side-chain coupling reaction. This side-chain coupling reaction can be a phosphonate chain coupling reaction, wherein the tricyclic aldehyde compound reacts with phosphonate compound 46 to form compound 47. The phosphonate chain coupling reaction can be carried out in a solvent (such as methyl tert-butyl ether) in the presence of a base (such as lithium hydroxide monohydrate, e.g., LiOH·H₂O).

[0232] Compound 47 can be converted to compound 48 in a reduction reaction. The reduction reaction can be a Luche reduction reaction, which can be carried out, for example, in the presence of sodium borohydride (NaBH4) and a lanthanide chloride (such as cerium trichloride (CeCl3)) in an alcohol (such as methanol or ethanol).

[0233] Compound 48 can be further converted to compound 49 in a reduction reaction. The reduction reaction can be a hydrogenation reaction carried out in the presence of a hydrogenation catalyst (such as carbon-supported palladium (Pd / C)).

[0234] Compound 49 can be converted to treprostinil 1 via a deprotection reaction.

[0235] Option 5

[0236] Figure 5A Scheme 5 in -B schematically illustrates an exemplary route for synthesizing a tricyclic aldehyde compound 45, which can be synthesized, for example, according to Scheme 3. Figure 5A The general process of Scheme 5 is shown, while Figure 5B An example of the conditions for scheme 5 is shown.

[0237] Tricyclic aldehyde compound 45 can be converted into compound 52 via a side-chain coupling reaction. This side-chain coupling reaction can be a phosphonate chain coupling reaction, in which the tricyclic aldehyde compound reacts with phosphonate compound 51 to form compound 52. This phosphonate chain coupling reaction can be carried out in a solvent (such as methyl tert-butyl ether) in the presence of a base (such as lithium hydroxide monohydrate, e.g., LiOH·H2O).

[0238] Compound 52 can be converted to compound 53 by a reduction reaction. This reduction reaction can be an enantioselective reduction reaction carried out in the presence of a chiral catalyst (such as a chiral oxazaborolidine catalyst, for example (R)-2-methyl-CBS-oxazaborolidine).

[0239] Compound 53 can be converted to compound 54 in a cyclopentyl deprotection reaction.

[0240] Compound 54 can be converted into compound 55 through deprotection reactions (such as alkaline hydrolysis).

[0241] Figure 6 Triprostene analogues prepared using the methods discussed above and below are shown.

[0242] Option 6

[0243] Figure 7A Scheme 6 in -B schematically illustrates an exemplary route for synthesizing compound 75 from compound 12, which can be synthesized, for example, according to scheme 1. Figure 7A The general process of Scheme 6 is shown, while Figure 7B Exemplary conditions for scheme 6 are shown.

[0244] Compound 12 can be converted to compound 71 via a deprotection reaction (which may be a selective deprotection reaction). This deprotection reaction may be a demethylation reaction, which can be carried out in the presence of demethylation conditions (such as a combination of Ph2PH and BuLi or the reaction product of such a combination, such as Ph2PLi).

[0245] Compound 71 can be converted into compound 72 by reacting with a protected haloacetic acid ester (such as benzyl bromoacetate).

[0246] Compound 72 can be converted into aldehyde compound 73. This reaction can be carried out in the presence of an oxidizing agent, such as pyridine dichromate (PDC).

[0247] Aldehyde compound 73 can be converted into compound 74 via an oxidation reaction. This oxidation reaction can be the Pinnick oxidation in the presence of NaClO2.

[0248] Compound 74 can be converted into treprostinil analog 75 through a deprotection reaction.

[0249] Option 7

[0250] Figure 8A Scheme 7 in -B schematically illustrates an exemplary route for synthesizing compound 89 from compound 12, which can be synthesized, for example, according to scheme 1. Figure 8A The general process of Scheme 7 is shown, while Figure 8BAn example of the conditions for scheme 7 is shown.

[0251] Compound 12 can be converted to compound 81 by replacing the terminal hydroxyl group with a halogen (e.g., Br or I). For example, such a conversion can be carried out by reacting compound 12 with methanesulfonyl chloride, followed by a halide salt of an alkali metal (such as Na or K). For example, compound 12 can be reacted with methanesulfonyl chloride, followed by NaI, NaBr, KI, or KBr. The reaction can be carried out in one or more of the aforementioned solvents. In some embodiments, the reaction can be carried out in 2-butanone.

[0252] Compound 81 can be converted into tricyclic olefin compound 82. Such a conversion can be carried out, for example, by reacting compound 81 with a base (e.g., potassium tert-butoxide). This reaction can be carried out in one or more of the aforementioned solvents. In some embodiments, the reaction can be carried out in DMF.

[0253] Compound 82 can be converted into compound 83 by an oxidation reaction, which can be carried out in the presence of an oxidant (such as OsO4).

[0254] Compound 83 can be converted to compound 84 via a deprotection reaction (which may be a selective deprotection reaction). This deprotection reaction may be a demethylation reaction, which can be carried out in the presence of demethylation conditions (such as a combination of Ph2PH and BuLi or the reaction product of such a combination, such as Ph2PLi).

[0255] Compound 84 can be converted into compound 85 by reacting with a protected haloacetic acid ester (such as benzyl bromoacetate).

[0256] Compound 85 can be converted to compound 86 via a deprotection reaction, which can be a selective deprotection of the cyclopentyl ring. Such deprotection can be carried out in the presence of a deprotecting agent such as pyridine p-toluenesulfonate (PPTS).

[0257] Compound 86 can be converted into tricyclic aldehyde compound 87 by an oxidation reaction, which can be carried out in the presence of an oxidant (such as OsO4, NaIO4, O3, or a combination of two or more thereof).

[0258] Compound 87 can be converted into compound 88 by reacting with N2CHCO2Et.

[0259] Compound 88 can be converted into treprostinil analog 89 via a deprotection reaction, which can be carried out in the presence of a base.

[0260] Option 8

[0261] Figure 9AScheme 8 in -B schematically illustrates an exemplary route for synthesizing a triprostene analogue 96A from compound 12, which can be synthesized, for example, according to Scheme 1. Figure 9A The general process of Scheme 8 is shown, while Figure 9B Exemplary conditions for scheme 8 are shown.

[0262] Compound 12 can be converted into aldehyde compound 92. This reaction can be carried out in the presence of an oxidizing agent, such as pyridine dichromate (PDC).

[0263] Aldehyde compound 92 can be converted into a mixture of compounds 93 and 94, which can be further converted into a mixture of compounds 96A, 96B and 95 through deprotection reactions.

[0264] Compound 96A can be separated from the mixture using separation techniques such as HPLC.

[0265] Option 9

[0266] Figure 10A Scheme 9 in -B schematically illustrates an exemplary route for synthesizing compound 108 from compound 12, which can be synthesized, for example, according to scheme 1. Figure 10A The general process of Scheme 9 is shown, while Figure 10B Exemplary conditions for scheme 9 are shown.

[0267] Compound 12 can be converted into aldehyde compound 101. This reaction can be carried out in the presence of an oxidizing agent, such as pyridine dichromate (PDC).

[0268] Then, compound 101 can be converted into compound 102.

[0269] Compound 102 can be converted to compound 103 via a deprotection reaction (which may be a selective deprotection reaction). This deprotection reaction may be a demethylation reaction, which can be carried out in the presence of demethylation conditions (such as a combination of Ph2PH and BuLi or the reaction product of such a combination, such as Ph2PLi).

[0270] Compound 103 can be converted into compound 104 by reacting with a protected haloacetic acid ester (such as benzyl bromoacetate).

[0271] Compound 104 can be converted into compound 105 by protecting the hydroxyl group.

[0272] Compound 105 can be converted to compound 106 in the presence of a deprotecting agent (such as pyridine p-toluenesulfonate (PPTS)).

[0273] Compound 106 can be converted to compound 107 by an oxidation reaction. This oxidation reaction can be the Pinnick oxidation in the presence of an oxidizing agent (such as NaClO2).

[0274] Compound 107 can then be converted to a mixture of compound 108L and treprostrinil analog 108 via a deprotection reaction. Treprostrinil analog 108 can be separated from this mixture using separation techniques such as HPLC. Treprostrinil analog 108 can be converted to its salt, such as its sodium salt.

[0275] Option 10

[0276] Figure 11A Scheme 10 in -B schematically illustrates an exemplary route for synthesizing compound 117 from treprogenyl. Figure 11A The general process of Scheme 10 is shown, while Figure 11B An example of the conditions for scheme 10 is shown.

[0277] Tripronil 1 can be converted into compound 111 by selectively protecting the carboxylic acid group.

[0278] Compound 111 can react with a silane protecting agent (such as tert-butyldimethylchlorosilane TBDMSCl or tert-butyldiphenylchlorosilane TBDPSCl). Such a reaction can produce a mixture of the desired compound 112 (whose silane protecting group is located on the hydroxyl group of the cyclopentyl group, but not on the hydroxyl group of the alkyl group), the undesirable compound 113 (whose silane protecting group is located on the hydroxyl group of the alkyl group, but not on the hydroxyl group of the cyclopentyl group), and a minor product 114 (whose silane protecting group is located on both the hydroxyl groups of the alkyl group and the hydroxyl group of the cyclopentyl group).

[0279] The desired compound 112 can be separated from the mixture using separation techniques such as column chromatography, HPLC, and SFC.

[0280] Compound 112 can be converted into compound 115. Such reactions can be carried out in the presence of an oxidizing agent, such as pyridine chlorochromate (PCC).

[0281] Compound 115 can be converted into compound 116 by benzyl esters with deprotected carboxylic acid groups (e.g., by hydrogenolysis).

[0282] Compound 116 can be converted into treprostinil analog 117 via a deprotection reaction.

[0283] Option 11

[0284] Figure 12A Scheme 11 in -B schematically illustrates an exemplary route for synthesizing a trepanenil analogue 126 from trepanenil. Figure 12AThe general process of Scheme 11 is shown, while Figure 12B An exemplary condition for scheme 11 is shown.

[0285] Triprostrinil 1 can be converted to compound 121 via esterification. Compound 121 can then be converted to a mixture of compounds 123, 124, and 125. This mixture can be converted to a mixture of compounds 126, 127, and 128 via alkaline hydrolysis. Compound 126 can be separated from the mixture using techniques such as HPLC.

[0286] The implementation schemes described herein are further illustrated by the following working examples, but are not limited thereto.

[0287] Working Example

[0288] 1. Synthesis of Treprostane and Treprostane analogues

[0289] 1.1. Synthesis of Tricyclic Aldehyde Cores

[0290]

[0291] experiment:

[0292] Synthesis of chiral benzyl alkynol (33):

[0293] Triethylamine (8.0 g, 0.0792 mol) and (1S,2R)-(+)-N-methylephedrine (10.6 g, 0.99 mol) were added to a solution of zinc trifluoromethanesulfonate (21.5 g, 0.99 mol) in toluene (50 mL), and the mixture was stirred at room temperature for 2 hours. 2-(3-butynoxy)tetrahydro-2H-pyran (32) (12.2 g, 0.0792 mol) was added to the mixture, and the mixture was stirred for 0.5 hours. A solution of 2-allyl-3-benzyloxybenzaldehyde (31) (5.0 g, 0.0198 mol) in toluene (10 mL) was added to the mixture. The reaction mixture was stirred overnight at room temperature. After completion, the reaction was post-processed to give crude product (33) (60.2 g), a viscous liquid. The crude product was purified by column chromatography to give pure chiral benzylalkynol (33) (7.22 g).

[0294] Synthesis of benzyl alkynol tert-butyl dimethyl silyl ether (34):

[0295] To a solution of chiral benzylalkynol (33) (7.15 g, 0.0176 mol) in dichloromethane (80 mL), 2,6-dimethylpyridine (2.45 g, 0.0229 mol) was added, and the mixture was stirred at ambient temperature under argon atmosphere. The mixture was stirred until a clear solution was obtained. The mixture was cooled, and a solution of tert-butyldimethylsilyltrifluoromethanesulfonate (6.05 g, 0.0229 mol) in dichloromethane (40 mL) was added dropwise. After the reaction was complete, the product was post-processed to give crude product (34) (9.6 g), which was a viscous liquid. Another batch of 7.15 g of product was combined and purified by column chromatography to give pure benzylalkynol tert-butyldimethylsilyl ether (34) (16.93 g).

[0296] Synthesis of tricyclic enones (35):

[0297] To a solution of benzylalkynol tert-butyl dimethyl silyl ether (34) (6.8 g, 0.0138 mol) in toluene (70 mL), cobalt octacarbonyl (4.7 g, 0.0138 mol) was added. The mixture was then heated to reflux for 2 hours. The reaction mixture was filtered through diatomaceous earth and evaporated under vacuum to give crude compound (35) (12.8 g) as a viscous liquid. The crude product was purified by column chromatography to give tricycloenone (35) (5.8 g).

[0298] Synthesis of tricyclic ketones (36):

[0299] Pd / C (2.69 g) was added to a solution of tricyclotenone (35) (5.4 g, 0.0098 mol) in ethanol (80 mL) and water (2.7 mL). The mixture was stirred under a hydrogen atmosphere. After 24 hours, the reaction mixture was passed through diatomaceous earth, and the filtrate was evaporated under vacuum to give crude tricyclotenone (36) (5.1 g) as a viscous liquid. The crude product was purified by column chromatography to give tricyclotenone (36) (3.08 g).

[0300] Synthesis of tricyclic alcohol (37):

[0301] At -10°C, a solution of sodium hydroxide (6.2 g, 0.155 mol) in water (20 mL) was added to an ethanol (90 mL) solution of tricyclic ketone (36) (5.1 g, 0.015 mol). Sodium borohydride (1.1 g, 0.031 mol) was then added to the mixture. The reaction mixture was stirred for 2 hours until the reaction was complete. The reaction mixture was then post-treated and concentrated under vacuum to obtain crude product (37) (4.95 g). The crude product could be used directly in the next reaction without further purification.

[0302] Synthesis of tricyclic methyl ester (38):

[0303] Potassium carbonate (4.0 g, 0.0288 mol) and methyl bromoacetate (2.2 g, 0.0158 mol) were added to a solution of tricyclool (37) (4.8 g, 0.0144 mol) in acetone (70 mL). The reaction mixture was stirred. After 72 hours, the reaction was complete. The reaction mixture was filtered, and the filtrate was evaporated under vacuum to give crude product (38) (6.3 g), which was a viscous liquid. The crude product (6.3 g) was purified by column chromatography to give tricyclomethyl ester (38) (5.5 g).

[0304] Synthesis of tricyclic tert-butyl dimethyl silyl ether (39):

[0305] Add 2,6-dimethylpyridine (1.1 g, 0.0103 mol) to a solution of tricyclomethyl ester (38) (2.8 g, 0.0069 mol) in dichloromethane (30 mL). Cool the mixture and add dropwise a solution of tert-butyldimethylsilyltrifluoromethanesulfonate (2.19 g, 0.0082 mol) in dichloromethane (20 mL). Stir the reaction mixture for 1 hour until the reaction is complete. Post-process the reaction mixture to give crude product (39) (4.2 g), a viscous liquid. Combine another batch of 2.8 g of crude product and purify by column chromatography to give tricyclotert-butyldimethylsilyl ether (39) (6.39 g).

[0306] Synthesis of tricyclic tert-butyldimethylsilyl ether alcohol (40):

[0307] Magnesium bromide (3.19 g, 0.0173 mol) was added to a solution of tricyclo-tert-butyldimethylsilyl ether (39) (1.5 g, 0.0028 mol) in diethyl ether (30 mL). The reaction mixture was stirred overnight. After 24 hours, the reaction mixture was post-treated to give crude product (40) (1.6 g), which was a viscous liquid. The crude product (1.6 g) was purified by column chromatography to give tricyclo-tert-butyldimethylsilyl ether alcohol (40) (1.1 g).

[0308] Synthesis of tricyclic methanesulfonate (41):

[0309] Triethylamine (0.58 g, 0.0057 mol) was added to a solution of tricyclo-tert-butyldimethylsilyl ether alcohol (40) (1.1 g, 0.0026 mol) in dichloromethane (30 mL). Methanesulfonyl chloride (0.36 g, 0.0031 mol) was then added to the cooled mixture. After addition, the reaction mixture was stirred for 2 hours. The reaction was then complete. The reaction was post-treated to give crude tricyclomethanesulfonate (41) (1.37 g). The crude product could be used directly in the next reaction without further purification.

[0310] Synthesis of tricyclic iodide (42):

[0311] Sodium iodide (2.45 g, 0.0164 mol) was added to a solution of tricyclic methanesulfonate (41) (1.37 g, 0.0027 mol) in 40 mL of 2-butanone. The reaction mixture was refluxed for 1.5 hours. At this point, the reaction was complete. The reaction mixture was evaporated and post-treated to give crude tricyclic iodide (42) (1.2 g), a viscous liquid. The crude product can be used directly in the next reaction without further purification.

[0312] Synthesis of tricyclic olefins (43):

[0313] Potassium tert-butoxide (2.97 g, 0.02646 mol) was added to a solution of tricyclic iodide (42) (2.34 g, 0.00429 mol) in N,N-dimethylformamide (35 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was post-treated to obtain crude tricyclic olefin (1.98 g). Potassium carbonate (2.72 g, excess) and methyl iodoform (2.79 g, excess) were added to a solution of the crude product in acetone (40 mL), and the mixture was stirred overnight at room temperature. The crude reaction mixture was passed through diatomaceous earth and evaporated under vacuum to obtain crude tricyclic olefin (43) (1.3 g). The crude product was purified by column chromatography to obtain tricyclic olefin (43) (0.85 g).

[0314] Synthesis of tricyclic diol (44):

[0315] Osmium tetroxide (0.01 g, 0.00005 mol) and 4-methylmorpholine-N-oxide (0.06 g, 0.00053 mol) were added to a solution of tricyclic olefin (43) (0.21 g, 0.00052 mol) in a mixture of tert-butanol (10 mL), tetrahydrofuran (3 mL), and water (1 mL) (ratio = 10:3:1), and the mixture was stirred at room temperature under argon atmosphere. After 4 hours, the reaction was complete, and the reaction mixture was post-treated to give crude tricyclic diol (44) (0.14 g). This crude compound could be used directly in the next reaction without further purification.

[0316] Synthesis of tricyclic aldehydes (45):

[0317] Sodium periodate (0.12 g, 0.00077 mol) was added to a solution of tricyclic diol (44) (0.14 g, 0.00031 mol) in a mixture of 1,2-dichloroethane (10 mL) and water (10 mL) (ratio = 1:1) at room temperature. After two nights, the crude reaction mixture was post-treated to give crude tricyclic aldehyde (45) (0.12 g). This crude compound could be used directly in the next reaction without further purification.

[0318] 1.2. Synthesis of pre-tristannin

[0319]

[0320] experiment:

[0321] Synthesis of tricyclic enones (47):

[0322] Lithium hydroxide monohydrate (0.01 g, 0.0004 mol) was added to a solution of dimethyl-2-oxohepylphosphonate (46) (0.08 g, 0.0004 mol) in tert-butyl methyl ether (5 mL), and the mixture was stirred at room temperature for 1.5 hours. A solution of tricyclic aldehyde (45) (0.12 g, 0.0002 mol) in tert-butyl methyl ether (5 mL) was then added to the mixture, and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, the mixture was post-processed to obtain crude tricyclic α,β-unsaturated ketone (47) (0.14 g). The crude product was purified by column chromatography to obtain pure tricyclic enone (47) (0.1 g).

[0323] Synthesis of tricycloenol (48):

[0324] At room temperature, cerium(III) heptahydrate (0.07 g, 0.0002 mol) was added to a methanol (10 mL) solution of a tricyclic α,β-unsaturated ketone (47) (0.1 g, 0.0002 mol). The mixture was cooled, and then sodium borohydride (0.007 g, 0.0002 mol) was added and stirred. After 1 hour, the reaction mixture was post-treated to give a crude product. The crude product was dissolved in methanol (10 mL), and 10% HCl aqueous solution (0.3 mL) was added. The mixture was stirred at room temperature. After 1 hour, the reaction mixture was post-treated to give crude tricycloenol (48) (0.07 g). This crude compound could be used in the next step without further purification.

[0325] Synthesis of treprostyl methyl ester (49):

[0326] Pd / C (0.1 g) was added to a solution of tricycloenol (48) (0.07 g) in a mixture of methanol (10 mL) and water (0.2 mL). The mixture was stirred overnight under a hydrogen atmosphere. The mixture was passed through diatomaceous earth and evaporated under vacuum to obtain crude treprostyl methyl ester (49) (0.07 g).

[0327] Synthesis of pre-tristanyl (1):

[0328] A solution of potassium hydroxide (0.09 g, 0.0002 mol) in water (1 mL) was added to a methanol (10 mL) solution of treprostyl methyl ester (49) (0.07 g, 0.0002 mol), and the mixture was stirred overnight. The reaction mixture was then post-treated and evaporated under vacuum to obtain solid treprostyl (1) (45 mg). This treprostyl methyl ester was... 1H NMR characterization.

[0329] 1.3. Synthesis of Triprostene Analogs

[0330]

[0331] experiment:

[0332] Synthesis of tricyclic enones (52):

[0333] Lithium hydroxide monohydrate (17 mg, 0.396 mmol) was added to a solution of tert-butyl methyl ether (1 mL) containing phosphonate side chain (51) (100 mg, 0.432 mmol), and the mixture was stirred at room temperature for 2 hours. A solution of tert-butyl methyl ether (2 mL) containing tricyclic aldehyde (45) (100 mg, 0.24 mol) was added to the mixture, and the mixture was stirred at room temperature for 4 hours. The reaction was post-treated to give crude tricyclic enone (52) (132 mg). This was combined with another batch of 301 mg crude product and purified by column chromatography to give pure tricyclic enone (52) (464 mg).

[0334] Synthesis of tricycloenol (53):

[0335] A toluene solution of (R)-(+)-2-methyl-CBS-oxazolborane (1.0 M, 114 μL, 0.114 mmol) was added to a toluene solution of borane dimethyl sulfide in toluene (0.3 mL) (2.0 M, 57 μL, 0.114 mmol), and the mixture was stirred for 1.5 h. After cooling, a toluene solution of tricycloenol (52) (30 mg, 0.057 mmol) (0.7 mL) was added, and the mixture was stirred for 1.5 h while maintaining the temperature at ambient temperature. The reaction mixture was post-treated to give crude product (53) (54 mg). Purification by column chromatography gave tricycloenol (53) (30 mg).

[0336] Synthesis of methyl ester (54):

[0337] 2.0 N hydrochloric acid (72 μL, 0.142 mmol) was added to a methanol (1 mL) solution of tricycloenol (53) (30 mg, 0.057 mmol), and the mixture was stirred for 2 hours. The reaction mixture was post-treated and evaporated under vacuum to give crude methyl ester (54) (22.6 mg). This crude compound could be used in the next reaction without further purification.

[0338] Synthesis of treprostinil analogues (55):

[0339] A solution of sodium hydroxide (5.2 mg, 0.131 mmol) in water (0.2 mL) was added to a methanol (1 mL) solution of methyl ester (54) (18 mg, 0.0044 mol), and the mixture was stirred for 4 hours. The crude reaction mixture was post-treated and evaporated under vacuum to obtain treprostil analog (55) (12.2 mg). This treprostil analog was obtained through... 1 H NMR characterization.

[0340] 1.3.2. Synthesis of Cyclohexyltriprostyl 60 analogue

[0341]

[0342] experiment

[0343] Synthesis of cyclohexyltricyclic TBDMS enone (57):

[0344] A solution of anhydrous tert-butyl methyl ether (MTBE) of cyclohexyl ketone phosphonate side chain (56) (0.078 g, 0.333 mmol) (2 mL) was added to a solution of tricyclic TBDMS aldehyde (45) (0.093 g, 0.221 mmol, freshly prepared from the corresponding alcohol) in anhydrous tert-butyl methyl ether (MTBE). The clear solution was stirred at room temperature under argon for 10 min, and then lithium hydroxide monohydrate (0.011 g, 0.262 mmol) was added in a single batch. The reaction mixture was stirred overnight at room temperature until complete. The mixture was quenched with water (10 mL) and the aqueous layer was separated. The aqueous layer was extracted with MTBE (2 × 15 mL). The combined MTBE extracts were washed with water (2 × 15 mL) and brine (1 × 5 mL), dried (Na₂SO₄), filtered, and concentrated under vacuum to give a viscous liquid (0.147 g). The crude product was purified by chromatography to obtain cyclohexyltricyclic TBDMS enone (57) (0.052 g), which was then analyzed by... 1 Characterized by ¹H NMR and MS, the purity was 85.7% by HPLC.

[0345] Synthesis of cyclohexyltricyclic TBDMS enol (58)

[0346] Under argon atmosphere, at room temperature, a solution of toluene (2.0 M) (0.10 mL, 0.20 mmol) of the borane-dimethyl sulfide complex was added to a solution of (R)-(+)-2-methyl-CBS-oxazolylborane in toluene (1.0 M) (0.20 mL, 0.20 mmol) and anhydrous toluene (1.0 mL). The mixture was stirred at room temperature for 1 hour, then cooled to -40 ± 5 °C. A solution of cyclohexyltricycloTBDMS enone (57) (0.05 g, 0.095 mmol) in anhydrous toluene (2.0 mL) was added dropwise to this cold solution. The reaction mixture was heated to -20 °C over 1 hour until the reaction was complete. The mixture was cooled to -50 ± 5 °C and then quenched by dropwise addition of anhydrous methanol (0.5 mL). The mixture was heated to 0 °C over 1 hour. The mixture was treated with saturated ammonium chloride (2.5 mL) and stirred for 15 minutes. The mixture was filtered to remove the white solid, and the solid was washed with MTBE (3 × 10 mL). The combined filtrates were transferred to a separatory funnel to separate the aqueous layer. The aqueous layer was extracted with MTBE (2 × 15 mL). The combined organic layers were washed with water (1 × 5 mL) and brine (1 × 5 mL), dried (Na₂SO₄), filtered, and concentrated under vacuum to give the crude product as a colorless viscous liquid (0.085 g). The crude product was chromatographically analyzed to obtain pure cyclohexyltricyclic TBDMS enol (58) (0.031 g), and the results were obtained by IR spectroscopy. 1 H NMR, 13 C NMR and MS characterization.

[0347] Synthesis of cyclohexyltricyclic hydroxyenol (59)

[0348] At room temperature, hydrochloric acid (2N) solution (0.08 mL, 0.16 mmol) was added to a methanol (1.5 mL) solution of cyclohexyltricycloTBDMS enol (58) (0.03 g, 0.057 mmol). The reaction mixture was stirred at room temperature for 30 minutes until complete. The mixture was neutralized to pH 7-8 with saturated sodium bicarbonate solution (2 mL), methanol was evaporated under vacuum, the aqueous residue was treated with water (10 mL), and then extracted with ethyl acetate (3 × 10 mL). The combined ethyl acetate extracts were washed with water (2 × 10 mL) and brine (1 × 5 mL), dried (Na₂SO₄), filtered, and concentrated under vacuum to give cyclohexyltricyclohydroxyenol (59), a pale yellow viscous liquid (0.021 g, 87.5%). 1 Characterized by 1H NMR, purity was determined by HPLC (92.2%).

[0349] Synthesis of cyclohexyltricyclomethyl ester (60)

[0350] At room temperature, 5 wt%, 50% wet palladium supported on carbon (0.01 g) was added to a methanol (1.5 mL) solution of cyclohexyltricyclohydroxyenol (59) (0.01 g, 0.024 mmol). The reaction mixture was stirred at room temperature for 3.5 h under a hydrogen atmosphere (filled in a balloon). The reaction mixture was filtered through a diatomaceous earth (0.05 g) pad and the solid was washed with methanol (3 × 2 mL). The filtrate was concentrated under vacuum to give cyclohexyltricyclomethyl ester (60) (0.011 g), a grayish-white solid, which was obtained by... 1 Characterization by H NMR and LSMS.

[0351] 2. Synthesis of treprostyl metabolites

[0352] 2.1. Figure 13 Synthesis of compound 89

[0353]

[0354] experiment:

[0355] Synthesis of racemic benzyl alkynol (4):

[0356] Under nitrogen atmosphere and at ambient temperature, a solution of ethyl magnesium bromide in an ether (3.0 M ether solution) (54 mL, 133.3 mmol, 1.10 eq) was slowly added dropwise over 30 minutes to a solution of tetrahydro-2-(3-butynoxy)-tetrahydro-2H-pyran (25.0 g, 162.1 mmol, 1.10 eq) in anhydrous tetrahydrofuran (200 mL), with the reaction mixture gently refluxed. After addition, the reaction mixture was cooled to room temperature over 1.5 hours, and then cooled to 0 to -10 °C. A solution of 2-allyl-3-methoxybenzaldehyde (3) (26.7 g, 147.4 mmol, 1.0 eq) in tetrahydrofuran (50 mL) was slowly added to this cold solution, maintaining the temperature of the reaction mixture between 0 and 10 °C for 30 minutes. The reaction mixture was then warmed to room temperature and stirred overnight. After 20 hours, the reaction was detected by TLC. The mixture was carefully quenched with a saturated ammonium chloride solution (approximately 20 mL), keeping the temperature below 35°C during the addition of the ammonium chloride solution. The white granular mixture was stirred for 30 minutes, diluted with ethyl acetate (200 mL), filtered, and washed with ethyl acetate (400 mL). The filtrate was concentrated under vacuum to give a viscous liquid (51 g). The crude product was purified by silica gel column chromatography to give pure racemic benzylalkynol (4) (42.5 g, 85%).

[0357] Synthesis of aryl alkynyl ketones (5):

[0358] Manganese oxide (IV) (approximately 85% purity, 132.0 g, 1290 mmol, 10.0 equivalent) was added in portions to a solution of racemic benzylalkynol (4) (42.5 g, 129 mmol, 1.0 equivalent) in acetone (1000 mL) while stirring at room temperature. The reaction mixture was stirred overnight. After 22 hours, the reaction was detected by TLC. The mixture was filtered through diatomaceous earth (55 g) in a sintered glass funnel and washed with acetone (1500 mL). The filtrate was concentrated under vacuum to give a viscous liquid (40 g). The crude product was purified by silica gel column chromatography to give arylalkynol ketone (5) as a clear, pale yellow viscous liquid (36 g, 85%).

[0359] Synthesis of benzyl alkynol (6):

[0360] At room temperature, under nitrogen atmosphere, an anhydrous tetrahydrofuran (300 mL) solution of arylynyl ketone (5) (35 g, 107 mmol, 1.0 equivalent) was added to a solution of (R)(+)-2-methyl-CBS-oxazolylborane (1.0 M toluene) (130 mL, 130 mmol, 1.2 equivalents). The mixture was stirred for 20 minutes, then cooled to -30 °C, and a borane dimethyl sulfide complex (16.8 g, 21 mL, 221 mmol, 2.1 equivalents) was slowly added, maintaining the temperature of the mixture between -40 and -30 °C. The mixture was stirred at -30 °C for 2 hours and then detected by TLC. Under nitrogen atmosphere, the mixture was carefully quenched with methanol (22 mL) over 20 minutes with stirring at -20 to -30 °C. The mixture was then allowed to warm to room temperature over 1 hour. The mixture was treated with a saturated ammonium chloride solution (approximately 100 mL) until a white granular solid was formed. The mixture was filtered and washed with ethyl acetate (500 mL). The filtrate was concentrated under vacuum to give a pale yellow viscous liquid containing some white solid residue (35 g). The crude product was purified by silica gel column chromatography to give chiral benzylalkynol (6), a clear, colorless viscous liquid (27.5 g, 78.1%).

[0361] Synthesis of benzylynyl tert-butyl dimethyl silyl ether (7):

[0362] At room temperature, imidazole (8.6 g, 126 mmol, 1.5 equivalent), 4-(dimethylamino)pyridine (0.38 g, 3.1 mmol, 0.04 equivalent), tert-butyldimethylchlorosilane (19.8 g, 131.4 mmol, 1.6 equivalent), and N,N'-dimethylformamide (5 mL) were added to a solution of chiral benzylynyl ethynol (6) in dichloromethane (300 mL). The reaction mixture was stirred overnight at room temperature. After 18 hours, the reaction was detected by TLC. The mixture was washed with water (2 × 100 mL) and brine (1 × 50 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give nearly pure benzylynyl tert-butyldimethylsilyl ether (7) as a clear, viscous liquid (37 g, 100%). This product was ready for use in the next reaction without further purification.

[0363] Synthesis of tricyclic THP-ethylenone (8):

[0364] At room temperature and under a nitrogen atmosphere, a single addition of octacarbonyldicobalt (28.7 g, 83.9 mmol, 1.0 equivalent) was made to an anhydrous toluene (390 mL) solution of benzylynyl tert-butyl dimethyl silyl ether (7) (37 g, 83.4 mmol, 1.0 equivalent). The dark brown reaction mixture was stirred at room temperature. Carbon monoxide was slowly released during stirring, and the solution turned reddish-brown after a period of time. The reaction was continued to be stirred for 2 hours, and the complex formed a spot as detected by TLC. The mixture was refluxed under nitrogen (using an oil bath preheated to 120 °C) for 2 hours, and no starting material was detected by TLC. Air was bubbled into the reaction mixture overnight at room temperature. The mixture was diluted with ethyl acetate (400 mL) and then with diatomaceous earth (50 g). The mixture was filtered and washed with ethyl acetate (250 mL). The filtrate was concentrated under vacuum to give a dark brown residue (36 g). The crude product was purified by silica gel column chromatography to give tricycloethyl ether enone (8) (25.3 g).

[0365] Synthesis of tricyclic THP ethyl ether ketone (9):

[0366] To an ethanol (8 mL) solution of tricyclic ethyl ether ketone (8) (0.42 g, purified and pretreated carbon, 0.89 mmol, 1.0 equivalent), water (5 drops), potassium carbonate (0.021 g, 0.15 mmol, 0.17 equivalent, 5% w / w), and 5% palladium (dry basis) supported on activated carbon, wet (50%), Degussa type (0.11 g, 25% w / w) were added. The mixture was stirred at room temperature for 3 h under a hydrogen atmosphere (filled in a balloon), and the reaction was found to be complete by TLC and IR. The mixture was filtered through a diatomaceous earth pad in a sintered glass funnel and washed with ethanol (20 mL). The hydrogenation product was ready for use in the next step without separation of the tricyclic THP ethyl ether ketone (9).

[0367] Synthesis of tricyclic THP ethyl ether alcohol (10):

[0368] At -10°C, sodium hydroxide solution (20.73 g, 518.25 mmol, 1.0 equivalent, yield calculated from the previous step) was added to an ethanol and water (approximately 540 mL) solution of tricyclic THP ethyl ether ketone (9) (17.85 g, 51.83 mmol, 1.0 equivalent, yield calculated from the previous step). The mixture was stirred at -10°C for 30 minutes, followed by the addition of sodium borohydride (3.92 g, 103.7 mmol, 2.0 equivalent) in portions. After the addition was complete, the mixture was stirred at -10°C for 15 minutes and then heated to room temperature over 1.5 hours, followed by TLC analysis. The reaction mixture was quenched with saturated ammonium chloride (100 mL, until the pH changed from 14 to 9). The mixture was filtered through a diatomaceous earth mat, and the filtrate was concentrated under vacuum to remove ethanol. The residue was dissolved in water (100 mL) and dichloromethane (150 mL). The aqueous layer was separated and then extracted with dichloromethane (2 × 70 mL). The dichloromethane extract was washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give a viscous liquid (17.59 g) of tricyclic THP ethyl ether alcohol (10). The purity of product (10) was sufficient for the next step.

[0369] Synthesis of tricyclic methoxy TBDMS THP ethyl ether (11):

[0370] Imidazole (2.53 g, 37.16 mmol, 1.5 equivalent), 4-(dimethylamino)pyridine (0.06 g, 0.491 mmol, 0.02 equivalent), and tert-butyldimethylchlorosilane (4.85 g, 32.18 mmol, 1.3 equivalent) were added to a solution of tricyclool (10) (8.57 g, 24.74 mmol, 1.0 equivalent) in dichloromethane (150 mL) at room temperature. The reaction mixture was stirred overnight at room temperature. After 18 hours, the reaction was confirmed to be complete by TLC. The mixture was washed with water (2 × 50 mL) and brine (1 × 20 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under vacuum to give almost pure tricyclomethoxy TBDMS THP ethyl ether (11), a clear viscous liquid (10.65 g, 93.40%). The pure compound (11) was subjected to... 1 H NMR and 13 Characterized by C10 NMR spectroscopy. The product can be used in the next reaction without further purification.

[0371] Synthesis of tricyclic methoxy TBDMS ethyl alcohol (12):

[0372] Magnesium bromide (12.87 g, 69.90 mmol, 6.0 equivalent) was added to a solution of tricyclomethoxyTBDMS THP ethyl ether (11) (5.36 g, 11.63 mmol, 1.0 equivalent) in ether (200 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature. After 16 hours, the mixture was detected by TLC to confirm the complete reaction. The reaction mixture was carefully quenched with water (100 mL). The ether layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 200 mL). The combined organic layers were washed with water (1 × 150 mL) and brine (1 × 150 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give tricyclomethoxyTBDMS ethyl alcohol (12), which was purified by silica gel column chromatography to give a pale yellow viscous liquid (3.48 g, 80%). Compound (12) was obtained by... 1 H NMR and 13 C10 NMR spectral characterization.

[0373] Synthesis of tricyclic methoxy TBDMS ethyl methanesulfonate (81'):

[0374] Triethylamine (0.15 mL, 0.11 g, 1.10 mmol, 2.27 equivalences) was added to a solution of tricyclomethoxyTBDMS ethyl alcohol (12) (0.18 g, 0.48 mmol, 1.0 equivalences) in dichloromethane (10 mL). The mixture was cooled to 0 °C, and then a solution of methanesulfonyl chloride (0.07 g, 0.58 mmol, 1.2 equivalences) in dichloromethane (1 mL) was added. The reaction mixture was stirred at 0 °C, and then allowed to warm to room temperature and maintained for 1.5 h. The mixture was analyzed by TLC to confirm that the reaction was complete. The reaction mixture was quenched with brine (10 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (2 × 20 mL). The dichloromethane extracts were combined, washed with brine (1 × 10 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give tricyclic methoxy TBDMS ethyl methanesulfonate (81'), a viscous amber liquid (0.24 g, 100%). This methanesulfonate ester was subjected to... 1 H NMR and 13 Characterized by C10 NMR spectroscopy. The methanesulfonate ester can be used in the next step without further purification.

[0375] Synthesis of tricyclic methoxy TBDMS ethyl iodine (81):

[0376] Sodium iodide (0.21 g, 1.40 mmol, 3.03 equivalents) was added in a single batch to a solution of crude methanesulfonate (81') (0.21 g, 0.46 mmol, 1.0 equivalent) in acetone (15 mL) at room temperature. The reaction mixture was stirred overnight at room temperature. After 42 hours, the reaction was detected by TLC. The product was very small, but the mixture was quenched with saturated sodium bicarbonate (5 mL) and acetone was removed under vacuum. The residue was extracted with dichloromethane (30 mL) and washed with saturated sodium bicarbonate (1 × 15 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give a viscous liquid product. 1 ¹H NMR analysis of the product revealed it to be a mixture of tricyclic methoxy TBDMS ethyl methanesulfonate (81') (major) and tricyclic methoxy TBDMS ethyl iodide (81) (minor), in the form of a viscous liquid (0.19 g).

[0377] The recovered methanesulfonate (81') (0.18 g, 0.39 mmol, 1.0 equivalent) was dissolved in 2-butanone (20 mL), and sodium iodide (0.35 g, 2.33 mmol, 6.0 equivalent) was added in a single addition at room temperature. The reaction mixture was gently heated to reflux for 3 hours. The mixture was examined by TLC (EtOAc / hexane, 3:7) and the reaction was found to be complete. The mixture was cooled to room temperature and then the 2-butanone was removed under vacuum. The residue was dissolved in water (10 mL) and then extracted with ethyl acetate (3 × 10 mL). The ethyl acetate extracts were combined, washed with saturated sodium bicarbonate (1 × 10 mL), 10% sodium thiosulfate solution (1 × 10 mL), and brine (1 × 10 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give tricyclic methoxy TBDMS ethyl iodide (81), a pale yellow viscous liquid, which solidified at room temperature (0.17 g, 89%). Compound (81) was subjected to 1 H NMR and 13 Characterized by C10 NMR spectroscopy. The product can be used in the next reaction without further purification.

[0378] Synthesis of tricyclic methoxy-TBDMS ethylene (82):

[0379] At room temperature, potassium tert-butoxide (0.07 g, 0.62 mmol, 2.14 equivalents) was added in a single batch to a solution of tricyclomethoxyTBDMS ethyl iodine (81) (0.14 g, 0.29 mmol, 1.0 equivalent) in tert-butanol (15 mL) (slightly exothermic!). The reaction mixture was gently heated to reflux for 1 hour and then detected by TLC. The reaction appeared to be complete. The mixture was quenched with water (10 mL), and then the tert-butanol was removed under vacuum. The residue was extracted with ethyl acetate (20 mL), washed with water (2 × 10 mL) and brine (1 × 10 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give a viscous liquid, which was then allowed to stand and solidify (0.13 g). The product... 1 ¹H NMR showed that the main components were the starting material (iodide) and a very small amount of the product tricyclomethoxytoxydimethylamine (TBDMS) ethylene (82).

[0380] The recovered tricyclic methoxy TBDMS ethyl iodine (81) (0.13 g, 0.27 mmol, 1.0 equivalent) was dissolved in N,N'-dimethylformamide (10 mL), and potassium tert-butoxide (0.16 g, 1.42 mmol, 5.26 equivalent) was added in a single addition at room temperature. The reaction mixture turned brown (slightly exothermic!). The mixture was stirred overnight at room temperature. After 16 hours, the reaction mixture was analyzed by TLC to confirm the complete reaction. The mixture was quenched with saturated ammonium chloride (20 mL), stirred for 1 hour, and then extracted with ethyl acetate (3 × 20 mL). The combined ethyl acetate solutions were washed with saturated ammonium chloride (3 × 15 mL) and brine (1 × 10 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give tricyclic methoxy TBDMS ethylene (82), a light yellow-brown liquid (0.08 g, 82%). Compound (82) was obtained by... 1 H NMR and 13 Characterized by C10 NMR spectroscopy. The product can be used in the next reaction without further purification.

[0381] Synthesis of tricyclic methoxy TBDMS ethylene glycol (83):

[0382] Osmium tetroxide (0.017 g, 0.067 mmol, 0.1 equivalent) was added to a solution of tricyclomethoxy-TBDMS ethylene (82) (0.24 g, 0.67 mmol, 1.0 equivalent) in a mixture of tert-butanol (10 mL), tetrahydrofuran (3 mL), and water (1 mL) (ratio = 10:3:1), followed by 4-methylmorpholine N-oxide (0.08 g, 0.68 mmol, 1.01 equivalent). The reaction mixture was covered with aluminum foil and stirred overnight at room temperature. After 16 hours, the reaction mixture was examined by TLC to confirm the completion of the reaction. The mixture was treated with sodium thiosulfate solution (1 M, 10 mL). The orange-red solution was stirred at room temperature for 1 hour. The mixture was extracted with dichloromethane (3 × 20 mL). The combined organic extracts were washed with brine (1 × 20 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give tricyclic methoxy-TBDMS ethylene glycol (83), a viscous liquid (0.29 g, 100%). Compound (83) was obtained by... 1 HNMR and 13 Characterized by C10 NMR spectroscopy. The crude product can be used directly in the next reaction without further purification.

[0383] Synthesis of tricyclic hydroxyl TBDMS ethylene glycol (84):

[0384] At -20°C under nitrogen, a solution of n-butyllithium in hexane (2.5 M, hexane, 2.8 mL, 7.0 mmol, 5.0 equivalent) was added to an anhydrous tetrahydrofuran (15 mL) solution of tricyclomethoxyTBDMS ethylene glycol (83) (0.55 g, 1.40 mmol, 1.0 equivalent), followed by diphenylphosphine (10 wt.%, hexane, 10.4 mL, 5.58 mmol, 4.0 equivalent). The reaction mixture (deep orange-red) was stirred at -20°C for 20 minutes, then allowed to return to room temperature over 1 hour. The mixture was slowly heated to reflux overnight. After 16 hours, the reaction mixture was analyzed by TLC, and the reaction was not complete. Additional n-butyllithium in hexane (2.5 M, 2.6 mL) and diphenylphosphine (10 wt.%, hexane, 8.0 mL) were added. The reaction mixture was refluxed overnight. After 18 hours, the reaction mixture was analyzed by TLC, confirming that the reaction was complete. The reaction mixture was quenched with saturated ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 × 25 mL). The combined ethyl acetate layers were washed with water (1 × 30 mL) and brine (1 × 10 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give a clear, viscous liquid (1.07 g). The crude product was purified by silica gel column chromatography to give tricyclic hydroxyl TBDMS ethylene glycol (84), a viscous liquid that solidified upon standing (0.19 g, 36%). The pure compound (84) was obtained by... 1 H NMR and 13 C10 NMR spectral characterization.

[0385] Synthesis of tricyclic TBDMS-benzyloxycarbonyl methyl ether glycol (85):

[0386] To a solution of tricyclic hydroxyl TBDMS ethylene glycol (84) (1.75 g, 4.62 mmol, 1.0 equivalent) in acetone (100 mL), powdered potassium carbonate (1.40 g, 10.13 mmol, 2.20 equivalent) and benzyl 2-bromoacetate (1.27 g, 5.54 mmol, 1.20 equivalent) were added. The mixture was gently heated to reflux overnight. After 18 hours, the reaction mixture was analyzed by TLC to confirm complete reaction. The mixture was cooled to room temperature, filtered, and washed with acetone. The filtrate was concentrated under vacuum to give tricyclic TBDMS-benzyloxycarbonyl methyl ether ethylene glycol (85), a viscous liquid (2.47 g, 100%). Compound (85) was obtained by... 1 H NMR and 13 Characterized by C10 NMR spectroscopy. The crude product can be used directly in the next step without further purification.

[0387] Synthesis of tricyclic benzyloxycarbonyl methyl ether triol (86):

[0388] At room temperature, pyridine p-toluenesulfonate (0.70 g, 4.63 mmol, 1.0 equivalent) was added to a solution of tricyclic TBDMS-benzyloxycarbonyl methyl ether glycol (85) (2.46 g, crude product calculated as 2.43 g, 4.61 mmol, 1.0 equivalent) in 100 mL of acetone and 5 mL of water. The reaction mixture was stirred overnight at room temperature. After 68 hours, the reaction was detected by TLC. The reaction was not complete, and another 1 equivalent of pyridine p-toluenesulfonate (0.70 g, 4.63 mmol, 1.0 equivalent) was added. The mixture was refluxed overnight. After 16 hours, the reaction mixture was detected by TLC to confirm that the reaction was complete. The reaction mixture was concentrated under vacuum to remove acetone. The aqueous layer was extracted with ethyl acetate (3 × 40 mL). The combined ethyl acetate extracts were washed with water (1 × 40 mL) and brine (1 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a viscous liquid (1.92 g). The crude product was purified by silica gel column chromatography to obtain tricyclic benzyloxycarbonyl methyl ether triol (86), which was a viscous liquid / semi-solid (0.97 g, 51%).

[0389] Synthesis of tricyclic benzyloxycarbonyl methyl ether hydroxy aldehyde (87):

[0390] At room temperature, a solution of sodium periodate (sodium metaiodate) (1.0 g, 4.67 mmol, 2.0 equivalent) in 1,2-dichloroethane (40 mL) was added to a solution of tricyclobenzyloxycarbonylmethyl ether triol (86) (0.96 g, 2.33 mmol, 1.0 equivalent). The reaction mixture was stirred overnight. After 16 hours, the reaction mixture was analyzed by TLC to confirm the complete reaction. The reaction mixture was a white emulsion. Water (70 mL) and dichloromethane (70 mL) were added to the mixture, followed by sodium chloride until the aqueous layer was saturated. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (3 × 30 mL). The combined dichloromethane extracts were washed with brine (1 × 20 mL), dried over sodium sulfate, and filtered through a silica gel pad in a sintered glass funnel. The compound was purified by silica gel column chromatography to give tricyclobenzyloxycarbonylmethyl ether hydroxyaldehyde (87), a clear viscous liquid (0.54 g, 61%). Compound (87) via 1 HNMR spectral characterization.

[0391] Synthesis of tricyclic benzyloxycarbonyl methyl ether β-ketoethyl ester (88):

[0392] At room temperature, ethyl diazonium (0.32 g, 2.80 mmol, 2.0 equivalent) and tin(II) chloride (0.06 g, 0.37 mmol, 0.27 equivalent) were added to a solution of tricyclic benzyloxycarbonylmethyl ether hydroxyaldehyde (87) (0.53 g, 1.39 mmol, 1.0 equivalent) in dichloromethane (25 mL). The reaction mixture was stirred overnight at room temperature. After 16 hours, the reaction mixture was analyzed by TLC to confirm the complete reaction. The reaction mixture was passed directly through a silica gel column using pure dichloromethane, followed by elution with a mixture of ethyl acetate in hexane (20–40%) to give pure tricyclic benzyloxycarbonylmethyl ether β-ketoethyl ester (88) as a clear viscous liquid (0.32 g) and slightly impure tricyclic benzyloxycarbonylmethyl ether β-ketoethyl ester (88) (0.19 g). Both the pure and slightly impure β-ketoethyl ester (88) were subjected to TLC. 1 H NMR spectral characterization.

[0393] Figure 13 Synthesis of compound 89

[0394] At room temperature, a 1.0 M sodium hydroxide solution (4.1 mL, 4.1 mmol, 6.03 equivalences) was added to a 20 mL solution of pure tricyclic benzyloxycarbonyl methyl ether β-ketoethyl ester (88) (0.32 g, 0.68 mmol, 1.0 equivalences) in tetrahydrofuran. The reaction mixture was stirred overnight at room temperature. After 66 hours, the reaction mixture was diluted with water (20 mL), and the tetrahydrofuran was removed under vacuum. The aqueous layer was extracted with dichloromethane (2 × 20 mL) to remove organic impurities. The aqueous layer was carefully acidified to pH 2–3 with 10% hydrochloric acid and extracted with ethyl acetate (3 × 25 mL). The combined ethyl acetate extracts were washed with brine (1 × 15 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give compound 89 as a pale yellow viscous liquid (0.24 g, 100%). Metabolite 89 was obtained by... 1 Detected by ¹H NMR and confirmed by HPLC.

[0395] (i) Using sodium hydroxide. Under similar conditions, a solution of tricyclic benzyloxycarbonyl methyl ether β-ketoethyl ester (88) (0.017 g, 0.036 mmol, 1.0 equivalent) in tetrahydrofuran (1.0 mL) was hydrolyzed at room temperature with 1.0 M sodium hydroxide solution (0.22 mL, 0.22 mmol, 6.04 equivalent) to give compound 89, a pale yellow viscous liquid / semi-solid (0.01 g, 77%). Metabolites were obtained by... 1 The results were detected by 1H NMR spectroscopy and confirmed by HPLC.

[0396] (ii) Using lithium hydroxide. Under similar conditions, a solution of tricyclic benzyloxycarbonyl methyl ether β-ketoester (88) (0.017 g, 0.036 mmol, 1.0 equivalent) in tetrahydrofuran (1.0 mL) was hydrolyzed at room temperature with 1.0 M lithium hydroxide solution (0.22 mL, 0.22 mmol, 6.04 equivalent) to give compound 89, a pale yellow viscous liquid / semi-solid (0.01 g, 77%). Metabolites were obtained via... 1 The results were detected by 1H NMR spectroscopy and confirmed by HPLC.

[0397] (iii) Using barium hydroxide. Under similar conditions, a solution of tricyclic benzyloxycarbonyl methyl ether β-ketoethyl ester (88) (0.017 g, 0.036 mmol, 1.0 equivalent) in tetrahydrofuran (1.0 mL) was hydrolyzed at room temperature with 1.0 M barium hydroxide solution (0.04 g, 0.23 mmol, 6.41 equivalent) to give compound 89, a pale yellow viscous liquid / semi-solid (0.01 g, 77%). Metabolites were obtained by... 1 The results were detected by 1H NMR spectroscopy and confirmed by HPLC.

[0398] 2.2. Figure 13 Synthesis of compounds 75 and 108

[0399] 2.2.1. Figure 13 Synthesis of the common intermediate (12a) of compounds 75 and 108

[0400] experiment:

[0401] Synthesis of 1-pentyne-O-tetrahydropyran-2-yl-5-ol (intermediate 2a):

[0402] At room temperature, under argon atmosphere, 4-pentyn-1-ol (1a, 20 g, 0.238 mol), dichloromethane (200 mL), 3,4-dihydro-2H-pyran (21 g, 0.250 mol), and pyridine p-toluenesulfonate (PPTS, 5.98 g, 0.024 mol) were charged into a 500 mL three-necked round-bottom flask equipped with a mechanical stirrer and an argon inlet / outlet adapter connected to a bubbler. The reaction mixture was stirred overnight at room temperature. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was washed with water (1 × 250 mL) and brine (1 × 250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give crude product 2a (39 g, 98% yield). The crude product can be used directly in the next step.

[0403] Synthesis of intermediate 4a:

[0404] To a 1L three-necked round-bottom flask equipped with a mechanical stirrer, feeding funnel, thermocouple, and argon inlet / outlet adapter connected to a bubbler, add 31.5 g (0.187 mol) of 1-pentyn-O-tetrahydropyran-2-yl-5-ol (2a) and 200-300 mL of anhydrous tetrahydrofuran. Over 20-30 minutes, under argon atmosphere, add 62.4 mL (0.187 mol) of ethyl magnesium bromide (3M, diethyl ether solution) to solution 2a, maintaining the temperature below 40°C. After the addition is complete, stir the reaction mixture at 30-45°C for 2 hours. The reaction mixture was cooled to 0°C (ice-water bath), and an anhydrous tetrahydrofuran (50 mL) solution of 30.0 g (0.170 mol) of 2-allyl-3-methoxybenzaldehyde (3a) was added over 10 minutes. The reaction mixture was stirred overnight at room temperature, and then the temperature of the reaction mixture was raised to ambient temperature. After 16 hours, the reaction was complete. The reaction mixture was quenched with saturated ammonium chloride at ambient temperature to give a suspension of particulate solids. The mixture was filtered to remove particulate inorganic solids, and the filtrate was concentrated under vacuum to give crude product 4a (59 g). The crude product was purified by column chromatography to give pure 3-methoxy-2-(2-propenyl)-[5-[(tetrahydro-2H-pyran-4-yl)oxy]-1-pentyl]benzene-methanol (intermediate 4a), a pale yellow viscous liquid (46.3 g, yield 79%).

[0405] Synthesis of intermediate 5a:

[0406] Intermediate 4a (46.0 g, 0.134 mol), dichloromethane (500 mL), diatomaceous earth (40 g), and sodium acetate (22 g, 0.268 mol) were charged into a 2 L double-necked round-bottom flask equipped with a mechanical stirrer and thermocouple. The stirred suspension was cooled to 0 °C, and pyridine chlorochromate (PCC, 57.6 g, 0.238 mol) was added while stirring. The reaction mixture was slowly heated to ambient temperature and stirred for 5 hours. The mixture was filtered through a diatomaceous earth pad in a Buchner funnel. The dark brown, gummy solid in the reaction flask and Buchner funnel was washed with ethyl acetate to recover the maximum amount of product. The solvent was removed under vacuum, and the crude product was purified by column chromatography to give 1-[3-methoxy-2-(2-propenyl)phenyl]-6-[(tetrahydro-2H-pyran-4-yl)oxy]-2-hexyn-1-one (intermediate 5a), which was a light yellow viscous oil (30.67 g, yield 67%).

[0407] Synthesis of intermediate 6a:

[0408] Aryl intermediate 5a (21 g, 0.061 mol) and anhydrous tetrahydrofuran (200-300 mL) were charged into a 1 L three-necked round-bottom flask equipped with a mechanical stirrer, thermocouple, and argon inlet / outlet traps. A solution of (R)-methyloxazolylborane (1.0 M toluene solution, 73.6 mL, 0.074 mol) was added under argon atmosphere at room temperature. The mixture was cooled to -30 °C (dry ice / acetone bath), and a borane-dimethyl sulfide complex (9.32 mL, 0.122 mol) was slowly added, maintaining the temperature at -25 °C to -30 °C. After the addition was complete, the reaction mixture was stirred at the same temperature for 1 hour. The reaction was monitored by TLC. The reaction mixture was carefully quenched over 20 minutes by the slow addition of methanol, maintaining the temperature of the exothermic reaction at -10 °C to -15 °C. The reaction mixture was then warmed to room temperature. A 5% ammonium chloride aqueous solution was added and stirred (no exothermic reaction observed!). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate (approximately 10 g), filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by column chromatography to give intermediate 6a (a semi-solid product) (11 g, yield 52%).

[0409] Synthesis of intermediate 7a:

[0410] At room temperature, under argon atmosphere, a solution of chiral benzylalkynol (6a) (10.60 g, 30.77 mmol), dichloromethane (150 mL), imidazole (2.93 g, 43.08 mmol), and dimethylformamide (2 mL) was added to a 1 L three-necked round-bottom flask equipped with a mechanical stirrer, thermocouple, and argon inlet / outlet traps. The mixture was stirred until a clear solution was obtained. Tert-butyldimethylchlorosilane (6.03 g, 40.00 mmol) was added while maintaining the temperature below 20 °C. The reaction mixture was stirred overnight. The temperature of the reaction mixture was raised to ambient temperature. After approximately 16 hours, the reaction progress was monitored by TLC. The mixture was washed with water (3 × 150 mL) and saturated sodium chloride (1 × 150 mL). After drying with anhydrous sodium sulfate (10 g), the mixture was filtered, concentrated under vacuum, and crude product 7a was obtained as a viscous oil. The crude product was purified by column chromatography to obtain benzylynyl tert-butyl dimethyl silyl ether (intermediate 7a), a colorless viscous oil (12.66 g, 90%).

[0411] Synthesis of intermediate 8a:

[0412] Under argon atmosphere, a solution of benzylynyl tert-butyl dimethyl silyl ether (7a, 12 g, 26.16 mmol) in dichloromethane (120–150 mL) was added to a 1 L three-necked round-bottom flask equipped with a mechanical stirrer, thermocouple, and argon inlet / outlet traps. Cobalt octacarbonyl (8.947 g, 26.16 mmol) was added at room temperature, and the reaction mixture was stirred at ambient temperature. Carbon monoxide was slowly released, and the solution turned reddish-brown after a period of time. Stirring was continued for 2 hours. Dichloromethane was distilled from the reaction mixture under vacuum using a water bath (temperature not exceeding 30 °C). The resulting brown viscous liquid was dissolved in acetonitrile and transferred back to a 1 L three-necked round-bottom flask equipped with a mechanical stirrer, thermocouple, argon inlet / outlet traps, and condenser. The solution was heated under argon atmosphere and refluxed for 2 hours. The reaction mixture was cooled to room temperature, and air was bubbled through the mixture overnight. After the reaction was complete, the reaction mixture was diluted with saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate (3 × 150 mL). The combined organic layers were washed with brine (1 × 150 mL) and dried over anhydrous sodium sulfate (10 g). The organic phase was filtered. The filtrate was concentrated under vacuum to give crude product 8a, a brown oil. Crude product 8a was purified by column chromatography to give pure tricyclic enone (8a), a light brown oil (12 g, 94% yield). The crude substance was dissolved in ethanol (200 mL). Activated carbon (1.2 g) was added to the solution. The suspension was heated under reflux, and the hot solution was filtered through a diatomaceous earth mat. The filtrate was used directly for the next step.

[0413] Synthesis of intermediate 9a:

[0414] A 500 mL three-necked round-bottom flask equipped with a magnetic stirrer and a hydrogen-filled balloon was loaded with an anhydrous ethanol solution (100-150 mL, from the previous step) of intermediate 8a (10.9 g), anhydrous potassium carbonate (0.5 g), and 5% palladium supported on activated carbon (1.98 g, 10%, 50% wet). Air was removed from the reaction flask under vacuum, and the vacuum was replaced with hydrogen from the attached balloon. This step was repeated three times. The mixture was hydrogenated under balloon pressure for 16 hours (overnight) at ambient temperature. The reaction progress was monitored by TLC. The reaction was incomplete, so the reaction mixture was filtered through a diatomaceous earth pad, which was washed with more ethanol to recover substances. The volume of the reaction mixture was reduced by half by vacuum evaporation. The reaction was repeated with the same amount of reagent. After 16 hours, TLC showed that compound 8a (the starting material) was absent. The mixture was filtered through a diatomaceous earth pad. The filtrate was concentrated under vacuum to give a colorless, viscous, oily crude product 9a. Crude product 9a was purified by column chromatography using 230-400 mesh silica gel. The product was eluted from the column using a solvent gradient (0-20%) of ethyl acetate in hexane. The fraction containing the desired product was evaporated under vacuum to give pure tricyclic ketone (9a) as a colorless, viscous oil (6.38 g, 74% yield). Synthesis of intermediate 10a:

[0415] An ethanol solution of tricyclic ketone (9a, 17.30, 17.3 mmol) was added to a 500 mL three-necked round-bottom flask equipped with a mechanical stirrer. The solution was cooled to -4 °C, and a 20% sodium hydroxide aqueous solution (6.92 g, 173.00 mmol, dissolved in 30 mL of water) was added, followed by stirring for 10–15 minutes. The reaction mixture was stirred for an additional 0.5 hours, and then sodium borohydride (700 mg, 18.52 mmol) was added. Stirring was continued at -10 °C for 2 hours. After 2 hours, an additional equivalent of sodium borohydride (610 mg, 16.14 mmol) was added, and stirring was continued at -10 °C for another 2 hours. The reaction progress was monitored by TLC. The reaction mixture was carefully quenched dropwise with glacial acetic acid (approximately 12 mL) until the pH reached 5–6. The mixture was allowed to reach ambient temperature. Unwanted solid inorganic impurities were removed by filtration, and the filtrate was concentrated under vacuum. The residue obtained after evaporation was dissolved in ethyl acetate (300 mL), and the resulting solution was stirred for 15 minutes. The ethyl acetate solution of compound 10a was washed with sodium bicarbonate (2 × 100 mL). The aqueous layer was extracted with ethyl acetate (2 × 150 mL). The combined organic extracts were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product (tricyclool 10a) as an oil (6.3 g, yield approximately 100%).

[0416] Synthesis of intermediate 11a:

[0417] At room temperature, under argon atmosphere, crude intermediate 10a (1.250 g, 3.47 mmol), dichloromethane (20 mL), imidazole (473 mg, 6.95 mmol), and dimethylformamide (0.5 mL) solution were added to a 100 mL single-necked round-bottom flask equipped with a magnetic stirrer. The mixture was stirred until a clear solution was obtained. Tert-butyldimethylchlorosilane (1.045 g, 6.93 mmol) was added at room temperature. The reaction was stirred overnight. After approximately 16 hours, the reaction progress was monitored by TLC. The mixture was washed with water (1 × 50 mL) and saturated sodium chloride (1 × 50 mL). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give crude product 11a as a viscous oil. The crude product was purified by column chromatography to give intermediate 11a as a colorless viscous oil (1.45 g, 88%).

[0418] Synthesis of intermediate 12a:

[0419] At room temperature, under nitrogen atmosphere, intermediate 11a (1.40 g, 2.95 mmol), diethyl ether (50 mL), and magnesium bromide (3.26 g, 17.70 mmol) were added to a 100 mL single-necked round-bottom flask equipped with a magnetic stirrer. The reaction mixture was stirred for 3–4 hours. The reaction progress was monitored by TLC. The reaction mixture was slowly quenched with water (1 × 50 mL) (quenching is exothermic). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined organic phases were washed with saturated sodium chloride (1 × 50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give crude product 12a as a viscous oil. The crude product was purified by column chromatography to give intermediate 12a as a colorless, viscous oil (1.0 g, 87%).

[0420] 2.2.2 Figure 13 Synthesis of compound 75

[0421]

[0422] experiment:

[0423] Synthesis of intermediate 71

[0424] Under nitrogen atmosphere, anhydrous tetrahydrofuran (10 mL) and n-butyllithium (1.31 g, 20.45 mmol) were added to a 100 mL three-necked round-bottom flask equipped with a cooling bath, thermocouple, and argon inlet / outlet adapter connected to a bubbler. The mixture was cooled to -20 to -30 °C, and diphenylphosphine (3.34 g, 17.94 mmol) was added. The resulting orange-red solution was stirred for 10–15 minutes. Under nitrogen atmosphere, a THF solution of intermediate 12a (1.00 g, 2.56 mmol) in 10 mL was added to the reaction mixture at -20 °C. After the addition was complete, the deep red solution was stirred at -20 °C for 30 minutes, and then the temperature of the reaction mixture was raised to ambient temperature. The reaction mixture was heated under reflux overnight. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was cooled to ambient temperature, and then the reaction was quenched with water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried with anhydrous sodium sulfate (10 g), filtered, and concentrated under vacuum to give crude product 71. Crude product 71 was purified by column chromatography to give product 71, 1.3 g (yield over 100% (964 mg), possibly due to the presence of residual solvent).

[0425] Synthesis of intermediate 72:

[0426] Intermediate 71 (1.3 g, 3.45 mmol) and acetone were added to a 100 mL single-necked round-bottom flask equipped with a magnetic stirrer, an argon inlet / outlet adapter connected to a bubbler, and a condenser. The mixture was stirred to obtain a clear solution. Benzyl bromoacetate (1.186 g, 5.18 mmol) and potassium carbonate powder (1.431 g, 10.36 mmol) were added to the above solution. The reaction mixture was heated under reflux for 3–4 hours. The reaction progress was monitored by TLC. After 3.5 hours, the reaction was not complete (TLC), so additional amounts of the reagents benzyl bromoacetate (0.5 g, 2.18 mmol) and potassium carbonate (1.0 g, 7.24 mmol) were added. The reaction mixture was heated under reflux again. After the reaction was complete (TLC), the reaction mixture was cooled to ambient temperature and filtered through a diatomaceous earth pad. The diatomaceous earth pad was washed with acetone, and the filtrate was concentrated under vacuum to obtain a viscous liquid. The crude product 72 was purified by column chromatography to obtain a viscous liquid of pure product 72 (1.15 g, yield of 85% based on the 100% yield of the previous step).

[0427] Synthesis of intermediate 73:

[0428] Intermediate 72 (1.1 g, 2.10 mmol) and dichloromethane were charged into a 100 mL single-necked round-bottom flask equipped with a magnetic stirrer. The mixture was stirred to obtain a clear solution. Diatomaceous earth and sodium acetate (0.35 g, 4.27 mmol) were added to the above solution. After stirring the reaction mixture (5–10 min), PDC (1.58 g, 4.20 mmol) was added at ambient temperature. The reaction progress was monitored by TLC after 3–4 hours. The reaction was considered complete after 3.5 hours (TLC). Product 73 was purified by column chromatography on 230–400 mesh silica gel by direct loading of the reaction mixture onto a column, which was eluted with dichloromethane (100%). The fraction containing the desired compound 73 was evaporated under vacuum to give a viscous liquid of pure product 73 (0.90 g, 83% yield).

[0429] Synthesis of intermediate 74:

[0430] To a 50 mL single-necked round-bottom flask equipped with a magnetic stirrer, add intermediate 73 (0.82 g, 1.57 mmol), tert-butanol (15–20 mL), and water. Stir the mixture to obtain a clear solution. Add sodium dihydrogen phosphate (1.13 g, 9.42 mmol) and 2-methyl-2-butene (2.0 mL). Stir the mixture for 5–10 minutes. At ambient temperature, add sodium chlorate (1.30 g, 14.37 mmol) to the resulting suspension. Monitor the reaction progress by TLC after 2–3 hours. After the reaction is complete, evaporate the solvent under vacuum to obtain a viscous liquid. Add water to the residue, acidify the aqueous layer to pH 3–4, and extract with ethyl acetate (3 × 50 mL). Wash the organic layer with brine and dry with anhydrous sodium sulfate. Filter the mixture, and evaporate the filtrate under vacuum to obtain the crude product. Purify product 74 by column chromatography to obtain a viscous liquid of pure product 74 (0.740 g, 88% yield).

[0431] Figure 13 Synthesis of compound 75:

[0432] A methanol solution of intermediate 74 (1.37 g, 1.37 mmol) was added to a 50 mL single-necked round-bottom flask equipped with a magnetic stirrer. A solution of HCl (1.3 mL, 37%, 13.18 mmol, dissolved in 5 mL of water) was added to the reaction mixture. The mixture was stirred at room temperature for 6–7 hours. After 6–7 hours, a solution of sodium hydroxide (1.1 g, 27.5 mmol, dissolved in 2 mL of water) was added. The reaction mixture was heated under reflux overnight. The reaction progress was monitored by TLC. After the reaction was complete, the solvent was evaporated under vacuum. Water was added to the residue, and the aqueous layer was extracted with ethyl acetate (3 × 20 mL) to remove impurities. The extracted ethyl acetate layer was discarded after TLC examination. The aqueous layer was acidified to pH (1–2) and extracted with ethyl acetate (3 × 70 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was evaporated to give the crude product (425 mg). The crude material was ground with dichloromethane (15 mL) and then with hexane (15 mL). The solid suspension was filtered to separate the solid. The solid was washed with hexane, dried over a funnel, and then air-dried at room temperature in a fume hood to give 75 (385 mg, 84% yield) of pure product.

[0433] 2.2.3 Figure 13 Synthesis of sodium salt of compound 108

[0434]

[0435] experiment:

[0436] Synthesis of intermediate 101:

[0437] Intermediate 12a (3.60 g, 9.22 mmol) and dichloromethane (60–100 mL) were charged into a 100 mL single-necked round-bottom flask equipped with a magnetic stirrer. The mixture was stirred until a clear solution was obtained. Diatomaceous earth (7.0 g) and sodium acetate (1.80 g, 21.94 mmol) were added to the above solution. After stirring the reaction mixture (5–10 min), PDC (6.9 g, 18.34 mmol) was added at ambient temperature. The reaction progress was monitored by TLC after 3–4 hours. The reaction was considered complete after 3.5 hours (TLC). Product 101 was purified by column chromatography using 230–400 mesh silica gel. The reaction mixture was directly loaded onto the column and eluted with dichloromethane (100%). The fraction containing the desired compound 101 was evaporated under vacuum to give a viscous liquid of pure product 101 (2.846 g, 80% yield).

[0438] Synthesis of intermediate 102:

[0439] Under nitrogen atmosphere, anhydrous tetrahydrofuran (20 mL) and a 0.5 M solution of (1,3-dioxane-2-ylethyl)-magnesium bromide in THF (17.3 mL, 8.65 mmol) were added to a 250 mL three-necked round-bottom flask equipped with a cooling bath, thermocouple, and argon inlet / outlet adapter connected to a bubbler. The mixture was cooled to -20 °C, and a THF solution of intermediate 101 (2.8 g, 7.21 mmol, dissolved in anhydrous THF (20 mL)) was added. The temperature of the reaction mixture was raised from -20 °C to ambient temperature. The reaction progress was monitored by TLC after 3–4 hours. After 3.5 hours, the reaction was complete (TLC). The reaction mixture was quenched with a saturated ammonium chloride solution (2 mL) with stirring. The reaction mixture was converted into a suspension of white particulate solids. The resulting suspension was filtered, and the filtrate was evaporated under vacuum to give crude product 102. Product 102 was purified by column chromatography using 230-400 mesh silica gel, with the column eluted by a gradient of ethyl acetate in hexane (15-40%). The fractions containing the desired pure compound 102 were combined and evaporated under vacuum to give a viscous liquid of pure product 102 (3.698 g, quantitative yield).

[0440] Synthesis of intermediate 103:

[0441] Under nitrogen atmosphere, anhydrous tetrahydrofuran (20 mL) and n-butyllithium (20.3 mL, 50.73 mmol, 2.5 M hexane solution) were added to a 250 mL three-necked round-bottom flask equipped with a cooling bath, thermocouple, and argon inlet / outlet adapter connected to a bubbler. The mixture was cooled to -20°C to -30°C, and diphenylphosphine (8.30 g, 44.58 mmol) was added. The resulting orange-red solution was stirred for 10–15 minutes. Under nitrogen atmosphere, a THF solution of intermediate 102 (3.20 g, 6.34 mmol) in 20 mL was added to the reaction mixture at -20°C. After complete addition, the red solution was stirred at -20°C for 30 minutes, and then the temperature of the reaction mixture was raised to ambient temperature. The reaction mixture was heated under reflux overnight. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was cooled to ambient temperature, and then the reaction was quenched slowly with water, and the reaction color changed from red to colorless. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give crude product 103. Crude product 103 was purified by column chromatography to give product 103 (3.0 g, yield 96%).

[0442] Synthesis of intermediate 104:

[0443] Intermediate 103 (3.00 g, 6.11 mmol) and acetone (30–50 mL) were added to a 250 mL single-necked round-bottom flask equipped with a magnetic stirrer, an argon inlet / outlet adapter with an argon-connected bubbler, and a condenser. The mixture was stirred until a clear solution was obtained. Benzyl bromoacetate (2.10 g, 9.17 mmol) and potassium carbonate powder (4.23 g, 30.61 mmol) were added to the above solution. The reaction mixture was heated under reflux overnight. The reaction progress was monitored by TLC. After the reaction was complete (as checked by TLC), the reaction mixture was cooled to ambient temperature and filtered through a diatomaceous earth mat in a Buchner funnel. The diatomaceous earth mat was washed with acetone, and the combined filtrates were concentrated under vacuum to give a viscous liquid. The crude product 104 was purified by column chromatography to give a viscous liquid of pure product 104 (3.75 g, 96% yield).

[0444] Synthesis of intermediate 105:

[0445] Under argon atmosphere, at room temperature, a solution of crude intermediate 104 (3.70 g, 5.79 mmol), dichloromethane (50–100 mL), 4-dimethylaminopyridine (DMAP, 1.77 g, 14.49 mmol), and acetic anhydride (1.30 g, 12.73 mmol) was added to a 250 mL single-necked round-bottom flask equipped with a magnetic stirrer. The reaction was stirred overnight. After approximately 16 hours, the reaction progress was monitored by TLC. To purify product 105, the reaction mixture was directly loaded into a silica gel-filled column. The column was eluted with a gradient solvent of ethyl acetate in hexane. The fractions containing the desired compound were combined and evaporated under vacuum to give intermediate 105, a colorless viscous oil (3.72 g, 94% yield).

[0446] Synthesis of intermediate 106:

[0447] To a 250 mL single-necked round-bottom flask equipped with a magnetic stirrer and condenser, add intermediate 105 (3.70 g, 5.43 mmol) and acetone (100 mL). Stir the mixture until a clear solution is obtained. Add pyridine p-toluenesulfonate (PPTS) (2.50 g, 9.95 mmol) and water (50 mL) to the above solution. Heat the reaction mixture under reflux overnight. Analyze the solution by TLC and... 1 Monitor the reaction progress using ¹H-NMR. Continue heating the reaction mixture to reflux until the solution passes through the reflux chamber. 1 ¹H-NMR confirmed the completeness of the reaction. After the reaction was complete, the reaction mixture was cooled to ambient temperature, and the solvent was concentrated under vacuum to obtain an aqueous layer containing the product. Additional water was added, and the aqueous layer was extracted with dichloromethane (3 × 50 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to give crude product 106. The crude product was purified by column chromatography to give a viscous liquid of pure product 106 (1.693 g, yield 61%).

[0448] Synthesis of intermediate 107:

[0449] To a 100 mL single-necked round-bottom flask equipped with a magnetic stirrer, add intermediate 106 (0.628 g, 1.23 mmol), tert-butanol (20–30 mL), and water (10–15 mL). Stir the mixture until a clear two-phase solution is obtained. Add sodium dihydrogen phosphate (0.889 g, 7.41 mmol) and 2-methyl-2-butene (5–7 mL). Stir the mixture for 5–10 minutes. At ambient temperature, add sodium chlorate (1.117 g, 12.35 mmol) to the resulting suspension. After 2–3 hours, monitor the reaction progress by TLC. After the reaction is complete, evaporate the solvent under vacuum to obtain a viscous liquid. Add water to the residue, acidify the aqueous layer to pH 3–4, and extract with ethyl acetate (3 × 50 mL). Wash the organic layer with brine and dry with anhydrous sodium sulfate. Filter the mixture, evaporate the filtrate to obtain the crude product. Product 107 was purified by column chromatography to obtain a viscous liquid of pure product 107 (600 mg, yield 93%).

[0450] Synthesis of metabolites 108L and 108:

[0451] A methanol solution (15-20 mL) of intermediate 107 (1.1 g, 2.10 mmol) was added to a 50 mL single-necked round-bottom flask equipped with a magnetic stirrer. KOH solution (1.18 g, 21.03 mmol, dissolved in water (5 mL)) was added to the reaction mixture. The reaction mixture was heated under reflux for 2-6 hours. The reaction progress was monitored by TLC. After the reaction was complete, the solvent was evaporated under vacuum. Water was added to the residue, and the aqueous layer was extracted with dichloromethane (7 × 50 mL) to remove impurities. The aqueous layer was acidified to pH (1-2) and extracted with ethyl acetate (4 × 70 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was evaporated under vacuum to give the crude product (900 mg). 1 ¹H NMR and HPLC showed that the crude material was a mixture of two products, namely 10⁸ L lactone and 10⁸ L.

[0452] Synthesis of the racemic metabolite 10⁸Na:

[0453] A methanol (10 mL) solution of intermediate 108L (0.750 g, 2.00 mmol) was added to a 50 mL single-necked round-bottom flask equipped with a magnetic stirrer. NaOH solution (0.168 g, 4.20 mmol, dissolved in water (2-3 mL)) was added to the reaction mixture. The reaction mixture was heated under reflux for 3-4 hours, and the reaction progress was monitored by HPLC. After the reaction was complete, the solvent was evaporated under vacuum. The resulting substance was dissolved in anhydrous ethanol (5-10 mL), and water was removed by azeotropic evaporation under vacuum. The viscous substance was evaporated to dryness. A mixture of dichloromethane and hexane (1:1) (40-60 mL) was added to the substance. The mixture was stirred and ground for 1-2 hours. The fine solid was separated by filtration, and the solid was air-dried to obtain 108Na salt (800 mg, yield 92%).

[0454] 2.2.4. Figure 13 Synthesis of compound 117

[0455]

[0456] experiment:

[0457] Synthesis of treprostyl benzyl ester (111):

[0458] A THF:acetone (1:4, 10:40 mL) solution of treprostrin (1) (2 g, 0.0025 mol) was added to a 100 mL round-bottom flask equipped with a magnetic stirrer. Potassium carbonate (2.82 g, 0.0204 mol) was added to this clear solution in a single addition, followed by benzyl bromide (1.75 g, 0.0102 mol) with stirring at room temperature. The reaction mixture was stirred until complete (approximately 16–18 hours), and the reaction progress was monitored by TLC. The mixture was filtered through a Buchner funnel. The filtrate was removed under vacuum, and the crude product was ground with hexane (100 mL) to give treprostrin benzyl ester (111), a grayish-white solid (2 g, 83%). This was used in the next reaction without further purification.

[0459] Synthesis of TBDPS ether (112):

[0460] Under argon atmosphere, at room temperature, a 100 mL three-necked round-bottom flask equipped with a magnetic stirrer, thermocouple, and argon inlet / outlet traps was filled with treprostyl benzyl ester (111) (780 mg, 0.0016 mol), dichloromethane (15 mL), imidazole (143 mg, 0.0021 mol), and 4-(dimethylamino)pyridine (9 mg, 5 mol%). The mixture was stirred until a clear solution was obtained. The mixture was cooled to 0 °C (ice / water bath), and tert-butyldiphenylchlorosilane (535 mg, 0.0019 g) was added in portions while maintaining the temperature below 20 °C. The reaction mixture was stirred overnight. The temperature of the reaction mixture was then raised to ambient temperature. The reaction progress was monitored by TLC. The reaction was completed after approximately 16 hours. The reaction mixture was washed with water (10 mL) and saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give crude product 112, a viscous oil. The crude product was purified by column chromatography to obtain tert-butyldiphenylsilyl ether (112) (290 mg, 25%), which was a colorless, viscous oil.

[0461] Synthesis of ketone (115):

[0462] To a 100 mL round-bottom flask equipped with a magnetic stirrer, add a single-protected TBDPS alcohol (112) (297 mg, 0.0004 mol) and dichloromethane (10 mL). Add pyridine chlorochromate (PCC) (137 mg, 0.0064 mol) to the suspension with stirring. Stir the reaction mixture until complete (approximately 16–18 hours), monitoring the reaction progress by TLC. Filter the mixture through a diatomaceous earth mat in a Buchner funnel. Remove the solvent under vacuum, and purify the crude product by column chromatography to give ketone (115) as a pale yellow, viscous oil (290 mg, 95%).

[0463] Synthesis of TBDPS-protected keto acid (116):

[0464] To a methanol (60 mL) solution of a tricyclic enone monoprotected TBDPS ketone (115) (7.0 g, 0.0099 mol), 10% Pd / C (600 mg, 50% wet, 25% w / w) was added, and the mixture was hydrogenated at room temperature under atmospheric pressure (balloon pressure) for 15–18 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth and washed with ethanol. The ethanol solution was then evaporated under vacuum to give keto acid (116) (7.0 g crude yield), which was used in the next reaction without further purification.

[0465] Synthesis of compound 117:

[0466] Under argon atmosphere and at room temperature, a solution of tetrabutylammonium fluoride (30.5 g, 0.117 mol) in THF (15 mL) was added to a stirred solution of monoprotected TBDPS keto acid (116) (7.0 g, 0.011 mol) in tetrahydrofuran (85 mL). The reaction was stirred at room temperature until TLC indicated complete reaction. After complete reaction, the solvent was removed under vacuum to obtain a crude brown oily substance, which was purified by acid-base extraction to give compound 117 as a light brown solid (3.61 g, yield 80.2%).

[0467] 2.3 Figure 13 Synthesis of compound 126

[0468]

[0469] experiment:

[0470] Synthesis of treprostyl methyl ester (121):

[0471] A 1000 mL round-bottom flask equipped with a magnetic stirrer was filled with a methanol (400 mL) solution of treprostrin (1) (40 g, 0.110 mol). While stirring at room temperature, a catalytic amount of sulfuric acid (4 mL) was added to the clear solution. The reaction mixture was heated to reflux until the reaction was complete (approximately 2 hours), and the reaction progress was monitored by TLC. The solvent was removed under vacuum, and the crude product was purified by column chromatography to give treprostrin methyl ester (121) as a viscous oil (46.4 g, 99%).

[0472] Synthesis of protected glucuronide (123):

[0473] A 100 mL round-bottom flask equipped with a magnetic stirrer was filled with a solution of 1,2-dichloroethane (30 mL) containing treprostyl methyl ester (121) (1.0 g, 0.0024 mol). While stirring the mixture at room temperature, silver oxide (1.19 g, 0.0051 mol), α-bromotriacetoxymethyl ester (122), D-glucose, and molecular sieves were added to the clear solution. (Type). The reaction mixture was stirred at room temperature until complete (approximately 16-18 hours), and the reaction progress was monitored by TLC. The reaction mixture was filtered, the solvent was removed under vacuum, and the crude product (123) was used directly for the next step of the reaction (3.8 g, crude yield, theoretical yield 1.39 g).

[0474] Synthesis of compound 126:

[0475] A 100 mL round-bottom flask equipped with a magnetic stirrer was filled with a methanol (16 mL) solution of the protected glucuronide (123) (3.8 g, from the crude product of the previous step, 0.002 mol, based on 100% yield). While stirring the mixture at room temperature, an aqueous solution of sodium hydroxide (1.17 g, 0.029 mol, dissolved in 8 mL of water) was added to the clear solution. The reaction mixture was stirred at room temperature until hydrolysis was complete (approximately 16–18 hours), and the reaction progress was monitored by HPLC. The reaction mixture was neutralized to pH 5–7 with 2 M HCl (10 mL). The reaction mixture was extracted with ethyl acetate (2 × 25 mL), and the ethyl acetate layer of the crude mixture containing the isomer glucuronide (126 + 127) was washed with brine (10 mL), dried over sodium sulfate, and the solvent was removed under vacuum to give crude compound 126 (12.6 g, crude product). Pure metabolite 126 was collected by preparative HPLC (prep HPLC).

[0476] 2.4 Synthesis of Compound 96A

[0477]

[0478] experiment:

[0479] Synthesis of intermediate 4b:

[0480] A 1L three-necked round-bottom flask equipped with a mechanical stirrer, feeding funnel, thermocouple, and argon inlet / outlet adapter connected to a bubbler was filled with 26.90 g (0.148 mol) of 1-hexyn-O-tetrahydropyran-2-yl-5-ol and 300-350 mL of anhydrous tetrahydrofuran. Under argon atmosphere, ethyl magnesium bromide (3M, diethyl ether solution, 49.0 mL, 0.148 mol) was added to the solution, maintaining the temperature below 40°C for 20-30 minutes. After complete addition, the reaction mixture was stirred at 30-45°C for 2 hours. The reaction mixture was cooled to 0°C (ice-water bath), and a solution of 2-allyl-3-methoxybenzaldehyde (3, 20.0 g, 0.113 mol) in 50 mL of anhydrous tetrahydrofuran was added over 10 minutes. The reaction mixture was stirred overnight at room temperature to allow the temperature to rise to room temperature. The reaction was considered complete after 16 hours (TLC). The reaction mixture was quenched with saturated ammonium chloride at ambient temperature, resulting in the formation of particulate solids. The mixture was filtered to remove the particulate inorganic solids, and the filtrate was concentrated under vacuum to give crude product 4b (45 g). The crude product was purified by column chromatography to give pure intermediate 4b, a pale yellow viscous liquid (36 g).

[0481] Synthesis of intermediate 5b:

[0482] Intermediate 4b (36.0 g, 0.10 mol) and acetone (350–400 mL) were charged into a 2 L double-necked round-bottom flask equipped with a mechanical stirrer and thermocouple. Manganese dioxide (MnO2) (87.3 g, 1.00 mol) was added while stirring at ambient temperature. The reaction mixture was stirred overnight. The mixture was filtered through a diatomaceous earth mat in a Buchner funnel. The filtrate was concentrated under vacuum to give intermediate 5b as a pale yellow, viscous oil (35 g, 68% yield).

[0483] Synthesis of intermediate 6b:

[0484] Aryl intermediate 5b (35 g, 0.098 mol) and anhydrous tetrahydrofuran (300-400 mL) were charged into a 1 L three-necked round-bottom flask equipped with a mechanical stirrer, thermocouple, and argon inlet / outlet traps. A solution of (R)-methyloxazolylborane (117.8 mL, 1.0 M toluene solution, 0.118 mol) was added at room temperature under argon atmosphere. The mixture was cooled to -30 °C (dry ice / acetone bath), and a borane-dimethyl sulfide complex (17 mL, 0.196 mol) was slowly added, maintaining the temperature at -25 °C to -30 °C. After complete addition, the reaction mixture was stirred at the same temperature for 1 hour. The reaction progress was monitored by TLC. The reaction mixture was carefully quenched by the slow addition of methanol (30 mL), followed by the addition of saturated ammonium chloride (50 mL). Solids were removed by filtration. The filtrate was evaporated under vacuum to give a viscous solid. The viscous solid was dissolved in ethyl acetate, filtered again to remove insoluble impurities, and the filtrate was evaporated under vacuum to obtain the viscous solid. The crude product was purified by column chromatography to obtain intermediate 6b (semi-solid product) (16.1 g).

[0485] Synthesis of intermediate 7b:

[0486] Under argon atmosphere, at room temperature, a solution of crude chiral benzylalkynol (6b) (16.00 g), dichloromethane (160-250 mL), imidazole (4.860 g), and dimethylaminopyridine (0.273 g) was added to a 1 L three-necked round-bottom flask equipped with a mechanical stirrer, thermocouple, and argon inlet / outlet traps. The mixture was stirred until a clear solution was obtained, and tert-butyldimethylchlorosilane (10.1 g) was added while maintaining the temperature below 20 °C. The reaction was stirred overnight. The temperature of the reaction mixture was then raised to ambient temperature. After approximately 16 hours, the reaction progress was monitored by TLC. The mixture was washed with water (3 × 150 mL) and saturated sodium chloride (1 × 150 mL), dried with anhydrous sodium sulfate (10 g), filtered, and concentrated under vacuum to give crude product 7b, a viscous oil. The crude product was purified by column chromatography to give benzylynyl-tert-butyldimethylsilyl ether (intermediate 7b), a colorless viscous oil (16.1 g, 77%).

[0487] Synthesis of intermediate 8b:

[0488] Under argon atmosphere, a toluene (160 mL) solution of benzylynyl tert-butyl dimethyl silyl ether (7b, 16.10 g, 0.0341 mol) was added to a 250 mL three-necked round-bottom flask equipped with a mechanical stirrer, thermocouple, and argon inlet / outlet traps. Octacarbonyl dicobalt (11.60 g, 0.0341 mol) was added at room temperature, and the reaction mixture was stirred at ambient temperature. The reaction mixture slowly released carbon monoxide, and after a period of time, the solution turned reddish-brown. At this point, the solution was heated under argon atmosphere and refluxed for 2 hours. The reaction mixture was cooled to room temperature, and air was bubbled through the mixture overnight. After the reaction was complete, the reaction mixture was diluted with saturated ammonium chloride solution and extracted with ethyl acetate (2 × 125 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to give crude product 8b, a brown oily substance. The crude product 8b was purified by column chromatography to obtain pure tricycloenone (8b), which was a light brown oil (12.1 g, yield 71%).

[0489] Dissolve the crude material in ethanol (500 mL). Add activated carbon (1.2 g) to the solution. Heat the suspension under reflux, and filter the hot solution through a diatomaceous earth mat. Use the filtrate directly for the next reaction.

[0490] Synthesis of intermediate 9b:

[0491] A 1000 mL three-necked round-bottom flask equipped with a magnetic stirrer, stirring rod, and hydrogen-filled balloon was loaded with an anhydrous ethanol solution (600 mL, from the previous step) of intermediate 8b (12.1 g), anhydrous potassium carbonate (600 mg), and palladium supported on activated carbon (1.2 g, 10%, 50% wet). The reaction flask was evacuated under vacuum, and the vacuum was replaced with hydrogen from the attached balloon; this step was repeated three times. The mixture was hydrogenated at ambient temperature for 16 hours (overnight) under balloon pressure. The reaction progress was monitored by IR. After the reaction was complete (confirmed by IR), the reaction mixture was filtered through a diatomaceous earth pad. The filtrate was concentrated under vacuum to give approximately 200 mL of 9b solution, which was used for the next step of sodium borohydride reduction (8.9 g, 100% theoretical yield of 8b).

[0492] Synthesis of intermediate 10b:

[0493] An ethanol solution of tricycloone (9b) was placed in a 500 mL three-necked round-bottom flask equipped with a mechanical stirrer. The solution was cooled to -4 °C, and an aqueous solution of sodium hydroxide (9.1 g, dissolved in 90 mL of water) was added over 10–15 minutes with stirring. The reaction mixture was stirred for another 0.5 hours, followed by the addition of sodium borohydride (1.8 g). Stirring was continued at -10 °C for 2 hours. The reaction progress was monitored by TLC. The reaction mixture was carefully quenched by adding saturated ammonium chloride solution (50 mL) dropwise until pH 9–10 was reached. The mixture was heated to ambient temperature, and unwanted solids were removed by filtration. The filtrate was concentrated under vacuum to give crude product (tricyclool 10b) as an oil (8.1 g). The crude product was purified by column chromatography to give pure tricyclool 10b (7.1 g, two-step yield 80.3%).

[0494] Synthesis of intermediate 11b:

[0495] Under nitrogen atmosphere, anhydrous tetrahydrofuran (100 mL) and n-butyllithium were added to a 500 mL three-necked round-bottom flask equipped with a cooling bath, thermocouple, and argon inlet / outlet adapter connected to a bubbler. The mixture was cooled to -20 to -30 °C, and diphenylphosphine was added. The resulting orange-red solution was stirred for 10–15 minutes. Under nitrogen atmosphere, a THF solution (100 mL) of intermediate 10b was added to the reaction mixture at -20 °C. After complete addition, the deep red solution was stirred at -20 °C for 30 minutes, and then the temperature of the reaction mixture was raised to ambient temperature. The reaction mixture was heated under reflux overnight. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was cooled to ambient temperature, and then the reaction was quenched with water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give crude product 11b. Crude product 11b was purified by column chromatography to give compound 11b (6.61 g, 96% yield).

[0496] Synthesis of intermediate 11b':

[0497] A 100 mL solution of intermediate 11b (6.61 g, 0.183 g) in acetone was placed in a 250 mL single-necked round-bottom flask equipped with a magnetic stirrer, an argon inlet / outlet adapter connected to a bubbler, and a condenser. Benzyl bromoacetate (5.41 g, 0.023 mol) and potassium carbonate powder (10.8 g, 0.079 mol) were added to the above solution. The reaction mixture was heated under reflux for 3–4 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was cooled to ambient temperature and filtered through a diatomaceous earth mat. The diatomaceous earth mat was washed with acetone, and the filtrate was concentrated under vacuum to obtain a viscous liquid. The crude product 11b' was purified by column chromatography to obtain a viscous liquid of pure compound 11b' (7.7 g, 82.6%).

[0498] Synthesis of intermediate 11b:

[0499] Under argon atmosphere and at room temperature, a solution of intermediate 11b' (7.7 g, 0.015 mol) and dichloromethane (110 mL) was added to a 250 mL three-necked round-bottom flask equipped with a magnetic stirrer, thermocouple, and argon inlet / outlet traps. Under argon atmosphere and at room temperature, 4-(dimethylamino)pyridine (2.2 g, 0.018 mol) and acetic anhydride (1.84 g, 0.0180 mol) were added to the clear solution. The mixture was stirred overnight at room temperature. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was washed with saturated ammonium chloride (20 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give crude product 11b” as a viscous oil. The crude product was purified by column chromatography to give acetate (11b”) as a colorless, viscous oil (7.8 g, 92.8%).

[0500] Synthesis of intermediate 12b:

[0501] Under nitrogen atmosphere, at room temperature, a solution of crude intermediate 11b (7.6 g, 0.014 mol), diethyl ether (110 mL), and magnesium bromide (2.59 g, 0.140 mol) was placed in a 100 mL single-necked round-bottom flask equipped with a magnetic stirrer. The reaction mixture was stirred for 3–4 hours. The reaction progress was monitored by TLC. The reaction mixture was quenched with water (50 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give crude product 12b, a viscous oil. The crude product was purified by column chromatography to give intermediate 12b, a colorless viscous oil (2.06 g, 30%).

[0502] Synthesis of intermediate 92:

[0503] Intermediate 12b and dichloromethane (50 mL) were charged into a 100 mL single-necked round-bottom flask equipped with a magnetic stirrer. The mixture was stirred until a clear solution was obtained. Molecular sieve (500 mg) and PDC (2.9 g, 1.75 mol) were added to the clear solution, and the reaction mixture was stirred at ambient temperature. The reaction progress was monitored by TLC. The reaction was complete after 16 hours. The product was purified by column chromatography to give a viscous liquid of pure product 92 (1.14 g, yield 55.6%).

[0504] Synthesis of intermediates 96A and 96B (mixture):

[0505] Intermediate 92 (250 mg, 0.0005 mol) and DMF (8 mL) were charged into a 100 mL single-necked round-bottom flask equipped with a magnetic stirrer. The mixture was stirred until a clear solution was obtained. Monoethyl malonate (105 mg, 0.0008 mol), DMAP (22 mg, 0.00018 mol), piperidine (9 mg), and acetic acid (8 mg) were added to the clear solution at 5–10 °C, and the reaction mixture was stirred at ambient temperature. The reaction progress was monitored by TLC. The reaction was complete after 1 hour. At this point, the reaction mixture was quenched by adding saturated ammonium chloride solution (20 mL) and stirred for five minutes. The organic layer was separated, dried over sodium sulfate, filtered, and evaporated under vacuum to obtain a crude mixture of compounds 93 and 94 (270 mg). This crude mixture was dissolved in MeOH (8 mL), and an aqueous solution of sodium hydroxide (116 mg dissolved in 3 mL of water) was added to the clear solution at room temperature. The mixture was stirred at room temperature for 16 hours, and the reaction progress was monitored by HPLC. After the reaction was complete, the pH of the reaction mixture was adjusted to 1-2, and the mixture was extracted with ethyl acetate (2 × 30 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under vacuum to obtain the crude product. The crude product was purified by preparative HPLC to give compounds 96A and 96B (approximately 100 mg).

[0506] 3. Synthesis of treprost prodrug

[0507] 3.1. Synthesis of treprostyl side-chain acetate cyclopentylmethyl carbonate

[0508] experiment:

[0509] Synthesis of mono-TES treprostyl benzyl acetate side chain ester (3):

[0510] Acetic anhydride (2) (787 μL, 8.33 mmol) was added to a solution of mono-TES treprostyl benzyl ester (1) (3.30 g, 5.55 mmol) and DMAP (1.36 g, 11.10 mmol) in dichloromethane (DCM) under argon atmosphere and at room temperature. The reaction mixture was stirred at room temperature for 1 hour and examined by TLC. The mixture was concentrated under vacuum to give a crude product (5.28 g), which was purified by column chromatography to give mono-TES treprostyl benzyl ester side chain acetate (3) (3.47 g, 98% yield) (HPLC purity 99.95%). Compound 3 was obtained by... 1 Characterized by H NMR and MS.

[0511] Synthesis of treprostyl benzyl ester side chain acetate (4):

[0512] At room temperature, HCl (2N) (2.67 mL, 5.34 mmol) was added to a solution of mono-TES treprostyl benzyl acetate (3) (3.39 g, 5.33 mmol) in tetrahydrofuran (THF) (80 mL) and water (16 mL) under stirring. The reaction mixture was stirred at room temperature for 1 hour and examined by TLC. Water (50 mL) and ethyl acetate (50 mL) were added, and the layers separated. The aqueous layer was extracted with ethyl acetate (2 × 20 mL), and the combined organic layers were washed with brine and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under vacuum to give a crude product (3.53 g), which was purified by column chromatography to give treprostyl benzyl acetate (4) (2.76 g, 99% yield) (HPLC purity 99.82%). Compound 4 was obtained by... 1 Characterized by H NMR and MS.

[0513] Synthesis of treprostyl benzyl acetate cyclopentyl methyl carbonate (5):

[0514] Under argon atmosphere and at 0°C, methyl chloroformate (0.39 g, 4.14 mmol) was added to a stirred solution of treprostyl benzyl acetate (4) (0.72 g, 1.38 mmol) in 10 mL of DCM and pyridine (5 mL). The reaction mixture was stirred at room temperature for 2 hours, and the reaction was checked by TLC to confirm complete reaction. The reaction mixture was concentrated under vacuum to give crude product (1.38 g), which was purified by column chromatography to give treprostyl benzyl acetate cyclopentyl methyl carbonate (5) (0.77 g, 96% yield) (HPLC purity 99.90%). Compound 5 was obtained by... 1 Characterized by H NMR and MS.

[0515] Synthesis of treprostyl side-chain acetate cyclopentylmethyl carbonate (6):

[0516] To a stirred solution of treprostyl benzyl acetate cyclopentylmethyl carbonate (5) (0.70 g, 1.20 mmol) in ethyl acetate (20 mL) and water (1 mL), carbon-supported palladium (5 wt.%, 50% water) (100 mg) was added. The reaction mixture was evacuated under vacuum, purged with hydrogen (repeated twice), and connected to a hydrogen balloon, and stirred at room temperature for 2 hours. The reaction was checked by TLC and found to be complete. The mixture was filtered through a diatomaceous earth mat and washed with ethyl acetate. The filtrate was concentrated under vacuum to give treprostyl benzyl acetate cyclopentylmethyl carbonate (6) (0.58 g, 98% yield) (HPLC purity 99.73%). Compound 6 was obtained by... 1 H NMR, 13 Characterized by C NMR, IR and MS.

[0517] 3.2 Synthesis of cyclopentylpropionate, a side-chain phosphate ester of treprostyl

[0518]

[0519] experiment:

[0520] Synthesis of treprostyl benzyl ester dibenzyl phosphate cyclopentyl propionate (3):

[0521] Under argon atmosphere and at room temperature, propionic anhydride (2) (256 μL, 2.00 mmol) was added to a solution of treprostyl benzyl ester dibenzyl phosphate (1) (0.99 g, 1.33 mmol) in DCM (20 mL) and DMAP (325 mg, 2.66 mmol) with stirring. The reaction mixture was stirred at room temperature for 1 hour. The reaction was checked by TLC and found to be complete. The reaction mixture was concentrated under vacuum to give a crude product (1.91 g), which was purified by column chromatography to give treprostyl benzyl ester dibenzyl phosphate cyclopentylpropionate (3) (1.02 g, 96% yield) (HPLC purity 99.11%). Compound 3 was obtained by... 1 Characterized by H NMR and MS.

[0522] Synthesis of treprostyl side-chain phosphate cyclopentylpropionate (4):

[0523] To a stirred solution of treprostyl benzyl ester dibenzyl phosphate cyclopentyl propionate (3) (0.94 g, 1.17 mmol) in ethyl acetate (20 mL) and water (1 mL), 200 mg of carbon-supported palladium (5 wt.%, 50% water) was added. The reaction mixture was evacuated under vacuum, purged with hydrogen (repeated twice), and connected to a hydrogen balloon. The mixture was stirred at room temperature for 2 hours. The reaction was examined by TLC until complete. The mixture was filtered through a diatomaceous earth mat and washed with ethyl acetate. The filtrate was concentrated under vacuum to give treprostyl ester cyclopentyl propionate (4) (0.60 g, 97% yield) (HPLC purity 95.94%). Compound 4 was obtained by... 1 H NMR, 13 C NMR, 31 Characterized by P NMR, IR and MS.

[0524] 3.3 Synthesis of Triprostyl Side Chain Phosphate Cyclopentylmethyl Carbonate

[0525]

[0526] experiment:

[0527] Synthesis of treprostone benzyl ester dibenzyl phosphate cyclopentyl methyl carbonate (3):

[0528] Under argon atmosphere and at room temperature, methyl chloroformate (2) (260 mg, 2.76 mmol) was added to a stirred solution of treprostyl benzyl ester dibenzyl phosphate (1) (1.03 g, 1.38 mmol) in 20 mL of DCM and DMAP (675 mg, 5.52 mmol). The reaction mixture was stirred at room temperature for 2 hours, and the reaction was checked by TLC, indicating complete reaction. The reaction mixture was concentrated under vacuum to give crude product (2.20 g), which was purified by column chromatography to give treprostyl benzyl ester dibenzyl phosphate cyclopentyl methyl carbonate (3) (1.04 g, 95% yield) (HPLC purity 99.96%). Compound 3 was obtained by... 1 Characterized by H NMR and MS.

[0529] Synthesis of treprostyl side-chain phosphate cyclopentylmethyl carbonate (4):

[0530] To a stirred solution of treprostyl benzyl ester dibenzyl phosphate cyclopentyl methyl carbonate (3) (0.93 g, 1.16 mmol) in ethyl acetate (20 mL) and water (1 mL), carbon-supported palladium (5 wt.%, 50% water) (250 mg) was added. The reaction mixture was evacuated under vacuum, purged with hydrogen (repeated twice), and connected to a hydrogen balloon, and stirred at room temperature for 3 hours. The reaction was checked by TLC and found to be complete. The mixture was filtered through a diatomaceous earth mat and washed with ethyl acetate. The filtrate was concentrated under vacuum to give treprostyl benzyl phosphate cyclopentyl methyl carbonate (4) (0.62 g, 98% yield) (HPLC purity 99.48%). Compound 4 was obtained by... 1 H NMR, 13 C NMR, 31 Characterized by P NMR, IR and MS.

[0531] 3.4 Synthesis of Triprostyl Hydroxyacetic Acid Diacetate

[0532]

[0533] experiment:

[0534] Synthesis of treprostyl benzyl glycolate diacetate (3):

[0535] At room temperature, benzyl bromoacetate (2) (150 mg, 0.65 mmol) was added to a solution of treprostyl diacetate (1) (0.20 g, 0.43 mmol) in acetone (2 mL) and potassium carbonate (120 mg, 0.86 mmol) under stirring. The reaction mixture was stirred at room temperature for 2 hours, and the reaction was checked by TLC to confirm complete reaction. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give crude product (0.57 g), which was purified by column chromatography to give treprostyl benzyl hydroxyacetate diacetate (3) (0.23 g, yield 86%) (HPLC purity 99.99%). Compound 3 was obtained by... 1 Characterized by H NMR and MS.

[0536] Synthesis of treprostyl glycolic acid diacetate (4):

[0537] To a stirred solution of treprostyl benzyl glycolate diacetate (3) (0.22 g, 0.35 mmol) in ethyl acetate (10 mL), 50 mg of carbon-supported palladium (5 wt.%, 50% water) was added. The reaction mixture was evacuated under vacuum, purged with hydrogen (repeated twice), and connected to a hydrogen balloon. The mixture was stirred at room temperature for 1 hour. The reaction was checked by TLC and found to be complete. The mixture was filtered through a diatomaceous earth filter and washed with ethyl acetate. The filtrate was concentrated under vacuum to give treprostyl glycolate diacetate (4) (0.18 g, 99% yield) (HPLC purity 99.78%). Compound 4 was obtained by... 1 H NMR, 13 Characterized by C NMR, IR and MS.

[0538] Synthesis of 3,5-triprostyl glycolic acid dipropionate

[0539]

[0540] experiment:

[0541] Synthesis of treprostyl benzyl glycolate dipropionate (3):

[0542] At room temperature, benzyl bromoacetate (2) (0.31 g, 1.36 mmol) was added to a solution of treprostyl dipropionate (1) (0.46 g, 0.91 mmol) in acetone (10 mL) and potassium carbonate (0.25 g, 1.82 mmol) under stirring. The reaction mixture was stirred at room temperature for 4 hours. The reaction was checked by TLC and found to be complete. The mixture was filtered, and the filtrate was concentrated under vacuum to give a crude product (0.72 g), which was purified by column chromatography to give treprostyl benzyl hydroxyacetate dipropionate (3) (0.57 g, 97% yield) (HPLC purity 99.06%). Compound 3 was obtained by... 1Characterized by H NMR and MS.

[0543] Synthesis of treprostyl glycolic acid dipropionate (4):

[0544] To a stirred solution of treprostyl benzyl glycolate dipropionate (3) (0.52 g, 0.80 mmol) in ethyl acetate (15 mL) and water (1 mL), 100 mg of carbon-supported palladium (5 wt.%, 50% water) was added. The reaction mixture was evacuated under vacuum, purged with hydrogen (repeated twice), and connected to a hydrogen balloon, and stirred at room temperature for 1 hour. The reaction was checked by TLC and found to be complete. The mixture was filtered through a diatomaceous earth mat and washed with ethyl acetate. The filtrate was concentrated under vacuum to give treprostyl glycolate dipropionate (4) (0.45 g, 99% yield) (HPLC purity 99.99%). Compound 4 was obtained by... 1 H NMR, 13 CNMR, IR and MS characterization.

[0545] 3.6. Synthesis of treprostyl ester 2-((1,3-bisbenzyloxy)-propane-2-yloxy)acetate with side chain

[0546]

[0547] experiment:

[0548] Synthesis of mono-TES treprostyl benzyl ester side chain 2-((1,3-di(benzyloxy)propane-2-yl)oxy)acetate (3):

[0549] Under argon atmosphere and at room temperature, EDCI·HCl (1.05 g, 5.45 mmol) was added to a stirred solution of mono-TES treprostyl benzyl ester (1) (1.55 g, 2.61 mmol), 2-((1,3-di(benzyloxy)propane-2-yl)oxy)acetic acid (2) (0.72 g, 2.18 mmol), DIPEA (970 μL, 5.45 mmol), and DMAP (53 mg, 0.44 mmol) in dichloromethane (DCM) (25 mL). The reaction mixture was stirred overnight at room temperature and examined by TLC. Water (20 mL) was added, and the layers separated. The aqueous layer was extracted with DCM (2 × 10 mL). The combined DCM layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain a crude product (2.69 g). This crude product was purified by column chromatography to obtain mono-TES treprostyl benzyl ester side chain 2-((1,3-di(benzyloxy)propane-2-yl)oxy)acetate (3) (1.98 g) (HPLC purity 84.38%). Compound 3 was obtained by... 1 Characterized by H NMR and MS.

[0550] Synthesis of treprostyl benzyl ester side chain 2-((1,3-bis(benzyloxy)propane-2-yl)oxy)acetate (4):

[0551] At room temperature, HCl (2N) (2.11 mL, 4.22 mmol) was added to a solution of 2-((1,3-di(benzyloxy)propane-2-yl)oxy)acetate (3) (1.91 g, 2.11 mmol) of mono-TES treprostyl benzyl ester side chain in 50 mL of tetrahydrofuran (THF) and 10 mL of water. The reaction mixture was stirred at room temperature for 1 hour. The reaction was checked by TLC and found to be complete. Water (30 mL) and ethyl acetate (50 mL) were added, and the layers separated. The aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under vacuum to give crude product (2.20 g), which was purified by column chromatography to give treprostyl benzyl ester 2-((1,3-di(benzyloxy)propane-2-yl)oxy)acetate (4) (1.41 g, two-step yield 82%) (HPLC purity 99.09%). Compound 4 via 1 Characterized by H NMR and MS.

[0552] Synthesis of treprostyl side chain 2-((1,3-dihydroxy)propane-2-yl)oxy)acetate (5):

[0553] To a stirred solution of 2-((1,3-di(benzyloxy)propane-2-yl)oxy)acetate (4) (1.13 g, 1.42 mmol) in ethyl acetate (25 mL) and water (1.5 mL), carbon-supported palladium (5 wt.%, 50% water) (350 mg) was added. The reaction mixture was evacuated under vacuum, purged with hydrogen (repeated twice), and connected to a hydrogen balloon, and stirred at room temperature for 5 hours. The reaction mixture was analyzed by TLC and... 1 ¹H NMR analysis was performed. The reaction was complete. The mixture was filtered through a diatomaceous earth mat and washed with ethyl acetate. The filtrate was concentrated under vacuum to give treprostyl 2-((1,3-dihydroxy)propane-2-yl)oxy)acetate (5) (0.65 g, yield 88%) (HPLC purity 89.62%). Compound 5 was analyzed by… 1 H NMR, 13 Characterized by C NMR, IR and MS.

[0554] 3.7. Synthesis of treprostyl side-chain phosphate cyclopentyltrifluoroacetate

[0555]

[0556] experiment:

[0557] Synthesis of treprostone benzyl ester dibenzyl phosphate cyclopentyl trifluoroacetate (3):

[0558] At room temperature, trifluoroacetic anhydride (2) (280 μL, 2.00 mmol) was added to a solution of treprostyl benzyl ester dibenzyl phosphate (1) (0.74 g, 1.00 mmol) in DCM (15 mL) and DMAP (270 mg, 2.20 mmol) under stirring. The reaction mixture was stirred at room temperature for 1 hour, and the reaction was checked by TLC, indicating complete reaction. The reaction mixture was concentrated under vacuum to give crude product (1.60 g), which was purified by silica gel (approximately 35 g) column chromatography to give treprostyl benzyl ester dibenzyl phosphate cyclopentyl trifluoroacetate (3) (0.55 g, yield 65%) (HPLC purity 92.42%). Compound 3 was obtained by... 1 Characterized by H NMR and MS.

[0559] Synthesis of treprostyl side-chain phosphate cyclopentyl trifluoroacetate (4):

[0560] Carbon-supported palladium (160 mg) was added to a solution of treprostyl benzyl ester dibenzyl phosphate cyclopentyl trifluoroacetate (3) (0.54 g, 0.64 mmol) in tetrahydrofuran (THF) (15 mL) and water (1 mL) under stirring. The reaction mixture was evacuated under vacuum, purged with hydrogen (repeated twice), and connected to a hydrogen balloon. The mixture was stirred at room temperature for 5 hours. The reaction mixture was analyzed by TLC and... 1 The reaction was examined by HNMR and found to be complete. The mixture was filtered through a diatomaceous earth mat and washed with THF. The filtrate was concentrated under vacuum to give treprostyl cyclopentyl trifluoroacetate (4) (0.37 g, 99% yield).

[0561] 3.8. Synthesis of treprostyl trifluoroacetate cyclopentyl phosphate with side chain

[0562]

[0563] experiment:

[0564] Synthesis of treprostyl benzyl ester side chain trifluoroacetate cyclopentyl dibenzyl phosphate (3):

[0565] At room temperature, trifluoroacetic anhydride (2) (400 μL, 2.88 mmol) was added to a solution of treprostyl benzyl ester cyclopentyl dibenzyl phosphate (1) (1.07 g, 1.44 mmol) in DCM (20 mL) and DMAP (390 mg, 3.17 mmol) under stirring. The reaction mixture was stirred at room temperature for 1 hour. The reaction was checked by TLC and found to be complete. The reaction mixture was concentrated under vacuum to give a crude product (2.39 g), which was purified by column chromatography to give treprostyl benzyl ester trifluoroacetate cyclopentyl dibenzyl phosphate (3) (0.55 g, yield 65%) (HPLC purity 98.64%). Compound 3 was obtained by... 1 Characterized by H NMR and MS.

[0566] Synthesis of treprostyl trifluoroacetate cyclopentyl phosphate (4) with side chain:

[0567] To a stirred solution of treprostyl benzyl ester trifluoroacetate cyclopentyl dibenzyl phosphate (3) (0.99 g, 1.18 mmol) in tetrahydrofuran (THF) (20 mL) and water (1 mL), carbon-supported palladium (5 wt.%, 50% water) (300 mg) was added. The reaction mixture was evacuated under vacuum, purged with hydrogen (repeated twice), and connected to a hydrogen balloon. The mixture was stirred at room temperature for 4 hours. The reaction mixture was analyzed by TLC and... 1 The reaction was examined by 1H NMR and found to be complete. The mixture was filtered through a diatomaceous earth pad and washed with THF. The filtrate was concentrated under vacuum to give treprostyl trifluoroacetate cyclopentyl phosphate (4) (0.68 g, 99% yield).

[0568] 3.9. Synthesis of treprostyl trifluoroacetate side chain

[0569]

[0570] experiment:

[0571] Synthesis of mono-TES treprostyl benzyl ester side chain trifluoroacetate (3):

[0572] At room temperature, trifluoroacetic anhydride (2) (540 μL, 3.90 mmol) was added to a solution of mono-TES treprostyl benzyl ester (1) (1.16 g, 1.95 mmol) in DCM (20 mL) and DMAP (596 mg, 4.88 mmol) under stirring. The reaction mixture was stirred at room temperature for 1 hour, and the reaction was checked by TLC, indicating complete reaction. The reaction mixture was concentrated under vacuum to give crude product (1.91 g), which was purified by column chromatography to give mono-TES treprostyl benzyl ester side chain trifluoroacetate (3) (1.31 g, yield 96%) (HPLC purity 99.30%). Compound 3 was obtained by... 1Characterized by H NMR and MS.

[0573] Synthesis of treprostyl benzyl ester side chain trifluoroacetate (4):

[0574] At room temperature, HCl (2N) (0.89 mL, 1.78 mmol) was added to a solution of mono-TES treprostyl benzyl ester side chain trifluoroacetate (3) (1.22 g, 1.77 mmol) in tetrahydrofuran (THF) (25 mL) and water (5 mL) under stirring. The reaction mixture was stirred at room temperature for 1 hour. The reaction was checked by TLC and found to be complete. Water (20 mL) and ethyl acetate (20 mL) were added, and the layers separated. The aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under vacuum to give crude product (1.29 g), which was purified by column chromatography to give treprostyl benzyl ester side chain trifluoroacetate (4) (1.04 g, 99% yield) (HPLC purity 99.40%). Compound 4 was obtained by... 1 Characterized by H NMR and MS.

[0575] Synthesis of treprostyl side-chain trifluoroacetate (5):

[0576] To a stirred solution of treprostyl benzyl ester trifluoroacetate (4) (0.99 g, 1.72 mmol) in ethyl acetate (20 mL), carbon-supported palladium (5 wt.%, 50% water) (100 mg) was added. The reaction mixture was evacuated under vacuum, purged with hydrogen (repeated twice), and connected to a hydrogen balloon, and stirred at room temperature for 1 hour. The reaction was checked by TLC and found to be complete. The mixture was filtered through a diatomaceous earth filter and washed with ethyl acetate. The filtrate was concentrated under vacuum to give treprostyl ester trifluoroacetate (5) (0.95 g, 99% yield) (HPLC purity 97.68%). Compound 5 was obtained by... 1 H NMR, 13 Characterized by C NMR, IR and MS.

[0577] 3.10. Synthesis of treprostyl difluoroacetate side chain

[0578]

[0579] experiment:

[0580] Synthesis of mono-TES treprostyl benzyl ester side chain difluoroacetate (3):

[0581] At room temperature, difluoroacetic anhydride (2) (277 μL, 2.55 mmol) was added to a solution of mono-TES treprostyl benzyl ester (1) (1.01 g, 1.70 mmol) in DCM (20 mL) and DMAP (415 mg, 3.40 mmol) under stirring. The reaction mixture was stirred at room temperature for 1 hour, and the reaction was checked by TLC, indicating complete reaction. The reaction mixture was concentrated under vacuum to give crude product (1.87 g), which was purified by column chromatography to give mono-TES treprostyl benzyl ester side chain difluoroacetate (3) (0.96 g, yield 84%) (HPLC purity 99.19%). Compound 3 was obtained by... 1 Characterized by H NMR and MS.

[0582] Synthesis of treprostyl benzyl ester side chain difluoroacetate (4):

[0583] At room temperature, HCl (2N) (0.7 mL, 1.40 mmol) was added to a solution of mono-TES treprostyl benzyl ester side chain difluoroacetate (3) (0.94 g, 1.40 mmol) in tetrahydrofuran (THF) (20 mL) and water (4 mL) under stirring. The reaction mixture was stirred at room temperature for 1 hour. The reaction was checked by TLC and found to be complete. Water (20 mL) and ethyl acetate (20 mL) were added, and the layers separated. The aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give crude product (0.93 g), which was purified by column chromatography to give treprostyl benzyl ester side chain difluoroacetate (4) (0.77 g, 99% yield) (HPLC purity 98.92%). Compound 4 was obtained by... 1 Characterized by H NMR and MS.

[0584] Synthesis of treprostyl difluoroacetate (5) with side chain:

[0585] To a stirred solution of treprostyl benzyl ester difluoroacetate (4) (0.72 g, 1.29 mmol) in ethyl acetate (15 mL), carbon-supported palladium (5 wt.%, 50% water) (80 mg) was added. The reaction mixture was evacuated under vacuum, purged with hydrogen (repeated twice), and connected to a hydrogen balloon, and stirred at room temperature for 1 hour. The reaction was checked by TLC and found to be complete. The mixture was filtered through a diatomaceous earth mat and washed with ethyl acetate. The filtrate was concentrated under vacuum to give treprostyl benzyl ester difluoroacetate (5) (0.61 g, 99% yield) (HPLC purity 98.83%). Compound 5 was obtained by... 1 H NMR, 13 Characterized by C NMR, IR and MS.

[0586] 3.11. Synthesis of Treprostyl bis(trifluoroacetate)

[0587]

[0588] experiment:

[0589] Synthesis of treprostyl benzyl ester di(trifluoroacetate) (3):

[0590] At room temperature, trifluoroacetic anhydride (2) (1.39 mL, 9.99 mmol) was added to a solution of treprostyl benzyl ester (1) (1.60 g, 3.33 mmol) in DCM (35 mL) and DMAP (2.03 g, 16.55 mmol) under stirring. The reaction mixture was stirred at room temperature for 3 hours. The reaction was checked by TLC and found to be complete. The reaction mixture was concentrated under vacuum to give a crude product (6.51 g), which was purified by column chromatography to give treprostyl benzyl ester di(trifluoroacetate) (3) (0.79 g, yield 35%) (HPLC purity 98.79%). Compound 3 was obtained by... 1 Characterized by H NMR and MS.

[0591] Synthesis of treprostone di(trifluoroacetate) (4):

[0592] To a THF (15 mL) solution of treprostone benzyl ester di(trifluoroacetate) (3) (0.75 g, 1.11 mmol) under stirring, 50% palladium (5 wt.%, 50% water) (75 mg) was added. The reaction mixture was evacuated under vacuum, purged with hydrogen (repeated twice), and connected to a hydrogen balloon. The mixture was stirred at room temperature for 1 hour. The reaction was checked by TLC and found to be complete. The mixture was filtered through a diatomaceous earth mat and washed with THF. The filtrate was concentrated under vacuum to give treprostone benzyl ester di(trifluoroacetate) (4) (0.40 g, 62% yield) (HPLC purity 92.60%). Compound 4 was obtained by... 1 Characterized by H NMR and MS.

[0593] 3.12. Synthesis of Treprostyl di(difluoroacetate)

[0594]

[0595] experiment:

[0596] Synthesis of treprostyl benzyl ester di(difluoroacetate) (3):

[0597] At room temperature, difluoroacetic anhydride (2) (807 μL, 7.41 mmol) was added to a solution of treprostyl benzyl ester (1) (1.62 g, 3.37 mmol) in DCM (35 mL) and DMAP (1.65 g, 13.48 mmol) under stirring. The reaction mixture was stirred at room temperature for 1 hour. The reaction was checked by TLC and found to be complete. The reaction mixture was concentrated under vacuum to give a crude product (6.51 g), which was purified by column chromatography to give treprostyl benzyl ester di(difluoroacetate) (3) (1.61 g, yield 75%) (HPLC purity 98.82%). Compound 3 was obtained by... 1 Characterized by H NMR and MS.

[0598] Synthesis of treprostone di(difluoroacetate) (4):

[0599] To a stirred solution of treprostone benzyl ester di(difluoroacetate) (3) (0.73 g, 1.14 mmol) in ethyl acetate (15 mL), 80 mg of carbon-supported palladium (5 wt.%, 50% water) was added. The reaction mixture was evacuated under vacuum, purged with hydrogen (repeated twice), and connected to a hydrogen balloon, and stirred at room temperature for 1 hour. The reaction was checked by TLC and found to be complete. The mixture was filtered through a diatomaceous earth mat and washed with ethyl acetate. The filtrate was concentrated under vacuum to give treprostone benzyl ester di(difluoroacetate) (4) (0.65 g) as a viscous oil. Ethyl acetate (1 mL) was added to prepare a clear solution, which was then added to hexane under stirring to form a solid, which was filtered. The solid was dried in air overnight to give 0.48 g of the product (77% yield) (HPLC purity 98.44%) (melting point (MP): 38-40 °C). Compound 4 was obtained by... 1 H NMR, 13 Characterized by C NMR, IR and MS.

[0600] 3.13. Synthesis of treprostyl cyclopentyl difluoroacetate

[0601]

[0602] experiment:

[0603] Synthesis of TBDMS cyclopentyl difluoroacetate (3) with side chain of treprostyl benzyl ester:

[0604] At room temperature, difluoroacetic anhydride (2) (420 μL, 3.83 mmol) was added to a solution of treprostyl benzyl ester side chain TBDMS (1) (1.52 g, 2.55 mmol) in DCM (30 mL) and DMAP (623 mg, 5.10 mmol) under stirring. The reaction mixture was stirred at room temperature for 1 hour. The reaction was checked by TLC and found to be complete. The reaction mixture was concentrated under vacuum to give a crude product (2.12 g), which was purified by column chromatography to give treprostyl benzyl ester side chain TBDMS cyclopentyl difluoroacetate (3) (1.38 g, yield 81%) (HPLC purity 99.05%). Compound 3 was obtained by... 1 Characterized by H NMR and MS.

[0605] Synthesis of treprostyl benzyl ester cyclopentyl difluoroacetate (4):

[0606] At room temperature, HCl (2N) (3.0 mL, 6.00 mmol) was added to a 30 mL solution of treprostyl benzyl ester side chain TBDMS cyclopentyl difluoroacetate (3) (1.35 g, 2.01 mmol) in isopropanol (IPA) (30 mL). The reaction mixture was stirred at room temperature for 5 hours. The reaction was found to be substantially complete by TLC. Water (20 mL) was added, and the mixture was concentrated under vacuum to distill off most of the IPA. Ethyl acetate (EA) (20 mL) was added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under vacuum to give a crude product (1.19 g), which was purified by column chromatography to give treprostyl benzyl ester cyclopentyl difluoroacetate (4) (0.79 g, 70% yield) (HPLC purity 97.65%). Compound 4 was obtained by... 1 Characterized by H NMR and MS.

[0607] Synthesis of treprostyl cyclopentyl difluoroacetate (5):

[0608] To a stirred solution of treprostyl benzyl cyclopentyl difluoroacetate (4) (0.76 g, 1.37 mmol) in ethyl acetate (15 mL), carbon-supported palladium (5 wt.%, 50% water) (80 mg) was added. The reaction mixture was evacuated under vacuum, purged with hydrogen (repeated twice), and connected to a hydrogen balloon, and stirred at room temperature for 3 hours. The reaction was checked by TLC and found to be complete. The mixture was filtered through a diatomaceous earth mat and washed with ethyl acetate. The filtrate was concentrated under vacuum to give treprostyl cyclopentyl difluoroacetate (5) (0.62 g, 97% yield) (HPLC purity 96.69%). Compound 5 was obtained by... 1 H NMR, 13 Characterized by C NMR, IR and MS.

[0609] 3.14. Synthesis of treprostyl difluoroacetate cyclopentyl phosphate with side chain

[0610]

[0611] experiment:

[0612] Synthesis of treprostyl benzyl ester side chain difluoroacetate cyclopentyl dibenzyl phosphate (3):

[0613] At room temperature, difluoroacetic anhydride (2) (275 μL, 2.52 mmol) was added to a solution of treprostyl benzyl ester cyclopentyl dibenzyl phosphate (1) (1.25 g, 1.68 mmol) in DCM (25 mL) and DMAP (410 mg, 3.36 mmol) under stirring. The reaction mixture was stirred at room temperature for 1 hour. The reaction was checked by TLC and found to be complete. The reaction mixture was concentrated under vacuum to give a crude product (2.23 g), which was purified by column chromatography to give treprostyl benzyl ester difluoroacetate cyclopentyl dibenzyl phosphate (3) (1.25 g, 90% yield) (HPLC purity 99.60%). Compound 3 was obtained by... 1 Characterized by H NMR and MS.

[0614] Synthesis of treprostyl difluoroacetate cyclopentyl phosphate (4) with side chain:

[0615] To a stirred solution of treprostyl benzyl ester difluoroacetate cyclopentyl dibenzyl phosphate (3) (1.21 g, 1.48 mmol) in tetrahydrofuran (THF) (25 mL), carbon-supported palladium (5 wt.%, 50% water) (350 mg) was added. The reaction mixture was evacuated under vacuum, purged with hydrogen (repeated twice), and connected to a hydrogen balloon. The mixture was stirred at room temperature for 4 hours. The reaction mixture was analyzed by TLC. 1 H NMR, 31 The reaction was examined by P NMR, and TLC and NMR confirmed its completeness. The mixture was filtered through a diatomaceous earth mat and washed with THF. The filtrate was concentrated under vacuum to give treprostyl difluoroacetate cyclopentyl phosphate (4) (0.80 g, 99% yield). The crude compound was dissolved in ethyl acetate (2 mL). The solution was added to hexane (50 mL) with stirring to form a solid. The solid was filtered and dried in air to give compound 4 (0.65 g, 80% yield) (HPLC purity 97.83%) as a white solid (MP: 125-128 °C). Compound 4 was subjected to... 1 H NMR, 13 C NMR, 31 Characterized by P NMR, IR and MS.

[0616] 3.15. Synthesis of treprostyl side-chain phosphate cyclopentyl difluoroacetate

[0617]

[0618] experiment

[0619] Synthesis of treprostyl benzyl ester dibenzyl phosphate cyclopentyl difluoroacetate (3):

[0620] At room temperature, difluoroacetic anhydride (2) (222 μL, 2.04 mmol) was added to a solution of treprostyl benzyl ester dibenzyl phosphate (1) (1.26 g, 1.70 mmol) in DCM (25 mL) and DMAP (415 mg, 3.40 mmol) under stirring. The reaction mixture was stirred at room temperature for 3 hours. The reaction was checked by TLC and found to be complete. The reaction mixture was concentrated under vacuum to give a crude product (2.34 g), which was purified by column chromatography to give treprostyl benzyl ester dibenzyl phosphate cyclopentyl difluoroacetate (3) (1.13 g, yield 81%) (HPLC purity 99.60%). Compound 3 was obtained by... 1 Characterized by H NMR and MS.

[0621] Synthesis of treprostyl side-chain phosphate cyclopentyl difluoroacetate (4):

[0622] To a stirred solution of treprostone benzyl ester dibenzyl phosphate cyclopentyl difluoroacetate (3) (1.11 g, 1.35 mmol) in tetrahydrofuran (THF) (25 mL), carbon-supported palladium (5 wt.%, 50% water) (300 mg) was added. The reaction mixture was evacuated under vacuum, purged with hydrogen (repeated twice), and connected to a hydrogen balloon. The mixture was stirred at room temperature for 3 hours. The reaction mixture was analyzed by TLC. 1 H NMR, 31 P NMR analysis confirmed the reaction was complete. The mixture was filtered through a diatomaceous earth filter and washed with THF. The filtrate was concentrated under vacuum to give treprostyl phosphate cyclopentyl difluoroacetate (4). Compound 4 was obtained by... 1 H NMR, 13 C NMR, 31 Characterized by P NMR, IR and MS.

[0623] 3.16. Synthesis of treprostyl palmitate side chain

[0624]

[0625] experiment:

[0626] Synthesis of mono-TES treprostyl benzyl palmitate side chain palmitate (3):

[0627] Under argon atmosphere and at room temperature, EDCI·HCl (3.00 g, 15.63 mmol) was added to a solution of mono-TES treprostyl benzyl ester (1) (3.72 g, 6.25 mmol), palmitic acid (2) (1.92 g, 7.50 mmol), DIPEA (2.72 mL, 15.63 mmol), and DMAP (153 mg, 1.25 mmol) in dichloromethane (DCM) (70 mL) under stirring. The reaction mixture was stirred overnight at room temperature, and the reaction was found to be substantially complete by TLC. Water (20 mL) was added, and the layers separated. The aqueous layer was extracted with DCM (2 × 10 mL). The combined DCM layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give crude product (6.90 g), which was purified by column chromatography to give mono-TES treprostyl benzyl ester side chain palmitate (3) (4.58 g, 88% yield). Compound (3) was obtained by... 1 Characterized by H NMR and MS.

[0628] Synthesis of treprostyl benzyl palmitate side chain (4):

[0629] At room temperature, HCl (2N) (1.2 mL, 2.40 mmol) was added to a THF (50 mL) and water (10 mL) solution of mono-TES treprostyl benzyl palmitate (3) (1.98 g, 2.37 mmol) under stirring. The reaction mixture was stirred at room temperature for 1 hour. The reaction was checked by TLC and found to be complete. Water (50 mL) and ethyl acetate (50 mL) were added, and the layers separated. The aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under vacuum to give crude product (2.23 g), which was purified by column chromatography to give treprostyl benzyl palmitate (4) (1.72 g, 99% yield) (HPLC purity 99.89%). Compound 4 was obtained by... 1 Characterized by H NMR and MS.

[0630] Synthesis of treprostyl palmitate (5):

[0631] To a stirred solution of treprostyl benzyl palmitate (4) (1.58 g, 2.20 mmol) in ethyl acetate (30 mL), 150 mg of carbon-supported palladium (5 wt.%, 50% water) was added. The reaction mixture was evacuated under vacuum, purged with hydrogen (repeated twice), and connected to a hydrogen balloon. The mixture was stirred at room temperature for 2 hours. The reaction was checked by TLC and found to be complete. The mixture was filtered through a diatomaceous earth filter and washed with ethyl acetate. The filtrate was concentrated under vacuum to give treprostyl palmitate (5) (1.38 g, 99% yield) (HPLC purity 99.38%) (MP: 46-48 °C). Compound 5 was obtained by...1 H NMR, 13 Characterized by C NMR, IR and MS.

[0632] 3.17. Synthesis of treprostyl cyclopentyl palmitate

[0633]

[0634] experiment:

[0635] Synthesis of TBDMS cyclopentyl palmitate (3) of treprostyl benzyl ester side chain:

[0636] Under argon atmosphere and at room temperature, EDCI·HCl (1.29 g, 6.75 mmol) was added to a stirred solution of treprostyl benzyl ester side chain TBDMS (1) (1.61 g, 2.70 mmol), palmitic acid (2) (831 mg, 3.24 mmol), DIPEA (1.2 mL, 6.75 mmol), and DMAP (66 mg, 0.54 mmol) in dichloromethane (DCM) (40 mL). The reaction mixture was stirred overnight at room temperature and examined by TLC. Water (20 mL) was added, and the layers were separated. The aqueous layer was extracted with DCM (2 × 10 mL). The combined DCM layers were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under vacuum to give a crude product (3.08 g), which was purified by column chromatography to give treprostyl benzyl ester side chain TBDMS cyclopentyl palmitate (3) (2.13 g, yield 95%) (HPLC purity 87.03%). Compound 3 was obtained by... 1 Characterized by H NMR and MS.

[0637] Synthesis of treprostyl benzyl ester cyclopentyl palmitate (4):

[0638] HF.Py (4.3 mL, 36 mmol) was added to a THF solution (20 mL) of treprostyl benzyl ester side chain TBDMS cyclopentyl palmitate (3) (2.00 g, 2.40 mmol) cooled to 0 °C in a plastic tube under stirring. The reaction mixture was stirred at this temperature and slowly heated to room temperature for 5 hours. The reaction was checked by TLC and found to be complete. The reaction was quenched with saturated sodium bicarbonate aqueous solution to pH about 7, and the reaction mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under vacuum to give crude product (1.61 g), which was purified by column chromatography to give treprostyl benzyl ester cyclopentyl palmitate (4) (1.29 g, yield 75%) (HPLC purity 98.72%). Compound (4) was obtained by... 1 Characterized by H NMR and MS.

[0639] Synthesis of treprostyl cyclopentyl palmitate (5):

[0640] To a stirred solution of treprostone benzyl cyclopentyl palmitate (4) (1.19 g, 1.65 mmol) in ethyl acetate (25 mL), 120 mg of carbon-supported palladium (5 wt.%, 50% water) was added. The reaction mixture was evacuated under vacuum, purged with hydrogen (repeated twice), and connected to a hydrogen balloon. The mixture was stirred at room temperature for 2 hours. TLC analysis confirmed complete reaction. The mixture was filtered through a diatomaceous earth filter and washed with ethyl acetate. The filtrate was concentrated under vacuum to give treprostone benzyl cyclopentyl palmitate (5) (1.00 g, 99% yield) (HPLC purity 97.65%) (MP: 74-76 °C). Compound 5 was obtained by... 1 H NMR, 13 CNMR, IR and MS characterization.

[0641] 3.18. Synthesis of Triprostyl hexadecyl ester

[0642]

[0643] experiment

[0644] Synthesis of treprostone hexadecyl ester (3):

[0645] At room temperature, 1-bromohexadecane (2) (715 μL, 2.34 mmol) and cesium iodide (330 mg, 1.29 mmol) were added to a DMF (10 mL) solution of potassium treprostene (1) (0.50 g, 1.17 mmol) under stirring. The reaction mixture was stirred in an oil bath at 60 °C for 5 hours. The reaction was checked by TLC and found to be complete. A saturated aqueous solution of ammonium chloride (20 mL) was added, followed by ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under vacuum to give a crude product (1.19 g), which was purified by column chromatography to give treprostene hexadecyl ester (3) (0.73 g, 99% yield) (HPLC purity 99.70%) (MP: 51-53 °C). Compound 3 was obtained by... 1 H NMR, 13 Characterized by C NMR, IR and MS.

[0646] 3.19. Synthesis of treprostyl ethylene glycol phosphate

[0647]

[0648] experiment:

[0649] Synthesis of 2-TBDMS treprostyl benzyl glycol ester (3):

[0650] Under argon atmosphere and at room temperature, EDCI·HCl (3.97 g, 20.73 mmol) was added to a stirred solution of di-TBDMS treprostyl (1) (5.13 g, 8.29 mmol), benzyl ethylene glycol (2) (1.3 mL, 9.12 mmol), DIPEA (3.6 mL, 20.73 mmol), and DMAP (2.53 g, 20.73 mmol) in dichloromethane (DCM) (50 mL). The reaction mixture was stirred at room temperature for 2 hours and examined by TLC. Water (50 mL) was added, and the layers separated. The aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under vacuum to give a crude product (8.87 g), which was purified by column chromatography to give di-TBDMS treprostyl benzyl ethylene glycol ester (3) (5.13 g, yield 82%) (HPLC purity 97.08%). Compound (3) was obtained by... 1 Characterized by H NMR and MS.

[0651] Synthesis of 2-TBDMS treprostyl glycol ester (4):

[0652] To a stirred solution of 5.05 g (6.70 mmol) of di-TBDMS treprostyl benzyl glycol ester (3) in 80 mL of ethyl acetate, carbon-supported palladium (0.50 g, 5 wt.%, 50% water) was added. The system was evacuated and purged with hydrogen gas (from a hydrogen balloon) (repeated twice). The system was connected to the hydrogen balloon and stirred at room temperature for 6 hours, with TLC analysis. The mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under vacuum to give a crude product (4.93 g). This crude product was purified by column chromatography to give di-TBDMS treprostyl glycol ester (4) (4.07 g, 92% yield) (HPLC purity 98.90%). Compound 4 was characterized by 1H and MS.

[0653] Synthesis of 2-TBDMS treprostyl ethylene glycol dibenzyl phosphate (6):

[0654] Under argon atmosphere and at room temperature, dibenzyl-N,N-diisopropylphosphamide (5) (1.13 g, 3.26 mmol) was added to a stirred solution of di-TBDMS treprostyl glycol ester (4) (1.08 g, 1.63 mmol), tetrazolium (10.9 mL, 0.45 M acetonitrile solution, 4.89 mmol) in DCM (40 mL). The mixture was stirred for 3 hours, and the reaction was checked by TLC until complete. The system was cooled to -78 °C (dry ice-acetone), and mCPBA (70-75%) (0.87 g, 5.05 mmol) was added. The reaction mixture was stirred for 3 hours, and the reaction was checked by TLC until complete. A 10% sodium sulfite solution was added, and the mixture was stirred overnight. The layers were separated, and the DCM layer was examined with a Peroxide 100 Tip to ensure the absence of peroxides. The DCM layer was washed with saturated sodium bicarbonate solution, water, and brine, and dried over sodium sulfate. The product was filtered, and the filtrate was concentrated under vacuum to obtain a crude product (2.33 g). Purification by column chromatography yielded di-TBDMS treprostyl ethylene glycol dibenzyl phosphate (6) (1.42 g, yield 95%) (HPLC purity 86.27%). Compound 6 was obtained by... 1 Characterized by H NMR and MS.

[0655] Synthesis of treprostyl ethylene glycol dibenzyl phosphate (7):

[0656] A THF solution of 1.08 g (1.17 mmol) of treprostyl ethylene glycol dibenzyl phosphate (6) in di-TBDMS was added to a THF solution of pyridine hydrogen fluoride (2.5 mL). The mixture was stirred at room temperature for 4 hours and examined by TLC. The mixture was slowly quenched with sodium bicarbonate to a pH of approximately 8. Extraction was performed with EtOAc (50 mL, 2 × 20 mL), and the combined organic layers were washed with brine and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under vacuum to give a crude product (1.70 g), which was purified by column chromatography to give treprostyl ethylene glycol dibenzyl phosphate (7) (0.63 g, yield 77%) (HPLC purity 99.04%). Compound 7 was obtained by... 1 HNMR and MS characterization.

[0657] Synthesis of treprostyl ethylene glycol phosphate (8):

[0658] Carbon-supported palladium (50 mg, 5 wt.%, 50% water) was added to a stirred solution of treprostyl ethylene glycol dibenzyl phosphate (7) (0.21 g, 0.30 mmol) in ethyl acetate (10 mL). The system was evacuated and replaced with hydrogen from a hydrogen balloon (repeated twice). The system was then attached to a hydrogen balloon and stirred at room temperature for 2 hours, and the reaction was checked by TLC until complete. The mixture was filtered through a diatomaceous earth pad and washed with EtOAc (2 × 10 mL). The filtrate was concentrated under vacuum to give treprostyl ethylene glycol phosphate 8 (0.12 g, 78% yield) (HPLC purity 99.13%). Compound 8 was obtained by... 1 H NMR, 13 C NMR, 31 Characterized by P NMR, IR and MS.

[0659] While the foregoing describes specific preferred embodiments, it should be understood that the invention is not limited thereto. Those skilled in the art will recognize that various modifications can be made to the disclosed embodiments, and these modifications are intended to fall within the scope of the invention.

[0660] All publications, patent applications and patents cited in this specification are incorporated herein by reference in their entirety.

Claims

1. A compound of Formula (1), an enantiomer thereof, or a pharmaceutically acceptable salt thereof: wherein R 1 is H, C1-C3 alkyl, or a carboxylic acid protecting group; R 2 is H or an alcohol protecting group; and R 3 is wherein Y 1 is -C=C-; -CH=CH-; or -(CH2) m - m is an integer from 0 to 5; R 4 is H, OH, or =0; R 5 is H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted carbocyclyl; R 6 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, wherein each of R 1 and R 2 is H, R 3 is not 2. The compound of claim 1, wherein R 1 is H or CH3.

3. The compound of claim 1 or 2, wherein R 2 is H.

4. The compound according to any one of claims 1 to 3, wherein R 3 is wherein R 7 is alkyl, alkenyl or alkynyl; Z is O, CH2, NH or S, and R 8 is heterocyclyl.

5. The compound of any one of claims 1-3, wherein R 3 is wherein each Z is independently selected from CH, N, O, or S, n is 0 or 1, R 9 is alkyl, aryl, an electron-withdrawing group, an electron-donating group, a heterocycle, or a carbocycle.

6. The compound according to any one of claims 1-3, wherein R 3 is wherein R 10 is cycloalkyl having 3 to 8 carbon atoms, wherein one or more carbon atoms in the cycloalkyl group can optionally be replaced by a heteroatom selected from O, N and S.

7. The compound according to any one of claims 1-3, wherein R 3 is selected from 8. A compound of Formula (2), an enantiomer thereof, or a pharmaceutically acceptable salt thereof: wherein X 1 is hydrogen, wherein q is 1, 2 or 3, p1 is an integer from 1 to 20, R 12 is a phosphato group or COOH; X 2 and X 3 each independently is hydrogen, a phosphato group or wherein p2 is an integer from 1 to 20, R 11 is C1-C8 alkyl, one or more carbon atoms of which can optionally be replaced by O, one or more hydrogen atoms of which can optionally be replaced by halogen; X 2 is hydrogen, wherein X 1 , X 2 and X 3 are not all hydrogen; in case X 1 is hydrogen and one of X 2 and X 3 is a phosphato group, the other one of X 2 and X 3 is not a phosphato group or hydrogen; in case X 1 is hydrogen and one of X 2 and X 3 is and R 11 is unsubstituted C1-C8 alkyl, the other one of X 2 and X 3 is not hydrogen and X 2 or X 3 are not identical.

9. The compound of claim 8, wherein X 1 is 10. The compound of claim 9, wherein X 2 and X 3 are the same.

11. The compound of any one of claims 8-10, wherein each of X 2 and X 3 is hydrogen.

12. The compound of claim 9 or 10, wherein each of X 2 and X 3 is 13. The compound according to claim 8, wherein X 1 It is hydrogen.

14. The compound of claim 13, wherein X 2 and X 3 is a phosphonate group, and the other of X 2 and X 3 is 15. The compound of claim 13, wherein X 2 and at least one of X 3 is wherein R 11 is Ci-C8alkyl, one or more carbon atoms of which are substituted with O or one or more hydrogen atoms are substituted with halogen.

16. The compound of claim 15, wherein X 2 and at least one of X 3 is wherein R 11 is one or more hydrogen atoms replaced by halogen.

17. The compound of claim 16, wherein X 2 and each of X 3 is wherein R 11 is one or more hydrogen atoms replaced by halogen.

18. The compound of claim 17, wherein X 2 and X 3 are the same.

19. The compound of claim 8, wherein at least one of X 2 and X 3 is wherein p2 is an integer from 12 to 16, or X 1 is wherein p1 is an integer from 12 to 16.

20. The compound of claim 8, wherein (a) X 2 and X 3 are each hydrogen and X 1 is (b) X 3 is X 2 is and X 1 is hydrogen; (c) X 3 is X 2 is and X 1 is hydrogen; (d) X 3 is X 2 is and X 1 is hydrogen; (e) each of X 2 and X 3 is and X 1 is (f) each of X 2 and X 3 is and X 1 is (g) each of X 1 and X 2 is H and X 3 is (h) X 3 is X 2 is and X 1 is hydrogen; (i) X 2 is X 3 is and X 1 is hydrogen; (j) each of X 1 and X 2 is hydrogen and X 3 is (k) each of X 1 and X 2 is hydrogen and X 3 is (l) each of X 2 and X 3 is and X 1 is hydrogen; (m) each of X 2 and X 3 is and X 1 is hydrogen; (n) X 1 and X 3 Each of them is hydrogen and X 3 for (o)X 1 It is hydrogen; X 2 for And X 3 for (p)X 1 It is hydrogen; X 2 for And X 3 for (q)X 2 and X 3 Each of them is hydrogen and X 1 for (r)X 1 and X 2 Each of them is hydrogen and X 3 for (s)X 1 and X 3 Each of them is hydrogen and X 2 for or (t)X 1 for And X 2 and X 3 Each of them is 21. A pharmaceutical composition comprising a compound of any one of claims 1-20 and a pharmaceutically acceptable carrier.

22. A method of treating pulmonary hypertension comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-20.

23. A compound of Formula (3): wherein R 21 is a phenol protecting group or CH2COOR 24 ; R 22 is an alcohol protecting group; R 23 is a hydroxyl-terminated alkyl group, -C=CH2, -C≡CH, or R 24 is a carboxylic acid protecting group.

24. The compound of claim 23, wherein R 23 is a hydroxyl-terminated alkyl group.

25. The compound of claim 23, having Formula (31):

26. The compound of claim 23, having Formula (32):

27. The compound of claim 23, having Formula (33):

28. The compound according to any one of claims 23 to 27, wherein R 21 is C1-C4 alkyl, substituted or unsubstituted benzyl or CH2COOR 24 wherein R 24 is C1-C4 alkyl or substituted or unsubstituted benzyl.

29. The compound according to any one of claims 23 to 28, wherein R 22 is acetyl or a silyl-containing group.

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