Dry powder compositions of treprostinil and its prodrugs, and further comprising (E)-3,6-bis[4-(N-carbonyl-2-propenyl)amidobutyl]-2,5-diketopiperazine (FDKP)

Abstract

Treprostinil derivatives are provided that have a reduced tendency to form undesirable impurities in pharmaceutical formulations, such as dry powder formulations, and further include an inactive ingredient that contains a carboxyl group, such as fumaryl diketopiperazine.

Description

[Technical field]

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 63 / 156,110, filed March 3, 2021, which is incorporated herein by reference in its entirety. Summary of the Invention [Problem to be solved by the invention]

[0002] FIELD OF THE DISCLOSURE This disclosure relates generally to treprostinil derivatives, and more specifically to treprostinil derivatives that have a reduced propensity to form undesirable impurities in pharmaceutical formulations, and methods of making and using them. [Means for solving the problem]

[0003] summary One embodiment is a powder formulation comprising (a) a treprostinil prodrug, a treprostinil salt, or a salt of a treprostinil prodrug, and (b) fumaryl 2,5-diketopiperazine or (E)-3,6-bis[4-(N-carbonyl-2-propenyl)amidobutyl]-2,5-diketopiperazine (FDKP).

[0004] Another embodiment is a compound having the formula: [ka] In the formula, R 2 is the first pro component, R 3 is a second promoiety; and X is a salt moiety or a third promoiety; where OR 2 and OR 3 Each of these is less reactive with the carboxyl group than with the respective hydroxyl group of unsubstituted treprostinil, and C=OX is less reactive with the hydroxyl group than with the carboxyl group of unsubstituted treprostinil. [Brief description of the drawings]

[0005] [Figure 1] FIG. 1 shows impurities that can be formed by reaction of the hydroxyl group on the alkyl side chain of the treprostinil molecule with FDKP. [Diagram 2] FIG. 2 shows impurities that can be formed by reaction of the hydroxyl group on the cyclopentyl ring of the treprostinil molecule with FDKP. [Diagram 3] FIG. 3 shows impurities that can be formed by reaction of the carboxyl group of the treprostinil molecule with the hydroxyl group of ethanol. [Figure 4] Figures 4 and 5 each show a treprostinil dimeric impurity that can be formed via an intermolecular reaction between a carboxyl group of one treprostinil molecule and a hydroxyl group of another treprostinil. [Diagram 5] Figures 4 and 5 each show a treprostinil dimeric impurity that can be formed via an intermolecular reaction between a carboxyl group of one treprostinil molecule and a hydroxyl group of another treprostinil. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0006] Detailed Description of the Invention As used in the specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly indicates otherwise. Throughout this specification, unless otherwise indicated, "comprise," "comprises," and "comprising" are used inclusively rather than exclusively, such that a recited integer or group of integers may include one or more other unrecited integers or groups of integers. The term "or" is inclusive unless modified, for example, by "either." Thus, unless the context indicates otherwise, the term "or" means any one member of a particular list, and also includes any combination of members of that list. Except where specifically indicated or in the operating examples, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood to be modified in all instances by the term "about."

[0007] The headings are provided for convenience 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 those skilled in the art. The terms used herein are only for describing certain embodiments and are not intended to limit the scope of the invention, which is defined only by the claims. In order to make this disclosure more readily understandable, certain terms are defined at the beginning. Additional definitions are provided throughout the detailed description.

[0008] All numerical designations, e.g., pH, temperature, time, concentration, and molecular weight, including ranges, are approximations (+) or (-) that are varied by increments of 0.05%, 1%, 2%, 5%, 10%, or 20%. It is understood, although not necessarily expressly stated, that all numerical designations are preceded by the term "about." It is also understood, although not necessarily expressly stated, that the reagents described herein are merely exemplary and that equivalents of such reagents are known in the art.

[0009] "HPLC" refers to high performance liquid chromatography.

[0010] "NMR" stands for nuclear magnetic resonance.

[0011] As used herein, Cm-Cn, e.g., C 1 -C 12 , C 1- C 8 , or C 1 -C 6 when used before a group indicates a group containing m to n carbon atoms.

[0012] "Optionally substituted" refers to a group selected from the group and substitution patterns of that group. The substituents may include any of the groups defined below. In one embodiment, the substituents are 1 -C 10 Or C 1 -C 6 Alkyl, substituted C 1 -C 10 Or C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 6 -C 10 Aryl, C 3 -C 8 Cycloalkyl, C 2 -C 10 Heterocyclyl, C 1 -C 10 Heteroaryl, substituted C 2 -C 6 Alkenyl, substituted C 2 -C 6 Alkynyl, Substituted C 6 -C 10 Aryl, Substituted C 3 -C 8 Cycloalkyl, substituted C 2 -C 10 Heterocyclyl, substituted C 1 -C 10 Heteroaryl, halo, nitro, cyano, -CO 2 H or their C1 -C 6 The alkyl esters are selected from the group consisting of alkyl esters.

[0013] "Alkyl" refers to monovalent saturated aliphatic hydrocarbyl groups having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups, such as methyl (CH 3 -), ethyl (CH 3 CH 2 -), n-propyl (CH 3 CH 2 CH 2 -), isopropyl ((CH 3 ) 2 CH-), n-Butyl (CH 3 CH 2 CH 2 -), isobutyl ((CH 3 ) 2 CHCH 2 -), sec-butyl ((CH 3 )(CH 3 CH 2 )CH-), t-butyl ((CH 3 ) 3 C-), n-pentyl (CH 3 CH 2 CH 2 CH 2 ), and neopentyl ((CH 3 ) 3 CCH 2 -) is included.

[0014] "Alkenyl" refers to monovalent linear or branched hydrocarbyl groups having 2 to 10 carbon atoms and preferably 2 to 6 carbon atoms or preferably 2 to 4 carbon atoms and at least one site and preferably 1 to 2 sites of vinyl (>C=C<) unsaturation. Such groups are exemplified, for example, by vinyl, allyl, and 3-en-1-yl. Cis and trans isomers or mixtures of these isomers are included within this term.

[0015] "Alkynyl" refers to monovalent linear or branched hydrocarbyl groups having 2 to 10 carbon atoms and preferably 2 to 6 carbon atoms or preferably 2 to 3 carbon atoms and at least one site and preferably 1 to 2 sites of acetylenic (-C≡C-) unsaturation. Examples of such alkynyl groups include acetylenyl (-C≡CH) and propargyl (-CH2C≡CH).

[0016] Substituted alkyl refers to any of the following groups: alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl. Substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO 3 H, an alkyl group having 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are defined herein.

[0017] "Heteroalkyl" refers to an alkyl group in which one or more carbons are -O-, -S-, SO 2 , a P-containing moiety as provided herein, -NR Q -, [ka] In the formula, R Q is H or C 1 -C 6 Substituted heteroalkyl includes the following: alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl. Substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO 3H, a heteroalkyl group having 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are defined herein.

[0018] Substituted alkenyl includes the following: alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, substituted aryloxy, arylthio, substituted arylthio, carbo xyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxyl, heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO 3 H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, and preferably 1-2 substituents, wherein the substituents are defined herein, with the proviso that no hydroxy or thiol substituents are attached to a vinyl (unsaturated) carbon atom.

[0019] "Heteroalkenyl" refers to an alkyl group in which one or more carbons are -O-, -S-, SO 2 , a P-containing moiety as provided herein, -NR Q -, [ka] represents an alkenyl group substituted with Q is H or C 1 -C 6 It is an alkyl. Substituted heteroalkenyl means alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl. Substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO 3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, and the substituents are defined herein.

[0020] Substituted alkynyl groups include the following: alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl. Substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO 3 H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, and preferably 1-2 substituents, wherein the substituents are defined herein, with the proviso that no hydroxy or thiol substituents are attached to an acetylene carbon atom.

[0021] "Heteroalkynyl" refers to an alkyl group in which one or more carbons are -O-, -S-, SO 2 , a P-containing moiety as provided herein, -NR Q -, [ka] represents an alkenyl group substituted with Q is H or C 1 -C 6 It is an alkyl. Substituted heteroalkynyl includes the following: alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, substituted aryloxy, arylthio, substituted arylthio ... carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl ester, carboxyl ester, carboxyl ester, carboxyl ester, carboxyl ester, carboxyl ester, carboxyl ester, carboxyl ester, carboxyl ester, carboxyl ester, carboxyl ester, carboxyl ester, carboxyl ester, carboxyl ester, carboxyl ester, carboxyl ester, carboxyl ester, carboxyl ester, carboxyl ester, carboxyl ester, carboxyl ester, carboxyl carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO 3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, and the substituents are defined herein.

[0022] "Alkylene" refers to a linear or branched divalent saturated aliphatic hydrocarbyl group having 1 to 10 carbon atoms, preferably 1 to 6, and more preferably 1 to 3 carbon atoms. The term includes but is not limited to methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), n-propylene (-CH 2 CH 2 CH 2 -), iso-propylene (-CH 2 CH(CH 3 )- or CH(CH 3 )CH 2 -), butylene (-CH 2 CH 2 CH 2 CH 2 -), isobutylene (-CH 2 CH(CH 3 -)CH 2 -), sec-butylene (-CH 2 CH 2 (CH 3 Similarly, "alkenylene" and "alkynylene" refer to alkylene moieties that contain one or two carbon double or triple bonds, respectively.

[0023] Substituted alkylene refers to an alkylene group having 1-3 hydrogens substituted with a substituent selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl ester, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, and oxo, as defined herein. In some embodiments, the alkylene has 1-2 of the aforementioned groups or 1-3 carbon atoms substituted with an O-, -S-, or -NRQ- moiety, where R Q is H or C 1 ~C 6 It is an alkyl. Note that when an alkylene is substituted with an oxo group, two hydrogens bonded to the same carbon of the alkylene group are replaced with "=O". "Substituted alkenylene" and "substituted alkynylene" refer to alkenylene and substituted alkynylene moieties substituted with the substituents described for substituted alkylene.

[0024] "Alkynylene" refers to a linear or branched divalent hydrocarbyl group having 2 to 10 carbon atoms, and preferably 2 to 6 carbon atoms, or preferably 2 to 3 carbon atoms, and having at least one site of acetylenic (-C≡C-) unsaturation, and preferably 1 to 2 sites. Examples of such alkynylene groups are C≡C- and CH 2 Includes C≡C-.

[0025] Substituted alkynylene includes the following: alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl. Substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio and preferably 1 to 2 substituents selected from the group consisting of:

[0026] "Heteroalkylene" means that one or more carbons are -O-, -S-, SO 2 , a P-containing moiety as provided herein, -NR Q -, [ka] represents an alkylene group substituted with Q is H or C 1 -C 6 The term "substituted heteroalkylene" refers to a heteroalkynylene group having 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the substituents disclosed for substituted alkylene.

[0027] "Heteroalkenylene" refers to an alkenylene group in which one or more carbons are -O-, -S-, SO 2 , a P-containing moiety as provided herein, -NR Q -, [ka] R represents an alkenylene group substituted with Q is H or C 1 -C 6 It is an alkyl. The term "substituted alkenylene" refers to a heteroalkynylene group having 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the substituents disclosed for substituted alkenylene.

[0028] "Heteroalkynylene" refers to a heteroalkynylene group in which one or more carbons are -O-, -S-, SO 2 , a P-containing moiety as provided herein, -NR Q -, [ka] R represents an alkynylene group substituted with Q is H or C 1 -C 6 It is an alkyl. "Substituted heteroalkynylene" refers to a heteroalkynylene group having 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the substituents disclosed for substituted alkynylene.

[0029] "Alkoxy" refers to the group Oalkyl, where alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.

[0030] "Substituted alkoxy" refers to the group O(substituted alkyl), where substituted alkyl is defined herein.

[0031] "Acyl" refers to the 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)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-. , aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocycle-C(O)-, and substituted heterocycle-C(O)-, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein. Acyl refers to the "acetyl" group CH 3 Contains C(O)-.

[0032] "Acylamino" means -NR 47 C(O)alkyl, -NR 47 C(O) substituted alkyl, -NR 47 C(O)cycloalkyl, -NR 47 C(O)-substituted cycloalkyl, -NR 47 C(O)cycloalkenyl, -NR 47 C(O)-substituted cycloalkenyl, -NR 47 C(O)alkenyl, -NR 47 C(O) substituted alkenyl, -NR47 C(O)alkynyl, -NR 47 C(O) substituted alkynyl, -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)Heterocycle, NR 47 C(O) represents a substituted heterocycle, where R 47 is hydrogen or alkyl, and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

[0033] "Acyloxy" 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-, substituted cycloalkenyl-C(O)O-, heteroaryl-C(O )O—, substituted heteroaryl-C(O)O—, heterocyclic-C(O)O—, and substituted heterocyclic-C(O)O—, where 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.

[0034] "Amino" means NH 2 The group is shown.

[0035] "Substituted amino" refers to -NR 48 R 49 represents a group, where R 48 and R 49are independently selected from the following: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, SO 2 -Alkyl, -SO 2 -substituted alkyl, -SO 2 -Alkenyl, -SO 2 -substituted alkenyl, -SO 2 -Cycloalkyl, -SO 2 -substituted cycloalkyl, -SO 2 -Cycloalkenyl, -SO 2 -substituted cycloalkenyl, -SO 2 -Aryl, -SO 2 -Substituted aryl, -SO 2 -heteroaryl, -SO 2 -substituted heteroaryl, -SO 2 -heterocyclyl, -SO 2 -substituted heterocyclyl, and R 48 and R 49 is optionally attached to form, together with the nitrogen to which it is attached, a heterocyclic or substituted heterocyclic group, with R 48 and R 49 are not both hydrogen, where 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. 48 is hydrogen, R 49 When R is alkyl, the substituted amino group is sometimes referred to herein as alkylamino. 48 and R 49 When R is alkyl, the substituted amino group is sometimes referred to herein as dialkylamino. When referring to a monosubstituted amino, R 48 or R 49It is meant that either R is hydrogen, but not both. When referring to a disubstituted amino, R 48 Also 49 This means that neither is hydrogen.

[0036] "Aminocarbonyl" means -C(O)NR 50 R 51 represents a group, where R 50 and R 51 is 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; R 50 and R 51 is optionally attached, together with the nitrogen bound thereto, to form a heterocyclic or substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

[0037] "Aminothiocarbonyl" means -C(S)NR 50 R 51 R 50 and R 51 is 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; R 50 and R 51is optionally attached, together with the nitrogen bound thereto, to form a heterocyclic or substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

[0038] "Aminocarbonylamino" means -NR 47 C(O)NR 50 R 51 R 47 is hydrogen or alkyl, and R 50 and R 51 is 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, heterocycle, substituted heterocycle; R 50 and R 51 is optionally attached, together with the nitrogen bound thereto, to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

[0039] "Aminothiocarbonylamino" means -NR 47 C(S)NR 50 R 51 R 47 is hydrogen or alkyl, and R 50 and R 51is 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; R 50 and R 51 is optionally attached, together with the nitrogen bound thereto, to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

[0040] "Aminocarbonyloxy" is -OC(O)NR 50 R 51 R 50 and R 51 is 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; R 50 and R 51 is optionally attached, together with the nitrogen bound thereto, to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

[0041] "Aminosulfonyl" means -SO 2 NR 50 R 51 R 50 and R 51is 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; R 50 and R 51 is optionally attached, together with the nitrogen bound thereto, to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

[0042] "Aminosulfonyloxy" means O-SO 2 NR 50 R 51 R 50 and R 51 is 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; R 50 and R 51 is optionally attached, together with the nitrogen bound thereto, to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

[0043] "Aminosulfonylamino" means -NR 47 SO 2 NR 50 R 51 R 47is hydrogen or alkyl; R 50 and R 51 is 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; R 50 and R 51 is optionally attached, together with the nitrogen bound thereto, to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

[0044] "Amidino" means -C(=NR 52 )NR 50 R 51 R 50 , R 51 , and R 52 is 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; R 50 and R 51 is optionally attached, together with the nitrogen bound thereto, to form a heterocyclic or substituted heterocyclic group, and 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.

[0045] "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group having 6 to 14 carbon atoms with a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which may or may not be aromatic (e.g., 2 benzoxazolinone, 2H 1,4 benzoxazin 3(4H) one 7 yl, etc.), provided that the point of attachment is an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl.

[0046] "Substituted aryl" refers to any of the following: alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryloxy, heteroaryloxy, substituted heteroaryloxy, Heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO 3 It represents an allyl group substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio.

[0047] "Arylene" refers to a divalent aromatic carbocyclic group of a single ring or multiple condensed rings having 6 to 14 carbon atoms. "Substituted arylene" refers to an arylene having 1 to 5, preferably 1 to 3, and more preferably 1 to 2, substituents as defined for the aryl group.

[0048] The term "heteroarylene" refers to a divalent aromatic group having 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The term "substituted heteroarylene" refers to a heteroarylene 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 for the substituted aryl.

[0049] "Aryloxy" refers to the group -O-aryl, where aryl is as defined herein, and includes, by way of example, phenoxy and naphthoxy.

[0050] "Substituted aryloxy" refers to the group -O-(substituted aryl), where substituted aryl is as defined herein.

[0051] "Arylthio" refers to the group -S-aryl, where aryl is as defined herein.

[0052] "Substituted arylthio" refers to the group S(substituted aryl), where substituted aryl is as defined herein.

[0053] "Carbonyl" refers to the divalent group -C(O)- which is equivalent to -C(=O)-.

[0054] "Carboxyl" or "carboxy" refers to COOH or a salt thereof.

[0055] "Carboxyl ester" or "carboxy ester" refers to the groups -C(O)(O)-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)-substituted

[0043] The term "heteroaryl" refers to substituted cycloalkenyl, -C(O)(O)-heteroaryl, -C(O)(O)-substituted heteroaryl, -C(O)(O)-heterocyclic, and C(O)(O)-substituted heterocyclic, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

[0056] (Carboxyl ester)amino is the group -NR 47 C(O)(O)-alkyl, -NR 47 C(O)(O)-substituted alkyl, -NR 47 C(O)(O)-alkenyl, -NR 47 C(O)(O)-substituted alkenyl, -NR 47 C(O)(O)-alkynyl, -NR 47 C(O)(O)-substituted alkynyl, -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 and NR 47C(O)(O)-substituted heterocyclic ring; R 47 is alkyl or hydrogen, and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

[0057] "(Carboxyl ester)oxy" refers to the groups -OC(O)O-alkyl, -OC(O)O-substituted alkyl, -OC(O)O-alkenyl, -OC(O)O-substituted alkenyl, -OC(O)O-alkynyl, -OC(O)(O)-substituted alkynyl, -OC(O)O-aryl, -OC(O)O-substituted aryl, -OC(O)O-cycloalkyl, refers to -OC(O)O-substituted cycloalkyl, -OC(O)O-substituted cycloalkenyl, -OC(O)O-substituted cycloalkenyl, -OC(O)O-heteroaryl, -OC(O)O-substituted heteroaryl, -OC(O)O-heterocyclyl, and OC(O)O-substituted heterocyclyl, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

[0058] "Cyano" refers to the radical CN.

[0059] "Cycloalkyl" refers to cyclic alkyl groups having from 3 to 10 carbon atoms, either a single ring or multiple rings, including fused, bridged, and spiro ring systems. The fused ring may be an aryl ring, provided the non-aryl moiety is attached to the remainder of the molecule. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.

[0060] "Cycloalkenyl" refers to an aromatic cyclic alkyl group having a single or multiple cyclic rings having 3 to 10 carbon atoms and having at least one >C=C< ring unsaturation, and preferably having 1 to 2 sites of >C=C< ring unsaturation.

[0061] "Substituted cycloalkyl" and "substituted cycloalkenyl" include the following: oxo, thioxo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carbo xyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryloxy, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO 3 It represents a cycloalkyl group or a cycloalkenyl group having 1 to 5, or preferably 1 to 3, substituents selected from the group consisting of H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio.

[0062] "Cyclopropano" means any of the following: [ka] Shows.

[0063] "Cyclobutano" means any of the following: [ka] Shows.

[0064] "Cycloalkyloxy" refers to -O-cycloalkyl.

[0065] "Substituted cycloalkyloxy" refers to -O-(substituted cycloalkyl).

[0066] "Cycloalkylthio" refers to -S-cycloalkyl.

[0067] "Substituted cycloalkylthio" refers to --S-(substituted cycloalkyl).

[0068] "Cycloalkenyloxy" refers to -O-cycloalkenyl.

[0069] "Substituted cycloalkenyloxy" refers to -O-(substituted cycloalkenyl).

[0070] "Cycloalkenylthio" refers to -S-cycloalkenyl.

[0071] "Substituted cycloalkenylthio" refers to --S-(substituted cycloalkenyl).

[0072] "Guanidino" means -NHC(=NH)NH 2 The group shown is:

[0073] "Substituted guanidino" refers to -NR 53 C(=NR 53 )N(R 53 ) 2 Each R 53are 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 the two R bonded to the common guanidino nitrogen atom are 53 The group, optionally together with the nitrogen attached thereto, forms a heterocyclic or substituted heterocyclic group, provided that at least one R 53 is not hydrogen. The substituents are as defined herein.

[0074] "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0075] "Hydroxy" or "hydroxyl" refers to the group --OH.

[0076] "Heteroaryl" refers to an aromatic group having 1-10 carbon atoms and 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. Such heteroaryl groups may have a single ring (e.g., pyridinyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl), which may or may not be aromatic and / or may contain heteroatoms, provided that the point of attachment is through an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and / or sulfur ring atoms of the heteroaryl group are optionally oxidized to provide the N-oxide (N→O), sulfinyl, or sulfonyl moieties. Specific non-limiting examples include pyridinyl, pyrrolyl, indolyl, thiophenyl, oxazolyl, thizolyl, and furanyl.

[0077] The term "substituted heteroaryl" refers to a heteroaryl group substituted with 1 to 5, preferably 1 to 3, and more preferably 1 to 2, substituents selected from the group consisting of the same substituents as defined for substituted aryl.

[0078] "Heteroaryloxy" refers to -O-heteroaryl.

[0079] "Substituted heteroaryloxy" refers to the group -O-(substituted heteroaryl).

[0080] "Heteroarylthio" refers to the group -S-heteroaryl.

[0081] "Substituted heteroarylthio" refers to the group -S-(substituted heteroaryl).

[0082] "Heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially saturated, non-aromatic group having 1-10 ring carbon atoms and 1-4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen. Heterocycles include single or multiple fused rings, including fused bridged ring systems and spiro ring systems. In fused ring systems, one or more of the rings may be cycloalkyl, aryl, or heteroaryl, provided that the point of attachment is through the non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atoms of the heterocycle group are optionally oxidized to provide the N-oxide, sulfinyl, or sulfonyl moieties.

[0083] The terms "substituted heterocyclic" or "substituted heterocycloalkyl" or "substituted heterocyclyl" refer to a heterocyclyl group substituted with one to five, preferably one to three, of the same substituents as defined for substituted cycloalkyl.

[0084] "Heterocyclyloxy" refers to the group --O-heterocyclyl.

[0085] "Substituted heterocyclyloxy" refers to the group -O-(substituted heterocyclyl).

[0086] "Heterocyclylthio" refers to the group --S-heterocyclyl.

[0087] "Substituted heterocyclylthio" refers to the group -S-(substituted heterocyclyl).

[0088] Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, furan, thiophene, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinoxaline indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine. These include phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4 tetrahydroisoquinoline, 4,5,6,7 tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also called thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, and tetrahydrofuranyl.

[0089] "Nitro" means the group -NO 2 Shows.

[0090] "Oxo" refers to the atom (=O).

[0091] Phenylene refers to a divalent aryl ring containing 6 carbon atoms.

[0092] Substituted phenylene includes the following: alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano. no, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryloxy, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO 3 H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, with 1 to 4, preferably 1 to 3, or more preferably 1 to 2, substituents selected from the group consisting of substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio.

[0093] "Spirocycloalkyl" and "spiro ring system" refer to a ring having the following structure: [ka] As exemplified by: represents a divalent cyclic group having a spiro bond (a bond formed by a single atom that is the only common member of the ring) and a cycloalkyl or heterocycloalkyl ring having 3 to 10 carbon atoms.

[0094] "Sulfonyl" means the divalent group -S(O) 2 - indicates.

[0095] "Substituted sulfonyl" refers to the group -SO 2 -Alkyl, -SO 2 -substituted alkyl, -SO 2 -Alkenyl, -SO 2 -substituted alkenyl, SO 2 -Cycloalkyl, -SO 2 -substituted cycloalkyl, -SO 2 -Cycloalkenyl, -SO 2 -substituted cycloalkenyl, -SO 2 -Aryl, -SO 2 -Substituted aryl, -SO 2 -heteroaryl, -SO 2 -substituted heteroaryl, -SO 2 -heterocycle, -SO 2 -substituted heterocycle, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein. Substituted sulfonyl is methyl-SO 2 -, Phenyl-SO 2 - and 4-methylphenyl-SO 2 - and other groups.

[0096] "Substituted sulfonyloxy" refers to the group -OSO 2 -Alkyl, -OSO 2 -substituted alkyl, -OSO 2 -Alkenyl, -OSO 2 -substituted alkenyl, -OSO 2 -Cycloalkyl, -OSO 2 -substituted cycloalkyl, -OSO 2 -Cycloalkenyl, -OSO 2 -substituted cycloalkenyl, -OSO 2 -aryl, -OSO 2 -substituted aryl, -OSO 2-heteroaryl, -OSO 2 -substituted heteroaryl, -OSO 2 -heterocycle, -OSO 2 -represents a substituted heterocycle, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

[0097] "Thioacyl" refers to the 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)-, heterocycle-C(S)-, and substituted heterocycle-C(S)-, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

[0098] "Thiol" refers to an SH group.

[0099] "Thiocarbonyl" refers to the divalent group -C(S)- which is equivalent to -C(=S)-.

[0100] "Thioxo" refers to the atom (=S).

[0101] "Alkylthio" refers to an S-alkyl group, where alkyl is as defined herein.

[0102] "Substituted alkylthio" refers to the group -S-(substituted alkyl), where substituted alkyl is as defined herein.

[0103] The substituted rings may be substituted with one or more fused and / or spiro rings. Such fused rings include fused cycloalkyl, fused heterocyclyl, fused aryl, and fused heteroaryl rings, each of which may be unsubstituted or substituted. Such spiro rings include fused cycloalkyl and fused heterocyclyl, each of which may be unsubstituted or substituted.

[0104] It is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups), such impermissible substitution patterns being well known to those of skill in the art.

[0105] It is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups), such impermissible substitution patterns being well known to those of skill in the art.

[0106] "Pharmaceutically acceptable salt" refers to salts of a compound, which are suitable for pharmaceutical use and are derived from a variety of organic and inorganic counterions that are well known in the art, and include, by way of example, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like, when the compound contains an acidic functional group; and salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like, when the molecule contains a basic functional group (for a discussion of pharmaceutical salts, their selection, preparation, and use, see "Handbook of Pharmaceutically Acceptable Salts", edited by Stahl and Wermuth, (2002), Verlag Helvetica Chimica Acta, Zurich, Switzerland).

[0107] "Pulmonary hypertension" refers to all pulmonary hypertension in WHO Groups 1 to 5. Pulmonary arterial hypertension, also referred to as PAH, refers to pulmonary hypertension in WHO Group 1. PAH includes idiopathic, hereditary, drug- or toxin-induced, and persistent pulmonary hypertension of the newborn (PPHN).

[0108] In general, a pharma- ceutically acceptable salt is one that substantially retains one or more of the desired pharmacological activities of the parent compound and is suitable for in vivo administration. Pharmaceutically acceptable salts include acid addition salts formed with inorganic or organic acids. Inorganic acids suitable for forming pharma- ceutically 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, phosphoric acid, etc.

[0109] Examples of organic acids suitable for forming pharma- ceutically acceptable acid addition salts include, but are not limited to, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, alkylsulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, and the like), arylsulfonic acids (e.g., benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, and the like), glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like.

[0110] Pharmaceutically acceptable salts include salts formed when acidic protons present in the parent compound are replaced by metal ions (e.g., alkali metal ions, alkaline earth metal ions, or aluminum ions); ammonium ions (e.g., ammonium ions derived from organic bases such as ethanolamine, diethanolamine, triethanolamine, morpholine, piperidine, dimethylamine, diethylamine, triethylamine, and ammonium); and amino acid residues, i.e., residues of amino acids such as lysine, arginine, and the like.

[0111] Treprostinil, the active ingredient in Remodulin® (treprostinil) injection, Tyvaso® (treprostinil) inhalation, and Orenitram® (treprostinil) extended-release tablets, was described in US Pat. No. 4,306,075. Methods for preparing treprostinil 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, 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. Published Patent Application Nos. 2012-0197041, 2013-0331593, 2014-0024856, 2015-0299091, 2015-0376106, 2016-0107973, 2015-0315114, 2016-0152548, and 2016-0175319; PCT Published Application Nos. WO2016 / 0055819 and WO2016 / 081658.

[0112] Various uses and / or forms of treprostinil are described, for example, in U.S. Pat. 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, 8,6 09,728,8,350,079,8,349,892,7,999,007,8,658,694,8,653,137,9,029,607,8,765,813,9,050,311,9,199,908,9,278,901,8,747,897,9,358,240,9,339,507,9,255,064,9,278,902,9,278,903,9,758,465;9,422,223;9,8 78,972;9,624,156;U.S. Published Patent Application Nos. 2009-0036465, 2008-0200449, 2008-0280986, 2009-0124697, 2014-0275616, 2014-0275262, 2013-0184295, 2014-0323567, 2016-0030371, 2016-0051505, 2016 Nos. 2016-0143868, 2015-0328232, 2015-0148414, 2016-0045470, 2016-0129087, 2017-0095432; 2018-0153847 and PCT Publication Nos. WO00 / 57701, WO20160105538, WO2016038532, and WO2018 / 058124.

[0113] Treprostinil has the following chemical formula: [ka] has.

[0114] The treprostinil molecule has two hydroxyl groups: one on the cyclopentyl ring and one on the alkyl chain, as well as a carboxyl group. These reactive groups on the treprostinil molecule can lead to the formation of impurities in the treprostinil formulation. For example, the carboxyl group on one treprostinil molecule can react with one of the hydroxyl groups on another treprostinil molecule, thereby forming a dimer. The reactive groups on the treprostinil molecule can also form undesirable impurities when reacting with other components in the treprostinil formulation. For example, when the treprostinil formulation contains a carboxyl group-containing component, such as (E)-3,6-bis[4-(N-carbonyl-2-propenyl)amidobutyl]-2,5-diketopiperazine (FDKP) in the dry powder inhalation treprostinil formulation, the carboxyl group of such a component can react with one of the hydroxyl groups on the treprostinil molecule, thereby forming an undesirable impurity. The carboxyl groups on the treprostinil molecule may also react with the hydroxyl groups of hydroxyl-containing moieties such as alcohols, eg, methanol and ethanol, resulting in the formation of undesirable impurities.

[0115] WO2019 / 237028 discloses a dry powder composition comprising treprostinil and FDKP. In the preparation process, the dry powder composition is exposed to an alcohol such as methanol or ethanol. Figures 1-3 show undesirable impurities that may be formed by (a) reaction of an alkyl chain hydroxyl group of a treprostinil molecule with a carboxyl group of FDKP; (b) reaction of a cyclopentyl ring hydroxyl group of a treprostinil molecule with a carboxyl group of FDKP; and (c) reaction of a carboxyl group of treprostinil with a hydroxyl group of ethanol. Figures 4-5 show treprostinil dimer impurities that may be formed via intermolecular reaction of a carboxyl group of a treprostinil molecule with a hydroxyl group of another treprostinil, respectively.

[0116] Treprostinil formulations, such as the dry powder formulation comprising treprostinil and FDKP disclosed in WO2019 / 237028, are often stored at low temperatures, such as at or below room temperature, to reduce the rate of formation of undesirable impurities.

[0117] An embodiment is a formulation comprising a salt or prodrug of Treprostinil further comprising a carboxy group-containing component, e.g., FDKP, e.g., an FDKP-based powder formulation, which is preferably a dry powder formulation. By using a Treprostinil prodrug or Treprostinil salt instead of Treprostinil as the free acid, one or more undesirable impurities can be reduced and / or eliminated.

[0118] In some embodiments, the formulation that comprises a carboxyl group-containing component, for example FDKP, for example FDKP-based dry powder formulation, can comprise pharma- ceutically acceptable treprostinil salt.For example, the treprostinil salt can be the salt disclosed in one of the following documents, each of which is incorporated by reference in its entirety: PCT Publication No. WO2005 / 007081; U.S. Patent No. 7,417,070; U.S. Patent No. 9,701,611; U.S. Patent No. 9,988,334. Specific examples of treprostinil salts include treprostinil diethanolamine, treprostinil tromethamine, treprostinil arginine, treprostinil lysine salt, treprostinil N-methylglucamine, treprostinil magnesium, treprostinil ammonium; treprostinil potassium, treprostinil calcium, treprostinil ethylenediamine, treprostinil choline, treprostinil tris(hydroxymethyl)aminomethane (treprostinil TRIS), treprostinil procaine, treprostinil benzathine, treprostinil sodium, and the lysine salt of treprostinil, the arginine salt of treprostinil, and the potassium salt of treprostinil.

[0119] In some embodiments, a formulation that includes a carboxy group-containing component, such as FDKP, such as an FDKP-based dry powder formulation, may include a treprostinil prodrug or a pharma- ceutically acceptable salt thereof. For example, in some embodiments, the treprostinil prodrug may be a treprostinil prodrug disclosed in one of the following documents, each of which is incorporated by reference in its entirety: PCT Publication No. WO2005 / 007081, U.S. Pat. Nos. 7,384,978, 7,417,070, 7,544,713, 8,252,839, 8,410,169, 8,536,363, 9,050,311, 9,199,908, 9,278,901, 9,422,223; 9,624,156, 9,878,972, 9,371,264, 9,394,227, 9,505,737, 9,643,911, 9,701,616, 9,776,982, 9,845,305, 9,957,200, 10,053,414, 10,246, 403, 10,344,012, 10,450,290, 10,464,877, 10,464,878, 10,703,706, 10,752,733, 9,255,064, 9,469,600, 10,010,518, 10,343,979, 10,526,274; U. U.S. Patent Application Publication Nos. 2018-0153847, 2021-0054009, and 2021-0378996, and U.S. Patent Application No. 17 / 549,573, filed December 13, 2021.

[0120] In some embodiments, a prodrug may replace a carboxyl group of a corresponding unsubstituted treprostinil molecule with a moiety that has a lower chemical reactivity than the chemical reactivity of the carboxyl group of the unsubstituted treprostinil molecule. [ka] If X=O, then R 1 is alkyl, e.g. CH 3 , C 2 H 5aryl; substituted aryl, branched alkyl, such as pyvolyl, isopropyl, etc.; R when X=N 1 teeth, [ka] It is.

[0121] In some embodiments, a treprostinil prodrug may be a prodrug in which one hydroxyl group and one carboxyl group of the corresponding unsubstituted treprostinil molecule are substituted at a site that has a lower chemical reactivity than the chemical reactivity of the respective group in the unsubstituted treprostinil molecule.

[0122] In some embodiments, a treprostinil prodrug may be a prodrug in which each of the three reactive groups of the corresponding unsubstituted treprostinil molecule, i.e., the two hydroxyl groups and the carboxyl group, are replaced with a moiety that has a lower chemical reactivity than the chemical reactivity of each of the reactive groups in the unsubstituted treprostinil molecule.

[0123] For example, in some embodiments, the treprostinil prodrug has the following formula: [ka] The treprostinil prodrug may have the formula: R 2 is the first pro component, R 3 is a second promoiety, and X may be a salt moiety or a third promoiety. 2 and OR 3 may each be less chemically reactive with a carboxyl group, e.g., a carboxyl group of a carboxyl-containing compound, such as FDKP, than with the respective hydroxyl group of unsubstituted Treprostinil. The C=OX group in the prodrug may be less chemically reactive with a hydroxyl group, e.g., a hydroxyl group of an alcohol, such as methanol or ethanol, than the chemical reactivity of the carboxyl group (COOH) of unsubstituted Treprostinil.

[0124] Treprostinil prodrugs or treprostinil salts may result in lower amounts of impurities in Treprostinil formulations, such as Treprostinil formulations that include a carboxyl-containing moiety, such as FDKP, compared to Treprostinil formulations having unsubstituted treprostinil.

[0125] In some embodiments, the prodrug or treprostinil salt may also allow for the use of milder conditions for storing a treprostinil formulation, such as a dry powder formulation, containing a carboxyl group-containing component, such as FDKP, compared to a treprostinil formulation having unsubstituted treprostinil. For example, in some embodiments, a treprostinil formulation, such as a dry powder formulation, comprising (a) a treprostinil prodrug or treprostinil salt, and (b) a carboxyl group-containing component, such as FDKP, may be stored at room temperature, e.g., 18°C ​​to 30°C, 20°C to 28°C, 22°C to 25°C, or for at least 3 months, at least 6 months, at least 12 months, or 3 months to 36 months, 6 months to 30 months, 12 months to 18 months, or any value or subrange within these ranges.

[0126] In some embodiments, the prodrug may be water soluble. By using a water soluble prodrug, the use of organic solvents such as ethanol or methanol can be avoided, thus avoiding the formation of impurities due to reaction of the prodrug with the organic solvent.

[0127] In some embodiments, X is a salt moiety, i.e., O -The salt counterion may be a salt counterion. In some embodiments, the salt counterion may be a counterion from an amino acid. In some embodiments, the amino acid may be a naturally occurring amino acid. In some embodiments, the amino acid may be an L-isomer of a naturally occurring amino acid. In some embodiments, the amino acid may be a D-isomer of a naturally occurring amino acid. In some embodiments, the amino acid may be an amino acid selected from the 20 standard amino acids: alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In some embodiments, an amino acid salt moiety, such as an arginine salt moiety, may generate a water-soluble prodrug.

[0128] In some embodiments, X can be a third promoiety. For example, in some embodiments, X can be OR 9 or NR 1 R 6 and R 9 For example, the alkyl chain C 1 -C 20 , [ka] and R 1 is H or C 1 -C 4 is alkyl, R 6 below: [ka] and R 7 and R 8 are independently H or C 1 -C 4 It is an alkyl.

[0129] In some embodiments, R 2 and R 3 are independently a phosphorus-containing group, -C(O)R6 or ABC substituents, wherein: A is an optionally substituted C 1 -C 6 Alkylene, -NR 6 -, -C(O)-, -C(O)O-, or C(O)NR 6 - and; B is a bond, optionally substituted C 1 ~C 6 alkylene, -C(O)-, -O-, -S-, optionally substituted heterocyclyl; and C is optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, -(OCH 2 CH 2 )q-OR 6 , -C(O)N(R 6 ) 2 , -C(O)N(R 18 ) 2 , -C(O)R 6 , -CO 2 H, -OR 6 , -N(R 18 ) 2 , -N(R 6 ) 2 or [ka] where: R 18 together form an optionally substituted 3- to 8-membered heterocyclyl; Each R 6 are independently H, optionally substituted C 1 ~C 6 alkyl, optionally substituted heteroaryl, optionally substituted aryl, or R 6 together form a 4- to 8-membered optionally substituted heterocyclyl or a 5-membered optionally substituted heteroaryl; Or, the second promoiety and the third promoiety taken together form -C(O)-, -SO in the 8- to 12-membered heterocyclyl. 2 -, [ka] Form each R 10 is H, optionally substituted C 1 ~C 6 Alkyl, optionally substituted C 1 ~C 6 alkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted aryl; and q is 0, 1, 2, 3, 4, 5, or 6.

[0130] In some embodiments, R 2 and R 3 each independently represents a phosphorus-containing group or C(O)R 6 and R 6 is an arbitrarily substituted C 1 ~C 6 It is an alkyl.

[0131] In some embodiments, R 2 and R 3 Each of the groups may independently be CH 2 OBn, C.H. 2 OH, [ka] [ka] and [ka] wherein Z is O or CH 2 It is.

[0132] In some embodiments, R 2 and R 3 Each of C may independently be linear or branched. 1 -C 6 Alkyl and OR 20 , where R 20 represents one or more CH optionally substituted with O 2Linear or branched C 1 -C 6 Optionally substituted C such as alkyl 1 -C 6 is selected from alkyl.

[0133] In some embodiments, R 2 and R 3 may be the same chemical group. For example, in some embodiments, R 2 and R 3 may each be a phosphate group. In some embodiments, R 2 and R 3 are C(O)R, respectively. 6 R may be 6 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl or t-butyl, etc. 1 -C 6 In some embodiments, R 2 and R 3 are C such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, sec-butyl or isobutyl, respectively. 1 ~C 6 In some embodiments, R 2 and R 3 OMe, OEt, O i Pr or O(CH 2 ) 2 OR such as OMe 20 In some embodiments, R 2 and R 3 taken together to form -C(O)-. In some embodiments, the treprostinil prodrug or salt of the treprostinil prodrug is one of the following: [ka] may have one of:

[0134] In some embodiments, the treprostinil prodrug or a salt of a treprostinil prodrug may be one or more of the following: treprostinil diacetate potassium salt; treprostinil dipropionate potassium salt; treprostinil dibutyrate potassium salt; treprostinil methyldicarbonate potassium salt; treprostinil diacetate L-arginine salt; treprostinil dipropionate L-arginine salt; treprostinil dib Treprostinil methyldicarbonate L-arginine salt;Treprostinil diacetate L-lysine salt;Treprostinil dipropionate L-lysine salt;Treprostinil dibutyrate L-lysine salt;Treprostinil diisobutyrate L-lysine salt;Treprostinil dipivalate L-lysine salt;Treprostinil methyldicarbonate L-lysine salt;Treprostinil ethyldicarbonate L-lysine salt;Treprostinil Isopropyl dicarbonate L-lysine salt; Treprostinil bis(2-methoxyethyl carbonate) L-lysine salt; Treprostinil dihydroxyacetate L-lysine salt; Treprostinil bis(dimethylsuccinate) L-lysine salt; Treprostinil bis(morpholinosuccinate) L-lysine salt; Treprostinil bis(piperidinyl succinate) L-lysine salt; Treprostinil dimorpholinocarbamate L-lysine salt; and Treprostinil dipiperidinyl carbamate L-lysine salt.

[0135] In some embodiments, the prodrugs may be prepared by combining techniques from one or more of U.S. Patent Application Publication Nos. 2005-0085540 and 2018-0153847; U.S. Patent No. 9,701,611; and U.S. Patent Application Publication No. 2021-0054009, each of which is incorporated herein by reference in its entirety. For example, X is O - -arginine counterion, while R 2 and R 3For prodrugs where X is the same moiety selected from phosphate and C(O)R6, preparation techniques may include combining the synthesis of disubstituted prodrugs such as prodrugs LXX-LXXIII of US Patent Publication No. 2021-0054009 with the salt formation techniques of US Patent No. 9,701,611. 1 R 6 ;R 1 is H and R 6 But the following: [ka] and R 8 are independently H or C 1 ~C 4 alkyl, whereas R 2 and R 3 However, phosphate and C(O)R 6 For prodrugs that are identical moieties selected from, the preparation technique may include combining the synthesis of disubstituted prodrugs such as prodrugs LXX to LXXIII of U.S. Patent Application Publication No. 2021-0054009 with the synthesis technique of prodrug XIV of the same application. - Arginine counterion, while R 2 and R 3 For prodrugs in which X forms -C(O)-, the preparation technique may include combining the synthesis of prodrug XXIV of U.S. Patent Application Publication No. 2021-0054009 with the salt formation technique of U.S. Patent No. 9,701,611. 1 R 6 ;R 1 is H and R 6 But the following: [ka] and R 8 are independently H or C 1 ~C 4 alkyl, whereas R 2 and R 3For prodrugs in which -C(O)- is formed, the preparation technique may include combining the synthesis of prodrug XXIV in US Patent Application Publication No. 2021-0054009 with the synthesis technique of prodrug XIV in the same application. The prodrugs can be synthesized as outlined in the examples below.

[0136] One or more of the prodrugs and / or salts may be used in an effective amount in a pharmaceutical composition or formulation that may also include a carboxyl-containing inactive ingredient, such as FDKP. For example, the composition or formulation may be a dry powder formulation that includes one or more of the prodrugs and / or salts and a carboxyl-containing inactive ingredient, such as FDKP.

[0137] The term "effective amount" may refer to the amount of treprostinil prodrug, treprostil salt and / or treprostinil prodrug salt that may be required to treat a disease or condition. In some embodiments, the effective amount of treprostinil prodrug and / or salt may be the same or similar to the effective amount of treprostinil for treating the same disease or condition. In some embodiments, the effective amount of treprostinil prodrug and / or salt may be different from the effective amount of treprostinil for treating the same disease or condition. One of ordinary skill in the art will be able to determine the "effective amount" of a treprostinil prodrug and / or salt based on, for example, the relevant disease or condition, the amount of treprostinil known to treat, ameliorate or prevent the disease or condition, and the rate at which the prodrug and / or salt is converted to treprostinil in vivo.

[0138] In some embodiments, a method of treating a disease or condition is provided, the method comprising administering to a subject, such as a human, a compound (e.g., a prodrug and / or salt) or composition or formulation disclosed herein. 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 failure, peripheral neuropathy, digital ulcers, intermittent claudication, ischemic limb disease, peripheral ischemic lesions, pulmonary fibrosis, and asthma. In some embodiments, the disease is pulmonary hypertension.

[0139] In some embodiments, a formulation, such as a FDKP-based dry powder formulation, comprising (a) a carboxy group-containing component, e.g., FDKP, and (b) a treprostinil salt, a treprostinil prodrug, or a salt of a treprostinil prodrug, may be administered by inhalation, such as oral or nasal inhalation. In some embodiments, the formulation may be administered using a dry powder inhaler.

[0140] Dry powder inhalers are disclosed, for example, in U.S. Pat. Nos. 7,305,986, 7,464,706, 8,499,757, and 8,636,001, and PCT Publication No. WO29237028, each of which is incorporated by reference.

[0141] In some embodiments, the dry powder inhaler may include a cartridge, which may be a replaceable cartridge, containing an FDKP-based dry powder formulation including a treprostinil prodrug and / or salt. In some embodiments, the dry powder inhaler may be a compact, reusable or disposable respiratory inhaler. Dry powder inhalers can have a number of different shapes and sizes and can comprise a system of airflow conduit pathways for effective and rapid delivery of powdered medicaments to the lungs and / or systemic circulation. The embodiments described herein are further illustrated by, but not limited to, the following examples. EXAMPLES

[0142] Example 1 Scheme 1: General procedure for the synthesis of treprostinil disubstituted prodrug salts (4) [ka]

[0143] General procedure for the synthesis of treprostinil benzyl ester disubstituted prodrugs (acylation and carbomethoxylation): To a stirred solution of treprostinil benzyl ester (1) (1.0 eq) and DMAP (2.0 eq) in dichloromethane (DCM) (20 v / wt) was added the respective anhydride (1.5 eq) or methyl chloroformate (1.5 eq). The resulting mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo to give the crude product, which was purified by silica gel column chromatography to give the treptostinil benzyl ester diacetate (2a) or dipropionate (2b) or dibutanoate (2c) or dicarbonate (2d). These compounds (2a, 2b, 2c and 2d) were 1 Characterized by 1 H NMR and LCMS.

[0144] General procedure for the synthesis of treprostinil disubstituted prodrugs (3a-d) (Debenzylation): To treprostinil benzyl ester disubstituted prodrugs (2a-d) (1.0 eq) in ethyl acetate (20 v / wt) (and water 1 v / wt) was added 5% palladium on carbon (~50% water) (10-25 wt%) under argon. The mixture was evacuated and replaced with hydrogen (balloon filled) at room temperature and this process was repeated twice. The reaction mixture was stirred under hydrogen atmosphere at room temperature for 1-3 hours. The mixture was filtered through a pad of Celite and washed with EtOAc. The filtrate was evaporated in vacuo to give pure treprostinil disubstituted prodrugs (3a-d). The pure products were characterized by IR, 1 H NMR, 13 It was characterized by C NMR and LC-MS.

[0145] General procedure for salt formation of treprostinil disubstituted prodrugs (4a-d): Compounds (3a-d) were dissolved in acetone to obtain a clear solution, and then the base was added as an aqueous solution. This was heated to form the salt. The mixture was evaporated and the solid was triturated with isopropyl acetate and heptane. This was evaporated to obtain the salt as a free-flowing powder. Salts (4a-d) were 1 H NMR, 13 The compounds were characterized by C nuclear magnetic resonance (NMR), melting point (MP) measurements, liquid chromatography-mass spectrometry (LC-MS) and infrared (IR) spectroscopy. [Table 1]

[0146] Synthesis of Treprostinil Acetoxyacetate Acid (7) Scheme 2: Synthesis of Treprostinil Acetoxyacetate Acid [ka]

[0147] Synthesis of Treprostinil Acetoxyacetate Benzyl Ester (6): To a solution of treprostinil (5) (100.2 g, 256.58 mmol) in acetone (1.5 L) was added benzyl bromoacetate (44.3 mL, 282.23 mmol) and potassium carbonate (106.4 g, 769.74 mmol). To this was added acetone (800 mL) and the mixture was stirred vigorously at room temperature under an argon atmosphere. After 64 h, the reaction was found to be complete based on TLC. The reaction was filtered through Celite and evaporated in vacuo to give crude treprostinil acetoxyacetate benzyl ester (6). This was purified by column chromatography using ethyl acetate:hexane (0-60%) as the mobile phase to give three fractions of treprostinil acetoxyacetate benzyl ester (6) (A: 6.4 g, B: 65.3 g, C: 50.2 g). Fraction C (50.2 g) was crystallized from ethyl acetate (400 mL) and hexane (100 mL) at 65° C. to give 28.1 g of product (6). The mother liquor from this (21.8 g) and fraction A (6.4 g) were combined and crystallized from ethyl acetate (170 mL) and hexane (60 mL) at 65-70° C. to give pure product (6) (26.7 g) (total, 120.1 g, 86.9% yield). The pure product was 1 Characterized by 1 H NMR.

[0148] Synthesis of Treprostinil Acetoxyacetate Acid (7): To a solution of treprostinil benzyl acetoxyacetate (6) (73.5 g) in ethyl acetate (1.3 L) (solubilized at 60° C.) was added palladium on carbon (7.3 g) at RT. Tetrahydrofuran (100 mL) was then added to keep the compound in solution. The reaction was evacuated and replaced with hydrogen gas under balloon pressure (3 times). After stirring at room temperature for 3 hours, the reaction was found to be complete based on TLC. The reaction mixture was filtered through Celite, split into two portions, and evaporated in vacuo to give crude treprostinil acetoxyacetate acid (7) (43.5 g + 45.7 g). The two batches were crystallized (separately) at 40° C. using tert-butyl methyl ether (250 mL) and hexane (75 mL). They were combined and slurried in hexane (700 mL). The solid crystals were filtered through No. 4 filter paper and air-dried to give pure treprostinil acetoxyacetate acid (7) (51.4 g, 83.9% yield) as a white to off-white solid. 1 H NMR, 13 It was characterized by C NMR, IR and MS, with a melting point of 92.5°C to 95.2°C.

[0149] Example 2 Scheme 3: Synthesis of Treprostinil Disubstituted Esters and Carbonate Salts [ka] Scheme 4: Synthesis of treprostinil dialkylate and disuccinamate L-lysine salts [ka] Scheme 5: Synthesis of Treprostinil Dicarbamate L-Lysine Salt [ka]

[0150] General experimental procedure General Procedure for the Synthesis of Treprostinil Dialkylate Benzyl Esters (2a-2e) To a stirred solution of treprostinil benzyl ester (1) (1.0 eq.) in dichloromethane (DCM) was added DMAP (3.0 eq.) at room temperature under argon. The resulting reaction mixture was stirred for 5 min, after which the corresponding alkyl anhydride (3.0 eq.) was slowly added. After 1.5-4 h, TLC suggested the reaction was complete. After completion of the reaction, the reaction mixture was concentrated in vacuo and the crude compound was purified by silica gel column chromatography (EtOAc / Hexane) to obtain pure treprostinil dialkyl acid benzyl esters (2a-2e). The compounds were IR, 1 Characterized by 1 H NMR and LCMS.

[0151] General procedure for the synthesis of treprostinil alkyl dicarbonate benzyl esters (2f-2i) To a stirred solution of treprostinil benzyl ester (1) (1.0 eq.) in dichloromethane (DCM) and pyridine (1:1) under argon at 0-5 °C (water + dry ice), a solution of the corresponding alkyl chloroformate (2.5 eq.) in DCM was added dropwise. After 2-4 h, TLC suggested the reaction was complete. After completion of the reaction, the reaction mixture was concentrated in vacuo and dried under high vacuum, and the resulting crude compound was purified by silica gel column chromatography (EtOAc / Hexane) to give the pure treprostinil alkyl dicarbonate benzyl esters (2f-2i). The compounds were characterized by IR, 1 Characterized by 1 H NMR and LCMS.

[0152] General Procedure for the Synthesis of Treprostinil Dialkylate and Disuccinamate Benzyl Esters (2j-2m) To a stirred solution of treprostinil benzyl ester (1) (1.0 eq.) and the corresponding acid or succinic acid (3.0 eq.) in dichloromethane (DCM) was added DIPEA (4.0 eq.) and DMAP (0.5 eq.) at room temperature under argon. EDCI-HCl (4.0 eq.) was then added in portions and the resulting reaction mixture was stirred overnight at room temperature under argon. After 16-65 hours, TLC suggested the reaction was complete. After completion of the reaction, the reaction mixture was quenched with water, the DCM layer was separated, and the aqueous layer was extracted with DCM. The combined DCM layers were washed with brine and anhydrous sodium sulfate (Na 2 SO 4 ), filtered and concentrated in vacuo to give crude material, which was purified by silica gel column chromatography (EtOAc / Hexanes) to give pure treprostinil dialkylate or disuccinamate benzyl ester (2j-2m). 1 Characterized by 1 H NMR and LCMS.

[0153] General procedure for the synthesis of treprostinil dicarbamate benzyl ester (7a-7b) To a stirred solution of treprostinil benzyl ester (1) (1.0 eq.) in pyridine at room temperature under argon was added the corresponding carbamoyl chloride (8.0 eq.). The resulting reaction mixture was refluxed under argon. After 24-40 h, TLC suggested the reaction was complete. After completion of the reaction, the reaction mixture was concentrated in vacuo and dried under high vacuum, and the crude compound obtained was purified by silica gel column chromatography (EtOAc / Hexane) to give pure treprostinil dicarbamate benzyl ester (7a-7b). The compounds were IR, 4-methyl-4-phenyl-1,1-diphenyl-2,2-diphenyl-1,2 ... 1 Characterized by 1 H NMR and LCMS.

[0154] General hydrogenolysis procedure for the synthesis of treprostinil disubstituted compounds (3a-3m, 8a-8b) To a stirred solution of treprostinil disubstituted benzyl esters (2a-2m, 7a-7b) (1.0 eq.) in ethyl acetate (EtOAc) at room temperature was added 5% palladium on carbon (Pd-C, 50% water) (25-35 wt.% of 2a-2m, 7a-7b). The resulting reaction mixture was evacuated under house vacuum and flushed with hydrogen gas (filled into a 1 L balloon) three times, then stirred under hydrogen atmosphere at room temperature. After 3-8 h, TLC suggested the reaction was complete. After completion of the reaction, the reaction mixture was filtered through a pad of Celite, the solids were washed with EtOAc, and the combined EtOAc layers were concentrated in vacuo and dried under high vacuum to give the pure treprostinil disubstituted compounds (3a-3m, 8a-8b). The compounds were characterized by IR, 1 Characterized by 1 H NMR and LCMS.

[0155] General procedure for the synthesis of treprostinil disubstituted potassium salts (4a-4c, 4f) A stirred solution of treprostinil disubstituted compounds (3a-3c, 3f) (1.0 eq.) in acetone at 30 °C was added to the 2 CO 3 (0.5 eq.) aqueous solution was added dropwise. The resulting clear reaction mixture was stirred at 30-35°C. After 15-30 min, the reaction mixture was concentrated in vacuum and azeotropically dried with isopropyl acetate. The resulting viscous oil was triturated with heptane under sonication, concentrated in vacuum, and dried under high vacuum at 35°C (water bath) to give Treprostinil disubstituted potassium salts (4a-4c, 4f) as amorphous solids. The compounds were characterized by IR, 1 Characterized by 1 H NMR and LCMS. Compound 4a (Treprostinil diacetate potassium salt): mp 228-232 °C; HPLC purity: 100% Compound 4b (Treprostinil dipropionate potassium salt): mp 230-233 °C; HPLC purity: 99.89% Compound 4c (Treprostinil dibutyrate potassium salt): mp 214-219 °C; HPLC purity: 98.58% Compound 4f (Treprostinil methyldicarbonate potassium salt): mp 196-198 °C; HPLC purity: 99.58%

[0156] General procedure for the synthesis of treprostinil disubstituted L-arginine salts (5a-5c, 5f) To a stirred solution of treprostinil disubstituted compounds (3a-3c, 3f) (1.0 eq.) in isopropyl alcohol or acetone at 45° C. was added dropwise an aqueous solution of L-arginine (1.0 eq.). The resulting clear reaction mixture was stirred at 45° C. After 30 min, the reaction mixture was concentrated under reduced pressure and azeotropically dried with isopropyl acetate. The resulting viscous oil was triturated with heptane under sonication, concentrated in vacuo, and dried under high vacuum at 35° C. (water bath) to give the treprostinil disubstituted L-arginine salts (5a-5c, 5f) as amorphous solids. The compounds were analyzed by IR, 1 Characterized by 1 H NMR and LCMS. Compound 5a (Treprostinil diacetate L-arginine salt): mp 136-139 °C; HPLC purity: 99.65% Compound 5b (Treprostinil dipropionate L-arginine salt): mp 210-213 °C; HPLC purity: 99.79% Compound 5c (Treprostinil dibutyrate L-arginine salt): mp 195-198 °C; HPLC purity: 98.67% Compound 5f (Treprostinil methyldicarbonate L-arginine salt): mp 184-186 °C; HPLC purity: 98.66%

[0157] General procedure for the synthesis of treprostinil disubstituted L-lysine salts (6a-6m, 9a-9b) To a stirred solution of treprostinil disubstituted compounds (3a-3m, 8a-8b) (1.0 eq.) in acetone at 45° C. was added dropwise an aqueous solution of L-lysine (1.0 eq.). The resulting clear reaction mixture was stirred at 45° C. After 30 min, the reaction mixture was concentrated under reduced pressure and azeotropically dried with isopropyl acetate. The resulting viscous oil was triturated with heptane under sonication, concentrated in vacuo, and dried under high vacuum at 35° C. (water bath) to give the treprostinil disubstituted L-lysine salts (6a-6m, 9a-9b) as amorphous solids. The compounds were analyzed by IR, 1Characterized by 1 H NMR and LCMS. Compound 6a (Treprostinil diacetate L-lysine salt): mp 167-171 °C; HPLC purity: 100% Compound 6b (Treprostinil dipropionate L-lysine salt): mp 179-182 °C; HPLC purity: 99.67% Compound 6c (Treprostinil dibutyrate L-lysine salt): mp 178-181 °C; HPLC purity: 98.65% Compound 6d (Treprostinil diisobutyrate L-lysine salt): mp 184-186 °C; HPLC purity: 99.64% Compound 6e (Treprostinil dipivalate L-lysine salt): mp 182-184 °C; HPLC purity: 98.78% Compound 6f (Treprostinil methyldicarbonate L-lysine salt): mp 173-176 °C; HPLC purity: 99.68% Compound 6g (Treprostinil ethyl dicarbonate L-lysine salt): mp 178-181 °C; HPLC purity: 98.89% Compound 6h (Treprostinil isopropyl dicarbonate L-lysine salt): mp 179-182 °C; HPLC purity: 96.99% Compound 6i (Treprostinil bis(2-methoxyethyl carbonate) L-lysine salt): mp 178-181 °C; HPLC purity: 100% Compound 6j (Treprostinil dihydroxyacetate L-lysine salt): mp 108-111 °C; HPLC purity: 97.18% Compound 6k (Treprostinil bis(dimethylsuccinamate) L-lysine salt): mp 147-150 °C; HPLC purity: 95.84% Compound 6l (Treprostinil bis(morpholinosuccinamate) L-lysine salt): mp 146-149 °C; HPLC purity: 98.66% Compound 6m (Treprostinil bis(piperidinyl succinamate) L-lysine salt): mp 135-138 °C; HPLC purity: 95.42% Compound 9a (Treprostinil dimorpholinocarbamate L-lysine salt): mp 145-148 °C; HPLC purity: 97.74% Compound 9b (Treprostinil dipiperidinyl carbamate L-lysine salt): mp 165-167 °C; HPLC purity: 93.81%

[0158] Although certain preferred embodiments have been mentioned above, it will be understood that the present invention is not so limited. Those skilled in the art will recognize that various modifications can be made to the disclosed embodiments, and such modifications are intended to be within the scope of the present invention. All publications, patent applications, and patents cited herein are incorporated herein by reference in their entirety.

Claims

1. A dry powder formulation comprising: (a) a treprostinil prodrug, a treprostinil salt, or a salt of a treprostinil prodrug; and (b) fumaryl 2,5-diketopiperazine or (E)-3,6-bis[4-(N-carbonyl-2-propenyl)amidobutyl]-2,5-diketopiperazine (FDKP).

2. 2. The dry powder formulation of claim 1, comprising a treprostinil salt selected from treprostinil diethanolamine, treprostinil tromethamine, treprostinil arginine, treprostinil lysine salt, treprostinil N-methylglucamine, treprostinil magnesium, treprostinil ammonium; treprostinil potassium, treprostinil calcium, treprostinil ethylenediamine, treprostinil choline, treprostinil tris(hydroxymethyl)aminomethane (treprostinil TRIS), treprostinil procaine, and treprostinil benzathine.

3. The formula: 【Chemistry 1】 and a treprostinil prodrug having the formula: In the formula, R ２ is the first pro component, R ３ is a second promoiety; and X is a salt moiety or a third promoiety; In the formula, OR ２ and OR ３ 2. The dry powder formulation of claim 1, wherein each of has a lower reactivity with the carboxyl group of FDKP than the respective hydroxyl group of unsubstituted treprostinil, and C=OX has a lower reactivity with the hydroxyl than the carboxyl group of unsubstituted treprostinil.

4. X is O － 4. The dry powder formulation of claim 3, wherein the counter ion is a salt.

5. X is O － The dry powder formulation of claim 3, which is a salt counterion of an amino acid.

6. 6. The dry powder formulation of claim 5, wherein the amino acid is arginine or lysine.

7. 4. The dry powder formulation of claim 3, wherein X is a third promoiety.

8. X is OR ９ Or NR １ R ６ and R ９ But alkyl chain C １ -C ２０ ,below: 【Chemistry 2】 and R １ is H or C １ -C ４ alkyl, and R ６ but the following: 【Chemistry 3】 and R ７ is H or C １ -C ４ 4. The dry powder formulation of claim 3, wherein said aryl group is an alkyl group.

9. X is OR ９ and R ９ but the following: 【Chemistry 4】 9. The dry powder formulation of claim 8, wherein

10. X is NR １ R ６ and R １ is H, and R ６ but the following: 【Chemistry 5】 9. The dry powder formulation of claim 8, wherein

11. 1. A dry powder formulation comprising: R ２ and R ３ are independently a phosphorus-containing group, —C(O)R ６ or an ABC substituent; A is an optionally substituted C １ -C ６ Alkylene, -NR ６ -, -C(O)-, -C(O)O-, or C(O)NR ６ - and B is a bond, optionally substituted C １ -C ６ alkylene, —C(O)—, —O—, —S—, optionally substituted heterocyclyl; and C is an optionally substituted heterocyclyl, an optionally substituted heteroaryl, an optionally substituted aryl, an optionally substituted cycloalkyl, -(OCH ２ CH ２ ) ｑ -OR ６ , -C(O)N(R ６ ) ２ , -C(O)N(R １８ ) ２ , -C(O)R ６ , -CO ２ H, -OR ６ , -N(R １８ ) ２ , -N(R ６ ) ２ or the following: 【Chemistry 6】 and Here, R １８ together form an optionally substituted 3- to 8-membered heterocyclyl; Each R ６ are independently H, optionally substituted C １ -C ６ alkyl, optionally substituted heteroaryl, optionally substituted aryl, or R ６ together form a 4- to 8-membered optionally substituted heterocyclyl or a 5-membered optionally substituted heteroaryl; Or, the second promoiety and the third promoiety taken together can form -C(O)-, -SO in the 8- to 12-membered heterocyclyl. ２ -,below: 【Chemistry 7】 where each R １０ is H, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ alkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted aryl; and 4. The dry powder formulation of claim 3, wherein q is 0, 1, 2, 3, 4, 5 or 6.

12. R ２ and R ３ is a phosphorus-containing group or C(O)R ６ and R ６ is optionally substituted C １ -C ６ 12. The dry powder formulation of claim 11, wherein said alkyl group is an alkyl group.

13. R ２ and R ３ 13. The dry powder formulation of claim 12, wherein each of is a phosphate group.

14. R ２ and R ３ are -C(O)R ６ 13. The dry powder formulation of claim 12, wherein

15. R ２ and R ３ Each of them is independently CH ２ O.B.n., C.H. ２ O.H. below: 【Chemistry 8】 【Chemistry 9】 and 【Chemistry 10】 where Z is O or CH ２ 4. The dry powder formulation of claim 3, wherein

16. R ２ and R ３ However, each independently, C １ -C ６ Alkyl and O-R ２０ where R ２０ is optionally substituted C １ -C ６ 4. The dry powder formulation of claim 3, wherein said aryl group is an alkyl group.

17. R ２ and R ３ The dry powder formulation of claim 3, wherein:

18. R ２ and R ３ The dry powder formulation of claim 11, wherein:

19. The prodrug is selected from the group consisting of: 【Chemistry 11】 The dry powder formulation of claim 3, wherein the compound is one or more compounds selected from the group consisting of:

20. The prodrug is selected from the group consisting of treprostinil diacetate potassium salt; treprostinil dipropionate potassium salt; treprostinil dibutyrate potassium salt; treprostinil methyldicarbonate potassium salt; treprostinil diacetate L-arginine salt; treprostinil dipropionate L-arginine salt; treprostinil dibutyrate L-arginine salt; treprostinil methyldicarbonate L-arginine salt; treprostinil diacetate L-lysine salt; treprostinil dipropionate L-lysine salt; treprostinil dibutyrate L-lysine salt; treprostinil diisobutyrate L-lysine salt; treprostinil dipivalate L-lysine salt; treprostinil 4. The dry powder formulation of claim 3, wherein the treprostinil is selected from the group consisting of: treprostinil ethyl dicarbonate L-lysine salt; treprostinil ethyl dicarbonate L-lysine salt; treprostinil isopropyl dicarbonate L-lysine salt; treprostinil bis(2-methoxyethyl carbonate) L-lysine salt; treprostinil dihydroxyacetate L-lysine salt; treprostinil bis(dimethylsuccinamate) L-lysine salt; treprostinil bis(morpholinosuccinamate) L-lysine salt; treprostinil bis(piperidinyl succinamate) L-lysine salt; treprostinil dimorpholinocarbamate L-lysine salt; and treprostinil dipiperidinyl carbamate L-lysine salt.

21. 4. The dry powder composition of claim 3, wherein the prodrug is a water soluble prodrug.

22. The formula: 【Chemistry 12】 wherein X is a salt moiety or a promoiety; wherein OR 2 and OR 3 each have a lower reactivity with carboxyl groups than the respective hydroxyl groups of unsubstituted treprostinil, and C═OX has a lower reactivity with hydroxyl groups than the carboxyl groups of unsubstituted treprostinil, and each of R 2 and R 3 are independently CH 2 OBn, CH 2 OH, 【Chemistry 13】 【Chemistry 14】 and 【Chemistry 15】 and Z is O or CH 2 ; or R 2 and R 3 taken together are -C(O)-, -SO 2 -, or 【Chemistry 16】 and each R 10 is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted aryl.

23. The compound of claim 22, wherein X is an O − .salt counterion.

24. The compound of claim 22, wherein X is a salt counterion of an O − .amino acid.

25. The compound of claim 24, wherein the amino acid is arginine or lysine.

26. The compound of claim 22, wherein X is a promoiety.

27. A compound according to claim 27, wherein X is OR 9 or NR 1 R 6 ; R 9 is an alkyl chain C 1 -C 20 , as follows: 【Chemistry 17】 wherein R 1 is H or C 1 -C 4 alkyl, and R 6 is one of the following: 【Chemistry 18】 and R 7 is H or C 1 -C 4 alkyl.

28. X is OR 9 and R 9 is one of the following: 【Chemistry 19】 28. The compound of claim 27,

29. X is NR 1 R 6 , R 1 is H, and R 6 is one of the following: 【Chemistry 20】 28. The compound of claim 27,

30. R 2 and R 3 taken together represent -C(O)-, -SO 2 -, or 【Chemistry 21】 and each R 10 is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted aryl.

31. Each of R 2 and R 3 is independently CH 2 OBn, CH 2 OH, 【Chemical 22】 【Chemistry 23】 and 【Chemistry 24】 23. The compound of claim 22, selected from: wherein Z is O or CH2.

32. The compound of claim 22, wherein R 2 and R 3 are the same chemical group.

33. The compound of claim 22, wherein R 2 and R 3 together form an 8- to 12-membered heterocyclyl having —C(O)—.

34. The compound of claim 22, which is a water-soluble compound.

35. The compound of claim 34, wherein the compound is 【Chemistry 25】 23. The compound of claim 22, selected from:

36. Each of R 2 and R 3 is 【Chemistry 26】 and 【Chemical 27】 23. The compound of claim 22, selected from: wherein Z is O or CH2.

37. Each of R 2 and R 3 is 【Chemistry 28】 37. The compound of claim 36, wherein Z is O or CH2.

38. The compound of claim 37, wherein Z is O.

39. The compound of claim 37, wherein Z is CH 2 .

40. The compound of claim 37, wherein X is L-lysine.

41. The compound of claim 36, wherein X is L-lysine.

42. The compound of claim 22, wherein the compound is selected from the group consisting of treprostinil bis(dimethylsuccinamate) L-lysine salt; treprostinil bis(morpholinosuccinamate) L-lysine salt; treprostinil bis(piperidinyl succinamate) L-lysine salt; treprostinil dimorpholinocarbamate L-lysine salt; and treprostinil dipiperidinylcarbamate L-lysine.

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