Lalinepag Prodrugs and Uses Thereof

Abstract

Described herein are ralinepag prodrugs, and pharmaceutical compositions thereof, and methods of their use in the treatment of diseases or conditions that would benefit from treatment with prostacyclin (IP) receptor agonist compounds, such as, but not limited to, pulmonary hypertension (PH) diseases.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 321,032, filed March 17, 2022, which is incorporated by reference in its entirety.

[0002] Described herein are lalinepag prodrugs that are agonists of the prostacyclin (IP) receptor, as well as pharmaceutical compositions and methods of their use in the treatment of diseases or disorders that would benefit from treatment with lalinepag. [Background technology]

[0003] Prostacyclin (IP) receptors are expressed on platelets and smooth muscle cells of multiple tissues, including lungs, heart, aorta, liver, kidneys, and blood vessels. Activation of IP receptors leads to an increase in cellular cyclic AMP (cAMP) and subsequent vasodilation in arteries and inhibition of aggregation in platelets. Improvements in hemodynamics, exercise capacity, and survival have been clearly demonstrated with PGI2 replacement therapy, for example, for the treatment of pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH). Summary of the Invention

[0004] As used herein, the compound of formula (I):

[0005] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, Q is -NR 6 -S(=O)2R 7 and R 6 But, H, C1-C 24 Alkyl, C1-C 24 Haloalkyl, C1-C 24 Heteroalkyl, C2-C 24 Alkenyl, C2-C24 Alkynyl, -L 2 -cycloalkyl, -L 2 -heterocycloalkyl, -L 2 -aryl, or -L 2 -heteroaryl, where each of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from one or more R 7a Optionally replaced by R 7 But, C1-C 24 Alkyl, C1-C 24 Haloalkyl, C1-C 24 Heteroalkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, -L 2 -cycloalkyl, -L 2 -heterocycloalkyl, -L 2 -aryl, or -L 2 -heteroaryl, where each of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from one or more R 7a Optionally replaced by L 2 is absent, C1-C6 alkylene, C1-C6 heteroalkylene, C2-C6 alkenylene, or C2-C6 alkynylene, each of which is selected from one or more R 7a Optionally replaced by Or, Q is -OR 8 and R 8 is -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, C5-C 24 Alkyl, C1-C 24 Haloalkyl, C1-C 24 Heteroalkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, -L 3 -OP(=O)(OH)2, -L 3 -cycloalkyl, -L 3-heterocycloalkyl, or -L 3 -aryl, where each of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or aryl is selected from one or more R 8a Optionally replaced by L 3 is absent, or is C1-C6 alkylene, C1-C6 heteroalkylene, C2-C6 alkenylene, or C2-C 24 alkynylene, each of which may be one or more R 8a Optionally replaced by Or, Q is -NR 4 R 5 and R 4 But, H, C1-C 24 Alkyl, C1-C 24 Haloalkyl, C1-C 24 Heteroalkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, -L 5 -cycloalkyl, -L 5 -heterocycloalkyl, -L 5 -aryl, or -L 5 -heteroaryl, where each of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from one or more R 5a Optionally replaced by R 5 But, C1-C 24 Alkyl, C1-C 24 Haloalkyl, C1-C 24 Heteroalkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, -L 5 -cycloalkyl, -L 5 -heterocycloalkyl, -L 5 -aryl, or -L 5-heteroaryl, where each of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from one or more R 5a or R 4 and R 5 together with the nitrogen to which they are attached form a 3- to 12-membered heterocycloalkyl or heteroaryl, where each of the heterocycloalkyl or heteroaryl is selected from one or more R 5a Optionally replaced by L 5 is absent, or is C1-C6 alkylene, C1-C6 heteroalkylene, C2-C6 alkenylene, or C2-C 24 alkynylene, each of which may be one or more R 5a Optionally replaced by R 5a and R 7a are each independently halogen, -CN, -NO2, -OH, -OR a , oxo, -OC(=O)R a , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)R a , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR a , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R; R 8a But halogens, -CN, -NO2, -OH, -OR a , oxo, -OC(=O)R a , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)R a , N.R. b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R; R aare each independently C-C alkyl, C-C haloalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkyl(cycloalkyl), C-C alkyl(heterocycloalkyl), C-C alkyl(aryl), or C-C alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; R b are each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkyl(cycloalkyl), C-C alkyl(heterocycloalkyl), C-C alkyl(aryl), or C-C alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; R c and R d are each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkyl(cycloalkyl), C-C alkyl(heterocycloalkyl), C-C alkyl(aryl), or C-C alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R are each independently halogen, -CN, -OH, oxo, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl; Alternatively, Q is 1-carboxyethylamino, 1-carboxy-4-guanidinobutylamino, 3-amino-1-carboxy-3-oxopropylamino, 1,2-dicarboxyethylamino, 1-carboxy-2-mercaptoethylamino, 4-amino-1-carboxy-4-oxobutylamino, 3-carboxy-1-carboxylatepropylamino, 1-carboxy-2-(1H-imidazol-4-yl)ethylamino, 1-carboxy-2-methylbutylamino, 1-carboxy-3-methylbutylamino, 5-amino-1-carboxypentylamino, 1-carboxy-3-(methylthio)propylamino, 1-carboxy-2-phenylethylamino, 2-carboxypyrrolidin-1-yl, 1-carboxy-2-hydroxyethylamino, 1-carboxy-2-hydroxypropylamino, 1-carboxy-2-(1H-indol-3-yl)ethylamino, 1-carboxy-2-(4-hydroxyphenyl)ethylamino, and 1-carboxy-2-methylpropylamino.

[0006] Further described herein are pharmaceutical compositions comprising a compound described herein, or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable carrier or excipient.

[0007] Further described herein is a method of treating pulmonary arterial hypertension (PAH) in a subject in need thereof, comprising administering to the subject a compound described herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein.

[0008] Further described herein is a method for modulating a prostacyclin (PGI2) receptor in a subject in need of such modulation, comprising administering to the subject a compound described herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein.

[0009] Further described herein is a method for treating a disease or condition associated with the prostacyclin (PGI2) receptor in a subject in need of such treatment, comprising administering to the subject a compound described herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein.

[0010] Other objects, features and advantages of the compounds, methods, and compositions described herein will become apparent from the detailed description set forth below. However, it will be understood that the detailed description and specific examples, while illustrating specific embodiments, are given by way of example only, since various changes and modifications within the spirit and scope of the present disclosure will become apparent to those skilled in the art from the detailed description. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Disclosed herein are compounds suitable for use as prostacyclin (IP) receptor agonists, and methods of use thereof. In one aspect, described herein are prodrugs of ralinepag, and methods of use thereof. Ralinepag is an oral IP receptor agonist. Additionally, ralinepag is named 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, and has the following structure:

[0012] [ka] has.

[0013] definition In the following description, certain specific details are given to provide a thorough understanding of various embodiments. However, those skilled in the art will understand that the present disclosure may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless otherwise required by context, throughout the following specification and claims, the word "comprise" and variations thereof, such as "comprises" or "comprising," are to be construed in an open and inclusive sense, i.e., "including, but not limited to." Additionally, the headings provided herein are for convenience only and do not interpret the scope or meaning of the subject invention.

[0014] References throughout this specification to "some embodiments" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Moreover, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the term "or" is generally used in its sense to include "and / or" unless the content clearly dictates otherwise.

[0015] The following terms, as used herein, have the following meanings unless otherwise indicated:

[0016] "Oxo" refers to =O.

[0017] "Carboxyl" refers to --COOH.

[0018] "Cyano" refers to -CN.

[0019] "Alkyl" refers to a straight or branched chain saturated hydrocarbon monoradical having from 1 to about 10 carbon atoms, more preferably from 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, etc. Whenever a numerical range such as "C1-C6 alkyl" or "C1-6 alkyl" appears in this specification, it means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but this definition also includes occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, the alkyl is a C1-10 alkyl. In some embodiments, the alkyl is a C1-6 alkyl. In some embodiments, the alkyl is a C1-5 alkyl. In some embodiments, the alkyl is a C1-4 alkyl. In some embodiments, the alkyl is a C1-3 alkyl. Unless otherwise specified in this specification, the alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0020] "Alkenyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The group may be in either the cis or trans conformation about the double bond and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, and the like. Whenever a numerical range such as "C2-C6 alkenyl" or "C2-6 alkenyl" appears herein, it is meant that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the definition also includes occurrences of the term "alkenyl" where no numerical range is specified. Unless otherwise specified in the specification, an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkenyl is optionally substituted with halogen.

[0021] "Alkynyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever a numerical range such as "C2-C6 alkynyl" or "C2-6 alkynyl" appears in this specification, it means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but this definition also includes occurrences of the term "alkynyl" where no numerical range is specified. Unless otherwise specified in this specification, alkynyl groups may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0022] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specified in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, CO2H, -CO2Me, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkylene is optionally substituted with halogen.

[0023] "Alkoxy" means a group of the formula -OR a where R a is an alkyl radical as defined. Unless otherwise specified in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, CO2H, -CO2Me, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkoxy is optionally substituted with halogen.

[0024] "Aryl" refers to a radical derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene hydrocarbon ring systems. Unless otherwise specified herein, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, CO2H, -CO2Me, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, an aryl is optionally substituted with halogen.

[0025] "Cycloalkyl" refers to a partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused to an aryl or heteroaryl ring, the cycloalkyl is attached through a non-aromatic ring atom), spiro, or bridged ring systems. In some embodiments, cycloalkyls are fully saturated. Representative cycloalkyls include those having 3 to 15 carbon atoms (C3-C4, C5-C6, C7-C8, C9-C10, C11-C12, C13-C14, C15-C16, C17-C18, C18-C19, C20-C210, C22-C30, C23-C31, C24-C25-C32, C25-C33, C26-C34, C27-C35, C28-C36, C29-C37, C38-C39, C39-C40, C39-C41, C38-C42, C39-C43, C44-C45, C45-C46, C46-C47, C48-C49, C49-C51, C49-C52, C49-C53, C49-C54, C49-C55, C49-C56, C49-C57, C49-C58, C49-C59 15 Fully saturated cycloalkyl or C3-C 15Cycloalkenyl, 3 to 10 carbon atoms (C3-C 10 Fully saturated cycloalkyl or C3-C 10Examples of cycloalkyl include, but are not limited to, cycloalkyls having 3 to 8 carbon atoms (C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), 3 to 6 carbon atoms (C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), 3 to 5 carbon atoms (C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or 3 to 4 carbon atoms (C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3 to 10 membered fully saturated cycloalkyl or a 3 to 10 membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3 to 6 membered fully saturated cycloalkyl or a 3 to 6 membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5 to 6 membered fully saturated cycloalkyl or a 5 to 6 membered cycloalkenyl. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl include adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Examples of partially saturated cycloalkyl include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specified in the specification, cycloalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COH, COMe, -CF, -OH, -OMe, NH, or -NO.In some embodiments, the cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0026] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro.

[0027] "Haloalkyl" refers to an alkyl radical, as defined above, substituted by one or more halo radicals, as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0028] "Hydroxyalkyl" refers to an alkyl radical, as defined above, substituted with one or more hydroxyl groups. In some embodiments, the alkyl is substituted with one hydroxyl group. In some embodiments, the alkyl is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0029] "Aminoalkyl" refers to an alkyl radical as defined above that is substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0030] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl, composed of 1-6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, where the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CHOCH, -CHCHOCH, -CHCHOCHCHOCH, -CH(CH)OCH, -CHNHCH, -CHN(CH), -CHCHNHCH, or -CHCHN(CH). Unless otherwise specified herein, a heteroalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, OH, -OMe, NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, a heteroalkyl is optionally substituted with halogen.

[0031] "Heterocycloalkyl" refers to a 3-24 membered partially or fully saturated ring radical containing 2-23 carbon atoms and 1-8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, a heterocycloalkyl is fully saturated. In some embodiments, a heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heterocycloalkyl contains 1-3 nitrogens. In some embodiments, a heterocycloalkyl contains 1 or 2 nitrogens. In some embodiments, a heterocycloalkyl contains 1 nitrogen. In some embodiments, a heterocycloalkyl contains 1 nitrogen and 1 oxygen. Unless otherwise specified in the specification, a heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and may include fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom), spiro, or bridged ring systems, in which the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized and the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include those having 2 to 15 carbon atoms (C2-C4). 15 Fully saturated heterocycloalkyl or C2-C 15 Heterocycloalkenyl, 2 to 10 carbon atoms (C2-C 10 Fully saturated heterocycloalkyl or C2-C 10heterocycloalkenyl), heterocycloalkyl having 2 to 8 carbon atoms (C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), 2 to 7 carbon atoms (C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 6 carbon atoms (C2-C6 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 5 carbon atoms (C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or 2 to 4 carbon atoms (C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, and the like. Examples of heterocycloalkyl include, but are not limited to, pyrazolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all cyclic forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In some embodiments, heterocycloalkyls have 2 to 10 carbons in the ring. It is noted that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring).In some embodiments, the heterocycloalkyl is a 3-8 membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-7 membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-6 membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4-6 membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-6 membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-8 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-7 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-6 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-6 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-6 membered heterocycloalkenyl. Unless otherwise specified herein, a heterocycloalkyl may be optionally substituted as described below, e.g., with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, a heterocycloalkyl is optionally substituted with halogen.

[0032] "Heteroaryl" refers to a 5-14 membered ring system radical containing 1-13 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl contains 1-3 nitrogens. In some embodiments, the heteroaryl contains 1 or 2 nitrogens. In some embodiments, the heteroaryl contains 1 nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and may contain fused (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl is attached through an aromatic ring atom) or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized, and the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5-10 membered heteroaryl. In some embodiments, the heteroaryl is a 5-6 membered heteroaryl. In some embodiments, the heteroaryl is a 6 membered heteroaryl. In some embodiments, the heteroaryl is a 5 membered heteroaryl.Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, and benzothienyl. (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, Examples of heteroaryl include, but are not limited to, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl).Unless otherwise specified in the specification, heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COH, COMe, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe.In some embodiments, the heteroaryl is optionally substituted with halogen.

[0033] The term "optional" or "optionally" is intended to mean that the subsequently described event or circumstance may or may not occur, and that the description includes examples of when said event or circumstance occurs and when it does not occur. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. Furthermore, an optionally substituted group can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between fully and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). Those skilled in the art will understand that with respect to any group containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical and / or synthetically infeasible. Thus, it should be understood that any substituents described typically have a maximum molecular weight of about 1,000 daltons, more typically up to about 500 daltons.

[0034] When referring to optional substituents, the term "one or more" means that the subject group is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.

[0035] An "effective amount" or "therapeutically effective amount" refers to the amount of a compound administered to a mammalian subject, either in a single dose or as part of a series, effective to produce the desired therapeutic effect.

[0036] The terms "treat," "treating," or "treatment," as used herein, include alleviating, relieving, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, e.g., arresting the progression of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or arresting a symptom of a disease or condition.

[0037] The term "modulator" as used herein refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, those of an agonist, partial agonist, inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, the modulator is an agonist.

[0038] As used herein, "administer," "administering," "administration," "administration" and "administration" are used interchangeably. a Terms such as "oral administration" refer to methods that can be used to enable delivery of a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), and topical administration. Those skilled in the art are familiar with administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0039] Terms such as "co-administration," as used herein, are intended to encompass the administration of selected therapeutic agents to one patient and are intended to include treatment regimens in which the therapeutic agents are administered by the same or different routes of administration or at the same or different times.

[0040] compound Described herein are compounds, or pharma- ceutically acceptable salts, solvates, or stereoisomers thereof, that are useful for the treatment of diseases or disorders associated with pulmonary hypertension (PH), pulmonary vascular resistance (PVR), pulmonary arterial hypertension (PAH), pulmonary hypertension associated with interstitial lung disease (PH-ILD), or a combination thereof.

[0041] As used herein, the compound of formula (I):

[0042] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, Q is -NR 6 -S(=O)2R 7 and R 6 , H, C1-C 24 Alkyl, C1-C 24 Haloalkyl, C1-C 24 Heteroalkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, -L 2 -cycloalkyl, -L 2 -heterocycloalkyl, -L 2 -aryl, or -L 2 -heteroaryl, where each of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from one or more R 7a Optionally replaced by R 7 is C1-C 24 Alkyl, C1-C 24 Haloalkyl, C1-C 24 Heteroalkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, -L 2 -cycloalkyl, -L 2 -heterocycloalkyl, -L 2 -aryl, or -L 2-heteroaryl, where each of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from one or more R 7a Optionally replaced by L 2 is absent, C1-C6 alkylene, C1-C6 heteroalkylene, C2-C6 alkenylene, or C2-C6 alkynylene, each of which is selected from one or more R 7a Optionally replaced by Alternatively, Q is -OR 8 and R 8 -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, C5-C 24 Alkyl, C1-C 24 Haloalkyl, C1-C 24 Heteroalkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, -L 3 -OP(=O)(OH)2, -L 3 -cycloalkyl, -L 3 -heterocycloalkyl, or -L 3 -aryl, where each of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or aryl is selected from one or more R 8a Optionally replaced by L 3 is absent, C1-C6 alkylene, C1-C6 heteroalkylene, C2-C6 alkenylene, or C2-C 24 alkynylene, each of which may be one or more R 8a Optionally replaced by Alternatively, Q is -NR 4 R 5 and R 4 , H, C1-C 24 Alkyl, C1-C 24 Haloalkyl, C1-C 24 Heteroalkyl, C2-C 24Alkenyl, C2-C 24 Alkynyl, -L 5 -cycloalkyl, -L 5 -heterocycloalkyl, -L 5 -aryl, or -L 5 -heteroaryl, where each of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from one or more R 5a Optionally replaced by R 5 is C1-C 24 Alkyl, C1-C 24 Haloalkyl, C1-C 24 Heteroalkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, -L 5 -cycloalkyl, -L 5 -heterocycloalkyl, -L 5 -aryl, or -L 5 -heteroaryl, where each of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from one or more R 5a or R 4 and R 5 together with the nitrogen to which they are attached form a 3- to 12-membered heterocycloalkyl or heteroaryl, where each heterocycloalkyl or heteroaryl is selected from one or more R 5a Optionally replaced by L 5 is absent, C1-C6 alkylene, C1-C6 heteroalkylene, C2-C6 alkenylene, or C2-C 24 alkynylene, each of which may be one or more R 5a Optionally replaced by R 5a and R 7a are each independently halogen, -CN, -NO2, -OH, -OR a , oxo, -OC(=O)R a, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)R a , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR a , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R; R 8a But halogens, -CN, -NO2, -OH, -OR a , oxo, -OC(=O)R a , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)R a , N.R. b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R; R a are each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; R b are each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkyl(cycloalkyl), C-C alkyl(heterocycloalkyl), C-C alkyl(aryl), or C-C alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; R c and R dare each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkyl(cycloalkyl), C-C alkyl(heterocycloalkyl), C-C alkyl(aryl), or C-C alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R is, each independently, halogen, -CN, -OH, oxo, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl; Alternatively, Q is 1-carboxyethylamino, 1-carboxy-4-guanidinobutylamino, 3-amino-1-carboxy-3-oxopropylamino, 1,2-dicarboxyethylamino, 1-carboxy-2-mercaptoethylamino, 4-amino-1-carboxy-4-oxobutylamino, 3-carboxy-1-carboxylatepropylamino, 1-carboxy-2-(1H-imidazol-4-yl)ethylamino, 1-carboxy-2-methylbutylamino, 1-carboxy-3-methylbutylamino, 5-amino-1-carboxypentylamino, 1-carboxy-3-(methylthio)propylamino, 1-carboxy-2-phenylethylamino, 2-carboxypyrrolidin-1-yl, 1-carboxy-2-hydroxyethylamino, 1-carboxy-2-hydroxypropylamino, 1-carboxy-2-(1H-indol-3-yl)ethylamino, 1-carboxy-2-(4-hydroxyphenyl)ethylamino, and 1-carboxy-2-methylpropylamino.

[0043] As used herein, the compound of formula (V):

[0044] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, R 1 and R 2 are each independently selected from phenyl and monocyclic heteroaryl, where each of the phenyl and heteroaryl is optionally substituted with one or two substituents selected from C-C alkoxy, C-C alkyl, aryl, C-C haloalkoxy, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, and halogen; X is O or NR 3 and R 3 is selected from H and C1-C6 alkyl; Q is -NR6 -S(=O)2R 7 and R 6 , H, C1-C 24 Alkyl, C1-C 24 Haloalkyl, C1-C 24 Heteroalkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, -L 2 -cycloalkyl, -L 2 -heterocycloalkyl, -L 2 -aryl, or -L 2 -heteroaryl, where each of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from one or more R 7a Optionally replaced by R 7 is C1-C 24 Alkyl, C1-C 24 Haloalkyl, C1-C 24 Heteroalkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, -L 2 -cycloalkyl, -L 2 -heterocycloalkyl, -L 2 -aryl, or -L 2 -heteroaryl, where each of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from one or more R 7a Optionally replaced by L 2 is absent, C1-C6 alkylene, C1-C6 heteroalkylene, C2-C6 alkenylene, or C2-C6 alkynylene, each of which is selected from one or more R 7a Optionally replaced by Alternatively, Q is -OR 8 and R 8 -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, C5-C 24Alkyl, C1-C 24 Haloalkyl, C1-C 24 Heteroalkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, -L 3 -OP(=O)(OH)2, -L 3 -cycloalkyl, -L 3 -heterocycloalkyl, or -L 3 -aryl, where each of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or aryl is selected from one or more R 8a Optionally replaced by L 3 is absent, C1-C6 alkylene, C1-C6 heteroalkylene, C2-C6 alkenylene, or C2-C 24 alkynylene, each of which may be one or more R 8a Optionally replaced by Alternatively, Q is -NR 4 R 5 and R 4 , H, C1-C 24 Alkyl, C1-C 24 Haloalkyl, C1-C 24 Heteroalkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, -L 5 -cycloalkyl, -L 5 -heterocycloalkyl, -L 5 -aryl, or -L 5 -heteroaryl, where each of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from one or more R 5a Optionally replaced by R 5 is C1-C 24 Alkyl, C1-C 24 Haloalkyl, C1-C 24 Heteroalkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, -L5 -cycloalkyl, -L 5 -heterocycloalkyl, -L 5 -aryl, or -L 5 -heteroaryl, where each of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from one or more R 5a or R 4 and R 5 together with the nitrogen to which they are attached form a 3- to 12-membered heterocycloalkyl or heteroaryl, where each heterocycloalkyl or heteroaryl is selected from one or more R 5a Optionally replaced by L 5 is absent, C1-C6 alkylene, C1-C6 heteroalkylene, C2-C6 alkenylene, or C2-C 24 alkynylene, each of which may be one or more R 5a Optionally replaced by R 5a and R 7a are each independently halogen, -CN, -NO2, -OH, -OR a , oxo, -OC(=O)R a , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)R a , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR a , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R; R 8a But halogens, -CN, -NO2, -OH, -OR a , oxo, -OC(=O)R a , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)R a , N.R. b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R; R aare each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; R b are each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkyl(cycloalkyl), C-C alkyl(heterocycloalkyl), C-C alkyl(aryl), or C-C alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; R c and R d are each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkyl(cycloalkyl), C-C alkyl(heterocycloalkyl), C-C alkyl(aryl), or C-C alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R is, each independently, halogen, -CN, -OH, oxo, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl; Alternatively, Q is selected from 1-carboxyethylamino, 1-carboxy-4-guanidinobutylamino, 3-amino-1-carboxy-3-oxopropylamino, 1,2-dicarboxyethylamino, 1-carboxy-2-mercaptoethylamino, 4-amino-1-carboxy-4-oxobutylamino, 3-carboxy-1-carboxylatepropylamino, 1-carboxy-2-(1H-imidazol-4-yl)ethylamino, 1-carboxy-2-methylbutylamino, 1-carboxy-3-methylbutylamino, 5-amino-1-carboxypentylamino, 1-carboxy-3-(methylthio)propylamino, 1-carboxy-2-phenylethylamino, 2-carboxypyrrolidin-1-yl, 1-carboxy-2-hydroxyethylamino, 1-carboxy-2-hydroxypropylamino, 1-carboxy-2-(1H-indol-3-yl)ethylamino, 1-carboxy-2-(4-hydroxyphenyl)ethylamino, and 1-carboxy-2-methylpropylamino.

[0045] In some embodiments, the compound, or a pharma- ceutically acceptable salt or solvate thereof, has formula (IIIa):

[0046] [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0047] In some embodiments, the compound, or a pharma- ceutically acceptable salt or solvate thereof, has formula (IIIa):

[0048] [ka] It has the structure:

[0049] R 6 can be any suitable functional group known to one of skill in the art. In some embodiments, R 6 , H, C1-C 24 Alkyl, C1-C 24 Haloalkyl, C1-C 24 Heteroalkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, -L 2 -cycloalkyl, -L 2 -heterocycloalkyl, -L 2 -aryl, or -L 2 -heteroaryl, where each of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from one or more R 7a In some embodiments, R 6 , H, C1-C 24 Alkyl, C1-C 24 Haloalkyl, C1-C 24 Heteroalkyl, or C2-C 24 In some embodiments, R is alkenyl. 6 , H, C1-C 24 Alkyl, or C1-C 24 In some embodiments, R 6 is H or C1-C 24 In some embodiments, R 6 is H or C1-C 12 In some embodiments, R 6 is H or C1-C6 alkyl. In some embodiments, R 6is H.

[0050] R 7 can be any suitable functional group known to one of skill in the art. In some embodiments, R 7 is C1-C 24 Alkyl, C1-C 24 Haloalkyl, C1-C 24 Heteroalkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, -L 2 -cycloalkyl, -L 2 -heterocycloalkyl, -L 2 -aryl, or -L 2 -heteroaryl, where each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted. In some embodiments, R 7 is C1-C 24 Alkyl, C1-C 24 Haloalkyl, C1-C 24 Heteroalkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, -L 2 -cycloalkyl, -L 2 -heterocycloalkyl, -L 2 -aryl, or -L 2 -heteroaryl, where each of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from one or more R 7a In some embodiments, R 7 is C1-C 12 Alkyl, C1-C 12 Haloalkyl, C1-C 12 Heteroalkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, -L 2 -cycloalkyl, -L 2 -heterocycloalkyl, -L 2 -aryl, or -L 2-heteroaryl, where each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted. In some embodiments, R 7 is C1-C 24 Alkyl, C1-C 24 Haloalkyl, C1-C 24 Heteroalkyl, or C2-C 24 In some embodiments, R is alkenyl. 7 is C1-C 24 Alkyl, C1-C 24 Haloalkyl, or C1-C 24 heteroalkyl, where each of the alkyl or heteroalkyl is selected from one or more R 7a In some embodiments, R 7 is C1-C 12 Alkyl, C1-C 12 Haloalkyl, C1-C 12 Heteroalkyl, or C2-C 12 alkenyl, each of which is optionally substituted. In some embodiments, R 7 is C1-C 12 Alkyl, C1-C 12 Haloalkyl, or C1-C 12 heteroalkyl, each of which is optionally substituted. In some embodiments, R 7 is C-C alkyl, C-C haloalkyl, or C-C heteroalkyl, each of which is optionally substituted. In some embodiments, R 7 is an optionally substituted C1-C 12 In some embodiments, R 7 is C1-C 12 In some embodiments, R 7 is an optionally substituted C-C alkyl. In some embodiments, R 7 is C1-C6 alkyl. In some embodiments, R 7is an optionally substituted C-C alkyl. In some embodiments, R 7 is C1-C4 alkyl. In some embodiments, R 7 is optionally substituted with -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCHCH, -CH(CH), -CHCHCHCHCH, -CH(CH), -CHCHCHCHCHCH, or -CHCHCHCHCHCHCHCH. 7 is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH2CH2CH2CH2CH3, or -CH2CH2CH2CH2CH2CH2CH3. In some embodiments, R 7 is optionally substituted with -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCHCH, -CH(CH). In some embodiments, R 7 is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3), -CH2CH2CH2CH3, -CH2CH(CH3). In some embodiments, R 7 is methyl,

[0051] [ka] In some embodiments, R 7 is methyl.

[0052] In some embodiments, R 7 -L 2 -cycloalkyl, -L 2 -heterocycloalkyl, -L 2 -aryl, or -L 2 -heteroaryl, each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl being selected from one or more R 7a Optionally replaced by R 7a is halogen, -CN, -OH, -OR a , oxo, -OC(=O)Ra , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR a , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl, where each of the alkyl or heteroalkyl is optionally substituted with one or more R. In some embodiments, R 7 -L 2 -cycloalkyl, -L 2 -heterocycloalkyl, -L 2 -aryl, or -L 2 -heteroaryl, each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl being selected from one or more R 7a Optionally replaced by R 7a is halogen, -OH, -OR a , oxo, C1-C6 alkyl, or C1-C6 haloalkyl, where each of the alkyl or heteroalkyl is optionally substituted with one or more R. In some embodiments, R 7 -L 2 -cycloalkyl, -L 2 -heterocycloalkyl, -L 2 -aryl, or -L 2 -heteroaryl, each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl being selected from one or more R 7a Optionally replaced by R 7a is halogen, -OH, -OR a , oxo, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R 7 -L 2 -heterocycloalkyl, -L 2 -aryl, or -L 2-heteroaryl, each of the heterocycloalkyl, aryl, or heteroaryl being selected from one or more R 7a Optionally replaced by R 7a is halogen, -OH, -OR a , oxo, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R 7 -L 2 -heterocycloalkyl, -L 2 -aryl, or -L 2 -heteroaryl, each of the heterocycloalkyl, aryl, or heteroaryl being selected from one or more R 7a Optionally replaced by R 7a is halogen, -OH, -OR a , oxo, C1-C6 alkyl, or C1-C6 haloalkyl; R a is methyl or ethyl. In some embodiments, R 7 -L 2 -heterocycloalkyl, -L 2 -aryl, or -L 2 -heteroaryl, each of the heterocycloalkyl, aryl, or heteroaryl being selected from one or more R 7a Optionally replaced by R 7a is halogen, -OH, -OR a , oxo, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments, R 7 -L 2 -Thiochromanyl, -L 2 -Phenyl, L 2 -Naphthyl, -L 2 -thiophen-2-yl, or -L 2 -benzothiazolyl, where each of thiochromanyl, phenyl, naphthyl, thiophen-2-yl, or benzothiazolyl is selected from one or more of R 7a Optionally replaced by R 7a is halogen, -OH, -OR a , oxo, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments, R 7 -L2 -Thiochromanyl, -L 2 -Phenyl, L 2 -Naphthyl, -L 2 -thiophen-2-yl, or -L 2 -benzothiazolyl, where each of thiochromanyl, phenyl, naphthyl, thiophen-2-yl, or benzothiazolyl is selected from one or more of R 7a Optionally replaced by R 7a is chloro, -OH, -OCH, -OCHCH, oxo, -CH, or -CF. In some embodiments, R 7 -L 2 -phenyl or -L 2 naphthyl, where each of the phenyl or naphthyl is selected from one or more R 7a Optionally replaced by L 2 is absent, -CH2- or -CH2-, and R 7a is halogen, oxo, C-C alkyl, C-C haloalkyl, or C-C alkoxy. 7 -L 2 -phenyl or -L 2 naphthyl, where each of the phenyl or naphthyl is optionally substituted. In some embodiments, R 7 -L 2 -phenyl or -L 2 naphthyl, where each of the phenyl or naphthyl is selected from one or more R 7a Optionally replaced by L 2 does not exist, and R 7a is halogen, oxo, C-C alkyl, C-C haloalkyl, or C-C alkoxy. 7 is -phenyl or -naphthyl, where each of the phenyl or naphthyl is selected from one or more R 7a Optionally replaced by R 7a is halogen, oxo, C-C alkyl, C-C haloalkyl, or C-C alkoxy. 7-phenyl or -L 2 naphthyl, where each of the phenyl or naphthyl is optionally substituted. In some embodiments, R 7 is -phenyl or -naphthyl, where each of the phenyl or naphthyl is selected from one or more R 7a Optionally replaced by R 7a is chloro, oxo, -CH, -CF, or -OCH. In some embodiments, R 7 -L 2 -heteroaryl, where heteroaryl is bicyclic and one or more R 7a In some embodiments, R 7 -L 2 -heteroaryl, where heteroaryl is monocyclic and one or more R 7a In some embodiments, R 7 -L 2 -cycloalkyl, where cycloalkyl is bicyclic and one or more R 7a In some embodiments, R 7 -L 2 -cycloalkyl, where cycloalkyl is monocyclic and one or more R 7a In some embodiments, R 7 -L 2 -heterocycloalkyl, where heterocycloalkyl is bicyclic and one or more R 7a In some embodiments, R 7 -L 2 -heterocycloalkyl, where heterocycloalkyl is monocyclic and has one or more R 7a In some embodiments, R 7 -L 2 -naphthyl, where naphthyl is one or more R 7a is optionally replaced by

[0053] L2 may be any suitable linker known to one of skill in the art. In some embodiments, L 2 is absent, C1-C6 alkylene, C1-C6 heteroalkylene, C2-C6 alkenylene, or C2-C6 alkynylene, each of which is selected from one or more R 7a In some embodiments, L 2 is absent, CH-, or -CHCH-. In some embodiments, L 2 is absent, C1-C6 alkylene, C1-C6 heteroalkylene, C2-C6 alkenylene, or C2-C6 alkynylene, each of which is optionally substituted. 2 is absent or is C1-C6 alkylene. In some embodiments, L 2 is absent. In some embodiments, L 2 is C1-C6 alkylene or C1-C6 heteroalkylene, each of which is optionally substituted. In some embodiments, L 2 is C1-C6 alkylene. In some embodiments, L 2 is C1-C3 alkylene. In some embodiments, L 2 is C1-C3 heteroalkylene.

[0054] R 7a can be any suitable functional group known to one of skill in the art. In some embodiments, R 7a are halogens, -CN, -NO2, -OH, -OR a , oxo, -OC(=O)R a , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)R a , -NR b S(=O)2R a , -C(=O)Ra , -C(=O)OR a , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R. In some embodiments, R 7a is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R. In some embodiments, R 7a are halogens, -CN, -NO2, -OH, -OR a , oxo, -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR a , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. 7ais halogen, -OR a , oxo, C(=O)OR a , C1-C6 alkyl, or C1-C6 heteroalkyl. In some embodiments, R 7a is halogen, -OC1-C3 alkyl, oxo, C(=O)OC1-C3 alkyl, C1-C6 alkyl, or C1-C3 heteroalkyl. 7a is halogen, O-C alkyl, oxo, C-C alkyl, or C-C heteroalkyl. 7a is halogen, O-C-C alkyl, oxo, C-C alkyl, or C-C haloalkyl. 7a is chloro, -OCH3, -OCH2CH3, oxo, -CH3, or -CF3.

[0055] In some embodiments, R 7 is optionally substituted aryl or optionally substituted heteroaryl. In some embodiments, R 7 is aryl or heteroaryl, each of which is optionally substituted with one or more R. In some embodiments, R 7 teeth,

[0056] [ka] It is.

[0057] In some embodiments, R 6 is hydrogen or C1-C6 alkyl, R 7 is C1-C 24 Alkyl, -L 2 -cycloalkyl, -L 2 -aryl, or -L 2-heteroaryl, where each of the alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with halogen, -OH, oxo, C-C alkyl, C-C haloalkyl, or -OC-C alkyl. 6 is hydrogen or C1-C3 alkyl, R 7 is an optionally substituted C1-C 12 Alkyl, -L 2 -cycloalkyl, -L 2 -aryl, or -L 2 -heteroaryl. In some embodiments, R 6 is hydrogen, and R 7 is C1-C6 alkyl, -L 2 -aryl, or -L 2 -heteroaryl, wherein each of the alkyl, aryl, or heteroaryl is optionally substituted with halogen, oxo, C-C alkyl, C-C haloalkyl, or O-C alkyl. In some embodiments, R 6 is hydrogen, and R 7 is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3), -CH2CH2CH2CH3, -CH2CH(CH3). In some embodiments, R 6 is hydrogen, and R 7 -L 2 -Thiochromanyl, -L 2 -Phenyl, L 2 -Naphthyl, -L 2 -thiophen-2-yl, or -L 2 -benzothiazolyl, where each of thiochromanyl, phenyl, naphthyl, thiophen-2-yl, or benzothiazolyl is selected from one or more of R 7a Optionally replaced by R 7a is chloro, -OH, -OCH, -OCHCH, oxo, -CH, or -CF. In some embodiments, R 6 is hydrogen, and R 7 is -phenyl or -naphthyl, where each of the phenyl or naphthyl is selected from one or more R 7aOptionally replaced by R 7a is chloro, oxo, -CH, -CF, or -OCH. In some embodiments, R 6 is hydrogen, and R 7 is methyl. In some embodiments, the following structure:

[0058] [ka] teeth

[0059] [ka] It is.

[0060] In some embodiments, the structure:

[0061] [ka] teeth

[0062] [ka] It is.

[0063] In some embodiments, the compound, or a pharma- ceutically acceptable salt or solvate thereof, has formula (II):

[0064] [ka] It has the structure:

[0065] In some embodiments, the compound, or a pharma- ceutically acceptable salt or solvate thereof, has the formula (IIa):

[0066] [ka] It has the structure:

[0067] R 4can be any suitable functional group known to one of skill in the art. In some embodiments, R 4 , H, C1-C 24 Alkyl, C1-C 24 Haloalkyl, C1-C 24 Heteroalkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, -L 5 -cycloalkyl, -L 5 -heterocycloalkyl, -L 5 -aryl, or -L 5 -heteroaryl, where alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, respectively. In some embodiments, R 4 , H, C1-C 24 Alkyl, C1-C 24 Haloalkyl, or C1-C 24 In some embodiments, R 4 , H, C1-C 12 Alkyl, C1-C 12 Haloalkyl, or C1-C 12 In some embodiments, R 4 is H, C-C alkyl, C-C haloalkyl, or C-C heteroalkyl. In some embodiments, R 4 is H or C1-C 12 In some embodiments, R 4 is H or C1-C6 alkyl. In some embodiments, R 4 is H. In some embodiments, R 4 is C1-C6 alkyl. In some embodiments, R 4 is C1-C3 alkyl. In some embodiments, R 4 is -CH3.

[0068] R 5 can be any suitable functional group known to one of skill in the art. In some embodiments, R 5 is C1-C 24 Alkyl, C1-C 24Haloalkyl, C1-C 24 Heteroalkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, -L 5 -cycloalkyl, -L 5 -heterocycloalkyl, -L 5 -aryl, or -L 5 -heteroaryl, where each of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from one or more R 5a In some embodiments, R 5 is C1-C 24 Alkyl, C1-C 24 Heteroalkyl, -L 5 -aryl, or -L 5 -heteroaryl, each of alkyl, heteroalkyl, aryl, or heteroaryl being selected from one or more R 5a In some embodiments, R 5 is C1-C 12 Alkyl, C1-C 12 Haloalkyl, C1-C 12 Hydroxyalkyl, C1-C 12 Aminoalkyl, C1-C 12 heteroalkyl, where each of the alkyl or heteroalkyl is selected from one or more R 5a In some embodiments, R 5 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, where each alkyl or heteroalkyl is selected from one or more R 5a In some embodiments, R 5 is C1-C 12 Alkyl or C1-C 12 heteroalkyl, where each of the alkyl or heteroalkyl is selected from one or more R 5a In some embodiments, R 5 is C1-C12 alkyl, where alkyl is one or more R 5a In some embodiments, R 5 is C1-C 12 heteroalkyl, where heteroalkyl is one or more R 5a In some embodiments, R 5 is C1-C6 alkyl, where alkyl is one or more R 5a In some embodiments, R 5 is C1-C6 alkyl, where alkyl is one or more R 5a Optionally replaced by R 5a is halogen, oxo, or -C(=O)O-Ci_3 alkyl. In some embodiments, R 5 is C1-C6 alkyl, where alkyl is one or more R 5a Optionally replaced by R 5a is -C(=O)O-C1-3 alkyl. In some embodiments, R 5 is C1-C6 alkyl, where alkyl is one or more R 5a Optionally replaced by R 5a is -C(=O)O-CH3 or -C(=O)OC(CH3). In some embodiments, R 5 is C1-C6 heteroalkyl, where heteroalkyl is one or more R 5a In some embodiments, R 5 is C1-C6 heteroalkyl, where heteroalkyl is one or more R 5a Optionally replaced by R 5a is halogen, oxo, or -C(=O)O-Ci_3 alkyl. In some embodiments, R 5 is C1-C6 heteroalkyl, where heteroalkyl is one or more R 5a Optionally replaced by R 5a is -C(=O)O-C1-3 alkyl. In some embodiments, R 5is C1-C6 heteroalkyl, where heteroalkyl is one or more R 5a Optionally replaced by R 5a is -C(=O)O-CH3. In some embodiments, R 5 is -(CH2)3-S-CH3, where heteroalkyl is one or more R 5a In some embodiments, R 5 teeth

[0069] [ka] It is.

[0070] In some embodiments, R 5 teeth

[0071] [ka] It is.

[0072] In some embodiments, R 5 -L 5 -cycloalkyl, -L 5 -heterocycloalkyl, -L 5 -aryl, or -L 5 -heteroaryl, each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl being selected from one or more R 5a In some embodiments, R 5 -L 5 -cycloalkyl, -L 5 -heterocycloalkyl, -L 5 -aryl, or -L 5 -heteroaryl, where each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from halogen, oxo, -OH, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxyl. 5 -L 5-cycloalkyl, -L 5 -heterocycloalkyl, -L 5 -aryl, or -L 5 -heteroaryl, where each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from halogen, oxo, -OH, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxyl. 5 -L 5 -cycloalkyl, -L 5 -heterocycloalkyl, -L 5 -phenyl, or -L 5 -indolyl, wherein each of cycloalkyl, heterocycloalkyl, phenyl, or indolyl is selected from one or more R 5a In some embodiments, R 5 -L 5 -cycloalkyl, -L 5 -heterocycloalkyl, -L 5 -phenyl, or -L 5 -indolyl, where each of cycloalkyl, heterocycloalkyl, phenyl, or indolyl is selected from one or more R 5a Optionally replaced by L 5 is C1-C6 alkylene or C1-C6 heteroalkylene, each of which is one or more R 5a In some embodiments, R 5 -L 5 -cycloalkyl, -L 5 -heterocycloalkyl, -L 5 -phenyl, or -L 5 -indolyl, where each of the cycloalkyl, heterocycloalkyl, phenyl, or indolyl is optionally substituted with one or more substituents selected from halogen, oxo, -OH, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxyl. 5 Each of these consists of one or more R 5aOptionally replaced with -L 5 -phenyl or -L 5 In some embodiments, R 5 Each of these consists of one or more R 5a Optionally replaced with -L 5 Phenyl or -L 5 Indolyl, L 5 is C1-C6 alkylene or C1-C6 heteroalkylene, each of which is selected from one or more R 5a In some embodiments, R 5 -L, each of which is optionally substituted with one or more substituents selected from halogen, oxo, -OH, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; 5 Phenyl or -L 5 In some embodiments, R 5 Each of these consists of one or more R 5a Optionally replaced with -L 5 Phenyl or -L 5 Indolyl, R 5a is halogen, oxo, -OH, or C1-C6 alkyl. In some embodiments, R 5 Each of these consists of one or more R 5a Optionally replaced with -L 5 Phenyl or -L 5 Indolyl, R 5a is halogen, -OH, or oxo. In some embodiments, R 5 -L 5 -phenyl or -L 5 -indolyl, wherein each phenyl or indolyl is unsubstituted. 5 -L 5 Phenyl or -L 5 indolyl, each of which is unsubstituted; 5 is C1-C6 alkylene or C1-C6 heteroalkylene, each of which is selected from one or more R 5aIn some embodiments, R 5 -L 5 Phenyl or -L 5 indolyl, each of which is unsubstituted; 5 is C1-C6 alkylene or C1-C6 heteroalkylene, each of which is selected from one or more R 5a Optionally replaced by R 5a is -C(=O)O-CH3. In some embodiments, R 5 -L 5 Phenyl or -L 5 indolyl, each of which is unsubstituted; 5 is -CH2-, -CH2CH2-, or -CH2CH2-O-CH2-, each of which is selected from one or more R 5a Optionally replaced by R 5a is -C(=O)O-CH3. In some embodiments, R 5 teeth

[0073] [ka] It is.

[0074] L 5 is any suitable linker known to one of skill in the art. In some embodiments, L 5 is absent, C1-C6 alkylene, C1-C6 heteroalkylene, C2-C6 alkenylene, or C2-C 24 alkynylene, each of which may be one or more R 5a In some embodiments, L 5 is absent, C1-C6 heteroalkylene, or C2-C6 alkynylene, each of which is selected from the group consisting of one or more R 5a In some embodiments, L 5 is C1-C6 alkylene or C1-C6 heteroalkylene, each of which is one or more R 5aIn some embodiments, L is optionally substituted with 5 is C1-C6 alkylene or C1-C6 heteroalkylene, each of which is one or more R 5a Optionally replaced by R 5a -C(=O)OR a In some embodiments, L 5 is one or more R 5a In some embodiments, L is a C1-C6 alkylene optionally substituted with 5 is one or more R 5a and R is a C1-C6 alkylene optionally substituted with 5a -C(=O)OR a In some embodiments, L 5 is one or more R 5a and R is a C1-C6 alkylene optionally substituted with 5a is -C(=O)O-CH3. In some embodiments, L 5 is C1-C6 alkylene. In some embodiments, L 5 is C1-C3 alkylene. In some embodiments, L 5 is one or more R 5a In some embodiments, L is a C1-C6 heteroalkylene optionally substituted with 5 is one or more R 5a and R is a C1-C6 heteroalkylene optionally substituted with 5a -C(=O)OR a In some embodiments, L 5 is one or more R 5a and R is a C1-C6 heteroalkylene optionally substituted with 5a is -C(=O)O-CH3. In some embodiments, L 5 is C1-C6 heteroalkylene. In some embodiments, L 5 is C1-C3 heteroalkylene.

[0075] R 5a can be any suitable functional group known to one of skill in the art. In some embodiments, R 5aare each independently halogen, -CN, -NO2, -OH, -OR a , oxo, -OC(=O)R a , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)R a , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR a , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R. In some embodiments, R 5a are each independently halogen, -CN, -NO2, -OH, -OR a , oxo, -OC(=O)R a , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)R a , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR a , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. 5a are halogens, -CN, -NO2, -OH, -OR a , oxo, -OC(=O)R a , -OC(=O)OR b , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -NR c R d , -C(=O)R a , -C(=O)OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where each of the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R 5a is halogen, -OR a , oxo, -C(=O)OR a , C1-C6 alkyl, or C1-C6 heteroalkyl, where each of the alkyl or heteroalkyl is optionally substituted with one or more R. In some embodiments, R 5a is halogen, oxo, -C(=O)O-Ci-6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or C2-C5 heterocycloalkyl. 5a is halogen, oxo, -C(=O)O-Ci_3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or C2-C5 heterocycloalkyl. 5a is oxo, -C(=O)O-Ci_3 alkyl, or C2-C5 heterocycloalkyl. In some embodiments, R 5ais oxo, -C(=O)O-CH3, -C(=O)OC(CH3)3, or C5 heterocycloalkyl. In some embodiments, R 5a is -C(=O)O-CH3, -C(=O)OC(CH3)3, or piperazinyl.

[0076] In some embodiments, R 4 and R 5 taken together with the nitrogen to which they are attached form a heterocycloalkyl or heteroaryl. In some embodiments, R 4 and R 5 together with the nitrogen to which they are attached form a 3- to 12-membered heterocycloalkyl or heteroaryl, where each heterocycloalkyl or heteroaryl is selected from one or more R 5a In some embodiments, R 4 and R 5 taken together with the nitrogen to which they are attached form a heterocycloalkyl or heteroaryl. In some embodiments, R 4 and R 5 together with the nitrogen to which they are attached form a 3- to 12-membered heterocycloalkyl or heteroaryl, where each heterocycloalkyl or heteroaryl is selected from one or more R 5a Optionally replaced by R 5a is halogen, oxo, -C(=O)O-Ci_3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or C2-C5 heterocycloalkyl. 4 and R 5 together with the nitrogen to which they are attached form a 5- to 8-membered heterocycloalkyl or heteroaryl, where each heterocycloalkyl or heteroaryl is selected from one or more R 5a In some embodiments, R 4 and R 5together with the nitrogen to which they are attached form a 5- to 8-membered heterocycloalkyl or heteroaryl, where each heterocycloalkyl or heteroaryl is selected from one or more R 5a Optionally replaced by R 5a is halogen, oxo, -C(=O)O-Ci_3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or C2-C5 heterocycloalkyl. 4 and R 5 are taken together with the nitrogen to which they are attached to form a 5- or 6-membered heterocycloalkyl or heteroaryl, each of which is optionally substituted. In some embodiments, R 4 and R 5 are taken together with the nitrogen to which they are attached to form a 5- or 6-membered heterocycloalkyl or heteroaryl, each of which is optionally substituted and contains 1 or 2 nitrogens and 0-1 oxygen. In some embodiments, R 4 and R 5 together with the nitrogen to which they are attached form a 5-6 membered heterocycloalkyl. In some embodiments, R 4 and R 5 R together with the nitrogen to which they are attached form a 5-6 membered heterocycloalkyl, each of which is optionally substituted and contains 1 or 2 nitrogens and 0-1 oxygen. 4 and R 5 together with the nitrogen to which they are attached form a 5- to 6-membered heterocycloalkyl, each of which may be one or more R 5a In some embodiments, R 4 and R 5 together with the nitrogen to which they are attached form a 5- to 6-membered heterocycloalkyl, each of which may be one or more R 5a Optionally replaced by R 5ais halogen, oxo, -C(=O)O-Ci_3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or C2-C5 heterocycloalkyl. 4 and R 5 together with the nitrogen to which they are attached form a 5- to 6-membered heterocycloalkyl, each of which may be one or more R 5a Optionally replaced by R 5a is -C(=O)O-C1-3 alkyl or C2-C5 heterocycloalkyl. In some embodiments, R 4 and R 5 together with the nitrogen to which they are attached form pyrrolidinyl, morpholinyl, or piperidinyl, each of which may be selected from one or more R 5a In some embodiments, R 4 and R 5 together with the nitrogen to which they are attached form pyrrolidinyl, morpholinyl, or piperidinyl, each of which may be one or more R 5a Optionally replaced by R 5a is -C(=O)O-C1-3 alkyl or C2-C5 heterocycloalkyl. In some embodiments, R 4 and R 5 together with the nitrogen to which they are attached form pyrrolidinyl, morpholinyl, or piperidinyl, each of which may be one or more R 5a Optionally replaced by R 5a is -C(=O)O-CH3 or piperidinyl. In some embodiments, R 4 and R 5 together with the nitrogen to which they are attached form morpholinyl or piperidinyl, each of which may be one or more R 5a Optionally replaced by R 5a is piperidinyl. In some embodiments, the following structure:

[0077] [ka] teeth

[0078] [ka] It is.

[0079] In some embodiments, the structure:

[0080] [ka] teeth

[0081] [ka] It is.

[0082] In some embodiments, the structure:

[0083] [ka] teeth

[0084] [ka] It is.

[0085] In some embodiments, the structure:

[0086] [ka] teeth

[0087] [ka] It is.

[0088] In some embodiments, the structure:

[0089] [ka] teeth

[0090] [ka] It is.

[0091] In some embodiments, Q is (S)-1-carboxyethylamino, (S)-1-carboxy-4-guanidinobutylamino, (S)-3-amino-1-carboxy-3-oxopropylamino, (S)-1,2-dicarboxyethylamino, (S)-1-carboxy-2-mercaptoethylamino, (S)-4-amino-1-carboxy-4-oxobutylamino, (S)-3-carboxy-1-carboxylatepropylamino, (S)-1-carboxy-2-(1H-imidazol-4-yl)ethylamino, (1S,2S)-1-carboxy-2-methylbutylamino, (S)-1-carboxyethylamino, ( ... (S)-1-carboxy-3-methylbutylamino, (S)-5-amino-1-carboxypentylamino, (S)-1-carboxy-3-(methylthio)propylamino, (S)-1-carboxy-2-phenylethylamino, (S)-2-carboxypyrrolidin-1-yl, (S)-1-carboxy-2-hydroxyethylamino, (1S,2R)-1-carboxy-2-hydroxypropylamino, (S)-1-carboxy-2-(1H-indol-3-yl)ethylamino, (S)-1-carboxy-2-(4-hydroxyphenyl)ethylamino, or (S)-1-carboxy-2-methylpropylamino.

[0092] In some embodiments, the compound, or a pharma- ceutically acceptable salt or solvate thereof, has formula (IV):

[0093] [ka] It has the structure:

[0094] In some embodiments, the compound, or a pharma- ceutically acceptable salt or solvate thereof, has formula (IVa):

[0095] [ka] It has the structure:

[0096] R 8 can be any suitable functional group known to one of skill in the art. In some embodiments, R 8 -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, C5-C 24 Alkyl, C1-C 24 Haloalkyl, C1-C 24 Heteroalkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, -L 3 -OP(=O)(OH)2, -L 3 -cycloalkyl, -L 3 -heterocycloalkyl, or -L 3 -aryl, where each of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or aryl is selected from one or more R 8a In some embodiments, R 8 -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, C5-C 24 Alkyl, C1-C 24 Haloalkyl, C1-C 24 Heteroalkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, -L 3 -OP(=O)(OH)2, -L 3 -cycloalkyl, -L 3 -heterocycloalkyl, or -L 3 -aryl. In some embodiments, R 8 is C5-C 24 Alkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, -L 3 -OP(=O)(OH)2, or -L3 -aryl, where each of alkyl, alkenyl, alkynyl, or aryl is selected from one or more R 8a In some embodiments, R 8 is C5-C 24 Alkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, -L 3 -OP(=O)(OH)2, or -L 3 -aryl. In some embodiments, R 8 is C3-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, L 3 -(5- or 6-membered cycloalkyl), -L 3 -(5- or 6-membered heterocycloalkyl), -L 3 -phenyl, -L 3 -Naphthyl, or -L 3 -heteroaryl, where each of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, naphthyl, or heteroaryl is selected from one or more R 8a is optionally replaced by

[0097] In some embodiments, R 8 -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, C5-C 14 Alkyl, C1-C 14 Heteroalkyl, C2-C 12 Alkenyl, or C2-C 12 alkynyl, where each of the alkyl, heteroalkyl, alkenyl, or alkynyl groups is selected from one or more R 8a In some embodiments, R 8 -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, C5-C 12 Alkyl, C1-C 12 Heteroalkyl, C2-C12 Alkenyl, or C2-C 12 alkynyl, where each of the alkyl, heteroalkyl, alkenyl, or alkynyl groups is selected from one or more R 8a In some embodiments, R 8 -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, C5-C 12 Alkyl, C1-C 12 Heteroalkyl, C2-C 12 Alkenyl, or C2-C 12 In some embodiments, R is alkynyl. 8 , -CH2CH2CH2CH3, C5-C 12 Alkyl, C1-C6 heteroalkyl, C2-C 12 Alkenyl, or C2-C 12 Alkynyl, where each of alkyl, heteroalkyl, alkenyl, or alkynyl is selected from one or more R 8a Optionally replaced by R 8a is oxo. In some embodiments, R 8 , -CH2CH2CH2CH3, C5-C 12 alkyl, and C1-C6 heteroalkyl each having one or more R 8a Optionally replaced by R 8a is oxo.

[0098] In some embodiments, R 8 teeth

[0099] [ka] It is.

[0100] In some embodiments, R 8 teeth

[0101] [ka] It is.

[0102] In some embodiments, R 8 teeth

[0103] [ka] It is.

[0104] In some embodiments, R 8 teeth

[0105] [ka] It is.

[0106] In some embodiments, R 8 teeth

[0107] [ka] It is.

[0108] In some embodiments, R 8 -L 3 -(5- or 6-membered cycloalkyl), -L 3 -(5- or 6-membered heterocycloalkyl), -L 3 -phenyl, -L 3 -Naphthyl, or -L 3 -heteroaryl, each of cycloalkyl, heterocycloalkyl, phenyl, naphthyl, or heteroaryl being selected from one or more R 8a In some embodiments, R 8 -L 3 -(5- or 6-membered cycloalkyl), -L 3 -(5- or 6-membered heterocycloalkyl), -L 3 -phenyl, -L 3 -Naphthyl, or -L 3 -heteroaryl, each of cycloalkyl, heterocycloalkyl, phenyl, naphthyl, or heteroaryl being selected from one or more R 8a Optionally replaced by L3 is absent, C2-C6 alkenylene, C1-C6 alkylene, or C1-C6 heteroalkylene, each of which is optionally substituted. In some embodiments, R 8 -L 3 -(5- or 6-membered cycloalkyl), -L 3 -phenyl, -L 3 -Naphthyl, or -L 3 -heteroaryl, each of cycloalkyl, phenyl, naphthyl, or heteroaryl being selected from one or more R 8a In some embodiments, R 8 -L 3 -(5- or 6-membered cycloalkyl), -L 3 -(5- or 6-membered heterocycloalkyl), -L 3 -phenyl, -L 3 -Naphthyl, or -L 3 -heteroaryl, each of cycloalkyl, phenyl, naphthyl, or heteroaryl being selected from one or more R 8a where R 8a is halogen, oxo, C1-C6 alkyl, or C1-C6 haloalkyl; L 3 is absent, C1-C6 alkylene, C1-C3 heteroalkylene, or C2-C3 alkenylene. 8 -L 3 -Cyclohexyl, -L 3 -(1,3-dioxolyl), -L 3 -phenyl, or -L 3 -naphthyl, each of which is one or more R 8a In some embodiments, R 8 -L 3 -Cyclohexyl, -L 3 -(1,3-dioxolyl), -L 3 -phenyl, or -L 3 -naphthyl, each of which is one or more R 8a where R 8ais halogen, oxo, C1-C6 alkyl, or C1-C6 haloalkyl; L 3 is absent, C1-C6 alkylene, C1-C3 heteroalkylene, or C2-C3 alkenylene. 8 -L 3 -Cyclohexyl, -L 3 -(1,3-dioxolyl), -L 3 -phenyl, or -L 3 -naphthyl, each of which is one or more R 8a where R 8a is fluoro, oxo, -CH, or -CF. In some embodiments, R 8 -L 3 -Cyclohexyl, -L 3 -(1,3-dioxolyl), -L 3 -phenyl, or -L 3 -naphthyl, each of which is one or more R 8a where R 8a is fluoro, oxo, -CH3, or -CF3, and L 3 is absent, C1-C6 alkylene, C1-C3 heteroalkylene, or C2-C3 alkenylene. 8 -L 3 -Cyclohexyl, -L 3 -(1,3-dioxolyl), -L 3 -phenyl, or -L 3 -naphthyl, each of which is one or more R 8a where R 8a is fluoro, oxo, -CH3, or -CF3, and L 3 is absent, -CH2CH2-, -CH2CH2-O-, -CH2-, or -CH2CH=CH-.

[0109] In some embodiments, R 8 teeth

[0110] [ka] It is.

[0111] In some embodiments, R 8 teeth

[0112] [ka] It is.

[0113] In some embodiments, R 8 teeth

[0114] [ka] It is.

[0115] In some embodiments, R 8 teeth

[0116] [ka] It is.

[0117] In some embodiments, R 8 -L 3 -OP(=O)(OH). In some embodiments, R 8 teeth

[0118] [ka] It is.

[0119] L 3 is any suitable linker known to one of skill in the art. In some embodiments, L 3 is absent, C1-C6 alkylene, C1-C6 heteroalkylene, C2-C6 alkenylene, or C2-C 24 alkynylene, each of which may be one or more R 8a In some embodiments, L 3is absent, C1-C6 alkylene, C1-C6 heteroalkylene, or C2-C6 alkenylene. 3 is absent, C1-C6 alkylene, C1-C3 heteroalkylene, or C2-C3 alkenylene. 3 is absent, -CHCH-, -CHCH-O-, -CH-, or -CHCH=CH-. 3 does not exist.

[0120] R 8a can be any suitable functional group known to one of skill in the art. In some embodiments, R 8a are halogens, -CN, -NO2, -OH, -OR a , oxo, -OC(=O)R a , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)R a , N.R. b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R. In some embodiments, R 8a are halogens, -CN, -NO2, -OH, -OR a , oxo, -OC(=O)R a , -OC(=O)ORb , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each of the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R. In some embodiments, R 8a are halogens, -CN, -NO2, -OH, -OR a , oxo, -OC(=O)R a , -OC(=O)OR b , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR a , C-C alkyl, C-C haloalkyl, C-C heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments, R 8a is halogen, -OR a , oxo, C1-C6 alkyl, or C1-C6 haloalkyl, where each of the alkyl or haloalkyl is optionally substituted with one or more R. In some embodiments, R 8a is halogen, -OR a , oxo, C1-C6 alkyl, or C1-C6 haloalkyl, where each of the alkyl or haloalkyl is optionally substituted with one or more R. In some embodiments, R 8ais halogen, oxo, C-C alkyl, C-C haloalkyl, or C-C alkoxy. 8a is fluoro, oxo, -CH, -CF, or C-C alkoxy. 8a is fluoro, oxo, -CH3, or -CF3.

[0121] R can be any suitable functional group known to one of skill in the art. In some embodiments, R is independently halogen, -CN, -OH, oxo, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl. In some embodiments, R is independently halogen, -CN, -OH, oxo, -OC1-C6 alkyl, -NH2, -C(=O)OH, or -C(=O)OC1-C6 alkyl. In some embodiments, R is independently halogen, -OH, oxo, OC1-C6 alkyl, -C(=O)OH, or -C(=O)OC1-C6 alkyl. In some embodiments, R is independently oxo.

[0122] R can be any suitable functional group known to one of skill in the art. In some embodiments, each R is independently halogen, -CN, -OH, oxo, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl. In some embodiments, each R is independently halogen, -CN, -OH, oxo, or -OC1-C6 alkyl. In some embodiments, each R is independently halogen, -CN, -OH, or oxo. In some embodiments, each R is independently oxo.

[0123] In some embodiments of the compounds disclosed herein, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 5a , R 6 , R 7 , R 7a , R 8 , R 8a , R a , R b , R c , and R d One or more of the groups contains deuterium at a ratio higher than the natural abundance of deuterium.

[0124] In some embodiments of the compounds disclosed herein, one or more 1 H is the following R, R 1 , R 2 , R 3 , R 4 , R 5a , R 5 , R 6 , R 7 , R7a , R 8 , R 8a , R a , R b , R c , and R d is substituted with one or more deuterium atoms.

[0125] In some embodiments of the compounds disclosed herein, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 5a , R 6 , R 7 , R 7a , R 8 , R 8a , R a , R b , R c , and / or R d The abundance of deuterium in each of is independently, by molar fraction, at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%.

[0126] In some embodiments of the compounds disclosed herein, one or more of cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may be selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and heteroaryl. 1 H is replaced by one or more deuterium atoms.

[0127] Any combination of the above groups for the various modifications is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0128] In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is one of the compounds in Table 1.

[0129] [Table 1-1]

[0130] [Table 1-2]

[0131] In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is one of the compounds in Table 2.

[0132] [Table 2-1]

[0133] [Table 2-2]

[0134] Further forms of the compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers and their corresponding mixtures. In some circumstances, the compounds described herein have one or more chiral centers, each center being present in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms, as well as their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers resulting from a single preparation step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have distinctive physical properties (e.g., melting points, boiling points, solubility, reactivity, etc.) and are separated by taking advantage of these differences. In some embodiments, diastereomers are separated by chiral chromatography or, preferably, separation / resolution techniques based on solubility differences. In some embodiments, the optically pure enantiomers are recovered along with the resolving agent by any practical means that does not result in racemization.

[0135] labeled compound In some embodiments, the compounds described herein are present in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds, which are identical to those listed herein except for the fact that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein are respectively: 2 H(D), 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 The isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride, such as Cl. Compounds described herein and pharma- ceutically acceptable salts, solvates, or stereoisomers thereof that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present disclosure. Certain isotopically labeled compounds, e.g., 3 H and 14 Compounds that incorporate a radioactive isotope, such as C, are useful in drug and / or substrate tissue distribution assays. Tritiated (i.e. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred for their ease of preparation and detectability.

[0136] In some embodiments, the abundance of deuterium in each of the substituents disclosed herein is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% by mole. In some embodiments, one or more of the substituents disclosed herein contain deuterium in a proportion greater than the natural abundance of deuterium. In some embodiments, one or more 1 H is substituted with one or more deuterium in one or more of the substituents disclosed herein.

[0137] In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0138] Pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating disease by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0139] In some embodiments, the compounds described herein contain acidic or basic groups and therefore react with any of a number of inorganic or organic bases and inorganic and organic acids to form pharma- ceutically acceptable salts. In some embodiments, these salts are prepared during the final isolation and purification of the compounds disclosed herein, or solvates or stereoisomers thereof, or in situ by separately reacting the purified compounds in free form with the appropriate acid or base and isolating the salt thus formed.

[0140] Examples of pharma- ceutically acceptable salts include salts prepared by reaction of the compounds disclosed herein with a mineral, organic acid, or inorganic base, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride. , hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0141] Additionally, the compounds described herein can be prepared as pharma- ceutically acceptable salts formed by reacting the free base form of the compound with a pharma- ceutically acceptable inorganic or organic acid, including but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids, including but not limited to, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, 4-(4-hydroxybenzoyl)benzoic acid, 5 ... Examples of suitable acids include benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids, such as oxalic acid, while not themselves pharma-ceutically acceptable, are utilized in the preparation of the compounds disclosed herein, their solvates, or salts useful as intermediates in obtaining stereoisomers and their pharma-ceutically acceptable acid addition salts.

[0142] In some embodiments, the compounds described herein that contain free acid groups are reacted with a suitable base, such as hydroxide, carbonate, bicarbonate, sulfate, of a pharma- ceutically acceptable metal cation, with ammonia, or with a pharma-ceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts. Typical examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4alkyl)4.

[0143] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It is understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water- or oil-soluble or dispersible products are obtained by such quaternization.

[0144] solvate In some embodiments, the compounds described herein exist as solvates.The present disclosure provides a method for treating disease by administering such solvates.The present disclosure further provides a method for treating disease by administering such solvates as pharmaceutical compositions.

[0145] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and in some embodiments are formed during the process of crystallization with pharma- ceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the process described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous / organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0146] Tautomers In some circumstances, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that can be interconverted by the migration of a hydrogen atom with the switch of a single bond and adjacent double bond. When combining sequences that allow tautomerization, a chemical equilibrium of tautomers exists. All tautomers of the compounds disclosed herein are considered. The exact ratio of tautomers depends on various factors, including temperature, solvent, and pH.

[0147] Pulmonary Arterial Hypertension (PAH), PGI2, and IP Receptor Agonists Pulmonary hypertension (PH) is a rare progressive disease characterized by elevated pulmonary vascular resistance (PVR) that can lead to right ventricular enlargement, hypertrophy, dysfunction, and ultimately death. There are five different groups of PH based on different causes according to the current World Health Organization (WHO) classification. These are referred to as the WHO PH Groups. The first group is pulmonary arterial hypertension (PAH), which is characterized by thickening and stiffening of the pulmonary blood vessels. Although management of PAH has improved significantly over the past 15 years, mortality remains unacceptably high, with a median life expectancy of 7 years after diagnosis. The second WHO group includes PH due to left heart disease. In these patients, cardiac problems, rather than the pulmonary vasculature, are the primary cause of the condition. The third WHO group includes PH due to chronic lung disease and / or hypoxia (low oxygen levels). The third group includes pulmonary hypertension associated with interstitial lung disease (PH-ILD) and PH associated with pulmonary fibrosis. WHO group 4 is called chronic thromboembolic pulmonary hypertension (CTEPH). WHO group 5 is when PH occurs secondary to other, unspecified diseases. Treatment is determined by the form of PH; for example, PAH is often treated with prostacyclin. Regardless of classification, PH is a severe and often fatal disease.

[0148] The severity of PH, including PAH, is graded by four functional classes according to a system originally developed for heart failure by the New York Heart Association (NYHA) and then modified by the WHO for PAH patients. Patients are usually asymptomatic in the early stages of the disease (i.e., functional class I), but as the disease progresses, symptoms of the disease, including exertional dyspnea, fatigue, peripheral edema, and syncope, may be indistinguishable from other cardiorespiratory diseases. Many patients are never diagnosed until they develop symptoms of WHO / NYHA functional class II or III.

[0149] Pulmonary arterial hypertension (PAH) has a multifactorial pathobiology. Vasoconstriction, remodeling of the pulmonary vascular wall, and thrombosis lead to increased pulmonary vascular resistance in PAH (Humbert et al., J. Am. Coll. J. Am. Coll. Cardiol., 2004, 43:13 S-24S).

[0150] The compounds disclosed herein may be useful for treating pulmonary arterial hypertension (PAH) and its symptoms. PAH should be understood to include all forms of pulmonary arterial hypertension described in the World Health Organization (WHO) 2003 clinical classification of pulmonary arterial hypertension. These forms include idiopathic PAH (IPAH), familial PAH (FPAH), other disease-associated PAH (APAH), such as collagen vascular disease-associated PAH, congenital systemic-to-pulmonary shunt-associated PAH, portal hypertension-associated PAH, HTV infection-associated PAH, drug or toxin-associated PAH, or other-associated PAH, and venous or capillary-associated PAH.

[0151] Idiopathic PAH refers to PAH with an unknown cause.

[0152] Familial PAH refers to PAH with suspected or proven genetic inheritance.

[0153] PAH associated with collagen vascular disease should be understood to include PAH associated with scleroderma, PAH associated with CREST (calcinosis cutis, Raynaud's phenomenon, esophageal dysfunction, and digital sclerosis) and telangiectasia) syndrome, PAH associated with systemic lupus erythematosus (SLE), PAH associated with rheumatoid arthritis, PAH associated with Takayasu's arteritis, PAH associated with polymyositis, and PAH associated with dermatomyositis.

[0154] PAH associated with congenital systemic-to-pulmonary shunts should be understood to include PAH associated with atrial septal defect (ASD), PAH associated with ventricular septal defect (VSD), and PAH associated with patent ductus arteriosus.

[0155] PAHs associated with drugs or toxins should be understood to include PAHs associated with ingestion of Aminorex, PAHs associated with ingestion of fenfluramine compounds (e.g., PAHs associated with ingestion of fenfluramine or PAHs associated with ingestion of dexfenfluramine), PAHs associated with ingestion of certain toxic oils (e.g., PAHs associated with ingestion of rapeseed oil), PAHs associated with ingestion of pyrrolizidine alkaloids (e.g., PAHs associated with ingestion of bush tea), and PAHs associated with ingestion of monocrotaline.

[0156] Other associated PAH should be understood to include PAH associated with thyroid disorder, PAH associated with glycogen storage disease, PAH associated with Gaucher disease, PAH associated with hereditary hemorrhagic telangiectasia, PAH associated with hemochromatosis, PAH associated with myeloproliferative disorders, and PAH associated with splenectomy.

[0157] PAH associated with significant venous or capillary involvement should be understood to include PAH associated with pulmonary veno-occlusive disease (PVOD) and PAH associated with pulmonary capillary hemangiomatosis (PCH).

[0158] Evidence for the association of PAH with scleroderma and the beneficial effect of PGI2 receptor agonists on PAH has been shown by Badesch et al. (Badesch et al., Ann. Intern. Med., 2000, 132:425-434). Evidence for the association of PAH with collagen vascular disease mixed connective tissue disease (MCTD), systemic lupus erythematosus (SLE), Sjogren's syndrome, and CREST syndrome and the beneficial effect of PGI2 receptor agonists on PAH have been shown by Humbert et al. (Eur. Respir. J., 1999, 13:1351-1356). Evidence for the association of PAH with CREST syndrome and the beneficial effect of PGI2 receptor agonists on PAH have been shown by Miwa et al. (Int. Heart J., 2007, 48:417-422). Evidence for the association of PAH with SLE and the beneficial effect of PGI2 receptor agonists on PAH is presented by Robbins et al. (Chest, 2000, 117:14-18). Evidence for the association of PAH with HIV infection and the beneficial effect of PGI2 receptor agonists on PAH is presented by Aguilar et al. (Am. J. Respir. Crit. Care Med., 2000, 162:1846-1850). Evidence for the association of PAH with congenital heart defects (including ASD, VSD, and patent ductus arteriosus) and the beneficial effect of PGI2 receptor agonists on PAH is presented by Rosenzweig et al. (Circulation, 1999, 99:1858-1865). Evidence for an association between PAH and fenfluramine, and dexfenfluramine, an anorectic agent, is presented by Archer et al. (Am. J. Respir. Crit. Care Med., 1998, 158:1061-1067). Evidence for an association between AH and hereditary hemorrhagic telangiectasia is presented by McGoon et al. (Chest, 2004, 126:14-34).Evidence for the association between PAH and splenectomy is provided by Hoeper et al. (Ann. Intern. Med., 1999, 130:506-509). Evidence for the association between PAH and portal hypertension and the beneficial effect of PGI2 receptor agonists on PAH is provided by Hoeper et al. (Eur. Respir. J., 2005, 25:502-508).

[0159] Symptoms of PAH include dyspnea, angina, syncope, and edema (McLaughlin et al., Circulation, 2006, 114:1417-1431). The compounds disclosed herein are useful for treating the symptoms of PAH.

[0160] In some embodiments, the pulmonary arterial hypertension (PAH) is selected from idiopathic PAH, familial PAH, PAH associated with collagen vascular disease selected from scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis, and dermatomyositis, PAH associated with congenital heart disease selected from atrial septal defect (ASD), ventricular septal defect (VSD), and patent ductus arteriosus in patients, PAH associated with portal hypertension, PAH associated with HIV infection, PAH associated with drug or toxin ingestion, PAH associated with hereditary hemorrhagic telangiectasia, PAH associated with splenectomy, PAH associated with significant venous or capillary involvement, PAH associated with pulmonary veno-occlusive disease (PVOD), and PAH associated with pulmonary capillary hemangiomatosis (PCH) in patients.

[0161] Studies have shown that PAH patients have altered prostacyclin and thromboxane A2 activity, increased synthesis of endothelin in the pulmonary arterial system, and decreased expression of nitric oxide synthase, all of which contribute to vasoconstriction / vasodilation imbalance, thrombosis, cellular proliferation, and remodeling of the pulmonary arterial wall.Currently available pharmacologic therapies for PAH target the prostacyclin (also called prostaglandin I2 [PGI2]), endothelin, and nitric oxide pathways.

[0162] Treatment guidelines for PAH support the use of oral endothelin receptor antagonists (ERAs), phosphodiesterase type 5 inhibitors (PDE5-I), or soluble guanylate cyclase (sGC) stimulators as monotherapy or in combination in PAH patients with WHO / NHYA functional class III. ERAs target the endothelin pathway, while PDE5-I and sGC stimulators target the nitric oxide pathway. There are three commercially available ERAs, ambrisentan, bosentan, and macitentan, two commercially available PDE5-Is, sildenafil and tadalafil, and one sGC stimulator, riociguat, that are approved for the treatment of PAH. These agents can improve exercise capacity, symptoms, and / or cardiopulmonary hemodynamic variables in symptomatic PAH patients.

[0163] PGI2 is a metabolic product of arachidonic acid and is formed via the cyclooxygenase pathway. Endothelial cells are the major source of PGI2. The vascular effects of PGI2 and its mimetics are largely mediated by activation of the PGI2 (IP) receptor, which includes vasodilation, inhibition of smooth muscle cell proliferation, and inhibition of platelet aggregation. IP receptors are expressed on platelets and on smooth muscle cells of several tissues, including the lung, heart, aorta, liver, kidney, and blood vessels. Activation of IP receptors leads to an increase in cellular cyclic adenosine monophosphate (cAMP) and subsequent dilation of arterial blood vessels and inhibition of platelet aggregation. Replacement therapy with PGI2 has been clearly demonstrated to improve hemodynamics, exercise capacity, and survival.

[0164] Epoprostenol, a synthetic PGI2 analogue, is a potent vasodilator and platelet aggregation inhibitor and was the first approved targeted PAH therapy. Epoprostenol improves the prognosis of PAH patients compared with conventional therapy, supporting the utility of IP receptors as targets for PAH therapy. However, epoprostenol requires continuous infusion via a portable pump, is unstable at room temperature, and is associated with intravenous catheter-associated infections and thrombosis. According to the treatment algorithm presented by the 5th World Symposium and the European Society of Cardiology / European Respiratory Society (ESC / ERS) guidelines, injectable prostacyclin analogues should be administered in patients with PAH severity classified as WHO / NYHA functional class III-IV.

[0165] Subsequent PGI2 analogues, such as treprostinil (continuous subcutaneous and intravenous infusion, intermittent inhalation, and oral) and iloprost (intermittent inhalation), have demonstrated efficacy by improving exercise capacity and / or delaying clinical deterioration. These prostacyclins are prescribed for patients with PAH of WHO / NYHA functional class II-IV. Although these prostacyclin analogues address some of the limitations associated with epoprostenol, they also have drawbacks with regard to frequent administration (iloprost) and pain at the injection site (subcutaneous treprostinil), in addition to typical prostacyclin-related side effects such as headache, nausea, flushing, diarrhea, and jaw pain.

[0166] Selexipag is an oral selective IP receptor agonist approved for the treatment of PAH in the United States and elsewhere to slow disease progression and reduce the risk of hospitalization for PAH. The ESC / ERS guidelines recommend the use of selexipag to treat patients with PAH whose severity is WHO / NYHA functional class II-III. Selexipag and its active metabolites have a mode of action similar to that of endogenous prostacyclin (IP receptor agonism), but they are chemically distinct from prostacyclin analogues that have different pharmacological properties. Selexipag has been shown to reduce PVR after 17 weeks of treatment, with a 40% reduction in the composite morbidity and mortality endpoint. However, the short effective half-life (3-4 hours) of selexipag's active metabolites results in relatively large fluctuations between peak and trough plasma concentrations following BID administration.

[0167] Despite the availability of numerous treatments, functional limitations and survival of PAH patients remain poor. The success of selexipag in delaying disease progression and reducing the risk of hospitalization for PAH supports the utility of oral prostacyclin therapy and paves the way for further optimization of non-prostanoid IP receptor agonists. Research efforts are focused on optimizing non-prostanoid IP receptor activation, bioavailability, and PK with the goal of providing unremitting and potent target association with oral formulations that provide similar clinical efficacy as parenteral prostacyclin.

[0168] As described herein, the compounds herein may be attractive oral alternatives to currently approved oral prostacyclin analogs and non-prostanoid IP receptor agonists for treating PAH.

[0169] In some embodiments, the compounds disclosed herein are useful for treating PH other than PAH. For example, the compounds disclosed herein may be useful for treating Group 3 forms of PH, such as PH-ILD or PH associated with pulmonary fibrosis.

[0170] The disclosed methods and compositions may also be suitable for treating other diseases such as platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina pectoris, stroke, ischemia-reperfusion injury, restenosis, atrial fibrillation, blood clot formation in individuals who have had angioplasty or coronary artery bypass surgery or who suffer from atrial fibrillation, atherothrombosis, asthma or symptoms thereof, diabetes-related disorders such as diabetic peripheral neuropathy, diabetic nephropathy, or diabetic retinopathy, glaucoma or other eye diseases with abnormal intraocular pressure, hypertension, inflammation, psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus (SLE), ulcerative colitis, atherosclerosis, acne, type 1 diabetes, type 2 diabetes, sepsis, and chronic obstructive pulmonary disorder (COPD).

[0171] In some embodiments, the methods and compositions disclosed herein are useful for treating chronic thromboembolic pulmonary hypertension (CTEPH). In some embodiments, the methods and compositions disclosed herein are useful for treating CTEPH (WHO group 4) that persists / recurs after surgical treatment. In some embodiments, the methods and compositions disclosed herein are useful for treating inoperable CTEPH to improve exercise capacity and / or WHO functional class.

[0172] Other PGI2-related disorders and diseases Other PGI2-related diseases and disorders include, but are not limited to, antiplatelet therapy, atherosclerosis, asthma, diabetic-related conditions, glaucoma, hypertension, and anti-inflammatory therapy.

[0173] Antiplatelet therapy (diseases related to platelet aggregation) Antiplatelet agents (antiplatelets) are prescribed for a variety of conditions. For example, in coronary artery disease, they are used to help prevent myocardial infarction or stroke in patients at risk of developing occlusive blood clots (e.g., coronary artery thrombosis).

[0174] In a myocardial infarction ("MI" or "heart attack"), the heart muscle does not receive enough oxygen-rich blood as a result of a blockage in the coronary blood vessels. When taken while the attack is in progress or shortly thereafter (preferably within 30 minutes), antiplatelets can reduce damage to the heart.

[0175] A transient ischemic attack ("TIA" or "mini stroke") is a brief interruption of oxygen flow to the brain, usually due to reduced blood flow in an artery caused by a blocked blood clot. Antiplatelet drugs have been found to be effective in preventing TIAs.

[0176] Angina is a temporary and frequently recurring chest pain, pressure, or discomfort caused by insufficient flow of oxygen-rich blood to some parts of the heart (ischemia). In patients with angina, antiplatelet therapy can reduce the effects of angina and the risk of myocardial infarction.

[0177] A stroke is an event in which the brain does not receive enough oxygen-rich blood, usually due to blockage of a blood vessel in the brain by a blood clot. In high-risk patients, taking antiplatelet medication regularly has been found to prevent the formation of blood clots that lead to a first or second stroke.

[0178] Angioplasty is a catheter-based technique used to open arteries blocked by blood clots. Whether or not stent placement is performed immediately after the procedure to keep the artery open, antiplatelets can reduce the risk of further blood clot formation after the procedure.

[0179] Coronary artery bypass grafting is a surgical procedure in which an artery or vein is taken from elsewhere in the body and grafted onto a blocked coronary artery, rerouting blood around the blockage through the newly attached blood vessel. After the procedure, antiplatelet substances can reduce the risk of secondary blood clots.

[0180] Atrial fibrillation is the most common type of sustained irregular heart rhythm (arrhythmia). Atrial fibrillation affects about 2 million Americans each year. In atrial fibrillation, the atria (upper chambers of the heart) rapidly fire electrical signals that cause them to quiver instead of contract normally. As a result, the heart beats abnormally fast and very irregularly. When given after an episode of atrial fibrillation, antiplatelets can reduce the risk of blood clots forming in the heart and traveling to the brain (embolism).

[0181] There is evidence that PGI2 receptor agonists inhibit platelet aggregation and are therefore a promising treatment for antiplatelet therapy (see, for example, Moncada et al., Lancet, 1977, 1:18-20). Genetic deletion of the PGI2 receptor in mice has been shown to result in an increased tendency to thrombosis (Murata et al., Nature, 1997, 388:678-682).

[0182] PGI2 receptor agonists can be used, for example, to treat claudication or peripheral arterial disease, as well as cardiovascular complications, arterial thrombosis, atherosclerosis, serotonin-induced vasoconstriction, ischemia-reperfusion injury, and arterial restenosis after angioplasty or stent placement. For example, Fetalvero et al., Prostaglandins Other Lipid Mediat.,2007,82:109-118;Arehart et al.,Curr.Med.Chem.,2007,14:2161-2169;Davi et al.,N.Engl.J.Med.,2007,357:2482-2494;Fetalvero et al. al.,Am.J.Physiol.Heart.Circ.Physiol.,2006,290:H1337-H1346;Murata et al.,Nature,1997,388:678-682;Wang et al.,Proc.Natl.Acad.Sci.USA,2006,103:14507-14512;Xiao et al. al.,Circulation,2001,104:2210-2215;McCormick et al.,Biochem.Soc.Trans.,2007,35:910-911;Arehart et al.,Circ.Res.,2008,Mar.6, See pre-print electronic publication. )

[0183] PGI2 receptor agonists can be used alone or in combination with thrombolytic therapy, e.g., tissue plasminogen activator (t-PA), to provide cardioprotection after MI or postischemic myocardial dysfunction, or protection from ischemic injury (including complications resulting therefrom) during percutaneous coronary intervention.PGI2 receptor agonists can also be used in antiplatelet therapy, e.g., in combination with α-tocopherol (vitamin E), echistatin (disintegrin), or in hypercoagulable states, heparin. (e.g. Chan., J. Nutr., 1998, 128:1593-1596; Mardla et al., Platelets, 2004, 15:319-324; Bernabei et al., Ann. Thorac. Surg., 1995, 59:149-153; Gainza et al., J. Nephrol., 2006, 19:648-655).

[0184] The PGI2 receptor agonist disclosed herein can provide beneficial improvements in microcirculation to patients who need antiplatelet therapy, for example, but not limited to, by antagonizing the vasoconstriction products of aggregated platelets in the above indications.Thus, in some embodiments, the present disclosure provides a method for reducing platelet aggregation in a patient who needs to reduce platelet aggregation, comprising administering to the patient a composition comprising the PGI2 receptor agonist disclosed herein.In a further embodiment, the present disclosure provides a method for treating coronary artery disease, myocardial infarction, transient ischemic attack, angina pectoris, stroke, atrial fibrillation, or any of the symptoms of the above in a patient who needs treatment, comprising administering to the patient a composition comprising the PGI2 receptor agonist disclosed herein.

[0185] In a further embodiment, the present disclosure provides a method for reducing the risk of thrombus formation in a patient undergoing angioplasty or coronary artery bypass surgery, or in a patient suffering from atrial fibrillation, comprising administering a composition comprising a PGI2 receptor agonist as disclosed herein, if such a risk is present in the patient.

[0186] Atherosclerosis Atherosclerosis is a complex disease characterized by inflammation, lipid accumulation, cell death, and fibrosis. It is the leading cause of mortality in many countries, including the United States. Atherosclerosis, as the term is used herein, is understood to include disorders of large and medium-sized arteries that result in the progressive accumulation of smooth muscle cells and lipids within the intima.

[0187] It has been shown that agonists of the PGI2 receptor can provide protection from atherosclerosis, including from atherothrombosis. (Arehart et al., Curr. Med. Chem., 2007, 14:2161-2169; Stitham et al., Prostaglandins Other Lipid Mediat., 2007, 82:95-108; Fries et al., Hematology Am. Soc. Hematol. Educ. Program, 2005, :445-451; Egan et al., Science, 2004, 306:1954-1957; Kobayashi et al., J. Clin. Invest., 2004, 114:784-794; Arehart et al., Circ. Res., 2008 Mar. 6, epub ahead of print.)

[0188] It has been shown that defective PGI2 receptor signaling appears to promote atherothrombosis in humans; that is, agonists of the PGI2 receptor can confer protection from atherothrombosis in humans (Arehart et al., Circ. Res., 2008 Mar. 6, epub ahead of print).

[0189] The compounds of the present disclosure may be useful for treating atherosclerosis and treating its symptoms.Thus, in some embodiments, the present disclosure provides a method for treating atherosclerosis in a patient who needs treatment, comprising administering to the patient a composition comprising the PGI2 receptor agonist disclosed herein.In further embodiments, a method is provided for treating the symptoms of atherosclerosis in a patient who needs treatment, comprising administering to the patient a composition comprising the PGI2 receptor agonist disclosed herein.

[0190] asthma Asthma is a lymphocyte-mediated inflammatory airway disorder characterized by airway eosinophilia, increased mucus production by goblet cells, and structural remodeling of the airway wall. The prevalence of asthma has dramatically increased worldwide in the past few decades. Genetic deletion of the PGI2 receptor in mice has been shown to increase allergic airway inflammation (Takahashi et al., Br J Pharmacol, 2002, 137:315-322). It has been shown that agonists of the PGI2 receptor can suppress not only the progression of asthma when administered during the sensitization phase, but also the cardinal features of experimental asthma when administered during the elicitation phase, at least in part by significantly interfering with the function of antigen-presenting dendritic cells in the airways (Idzko et al., J. Clin. Invest., 2007, 117:464-472; Thou et al., 2007, 178:702-710; Jaffar et al., J. Immunol., 2007, 179:6193-6203; Jozefowski et al., Int. Immunopharmacol., 2003, 3:865-878). Cell Mol. Biol., 2003, 29:314-320). These cells are important in both the initiation and maintenance phases of allergic asthma, since depletion of airway dendritic cells during secondary challenge in sensitized mice abolishes all asthmatic characteristics, an effect that can be fully restored by adoptive transfer of wild-type dendritic cells. It has also been shown that agonists of PGI2 receptors can inhibit inflammatory cytokine secretion by human alveolar macrophages (Raychaudhuri et al., J. Biol. Chem., 2002, 277:33344-33348). The compounds of the present disclosure may be useful for treating asthma and treating its symptoms.Thus, in some embodiments, the present disclosure provides a method for treating asthma in a patient in need of treatment, comprising administering to the patient a composition comprising a PGI2 receptor agonist as disclosed herein.In a further embodiment, a method is provided for treating the asthma symptoms in a patient in need of treatment, comprising administering to the patient a composition comprising a PGI2 receptor agonist as disclosed herein.

[0191] Diabetes-related pathology Although hyperglycemia is a major contributor to the pathogenesis of diabetic complications such as diabetic peripheral neuropathy (DPN), diabetic nephropathy (DN), and diabetic retinopathy (DR), enhanced vasoconstriction and platelet aggregation in diabetic patients have also been implicated as playing a role in disease progression (Cameron et al., Naunyn Schmiedebergs Arch. Pharmacol., 2003, 367:607-614). Agonists of the PGI2 receptor promote vasodilation and inhibit platelet aggregation. Improvement of microvascular blood flow can benefit diabetic complications (Cameron, Diabetologia, 2001, 44:1973-1988).

[0192] It has been shown that agonists of the PGI2 receptor can prevent and reverse motor and sensory peripheral nerve conduction abnormalities in streptozotocin-diabetic rats (Cotter et Naunyn Schmiedebergs Arch. Pharmacol., 1993, 347:534-540). Further evidence for the beneficial effects of PGI2 receptor agonists in the treatment of diabetic peripheral neuropathy has been provided by Hotta et al. (Diabetes, 1996, 45:361-366), Ueno et al. (Jpn. J. Pharmacol., 1996, 70:177-182), Ueno et al. (Life Sci., 1996, 59:PL105-PL110), Hotta et al. (Prostaglandins, 1995, 49:339-349), Shindo et al. (Prostaglandins, 1991, 41:85-96), Okuda et al. (Prostaglandins, 1996, 52:375-384), and Koike et al. (FASEB J., 2003, 17:779-781). Evidence for the beneficial effect of PGI2 receptor agonists in the treatment of diabetic nephropathy is provided by Owada et al. (Nephron, 2002, 92:788-796) and Yamashita et al. (Diabetes Res. Clin. Pract., 2002, 57:149-161). Evidence for the beneficial effect of PGI2 receptor agonists in the treatment of diabetic retinopathy is provided by Yamagishi et al. (Mol. Med., 2002, 8:546-550), Burnette et al. (Exp. Eye Res., 2006, 83:1359-1365), and Hotta et al. (Diabetes, 1996, 45:361-366).It has been shown that PGI2 receptor agonists can reduce increased tumor necrosis factor-α (TNF-α) levels in diabetic patients, suggesting that PGI2 receptor agonists may contribute to preventing the progression of diabetic complications (Fujiwara et al., Exp. Clin. Endocrinol. Diabetes, 2004, 112:390-394).

[0193] Glaucoma Evidence that topical administration of a PGI2 receptor agonist could reduce intraocular pressure (IOP) in rabbits and dogs and thus have beneficial effects in the treatment of glaucoma was provided by Hoyng et al. (Hoyng et al., Invest. Ophthalmol. Vis. Sci., 1987, 28:470-476).

[0194] Hypertension Agonists of PGI2 receptors have been shown to have activity in regulating vascular tone, vasodilation, and improving pulmonary hypertension (see, for example, Strauss et al., Clin Chest Med, 2007, 28:127-142; Driscoll et al., Expert Opin. Pharmacother., 2008, 9:65-81). Evidence for the beneficial effect of agonists of PGI2 receptors in treating hypertension is provided by Yamada et al. (Peptides, 2008, 29:412-418). Evidence that agonists of PGI2 receptors prevent cerebral ischemia is provided by Dogan et al. (Gen. Pharmacol., 1996, 27:1163-1166) and Fang et al. (J. Cereb. Blood Flow Metab., 2006, 26:491-501).

[0195] anti-inflammatory therapy Anti-inflammatory drugs are prescribed for various diseases. For example, in inflammatory diseases, they are used to interfere with the harmful effects that cause them, thereby reducing their harmful effects. There is evidence that PGI2 receptor agonists can inhibit inflammation and therefore can be a promising treatment as anti-inflammatory therapy. It has been shown that agonists of the PGI2 receptor can inhibit the production of proinflammatory cytokines and chemokines (interleukin 12 (IL-12), tumor necrosis factor-α (TNF-α), IL-1α, IL-6, macrophage inflammatory protein-1α (MIP-1α), monocyte chemotactic protein-1 (MCP-1)) and the T cell stimulatory function of dendritic cells (Jozefowski et al., Int. Immunopharmacol., 2003, 865-878; Thou et al., J. Immunol., 2007, 178:702-710; Nagao et al., Am. J. Respir. Cell Mol. Biol., 2003, 29:314-320; Idzko et al., J. Clin. Invest., 2007, 117:464-472). It has been shown that agonists of the PGI2 receptor can inhibit the production of proinflammatory cytokines (TNF-α, IL-1β, IL-6, granulocyte-macrophage stimulating factor (GM-CSF)) by macrophages (Raychaudhuri et al., J. Biol. Chem., 2002, 277:33344-33348; Czeslick et al., Eur. J. Clin. Invest., 2003, 33:1013-1017; Di Renzo et al., Prostaglandin Leukot. Essent. Fatty Acids, 2005, 73:405-410; Shinomiya et al., Biochem. Pharmacol., 2001, 61:1153-1160).It has been shown that agonists of the PGI2 receptor can stimulate the production of anti-inflammatory cytokines (IL-10) by dendritic cells (Jozefowski et al., Int. Immunopharmacol., 2003, 865-878; Zhou et al., J. Immunol., 2007, 178:702-710). It has been shown that agonists of the PGI2 receptor can stimulate the production of anti-inflammatory cytokines (IL-10) by macrophages (Shinomiya et al., Biochem. Pharmacol., 2001, 61:1153-1160). It has been shown that agonists of the PGI2 receptor can inhibit chemokine (CCL17)-induced chemotaxis of leukocytes (CD4+Th2 T cells) (Jaffar et al., J. Immunol., 2007, 179:6193-6203). It has been shown that agonists of the PGI2 receptor can provide protection from atherosclerosis, such as from atherothrombosis. (Arehart et al., Curr. Med. Chem., 2007, 14:2161-2169; Stitham et al., Prostaglandins Other Lipid Mediat., 2007, 82:95-108; Fries et al., Hematology Am. Soc. Hematol. Educ. Program, 2005, :445-451; Egan et al., Science, 2004, 306:1954-1957; Kobayashi et al., J. Clin. Invest., 2004, 114:784-794; Arehart et al., Circ. Res., 2008 Mar. 6, electronic publication ahead of print.It has been shown that agonists of the PGI2 receptor can attenuate asthma (Idzko et al., J. Clin. Invest., 2007, 117:464-472; Jaffar et al., J. Immunol., 2007, 179:6193-6203; Nagao et al., Am. J. Respir. Cell. Mol. Biol., 2003, 29:314-320). It has been shown that agonists of the PGI2 receptor can reduce TNF-α production in type 2 diabetes patients (Fujiwara et al., Exp. Clin. Endocrinol. Diabetes, 2004, 112:390-394; Goya et al., Metabolism, 2003, 52:192-198). It has been shown that PGI2 receptor agonists can inhibit ischemia-reperfusion injury (Xiao et al., Circulation, 2001, 104:2210-2215). It has been shown that PGI2 receptor agonists can inhibit restenosis (Cheng et al., Science, 2002, 296:539-541). It has been shown that PGI2 receptor agonists can attenuate pulmonary vascular injury and shock in a rat model of septic shock (Harada et al., Shock, 2008 Feb. 21, epub). It has been shown that PGI2 receptor agonists can reduce blood levels of TNF-α in vivo in patients with rheumatoid arthritis, which is associated with improvements in the clinical course of the disease (Gao et al., Rheumatol. Int., 2002, 22:45-51; Boehme et al., Rheumatol. Int., 2006, 26:340-347).

[0196] The compounds of the present disclosure can provide a beneficial reduction in inflammation. The compounds of the present disclosure can provide a beneficial reduction in the harmful inflammatory response associated with inflammatory disease. Thus, in some embodiments, the present disclosure provides a method for reducing inflammation in a patient in need of a reduction in inflammation, comprising administering to the patient a composition comprising a PGI2 receptor agonist as disclosed herein. In some embodiments, the present disclosure provides a method for reducing the production of IL-12, TNF-α, IL-1α, IL-1β, IL-6, MIP-1α, MCP-1 in a patient in need of a reduction, comprising administering to the patient a composition comprising a PGI2 receptor agonist as disclosed herein. In some embodiments, the present disclosure provides a method for reducing TNF-α in a patient in need of a reduction in TNF-α, comprising administering to the patient a composition comprising a PGI2 receptor agonist as disclosed herein. In some embodiments, the present disclosure provides a method for increasing IL-10 in a patient in need of increasing IL-10, comprising administering to the patient a composition comprising a PGI2 receptor agonist as disclosed herein. In some embodiments, the present disclosure provides a method for reducing an adverse inflammatory response associated with an inflammatory disease in a patient in need of reduction, comprising administering to the patient a composition comprising a PGI2 receptor agonist as disclosed herein. In some embodiments, the present disclosure provides a method for treating an inflammatory disease or a symptom thereof in a patient in need of treatment, comprising administering to the patient a composition comprising a PGI2 receptor agonist as disclosed herein. In some embodiments, the present disclosure provides a method for treating an inflammatory disease or a symptom thereof in a patient in need of treatment, comprising administering to the patient a composition comprising a PGI2 receptor agonist as disclosed herein.In some embodiments, the present disclosure provides a method for treating an inflammatory disease or a symptom thereof in a patient in need of treatment, comprising administering to the patient a composition comprising a PGI2 receptor agonist disclosed herein, wherein the inflammatory disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus (SLE), ulcerative colitis, ischemia-reperfusion injury, restenosis, atherosclerosis, acne, diabetes (including type 1 diabetes and type 2 diabetes), sepsis, chronic obstructive pulmonary disease (COPD), and asthma.

[0197] In one aspect, a method for treating a disease or condition associated with PGI2 receptor is described herein. In some embodiments, the disease or condition is PAH. In some embodiments, the disease or condition is pulmonary arterial hypertension (PAH); idiopathic PAH, familial PAH, collagen vascular disease, congenital heart disease, portal hypertension, HIV infection, drug or toxin intake, hereditary hemorrhagic telangiectasia, splenectomy, pulmonary veno-occlusive disease (PVOD), or PAH associated with pulmonary capillary hemangiomatosis (PCH), PAH with significant venous or capillary involvement, platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina pectoris, stroke, ischemia-reperfusion injury, restenosis, atrial fibrillation, angioplasty or coronary artery bypass surgery, or atrial fibrillation. The disease is selected from thrombus formation in individuals with fibrillation, atherosclerosis, atherothrombosis, asthma or symptoms thereof, diabetes-related disorders such as diabetic peripheral neuropathy, diabetic nephropathy, or diabetic retinopathy, glaucoma or other eye diseases with abnormal intraocular pressure, hypertension, inflammation, psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus (SLE), ulcerative colitis, ischemia-reperfusion injury, restenosis, atherosclerosis, acne, type 1 diabetes, type 2 diabetes, sepsis, and chronic obstructive pulmonary disorder (COPD).

[0198] Disclosed herein is a method of treating pulmonary arterial hypertension (PAH) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein.

[0199] The methods described herein can be administered to a subject with any suitable condition known to one of skill in the art. In some embodiments, the subject has one or more symptoms of World Health Organization (WHO) / New York Heart Association (NYHA) Functional Classification (FC) II-III. In some embodiments, the symptoms include, but are not limited to, slight limitation of physical activity (comfortable at rest) and / or normal physical activity causing excessive dyspnea or fatigue, chest pain, or near syncope. In some embodiments, the symptoms include, but are not limited to, severe limitation of physical activity (comfortable at rest) and / or normal activity causing excessive dyspnea or fatigue, chest pain, or near syncope.

[0200] Pulmonary arterial hypertension (PAH) can be any pulmonary arterial hypertension known to those skilled in the art.In some embodiments, PAH is selected from idiopathic PAH, familial PAH, scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis associated with collagen vascular disease, PAH in individual selected from atrial septal defect (ASD), ventricular septal defect (VSD) and patent ductus arteriosus associated with congenital heart disease, PAH in individual associated with portal hypertension, PAH in individual associated with HIV infection, PAH in individual associated with drug or toxin intake, PAH in individual associated with hereditary hemorrhagic telangiectasia, PAH in individual associated with splenectomy, PAH in individual associated with venous or capillary involvement, PAH in individual associated with pulmonary veno-occlusive disease (PVOD) and PAH in individual associated with pulmonary capillary hemangiomatosis (PCH). In some embodiments, the PAH is hereditary pulmonary arterial hypertension (HPAH), familial PAH, simple PAH, or familial primary pulmonary hypertension. In some embodiments, the PAH is familial primary pulmonary hypertension.

[0201] In one aspect, disclosed herein is a method of modulating a prostacyclin (PGI2) receptor in a subject in need of such modulation, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein.

[0202] In one aspect, disclosed herein is a method of treating a disease or condition associated with the prostacyclin (PGI2) receptor in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein.

[0203] The disease or condition associated with the PGI2 receptor may be any disease known to those skilled in the art. In some embodiments, the disease or condition is selected from inflammatory diseases. In some embodiments, the disease or condition is selected from allergic inflammation, cytokine-mediated inflammation, emphysema, fibrosis, angina, infarction, myocardial infarction, pulmonary arterial hypertension (PAH), pulmonary hypertension, hypertension, connective tissue disease, vascular disease, cardiovascular disease, pulmonary disease, and respiratory disease. In some embodiments, the disease or condition is selected from angina, infarction, myocardial infarction, pulmonary arterial hypertension (PAH), pulmonary hypertension, hypertension, connective tissue disease, vascular disease, cardiovascular disease, pulmonary disease, and respiratory disease. In some embodiments, the disease or condition is selected from pulmonary arterial hypertension (PAH), pulmonary hypertension, hypertension, connective tissue disease, vascular disease, cardiovascular disease, pulmonary disease, and respiratory disease. In some embodiments, the disease or condition is selected from pulmonary arterial hypertension (PAH), pulmonary hypertension, hypertension, connective tissue disease, vascular disease, cardiovascular disease, pulmonary disease, and respiratory disease. In some embodiments, the disease or condition is selected from pulmonary arterial hypertension (PAH), pulmonary hypertension, hypertension, connective tissue disease, vascular disease, cardiovascular disease, pulmonary disease, and respiratory disease.

[0204] The compounds administered in the methods described herein can be administered by any suitable method known to one of skill in the art, hi some embodiments, the compounds are administered via a titration scheme.

[0205] In some embodiments, the compound is administered once a day. In some embodiments, the compound is administered twice a day. In some embodiments, the compound is administered in an amount described herein. In some embodiments, the compound is administered in an amount of about 0.01 mg to about 10 mg per day. In some embodiments, the compound is administered in an amount of about 0.01 mg to about 5 mg per day. In some embodiments, the compound is administered in an amount of about 0.01 mg to about 2 mg per day. In some embodiments, the compound is administered in an amount of about 0.05 mg to about 1.5 mg per day. In some embodiments, the compound is administered in an amount of about 0.05 mg to about 1.2 mg per day.

[0206] In one aspect, disclosed herein is the use of a compound disclosed herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein, in the manufacture of a medicament for the treatment of pulmonary arterial hypertension (PAH).

[0207] dosage In certain embodiments, the compositions containing the compounds described herein are administered for therapeutic treatment. In certain therapeutic applications, the compositions are administered to patients who already suffer from a disease or illness in an amount sufficient to cure or at least partially prevent at least one of the symptoms of the disease or illness. The amount effective for this use depends on the severity and course of the disease or illness, previous treatments, the patient's health status, weight, and response to drugs, and the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation and / or dose-finding clinical trials.

[0208] In certain embodiments where the patient's condition does not improve, at the physician's discretion, administration of the compound may be administered chronically, i.e., for an extended period of time, including the patient's lifetime, to ameliorate or otherwise control or limit the symptoms of the patient's disease or disorder.

[0209] In certain embodiments where the patient's condition improves, the dosage of the administered drug is temporarily reduced or stopped for a period of time (ie, a "drug holiday").

[0210] Once improvement of the patient's condition occurs, a maintenance dose is administered as necessary. Thereafter, in certain embodiments, the dosage or frequency of administration, or both, are reduced as a function of symptoms.

[0211] The amount of a given agent that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity (e.g., weight, sex) of the subject or host requiring treatment, but may nevertheless be determined according to the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the disease being treated, and the subject or host being treated.

[0212] In some embodiments, the dosage utilized for adult treatment typically ranges from 0.01 mg to 5000 mg per day. In some embodiments, a suitable daily dosage of a compound described herein, or a pharma- ceutically acceptable salt thereof, is about 0.01 to about 50 mg / kg of body weight. In various embodiments, the daily dosage and unit dosage will vary depending on many variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the medical practitioner.

[0213] The dosage when using the compounds of the present disclosure may vary within a wide range and, as is customary and known to the physician, is adapted to the individual conditions in each individual case. The dosage depends, for example, on the nature and severity of the disease to be treated, the condition of the patient, the compound utilized, or whether an acute or chronic disease state is treated or a prophylactic treatment is performed, or whether an additional active compound is administered in addition to the compounds of the present disclosure. Representative dosages of the present disclosure include, but are not limited to, about 0.001 mg to about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about 1000 mg, 0.001 mg to about 500 mg, 0.001 mg to about 250 mg, about 0.001 mg to 100 mg, about 0.001 mg to about 50 mg, and about 0.001 mg to about 25 mg. Multiple doses, for example, 2, 3, or 4 doses, may be administered during the day, especially when a relatively large amount is deemed necessary. Depending on the individual, and as deemed appropriate by the patient's physician or caregiver, it may be necessary to deviate upwards or downwards from the doses set forth herein.

[0214] The amount of active ingredient or its active salt or derivative required for use in treatment varies depending on the specific salt selected, as well as the route of administration, the characteristics of the disease being treated, and the age and condition of the patient, and is ultimately at the discretion of the attending physician or clinician. Generally, those skilled in the art understand how to extrapolate in vivo data obtained in a model system, typically an animal model, to another, such as a human. In some circumstances, these estimates may be based simply on the body weight of the animal model compared to another animal model, such as a mammal, preferably a human, but more often these estimates are not simply based on body weight, but rather incorporate a variety of factors. Representative factors include the type, age, body weight, sex, diet, and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations, such as the activity, efficacy, pharmacokinetics, and toxicology profile of the particular compound being utilized, whether a drug delivery system is utilized, whether an acute or chronic disease state is being treated or a prophylactic treatment is being performed, or whether additional active compounds are administered in addition to the compounds of the present disclosure and as part of a combined formulation. The dosage regimen for treating disease state with the compound and / or composition of the present disclosure is selected according to various factors as cited above.Accordingly, the dosage regimen that is actually utilized may vary widely and therefore may deviate from the preferred dosage regimen, and those skilled in the art understand that dosages and dosage regimens that are beyond these typical ranges may be tested and, if appropriate, may be used in the method of the present disclosure.

[0215] The desired dosage may be presented as a single dose or as a divided dose administered at appropriate intervals, for example, 2, 3, or 4 or more doses per day.The sub-dose itself may be further divided, for example, into several separate loosely spaced administrations.The daily dose may be divided into several, for example, 2, 3, or 4 administrations, especially when a relatively large amount is considered appropriate.In appropriate cases, depending on individual behavior, it may be necessary to deviate upwards or downwards from the daily dose indicated.

[0216] The compounds of the present disclosure can be administered in a wide variety of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the following dosage forms may contain, as the active ingredient, either a compound of the present disclosure or a pharma- ceutically acceptable salt, solvate or hydrate of a compound of the present disclosure.

[0217] In certain embodiments, compositions containing the compounds and solid forms described herein are administered for preventive and / or therapeutic treatment. In certain therapeutic applications, the compositions are administered to patients already suffering from a disease or condition in an amount sufficient to cure or at least partially prevent at least one of the symptoms of the disease or condition. The amount effective for this use depends on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and / or dose-finding clinical trials.

[0218] The amount of a given agent that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity (e.g., weight, sex) of the subject or host requiring treatment, but may nevertheless be determined according to the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the disease being treated, and the subject or host being treated.

[0219] However, the doses typically utilized for adult treatment typically range from 0.01 mg to 0.6 mg per day. In one embodiment, the desired dose is suitably presented as a single dose or divided doses administered simultaneously or at appropriate intervals, for example, two or more subdoses per day. In some embodiments, the daily dose or amount of active ingredient in the dosage form will be less than or greater than the ranges set forth herein, based on many variables related to the individual treatment regimen. In various embodiments, the daily dose and unit dose will vary depending on many variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the medical practitioner.

[0220] In any of the foregoing aspects, in a further embodiment, an effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is (a) administered systemically to the mammal, and / or (b) administered orally to the mammal.

[0221] In some embodiments, a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered at a dose of about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg, about 0.12 mg, about 0.13 mg, about 0.14 mg, about 0.15 mg, about 0.17 mg, about 0.18 mg, about 0.19 mg, about 0.2 mg, about 0.21 mg, about 0.22 mg, about 0.23 mg, about 0.24 mg, about 0.25 mg, about 0.26 mg, about 0.27 mg, about 0.28 mg, about 0.29 mg, about 0.3 mg, about 0.31 mg, about 0.32 mg, about 0.33 mg, about 0.34 mg, about 0.35 mg, about 0.36 mg, about 0.37 mg, about 0.38 mg, about 0.39 mg, about 10 ... g, approx. 0.34mg, approx. 0.35mg, approx. 0.36mg, approx. 0.37mg, approx. 0.38mg, approx. 0.39mg, approx. 0.4mg, approx. 0.41mg, approx. 0.42m g, about 0.43mg, about 0.44mg, about 0.45mg, about 0.46mg, about 0.47mg, about 0.48mg, about 0.49mg, about 0.5mg, about 0.51mg , about 0.52 mg, about 0.53 mg, about 0.54 mg, about 0.55 mg, about 0.56 mg, about 0.57 mg, about 0.58 mg, about 0.59 mg, about 0.6 mg, about 0.8 mg, about 1.0 mg, about 1.2 mg, about 1.4 mg, about 1.6 mg, about 1.8 mg, about 2.0 mg, about 2.5 mg, or about 3 mg.In some embodiments, a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered at a concentration of about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg, about 0.12 mg, about 0.13 mg, about 0.14 mg, about 0.15 mg, about 0.16 mg, about 0.17 mg, about 0.18 mg, about 0.19 mg, about 0.2 mg, about 0.21 mg, about 0.22 mg, about 0.23 mg, about 0.24 mg, about 0.25 mg, about 0.26 mg, about 0.27 mg, about 0.28 mg, about 0.29 mg, about 0.3 mg, about 0.31 mg, about 0.32 mg, about 0.33 mg , about 0.34 mg, about 0.35 mg, about 0.36 mg, about 0.37 mg, about 0.38 mg, about 0.39 mg, about 0.4 mg, about 0.41 mg, about 0.42 mg, about 0.43 mg, about 0.44 mg, about 0.45 mg, about 0.46 mg, about 0.47 mg, about 0.48 mg, about 0.49 mg, about 0.5 mg, about 0.51 mg, about 0.5 The dose is administered at a dose equivalent to about 2 mg, about 0.53 mg, about 0.54 mg, about 0.55 mg, about 0.56 mg, about 0.57 mg, about 0.58 mg, about 0.59 mg, about 0.6 mg, about 0.8 mg, about 1.0 mg, about 1.2 mg, about 1.4 mg, about 1.6 mg, about 1.8 mg, about 2.0 mg, about 2.5 mg, or about 3 mg of the compound. In some embodiments, the dose is administered once a day. In some embodiments, the dose is administered twice a day.

[0222] In some embodiments, a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered at a dose of about 0.1 mg, about 0.12 mg, about 0.13 mg, about 0.14 mg, about 0.15 mg, about 0.16 mg, about 0.17 mg, about 0.18 mg, about 0.19 mg, about 0.2 mg, about 0.3 mg, about 0.40 mg, about 0.42 mg, about 0.45 mg, about 0.48 mg, about 0.5 mg, about 0.53 mg, about 0.55 mg, about 0.58 mg, about 0.6 mg, about 0.8 mg, about 1.0 mg, about 1.2 mg, about 1.4 mg, about 1.6 mg, about 1.8 mg, about 2.0 mg, about 2.5 mg, or about 3 mg. In some embodiments, a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered at a dose equivalent to about 0.1 mg, about 0.12 mg, about 0.13 mg, about 0.14 mg, about 0.15 mg, about 0.16 mg, about 0.17 mg, about 0.18 mg, about 0.19 mg, about 0.2 mg, about 0.3 mg, about 0.40 mg, about 0.42 mg, about 0.45 mg, about 0.48 mg, about 0.5 mg, about 0.53 mg, about 0.55 mg, about 0.58 mg, about 0.6 mg, about 0.8 mg, about 1.0 mg, about 1.2 mg, about 1.4 mg, about 1.6 mg, about 1.8 mg, about 2.0 mg, about 2.5 mg, or about 3 mg of the compound. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered at a dose of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 1.0 mg, about 1.2 mg, about 1.4 mg, about 1.6 mg, about 1.8 mg, or about 2.0 mg. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered at a dose equivalent to about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 1.0 mg, about 1.2 mg, about 1.4 mg, about 1.6 mg, about 1.8 mg, or about 2.0 mg of the compound. In some embodiments, the dose is administered once a day. In some embodiments, the dose is administered twice a day.

[0223] In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered at 0.05 mg per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered at 0.10 mg per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered at 0.15 mg per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered at 0.20 mg per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered at 0.25 mg per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered at 0.30 mg per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered at 0.35 mg per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered at 0.40 mg per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered at 0.45 mg per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered at 0.5 mg per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered at 0.55 mg per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered at 0.60 mg per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered at 0.65 mg per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered at 0.70 mg per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered at 0.75 mg per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered at 0.80 mg per day.In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is administered at 0.85 mg per day. In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is administered at 0.9 mg per day. In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is administered at 0.95 mg per day. In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is administered at 1 mg per day.

[0224] In some embodiments, a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered at 0.05 mg per day, 0.10 mg per day, 0.15 mg per day, 0.20 mg per day, 0.25 mg per day, 0.30 mg per day, 0.35 mg per day, 0.40 mg per day, 0.45 mg per day, 0.5 mg per day, 0.55 mg per day, 0.60 mg per day, 0.65 mg per day, 0.70 mg per day, 0.75 mg per day, 0.80 mg per day, 0.85 mg per day, 0.9 mg per day, 0.95 mg per day, 1 mg per day, 1.2 mg per day, 1.5 mg per day, 2.0 mg per day, 2.5 mg per day, or 3.0 mg per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered at 0.5 mg per day, 0.55 mg per day, 0.60 mg per day, 0.65 mg per day, 0.70 mg per day, 0.75 mg per day, 0.80 mg per day, 0.85 mg per day, 0.9 mg per day, 0.95 mg per day, 1 mg per day, 1.2 mg per day, 1.5 mg per day, 2.0 mg per day, 2.5 mg per day, or 3.0 mg per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered at 0.9 mg per day, 0.95 mg per day, 1 mg per day, 1.2 mg per day, 1.5 mg per day, 2.0 mg per day, 2.5 mg per day, or 3.0 mg per day.

[0225] In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered in an amount equivalent to 0.05 mg of the compound per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered in an amount equivalent to 0.1 mg of the compound per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered in an amount equivalent to 0.15 mg of the compound per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered in an amount equivalent to 0.2 mg of the compound per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered in an amount equivalent to 0.25 mg of the compound per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered in an amount equivalent to 0.3 mg of the compound per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered in an amount equivalent to 0.35 mg of the compound per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered in an amount equivalent to 0.4 mg of the compound per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered in an amount equivalent to 0.45 mg of the compound per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered in an amount equivalent to 0.5 mg of the compound per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered in an amount equivalent to 0.55 mg of the compound per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered in an amount equivalent to 0.6 mg of the compound per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered in an amount equivalent to 0.65 mg of the compound per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered in an amount equivalent to 0.7 mg of the compound per day.In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered in an amount equivalent to 0.75 mg of the compound per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered in an amount equivalent to 0.8 mg of the compound per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered in an amount equivalent to 0.85 mg of the compound per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered in an amount equivalent to 0.9 mg of the compound per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered in an amount equivalent to 0.95 mg of the compound per day. In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is administered in an amount equivalent to 0.1 mg of the compound per day.

[0226] In some embodiments, the dose is administered once daily. In some embodiments, the dose is administered twice daily.

[0227] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is administered once a day. In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is administered twice a day. In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is administered once or twice a week. In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is administered every other day.

[0228] Route of administration Suitable routes of administration include, but are not limited to, oral, intravenous, aerosol, parenteral, pulmonary, mucosal, transdermal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, and intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, and intranasal injections.

[0229] In some embodiments, the compounds of the present disclosure are administered orally once daily. In some embodiments, the compounds of the present disclosure are administered orally twice daily.

[0230] In certain embodiments, compounds as described herein are administered locally rather than systemically, often in a depot or sustained release formulation, for example by injection of the compound directly into an organ. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Furthermore, in other embodiments, drugs are delivered in targeted drug delivery systems, for example in liposomes coated with organ-specific antibodies. In such embodiments, the liposomes are targeted to and selectively absorbed by the organ. In still other embodiments, compounds as described herein are provided in the form of immediate release formulations, extended release formulations, or intermediate release formulations.

[0231] For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension, or liquid. The pharmaceutical composition is suitably made in the form of a dosage unit containing a specific amount of active ingredient. Examples of such dosage units are capsules, tablets, powders, granules, or suspensions with conventional additives such as lactose, mannitol, corn starch, or potato starch, binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch, or gelatin, disintegrants such as corn starch, potato starch, or sodium carboxymethylcellulose, and lubricants such as talc or magnesium stearate. The active ingredient may be administered by injection as a composition, and for example, saline, dextrose, or water may be used as a suitable pharma- ceutically acceptable carrier.

[0232] The formulations may be prepared by any suitable method, typically by uniformly admixing the active compound with liquid or finely divided solid carriers, or both, in the required proportions and then, if necessary, shaping the resulting mixture into the desired form.

[0233] Conventional excipients such as binders, fillers, acceptable wetting agents, tableting lubricants, and disintegrants may be used in tablets and capsules for oral administration. Liquid preparations for oral administration may be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups. Alternatively, oral preparations may be in the form of dry powders that can be reconstituted with water or another suitable liquid vehicle before use. Further additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives, and flavoring and coloring agents may be added to liquid preparations. Parenteral dosage forms may be prepared by dissolving the compounds of the present disclosure in a suitable liquid vehicle, filtering and sterilizing the solution, and then sealing the solution in a suitable vial or ampoule. These are just a few examples of the many suitable methods well known in the art for preparing dosage forms.

[0234] Pharmaceutical formulations include those suitable for oral, topical (including buccal, sublingual), or parenteral (including intramuscular, subcutaneous, and intravenous) administration, or in a form suitable for administration by inhalation, insufflation, or a transdermal patch.

[0235] Thus, the compounds of the present disclosure, together with conventional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical preparations and unit dosages thereof, which may be utilized as solids, such as tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, gels, or capsules filled therewith, all for oral use, as suppositories for rectal administration, or as sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may contain conventional ingredients in conventional proportions, with or without additional active compounds or ingredients, and such unit dosage forms may contain any suitable effective amount of the active ingredients depending on the intended daily dose range to be used.

[0236] Pharmaceutical Compositions / Formulations Described herein is a pharmaceutical composition comprising the compound described herein or its pharmaceutically acceptable salt or solvate and a pharmaceutically acceptable carrier or excipient.In some embodiments, the pharmaceutical composition is a solid dosage form.In some embodiments, the pharmaceutical composition is a tablet or capsule.

[0237] The compounds described herein are administered to a subject in need thereof in a pharmaceutical composition, either alone or in combination with a pharma- ceutically acceptable carrier, excipient, or diluent, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to an animal.

[0238] In another aspect, provided herein is a pharmaceutical composition comprising the compound described herein or its pharmaceutically acceptable salt, solvate or stereoisomer and at least one pharmaceutically acceptable excipient.The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of active compound into a preparation that can be used pharmaceutically.The suitable formulation depends on the route of administration selected. Summaries of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995), Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for their disclosure.

[0239] In some embodiments, the pharma- ceutically acceptable excipient is selected from carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, humectants, plasticizers, stabilizers, permeation enhancers, wetting agents, antifoaming agents, antioxidants, preservatives, and any combination thereof.

[0240] Pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast dissolve formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and combined immediate and controlled release formulations.

[0241] To prepare pharmaceutical compositions from the compounds of the present disclosure, the selection of suitable pharma- ceutical acceptable carriers can be either solid, liquid, or a mixture of both.Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.Solid carriers can be one or more substances, and can also act as diluents, flavorings, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials.

[0242] In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.

[0243] In tablets, the active ingredient is mixed with a carrier having the necessary binding capacity in suitable proportions and compressed into the desired shape and size. Powders and tablets may contain various percentage amounts of the active compound. A typical amount in a powder or tablet may contain 0.5 to about 90% of the active compound, although one skilled in the art will know when amounts outside this range are required. Suitable carriers for powders and tablets are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter, and the like. The term "preparation" is intended to include formulations of the active compound with an encapsulating material as a carrier to provide a capsule in which the active ingredient is surrounded by the carrier with or without a carrier, thereby associating with the carrier. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges may be used as solid forms suitable for oral administration.

[0244] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, liquid preparations for parenteral injection can be formulated as solutions in aqueous polyethylene glycol solution. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be utilized are water, Ringer's solution, and isotonic saline. In addition, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any sterile, bland, fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0245] Thus, the compounds according to the present disclosure may be formulated for parenteral administration (e.g., injection, e.g., bolus injection or continuous infusion), and may be provided in unit dose form in ampoules, prefilled syringes, small injections, or in multi-dose containers with added preservatives.The pharmaceutical compositions may take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, and / or dispersing agents.Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, to be constituted with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0246] Aqueous preparations suitable for oral use can be prepared by dissolving or suspending the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired.

[0247] Aqueous suspensions suitable for oral use may be made by dispersing the finely divided active ingredient in water with adhesive materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.

[0248] Also included are solid preparations that are intended to be converted immediately before use into liquid preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0249] For topical administration to the epidermis, the compounds according to the disclosure may be formulated as ointments, creams or lotions, or as a transdermal patch.

[0250] The solution or suspension is directly applied to the nasal cavity by conventional means, for example, by dropper, pipette or sprayer.The formulation can be provided in single or multiple dose form.In the latter case of dropper or pipette, this can be achieved by the patient administering an appropriate predetermined volume of the solution or suspension.In the case of sprayer, this can be achieved, for example, by a metered atomizing spray pump.

[0251] Administration to the respiratory tract can also be achieved by aerosol formulations, in which the active ingredient is provided in a pressurized pack with a suitable propellant. When the compounds of the present disclosure or pharmaceutical compositions containing them are administered as aerosols, for example as nasal aerosols or by inhalation, they can be carried out, for example, using a nebulizer, nebulizer, pump nebulizer, inhalation device, metered dose inhaler, or dry powder inhaler. Pharmaceutical forms for administration of the compounds of the present disclosure as aerosols can be prepared by processes well known to those skilled in the art. For their preparation, for example, solutions or dispersions of the compounds of the present disclosure in water, water / alcohol mixtures, or suitable saline can be utilized using conventional additives, for example, benzyl alcohol or other suitable preservatives, absorption enhancers for increasing bioavailability, solubilizers, dispersants, etc., and where appropriate, include conventional propellants, for example, carbon dioxide, CFCs, for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, etc. The aerosol can further advantageously include a surfactant, such as lecithin. The dose of drug may be controlled by provision of a metered valve.

[0252] In the formulations intended for administration to the respiratory tract, including intranasal formulations, compound generally has a small particle size, for example, about 10 microns or less.Such a particle size can be obtained by means known in the art, for example, by micronization.If desired, the formulations adapted to give sustained release of active ingredient can be utilized.

[0253] Alternatively, the active ingredient can be provided in the form of a dry powder, for example, a powder mixture of the compound in a suitable powder base, such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose, and polyvinylpyrrolidone (PVP).The powder carrier conveniently forms a gel in the nasal cavity.The powder composition can be presented in unit dose form, for example, in gelatin capsules or cartridges, or blister packs, in which the powder can be administered by inhaler.

[0254] The pharmaceutical preparation is preferably in unit dosage form.In this form, the preparation is divided into unit doses containing appropriate amounts of active ingredients.The unit dosage form can be a packaged preparation, the package containing individual amounts of preparation, such as packaged tablets, capsules, and powders in vials or ampoules.The unit dosage form can also be a capsule, tablet, cachet, or lozenge itself, or any of these in the appropriate number of packaged form.

[0255] combination Disclosed herein are methods of treating a disease or disorder associated with pulmonary hypertension (PH), pulmonary vascular resistance (PVR), pulmonary arterial hypertension (PAH), pulmonary hypertension associated with interstitial lung disease (PH-ILD), or a combination thereof, using a compound disclosed herein, or a pharmacologic acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.

[0256] In some embodiments, the additional therapeutic agent is administered simultaneously with the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior to administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after administration of the compound disclosed herein. EXAMPLES

[0257] Example 1: Synthesis of Lalinepag n-butyl ester (2a)

[0258] [ka]

[0259] To a suspension of lalinepag acid (1) (0.21 g, 0.486 mmol) in n-butanol (5.0 mL) was added concentrated sulfuric acid (25 μL) at room temperature under argon. The resulting reaction mixture was heated at 80° C. under argon for 3 h. After 3 h, the reaction was found to be complete based on TLC. The solvent was removed under vacuum at 50° C., diluted with EtOAc (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give crude lalinepag n-butyl ester (2a) (0.31 g), which was purified by silica gel column chromatography. The combined fractions were evaporated under vacuum and dried under high vacuum to give pure lalinepag n-butyl ester (2a) (0.23 g) in 96.2% yield as a colorless viscous oil. The pure product was identified by IR, 1 It was characterized by H NMR, and LC-MS. The HPLC purity of the product was found to be 99.14% and was free of any traces of lalinepagic acid (1).

[0260] Example 2: Synthesis of Lalinepag n-dodecyl ester (2b)

[0261] [ka]

[0262] To a solution of lalinepagic acid (1) (0.214 g, 0.495 mmol) in anhydrous DMF (2.0 mL) was added 1-dodecanol (0.093 g, 0.499 mmol) followed by EDCI·HCl. (0.142 g, 0.741 mmol) and DMAP (0.181 g, 1.48 mmol) at room temperature under argon. The resulting reaction mixture was stirred overnight at room temperature under argon. After 22 h, the reaction was found to be complete based on TLC. The reaction mixture was diluted with EtOAc (15 mL), treated with saturated aqueous NH4Cl (15 mL), and the layers were separated. The organic layer was washed with saturated aqueous NH4Cl (10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give crude lalinepag n-dodecyl ester (2b) (0.18 g), which was purified by column chromatography. The combined fractions were evaporated under vacuum and dried under high vacuum to give pure lalinepag n-dodecyl ester (2b) (0.11 g) as a waxy solid in 35.7% yield. The pure product was identified by IR, 1 It was characterized by H NMR, and LC-MS. The HPLC purity of the product was found to be 96.68% and was free of any traces of lalinepagic acid (1).

[0263] Example 3: Synthesis of Lalinepag Cyclic Carbonate (2c)

[0264] [ka]

[0265] To a solution of lalinepag acid (1) (0.208 g, 0.48 mmol) in acetone (5.0 mL) was added a solution of 4-(iodomethyl)-5-methyl-1,3-dioxol-2-one (0.138 g, 0.58 mmol) in acetone (1.0 mL) followed by K2CO3 (0.200 g, 1.44 mmol) at room temperature under argon. The resulting reaction mixture was stirred overnight at room temperature under argon. After 23 h, the reaction was found to be complete based on TLC. The reaction mixture was filtered and concentrated under vacuum to give crude lalinepag cyclic carbonate (2c) (0.468 g), which was purified by silica gel column chromatography. The combined fractions were evaporated under vacuum and dried under high vacuum to give pure lalinepag cyclic carbonate (2c) (0.23 g) in 88.1% yield as a clear viscous oil. The pure product was identified by IR, 1 It was characterized by H NMR, and LC-MS. The HPLC purity of the product was found to be 96.29% and was free of any traces of larinepagic acid (1).

[0266] Example 4: Synthesis of Lalinepag n-Octyl Ester (4a)

[0267] [ka]

[0268] To a solution of lalinepag sodium salt (3) (0.251 g, 0.522 mmol) in anhydrous DMF (3.0 mL) was added cesium iodide (0.173 g, 0.666 mmol) followed by 1-bromooctane (0.19 mL, 1.103 mmol) at room temperature under argon. The resulting reaction mixture was brought to 60 °C for 3 h. After 3 h, the reaction was found to be complete based on TLC. The reaction mixture was cooled, diluted with EtOAc (20 mL), treated with saturated aqueous NH4Cl (20 mL), and the layers were separated. The organic layer was washed with saturated aqueous NH4Cl (10 mL), water (20 mL), brine (5 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give crude lalinepag n-octyl ester (4a) (0.90 g, combined with previous batch), which was purified by silica gel chromatography. The combined fractions were evaporated in vacuo and dried under high vacuum to give pure lalinepag n-octyl ester (4a) (0.21 g) in 49.8% yield as a viscous oil. The pure product was identified by IR, 1 It was characterized by H NMR, and LC-MS. The HPLC purity of the product was found to be 99.16% and was free of any traces of lalinepagic acid (1).

[0269] Example 5: Synthesis of Lalinepag Glycolic Acid tert-Butyl Ester (4b)

[0270] [ka]

[0271] To a solution of lalinepag sodium salt (3) (0.50 g, 1.10 mmol) in anhydrous DMF (10.0 mL) was added cesium iodide (0.34 g, 1.32 mmol) followed by tert-butyl bromoacetate (0.82 mL, 5.50 mmol) at room temperature under argon. The resulting reaction mixture was brought to 60° C. for 6 h. After 6 h, the reaction was found to be complete based on TLC. The reaction mixture was cooled, treated with saturated aqueous NH4Cl (30 mL), and extracted with EtOAc (3×30 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give crude lalinepag glycolic acid tert-butyl ester (4b) (5.3 g, combined with previous batch), which was purified by silica gel chromatography. The combined fractions were evaporated in vacuo and dried under high vacuum to give pure lalinepag glycolic acid tert-butyl ester (4b) (0.56 g) in 77.8% yield as a viscous oil. The pure product was identified by IR, 1 It was characterized by H NMR, and LC-MS. The HPLC purity of the product was found to be 99.17% and was free of any traces of larinepagic acid (1).

[0272] Example 6: Synthesis of Lalinepagmethanesulfonamide (6)

[0273] [ka]

[0274] To a stirred solution of larinepagic acid (1) (0.20 g, 0.46 mmol) in THF (3.0 mL) was added CDI (0.11 g, 0.69 mmol) in one portion at room temperature under argon. The resulting reaction mixture was stirred for 1 h and refluxed under argon for 1 h. The reaction mixture was cooled to room temperature and methanesulfonamide (0.13 g, 1.39 mmol) was added and stirred for 10 min. A solution of DBU (0.35 mL, 2.32 mmol) in THF (2.0 mL) was added slowly and stirred overnight at room temperature under argon. After 24 h, the reaction was found to be complete based on TLC. Completion of the reaction was confirmed by LCMS. The solvent was removed under vacuum and diluted with saturated aqueous NH4Cl (10 mL) and EtOAc (10 mL). The layers were separated and the organic layer was washed with water (2×10 mL), brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo to give crude lalinepag methanesulfonamide (6) (0.33 g). The crude material was purified by silica gel column chromatography. The combined fractions were evaporated in vacuo and dried under high vacuum to give pure lalinepag methanesulfonamide (6) (0.125 g) in 54.3% yield as a white solid. The melting point was found to be 117.2-119.2 °C. The pure product was identified by IR, 1 It was characterized by H NMR, and LC-MS. The HPLC purity of the product was found to be 98.43% and was free of any traces of larinepagic acid (1).

[0275] Example 7: Synthesis of Lalinepag Acid Chloride (7)

[0276] [ka]

[0277] To a stirred solution of larinepagic acid (1) (1.0 g, 2.32 mmol) in DCM (10.0 mL) was added oxalyl chloride (0.60 mL, 6.95 mmol) dropwise at room temperature under argon, followed by a catalytic amount of DMF (50 μL) (formation of foam was observed). The resulting reaction mixture was stirred at room temperature under argon for 2 h. After 2 h, the reaction was found to be complete.1 The reaction was confirmed based on H NMR. The solvent was removed under vacuum and dried under high vacuum to give pure lalinepagic acid chloride (7) (1.06 g) as a yellow solid in 100% yield. The product was characterized by IR, 1 Characterized by 1 H NMR and LC-MS. The compound is pure enough to be used in the next step without further purification.

[0278] Example 8: Synthesis of Lalinepag Glycinamide Methyl Ester (8a)

[0279] [ka]

[0280] To a stirred solution of lalinepag acid chloride (7) (0.20 g, 0.44 mmol) in DCM (5.0 mL) was added triethylamine (TEA) (0.15 mL, 1.11 mmol) under argon at 0° C. and stirred for 30 min. Glycine methyl ester hydrochloride (0.08 g, 0.67 mmol) was then added and the resulting reaction mixture was allowed to slowly warm to room temperature under argon. After 1 h, the reaction was found to be complete based on TLC. The reaction mixture was diluted with DCM (10 mL), washed with water (2×15 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give crude lalinepag glycine amide methyl ester (8a) (0.215 g), which was purified by silica gel chromatography. The combined fractions were evaporated under vacuum and dried under high vacuum to give pure lalinepag glycine amide methyl ester (8a) (0.13 g) in 60.9% yield as a white solid, melting point was found to be 78.3-80.3 °C. The pure product was identified by IR, 1 It was characterized by H NMR, and LC-MS. The HPLC purity of the product was found to be 99.51% and was free of any traces of larinepagic acid (1).

[0281] Example 9: Synthesis of Lalinepag L-Valinamide Methyl Ester (8b)

[0282] [ka]

[0283] To a stirred solution of lalinepag acid chloride (7) (0.20 g, 0.44 mmol) in DCM (5.0 mL) was added triethylamine (TEA) (0.15 mL, 1.11 mmol) under argon at 0° C. and stirred for 30 min. L-valine methyl ester hydrochloride (0.11 g, 0.67 mmol) was then added and the resulting reaction mixture was allowed to slowly warm to room temperature under argon. After 2 h, the reaction was found to be complete based on TLC. The reaction mixture was quenched with saturated aqueous NH4Cl (5 mL) and extracted with DCM (2×10 mL). The layers were separated and the DCM layer was washed with water (10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give crude lalinepag L-valinamide methyl ester (8b) (0.34 g), which was purified by silica gel chromatography. The combined fractions were evaporated under vacuum and dried under high vacuum to give pure lalinepag L-valinamide methyl ester (8b) (0.19 g) in 77.9% yield as a clear viscous oil. The pure product was identified by IR, 1 It was characterized by H NMR, and LC-MS. The HPLC purity of the product was found to be 98.20% and was free of any traces of larinepagic acid (1).

[0284] Example 10: Synthesis of Lalinepagbipiperidine Amide (8c)

[0285] [ka]

[0286] To a stirred solution of lalinepag acid chloride (7) (0.20 g, 0.44 mmol) in DCM (5.0 mL) was added triethylamine (TEA) (0.15 mL, 1.11 mmol) under argon at 0° C. and stirred for 30 min. Then, 4-piperidinopiperidine (0.11 g, 0.67 mmol) was added and the resulting reaction mixture was allowed to slowly warm to room temperature under argon. After 1 h, the reaction was found to be approximately 90% complete based on TLC. The reaction mixture was quenched with saturated aqueous NH4Cl (5 mL) and extracted with DCM (2×15 mL). The layers were separated and the DCM layer was washed with water (2×10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give crude lalinepag bipiperidine amide (8c) (0.30 g), which was purified by chromatography. The combined fractions were evaporated in vacuo and dried under high vacuum to give pure lalinepagbipiperidine amide (8c) (0.17 g) as a waxy solid in 67.3% yield. The pure product was identified by IR, 1 It was characterized by H NMR, and LC-MS. The HPLC purity of the product was found to be 98.27% and was free of any traces of larinepagic acid (1).

[0287] Example 11: Synthesis of Lalinepag Morpholine Amide (9)

[0288] [ka]

[0289] To a solution of lalinepagic acid (1) (0.20 g, 0.46 mmol) in anhydrous DMF (2.5 mL) was added morpholine (0.044 mL, 0.51 mmol) followed by EDCI·HCl. (0.13 g, 0.69 mmol) and DMAP (0.17 g, 1.39 mmol) at room temperature under argon. The resulting reaction mixture was stirred overnight. After 19 h, the reaction was found to be complete based on TLC. The reaction mixture was treated with saturated aqueous NH4Cl (2 mL) and extracted with EtOAc (10 mL). The aqueous layer was extracted with EtOAc (2×10 mL) and the combined organic layers were washed with water (2×10 mL), brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo to give crude lalinepag morpholine amide (9) (0.34 g), which was purified by silica gel column chromatography. The combined fractions were evaporated under vacuum and dried under high vacuum to give pure lalinepag morpholine amide (9) (0.19 g) in 82.6% yield as a viscous oil that slowly turned to a waxy solid over time. The pure product was identified by IR, 1 It was characterized by H NMR, and LC-MS. The HPLC purity of the product was found to be 99.62% and was free of any traces of larinepagic acid (1).

Claims

1. Formula (IV): 【Chemistry 1】 A compound having the structure, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, R ８ is C ５ -C ２４ -alkyl, C １ -C ２４ -haloalkyl, C ２ -C ２４ -alkenyl, C ２ -C ２４ -alkynyl, -L ３ -O-P(=O)(OH) ２ , -L ３ , -cycloalkyl, -L ３ , -heterocycloalkyl, or -L ３ , -aryl, where each of alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or aryl is optionally substituted with one or more R ８ａ and L ３ It does not exist, or C １ -C ６ Alkylene, C １ -C ６ Heteroalkylene, C ２ -C ６ Alkenylene, or C ２ -C ２４ It is alkynylene, R 8a are each independently: halogen, -CN, -NO₂, -OH, -OR a, oxo, -OC(=O)R a, -SH, -SR a, -S(=O)R a, -S(=O)₂R a, -S(=O)₂OR b, -S(=O)₂NR c R d, -NR c R d, -NR b C(=O)R a, -NR b S(=O)₂R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C 6 Alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more Rs. Each R a is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R. R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R. R ｃ and R ｄ These are, independently, hydrogen and C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkyl (cycloalkyl), C １ -C ６ Alkyl (heterocycloalkyl), C １ -C ６ Alkyl (aryl), or C １ -C ６ Alkyl (heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R, or R ｃ and R ｄ These, together with the atoms to which they are bonded, form a heterocycloalkyl group optionally substituted with one or more R atoms. R is independently halogen, -CN, -OH, oxo, and -OC. １ -C ６ Alkyl, -S(=O)C １ -C ６ Alkyl, -S (=O) ２ C １ -C ６ Alkyl, -S (=O) ２ NH ２ , -S (=O) ２ NHC １ -C ６ Alkyl, -S (=O) ２ N(C) １ -C ６ Alkyl) ２ , -NH ２ , - NHC １ -C ６ Alkyl, -N(C) １ -C ６ Alkyl) ２ , -C(=O)C １ -C ６ Alkyl, -C(=O)OH, -C(=O)OC １ -C ６ Alkyl, -C(=O)NH ２ , -C(=O)N(C １ -C ６ Alkyl) ２ , -C(=O)NHC １ -C ６ Alkyl, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, or C １ -C ６ It is a heteroalkyl group. A compound, or a pharmaceutically acceptable salt or solvate thereof.

2. Formula (IVa): 【Chemistry 2】 A compound according to claim 1 having the structure, or a pharmaceutically acceptable salt or solvate thereof.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is a linear C5-C24 alkyl group.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is a linear C5-C14 alkyl substituted with a linear C1-C6 alkyl.

5. R 8 is, 【Transformation 3】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein each of these is optionally substituted with one R 8a, and R 8a is a linear C1-C6 alkyl group.

6. R 8 is, 【Chemistry 4】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein each of these is optionally substituted with one R 8a, where R 8a is methyl, ethyl, n-propyl, or n-butyl.

7. R 8 is, 【Transformation 5】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof.

8. R 8 is, 【Transformation 6】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof.

9. R 8 is -L 3-(5-membered or 6-membered cycloalkyl), -L 3-(5-membered or 6-membered heterocycloalkyl), -L 3-phenyl, -L 3-naphthyl, or -L 3-heteroaryl, where each of the cycloalkyl, heterocycloalkyl, phenyl, naphthyl, or heteroaryl is optionally substituted with one or more R 8a. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein L3 is absent or is a C2-C6 alkenylene, a C1-C6 alkylene, or a C1-C6 heteroalkylene.

10. R 8 is, 【Transformation 7】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, which is -L3-O-P(=O)(OH)2. 【Request Item 11】 【Chemistry 8】 A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, selected from the above.

12. Formula (II): 【Chemistry 9】 A compound having the structure, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, R4 and R5, together with the nitrogen to which they are bound, form morpholinyl or piperidinyl, each of which is optionally substituted with one or more R5a. R 5a are each independently: halogen, -CN, -NO₂, -OH, -OR a, oxo, -OC(=O)R a, -SH, -SR a, -S(=O)R a, -S(=O)₂R a, -S(=O)₂NR c R d, -NR c R d, -NR b C(=O)R a, -NR b S(=O)₂R a, -C(=O)R a, -C(=O)OR a, -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more Rs. Each R a is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R. R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R. R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R, or R c and R d, together with the atom to which they are bonded, form a heterocycloalkyl group optionally substituted with one or more R atoms. R is independently halogen, -CN, -OH, oxo, -OC1 -C6 alkyl, -S(=O)C1 -C6 alkyl, -S(=O)2 C1 -C6 alkyl, -S(=O)2 NH2, -S(=O)2 NHC1 -C6 alkyl, -S(=O)2 N(C1 -C6 alkyl)2, -NH2, -NHC1 -C6 alkyl, -N(C1 -C6 alkyl)2, -C(=O)C1 -C6 alkyl, -C(=O)OH, -C(=O)OC1 -C6 alkyl, -C(=O)NH2, -C(=O)N(C1 -C6 Alkyl) 2, -C(=O)NHC1 -C6 alkyl, C1 -C6 alkyl, C1 -C6 haloalkyl, or C1 -C6 heteroalkyl, A compound, or a pharmaceutically acceptable salt or solvate thereof.

13. Formula (IIa): 【Chemistry 10】 A compound according to claim 12 having the structure, or a pharmaceutically acceptable salt or solvate thereof.

14. The compound according to claim 12 or 13, or a pharmaceutically acceptable salt or solvate thereof, wherein R4 and R5, together with the nitrogen to which they are bound, form morpholinyl or piperidinyl, and each of these is optionally substituted with one or more R5a.

15. The compound according to claim 12 or 13, or a pharmaceutically acceptable salt or solvate thereof, wherein R4 and R5, together with the nitrogen to which they are bonded, form morpholinyl or piperidinyl, each of which is optionally substituted with one or more R5a, and R5a is a -C(=O)O-C1-3 alkyl or C2-C5 heterocycloalkyl. 【Request Item 16】 【Chemistry 11】 but 【Chemistry 12】 The compound according to claim 12 or 13, or a pharmaceutically acceptable salt or solvate thereof. 【Request Item 17】 【Chemistry 13】 A compound according to claim 12 or 13, or a pharmaceutically acceptable salt or solvate thereof, selected from the above.

18. A pharmaceutical composition comprising a compound according to any one of claims 1, 2, 12, or 13, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

19. A composition comprising the compound according to any one of claims 1, 2, 12, or 13, or a pharmaceutically acceptable salt or solvate thereof, for treating pulmonary hypertension (PAH) in a subject requiring treatment.

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