RALINEPAG prodrugs and uses thereof

Abstract

Described herein are rainepg 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 arterial hypertension (PH) disease.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 321,032, filed on March 17, 2022, which is incorporated herein by reference in its entirety. Technical Field

[0003] Described herein are ralinepag prodrugs that are agonists of the prostacyclin (IP) receptor and pharmaceutical compositions thereof, as well as methods of use thereof in treating diseases or conditions that would benefit from treatment with ralinepag. Background Art

[0004] Prostacyclin (IP) receptors are expressed on platelets and smooth muscle cells of several tissues, including the lungs, heart, aorta, liver, kidneys, and blood vessels. Activation of IP receptors leads to an increase in cellular cyclic adenosine monophosphate (cAMP), followed by arterial vasodilation and inhibition of platelet aggregation. Improved hemodynamics, exercise capacity, and survival have clearly demonstrated the use of PGI for the treatment of, for example, pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH). 2 Alternative therapy. Summary of the invention

[0005] Disclosed herein are compounds of formula (I) or pharmaceutically acceptable salts, solvates or stereoisomers thereof:

[0006]

[0007] in:

[0008] Q is -NR 6 -S(=O) 2 R 7 ;

[0009] R 6 It is H, C 1 -C 24 Alkyl, C 1 -C 24 Haloalkyl, C 1 -C 24 Heteroalkyl, C 2 -C 24 Alkenyl, C 2 -C 24 Alkynyl, -L 2 -cycloalkyl, -L 2 -heterocycloalkyl, -L 2 -Aryl or -L 2-heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R 7a replace;

[0010] R 7 It is C 1 -C 24 Alkyl, C 1 -C 24 Haloalkyl, C 1 -C 24 Heteroalkyl, C 2 -C 24 Alkenyl, C 2 -C 24 Alkynyl, -L 2 -cycloalkyl, -L 2 -heterocycloalkyl, -L 2 -Aryl or -L 2 -heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R 7a replace;

[0011] L 2 does not exist, C 1 -C 6 Alkylene, C 1 -C 6 Heteroalkylene, C 2 -C 6 Alkenylene or C 2 -C 6 alkynylene, each of which is optionally substituted by one or more R 7a replace;

[0012] or Q is -OR 8 ;

[0013] R 8 Yes-CH 2 CH 2 CH 3 、-CH(CH 3 ) 2 、-CH 2 CH 2 CH 2 CH 3 、-CH 2 CH(CH 3 ) 2 , C 5 -C 24 Alkyl, C 1 -C 24 Haloalkyl, C 1 -C 24Heteroalkyl, C 2 -C 24 Alkenyl, C 2 -C 24 Alkynyl, -L 3 -OP(=O)(OH) 2 , -L 3 -cycloalkyl, -L 3 -heterocycloalkyl or -L 3 -aryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl or aryl is optionally substituted by one or more R 8a replace;

[0014] L 3 does not exist, C 1 -C 6 Alkylene, C 1 -C 6 Heteroalkylene, C 2 -C 6 Alkenylene or C 2 -C 24 alkynylene, each of which is optionally substituted by one or more R 8a replace;

[0015] or Q is -NR 4 R 5 ;

[0016] R 4 It is H, C 1 -C 24 Alkyl, C 1 -C 24 Haloalkyl, C 1 -C 24 Heteroalkyl, C 2 -C 24 Alkenyl, C 2 -C 24 Alkynyl, -L 5 -cycloalkyl, -L 5 -heterocycloalkyl, -L 5 -Aryl or -L 5 -heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R 5a replace;

[0017] R 5 It is C 1 -C 24 Alkyl, C 1 -C 24 Haloalkyl, C 1 -C 24 Heteroalkyl, C 2 -C24 Alkenyl, C 2 -C 24 Alkynyl, -L 5 -cycloalkyl, -L 5 -heterocycloalkyl, -L 5 -Aryl or -L 5 -heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or

[0018] Each of the heteroaryl groups is optionally substituted by one or more R 5a Replace; or R 4 and R 5 Together with the nitrogen to which they are attached, they form a 3- to 12-membered heterocycloalkyl or heteroaryl, wherein each of the heterocycloalkyl or heteroaryl is optionally substituted by one or more R 5a replace;

[0019] L 5 does not exist, C 1 -C 6 Alkylene, C 1 -C 6 Heteroalkylene, C 2 -C 6 Alkenylene or C 2 -C 24 alkynylene, each of which is optionally substituted by one or more R 5a replace;

[0020] R 5a and R 7a are independently selected from halogen, -CN, -NO 2 、-OH、-OR a , oxo, -OC(=O)R a , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)R a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR a 、-C(=O)NR c R d , C 1 -C6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more R;

[0021] R 8a Selected from halogen, -CN, -NO 2 、-OH、-OR a , oxo, -OC(=O)R a , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 OR b 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)R a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more R;

[0022] Each R a Independently C 1 -C 6 Alkyl, C 1 -C6 Haloalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, 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); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R;

[0023] Each R b are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, 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); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R;

[0024] Each R c and R d are independently hydrogen, 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 Alkenyl, C2 -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); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R; or

[0025] R c and R d together with the atoms to which they are attached form heterocycloalkyl, which is optionally substituted with one or more R; and

[0026] Each R is independently halogen, -CN, -OH, oxo, -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, C1 -C 6 Haloalkyl or C 1 -C 6 heteroalkyl;

[0027] or 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.

[0028] Also described herein is a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier or excipient.

[0029] Also 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 pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein.

[0030] Also described herein is a method of modulating a prostacyclin (PGI2) receptor in a subject in need thereof, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein.

[0031] Also described herein is a method of treating a disease or condition associated with a prostacyclin (PGI2) receptor in a subject in need thereof, comprising administering to the subject a compound described herein or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein.

[0032] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while indicating specific embodiments, are given by way of illustration 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 this detailed description. DETAILED DESCRIPTION

[0033] 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. Ralinepag is also named 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid and has the following structure:

[0034]

[0035] definition

[0036] In the following description, certain specific details are set forth to provide a thorough understanding of the various embodiments. However, those skilled in the art will appreciate that the present disclosure may be practiced without these details. In other cases, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context otherwise requires, throughout the specification and the claims that follow, the word "comprise" and its variations such as "comprises" and "comprising" should be interpreted in an open, inclusive sense, that is, as "including but not limited to". In addition, the headings provided herein are for convenience only and do not explain the scope or meaning of the claimed invention.

[0037] References to "some embodiments" or "an embodiment" throughout this specification mean that a particular feature, structure, or characteristic described in association with the embodiment is included in at least one embodiment. Therefore, the phrase "in one embodiment" or "in one embodiment" appearing in various places throughout this specification may not all relate to the same embodiment. In addition, the particular features, structures, or characteristics may be combined in one or more embodiments in any suitable manner. In addition, unless the content clearly provides otherwise, as used in this specification and the appended claims, the singular forms "a / an" and "the" include plural referents. It should also be noted that unless the content clearly provides otherwise, the term "or" is generally used in its sense including "and / or".

[0038] Unless otherwise indicated, the following terms as used herein have the following meanings:

[0039] "Oxo" refers to =0.

[0040] "Carboxyl" refers to -COOH.

[0041] "Cyano" refers to -CN.

[0042] "Alkyl" refers to a straight or branched saturated hydrocarbon monovalent group having one to about ten carbon atoms, more preferably one to six 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, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl and hexyl, as well as longer alkyl groups such as heptyl, octyl, etc. Whenever it appears in this document, numerical ranges such as "C 1 -C 6 Alkyl" or "C 1-6 The term "alkyl" means that the alkyl group can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but the definition also covers the occurrence of the term "alkyl" in which no numerical range is specified. In some embodiments, the alkyl group is C 1-10 In some embodiments, the alkyl group is C 1-6 In some embodiments, the alkyl group is C 1-5 In some embodiments, the alkyl group is C 1 - 4 In some embodiments, the alkyl group is C 1-3 Alkyl. Unless otherwise specifically stated in the specification, alkyl can be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkyl is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 or-NO 2 In some embodiments, the alkyl group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl group is optionally substituted with halogen.

[0043] "Alkenyl" refers to a straight or branched hydrocarbon monovalent group having one or more carbon-carbon double bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. The group may be in a cis or trans configuration about the one or more double bonds and is understood to include both isomers. Examples include, but are not limited to, vinyl (-CH=CH 2 ), 1-propenyl (-CH 2 CH=CH 2 ), isopropenyl [-C(CH3 )=CH 2 ], butenyl, 1,3-butadienyl, etc. Whenever it appears in this document, a numerical range such as "C 2 -C 6 "Alkenyl" or "C 2-6 "Alkenyl" means that the alkenyl group can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but the present definition also covers the occurrence of the term "alkenyl" in which no numerical range is specified. Unless otherwise specifically stated in the specification, the alkenyl group can be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkenyl group is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 or-NO 2 In some embodiments, the alkenyl group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl group is optionally substituted with halogen.

[0044] "Alkynyl" refers to a straight or branched hydrocarbon monovalent group having one or more carbon-carbon triple bonds and having two to about ten carbon atoms, more preferably two to about six 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 "C 2 -C 6 Alkynyl" or "C 2-6 "Alkynyl" means that the alkynyl group can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but the present definition also covers the occurrence of the term "alkynyl" in which no numerical range is specified. Unless otherwise specifically stated in the specification, the alkynyl group can be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkynyl group is optionally substituted by oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 or-NO 2 In some embodiments, the alkynyl group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl group is optionally substituted with halogen.

[0045] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specifically stated in the specification, alkylene may be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkylene is optionally substituted by oxo, halogen, -CN, -CO 2 H, CO 2 Me, -OH, -OMe, -NH 2 or-NO 2 In some embodiments, the alkylene group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene group is optionally substituted with halogen.

[0046] "Alkoxy" refers to a group of the formula -OR a Group, where R a is alkyl as defined. Unless otherwise specifically stated in the specification, alkoxy may be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkoxy is optionally substituted by halogen, -CN, -CO 2 H, -CO 2 Me, -OH, -OMe, -NH 2 or-NO 2 In some embodiments, the alkoxy group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy group is optionally substituted with halogen.

[0047] "Aryl" refers to a group derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. The aryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a fused (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl group is bonded through an aromatic ring atom) or a bridged ring system. In some embodiments, the aryl group is a 6- to 10-membered aryl group. In some embodiments, the aryl group is a 6-membered aryl (phenyl). Aryl groups include, but are not limited to, anthracene, naphthyl, phenanthrenyl, anthracene, azulene, benzene, The aromatic groups are substituted with halogen, methyl, ethyl, -CN, -CO, -C, -D, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P, -P 2 H, -CO2 Me, -CF 3 , -OH, -OMe, -NH 2 or-NO 2 In some embodiments, the aryl group is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 In some embodiments, the aryl group is optionally substituted with halogen.

[0048] "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 bonded through a non-aromatic ring atom), spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having three to fifteen carbon atoms (C 3 -C 15 Fully saturated cycloalkyl or C 3 -C 15 cycloalkenyl), three to ten carbon atoms (C 3 -C 10 Fully saturated cycloalkyl or C 3 -C 10 Cycloalkenyl), three to eight carbon atoms (C 3 -C 8 Fully saturated cycloalkyl or C 3 -C 8 Cycloalkenyl), three to six carbon atoms (C 3 -C 6 Fully saturated cycloalkyl or C 3 -C 6 Cycloalkenyl), three to five carbon atoms (C 3 -C 5 Fully saturated cycloalkyl or C 3 -C 5 Cycloalkenyl) or three to four carbon atoms (C 3 -C 4 Fully saturated cycloalkyl or C 3 -C 4In 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. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, 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]heptane. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Unless otherwise specifically stated in the specification, cycloalkyls are optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the cycloalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CO 2 H, CO 2 Me, -CF 3 , -OH, -OMe, -NH 2 or-NO 2 In some embodiments, the cycloalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0049] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0050] "Haloalkyl" refers to an alkyl group as defined above substituted with one or more halo groups as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0051] "Hydroxyalkyl" refers to an alkyl group as defined above that is substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl or hydroxypentyl. In some embodiments, aminoalkyl groups are hydroxymethyl groups.

[0052] "Aminoalkyl" refers to an alkyl group as defined above that is substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two or three amines. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl or aminopentyl. In some embodiments, the aminoalkyl group is aminomethyl.

[0053] "Heteroalkyl" refers to an alkyl group in which one or more of the backbone atoms of the alkyl group is selected from atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof. The heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. In one aspect, the heteroalkyl group is C 1 -C 6 A heteroalkyl group, wherein the heteroalkyl group consists of 1 to 6 carbon atoms and one or more atoms other than carbon (e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof), wherein the heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. Examples of such heteroalkyl groups are, for example, -CH 2 OCH 3 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 2 OCH 3 、-CH(CH 3 )OCH 3 、-CH 2 NHCH 3 、-CH 2 N(CH 3 ) 2 、-CH 2 CH 2 NHCH 3 or -CH 2 CH 2 N(CH 3 ) 2 Unless otherwise specifically stated in the specification, heteroalkyl is optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 or-NO 2 In some embodiments, the heteroalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3In some embodiments, the heteroalkyl group is optionally substituted with halogen.

[0054] "Heterocycloalkyl" refers to a 3 to 24-membered partially or fully saturated ring group containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from nitrogen, oxygen, phosphorus, silicon and sulfur. In some embodiments, heterocycloalkyl is fully saturated. In some embodiments, heterocycloalkyl contains one to three heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, heterocycloalkyl contains one to three heteroatoms selected from nitrogen and oxygen. In some embodiments, heterocycloalkyl contains one to three nitrogens. In some embodiments, heterocycloalkyl contains one or two nitrogens. In some embodiments, heterocycloalkyl contains one nitrogen. In some embodiments, heterocycloalkyl contains one nitrogen and one oxygen. Unless otherwise specifically stated in the specification, heterocycloalkyl may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include a fused (when fused with an aryl or heteroaryl ring, the heterocycloalkyl is bonded by a non-aromatic ring atom), a spiro or a bridged ring system; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyl groups include, but are not limited to, groups having two to fifteen carbon atoms (C 2 -C 15 Fully saturated heterocycloalkyl or C 2 -C 15 Heterocycloalkenyl), two to ten carbon atoms (C 2 -C 10 Fully saturated heterocycloalkyl or C 2 -C 10 Heterocycloalkenyl), two to eight carbon atoms (C 2 -C 8 Fully saturated heterocycloalkyl or C 2 -C 8 Heterocycloalkenyl), two to seven carbon atoms (C 2 -C 7 Fully saturated heterocycloalkyl or C 2 -C 7 Heterocycloalkenyl), two to six carbon atoms (C 2 -C 6 Fully saturated heterocycloalkyl or C 2 -C 7 Heterocycloalkenyl), two to five carbon atoms (C 2 -C 5 Fully saturated heterocycloalkyl or C 2 -C 5 Heterocycloalkenyl) or two to four carbon atoms (C 2 -C 4 Fully saturated heterocycloalkyl or C 2 -C 4Examples of such heterocycloalkyl groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl , pyrazolidinyl, quinuclidine, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 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 ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. In some embodiments, heterocycloalkyl has 2 to 10 carbons in the ring. It should be understood that when referring to the number of carbon atoms in heterocycloalkyl, the number of carbon atoms in heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) constituting heterocycloalkyl (i.e., the skeleton atoms of the heterocycloalkyl ring). In some embodiments, heterocycloalkyl is a 3 to 8-membered fully saturated heterocycloalkyl. In some embodiments, heterocycloalkyl is a 3 to 7-membered fully saturated heterocycloalkyl. In some embodiments, heterocycloalkyl is a 3 to 6-membered fully saturated heterocycloalkyl. In some embodiments, heterocycloalkyl is a 4 to 6-membered fully saturated heterocycloalkyl. In some embodiments, heterocycloalkyl is a 5 to 6-membered fully saturated heterocycloalkyl. In some embodiments, heterocycloalkyl is a 3 to 8-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 3 to 7-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 3 to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 4 to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 5 to 6-membered heterocycloalkenyl. Unless otherwise specifically stated in the specification, the heterocycloalkyl radical may be optionally substituted as described below, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heterocycloalkyl radical is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF 3 , -OH, -OMe, -NH 2 or-NO 2 In some embodiments, the heterocycloalkyl group is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0055] "Heteroaryl" refers to a 5 to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from nitrogen, oxygen, phosphorus and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. The heteroaryl may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include a fused (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded by an aromatic ring atom) or a bridged ring system; and the nitrogen, carbon or sulfur atoms in the heteroaryl may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5 to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5 to 6-membered heteroaryl. In some embodiments, the heteroaryl group is a 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothienyl / benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanone, isothiophenyl, Thiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoaziridine, oxazolyl, oxirane, 1-oxopyridinyl, 1-oxopyrimidinyl, 1-oxopyrazinyl, 1-oxopyridazinyl, 1-phenyl-1H- The term "heteroaryl" refers to a group consisting of phenyl, ...In some embodiments, the heteroaryl group is optionally substituted with halogen, methyl, ethyl, -CN, -CO. 2 H, CO 2 Me, -CF 3 , -OH, -OMe, -NH 2 or-NO 2 In some embodiments, the heteroaryl group is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 In some embodiments, the heteroaryl group is optionally substituted with halogen.

[0056] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. In addition, an optionally substituted group may be unsubstituted (e.g., -CH 2 CH 3 ), is completely replaced (e.g. -CF 2 CF 3 ), is substituted by a single (e.g. -CH 2 CH 2 F) or substituted at any level between fully substituted and monosubstituted (e.g., -CH 2 CHF 2 、-CH 2 CF 3 , -CF 2 CH 3 ,-CFHCHF 2 With respect to any group containing one or more substituents, one skilled in the art will appreciate that such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical and / or synthetically infeasible. Thus, any substituent described should generally be understood to have a maximum molecular weight of about 1,000 Daltons, and more typically up to about 500 Daltons.

[0057] When referring to optional substituents, the term "one or more" means that the subject group is optionally substituted by one, two, three, four or more substituents. In some embodiments, the subject group is optionally substituted by one, two, three or four substituents. In some embodiments, the subject group is optionally substituted by one, two or three substituents. In some embodiments, the subject group is optionally substituted by one or two substituents. In some embodiments, the subject group is optionally substituted by a substituent. In some embodiments, the subject group is optionally substituted by two substituents.

[0058] "Effective amount" or "therapeutically effective amount" refers to an amount of a compound that is administered to a mammalian subject in a single dose or as part of a series of doses effective to produce the desired therapeutic effect.

[0059] As used herein, the terms "treat," "treating," or "treatment" include alleviating, reducing, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, palliating the disease or condition, causing regression of the disease or condition, alleviating a condition caused by the disease or condition, or eliminating symptoms of the disease or condition.

[0060] As used herein, the term "modulator" refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, interactions of agonists, partial agonists, inverse agonists, antagonists, degraders, or combinations thereof. In some embodiments, the modulator is an agonist.

[0061] As used herein, the terms "administer", "administering", "administration", etc. refer to methods that can be used to achieve 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 injections (including intravenous injections, subcutaneous injections, intraperitoneal injections, intramuscular injections, intravascular injections or infusions), and topical administration. Those skilled in the art are familiar with administration techniques that can be used for the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0062] As used herein, the terms "co-administered," "co-administered," and the like are meant to encompass administration of selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration, or at the same or different times.

[0063] Compound

[0064] Described herein are compounds or pharmaceutically acceptable salts, solvates or stereoisomers thereof for use in treating diseases or conditions associated with pulmonary hypertension (PH), pulmonary vascular resistance (PVR), arterial pulmonary hypertension (PAH), pulmonary hypertension associated with interstitial lung disease (PH-ILD), or a combination thereof.

[0065] Disclosed herein are compounds of formula (I) or pharmaceutically acceptable salts, solvates or stereoisomers thereof:

[0066]

[0067] in:

[0068] Q is -NR 6 -S(=O) 2 R 7 ;

[0069] R 6 It is H, C 1 -C 24 Alkyl, C 1 -C 24 Haloalkyl, C 1 -C 24 Heteroalkyl, C 2 -C 24 Alkenyl, C 2 -C 24 Alkynyl, -L 2 -cycloalkyl, -L 2 -heterocycloalkyl, -L 2 -Aryl or -L 2 -heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R 7a replace;

[0070] R 7 It is C 1 -C 24 Alkyl, C 1 -C 24 Haloalkyl, C 1 -C 24 Heteroalkyl, C 2 -C 24 Alkenyl, C 2 -C 24 Alkynyl, -L 2 -cycloalkyl, -L 2 -heterocycloalkyl, -L 2 -Aryl or -L 2 -heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R 7a replace;

[0071] L 2 does not exist, C 1 -C 6 Alkylene, C 1 -C 6 Heteroalkylene, C 2 -C 6 Alkenylene or C 2 -C 6 alkynylene, each of which is optionally substituted by one or more R 7a replace;

[0072] or Q is -OR8 ;

[0073] R 8 Yes-CH 2 CH 2 CH 3 、-CH(CH 3 ) 2 、-CH 2 CH 2 CH 2 CH 3 、-CH 2 CH(CH 3 ) 2 , C 5 -C 24 Alkyl, C 1 -C 24 Haloalkyl, C 1 -C 24 Heteroalkyl, C 2 -C 24 Alkenyl, C 2 -C 24 Alkynyl, -L 3 -OP(=O)(OH) 2 , -L 3 -cycloalkyl, -L 3 -heterocycloalkyl or

[0074] -L 3 -aryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl or aryl is optionally substituted by one or more R 8a replace;

[0075] L 3 does not exist, C 1 -C 6 Alkylene, C 1 -C 6 Heteroalkylene, C 2 -C 6 Alkenylene or C 2 -C 24 alkynylene, each of which is optionally substituted by one or more R 8a replace;

[0076] or Q is -NR 4 R 5 ;

[0077] R 4 It is H, C 1 -C 24 Alkyl, C 1 -C 24 Haloalkyl, C 1 -C 24Heteroalkyl, C 2 -C 24 Alkenyl, C 2 -C 24 Alkynyl, -L 5 -cycloalkyl, -L 5 -heterocycloalkyl, -L 5 -Aryl or -L 5 -heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R 5a replace;

[0078] R 5 It is C 1 -C 24 Alkyl, C 1 -C 24 Haloalkyl, C 1 -C 24 Heteroalkyl, C 2 -C 24 Alkenyl, C 2 -C 24 Alkynyl, -L 5 -cycloalkyl, -L 5 -heterocycloalkyl, -L 5 -Aryl or -L 5 -heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R 5a replace;

[0079] or

[0080] R 4 and R 5 Together with the nitrogen to which they are attached, they form a 3- to 12-membered heterocycloalkyl or heteroaryl, wherein each of the heterocycloalkyl or heteroaryl is optionally substituted by one or more R 5a replace;

[0081] L 5 does not exist, C 1 -C 6 Alkylene, C 1 -C 6 Heteroalkylene, C 2 -C 6 Alkenylene or

[0082] C 2 -C 24 alkynylene, each of which is optionally substituted by one or more R 5a replace;

[0083] R 5a and R 7aare independently selected from halogen, -CN, -NO 2 、-OH、-OR a , oxygen,

[0084] -OC(=O)R a , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d ,

[0085] -NR c R d 、-NR b C(=O)R a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR a ,

[0086] -C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more R;

[0087] R 8a Selected from halogen, -CN, -NO 2 、-OH、-OR a , oxo, -OC(=O)R a , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 OR b 、-S(=O) 2 NR c R d 、-NR c Rd 、-NR b C(=O)R a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more R;

[0088] Each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, 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); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R;

[0089] Each R b are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C2 -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); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R;

[0090] Each R c and R d are independently hydrogen, 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 Alkenyl, 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); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R; or

[0091] R c and R d together with the atoms to which they are attached form heterocycloalkyl, which is optionally substituted with one or more R; and

[0092] Each R is independently halogen, -CN, -OH, oxo, -OC 1 -C 6 Alkyl, -S(=O)C 1 -C 6 Alkyl, -S(=O) 2 C 1 -C 6Alkyl, -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 heteroalkyl;

[0093] or Q is: 1-carboxyethylamino, 1-carboxy-4-guanidinobutylamino, 3-amino-1-carboxy

[0094] -3-oxopropylamino, 1,2-dicarboxyethylamino, 1-carboxy-2-mercaptoethylamino,

[0095] 4-amino-1-carboxy-4-oxobutylamino, 3-carboxy-1-carboxylate propylamino,

[0096] 1-carboxy-2-(1H-imidazol-4-yl)ethylamino, 1-carboxy-2-methylbutylamino,

[0097] 1-carboxy-3-methylbutylamino, 5-amino-1-carboxypentylamino, 1-carboxy-3-

[0098] (Methylthio)propylamino, 1-carboxy-2-phenylethylamino, 2-carboxypyrrolidin-1-yl, 1-carboxy-2-hydroxyethylamino, 1-carboxy-2-hydroxypropylamino, 1-carboxy

[0099] -2-(1H-indol-3-yl)ethylamino, 1-carboxy-2-(4-hydroxyphenyl)ethylamino and 1-carboxy-2-methylpropylamino.

[0100] Disclosed herein are compounds of formula (V) or pharmaceutically acceptable salts, solvates or stereoisomers thereof:

[0101]

[0102] in:

[0103] R 1 and R 2 Each independently selected from: phenyl and monocyclic heteroaryl; wherein the phenyl and heteroaryl are each optionally substituted by one or two substituents selected from the following: C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl, aryl, C 1 -C 6 Haloalkoxy, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 heteroalkyl and halogen;

[0104] X is O or NR 3 ;

[0105] R 3 Selected from H and C 1 -C 6 Alkyl; and

[0106] Q is -NR 6 -S(=O) 2 R 7 ;

[0107] R 6 It is H, C 1 -C 24 Alkyl, C 1 -C 24 Haloalkyl, C 1 -C 24 Heteroalkyl, C 2 -C 24 Alkenyl, C 2 -C 24 Alkynyl, -L 2 -cycloalkyl, -L 2 -heterocycloalkyl, -L 2 -Aryl or -L2 -heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R 7a replace;

[0108] R 7 It is C 1 -C 24 Alkyl, C 1 -C 24 Haloalkyl, C 1 -C 24 Heteroalkyl, C 2 -C 24 Alkenyl,

[0109] C 2 -C 24 Alkynyl, -L 2 -cycloalkyl, -L 2 -heterocycloalkyl, -L 2 -Aryl or -L 2 -heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R 7a replace;

[0110] L 2 does not exist, C 1 -C 6 Alkylene, C 1 -C 6 Heteroalkylene, C 2 -C 6 Alkenylene or C 2 -C 6 alkynylene, each of which is optionally substituted by one or more R 7a replace;

[0111] or Q is -OR 8 ;

[0112] R 8 Yes-CH 2 CH 2 CH 3 、-CH(CH 3 ) 2 、-CH 2 CH 2 CH 2 CH 3 、-CH 2 CH(CH 3 ) 2 , C 5 -C 24 Alkyl, C 1 -C 24Haloalkyl, C 1 -C 24 Heteroalkyl, C 2 -C 24 Alkenyl, C 2 -C 24 Alkynyl, -L 3 -OP(=O)(OH) 2 , -L 3 -cycloalkyl, -L 3 -heterocycloalkyl or

[0113] -L 3 -aryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl or aryl is optionally substituted by one or more R 8a replace;

[0114] L 3 does not exist, C 1 -C 6 Alkylene, C 1 -C 6 Heteroalkylene, C 2 -C 6 Alkenylene or C 2 -C 24 alkynylene, each of which is optionally substituted by one or more R 8a replace;

[0115] or Q is -NR 4 R 5 ;

[0116] R 4 It is H, C 1 -C 24 Alkyl, C 1 -C 24 Haloalkyl, C 1 -C 24 Heteroalkyl, C 2 -C 24 Alkenyl, C 2 -C 24 Alkynyl, -L 5 -cycloalkyl, -L 5 -heterocycloalkyl, -L 5 -Aryl or -L 5 -heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R 5a replace;

[0117] R 5 It is C 1 -C 24 Alkyl, C 1 -C24 Haloalkyl, C 1 -C 24 Heteroalkyl, C 2 -C 24 Alkenyl, C 2 -C 24 Alkynyl, -L 5 -cycloalkyl, -L 5 -heterocycloalkyl, -L 5 -Aryl or -L 5 -heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R 5a replace;

[0118] or

[0119] R 4 and R 5 Together with the nitrogen to which they are attached, they form a 3- to 12-membered heterocycloalkyl or heteroaryl, wherein each of the heterocycloalkyl or heteroaryl is optionally substituted by one or more R 5a replace;

[0120] L 5 does not exist, C 1 -C 6 Alkylene, C 1 -C 6 Heteroalkylene, C 2 -C 6 Alkenylene or

[0121] C 2 -C 24 alkynylene, each of which is optionally substituted by one or more R 5a replace;

[0122] R 5a and R 7a are independently selected from halogen, -CN, -NO 2 、-OH、-OR a , oxo, -OC(=O)R a , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR 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 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more R;

[0123] R 8a Selected from halogen, -CN, -NO 2 、-OH、-OR a , oxo, -OC(=O)R a , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 OR b 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)R a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more R;

[0124] Each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, 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); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R;

[0125] Each R b are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, 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); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R;

[0126] Each R c and R d are independently hydrogen, C 1 -C 6 Alkyl, C1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, 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); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R; or

[0127] R c and R d together with the atoms to which they are attached form heterocycloalkyl, which is optionally substituted with one or more R; and

[0128] Each R is independently halogen, -CN, -OH, oxo, -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,

[0129] -S(=O) 2 N(C 1 -C 6 alkyl) 2 、-NH 2 、-NHC 1 -C 6 Alkyl, -N(C 1 -C 6 alkyl) 2 ,

[0130] -C(=O)C 1 -C6 Alkyl, -C(=O)OH, -C(=O)OC 1 -C 6 Alkyl, -C(=O)NH 2 ,

[0131] -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 heteroalkyl;

[0132] or 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

[0133] -3-(Methylthio)propylamino, 1-carboxy-2-phenylethylamino, 2-carboxypyrrolidine

[0134] 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.

[0135] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of formula (IIIa) or a pharmaceutically acceptable salt or solvate thereof:

[0136]

[0137] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of Formula (IIIa):

[0138]

[0139] R 6 Can be any suitable functional group known to those skilled in the art. 6 It is H, C1 -C 24 Alkyl, C 1 -C 24 Haloalkyl, C 1 -C 24 Heteroalkyl, C 2 -C 24 Alkenyl, C 2 -C 24 Alkynyl, -L 2 -cycloalkyl, -L 2 -heterocycloalkyl, -L 2 -Aryl or -L 2 -heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R 7a In some embodiments, R 6 It is H, C 1 -C 24 Alkyl, C 1 -C 24 Haloalkyl, C 1 -C 24 Heteroalkyl or C 2 -C 24 In some embodiments, R 6 It is H, C 1 -C 24 Alkyl or C 1 -C 24 In some embodiments, R 6 Is H or C 1 -C 24 In some embodiments, R 6 Is H or C 1 -C 12 In some embodiments, R 6 Is H or C 1 -C 6 In some embodiments, R 6 It's H.

[0140] R 7 Can be any suitable functional group known to those skilled in the art. 7 It is C 1 -C 24 Alkyl, C 1 -C 24 Haloalkyl, C 1 -C 24 Heteroalkyl, C 2 -C 24 Alkenyl, C 2 -C 24Alkynyl, -L 2 -cycloalkyl, -L 2 -heterocycloalkyl, -L 2 -Aryl or -L 2 -heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted. 7 It is C 1 -C 24 Alkyl, C 1 -C 24 Haloalkyl, C 1 -C 24 Heteroalkyl, C 2 -C 24 Alkenyl, C 2 -C 24 Alkynyl, -L 2 -cycloalkyl, -L 2 -heterocycloalkyl, -L 2 -Aryl or -L 2 -heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R 7a In some embodiments, R 7 It is C 1 -C 12 Alkyl, C 1 -C 12 Haloalkyl, C 1 -C 12 Heteroalkyl, C 2 -C 12 Alkenyl, C 2 -C 12 Alkynyl, -L 2 -cycloalkyl, -L 2 -heterocycloalkyl, -L 2 -Aryl or -L 2 -heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted. 7 It is C 1 -C 24 Alkyl, C 1 -C 24 Haloalkyl, C 1 -C 24 Heteroalkyl or C 2 -C 24 In some embodiments, R 7 It is C 1 -C 24 Alkyl, C 1 -C24 Haloalkyl or C 1 -C 24 wherein each of the alkyl or heteroalkyl groups is optionally substituted with one or more R 7a In some embodiments, R 7 It is C 1 -C 12 Alkyl, C 1 -C 12 Haloalkyl, C 1 -C 12 Heteroalkyl or C 2 -C 12 In some embodiments, R 7 It is C 1 -C 12 Alkyl, C 1 -C 12 Haloalkyl or C 1 -C 12 In some embodiments, R 7 It is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 In some embodiments, R 7 is an optionally substituted C 1 -C 12 In some embodiments, R 7 It is C 1 -C 12 In some embodiments, R 7 is an optionally substituted C 1 -C 6 In some embodiments, R 7 It is C 1 -C 6 In some embodiments, R 7 is an optionally substituted C 1 -C 4 In some embodiments, R 7 It is C 1 -C 4 In some embodiments, wherein R 7 is optionally substituted -CH 3 、-CH 2 CH 3 、-CH 2 CH 2 CH3 、-CH(CH 3 ) 2 、-CH 2 CH 2 CH 2 CH 3 、-CH 2 CH(CH 3 ) 2 、-CH 2 CH 2 CH 2 CH 2 CH 3 or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 In some embodiments, R 7 Yes-CH 3 、-CH 2 CH 3 、-CH 2 CH 2 CH 3 、-CH(CH 3 ) 2 、-CH 2 CH 2 CH 2 CH 3 、-CH 2 CH(CH 3 ) 2 、-CH 2 CH 2 CH 2 CH 2 CH 3 or -CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 In some embodiments, wherein R 7 is optionally substituted -CH 3 、-CH 2 CH 3 、-CH 2 CH 2 CH 3 、-CH(CH 3 ) 2 、-CH 2 CH 2 CH 2 CH 3 、-CH 2CH(CH 3 ) 2 In some embodiments, R 7 Yes-CH 3 、-CH 2 CH 3 、-CH 2 CH 2 CH 3 、-CH(CH 3 ) 2 、-CH 2 CH 2 CH 2 CH 3 、-CH 2 CH(CH 3 ) 2 In some embodiments, R 7 It is methyl, In some embodiments, R 7 It's methyl.

[0141] In some embodiments, R 7 Yes-L 2 -cycloalkyl, -L 2 -heterocycloalkyl, -L 2 -Aryl or -L 2 -heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R 7a Replace; and R 7a Halogen, -CN, -OH, -OR a , oxo, -OC(=O)R a , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-C(=O)R a 、-C(=O)OR a , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 wherein each of the alkyl or heteroalkyl groups is optionally substituted with one or more R. In some embodiments, R 7 Yes-L 2 -cycloalkyl, -L 2-heterocycloalkyl, -L 2 -Aryl or -L 2 -heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R 7a Replace; and R 7a Halogen, -OH, -OR a , oxo, C 1 -C 6 Alkyl or C 1 -C 6 wherein each of the alkyl or heteroalkyl groups is optionally substituted with one or more R. In some embodiments, R 7 Yes-L 2 -cycloalkyl, -L 2 -heterocycloalkyl, -L 2 -Aryl or -L 2 -heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R 7a Replace; and R 7a Halogen, -OH, -OR a , oxo, C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments, R 7 Yes-L 2 -heterocycloalkyl, -L 2 -Aryl or -L 2 -heteroaryl, wherein each of the heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R 7a Replace; and R 7a Halogen, -OH, -OR a , oxo, C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments, R 7 Yes-L 2 -heterocycloalkyl, -L 2 -Aryl or -L 2 -heteroaryl, wherein each of the heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R 7a Replace; and R 7a Halogen, -OH, -OR a , oxo, C 1 -C 6 Alkyl or C 1 -C 6 haloalkyl, and R ais methyl or ethyl. In some embodiments, R 7 Yes-L 2 -heterocycloalkyl, -L 2 -Aryl or -L 2 -heteroaryl, wherein each of the heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R 7a Replace; and R 7a Halogen, -OH, -OR a , oxo, C 1 -C 3 Alkyl or C 1 -C 3 In some embodiments, R 7 Yes-L 2 -thiochromanyl, -L 2 -phenyl, L 2 -Naphthyl, -L 2 -thiophen-2-yl or -L 2 -benzothiazolyl, wherein each of the thiochromanyl, phenyl, naphthyl, thien-2-yl or benzothiazolyl is optionally replaced by one or more R 7a Replace; and R 7a Halogen, -OH, -OR a , oxo, C 1 -C 3 Alkyl or C 1 -C 3 In some embodiments, R 7 Yes-L 2 -thiochromanyl, -L 2 -phenyl, L 2 -Naphthyl, -L 2 -thiophen-2-yl or -L 2 -benzothiazolyl, wherein each of the thiochromanyl, phenyl, naphthyl, thien-2-yl or benzothiazolyl is optionally replaced by one or more R 7a Replace; and R 7a Chlorine, -OH, -OCH 3 、-OCH 2 CH 3 , oxo, -CH 3 or -CF 3 In some embodiments, R 7 Yes-L 2 -phenyl or -L 2 -naphthyl, wherein each of the phenyl or naphthyl groups is optionally substituted with one or more R 7a Replacement; L 2 Does not exist, -CH 2 -or-CH2 CH 2 -; and R 7a It is halogen, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 In some embodiments, R 7 Yes-L 2 -phenyl or -L 2 -naphthyl, wherein each of the phenyl or naphthyl is optionally substituted. 7 Yes-L 2 -phenyl or -L 2 -naphthyl, wherein each of the phenyl or naphthyl groups is optionally substituted with one or more R 7a Replacement; L 2 does not exist, and R 7a It is halogen, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 In some embodiments, R 7 is -phenyl or -naphthyl, wherein each of the phenyl or naphthyl groups is optionally replaced by one or more R 7a Replace, and R 7a It is halogen, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 In some embodiments, R 7 is -phenyl or -naphthyl, wherein each of the phenyl or naphthyl is optionally substituted. 7 is -phenyl or -naphthyl, wherein each of the phenyl or naphthyl groups is optionally replaced by one or more R 7a Replace, and R 7a Chloro, oxo, -CH 3 , -CF 3 or -OCH 3 In some embodiments, R 7 Yes-L 2 -heteroaryl, wherein the heteroaryl is bicyclic and optionally substituted by one or more R 7a In some embodiments, R 7 Yes-L 2-heteroaryl, wherein the heteroaryl is a monocyclic ring and is optionally substituted by one or more R 7a In some embodiments, R 7 Yes-L 2 -cycloalkyl, wherein the cycloalkyl is bicyclic and optionally substituted by one or more R 7a In some embodiments, R 7 Yes-L 2 -cycloalkyl, wherein the cycloalkyl is a monocyclic ring and is optionally substituted by one or more R 7a In some embodiments, R 7 Yes-L 2 -heterocycloalkyl, wherein the heterocycloalkyl is bicyclic and optionally substituted by one or more R 7a In some embodiments, R 7 Yes-L 2 -heterocycloalkyl, wherein the heterocycloalkyl is a monocyclic ring and is optionally substituted by one or more R 7a In some embodiments, R 7 Yes-L 2 -naphthyl, wherein the naphthyl is optionally substituted by one or more R 7a replace.

[0142] L 2 Can be any suitable linker known to those skilled in the art. In some embodiments, L 2 does not exist, C 1 -C 6 Alkylene, C 1 -C 6 Heteroalkylene, C 2 -C 6 Alkenylene or C 2 -C 6 alkynylene, each of which is optionally substituted by one or more R 7a In some embodiments, L 2 Does not exist, -CH 2 -or-CH 2 CH 2 -. In some embodiments, L 2 does not exist, C 1 -C 6 Alkylene, C 1 -C 6 Heteroalkylene, C 2 -C 6 Alkenylene or C 2 -C 6 In some embodiments, L 2 is non-existent or C 1 -C6 In some embodiments, L 2 In some embodiments, L 2 It is C 1 -C 6 Alkylene or C 1 -C 6 In some embodiments, L 2 It is C 1 -C 6 In some embodiments, L 2 It is C 1 -C 3 In some embodiments, L 2 It is C 1 -C 3 Heteroalkylene.

[0143] R 7a Can be any suitable functional group known to those skilled in the art. 7a Halogen, -CN, -NO 2 、-OH、-OR a , oxo, -OC(=O)R a , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)R a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR a 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein 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, wherein each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R. In some embodiments, R 7a Halogen, -CN, -NO 2 、-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) 2 R a 、-S(=O) 2 NR 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) 2 R a 、-C(=O)R a 、-C(=O)OR a 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 In some embodiments, R 7a Is halogen, -OR a , oxo, -C(=O)OR a , C 1 -C 6 Alkyl or C 1 -C6 In some embodiments, R 7a Is halogen, -OC 1 -C 3 Alkyl, oxo, -C(=O)OC 1 -C 3 Alkyl, C 1 -C 3 Alkyl or C 1 -C 3 In some embodiments, R 7a Is halogen, -OC 1 -C 3 Alkyl, oxo, C 1 -C 3 Alkyl or C 1 -C 3 In some embodiments, R 7a Is halogen, -OC 1 -C 3 Alkyl, oxo, C 1 -C 3 Alkyl or C 1 -C 3 In some embodiments, R 7a Chloro, -OCH 3 、-OCH 2 CH 3 , oxo, -CH 3 or -CF 3 .

[0144] In some embodiments, R 7 is optionally substituted aryl or optionally substituted heteroaryl. In some embodiments, R 7 is aryl or heteroaryl, wherein each of the aryl or heteroaryl is optionally substituted with one or more R. In some embodiments, R 7 yes

[0145] In some embodiments, R 6 is hydrogen or C 1 -C 6 Alkyl, and R 7 It is C 1 -C 24 Alkyl, -L 2 -cycloalkyl, -L 2 -Aryl or -L 2 -heteroaryl, wherein each of the alkyl, cycloalkyl, aryl or heteroaryl groups is optionally substituted with halogen, -OH, oxo, C 1 -C 6 Alkyl, C1 -C 6 Haloalkyl or -OC 1 -C 6 In some embodiments, R 6 is hydrogen or C 1 -C 3 Alkyl, and R 7 It is C 1 -C 12 Alkyl, -L 2 -cycloalkyl, -L 2 -Aryl or -L 2 -heteroaryl, optionally substituted. In some embodiments, R 6 is hydrogen and R 7 It is C 1 -C 6 Alkyl, -L 2 -Aryl or -L 2 -heteroaryl, wherein each of the alkyl, aryl or heteroaryl is optionally substituted by halogen, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or -OC 1 -C 6 In some embodiments, R 6 is hydrogen and R 7 Yes-CH 3 、-CH 2 CH 3 、-CH 2 CH 2 CH 3 、-CH(CH 3 ) 2 、-CH 2 CH 2 CH 2 CH 3 、-CH 2 CH(CH 3 ) 2 In some embodiments, R 6 is hydrogen and R 7 Yes-L 2 -thiochromanyl, -L 2 -phenyl, L 2 -Naphthyl, -L 2 -thiophen-2-yl or -L 2 -benzothiazolyl, wherein each of the thiochromanyl, phenyl, naphthyl, thien-2-yl or benzothiazolyl is optionally replaced by one or more R 7a Replace; and R 7aChlorine, -OH, -OCH 3 、-OCH 2 CH 3 , oxo, -CH 3 or -CF 3 In some embodiments, R 6 is hydrogen and R 7 is -phenyl or -naphthyl, wherein each of the phenyl or naphthyl groups is optionally replaced by one or more R 7a Replace, and R 7a Chloro, oxo, -CH 3 , -CF 3 or -OCH 3 In some embodiments, R 6 is hydrogen and R 7 is methyl. In some embodiments, the structure

[0146] In some embodiments, the structure

[0147] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of formula (II):

[0148]

[0149] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of Formula (IIa):

[0150]

[0151] R 4 Can be any suitable functional group known to those skilled in the art. 4 It is H, C 1 -C 24 Alkyl, C 1 -C 24 Haloalkyl, C 1 -C 24 Heteroalkyl, C 2 -C 24 Alkenyl, C 2 -C 24 Alkynyl, -L 5 -cycloalkyl, -L 5 -heterocycloalkyl, -L 5 -Aryl or -L 5 -heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl. In some embodiments, R 4 It is H, C 1 -C24 Alkyl, C 1 -C 24 Haloalkyl or C 1 -C 24 In some embodiments, R 4 It is H, C 1 -C 12 Alkyl, C 1 -C 12 Haloalkyl or C 1 -C 12 In some embodiments, R 4 It is H, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 In some embodiments, R 4 Is H or C 1 -C 12 In some embodiments, R 4 Is H or C 1 -C 6 In some embodiments, R 4 is H. In some embodiments, R 4 It is C 1 -C 6 In some embodiments, R 4 It is C 1 -C 3 In some embodiments, R 4 Yes-CH 3 .

[0152] R 5 Can be any suitable functional group known to those skilled in the art. 5 It is C 1 -C 24 Alkyl, C 1 -C 24 Haloalkyl, C 1 -C 24 Heteroalkyl, C 2 -C 24 Alkenyl, C 2 -C 24 Alkynyl, -L 5 -cycloalkyl, -L 5 -heterocycloalkyl, -L 5 -Aryl or -L 5-heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R 5a In some embodiments, R 5 It is C 1 -C 24 Alkyl, C 1 -C 24 Heteroalkyl, -L 5 -Aryl or -L 5 -heteroaryl, wherein each of the alkyl, heteroalkyl, aryl or heteroaryl groups is optionally substituted with one or more R 5a In some embodiments, R 5 It is C 1 -C 12 Alkyl, C 1 -C 12 Haloalkyl, C 1 -C 12 Hydroxyalkyl, C 1 -C 12 Aminoalkyl, C 1 -C 12 wherein each of the alkyl or heteroalkyl groups is optionally substituted with one or more R 5a In some embodiments, R 5 It is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 wherein each of the alkyl or heteroalkyl groups is optionally substituted with one or more R 5a In some embodiments, R 5 It is C 1 -C 12 Alkyl or C 1 -C 12 wherein each of the alkyl or heteroalkyl groups is optionally substituted with one or more R 5a In some embodiments, R 5 It is C 1 -C 12 Alkyl, wherein the alkyl is optionally substituted by one or more R 5a In some embodiments, R 5 It is C 1 -C 12 wherein the heteroalkyl group is optionally substituted with one or more R5a In some embodiments, R 5 It is C 1 -C 6 Alkyl, wherein the alkyl is optionally substituted by one or more R 5a In some embodiments, R 5 It is C 1 -C 6 Alkyl, wherein the alkyl is optionally substituted by one or more R 5a Replace and R 5a is halogen, oxo or -C(=O)OC 1-3 In some embodiments, R 5 It is C 1 -C 6 Alkyl, wherein the alkyl is optionally substituted by one or more R 5a Replace and R 5a Yes -C(=O)OC 1-3 In some embodiments, R 5 It is C 1 -C 6 Alkyl, wherein the alkyl is optionally substituted by one or more R 5a Replace and R 5a is -C(=O)O-CH 3 or -C(=O)OC(CH 3 ) 3 In some embodiments, R 5 It is C 1 -C 6 wherein the heteroalkyl group is optionally substituted with one or more R 5a In some embodiments, R 5 It is C 1 -C 6 wherein the heteroalkyl group is optionally substituted with one or more R 5a Replace, and R 5a is halogen, oxo or -C(=O)OC 1-3 In some embodiments, R 5 It is C 1 -C 6 wherein the heteroalkyl group is optionally substituted with one or more R 5a Replace, and R 5a Yes -C(=O)OC 1-3 In some embodiments, R 5 It is C 1 -C 6 wherein the heteroalkyl group is optionally substituted with one or more R 5a Replace, and R 5ais -C(=O)O-CH 3 In some embodiments, R 5 Yes-(CH 2 ) 3 -S-CH 3 wherein the heteroalkyl group is optionally replaced by one or more R 5a In some embodiments, R 5 yes

[0153]

[0154]

[0155] In some embodiments, R 5 yes

[0156] In some embodiments, R 5 Yes-L 5 -cycloalkyl, -L 5 -heterocycloalkyl, -L 5 -Aryl or -L 5 -heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R 5a In some embodiments, R 5 Yes-L 5 -cycloalkyl, -L 5 -heterocycloalkyl, -L 5 -Aryl or -L 5 -heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally selected from halogen, oxo, -OH, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl and C 1 -C 6 In some embodiments, R 5 Yes-L 5 -cycloalkyl, -L 5 -heterocycloalkyl, -L 5 -Aryl or -L 5 -heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally selected from halogen, oxo, -OH, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl and C 1 -C 6 In some embodiments, R5 Yes-L 5 -cycloalkyl, -L 5 -heterocycloalkyl, -L 5 -phenyl or -L 5 -indolyl, wherein each of the cycloalkyl, heterocycloalkyl, phenyl or indolyl is optionally substituted with one or more R 5a In some embodiments, R 5 Yes-L 5 -cycloalkyl, -L 5 -heterocycloalkyl, -L 5 -phenyl or -L 5 -indolyl, wherein each of the cycloalkyl, heterocycloalkyl, phenyl or indolyl is optionally substituted with one or more R 5a Replace and L 5 It is C 1 -C 6 Alkylene or C 1 -C 6 heteroalkylene, each of which is optionally substituted by one or more R 5a In some embodiments, R 5 Yes-L 5 -cycloalkyl, -L 5 -heterocycloalkyl, -L 5 -phenyl or -L 5 -indolyl, wherein each of the cycloalkyl, heterocycloalkyl, phenyl or indolyl is optionally selected from halogen, oxo, -OH, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl and C 1 -C 6 In some embodiments, R 5 YesL 5 -phenyl or -L 5 -indolyl, each of which is optionally substituted by one or more R 5a In some embodiments, R 5 are each optionally replaced by one or more R 5a Replaced by -L 5 -phenyl or -L 5 -indolyl and L 5 It is C 1 -C 6 Alkylene or C 1 -C 6 heteroalkylene, each of which is optionally substituted by one or more R 5a In some embodiments, R 5 are each optionally selected from halogen, oxo, -OH, C1 -C 6 Alkyl, C 1 -C 6 Haloalkyl and C 1 -C 6 -L substituted by one or more substituents of alkoxy 5 -phenyl or -L 5 -indolyl. In some embodiments, R 5 are each optionally replaced by one or more R 5a Replaced by -L 5 -phenyl or -L 5 -indolyl, where R 5a is halogen, oxo, -OH or C 1 -C 6 In some embodiments, R 5 are each optionally replaced by one or more R 5a Replaced by -L 5 -phenyl or -L 5 -indolyl, where R 5a is halogen, -OH or oxo. 5 Yes-L 5 -phenyl or -L 5 -indolyl, wherein the phenyl or indolyl is each unsubstituted. 5 Yes-L 5 -phenyl or -L 5 -indolyl, wherein the phenyl or indolyl is each unsubstituted and L 5 It is C 1 -C 6 Alkylene or C 1 -C 6 heteroalkylene, each of which is optionally substituted by one or more R 5a In some embodiments, R 5 Yes-L 5 -phenyl or -L 5 -indolyl, wherein the phenyl or indolyl is each unsubstituted and L 5 It is C 1 -C 6 Alkylene or C 1 -C 6 heteroalkylene, each of which is optionally substituted by one or more R 5a Replace, and R 5a is -C(=O)O-CH 3 In some embodiments, R 5 Yes-L 5 -phenyl or -L 5-indolyl, wherein the phenyl or indolyl is each unsubstituted and L 5 Yes-CH 2 -、-CH 2 CH 2 -or-CH 2 CH 2 -O-CH 2 -, each of which is optionally replaced by one or more R 5a Replace, and R 5a is -C(=O)O-CH 3 In some embodiments, R 5 yes

[0157]

[0158] L 5 is any suitable linker known to those skilled in the art. 5 does not exist, C 1 -C 6 Alkylene, C 1 -C 6 Heteroalkylene, C 2 -C 6 Alkenylene or C 2 -C 24 alkynylene, each of which is optionally substituted by one or more R 5a In some embodiments, L 5 does not exist, C 1 -C 6 Alkylene, C 1 -C 6 Heteroalkylene or C 2 -C 6 alkenylene, each of which is optionally substituted by one or more R 5a In some embodiments, L 5 It is C 1 -C 6 Alkylene or C 1 -C 6 heteroalkylene, each of which is optionally substituted by one or more R 5a In some embodiments, L 5 It is C 1 -C 6 Alkylene or C 1 -C 6 heteroalkylene, each of which is optionally substituted by one or more R 5a Substitution, where R 5a Yes -C(=O)OR a In some embodiments, L 5 is optionally replaced by one or more R5a Substituted C 1 -C 6 In some embodiments, L 5 is optionally replaced by one or more R 5a Substituted C 1 -C 6 Alkylene, where R 5a Yes -C(=O)OR a In some embodiments, L 5 is optionally replaced by one or more R 5a Substituted C 1 -C 6 Alkylene, where R 5a is -C(=O)O-CH 3 In some embodiments, L 5 It is C 1 -C 6 In some embodiments, L 5 It is C 1 -C 3 In some embodiments, L 5 YesL 5 is optionally replaced by one or more R 5a Substituted C 1 -C 6 In some embodiments, L 5 is optionally replaced by one or more R 5a Substituted C 1 -C 6 Heteroalkylene, wherein R 5a Yes -C(=O)OR a In some embodiments, L 5 is optionally replaced by one or more R 5a Substituted C 1 -C 6 Heteroalkylene, wherein R 5a is -C(=O)O-CH 3 In some embodiments, L 5 YesL 5 It is C 1 -C 6 In some embodiments, L 5 YesL 5 It is C 1 -C 3 Heteroalkylene.

[0159] R 5a Can be any suitable functional group known to those skilled in the art. In some embodiments, each R 5a are independently halogen, -CN, -NO2 、-OH、-OR a , oxo, -OC(=O)R a , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)R a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR a 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more R. In some embodiments, each R 5a are independently halogen, -CN, -NO 2 、-OH、-OR a , oxo, -OC(=O)R a , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)R a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR a 、-C(=O)NRc R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 In some embodiments, R 5a Halogen, -CN, -NO 2 、-OH、-OR a , oxo, -OC(=O)R a 、-OC(=O)OR b , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-NR c R d 、-C(=O)R a 、-C(=O)OR a , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 wherein 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 , C 1 -C 6 Alkyl or C 1 -C 6 wherein each of the alkyl or heteroalkyl groups is optionally substituted with one or more R. In some embodiments, R 5a is halogen, oxo, -C(=O)OC 1-6 Alkyl, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C6 Alkoxy, C 3 -C 6 Cycloalkyl or C 2 -C 5 In some embodiments, R 5a is halogen, oxo, -C(=O)OC 1-3 Alkyl, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl or C 2 -C 5 In some embodiments, R 5a Oxo, -C(=O)OC 1-3 Alkyl or C 2 -C 5 In some embodiments, R 5a Oxo, -C(=O)O-CH 3 、-C(=O)OC(CH 3 ) 3 or C 5 In some embodiments, R 5a is -C(=O)O-CH 3 、-C(=O)OC(CH 3 ) 3 or piperidinyl.

[0160] In some embodiments, R 4 and R 5 Together with the nitrogen to which they are attached, they form a heterocycloalkyl or heteroaryl. 4 and R 5 Together with the nitrogen to which they are attached, they form a 3- to 12-membered heterocycloalkyl or heteroaryl, wherein each of the heterocycloalkyl or heteroaryl is optionally substituted by one or more R 5a In some embodiments, R 4 and R 5 Together with the nitrogen to which they are attached, they form a heterocycloalkyl or heteroaryl. 4 and R 5 Together with the nitrogen to which they are attached, they form a 3- to 12-membered heterocycloalkyl or heteroaryl, wherein each of the heterocycloalkyl or heteroaryl is optionally substituted by one or more R 5a Substitution, where R 5a is halogen, oxo, -C(=O)OC 1-3 Alkyl, C1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl or C 2 -C 5 In some embodiments, R 4 and R 5 Together with the nitrogen to which they are attached, they form a 5- to 8-membered heterocycloalkyl or heteroaryl, wherein each of the heterocycloalkyl or heteroaryl is optionally substituted by one or more R 5a In some embodiments, R 4 and R 5 Together with the nitrogen to which they are attached, they form a 5- to 8-membered heterocycloalkyl or heteroaryl, wherein each of the heterocycloalkyl or heteroaryl is optionally substituted by one or more R 5a Substitution, where R 5a is halogen, oxo, -C(=O)OC 1-3 Alkyl, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl or C 2 -C 5 In some embodiments, R 4 and R 5 Together with the nitrogen to which they are attached, they form a 5- to 6-membered heterocycloalkyl or heteroaryl, each of which is optionally substituted. 4 and R 5 Together with the nitrogen to which they are attached, they form a 5- to 6-membered heterocycloalkyl or heteroaryl, each of which is optionally substituted and contains 1 or 2 nitrogens and 0-1 oxygens. 4 and R 5 Together with the nitrogen to which they are attached, they form a 5- to 6-membered heterocycloalkyl. 4 and R 5 Together with the nitrogen to which they are attached they form a 5 to 6 membered heterocycloalkyl group, 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, they form a 5- to 6-membered heterocycloalkyl group, each of which is optionally substituted by one or more R 5a In some embodiments, R 4 and R5 Together with the nitrogen to which they are attached, they form a 5- to 6-membered heterocycloalkyl group, each of which is optionally substituted by one or more R 5a Substitution, where R 5a is halogen, oxo, -C(=O)OC 1-3 Alkyl, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl or C 2 -C 5 In some embodiments, R 4 and R 5 Together with the nitrogen to which they are attached, they form a 5- to 6-membered heterocycloalkyl group, each of which is optionally substituted by one or more R 5a Substitution, where R 5a Yes -C(=O)OC 1-3 Alkyl or C 2 -C 5 In some embodiments, R 4 and R 5 Together with the nitrogen to which they are attached, they form a pyrrolidinyl, morpholinyl or piperidinyl group, each of which is optionally substituted by one or more R 5a In some embodiments, R 4 and R 5 Together with the nitrogen to which they are attached, they form a pyrrolidinyl, morpholinyl or piperidinyl group, each of which is optionally substituted by one or more R 5a Substitution, where R 5a Yes -C(=O)OC 1-3 Alkyl or C 2 -C 5 In some embodiments, R 4 and R 5 Together with the nitrogen to which they are attached, they form a pyrrolidinyl, morpholinyl or piperidinyl group, each of which is optionally substituted by one or more R 5a Substitution, where R 5a is -C(=O)O-CH 3 In some embodiments, R 4 and R 5 Together with the nitrogen to which they are attached, they form a morpholinyl or piperidinyl group, each of which is optionally substituted by one or more R 5a Substitution, where R 5a In some embodiments, the structure

[0161]

[0162] In some embodiments, the structure

[0163] In some embodiments, the structure

[0164]

[0165]

[0166] In some embodiments, the structure

[0167]

[0168] In some embodiments, the structure

[0169]

[0170] 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 -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.

[0171] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of formula (IV):

[0172]

[0173] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of Formula (IVa):

[0174]

[0175] R 8 Can be any suitable functional group known to those skilled in the art. 8 Yes-CH 2 CH 2 CH 3 、-CH(CH 3 ) 2 、-CH 2 CH 2 CH 2 CH 3 、-CH 2 CH(CH 3 ) 2 , C 5 -C 24 Alkyl, C 1 -C 24 Haloalkyl, C 1 -C 24 Heteroalkyl, C 2 -C 24 Alkenyl, C 2 -C 24 Alkynyl, -L 3 -OP(=O)(OH) 2 , -L 3 -cycloalkyl, -L 3 -heterocycloalkyl or -L 3 -aryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl or aryl is optionally substituted by one or more R 8a In some embodiments, R 8 Yes-CH 2 CH 2 CH 3 、-CH(CH 3 ) 2 、-CH 2 CH 2 CH 2 CH 3 、-CH 2 CH(CH 3 ) 2 , C 5 -C 24 Alkyl, C 1 -C 24 Haloalkyl, C 1 -C 24 Heteroalkyl, C 2 -C 24 Alkenyl, C 2 -C 24 Alkynyl, -L 3 -OP(=O)(OH)2 , -L 3 -cycloalkyl, -L 3 -heterocycloalkyl or -L 3 -aryl. In some embodiments, R 8 It is C 5 -C 24 Alkyl, C 2 -C 24 Alkenyl, C 2 -C 24 Alkynyl, -L 3 -OP(=O)(OH) 2 or -L 3 -aryl, wherein each of the alkyl, alkenyl, alkynyl or aryl groups is optionally substituted with one or more R 8a In some embodiments, R 8 It is C 5 -C 24 Alkyl, C 2 -C 24 Alkenyl, C 2 -C 24 Alkynyl, -L 3 -OP(=O)(OH) 2 or -L 3 -aryl. In some embodiments, R 8 It is C 3 -C 12 Alkyl, C 2 -C 12 Alkenyl, C 2 -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, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, naphthyl or heteroaryl is optionally substituted by one or more R 8a replace.

[0176] In some embodiments, R 8 Yes-CH 2 CH 2 CH 3 、-CH(CH 3 ) 2 、-CH 2 CH 2 CH 2 CH 3 、-CH 2 CH(CH 3) 2 , C 5 -C 14 Alkyl, C 1 -C 12 Heteroalkyl, C 2 -C 12 Alkenyl or C 2 -C 12 wherein each of the alkyl, heteroalkyl, alkenyl or alkynyl groups is optionally substituted with one or more R 8a In some embodiments, R 8 Yes-CH 2 CH 2 CH 3 、-CH(CH 3 ) 2 、-CH 2 CH 2 CH 2 CH 3 、-CH 2 CH(CH 3 ) 2 , C 5 -C 12 Alkyl, C 1 -C 12 Heteroalkyl, C 2 -C 12 Alkenyl or C 2 -C 12 wherein each of the alkyl, heteroalkyl, alkenyl or alkynyl groups is optionally substituted with one or more R 8a In some embodiments, R 8 Yes-CH 2 CH 2 CH 3 、-CH(CH 3 ) 2 、-CH 2 CH 2 CH 2 CH 3 、-CH 2 CH(CH 3 ) 2 , C 5 -C 12 Alkyl, C 1 -C 12 Heteroalkyl, C 2 -C 12 Alkenyl or C 2 -C 12 In some embodiments, R 8 Yes-CH 2 CH 2 CH 2 CH3 , C 5 -C 12 Alkyl, C 1 -C 6 Heteroalkyl, C 2 -C 12 Alkenyl or C 2 -C 12 wherein each of the alkyl, heteroalkyl, alkenyl or alkynyl groups is optionally substituted with one or more R 8a Replace, and R 8a In some embodiments, R 8 are each optionally replaced by one or more R 8a Substituted -CH 2 CH 2 CH 2 CH 3 , C 5 -C 12 Alkyl, C 1 -C 6 heteroalkyl, and R 8a It's oxygen.

[0177] In some embodiments, R 8 yes

[0178]

[0179] In some embodiments, R 8 yes

[0180]

[0181] In some embodiments, R 8 yes

[0182]

[0183] In some embodiments, R 8 yes

[0184]

[0185] In some embodiments, R 8 yes

[0186] In some embodiments, R 8 Yes-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 the cycloalkyl, heterocycloalkyl, phenyl, naphthyl or heteroaryl groups is optionally substituted by one or more R 8a In some embodiments, R 8 Yes-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 the cycloalkyl, heterocycloalkyl, phenyl, naphthyl or heteroaryl groups is optionally substituted by one or more R 8a Replacement; L 3 does not exist, C 2 -C 6 Alkenylene, C 1 -C 6 Alkylene or C 1 -C 6 In some embodiments, R 8 Yes-L 3 -(5- or 6-membered cycloalkyl), -L 3 -phenyl, -L 3 -Naphthyl or -L 3 -heteroaryl, each of the cycloalkyl, phenyl, naphthyl or heteroaryl groups is optionally substituted by one or more R 8a In some embodiments, R 8 Yes-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 the cycloalkyl, phenyl, naphthyl or heteroaryl groups is optionally substituted by one or more R 8a Substitution, where R 8a It is halogen, oxo, C 1 -C 6 Alkyl or C 1 -C 6 haloalkyl, and L 3 does not exist, C 1 -C 6 Alkylene, C 1 -C 3 Heteroalkylene or C 2 -C 3 In some embodiments, R 8 are each optionally replaced by one or more R 8a Replaced by -L 3 -cyclohexyl, -L3 -(1,3-dioxolyl), -L 3 -phenyl or -L 3 -naphthyl. In some embodiments, R 8 are each optionally replaced by one or more R 8a Replaced by -L 3 -cyclohexyl, -L 3 -(1,3-dioxolyl), -L 3 -phenyl or -L 3 -naphthyl, where R 8a It is halogen, oxo, C 1 -C 6 Alkyl or C 1 -C 6 haloalkyl and L 3 does not exist, C 1 -C 6 Alkylene, C 1 -C 3 Heteroalkylene or C 2 -C 3 In some embodiments, R 8 are each optionally replaced by one or more R 8a Replaced by -L 3 -cyclohexyl, -L 3 -(1,3-dioxolyl), -L 3 -phenyl or -L 3 -naphthyl, where R 8a It is fluorine, oxo, -CH 3 or -CF 3 In some embodiments, R 8 are each optionally replaced by one or more R 8a Replaced by -L 3 -cyclohexyl, -L 3 -(1,3-dioxolyl), -L 3 -phenyl or -L 3 -naphthyl, where R 8a It is fluorine, oxo, -CH 3 or -CF 3 , and where L 3 does not exist, C 1 -C 6 Alkylene, C 1 -C 3 Heteroalkylene or C 2 -C 3 In some embodiments, R 8 are each optionally replaced by one or more R 8a Replaced by -L 3-cyclohexyl, -L 3 -(1,3-dioxolyl), -L 3 -phenyl or -L 3 -naphthyl, where R 8a It is fluorine, oxo, -CH 3 or -CF 3 , and where L 3 Does not exist, -CH 2 CH 2 -、-CH 2 CH 2 -O-, -CH 2 -or-CH 2 CH=CH-.

[0187] In some embodiments, R 8 yes

[0188] In some embodiments, R 8 yes

[0189] In some embodiments, R 8 yes

[0190] In some embodiments, R 8 yes

[0191] In some embodiments, R 8 Yes-L 3 -OP(=O)(OH) 2 In some embodiments, R 8 yes

[0192]

[0193] L 3 is any suitable linker known to those skilled in the art. 3 does not exist, C 1 -C 6 Alkylene, C 1 -C 6 Heteroalkylene, C 2 -C 6 Alkenylene or C 2 -C 24 alkynylene, each of which is optionally substituted by one or more R 8a In some embodiments, L 3 does not exist, C 1 -C 6 Alkylene, C1 -C 6 Heteroalkylene or C 2 -C 6 In some embodiments, L 3 does not exist, C 1 -C 6 Alkylene, C 1 -C 3 Heteroalkylene or C 2 -C 3 In some embodiments, L 3 Does not exist, -CH 2 CH 2 -、-CH 2 CH 2 -O-, -CH 2 -or-CH 2 CH=CH-. In some embodiments, L 3 does not exist.

[0194] R 8a Can be any suitable functional group known to those skilled in the art. 8a Halogen, -CN, -NO 2 、-OH、-OR a , oxo, -OC(=O)R a , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 OR b 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)R a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6Alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein 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 Halogen, -CN, -NO 2 、-OH、-OR a , oxo, -OC(=O)R a 、-OC(=O)OR b , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-C(=O)R a 、-C(=O)OR a , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 wherein each of the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more R. In some embodiments, R 8a Halogen, -CN, -NO 2 、-OH、-OR a , oxo, -OC(=O)R a 、-OC(=O)OR b , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-C(=O)R a 、-C(=O)OR a , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6In some embodiments, R 8a Is halogen, -OR a , oxo, C 1 -C 6 Alkyl or C 1 -C 6 wherein each of the alkyl or haloalkyl is optionally substituted with one or more R. In some embodiments, R 8a Is halogen, -OR a , oxo, C 1 -C 6 Alkyl or C 1 -C 6 wherein each of the alkyl or haloalkyl is optionally substituted with one or more R. In some embodiments, R 8a It is halogen, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 In some embodiments, R 8a It is fluorine, oxo, -CH 3 , -CF 3 or C 1 -C 3 In some embodiments, R 8a It is fluorine, oxo, -CH 3 or -CF 3 .

[0195] R can be any suitable functional group known to those skilled in the art. In some embodiments, R is independently halogen, -CN, -OH, oxo, -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 6Alkyl, -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 In some embodiments, R is independently halogen, -CN, -OH, oxo, -OC 1 -C 6 Alkyl, -NH 2 , -C(=O)OH or -C(=O)OC 1 -C 6 In some embodiments, R is independently halogen, -OH, oxo, -OC 1 -C 6 Alkyl, -C(=O)OH or -C(=O)OC 1 -C 6 In some embodiments, R is independently oxo.

[0196] R can be any suitable functional group known to those skilled in the art. In some embodiments, each R is independently halogen, -CN, -OH, oxo, -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 -C6 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 In some embodiments, each R is independently halogen, -CN, -OH, oxo, or -OC 1 -C 6 In some embodiments, each R is independently halogen, -CN, -OH, or oxo. In some embodiments, each R is independently oxo.

[0197] 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 percentage above the natural abundance of deuterium.

[0198] In some embodiments of the compounds disclosed herein, one or more of the following groups R, R 1 , R 2 , R 3 , R 4 , R 5 , R 5a , R 6 , R 7 , R 7a , R 8 , R 8a , Ra , R b , R c and R d One or more of 1 H is replaced by one or more deuteriums.

[0199] In some embodiments of the compounds disclosed herein, on a molar basis, each of 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 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%.

[0200] In some embodiments of the compounds disclosed herein, one or more of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups 1 H is replaced by one or more deuteriums.

[0201] Any combination of the above groups for the various variables is contemplated herein. Throughout the specification, one skilled in the art selects groups and substituents to provide stable moieties and compounds.

[0202] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is one of the compounds in Table 1.

[0203] Table 1: Ralinepag prodrugs

[0204]

[0205]

[0206] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is one of the compounds in Table 2.

[0207] Table 2: Other prodrug moieties

[0208]

[0209]

[0210]

[0211] Other forms of the compounds disclosed herein

[0212] Isomers / stereoisomers

[0213] In some embodiments, the compounds described herein exist in the form of 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, E-type (entgegen, E) and Z-type (zusammen, Z) isomers and their corresponding mixtures. In some cases, the compounds described herein have one or more chiral centers, and each center exists in R configuration or S configuration. The compounds described herein include all diastereomeric forms, enantiomeric forms and epimeric forms and their corresponding mixtures. In additional embodiments of the compounds and methods provided herein, the mixture of enantiomers and / or diastereomers produced by a single preparation step, combination or mutual conversion can be used for the applications described herein. In some embodiments, the compounds described herein are prepared into their single stereoisomers by the following manner: reacting the racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds, separating diastereomers, and recovering optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting points, boiling points, solubility, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based on solubility differences. In some embodiments, the optically pure enantiomers and the resolving agent are then recovered by any practical means that do not result in racemization.

[0214] Labeled compounds

[0215] In some embodiments, the compounds described herein exist in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds in the form of pharmaceutical compositions. Therefore, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those described herein, with the exception 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 include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H(D), 3 H. 13 C. 14 C. l5 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Cl. Compounds described herein and pharmaceutically acceptable salts, solvates or stereoisomers thereof containing the above-mentioned isotopes and / or other isotopes of other atoms are within the scope of the present disclosure. Certain isotopically labeled compounds, for example radioactive isotopes such as 3 H and 14 Those into which C is incorporated can be used in drug and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability.

[0216] 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% on a molar basis. In some embodiments, one or more substituents disclosed herein comprise deuterium at a percentage greater than the natural abundance of deuterium. In some embodiments, one or more of the one or more substituents disclosed herein 1 H is replaced by one or more deuteriums.

[0217] 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.

[0218] Pharmaceutically acceptable salts

[0219] In some embodiments, the compounds described herein exist in the form of their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts in the form of pharmaceutical compositions.

[0220] In some embodiments, the compounds described herein have acidic or basic groups and therefore react with any of a number of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein or their solvates or stereoisomers, or by separately reacting the purified compound in its free form with a suitable acid or base and isolating the salt thus formed.

[0221] Examples of pharmaceutically acceptable salts include those prepared by reaction of the compounds described herein with mineral acids, organic acids or inorganic bases, such salts include acetates, acrylates, adipates, alginate, aspartates, benzoates, benzenesulfonates, bisulfates, bisulfites, bromides, butyrates, butyne-1,4-dioates, camphorates, camphorsulfonates, hexanoates, octanoates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, digluconates, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfonates, formates, fumarates, gluconate heptanoates, glycerophosphates, glycolates, hemisulfates, heptanoates, hexanoates, hexyne-1,6-dioates, hydroxybenzoates, gamma-hydroxybutyrates, hydrochlorides salt, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 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, toluenesulfonate, undecanoate, and xylenesulfonate.

[0222] In addition, the compounds described herein can be prepared as pharmaceutically acceptable salts by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as 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, benzenesulfonic acid, Formic acid, 3-(4-hydroxybenzoyl)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 pharmaceutically acceptable per se, are used to prepare salts that can be used as intermediates in obtaining the compounds disclosed herein, their solvates or stereoisomers, and their pharmaceutically acceptable acid addition salts.

[0223] In some embodiments, those compounds described herein that contain free acid groups are reacted with a suitable base, such as a pharmaceutically acceptable metal cation hydroxide, carbonate, bicarbonate, sulfate; with ammonia; or with a pharmaceutically acceptable organic primary, secondary, tertiary or quaternary amine. Representative salts include alkali metal or alkaline earth metal salts, such as lithium, sodium, potassium, calcium, magnesium and aluminum salts, etc. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl) 4 wait.

[0224] Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be 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.

[0225] Solvate

[0226] In some embodiments, the compounds described herein exist in the form of solvates. The present disclosure provides methods for treating diseases by administering such solvates. The present disclosure also provides methods for treating diseases by administering such solvates in the form of pharmaceutical compositions.

[0227] Solvates contain a stoichiometric or non-stoichiometric amount of solvent, and in some embodiments, are formed during the process of crystallization with a pharmaceutically acceptable solvent such as water, ethanol, etc. When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcoholate is formed. Solvates of the compounds described herein can be conveniently prepared or formed during the methods 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 an organic solvent including but not limited to dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein can exist in unsolvated forms as well as solvated forms. In general, for the purposes of the compounds and methods provided herein, solvated forms are considered to be equivalent to unsolvated forms.

[0228] Tautomer

[0229] In some cases, compounds exist as tautomers. The compounds described herein include all possible tautomers within the structural formulas described herein. Tautomers are compounds that can be interconverted by the migration of hydrogen atoms, which is accompanied by a conversion of a single bond and an adjacent double bond. In bonding arrangements in which tautomerism is possible, a chemical equilibrium of tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Pulmonary hypertension (PAH), PGI 2 and IP receptor agonists

[0230] Pulmonary hypertension (PH) is a rare, progressive disease characterized by elevated pulmonary vascular resistance (PVR), which can lead to right ventricular enlargement, hypertrophy, failure, and ultimately death. According to the current World Health Organization (WHO) classification, there are five different groups of PH based on different causes. These are referred to as PH WHO groups. Group 1 is arterial pulmonary hypertension (PAH), which is characterized by thickening and sclerosis of the lung vasculature. Although the 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. WHO Group 2 includes PH due to left heart disease. In these patients, problems with the heart, rather than the lung vasculature, are the primary cause of the disease state. WHO Group 3 includes PH due to chronic lung disease and / or hypoxia (low oxygen levels). Group 3 includes PH associated with interstitial lung disease (PH-ILD) and PH associated with pulmonary fibrosis. WHO Group 4 is known as chronic thromboembolic pulmonary hypertension (CTEPH). WHO Group 5 is when PH is secondary to other diseases in a way that is not well understood. Treatment depends on the form of PH. For example, PAH is often treated with prostacyclin. Regardless of classification, PH is a serious and often fatal disease.

[0231] The severity of PH, including PAH, is graded in 4 functional classes according to a system originally developed by the New York Heart Association (NYHA) for heart failure and then modified by the WHO for patients with PAH. Patients are usually asymptomatic in the earliest stages of the disease (i.e., functional class I), but as the disease progresses, their symptoms (including exertional dyspnea, fatigue, peripheral edema, and syncope) may be indistinguishable from other cardiopulmonary diseases. Many patients are not diagnosed until they develop symptoms of WHO / NYHA functional class II or III.

[0232] Pulmonary arterial hypertension (PAH) has a multifactorial pathobiology. Vasoconstriction, pulmonary vascular wall remodeling, and thrombosis lead to increased pulmonary vascular resistance in PAH (Humbert et al., J. Am. Coll. Cardiol., 2004, 43: 13S-24S.).

[0233] The compounds disclosed herein can be used to treat arterial pulmonary hypertension (PAH) and its symptoms. PAH should be understood to include all forms of pulmonary hypertension described in the 2003 World Health Organization (WHO) clinical scale of pulmonary hypertension. These forms include idiopathic PAH (IPAH); familial PAH (FPAH); PAH associated with other conditions (APAH), such as PAH associated with collagen vascular disease, PAH associated with congenital systemic-pulmonary artery shunts, PAH associated with portal hypertension, PAH associated with HIV infection, PAH associated with drugs or toxins, or PAH associated with others; and PAH associated with significant venous or capillary involvement.

[0234] Idiopathic PAH refers to PAH of unknown cause.

[0235] Familial PAH refers to PAH in which genetic transmission is suspected or documented.

[0236] PAH associated with collagen vascular disease should be understood to include PAH associated with scleroderma, PAH associated with CREST (calcification cutis, Raynaud's phenomenon, esophageal dysfunction, digital scleroderma, 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.

[0237] 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.

[0238] 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 bispyrrolidine alkaloids (e.g., PAHs associated with ingestion of bush teas), and PAHs associated with ingestion of monocrotaline.

[0239] PAH associated with others should be understood to include PAH associated with thyroid disorders, PAH associated with glycogen storage diseases, PAH associated with Gaucher disease, PAH associated with hereditary hemorrhagic telangiectasia, PAH associated with hemoglobinopathies, PAH associated with myeloproliferative disorders, and PAH associated with splenectomy.

[0240] 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 hemangioma (PCH).

[0241] Badesch et al. provided evidence of the association between PAH and scleroderma and the beneficial effects of PGI2 receptor agonists on PAH (Badesch et al., Ann. Intern. Med., 2000, 132: 425-434). Humbert et al. provided evidence of the association between PAH and collagen vascular disease mixed connective tissue disease (MCTD), systemic lupus erythematosus (SLE), Sjogren syndrome and CREST syndrome and the beneficial effects of PGI2 receptor agonists on PAH (Eur. Respir. J., 1999, 13: 1351-1356). Miwa et al. provided evidence of the association between PAH and CREST syndrome and the beneficial effects of PGI2 receptor agonists on PAH (Int. Heart J., 2007, 48: 417-422). Robbins et al. provided evidence of the association between PAH and SLE and the beneficial effects of PGI2 receptor agonists on PAH (Chest, 2000, 117: 14-18). Aguilar et al. provided evidence that PAH is associated with HIV infection and that agonists of the PGI2 receptor have a beneficial effect on PAH (Am. J. Respir. Crit. Care Med., 2000, 162: 1846-1850). Rosenzweig et al. provided evidence that PAH is associated with congenital heart defects (including ASD, VSD, and patent ductus arteriosus) and that agonists of the PGI2 receptor have a beneficial effect on PAH (Circulation, 1999, 99: 1858-1865). Archer et al. provided evidence that PAH is associated with fenfluramine and dextrofenfluramine and anorexigens (Am. J. Respir. Crit. Care Med., 1998, 158: 1061-1067). McGoon et al. provided evidence that PAH is associated with hereditary hemorrhagic telangiectasia (Chest, 2004, 126: 14-34). Hoeper et al. provided evidence that PAH is associated with splenectomy (Ann. Intern. Med., 1999, 130: 506-509). Hoeper et al. provided evidence that PAH is associated with portal hypertension and that agonists of the PGI2 receptor have beneficial effects on PAH (Eur. Respir. J., 2005, 25: 502-508).

[0242] 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 symptoms of PAH.

[0243] In some embodiments, arterial pulmonary hypertension (PAH) is selected from: idiopathic PAH; familial PAH; PAH associated with a collagen vascular disease selected from the group consisting of scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis, and dermatomyositis; PAH associated with a congenital heart disease selected from the group consisting of atrial septal defect (ASD), ventricular septal defect (VSD), and patent ductus arteriosus in a patient; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with ingestion of drugs or toxins; 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 hemangioma (PCH) in a patient.

[0244] Studies have shown that PAH patients have altered prostacyclin and thromboxane A2 activity, increased endothelin synthesis, and decreased nitric oxide synthase expression in the pulmonary arterial system, all of which lead to vasoconstriction / vasodilation imbalance, thrombosis, cell proliferation, and pulmonary artery wall remodeling. Currently available drug treatments for PAH target prostacyclin (also known as prostaglandin I 2 [PGI 2 ]), endothelin, and nitric oxide pathways.

[0245] 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 combination therapy in patients with PAH of WHO / NHYA functional class III. ERAs target the endothelin pathway, while PDE5-I and sGC stimulators target the nitric oxide pathway. There are 3 commercially available ERAs, ambrisentan, bosentan, and macitentan; 2 commercially available PDE5-Is, sildenafil and tadalafil; and 1 sGC stimulator, Riociguat, which is approved for the treatment of PAH. These drugs can improve exercise capacity, symptoms, and / or cardiopulmonary hemodynamic variables in symptomatic PAH patients.

[0246] PGI 2 It is a metabolite of arachidonic acid and is formed via the cyclooxygenase pathway. Endothelial cells are PGI 2 The main source of PGI 2 The vascular effects of its mimetics are largely through activation of PGI 2(IP) receptors, and the vascular effects include vasodilation, inhibition of smooth muscle cell proliferation, and inhibition of platelet aggregation. IP receptors are expressed on platelets and smooth muscle cells of several tissues, including the lungs, heart, aorta, liver, kidneys, and blood vessels. Activation of IP receptors leads to an increase in cellular cyclic adenosine monophosphate (cAMP), followed by arterial vasodilation and inhibition of platelet aggregation. Improved hemodynamics, exercise capacity, and survival have been clearly demonstrated with PGI. 2 Alternative therapy.

[0247] Epoprostenol (a synthetic PGI 2 Epoprostenol (IPR) is a potential vasodilator and inhibitor of platelet aggregation and is the first targeted PAH therapy to be approved. Epoprostenol improves outcomes in patients with PAH compared with conventional therapy, supporting the utility of IP receptors as a therapeutic target for PAH. However, epoprostenol requires continuous infusion via a portable pump, is unstable at room temperature, and is associated with intravenous catheter-related infections and thrombosis. According to the treatment algorithm proposed by the Fifth World Symposium and the European Society of Cardiology / European Respiratory Society (ESC / ERS) guidelines, injectable prostacyclin analogs should be administered in patients with PAH severity of WHO / NYHA functional class III to IV.

[0248] Subsequent PGI 2 Analogs 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 to IV. Although these prostacyclin analogs address some of the limitations associated with epoprostenol, they also have disadvantages in terms of frequent dosing (iloprost) and injection site pain (subcutaneous treprostinil), in addition to typical prostacyclin-related side effects such as headache, nausea, flushing, diarrhea, and jaw pain.

[0249] Selexipag is an oral selective IP receptor agonist approved in the United States and elsewhere for the treatment of PAH to delay disease progression and reduce the risk of PAH-specific hospitalization. ESC / ERS guidelines recommend the use of selexipag to treat patients with PAH severity of WHO / NYHA functional class II to III. Although selexipag and its active metabolite have a similar mode of action to endogenous prostacyclins (IP receptor agonism), they are chemically distinct from prostacyclin analogs with different pharmacological properties. Selexipag has been shown to reduce PVR after 17 weeks of treatment and has demonstrated a 40% reduction in the composite morbidity and mortality endpoint. However, the short effective half-life of the active metabolite of selexipag (3 to 4 hours) results in relatively large fluctuations between peak and trough plasma concentrations after BID administration.

[0250] Despite the many available treatments, functional limitations and survival rates for patients with PAH remain unsatisfactory. 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 have focused on optimizing non-prostanoid IP receptor activation, bioavailability, and PK, aiming to provide sustained and effective target engagement through an oral formulation that provides clinical efficacy similar to that of parenteral prostacyclins.

[0251] As described herein, the compounds described herein may be attractive oral alternatives to currently approved oral prostacyclin analogs and non-prostanoid IP receptor agonists for the treatment of PAH.

[0252] In some embodiments, the compounds disclosed herein are used to treat PH other than PAH. For example, the compounds disclosed herein are used to treat forms of Group 3 PH, such as PH-ILD or PH associated with pulmonary fibrosis.

[0253] The methods and compositions of the present disclosure may also be useful for treating other conditions such as platelet aggregation; coronary artery disease; myocardial infarction; transient ischemic attack; angina; stroke; ischemia-reperfusion injury; restenosis; atrial fibrillation; thrombosis in individuals undergoing angioplasty or coronary bypass or in individuals suffering from atrial fibrillation; atherothrombosis; asthma or its symptoms; diabetes-related conditions 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 disease (COPD).

[0254] In some embodiments, the methods and compositions disclosed herein are used to treat chronic thromboembolic pulmonary hypertension (CTEPH). In some embodiments, the methods and compositions disclosed herein are used to treat persistent / recurrent CTEPH (WHO Group 4) after surgical treatment. In some embodiments, the methods and compositions disclosed herein are used to treat inoperable CTEPH to improve exercise capacity and / or WHO functional class.

[0255] Other PGI2-related diseases and conditions

[0256] Other PGI2-related diseases and conditions include, but are not limited to, antiplatelet therapy, atherosclerosis, asthma, diabetes-related pathologies, glaucoma, hypertension, and anti-inflammatory therapy. Antiplatelet therapy (conditions associated with platelet aggregation)

[0257] Antiplatelet agents (antiplatelet drugs) 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 who are at risk of developing an obstructive blood clot (e.g., coronary thrombosis).

[0258] In a myocardial infarction ("MI" or "heart attack"), the heart muscle does not get enough oxygen-rich blood because of a blockage in a coronary blood vessel. Antiplatelet drugs can reduce damage to the heart if taken during or soon after the attack (preferably within 30 minutes).

[0259] A transient ischemic attack ("TIA" or "mini-stroke") is a brief interruption in the flow of oxygen to the brain caused by a decrease in blood flow through an artery (usually due to an obstructive blood clot). Antiplatelet drugs have been found to be effective in preventing TIAs.

[0260] Angina is a temporary and often recurring chest pain, pressure, or discomfort caused by insufficient oxygen-rich blood flow (ischemia) to certain parts of the heart. In patients with angina, antiplatelet therapy can reduce the effects of angina and the risk of myocardial infarction.

[0261] A stroke is an event in which the brain does not get enough oxygen-rich blood, usually due to a blood clot blocking a blood vessel in the brain. In high-risk patients, regular use of antiplatelet drugs has been found to be effective in preventing the formation of blood clots that cause a first or second stroke.

[0262] Angioplasty is a catheter-based technique used to open an artery blocked by a blood clot. Whether or not a stent is placed immediately after the procedure to keep the artery open, antiplatelet drugs can reduce the risk of additional blood clots forming after the procedure.

[0263] Coronary bypass surgery is a surgical procedure in which an artery or vein is taken from elsewhere in the body and grafted onto a blocked coronary artery, allowing blood to bypass the blockage and pass through the newly connected vessel. After this procedure, antiplatelet drugs can reduce the risk of secondary blood clots.

[0264] Atrial fibrillation is the most common type of persistent irregular heart rhythm (arrhythmia). Atrial fibrillation affects about 2 million Americans each year. In atrial fibrillation, the atria (the upper chambers of the heart) rapidly send out electrical signals that cause them to quiver instead of contracting normally. The result is an abnormally fast and highly irregular heartbeat. Taking antiplatelet drugs after an episode of atrial fibrillation can reduce the risk of blood clots forming in the heart and traveling to the brain (embolism).

[0265] There is evidence that PGI2 receptor agonists will inhibit platelet aggregation and are therefore a potential treatment as an antiplatelet therapy (see, e.g., Moncada et al., Lancet, 1977, 1: 18-20). It has been demonstrated that genetic deficiency of the PGI2 receptor in mice leads to an increased tendency to thrombosis (Murata et al., Nature, 1997, 388: 678-682).

[0266] PGI2 receptor agonists can be used to treat, for example, claudication or peripheral arterial disease and cardiovascular complications, arterial thrombosis, atherosclerosis, vasoconstriction caused by serotonin, ischemia-reperfusion injury, and arterial restenosis after angioplasty or stenting. (See, 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., Am. J. Physiol. Heart. Circ. Physiol., 2006, 290: H1337-H1346; Murata et al., Nat ure, 1997, 388: 678-682; Wang et al., Proc. Natl. Acad. Sci. USA, 2006, 103: 14507-14512; Xiao et al., Circulation, 2001, 104: 2210-2215; McCormick et al., Biochem. Soc. Trans., 2007, 35: 910-911; Arehart et al., Circ. Res., March 6, 2008 Epub ahead of print.)

[0267] PGI2 receptor agonists can also be used alone or in combination with thrombolytic therapy (e.g., tissue plasminogen activator (t-PA)) to provide cardioprotection after MI or post-ischemic myocardial dysfunction (including complications caused thereby), or during percutaneous coronary intervention to provide protection from ischemic injury (including complications caused thereby), etc. PGI2 receptor agonists can also be used in antiplatelet therapy, for example, in combination with α-tocopherol (vitamin E), disintegrin (a disintegrin), or in combination with heparin in hypercoagulable states. (See, for example, 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.)

[0268] The PGI2 receptor agonists disclosed herein can provide beneficial microcirculatory improvements for patients in need of antiplatelet therapy by antagonizing the vasoconstriction products of platelets that are aggregated, such as but not limited to the above-mentioned indications. Therefore, in some embodiments, the present disclosure provides a method for reducing platelet aggregation in patients in need thereof, comprising administering to the patient a composition comprising a 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, stroke, atrial fibrillation, or any of the foregoing symptoms in patients in need of treatment, comprising administering to the patient a composition comprising a PGI2 receptor agonist disclosed herein.

[0269] In a further embodiment, the present disclosure provides a method of reducing the risk of thrombosis in angioplasty or coronary bypass patients or patients suffering from atrial fibrillation, comprising administering to the patient a composition comprising a PGI2 receptor agonist disclosed herein when such risk exists.

[0270] Atherosclerosis

[0271] Atherosclerosis is a complex disease characterized by inflammation, lipid accumulation, cell death and fibrosis. It is a leading cause of mortality in many countries, including the United States. Atherosclerosis, as the term is used herein, should be understood to include conditions that lead to progressive accumulation of smooth muscle cells and lipids within the intima of large and medium-sized arteries.

[0272] It has been demonstrated 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 Epub ahead of print).

[0273] It has been demonstrated that defects in PGI2 receptor signaling appear to accelerate atherothrombosis in humans, ie, agonists of the PGI2 receptor can provide protection from atherothrombosis in humans (Arehart et al., Circ. Res., 2008 Mar 6 Epub ahead of print).

[0274] The compounds of the present disclosure can be used to treat atherosclerosis and treat its symptoms. Therefore, in some embodiments, the present disclosure provides a method for treating atherosclerosis in a patient in need of treatment, comprising administering to the patient a composition comprising a PGI2 receptor agonist disclosed herein. In a further embodiment, a method for treating atherosclerotic symptoms in a patient in need of treatment is provided, comprising administering to the patient a composition comprising a PGI2 receptor agonist disclosed herein.

[0275] asthma

[0276] Asthma is a lymphocyte-mediated inflammatory airway disorder characterized by increased airway eosinophilia, increased mucus produced by goblet cells, and structural remodeling of the airway wall. The prevalence of asthma has increased dramatically throughout the world in recent decades. It has been shown that genetic deficiency of the PGI2 receptor in mice enhances allergic airway inflammation (Takahashi et al., Br J Pharmacol, 2002, 137: 315-322). It has been demonstrated that agonists of the PGI2 receptor can inhibit not only the development of asthma when administered during the sensitization phase, but also the basic features of experimental asthma when administered during the challenge phase (Idzko et al., J. Clin. Invest., 2007, 117:464-472; Nagao et al., Am. J. Respir. Cell Mol. Biol., 2003, 29:314-320), at least in part by significantly interfering with the function of antigen-presenting dendritic cells in the respiratory tract (Idzko et al., J. Clin. Invest., 2007, 117:464-472; Thouet Immunol., 2007, 178:702-710; Jaffar et al., J. Immunol., 2007, 179:6193-6203; Jozefowski et al., Int. Immunopharmacol., 2003, 3:865-878). These cells are crucial for both the initiation and maintenance phases of allergic asthma, because depletion of airway dendritic cells during secondary challenge in sensitized mice eliminates all features of asthma, an effect that can be fully restored by adoptive transfer of wild-type dendritic cells (van Rijt et al., J. Exp. Med., 2005, 201: 981-991). It has also been shown that agonists of the PGI2 receptor can inhibit proinflammatory cytokines secreted by human alveolar macrophages (Raychaudhuri et al., J. Biol. Chem., 2002, 277: 33344-33348). The compounds of the present disclosure can be used to treat asthma and treat its symptoms. Therefore, 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 disclosed herein. In a further embodiment, a method for treating asthma symptoms in a patient in need of treatment is provided, comprising administering to the patient a composition comprising a PGI2 receptor agonist disclosed herein.

[0277] Diabetes-related pathologies

[0278] Although hyperglycemia is the main cause of the pathogenesis of diabetic complications such as diabetic peripheral neuropathy (DPN), diabetic nephropathy (DN) and diabetic retinopathy (DR), vasoconstriction and enhanced platelet aggregation in diabetic patients have also been implicated in disease progression (Cameron et al., Naunyn Schmiedebergs Arch. Pharmacol., 2003 67: 607-614). Agonists of PGI2 receptors promote vasodilation and inhibit platelet aggregation. Improving microvascular blood flow is beneficial to diabetic complications (Cameron, Diabetologia, 2001, 44: 1973-1988).

[0279] It has been demonstrated that agonists of the PGI2 receptor can prevent and reverse abnormalities in motor and sensory peripheral nerve conduction in streptozotocin diabetic rats (Cotter et Naunyn Schmiedebergs Arch. Pharmacol., 1993, 347: 534-540). 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) provide further evidence for the beneficial effects of agonists of the PGI2 receptor in the treatment of diabetic peripheral neuropathy. Owada et al. (Nephron, 2002, 92: 788-796) and Yamashita et al. (Diabetes Res. Clin. Pract., 2002, 57: 149-161) provide evidence for the beneficial effects of agonists of the PGI2 receptor in treating diabetic nephropathy. 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) provide evidence for the beneficial effects of agonists of the PGI2 receptor in treating diabetic retinopathy. It has been shown that agonists of the PGI2 receptor can reduce elevated tumor necrosis factor-α (TNF-α) levels in diabetic patients, suggesting that agonists of the PGI2 receptor may help prevent the progression of diabetic complications (Fujiwara et al., Exp. Clin. Endocrinol. Diabetes, 2004, 112:390-394).

[0280] glaucoma

[0281] Hoyng et al. showed that topical administration of an agonist of the PGI2 receptor can result in a decrease in intraocular pressure (IOP) in rabbits and dogs, thereby having a beneficial effect in the treatment of glaucoma (Hoyng et al., Invest. Ophthalmol. Vis. Sci., 1987, 28:470-476).

[0282] hypertension

[0283] Agonists of the PGI2 receptor have been shown to have activity for regulating vascular tone, vasodilation, and for improving pulmonary hypertension (see, e.g., Strauss et al., Clin Chest Med, 2007, 28: 127-142; Driscoll et al., Expert Opin. Pharmacother., 2008, 9: 65-81). Yamada et al. provided evidence of the beneficial effects of agonists of the PGI2 receptor in treating hypertension (Peptides, 2008, 29: 412-418). Dogan et al. (Gen. Pharmacol., 1996, 27: 1163-1166) and Fang et al. (J. Cereb. Blood Flow Metab., 2006, 26: 491-501) provided evidence that agonists of the PGI2 receptor can prevent cerebral ischemia.

[0284] Anti-inflammatory therapy

[0285] Anti-inflammatory agents are prescribed for a variety of conditions. For example, in inflammatory diseases, they are used to interfere with and thereby reduce potentially harmful substances. There is evidence that PGI2 receptor agonists can inhibit inflammation and are therefore a potential treatment as an 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 chemoattractant protein-1 (MCP-1)) and T cell stimulation 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 the chemotaxis of leukocytes (CD4+ Th2 T cells) induced by chemokines (CCL17) (Jaffar et al., J. Immunol., 2007, 179: 6193-6203).It has been demonstrated 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 Epub ahead of print). It has been shown that agonists of the PGI2 receptor can alleviate 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 patients with type 2 diabetes (Fujiwara et al., Exp. Clin. Endocrinol. Diabetes, 2004, 112: 390-394; Goya et al., Metabolism, 2003, 52: 192-198). It has been shown that agonists of the PGI2 receptor can inhibit ischemia-reperfusion injury (Xiao et al., Circulation, 2001, 104: 2210-2215). It has been shown that agonists of the PGI2 receptor can inhibit restenosis (Cheng et al., Science, 2002, 296: 539-541). It has been shown that agonists of the PGI2 receptor can reduce pulmonary vascular injury and shock in a rat model of septic shock (Harada et al., Shock, Epub ahead of print Feb. 21, 2008). It has been shown that agonists of the PGI2 receptor can reduce serum levels of TNF-α in patients with rheumatoid arthritis, and this is associated with an improvement 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).

[0286] The compounds of the present disclosure can provide beneficial inflammation reduction. The compounds of the present disclosure can provide beneficial harmful inflammatory responses associated with inflammatory diseases. Therefore, in some embodiments, the present disclosure provides a method for reducing inflammation in a patient in need, comprising administering to the patient a composition comprising a PGI2 receptor agonist 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 or MCP-1 in a patient in need, comprising administering to the patient a composition comprising a PGI2 receptor agonist disclosed herein. In some embodiments, the present disclosure provides a method for reducing the production of TNF-α in a patient in need, comprising administering to the patient a composition comprising a PGI2 receptor agonist disclosed herein. In some embodiments, the present disclosure provides a method for increasing the production of IL-10 in a patient in need, comprising administering to the patient a composition comprising a PGI2 receptor agonist disclosed herein. In some embodiments, the present disclosure provides a method for reducing harmful inflammatory responses associated with inflammatory diseases in a patient in need, comprising administering to the patient a composition comprising a PGI2 receptor agonist disclosed herein. In some embodiments, the present disclosure provides a method for treating an inflammatory disease or its symptoms in a patient in need of treatment, comprising administering to the patient a composition comprising a PGI2 receptor agonist disclosed herein. In some embodiments, the present disclosure provides a method for treating an inflammatory disease or its symptoms in a patient in need of treatment, comprising administering to the patient a composition comprising a PGI2 receptor agonist disclosed herein. In some embodiments, the present disclosure provides a method for treating an inflammatory disease or its symptoms 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 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.

[0287] In one aspect, described herein are methods of treating a disease or condition associated with the PGI2 receptor. In some embodiments, the disease or condition is PAH. In some embodiments, the disease or condition is selected from: arterial pulmonary hypertension (PAH); idiopathic PAH; familial PAH; PAH associated with collagen vascular disease, congenital heart disease, portal hypertension, HIV infection, ingested drugs or toxins, hereditary hemorrhagic telangiectasia, splenectomy, pulmonary veno-occlusive disease (PVOD), or pulmonary capillary hemangioma (PCH); PAH with significant venous or capillary involvement; platelet aggregation; coronary artery disease; myocardial infarction; transient ischemic attack; angina; stroke; ischemia-reperfusion injury; restenosis; atrial fibrillation; thrombosis in angioplasty or coronary bypass subjects or subjects with atrial fibrillation; atherosclerosis; atherothrombosis; asthma or its symptoms; diabetes-related conditions 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 (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 disease (COPD).

[0288] Disclosed herein are methods of treating pulmonary arterial hypertension (PAH) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein.

[0289] Methods described herein may be applied to subjects suffering from any suitable symptoms known to those skilled in the art. In some embodiments, subjects have one or more World Health Organization (WHO) / New York Heart Association (NYHA) functional class (FC) II to III symptoms. In some embodiments, symptoms include but are not limited to slight limitations of physical activity, comfort during rest and / or common physical activity causing excessive dyspnea or fatigue, chest pain or near syncope. In some embodiments, symptoms include but are not limited to obvious limitations of physical activity, comfort during rest and / or common activity causing excessive dyspnea or fatigue, chest pain or near syncope.

[0290] Arterial pulmonary hypertension (PAH) can be any arterial pulmonary hypertension known to those skilled in the art. In some embodiments, PAH is selected from: idiopathic PAH; familial PAH; PAH associated with a collagen vascular disease selected from scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis, and dermatomyositis; PAH associated with a congenital heart disease selected from atrial septal defect (ASD), ventricular septal defect (VSD), and patent ductus arteriosus in an individual; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with ingested drugs or toxins; 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 hemangioma (PCH) in an individual. In some embodiments, PAH is hereditary pulmonary arterial hypertension (HPAH), familial PAH, isolated PAH, or familial primary pulmonary arterial hypertension. In some embodiments, PAH is familial primary pulmonary arterial hypertension.

[0291] In one aspect, disclosed herein is a method of modulating a prostacyclin (PGI2) receptor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein.

[0292] 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 thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein.

[0293] The disease or condition associated with the PGI2 receptor can 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, arterial pulmonary hypertension (PAH), pulmonary hypertension, hypertension, connective tissue disease, vascular disease, cardiovascular disease, lung disease and respiratory disease. In some embodiments, the disease or condition is selected from angina infarction, myocardial infarction, arterial pulmonary hypertension (PAH), pulmonary hypertension, hypertension, connective tissue disease, vascular disease, cardiovascular disease, lung disease and respiratory disease. In some embodiments, the disease or condition is selected from arterial pulmonary hypertension (PAH), pulmonary hypertension, hypertension, connective tissue disease, vascular disease, cardiovascular disease, lung disease and respiratory disease. In some embodiments, the disease or condition is selected from arterial pulmonary hypertension (PAH), pulmonary hypertension, hypertension, connective tissue disease, vascular disease, cardiovascular disease, lung disease and respiratory disease. In some embodiments, the disease or condition is selected from arterial pulmonary hypertension (PAH), pulmonary hypertension, hypertension or cardiovascular disease.

[0294] The compounds administered in the methods described herein can be administered by suitable methods known to those skilled in the art. In some embodiments, the compound is administered via a titration regimen.

[0295] In some embodiments, the compound is administered once daily. In some embodiments, the compound is administered twice daily. In some embodiments, the compound is administered in an amount as 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.

[0296] In one aspect, disclosed herein is the use of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein, in the preparation of a medicament for treating arterial pulmonary hypertension (PAH).

[0297] Drug administration

[0298] In certain embodiments, a composition containing one or more compounds described herein is administered for therapeutic treatment. In certain therapeutic applications, the composition is administered to a patient already suffering from the disease or condition in an amount sufficient to cure or at least partially arrest at least one symptom of the disease or condition. The amount effective for this purpose will depend on the severity and course of the disease or condition; previous therapy; the patient's health, weight, and response to the drug; 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 range clinical trials.

[0299] In certain embodiments where the patient's condition does not improve, at the discretion of the physician, administration of the compound is performed chronically, that is, for an extended period of time, including for the entire duration of the patient's life, to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.

[0300] In certain embodiments where the patient's condition does improve, the dose of the administered drug is temporarily reduced or temporarily stopped for a certain period of time (ie, a "drug holiday").

[0301] Once the patient's condition has improved, a maintenance dose is administered as necessary. Subsequently, in a specific embodiment, the dosage or frequency of administration, or both, is reduced as a function of symptoms.

[0302] The amount corresponding to such an amount for a given agent varies depending on factors such as the specific compound, the disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but will still be determined according to the particular circumstances surrounding the case, including, for example, the specific agent administered, the route of administration, the condition being treated, and the subject or host being treated.

[0303] In some embodiments, the dosage for adult treatment is generally in the range of 0.01 mg-5000 mg per day. In some embodiments, the daily dosage suitable for the compounds described herein or their pharmaceutically acceptable salts is about 0.01 to about 50 mg per kg body weight. In various embodiments, the daily dosage and unit dosage are changed depending on many variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the needs of a single subject, the severity of the disease or condition to be treated, and the judgment of the practitioner.

[0304] The dosage when using the compound of the present disclosure can vary in a wide range, and according to convention and physicians, it should be customized according to the individual condition of each case. For example, this depends on the nature and severity of the disease to be treated, the patient's condition, the compound used, or whether the acute or chronic disease state is treated or prevented, or whether a further active compound is applied in addition to the compound of the present disclosure. The representative dosage of the present disclosure includes but is not limited to about 0.001mg to about 5000mg, about 0.001mg to about 2500mg, about 0.001mg to about 1000mg, 0.001mg to about 500mg, 0.001mg to about 250mg, about 0.001mg to 100mg, about 0.001mg to about 50mg and about 0.001mg to about 25mg. Multiple dosages can be applied during one day, particularly when it is considered that a relatively large amount is needed, such as 2, 3 or 4 dosages. Depending on the individual and patient's physician or nursing staff, it is considered appropriate that it may be necessary to deviate upward or downward from the dosage described herein.

[0305] The amount of the active ingredient or its active salt or derivative required for use in the treatment will vary not only due to the selected specific salt, but also due to the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be determined by the assistant physician or clinician. In general, those skilled in the art understand how to extrapolate the in vivo data obtained in a model system (usually an animal model) to another system, such as humans. In some cases, these extrapolations can be based solely on the weight of an animal model compared to another animal model (such as a mammal, preferably a human), however, more commonly, these extrapolations are not simply based on weight, but incorporate various factors. Representative factors include the type, age, 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, pharmacokinetic and toxicological characteristics of the specific compound used, whether a drug delivery system is used, whether an acute or chronic disease state is treated or prevented, or whether a further active compound is administered in addition to the compounds of the present invention and as part of a drug combination. The dosage regimen for treating a disease with the compounds and / or compositions of the present invention is selected according to various factors such as those cited above. Thus, the actual dosage regimen used may vary widely and may therefore deviate from the preferred dosage regimen, and one skilled in the art will recognize that dosages and dosage regimens outside of these typical ranges can be tested and, where appropriate, used in the methods of the present disclosure.

[0306] The desired dosage can conveniently be present in a single dose or in divided doses (e.g., twice, three times, four times or more sub-doses per day) administered at appropriate intervals. The sub-doses themselves can be further divided, for example, into a plurality of discrete loosely spaced administrations. The daily dose can be divided, particularly when it is considered appropriate to administer a relatively large amount, the daily dose can be divided into several portions, for example, 2, 3 or 4 portions for administration. If appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the indicated daily dose.

[0307] The compounds of the present disclosure can be administered in a 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 an active ingredient, a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, or hydrate of a compound of the present disclosure.

[0308] In certain embodiments, compositions containing the compounds described herein and solid forms are administered for prevention and / or treatment. In certain therapeutic applications, the composition is administered to a patient who has suffered from the disease or condition in an amount sufficient to cure or at least partially arrest at least one symptom of the disease or condition. The amount effective for this purpose will depend on the severity and course of the disease or condition; previous therapy; the patient's health, weight, and response to the drug; 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 range clinical trials.

[0309] The amount corresponding to such an amount for a given agent varies depending on factors such as the specific compound, the disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, and is however determined according to the particular circumstances surrounding the case, including, for example, the specific agent administered, the route of administration, the condition being treated, and the subject or host being treated.

[0310] However, in general, the dosage for adult treatment is usually within the range of 0.01 mg-0.6 mg per day. In one embodiment, the desired dosage is conveniently present in a single dose or in divided doses (e.g., twice or more divided doses per day) administered simultaneously or at appropriate intervals. In some embodiments, based on multiple variables related to individual treatment regimens, the daily dose or amount of activity in the dosage form is lower or higher than the scope indicated herein. In various embodiments, the daily dose and unit dose are changed depending on many variables, including but not limited to the activity of the compound used, the disease to be treated or the condition, the mode of administration, the needs of a single subject, the severity of the disease or condition treated, and the judgment of the practitioner.

[0311]

[0013] Within any of the above mentioned aspects are further embodiments wherein an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to a mammal; and / or (b) orally administered to a mammal.

[0312] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is present in an amount 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 0.52 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, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are administered in an amount equivalent to 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, A dose of 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 0.52 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 of Compound 1 is administered. In some embodiments, the dose is administered once a day. In some embodiments, the dose is administered twice a day.

[0313] In some embodiments, a compound disclosed herein, or a pharmaceutically 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 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 pharmaceutically 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 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 Compound 1. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are 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 compounds disclosed herein or their pharmaceutically acceptable salts are 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 compound 1. In some embodiments, the dose is administered once a day. In some embodiments, the dose is administered twice a day.

[0314] In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are administered at 0.05 mg per day. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are administered at 0.10 mg per day. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are administered at 0.15 mg per day. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are administered at 0.20 mg per day. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are administered at 0.25 mg per day. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are administered at 0.30 mg per day. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are administered at 0.35 mg per day. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are administered at 0.40 mg per day. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are administered at 0.45 mg per day. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are administered at 0.5 mg per day. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are administered at 0.55 mg per day. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are administered at 0.60 mg per day. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are administered at 0.65 mg per day. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are administered at 0.70 mg per day. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are administered at 0.75 mg per day. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are administered at 0.80 mg per day. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are administered at 0.85 mg per day. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are administered at 0.9 mg per day. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are administered at 0.95 mg per day. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are administered at 1 mg per day.

[0315] In some embodiments, a compound disclosed herein, or a pharmaceutically 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 compounds disclosed herein or their pharmaceutically acceptable salts are 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 compounds disclosed herein or their pharmaceutically acceptable salts are 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.

[0316] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are administered in an amount equivalent to about 0.05 mg of compound 1 per day. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are administered in an amount equivalent to about 0.1 mg of compound 1 per day. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are administered in an amount equivalent to about 0.15 mg of compound 1 per day. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are administered in an amount equivalent to about 0.2 mg of compound 1 per day. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are administered in an amount equivalent to about 0.25 mg of compound 1 per day. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are administered in an amount equivalent to about 0.3 mg of compound 1 per day. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are administered in an amount equivalent to about 0.35 mg of compound 1 per day. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are administered in an amount equivalent to about 0.4 mg of compound 1 per day. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are administered in an amount equivalent to about 0.45 mg of compound 1 per day. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are administered in an amount equivalent to about 0.5 mg of compound 1 per day. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are administered in an amount equivalent to about 0.55 mg of compound 1 per day. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are administered in an amount equivalent to about 0.6 mg of compound 1 per day. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are administered in an amount equivalent to about 0.65 mg of compound 1 per day. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are administered in an amount equivalent to about 0.7 mg of compound 1 per day. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are administered in an amount equivalent to about 0.75 mg of compound 1 per day. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are administered in an amount equivalent to about 0.8 mg of compound 1 per day. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are administered in an amount equivalent to about 0.85 mg of compound 1 per day. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are administered in an amount equivalent to about 0.9 mg of compound 1 per day. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are administered in an amount equivalent to about 0.95 mg of compound 1 per day. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are administered in an amount equivalent to about 0.1 mg of compound 1 per day.

[0317] In some embodiments, the dose is administered once a day. In some embodiments, the dose is administered twice a day.

[0318] In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are administered once a day. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are administered twice a day. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are administered 1 or 2 times a week. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are administered every other day.

[0319] Route of administration

[0320] Suitable routes of administration include, but are not limited to, oral, intravenous, aerosol, parenteral, pulmonary, transmucosal, transdermal, and topical administration. In addition, parenteral delivery includes, by way of example only, intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, and intranasal injection.

[0321] 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.

[0322] In certain embodiments, the compounds as described herein are administered in a local rather than systemic manner, for example by direct injection of the compound into an organ, often in the form of a reservoir formulation or a sustained release formulation. In a specific embodiment, the long-acting formulation is administered by implantation (e.g., subcutaneous or intramuscular implantation) or by intramuscular injection. In addition, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. In such embodiments, the liposome is targeted to an organ and is selectively absorbed by the organ. In other embodiments, the compound as described herein is provided in a rapid release formulation, in an extended release formulation, or in a medium release formulation.

[0323] For oral administration, the pharmaceutical composition can be in the form of, for example, tablets, capsules, suspensions or liquids. The pharmaceutical composition is preferably prepared in the form of a dosage unit containing a specific amount of the active ingredient. Examples of such dosage units are capsules, tablets, powders, granules or suspensions, containing conventional additives such as lactose, mannitol, corn starch or potato starch; containing binders such as crystalline cellulose, cellulose derivatives, gum arabic, corn starch or gelatin; containing disintegrants such as corn starch, potato starch or sodium carboxymethylcellulose; and containing lubricants such as talc or magnesium stearate. The active ingredient can also be administered as a composition by injection, wherein, for example, saline, glucose or water can be used as a suitable pharmaceutically acceptable carrier.

[0324] The formulations can be prepared by any suitable method, generally by uniformly admixing the active compound or compounds with a liquid or finely divided solid carrier or both in the required proportions and then, if necessary, shaping the resulting mixture into the desired presentation.

[0325] Conventional excipients (such as adhesives, fillers, acceptable wetting agents, tableting lubricants and disintegrants) can be used in tablets and capsules for oral administration. Orally administered liquid preparations can be in the form of solutions, emulsions, aqueous or oily suspensions and syrups. Alternatively, oral preparations can be in the form of dry powders, which can be redissolved with water or another suitable liquid vehicle before use. Additional additives (such as suspending agents or emulsifiers, non-aqueous vehicles (including edible oils), preservatives and flavoring agents and coloring agents) can be added to the liquid preparation. Parenteral dosage forms can be prepared by dissolving the compound of the present disclosure in a suitable liquid vehicle and filtering and sterilizing the solution before filling and sealing a suitable vial or ampoule. These are just a few examples of many suitable methods for preparing dosage forms well known in the art.

[0326] Pharmaceutical formulations include those suitable for oral, topical (including buccal and sublingual) or parenteral (including intramuscular, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation, insufflation or transdermal patch.

[0327] Therefore, the compounds of the present disclosure can be made into pharmaceutical preparations and unit dosage forms thereof together with conventional adjuvants, carriers or diluents, and in this form can be used as solids (such as tablets or filled capsules), or liquids (such as solutions, suspensions, emulsions, elixirs, gels or capsules filled with them), all for oral use in the form of suppositories for rectal administration; or in the form of sterile injection solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof can contain conventional ingredients in conventional proportions, with or without additional active compounds or ingredients, and such unit dosage forms can contain any suitable effective amount of active ingredients commensurate with the expected daily dosage range to be adopted.

[0328] Pharmaceutical compositions / preparations

[0329] A pharmaceutical composition is described herein, comprising a compound described herein or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition is in solid dosage form. In some embodiments, the pharmaceutical composition is a tablet or capsule.

[0330] The compounds described herein are administered to a subject in need thereof, alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent in accordance with standard pharmaceutical practice as a pharmaceutical composition. In some embodiments, the compounds described herein are administered to animals.

[0331] In another aspect, provided herein is a pharmaceutical composition comprising a compound as described herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof and at least one pharmaceutically acceptable excipient. The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable excipients that aid in processing the active compound into a pharmaceutically usable preparation. Appropriate formulations depend on the selected route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Edition (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 Edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for such disclosure.

[0332] In some embodiments, the pharmaceutically acceptable excipient is selected from a carrier, a binder, a filler, a suspending agent, a flavoring agent, a sweetener, a disintegrant, a dispersant, a surfactant, a lubricant, a colorant, a diluent, a solubilizer, a humectant, a plasticizer, a stabilizer, a penetration enhancer, a wetting agent, a defoaming agent, an antioxidant, a preservative, and any combination thereof.

[0333] The 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 melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0334] For preparing pharmaceutical compositions from the compounds of the present disclosure, the choice of suitable pharmaceutically acceptable carriers can be solid, liquid or a mixture of the two. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories and dispersed granules. A solid carrier can be one or more substances which can also be used as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or encapsulating materials.

[0335] In powders, the carrier is a finely divided solid, which is in admixture with the finely divided active component.

[0336] In tablets, the active ingredient is mixed with a carrier having the necessary binding capacity in suitable proportions and compacted into the desired shape and size. Powders and tablets may contain varying percentages of the active compound. A representative amount in a powder or tablet may contain 0.5% to about 90% of the active compound; however, the skilled person 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 the preparation of the active compound with an encapsulating material as a carrier, providing a capsule in which the active ingredient (with or without an added carrier) is surrounded by a carrier and thereby associated with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.

[0337] Liquid form preparations include solutions, suspensions and emulsions, such as water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated into polyethylene glycol aqueous solutions. Injectable preparations (such as sterile injectable aqueous or oily suspensions) can be prepared using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable preparations can also be sterile injectable solutions or suspensions in nontoxic parenteral acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspension media. For this reason, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are found to be used in the preparation of injections.

[0338] Therefore, the compounds according to the present disclosure can be formulated for parenteral administration (e.g., by injection, such as bolus injection or continuous infusion), and can be present in a unit dosage form in an ampoule, a prefilled syringe, a small volume infusion, or a multi-dose container with a preservative added. The pharmaceutical composition can take the form of a suspension, solution, or emulsion such as in an oil or aqueous vehicle, and can contain a formulation agent such as a suspending agent, a stabilizer, and / or a dispersant. Alternatively, the active ingredient can be in the form of a powder, obtained by aseptic separation of sterile solids or lyophilization from a solution, so as to be constituted with a suitable vehicle (e.g., sterile pyrogen-free water) before use.

[0339] Aqueous preparations suitable for oral use can be prepared by dissolving or suspending the active component in water and adding suitable colorants, flavors, stabilizers and thickeners as desired.

[0340] Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active component in water with viscous material, such as a natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.

[0341] Also included are solid form preparations that are intended to be converted into liquid form preparations for oral administration shortly before use. Such liquid forms include solutions, suspensions, and emulsions. In addition to the active ingredient, these preparations may contain coloring agents, spices, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, etc.

[0342] 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.

[0343] The solution or suspension is applied directly to the nasal cavity by conventional means (e.g., with a dropper, pipette, or sprayer). The preparation can be provided in the form of a single dose or multiple doses. In the latter case of a dropper or pipette, this can be achieved by the patient administering a solution or suspension of an appropriate predetermined volume. In the case of a sprayer, this can be achieved by, for example, a metered atomizing spray pump.

[0344] Application to the respiratory tract can also be achieved by means of aerosol formulations, in which the active ingredient is provided in a pressurized package together with a suitable propellant. If the compounds of the present disclosure or pharmaceutical compositions comprising them are administered as an aerosol (e.g., as a nasal aerosol) or by inhalation, this can be performed, for example, using a sprayer, atomizer, a pump atomizer, an inhalation device, a metered-dose inhaler, or a dry powder inhaler. The pharmaceutical form of the compounds of the present disclosure administered as an aerosol can be prepared by methods well known to those skilled in the art. For example, in order to prepare them, a solution or dispersion of the compounds of the present disclosure in water, a water / alcohol mixture, or a suitable saline solution can be used using the following: conventional additives (e.g., benzyl alcohol or other suitable preservatives), absorption enhancers, solubilizers, dispersants, and other substances for increasing bioavailability, and, if appropriate, conventional propellants, for example, including carbon dioxide, CFCs such as dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane; Etc. Aerosols can also conveniently contain surfactants, such as lecithin. The dosage of the drug can be controlled by providing a metering valve.

[0345] In preparations for administration to the respiratory tract, including intranasal preparations, the compound typically has a small particle size, such as 10 microns or less. Such particle sizes can be obtained by methods known in the art (e.g., by micronization). When necessary, a preparation suitable for administering sustained release of the active ingredient can be used.

[0346] Alternatively, the active ingredient may be provided in the form of a dry powder (e.g., a powder mixture of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP)). Conveniently, the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dosage form (e.g., capsules or cartridges such as gelatin, or blister packs) from which the powder can be administered by means of an inhaler.

[0347] The pharmaceutical formulation is preferably in unit dosage form. In this form, the formulation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged formulation that contains discrete quantities of the formulation, such as packaged tablets, capsules, and powders in vials or ampoules. Additionally, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of them in packaged form.

[0348] combination

[0349] Disclosed herein are methods of using a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent, to treat a disease or condition associated with pulmonary hypertension (PH), pulmonary vascular resistance (PVR), arterial pulmonary hypertension (PAH), pulmonary hypertension associated with interstitial lung disease (PH-ILd), or a combination thereof.

[0350] In some embodiments, the additional therapeutic agent is administered simultaneously with the compounds disclosed herein. In some embodiments, the additional therapeutic agent and the compounds disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered at a frequency less than that of the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered at a frequency greater than that of the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered prior to the administration of the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compounds disclosed herein.

[0351] Example

[0352] Example 1: Synthesis of Ralinepag n-butyl ester (2a)

[0353]

[0354] To a suspension of ralinepag 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 for 3 h under argon. After 3 h, the reaction was found to be complete based on TLC. The solvent was removed in vacuo at 50 °C, diluted with EtOAc (30 mL), and washed with Na 2 SO 4 The crude ralinepag n-butyl ester (2a) (0.31 g) was dried, filtered and concentrated in vacuo to obtain crude ralinepag n-butyl ester (2a) (0.31 g). It was purified by silica gel column chromatography. The combined fractions were evaporated in vacuo and dried under high vacuum to give 96.2% yield of pure ralinepag n-butyl ester (2a) (0.23 g) as a colorless viscous oil. The pure product was analyzed by IR, 1 The product was characterized by H NMR and LC-MS. The HPLC purity of the product was found to be 99.14% and did not contain any ralinepag acid (1).

[0355] Example 2: Synthesis of Ralinepag n-dodecyl ester (2b)

[0356]

[0357] At room temperature, under argon, to a solution of ralinepag 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. After 22 h, the reaction was found to be complete based on TLC. The reaction mixture was diluted with EtOAc (15 mL) and saturated with NH 4 Treat with aqueous Cl (15 mL) and separate the layers. The organic layer was washed with saturated NH 4 The mixture was washed with aqueous Cl solution (10 mL) and brine (10 mL), and then with Na 2 SO 4 The mixture was dried, filtered and concentrated in vacuo to obtain crude ralinepag n-dodecyl ester (2b) (0.18 g). It was purified by column chromatography. The combined fractions were evaporated in vacuo and dried under high vacuum to give pure ralinepag n-dodecyl ester (2b) (0.11 g) in 35.7% yield as a waxy solid. The pure product was analyzed by IR, 1 The product was characterized by H NMR and LC-MS. The HPLC purity of the product was found to be 96.68% and did not contain any ralinepag acid (1).

[0358] Example 3: Synthesis of Ralinepag Cyclic Carbonate (2c)

[0359]

[0360] To a solution of ralinepag 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) at room temperature under argon, followed by the addition of K 2 CO 3 (0.200 g, 1.44 mmol). At room temperature, under argon, the resulting reaction mixture was stirred overnight. After 23 h, the reaction was found to be complete based on TLC. The reaction mixture was filtered and concentrated in vacuo to obtain crude ralinepag cyclic carbonate (2c) (0.468 g). It was purified by silica gel column chromatography. The combined fractions were evaporated in vacuo and dried under high vacuum to obtain pure ralinepag cyclic carbonate (2c) (0.23 g) in an 88.1% yield as a transparent viscous oil. The pure product was analyzed by IR, 1The product was characterized by H NMR and LC-MS. The HPLC purity of the product was found to be 96.29% and did not contain any ralinepag acid (1).

[0361] Example 4: Synthesis of Ralinepag n-octyl ester (4a)

[0362]

[0363] At room temperature, under argon, to a solution of ralinepag 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). The resulting reaction mixture was incubated at 60 °C for 3 h. After 3 h, the reaction was found to be complete based on TLC. The reaction mixture was cooled and diluted with EtOAc (20 mL) and washed with saturated NH 4 Treat with aqueous Cl (20 mL) and separate the layers. The organic layer was washed with saturated NH 4 The mixture was washed with aqueous Cl solution (10 mL), water (20 mL), and brine (10 mL), and then with Na 2 SO 4 The crude ralinepag n-octyl ester (4a) (0.90 g; combined with the previous batch) was dried, filtered and concentrated in vacuo to obtain crude ralinepag n-octyl ester (4a) (0.90 g; combined with the previous batch). It was purified by silica gel chromatography. The combined fractions were evaporated in vacuo and dried under high vacuum to give 49.8% yield of pure ralinepag n-octyl ester (4a) (0.21 g) as a viscous oil. The pure product was analyzed by IR, 1 The product was characterized by H NMR and LC-MS. The HPLC purity of the product was found to be 99.16% and did not contain any ralinepag acid (1).

[0364] Example 5: Synthesis of Ralinepag glycolic acid tert-butyl ester (4b)

[0365]

[0366] To a solution of ralinepag 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) and then tert-butyl bromoacetate (0.82 mL, 5.50 mmol) at room temperature under argon. The resulting reaction mixture was incubated at 60 °C for 6 h. After 6 h, the reaction was found to be complete based on TLC. The reaction mixture was cooled and washed with saturated NH 4 The organic layer was washed with brine (30 mL) and purified by Na2 SO 4 The mixture was dried, filtered and concentrated in vacuo to obtain crude ralinepag glycolic acid tert-butyl ester (4b) (5.3 g; combined with previous batch). It was purified by silica gel chromatography. The combined fractions were evaporated in vacuo and dried under high vacuum to give 77.8% yield of pure ralinepag glycolic acid tert-butyl ester (4b) (0.56 g) as a viscous oil. The pure product was analyzed by IR, 1 The product was characterized by HNMR and LC-MS. The HPLC purity of the product was found to be 99.17% and did not contain any ralinepag acid (1).

[0367] Example 6: Synthesis of Ralinepag Methanesulfonamide (6)

[0368]

[0369] At room temperature, under argon, CDI (0.11 g, 0.69 mmol) was added to a stirred solution of ralinepag acid (1) (0.20 g, 0.46 mmol) in THF (3.0 mL) in one go. Under argon, the resulting reaction mixture was stirred for 1 h and then refluxed 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. Under argon, a solution of DBU (0.35 mL, 2.32 mmol) in THF (2.0 mL) was slowly added and stirred overnight at room temperature. After 24 h, the reaction was found to be complete based on TLC. The reaction was confirmed to be complete by LCMS. The solvent was removed in vacuo and the mixture was washed with saturated NH 4 The mixture was diluted with aqueous Cl (10 mL) and EtOAc (10 mL). The layers were separated and the organic layer was washed with water (2 x 10 mL), brine (10 mL), and purified by Na 2 SO 4 The crude material was purified by silica gel column chromatography. The combined fractions were evaporated in vacuo and dried under high vacuum to afford pure ralinepag 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 purified by IR, 1 The product was characterized by H NMR and LC-MS. The HPLC purity of the product was found to be 98.43% and did not contain any ralinepag acid (1).

[0370] Example 7: Synthesis of Ralinepag Acyl Chloride (7)

[0371]

[0372] To a stirred solution of ralinepag 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) (bubbling was observed). The resulting reaction mixture was stirred at room temperature under argon for 2 h. After 2 h, based on 1 The reaction was found to be complete by H NMR. The solvent was removed in vacuo and dried under high vacuum to give 100% yield of pure ralinepag acid chloride (7) (1.06 g) as a slightly yellow solid. The product was analyzed by IR, 1 The compound was characterized by H NMR and LC-MS. The compound was pure enough to be used in the next step without further purification.

[0373] Example 8: Synthesis of Ralinepag Glycine Amide Methyl Ester (8a)

[0374]

[0375] To a stirred solution of ralinepag chloride (7) (0.20 g, 0.44 mmol) in DCM (5.0 mL) was added triethylamine (TEA) (0.15 mL, 1.11 mmol) and stirred for 30 min under argon at 0 °C. Glycine methyl ester hydrochloride (0.08 g, 0.67 mmol) was then added under argon and the resulting reaction mixture was slowly warmed to room temperature. 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 x 15 mL), brine (10 mL), and purified by Na 2 SO 4 The crude ralinepag glycine amide methyl ester (8a) (0.215 g) was dried, filtered and concentrated in vacuo to obtain crude ralinepag glycine amide methyl ester (8a) (0.215 g). It was purified by silica gel chromatography. The combined fractions were evaporated in vacuo and dried under high vacuum to obtain pure ralinepag glycine amide methyl ester (8a) (0.13 g) in 60.9% yield as a white solid. The melting point was found to be 78.3-80.3°C. The pure product was analyzed by IR, 1 The product was characterized by H NMR and LC-MS. The HPLC purity of the product was found to be 99.51% and did not contain any ralinepag acid (1).

[0376] Example 9: Synthesis of Ralinepag L-valine amide methyl ester (8b)

[0377]

[0378] At 0 ° C, under argon, triethylamine (TEA) (0.15 mL, 1.11 mmol) was added to a stirred solution of ralinepag chloride (7) (0.20 g, 0.44 mmol) in DCM (5.0 mL) and stirred for 30 min. Then, under argon, L-valine methyl ester hydrochloride (0.11 g, 0.67 mmol) was added and the resulting reaction mixture was slowly warmed to room temperature. After 2 h, the reaction was found to be complete based on TLC. The reaction mixture was washed with saturated NH 4 The mixture was quenched with aqueous Cl (5 mL) and extracted with DCM (2 x 10 mL). The layers were separated and the DCM layer was washed with water (10 mL), brine (10 mL), and then purified by Na 2 SO 4 The mixture was dried, filtered and concentrated in vacuo to obtain crude L-valine amide methyl ester (8b) (0.34 g). It was purified by silica gel chromatography. The combined fractions were evaporated in vacuo and dried under high vacuum to give pure ralinepag L-valine amide methyl ester (8b) (0.19 g) in 77.9% yield as a clear viscous oil. The pure product was analyzed by IR, 1 The product was characterized by H NMR and LC-MS. The HPLC purity of the product was found to be 98.20% and did not contain any ralinepag acid (1).

[0379] Example 10: Synthesis of Ralinepag Bipiperidinamide (8c)

[0380]

[0381] At 0 ° C, under argon, triethylamine (TEA) (0.15 mL, 1.11 mmol) was added to a stirred solution of ralinepag chloride (7) (0.20 g, 0.44 mmol) in DCM (5.0 mL) and stirred for 30 min. Then under argon, 4-piperidinopiperidine (0.11 g, 0.67 mmol) was added and the resulting reaction mixture was slowly warmed to room temperature. After 1 h, the reaction was found to be about 90% complete based on TLC. The reaction mixture was washed with saturated NH 4 The mixture was quenched with aqueous Cl (5 mL) and extracted with DCM (2 x 15 mL). The layers were separated and the DCM layer was washed with water (2 x 10 mL), brine (10 mL), and then purified by Na 2 SO 4The crude ralinepag bipiperidinamide (8c) (0.30 g) was dried, filtered and concentrated in vacuo to obtain crude ralinepag bipiperidinamide (8c) (0.30 g). It was purified by chromatography. The combined fractions were evaporated in vacuo and dried under high vacuum to obtain pure ralinepag bipiperidinamide (8c) (0.17 g) in 67.3% yield as a waxy solid. The pure product was analyzed by IR, 1 The product was characterized by H NMR and LC-MS. The HPLC purity of the product was found to be 98.27% and did not contain any ralinepag acid (1).

[0382] Example 11: Synthesis of Ralinepag Morpholine Amide (9)

[0383]

[0384] To a solution of ralinepag 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 complete based on TLC. The reaction mixture was washed with saturated NH 4 The mixture was treated with aqueous Cl solution (2 mL) and extracted with EtOAc (10 mL). The aqueous layer was extracted with EtOAc (2 x 10 mL) and the combined organic layers were washed with water (2 x 10 mL), brine (10 mL), and purified by Na 2 SO 4 The crude ralinepag morpholine amide (9) (0.34 g) was dried, filtered and concentrated in vacuo to afford crude ralinepag morpholine amide (9) (0.34 g). It was purified by silica gel column chromatography. The combined fractions were evaporated in vacuo and dried under high vacuum to afford 82.6% yield of pure ralinepag morpholine amide (9) (0.19 g) as a viscous oil which slowly turned into a waxy solid over time. The pure product was analyzed by IR, 1 The product was characterized by H NMR and LC-MS. The HPLC purity of the product was found to be 99.62% and did not contain any ralinepag acid (1).

Claims

1. A compound having a structure of formula (I) or a pharmaceutically acceptable salt or solvate thereof: in: Q is -NR 6 -S(=O)2R 7 ; R 6 Yes H, C1-C 24 Alkyl, C1-C 24 Halogenated alkyl, 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, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R 7a replace; R 7 It is C1-C 24 Alkyl, C1-C 24 Halogenated alkyl, 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, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R 7a replace; L 2 is absent, C1-C6 alkylene, C1-C6 heteroalkylene, C2-C6 alkenylene or C2-C6 alkynylene, each of which is optionally replaced by one or more R 7a replace; or Q is -OR 8 ; R 8 is -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, C5-C 24 Alkyl, C1-C 24 Halogenated alkyl, 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, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl or aryl is optionally substituted with one or more R 8a replace; L 3 is absent, C1-C6 alkylene, C1-C6 heteroalkylene, C2-C6 alkenylene or C2-C 24 alkynylene, each of which is optionally substituted by one or more R 8a substituted; or Q is -NR 4 R 5 ; R 4 Yes H, C1-C 24 Alkyl, C1-C 24 Halogenated alkyl, 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, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R 5a replace; R 5 It is C1-C 24 Alkyl, C1-C 24 Halogenated alkyl, 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, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R 5a replace; or R 4 and R 5 Together with the nitrogen to which they are attached, they form a 3- to 12-membered heterocycloalkyl or heteroaryl, wherein each of the heterocycloalkyl or heteroaryl is optionally substituted by one or more R 5a replace; L 5 is absent, C1-C6 alkylene, C1-C6 heteroalkylene, C2-C6 alkenylene or C2-C 24 alkynylene, each of which is optionally substituted by one or more R 5a replace; R 5a and R 7a are 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, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more R; R 8a 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-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl or heteroaryl, each of which is optionally substituted with one or more R; Each R a are 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); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted by one or more R; each R b are 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); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, Heterocycloalkyl, aryl and heteroaryl are independently optionally substituted with one or more R; each R c and R d are 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); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted by one or more R; or R c and R d together with the atoms to which they are attached form heterocycloalkyl, which is optionally substituted with one or more R; and 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; or 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.

2. The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of formula (IIIa):

3. The compound according to claim 2 or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of formula (IIIa):

4. The compound according to claim 2 or 3, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 It is H or C1-C6 alkyl.

5. The compound according to claim 4 or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 It's H.

6. The compound according to any one of claims 2 to 5, or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 It is C1-C 24 Alkyl, C1-C 24 Halogenated alkyl or C1-C 24 wherein each of the alkyl or heteroalkyl groups is optionally substituted with one or more R 7a replace.

7. A compound according to any one of claims 2 to 6, or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 is optionally substituted -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH2CH2CH2CH2CH3 or -CH2CH2CH2CH2CH2CH3.

8. A compound according to any one of claims 2 to 7, or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 It is methyl, 9. The compound according to any one of claims 2 to 5, or a pharmaceutically acceptable salt or solvate thereof, wherein: R 2 Yes-L 2 -cycloalkyl, -L 2 -heterocycloalkyl, -L 2 -Aryl or -L 2 -heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R 7a replace; and R 7a Halogen, -CN, -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 、-C(=O)R a 、-C(=O)OR a , C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 heteroalkyl, wherein each of the alkyl or heteroalkyl is optionally substituted with one or more R.

10. The compound according to any one of claims 2 to 5, or a pharmaceutically acceptable salt or solvate thereof, wherein: R 7 Yes-L 2 -phenyl or -L 2 -naphthyl, wherein each of the phenyl or naphthyl groups is optionally substituted with one or more R 7a replace; L 2 is absent, -CH2- or -CH2CH2-; and R 7a It is halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy.

11. A compound according to any one of claims 2 to 5, or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 yes 12. The compound according to claim 2 or 3, or a pharmaceutically acceptable salt or solvate thereof, wherein yes 13. The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of formula (II):

14. The compound according to claim 13 or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of formula (IIa):

15. The compound according to claim 13 or 14, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 and R 5 Together with the nitrogen to which they are attached, they form a 3- to 12-membered heterocycloalkyl or heteroaryl, wherein each of the heterocycloalkyl or heteroaryl is optionally substituted by one or more R 5a replace.

16. The compound according to claim 15 or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 and R 5 Together with the nitrogen to which they are attached they form a 5- to 6-membered heterocycloalkyl.

17. A compound according to any one of claims 13 to 16, or a pharmaceutically acceptable salt or solvate thereof, wherein yes 18. The compound according to claim 13 or 14, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 It is H or C1-C6 alkyl.

19. The compound according to claim 18 or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 It's H.

20. The compound according to claim 18 or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 It is a C1-C6 alkyl group.

21. The compound according to claim 13 or 14, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 It is C1-C 12 Alkyl, C1-C 12 Halogenated alkyl, C1-C 12 Hydroxyalkyl, C1-C 12 Aminoalkyl, C1-C 12 wherein each of the alkyl or heteroalkyl groups is optionally substituted with one or more R5a replace.

22. The compound of claim 21 or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, wherein each of the alkyl or heteroalkyl is optionally replaced by one or more R 5a replace.

23. The compound of claim 13 or 14, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 yes 24. The compound of claim 13 or 14, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 Yes-L 5 -cycloalkyl, -L 5 -heterocycloalkyl, -L 5 -Aryl or -L 5 -heteroaryl, wherein 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 alkoxy.

25. The compound of claim 24 or a pharmaceutically acceptable salt or solvate thereof, wherein L 5 is C1-C6 alkylene or C1-C6 heteroalkylene, each of which is optionally substituted by one or more R 5a replace.

26. The compound of claim 13 or 14, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 yes 27. A compound as described in any one of claims 13 to 26, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5a Halogen, -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, wherein each of the alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R.

28. A compound as described in any one of claims 13 to 27, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5a is halogen, oxo, -C(=O)OC 1-3 The group consisting of: a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, and a C2-C5 heterocycloalkyl group.

29. The compound of claim 13 or 14, or a pharmaceutically acceptable salt or solvate thereof, wherein yes 30. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein 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-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.

31. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of formula (IV):

32. The compound of claim 31 or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of formula (IVa):

33. The compound of claim 31 or 32, or a pharmaceutically acceptable salt or solvate thereof, wherein R 8is -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, C5-C 12 Alkyl, C1-C 12 Heteroalkyl, C2-C 12 Alkenyl or C2-C 12 wherein each of the alkyl, heteroalkyl, alkenyl or alkynyl groups is optionally substituted with one or more R 8a replace.

34. The compound of claim 31 or 32, or a pharmaceutically acceptable salt or solvate thereof, wherein R 8 yes 35. The compound of claim 31 or 32, or a pharmaceutically acceptable salt or solvate thereof, wherein R 8 yes 36. The compound of claim 31 or 32, or a pharmaceutically acceptable salt or solvate thereof, wherein R 8 Yes-L 3 -(5- or 6-membered cycloalkyl), -L 3 -(5- or 6-membered heterocycloalkyl), -L 3 -phenyl, -L 3 -Naphthyl or -L 3 -heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, phenyl, naphthyl or heteroaryl is optionally substituted by one or more R 8a Replacement; L 3 is absent, C2-C6 alkenylene, C1-C6 alkylene, or C1-C6 heteroalkylene, each of which is optionally substituted.

37. The compound of claim 31 or 32, or a pharmaceutically acceptable salt or solvate thereof, wherein R 8 yes 38. The compound of claim 31 or 32, or a pharmaceutically acceptable salt or solvate thereof, wherein R 8 yes 39. The compound of claim 31 or 32, or a pharmaceutically acceptable salt or solvate thereof, wherein R 8 Yes-L 3 -OP(=O)(OH)2.

40. The compound of claim 29 or 30, or a pharmaceutically acceptable salt or solvate thereof, wherein R 8 yes 41. A compound as described in any one of claims 31 to 40, or a pharmaceutically acceptable salt or solvate thereof, wherein R 8a Halogen, -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 , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each of the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more R.

42. A compound as described in any one of claims 31 to 41, or a pharmaceutically acceptable salt or solvate thereof, wherein R 8a It is halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy.

43. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from the compounds of Table 1.

44. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 43 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier or excipient.

45. The pharmaceutical composition of claim 44, wherein the pharmaceutical composition is in solid dosage form.

46. ​​The pharmaceutical composition of claim 44 or 45, wherein the pharmaceutical composition is a tablet or a capsule.

47. A method of treating pulmonary arterial hypertension (PAH) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described in any one of claims 1 to 43, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as described in any one of claims 44 to 46.

48. The method of claim 47, wherein the subject has one or more World Health Organization (WHO) / New York Heart Association (NYHA) functional class (FC) class II to III symptoms.

49. The method of claim 47 or 48, wherein the PAH is selected from: Idiopathic PAH; Familial PAH; PAH associated with a collagen vascular disease selected from the group consisting of scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis, and dermatomyositis; PAH associated with a congenital heart disease selected from the group consisting of: atrial septal defect (ASD), ventricular septal defect (VSD), and patent ductus arteriosus in an individual; PAH associated with portal hypertension; PAH associated with HIV infection; PAHs associated with ingested drugs or toxins; 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 hemangioma (PCH) in individuals.

50. The method of claim 47 or 48, wherein the PAH is familial primary pulmonary arterial hypertension.

51. A method of modulating a prostacyclin (PGI2) receptor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described in any one of claims 1 to 43, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as described in any one of claims 44 to 46.

52. A method of treating a disease or condition associated with a prostacyclin (PGI2) receptor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described in any one of claims 1 to 43, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as described in any one of claims 44 to 46.

53. The method of claim 52, wherein the disease or condition is selected from the group consisting of pulmonary arterial hypertension (PAH), pulmonary hypertension, hypertension, connective tissue disease, vascular disease, cardiovascular disease, lung disease, and respiratory disease.

54. The method of any one of claims 47 to 53, wherein the compound is administered via a titration regimen.

55. The method of any one of claims 47 to 54, wherein the compound is administered once daily.

56. The method of any one of claims 47 to 54, wherein the compound is administered twice daily.

57. The method of any one of claims 47 to 56, wherein the compound is administered in an amount of about 0.01 mg to about 2 mg per day.

58. The method of any one of claims 47 to 56, wherein the compound is administered in an amount of about 0.05 mg to about 1.2 mg per day.

59. Use of a compound as described in any one of claims 1 to 43, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as described in any one of claims 44 to 46, in the preparation of a medicament for the treatment of pulmonary arterial hypertension (PAH).

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