A treprostacyclin derivative and its uses

Abstract

A treprostol derivative and its uses are provided. Specifically, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein each group is as defined in the specification. The compound of formula (I) or a pharmaceutically acceptable salt thereof can be used to treat pulmonary hypertension.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field, specifically relating to a treprostol derivative, its preparation method, and its uses. Background Technology

[0002] Pulmonary arterial hypertension (PAH) is a progressive disease characterized by a mean pulmonary artery pressure ≥25 mmHg at rest. It is characterized by progressive pulmonary vascular remodeling, leading to increased vascular resistance, right ventricular hypertrophy, and ultimately right heart failure and death. Globally, approximately 1% of the population is affected by PAH, with an incidence rate of 5%–10% in people over 65 years of age.

[0003] Currently available anti-PH drugs include prostacyclin analogs, prostacyclin receptor agonists, endothelial receptor antagonists (ERA), phosphodiesterase-5 inhibitors (PDE-5i), and soluble guanylate cyclase stimulators (sGC). They exert their therapeutic effects by inhibiting certain pathways, but all have varying degrees of drawbacks.

[0004] Treprostinil is a stable prostacyclin analog. In clinical studies of PAH, subcutaneous, intravenous, and inhalation administration have demonstrated good efficacy and safety. The subcutaneous and intravenous formulation (treprostinil injection; trade name: Remodulin; manufacturer: United Therapeutics; strengths: 20, 50, 100, 200 mg per vial) was approved by the US FDA in May 2002 for the treatment of PAH to improve exercise tolerance; its inhalation formulation (treprostinil inhalation solution; trade name: Tyvaso; manufacturer: United Therapeutics; strength: 1.74 mg per vial) was also approved by the US FDA in the same year. Treprostinil extended-release tablets (trade name: Orenitram; manufacturer: United Therapeutics; strengths: 0.125, 0.25, 1, 2.5 mg per tablet) were also approved by the US FDA on December 20, 2013, for the treatment of PAH. The relative molecular mass of treprostol is 390.52, and its chemical formula is C. 23 H 34 O5, the structural formula is shown in the figure below.

[0005]

[0006] Prostacyclin analogs have a short half-life (currently marketed inhalation solutions are taken 4-9 times daily). Existing technologies have been used to address this issue, such as CN108947843A, CN108349926A, and CN110678174A, which disclose prodrug compounds.

[0007] CN105848479A discloses a class of treprostacyclin derivatives, wherein compound C 16 -TR has good therapeutic effects. C 16 The Phase I clinical trial of TR (European Respiratory Journal 2016 48:PA2403) showed that in healthy volunteers, no cough or sore throat side effects occurred at a dose of 54 μg / kg. However, as the dose was increased to 170 μg / kg and 340 μg / kg, cough and sore throat side effects occurred in the subjects. Summary of the Invention

[0008] The purpose of this disclosure is to provide a treprostol derivative and its pharmaceutical uses.

[0009] This disclosure provides, in one aspect, the compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0010]

[0011] in,

[0012] X is selected from O, S, and NH;

[0013] Y is a divalent group with the following definition:

[0014] a)

[0015] - A straight-chain or branched alkylene group, a straight-chain or branched alkenylene group, or a straight-chain or branched alkyne group, optionally substituted by one or more substituents selected from the following groups: halogen atom, hydroxyl group, mercapto group, nitro group, cyano group, oxo group, thio group, -ONO2 or T, wherein T is -OC(O)(C1-C 10 Alkyl)-ONO2 or -O(C1-C 10 Alkyl)-ONO2;

[0016] b)

[0017]

[0018] in,

[0019] Ring A is selected from the following groups that are optionally substituted by one or more substituents Q1: aryl, heteroaryl, fused-ring aryl, fused-heteroaryl, cycloalkyl, heterocyclic;

[0020] X and Y are each independently selected from -OCO- and -COO-;

[0021] n is an integer from 0 to 20, m is an integer from 1 to 20, and p and q are selected from 0 or 1;

[0022] c)

[0023] The B ring may be optionally replaced by one or more substituents Q2, wherein the B ring is selected from aryl, heteroaryl, fused aryl, fused heteroaryl, cycloalkyl, and heterocyclic groups;

[0024] Q1 and Q2 are each independently selected from: C1-C6 alkyl, halogen, deuterium, hydroxyl, mercapto, -NR i R j Oxygenated, thiolated, -ONO2, -C(O)R k -C(O)OR k -S(O)R k -S(O)OR k -S(O)(O)R k -S(O)(O)OR k -C(S)R k Nitro, cyano, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclic, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 8- to 12-membered fused-ring aryl and 5- to 12-membered fused-heteroaryl;

[0025] R i R j Each is independently selected from hydrogen atom, hydroxyl group, C1-C6 alkyl group, and C1-C6 alkoxy group;

[0026] R k Independently selected from hydrogen atom, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxyl, -NR i R j The alkyl, alkoxy, or haloalkyl groups thereon are optionally selected from C1-C6 alkyl groups, halogens, hydroxyl groups, mercapto groups, and -NR groups. i R j It is substituted by one or more of the following substituents: oxo, thio, carboxyl, nitro, cyano, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclic, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl.

[0027] d)

[0028] -(CH(R1)-CH2-Z) o -CH(R1)-CH2-;

[0029] -(CH2-CH(R1)-Z) o -CH2-CH(R1)-;

[0030] Where Z is O or S, o is an integer from 1 to 6, and R1 is H or -CH3.

[0031] In some implementations, X is 0.

[0032] In some embodiments, Y is an alkylene group, optionally substituted with one or more substituents selected from the following groups: halogen atom, hydroxyl group, -ONO2, or T.

[0033] In some embodiments, Y is an alkylene group, optionally substituted with one or more substituents selected from the following groups: halogen atom, hydroxyl group, -ONO2.

[0034] In some embodiments, Y is an alkylene group, optionally substituted with one or more substituents selected from the group consisting of halogen atoms.

[0035] In some embodiments, Y is C1-C 20 Alkylene.

[0036] In some implementations, Y is C 10 -C 20 Alkylene.

[0037] In some implementations, Y is C 12 -C 20 Alkylene.

[0038] In some implementations, Y is C 14 -C 18 Alkylene.

[0039] In some implementations, Y is C 16 Alkylene.

[0040] In some embodiments, Y is an alkenyl group, optionally substituted by one or more substituents selected from the following groups: halogen atom, hydroxyl group, -ONO2, or T.

[0041] In some embodiments, Y is an alkenyl group, optionally substituted by one or more substituents selected from the following groups: halogen atom, hydroxyl group, -ONO2.

[0042] In some embodiments, Y is an alkenyl group, optionally substituted by one or more substituents selected from the group consisting of halogen atoms.

[0043] In some embodiments, Y is C2-C 20 Alkenyl group.

[0044] In some embodiments, Y is C2-C 10 Alkenyl group.

[0045] In some embodiments, the Y is a C2-C6 alkenyl group.

[0046] In some embodiments, the Y is a C2-C4 alkenyl group.

[0047] In some embodiments, Y is a butene group.

[0048] In some embodiments, Y is an alkyne group, optionally substituted by one or more substituents selected from the following groups: halogen atom, hydroxyl group, -ONO2, or T.

[0049] In some embodiments, Y is an alkyne group, optionally substituted by one or more substituents selected from the following groups: halogen atom, hydroxyl group, -ONO2.

[0050] In some embodiments, Y is an alkyne group, optionally substituted by one or more substituents selected from the group consisting of halogen atoms.

[0051] In some embodiments, Y is C2-C 20 Alynyl group.

[0052] In some embodiments, Y is C2-C 10 Alynyl group.

[0053] In some embodiments, Y is a C2-C6 acetylenoid.

[0054] In some embodiments, Y is a C2-C4 alkyne group.

[0055] In some embodiments, Y is a butyrynyl group.

[0056] In some embodiments, rings A and B are each independently selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 8- to 12-membered fused-ring aryl, 5- to 12-membered fused-ring heteroaryl, 3- to 12-membered cycloalkyl or 3- to 12-membered heterocyclic groups, containing 1 to 4 heteroatoms.

[0057] In some embodiments, rings A and B are each independently selected from 6- to 10-membered aryl groups.

[0058] In some embodiments, rings A and B are each independently selected from phenyl groups.

[0059] In some embodiments, Q1 and Q2 are each independently selected from C1-C6 alkyl, halogen, deuterium, hydroxyl, and -NR. i R j Oxygenation, thioation, -C(O)Rk -C(O)OR k -S(O)R k -S(O)OR k Nitro, cyano, C1-C6 alkoxy, C1-C6 alkyl thioether, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl.

[0060] In some embodiments, Q1 and Q2 are each independently selected from C1-C6 alkyl, halogen, deuterium, hydroxyl, and -NR. i R j Oxygenation, thioation, -C(O)R k -C(O)OR k Cyano, C1-C6 alkoxy, C1-C6 alkyl thioether, halo-C1-C6 alkyl and halo-C1-C6 alkoxy.

[0061] In some embodiments, Q1 and Q2 are each independently selected from C1-C6 alkyl, halogen, hydroxyl, and -NR. i R j -C(O)OR k Cyano, C1-C6 alkoxy, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy.

[0062] In some implementations, n is an integer from 0 to 10.

[0063] In some implementations, n is an integer from 0 to 6.

[0064] In some implementations, n is an integer from 0 to 3.

[0065] In some implementations, n is 0.

[0066] In some implementations, m is an integer from 1 to 10.

[0067] In some implementations, m is an integer from 1 to 6.

[0068] In some implementations, m is an integer from 1 to 3.

[0069] In some implementations, m is 1.

[0070] In some implementations, p is 1.

[0071] In some implementations, p is 0.

[0072] In some implementations, q is 1.

[0073] In some implementations, q is 0.

[0074] In some implementations, Z is O.

[0075] In some implementations, o is an integer from 1 to 3.

[0076] In some implementations, o is 1.

[0077] In some embodiments, the compound is selected from...

[0078]

[0079] The "alkyl" mentioned in this disclosure is preferably C. 10 -C 20 alkyl.

[0080] The "alkenyl" as described in this disclosure is preferably a C2-C6 alkenyl.

[0081] The "alkynyl group" described in this disclosure is preferably a C2-C6 alkynyl group.

[0082] The "alkylene" described in this disclosure is preferably C 10 -C 20 Alkylene.

[0083] The "sub-alkenyl" described in this disclosure is preferably a C2-C6 sub-alkenyl.

[0084] The "sub-chain alkynyl" described in this disclosure is preferably a C2-C6 sub-chain alkynyl.

[0085] The "alkoxy group" described in this disclosure is preferably a C1-C6 alkoxy group.

[0086] The "alkyl thioether group" described in this disclosure is preferably a C1-C6 alkyl thioether group.

[0087] The "cycloalkyl" in this disclosure is preferably 3 to 12-membered, and more preferably 3 to 10-membered cycloalkyl.

[0088] The "heterocyclic group" described in this disclosure is preferably a 3- to 12-membered heterocyclic group, more preferably a 3- to 10-membered heterocyclic group.

[0089] The "aryl" in this disclosure is preferably 6 to 14 methyl groups, and more preferably 6 to 10 methyl groups.

[0090] The "fused-ring aryl" group described in this disclosure is preferably 8 to 14 quinones, and more preferably 8 to 12 quinones.

[0091] The "heteroaryl" as described in this disclosure is preferably 5 to 12 quinones, and more preferably 5 to 10 quinones.

[0092] The "heterogeneous aryl" described in this disclosure is preferably 5 to 14 quinones, and more preferably 5 to 12 quinones.

[0093] This disclosure also provides a pharmaceutical composition comprising at least one of the aforementioned compounds or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0094] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0095] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% of the aforementioned compound based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% of the aforementioned compound. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% of the aforementioned compound. In some embodiments, the pharmaceutical composition contains 1% to 99% of the aforementioned compound. In some embodiments, the pharmaceutical composition contains 2% to 98% of the aforementioned compound.

[0096] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable carriers, diluents, or excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable carriers, diluents, or excipients.

[0097] This disclosure also provides the use of pharmaceutically acceptable salts of the compounds described herein or pharmaceutical compositions in the preparation of medicaments for the treatment and / or prevention of pulmonary hypertension.

[0098] This disclosure further provides a method for treating pulmonary hypertension, wherein the mammal may be human or a non-human mammal, for therapeutic purposes, comprising administering to the mammal the compound described in this disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0099] This disclosure further provides a kit comprising the compounds described herein or their pharmaceutically acceptable salts, or pharmaceutical compositions.

[0100] Terminology Explanation:

[0101] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0102] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. More preferably, alkyl groups containing 1 to 6 carbon atoms are used. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0103] The term "alkylene" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having two residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane. It is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably 10 to 20 carbon atoms, and more preferably 14 to 18 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), etc. Alkylenes can be substituted or unsubstituted; when substituted, the substituent can be replaced at any usable linking point.

[0104] The term "alkenyl" refers to a linear alkenyl group having 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, and having at least one double bond at any position, including, for example, vinylene, allylene, propenylene, butenylene, prenylene, butadienylene, pentenylene, pentenylene, hexenylene, hexadienylene, etc.

[0105] The term "subchain ynyl" includes linear subchain ynyl groups having 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms and having at least one triple bond at any position, including, for example, ethynylene, propynylene, butynylene, pentylyne, hexynylene, etc.

[0106] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. "Carbocyclic" refers to the ring system within the cycloalkyl group.

[0107] The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0108] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m The heteroatom (where m is an integer from 0 to 2) excluding the ring portion of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably piperidinyl or pyrrolidinyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups. "Heterocyclic" refers to the ring system within the heterocyclic group.

[0109] The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0110] wait.

[0111] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0112] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring. "Aromatic ring" refers to the ring system within the aryl group. Non-limiting examples of aryl groups include:

[0113]

[0114] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group, preferably phenyl.

[0115] The term "fused-ring aryl" can refer to an unsaturated aromatic fused-ring structure containing 8-14 ring atoms, formed by two or more ring structures sharing two adjacent atoms. Preferably, it contains 8-12 ring atoms. Examples include fully unsaturated fused-ring aryl groups such as naphthalene and phenanthrene, as well as partially saturated fused-ring aryl groups such as benzo[3-8] saturated monocyclic cycloalkyl groups and benzo[3-8] partially saturated monocyclic cycloalkyl groups. "Fused aromatic ring" refers to the ring system within the fused-ring aryl group. Specific examples of fused-ring aryl groups include 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetrahydronaphthyl, and 1,4-dihydronaphthyl.

[0116] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 12-membered, such as imidazolyl, furanyl, thiophenel, thiazolyl, pyrazolyl, oxazolyl, pyrrololyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, pyrazolyl, pyrimidinyl, or thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is the heteroaryl ring. "Heteroaryl ring" refers to the ring system within the heteroaryl group. Non-limiting examples of heteroaryl groups include:

[0117]

[0118] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0119] The term "fused aryl" can refer to an unsaturated aromatic fused ring structure containing 5-14 ring atoms (including at least one heteroatom) formed by two or more ring structures sharing two adjacent atoms. The carbon, nitrogen, and sulfur atoms can be substituted with oxygen. Preferably, it includes "5-12 fused aryl", "7-12 fused aryl", "9-12 fused aryl", etc., such as benzofuranyl, benzoisofuranyl, benzothiopheneyl, indole, isoindole, benzoxazolyl, benzoimidazolyl, indazole, benzotriazolyl, quinolinyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolinyl, acridinel, phenanthridinel, benzopyridinyl, phthalazinyl, quinazolinyl, quinoxalinyl, quinoxalinyl, phenoxalinyl, phenazinyl, pteridinel, purinel, naphthidyl, phenazine, phenothiazine, etc. "Dense aromatic rings" refers to the ring system in dense aromatic groups.

[0120] The fused heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0121] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0122] The term "alkathio" refers to -S- (alkyl) and -S- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkathio groups include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, and cyclohexylthio. Alkathio groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkathio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkathio, and heterocycloalkathio.

[0123] The term "halogenated alkyl" refers to an alkyl group that has been substituted with a halogen, wherein the alkyl group is as defined above.

[0124] The term "hydroxyl group" refers to the -OH group.

[0125] The term "oxo" refers to an =O group. For example, a carbon atom is connected to an oxygen atom by a double bond, forming a ketone or aldehyde group.

[0126] The term "thio" refers to the =S group. For example, a carbon atom and a sulfur atom are linked by a double bond to form a thiocarbonyl group -C(S)-.

[0127] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0128] The term "amino" refers to -NH2.

[0129] The term "cyano" refers to -CN.

[0130] The term "nitro" refers to -NO2.

[0131] The term "carboxyl group" refers to -C(O)OH.

[0132] The term "carboxylic acid ester group" refers to -C(O)O (alkyl) or -C(O)O (cycloalkyl), where alkyl and cycloalkyl are as defined above.

[0133] The “electron isosteres” of a chemical group are other chemical groups that exhibit the same or similar properties. For example, tetrazolium is an electron isostere of carboxylic acids because it mimics the properties of carboxylic acids, even though the two have very different molecular formulas. Tetrazolium is one of many possible electron isostere substitutions for carboxylic acids. Other anticipated electron isosteres of carboxylic acids include -SO3H, -SO2HNR, -PO2(R)2, -PO3(R)2, -CONHNHSO2R, -COHNSO2R, and -CONRCN, where R is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups as defined herein. Furthermore, electron isosteres of carboxylic acids may contain a 5- to 7-membered carbon ring or heterocycle, which contains any combination of CH2, O, S, or N in any chemically stable oxidation state, wherein any atom of the ring structure is optionally substituted at one or more positions. It is also expected that when chemical substituents are added to carboxyl isosteres, the compounds retain the properties of the carboxyl isosteres. It is anticipated that when the carboxyl isostere is optionally substituted by one or more portions of R as defined above, the degree of substitution and substitution position will be chosen so as not to eliminate the carboxylic acid isosteric property of the compound. Similarly, it should also be anticipated that if one or more R substituents would disrupt the carboxylic acid isosteric property of the compound, such substituents will not be located on the carbocyclic or heterocyclic carboxylic acid isostere at one or more atoms that would preserve or complete the carboxylic acid isosteric property of the compound.

[0134] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0135] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0136] In the chemical structure of the compounds described in this disclosure, the bonds... No configuration was specified, i.e., key It can be or Or simultaneously include and Two configurations. In the chemical structure of the compounds described in this disclosure, the bonds... No configuration is specified, meaning it can be Z configuration, E configuration, or both configurations.

[0137] Although all the above structural formulas are shown in some isomer form for simplicity, this disclosure can include all isomers, such as tautomers, rotational isomers, geometric isomers, diastereomers, racemates and enantiomers.

[0138] Tautomers are structural isomers of organic compounds that readily interconvert through a chemical reaction called tautomerization. This reaction often results in the migration of hydrogen atoms or protons, accompanied by the conversion of single bonds and adjacent double bonds. Some common tautomer pairs are keto-enol and lactam-lactamimide. An example of a lactam-lactamimide equilibrium is between A and B as shown below.

[0139]

[0140] All compounds in this disclosure can be classified as type A or type B. All tautomers are within the scope of this disclosure. The nomenclature of compounds does not exclude any tautomers.

[0141] The compounds described in this disclosure, or any isotopically labeled derivatives thereof, or isomers thereof, are covered by this disclosure. Atoms capable of being isotopically labeled include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine. They can be labeled with isotopes. 2 H(D), 3 H, 11 C 13 C 14 C 15 N、 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I, etc. are used instead. Unless otherwise stated, when a position is specifically designated as deuterium (D), the position shall be understood as having a deuterium abundance of at least 3,000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 45% deuterium incorporation).

[0142] The compounds of the present invention can be synthesized as follows.

[0143] Synthesis method

[0144] The compound represented by formula (I) as defined above can be obtained as follows:

[0145] Step i) Make the compound shown in formula (II)

[0146]

[0147] Wherein, P is H or a hydroxyl protecting group, such as silyl ether, such as trimethylsilyl, tert-butyl-dimethylsilyl or acetyl; W is hydroxyl, Cl or -OC(O)R2, where R2 is a straight-chain or branched C1-C5 alkyl group.

[0148] Reaction with the compound shown in formula (III), wherein Y is as defined above, Z is HX or Z1, X is as defined above, and Z1 is selected from chlorine, bromine, iodine, methanesulfonyl, and benzyl.

[0149] If P is a hydroxyl protecting group, it also includes deprotecting the compound obtained in step i), and fluoride ions are a preferred method for removing silyl ether protecting groups.

[0150] The reaction of the compound represented by formula (II) (where W is a hydroxyl group and P is as defined above) with the compound represented by formula (III) (where Y is as defined above and Z is HX) may be carried out in the presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC) or N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDAC) and a catalyst such as N,N-dimethylaminopyridine (DMAP). The reaction is carried out at temperatures from -20°C to 40°C in an inert anhydrous organic solvent such as N,N'-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, or polyhalogenated aliphatic hydrocarbons. The reaction is completed in a time range of 30 minutes to 36 hours.

[0151] The reaction of compound (II) (where W = -OC(O)R2, and R2 and P are as defined above) with compound (III) (where Y is as defined above, and Z is -OH) can be carried out in the presence of a catalyst such as N,N-dimethylaminopyridine (DMAP). The reaction is conducted at temperatures from -20°C to 40°C in inert organic solvents such as N,N'-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, or polyhalogenated aliphatic hydrocarbons. The reaction is completed in a time range of 30 minutes to 36 hours.

[0152] The reaction of compound (II) (wherein W = -OH, P = H) with compound (III) (wherein Y is as defined above, and Z is Z1) can be carried out in the presence of an organic base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N,N-diisopropylethylamine, diisopropylamine, or an inorganic base, such as an alkaline earth metal carbonate or hydroxide, potassium carbonate, cesium carbonate, in an inert organic solvent such as N,N'-dimethylformamide, tetrahydrofuran, acetone, methyl ethyl ketone, acetonitrile, polyhalogenated aliphatic hydrocarbons (such as dichloromethane), at a temperature of -20°C to 50°C, preferably 5°C to 25°C. The reaction is carried out over a time range of 1 to 8 hours. When Z1 is selected from chlorine or bromine, the reaction is carried out in the presence of an iodine compound such as KI.

[0153] The reaction of compound (II) (where W = Cl, P as defined above) with compound (III) (where Y as defined above, Z is -OH) can be carried out in the presence of an organic base, such as N,N-dimethylaminopyridine (DMAP), triethylamine, or pyridine. The reaction is carried out in an inert organic solvent, such as N,N'-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, or polyhalogenated aliphatic hydrocarbons, at a temperature ranging from -20°C to 40°C. The reaction completes in a time range of 30 minutes to 36 hours. Detailed Implementation

[0154] The following examples further describe the preparation of the compounds and pharmaceutically acceptable salts described in this disclosure, but these examples are not intended to limit the scope of this disclosure.

[0155] Example 1

[0156] Preparation of compound IA:

[0157]

[0158] 1) Preparation of 4-bromobutyl nitrate

[0159] Under nitrogen protection, tetrahydrofuran (10.0 g, 138 mmol) was loaded into a reactor cooled to 5-10 °C. Hydrogen bromide (5.6 g, 69.2 mmol) was slowly added, and the reaction was stirred for 4-6 h. The mixture was diluted with cold water (20 mL), and the temperature was maintained at 5-10 °C. Sodium hydroxide solution was added to adjust the pH to 5-7. Dichloromethane (10 mL) was added, and the mixture was extracted twice. The extract was washed with saturated NaCl water, dried over anhydrous magnesium sulfate, and concentrated to obtain crude 4-bromobutanol (8.2 g).

[0160] In a reactor cooled to -5 to 5°C, fuming nitric acid (6.8 g, 108 mmol) was slowly added to a solution of 98% sulfuric acid (10.4 g, 104 mmol) in dichloromethane (10 mL). Then, 4-bromobutanol (8.2 g, 53.5 mmol) was added to the reaction solution, and the mixture was stirred for 2–5 h. The reaction solution was poured into 100 mL of cold water, sodium hydroxide solution was added, and the pH was adjusted to 5–7. The aqueous phase was extracted with dichloromethane, the organic phases were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to obtain 4-bromobutyl nitrate (10.1 g, 51.2 mmol).

[0161] 2) Preparation of IA

[0162] Treprostolatum sodium salt (300 mg, 0.73 mmol) was dissolved in anhydrous DMF (4 mL), and potassium carbonate (302 mg, 2.19 mmol), potassium iodide (122 mg, 0.73 mmol), and 4-bromobutyl nitrate (216 mg, 1.10 mmol, dissolved in 4 mL dichloromethane) were added. The reaction was stirred at 45–50 °C for 2 h. The mixture was diluted with ethyl acetate, washed with water, and the organic phase was dried over anhydrous magnesium sulfate. The crude phase was concentrated and purified by silica gel column chromatography (dichloromethane / methanol) to obtain IA (280 mg, 0.55 mmol), with a yield of 75.6%.

[0163] MS(ESI):([M+H) + 508.24)

[0164] 1H-NMR (DMSO-d6, 400MHz): δ7.050-7.011(m,1H), 6.778-6.760(m,1H), 6.713-6.693(m,1H), 4.759(s,2H ),4.505(m,1H),4.149-4.119(m,2H),3.503-3.480(m,2H),3.465-3.351(m,2H),3.273-3.239(t,1H,J=6 .8),2.731-2.685(m,2H),2.481-2.427,2.103(m,1H),1.950(m,1H),1.789-1.752(m,1H),1.673-1.666 (m,4H),1.659-1.639(m,1H),1.454-1.242(m,12H),1.022-0.975(m,2H),0.882-0.848(t,3H,J=6.8Hz).

[0165] Example 2

[0166] Preparation of compound IB:

[0167]

[0168] 1) Preparation of 16-bromohexadecyl nitrate

[0169] In a reactor cooled to -5 to 5°C, fuming nitric acid (6.8 g, 108 mmol) was slowly added to a solution of 98% sulfuric acid (10.4 g, 104 mmol) in dichloromethane (10 mL). Then, 16-bromohexadecanol (17.1 g, 53.5 mmol) was added to the reaction solution, and the mixture was stirred for 2–5 h. The reaction solution was poured into cold water (100 mL), sodium hydroxide solution was added, and the pH was adjusted to 5–7. The aqueous phase was extracted with dichloromethane, the organic phases were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to obtain 4-bromohexadecanol nitrate (16.5 g, 45.0 mmol).

[0170] 2) Preparation of IB

[0171] Treprostolatum sodium salt (300 mg, 0.73 mmol) was dissolved in anhydrous DMF (4 mL), and potassium carbonate (302 mg, 2.19 mmol), potassium iodide (122 mg, 0.73 mmol), and 4-bromohexadecyl nitrate (403 mg, 1.10 mmol, dissolved in 4 mL dichloromethane) were added. The reaction was stirred at 45–50 °C for 2 h. The mixture was diluted with ethyl acetate, washed with water, and the organic phase was dried over anhydrous magnesium sulfate. The crude phase was concentrated and purified by silica gel column chromatography (dichloromethane / methanol) to give IB (392 mg, 0.58 mmol), with a yield of 79.4%.

[0172] MS(ESI):([M+H) + 676.48)

[0173] 1 H-NMR (DMSO-d6, 400MHz): δ7.021-7.001(m,1H), 6.771-6.752(m,1H), 6.7023-6.682(m,1H), 4. 744(s,2H),4.513-4.473(m,,2H),4.228-4.214(m,1H),4.107-4.075(m,1H),3.513(m,1H),3.3 21(m,1H),2.731(m,2H),2.510-2.404(m,2H),2.105(m,1H),1.952(m,1H),1.788-1.750(m,2H) ,1.640-1.529(m,4H),1.389-1.222(m,35H),1.022-0.975(m,2H),0.881-0.847(t,3H,J=6.8).

[0174] Example 3: Stability determination of troprostacyclin derivatives

[0175] Metabolic stability assay in human liver microsomes: The stability of human liver microsomes was determined by incubating 2.5 μM of the test compound at 37 °C in 100 mM potassium phosphate buffer (pH 7.4) for 10 min. The potassium phosphate buffer contained 0.5 mg / mL microsomal protein and 25 μL of a 10 mM NADPH system (7.8 mg glucose-6-phosphate, 1.7 mg NADPH, and 6 U glucose-6-phosphate dehydrogenase per mL in 2% w / v sodium bicarbonate). Aliquots were removed at 0.5, 5, 15, 30, and 60 min and quenched with a stop solution containing an internal standard. After incubation, the samples were analyzed by LC-MS / MS. The intrinsic clearance was calculated using the peak area ratio of the analyte to the internal standard. The intrinsic clearance (CLint) was determined by nonlinear regression using the first-order elimination constant.

[0176] Table 3-1 Metabolic stability of the tested compounds in human liver microsomes

[0177]

[0178] The above results indicate that:

[0179] 1) In human liver microsome experiments, the long-chain fatty acid compound (IB) showed significantly improved stability compared to treprostacyclin sodium. The short-chain fatty acid compound (IA) exhibited poor stability, likely due to rapid hydrolysis to the parent drug and subsequent rapid metabolism of the parent drug.

[0180] 2) Compared with IB, the long chain (C16) can significantly prolong the half-life.

[0181] Example 4: Prodrug Conversion Efficiency Test

[0182] The present disclosure is further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present disclosure.

[0183] Experimental objective: To investigate the conversion efficiency of prodrug IB in rat lung tissue by measuring the plasma treprostacyclin content and residual amount of treprostacyclin in the lungs of ventilated rats after inhalation of treprostacyclin prodrug IB prepared in Example 1 and treprostacyclin.

[0184] Test drug:

[0185] Treprostacycline prodrug IB was prepared into lipid nanoparticles according to the method disclosed in CN105848479B. The formulation is as follows (mol%): prodrug IB 40%, squalane 40%, DOPC 10%, Chol-PEG2k 10%.

[0186] Treprostacycline was prepared into a treprostacycline solution by diluting it with physiological saline.

[0187] Experimental Methods: Twelve SPF-grade male Sprague Dawley rats were randomly divided into two groups, Group A and Group B, with six rats in each group. The male SD rats were anesthetized and endotracheal tubes were prepared for ventilation. A cannula was inserted into the right femoral vein to facilitate blood collection. The treprostacyclin derivative prepared in Example 1 was administered to the rats. The drug was nebulized into the rat's airway using a nebulizer. Blood samples were collected from each group at 5 min, 30 min, 1 h, 2 h, 4 h, and 6 h after administration for analysis. Lung tissue samples were collected after 6 h, diluted 10-fold, and analyzed. The specific experimental protocol is shown in the table.

[0188] Table 4-1 Summary Table of Test Plans

[0189]

[0190] Experimental results:

[0191] 1) Six hours after administration, the amount of drug retained in the lung tissue of the treprostol solution group (T1) was relatively low, at 2.56 ng / g (Table 4-2).

[0192] 2) Six hours after administration, the concentrations of the original drug and prodrug in the lung tissue of the prodrug (IB) were 1650 ng / g (Table 4-3) and 604 ng / g (Table 4-4), respectively. It can be seen that the prodrug preparation can significantly increase the residence time and exposure of the drug in the lungs.

[0193] 3) Comparison with historical experimental data: Using the same experimental method, the data was compared with compound C in patent (CN 105848479B). 16 -TR prodrug conversion rate data comparison: IB dosage is C 16 -TR was 4.5 times higher (converted to the original drug treprostacyclin Q), the original drug concentration in lung tissue was 33 times higher, and the prodrug concentration in lung tissue was 1.5 times higher. This indicates that in lung tissue, IB and C... 16 Compared to -TR, the prodrug is converted to the original drug more efficiently and has a higher utilization rate (Tables 4-5). Therefore, in clinical practice, the compounds disclosed herein can reduce the dosage of the drug, achieving the same therapeutic effect while reducing the occurrence of side effects such as cough and sore throat.

[0194] Table 4-2 Concentration of treprostacyclin Q in rat lung tissue 6 hours after administration in group A

[0195]

[0196] Table 4-3 Concentration of treprostacyclin Q in rat lung tissue 6 hours after administration in group B

[0197]

[0198] Table 4-4 Concentration of IB in lung tissue of rats 6 hours after administration in group B

[0199]

[0200] Table 4-5 Comparison of C16-TR and IB in lung tissue transformation rate

[0201]

Claims

1. A compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein, X is O; Y is C 14 -C 18 alkylene.

2. A compound selected from ###0002### or a pharmaceutically acceptable salt thereof.

3. An isotopically substituted compound of a compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof.

4. The isotopically substituted compound of claim 3, wherein the isotopic substitution is deuterium atom substitution.

5. A pharmaceutical composition comprising a compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof or an isotopically substituted compound of claim 3 or 4, and a pharmaceutically acceptable excipient.

6. Use of a compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, an isotopically substituted compound of claim 3 or 4 or a pharmaceutical composition of claim 5 for the manufacture of a medicament for the treatment and / or prevention of pulmonary arterial hypertension.

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