Tetrahydronaphthalene compounds, pharmaceutical compositions thereof and uses thereof

Abstract

A novel tetrahydronaphthalene compound, its stereoisomer, solvate, or pharmaceutically acceptable salt, a pharmaceutical composition comprising said compound, and the use of said compound or composition for preventing and / or treating diseases of the central nervous system, wherein said compound has the structure shown in formula (I): [C90] JPEG2023547209000100.jpg39160

Description

[Technical field]

[0001] The present invention relates to the field of medicinal chemistry, in particular to tetrahydronaphthalene compounds, their stereoisomers, solvates, or pharma- ceutically acceptable salts, pharmaceutical compositions comprising said compounds, and the use of said compounds or compositions in the manufacture of medicaments for the prevention and / or treatment of diseases of the central nervous system. [Background technology]

[0002] Parkinson's disease (PD), also known as paralysis agitans, is a common neurodegenerative disease characterized by progressive, multiple, and insidious onset. Clinical symptoms include motor symptoms such as bradykinesia, resting tremor, and muscle stiffness, as well as non-motor symptoms such as constipation, sleep disorders, dysphagia, and restless legs syndrome (RLS). PD is the second most common neurodegenerative disease after Alzheimer's disease, and according to statistics from the National Parkinson Foundation in the United States in 2013, there are 4 to 6 million patients worldwide. The incidence of PD in developed countries is nearly 0.3% of the total population, with 1% of those aged 60 years or older and increasing rapidly to 4 to 5% after the age of 85. A study of the 10 most populous countries in the world and the five most populous countries in Western Europe indicates that the number of PD patients in these 15 countries will reach 8.7 to 9.3 million by 2030, approximately double the current incidence rate.

[0003] Restless Legs Syndrome (RLS) is a disease of the central nervous system that was first described by the English physician Thomas Willis in 1672, but it did not attract the attention of clinicians until the 1980s. Its clinical symptoms are generally extreme discomfort in both legs while sleeping at night, forcing patients to constantly move their legs or get out of bed to walk, which seriously affects the patients' sleep and quality of life, causing them to suffer from depression, anxiety, etc.

[0004] Statistics show that the incidence of RLS (pRLS) among PD patients is significantly higher than that of the general population, with the incidence of pRLS in Asia being 0.98-27.5% and in Western countries being 5.5-27%. The incidence of primary RLS (iRLS) in Asia is 0.9-12.1%, significantly lower than that in Western countries, 3.9-18.8%. The incidence of sleep disorders in PD is about 70%, and pRLS is one of the factors that cause sleep disorders. The use of dopamine agonists is advantageous in the treatment of PD and RLS. Dopamine replacement therapy, mainly using levodopa, is still considered the "gold standard" for PD treatment. However, with the extension of the treatment time with levodopa, motor complications that appear after long-term use have a serious impact on the quality of life of patients. Studies have shown that the occurrence of motor complications can be prevented and improved by extending the action time of dopamine drugs and providing continuous dopaminergic stimulation.

[0005] Rotigotine is a non-ergot dopamine receptor agonist that has therapeutic effects for Parkinson's disease by stimulating dopamine receptors. Rotigotine is also recommended as an effective treatment for RLS by the Federation of European Neuroscience Societies, the European Neurological Society, and the European Society for Sleep Research. Oral administration of rotigotine is not recommended because of its poor bioavailability and strong first-pass effect. Rotigotine currently approved for sale is a once-daily transdermal controlled release patch that was approved by the US FDA in May 2007 for use in adjuvant therapy for early primary Parkinson's disease and late stage Parkinson's disease, and in February 2012, the FDA recognized Restless Legs Syndrome (RLS) as a new indication. However, as a transdermal formulation, local skin reactions such as erythema, dermatitis, and itching always occur, which seriously affects patient compliance and may force the interruption of administration. The interruption of administration may cause the repeated peaks and valleys of blood drug concentration, leading to the deterioration of the disease, and may bring more serious mental and economic burdens to patients or their families. Patent applications CN108341798 and CN109415335 disclose long-acting prodrug derivatives of rotigotine, and the melting points of all the compounds disclosed in the patents do not exceed 53°C. The low melting points of the compounds pose great challenges to the large-scale production of the preparations, while the properties of the drugs are easily changed when stored for a long time, which may affect the stable release of the long-acting drugs in the body, causing fluctuations in the effective blood drug concentration in the body, and ultimately causing the long-acting drugs to lose their long-acting effect. Therefore, by changing the compound structure of rotigotine to obtain a new tetrahydronaphthalene compound and producing a long-acting preparation, it is possible to reduce the administration frequency, improve the compliance of the administered patients, or avoid forgetting to take the drug due to amnesia, which is common in elderly PD patients, ensure the continuity of administration, and further improve the therapeutic effect, which will be of great benefit to patients or their families, and even to society. The compound of the present invention has a high melting point and low water solubility, and can be used to prepare an excellent suspension formulation. The compound has a slow dissolution rate, and the efficacy lasts for several weeks after a single administration. Summary of the Invention

[0006] "Definitions and General Terms" Unless otherwise specified, all technical terms used herein have the same meaning as commonly understood by those skilled in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0007] As used herein, the modifiers "a," "an," and "said" are intended to include "at least one" or "one or more," unless otherwise specified or clearly contradicted by context. Thus, as used herein, these modifiers refer to one or more than one (i.e., at least one) of an object. For example, "a component" refers to one or more components, i.e., one or more components are contemplated for use or adoption in embodiments of the proposed implementations.

[0008] "Stereoisomers" refer to compounds that have the same chemical constitution, but differ with respect to the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric (cis / trans) isomers, atropisomers, etc.

[0009] The stereochemical definitions and rules used in the present invention are generally in accordance with S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York, and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

[0010] Any of the asymmetric atoms (e.g., carbon, etc.) of the compounds disclosed herein may be present in racemic or enantiomerically enriched form, e.g., in the (R)-, (S)-, or (R,S)-configuration. In some embodiments, each asymmetric atom is in the (R)- or (S)-configuration in at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

[0011] "Pharmaceutically acceptable" refers to the set of compounds, ingredients, compositions, and / or dosage forms that, in reasonable medical judgment, are suitable for contact with the tissues of a patient without undue toxicity, irritation, allergy, or other problem or complication disproportionate to the reasonable benefit-to-risk and are effective for their intended use.

[0012] In general, the term "substituted" refers to one or more hydrogen atoms in the subject structure being replaced by a specified substituent. Unless otherwise specified, in a substituted group, one substituent may be substituted at each substitutable position of the group. When more than one position in the subject structure may be substituted by one or more substituents selected from a specified group, the substituents may be the same or different and substituted at each position.

[0013] The term "unsubstituted" refers to a given group not bearing any substituents.

[0014] The term "optionally substituted by" can be used interchangeably with the term "unsubstituted or substituted by," i.e., the structure is unsubstituted or substituted by one or more substituents according to the invention, the substituents according to the invention being H, D, oxo (=O), thio (=S), F, Cl, Br, I, N, CN, NO, OH, SH, NH, carbonyl, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, -C(=O)NH-R 4a , -NHC(=O)-R 4a , -S(=O) 1-2 NH-R 4b , -NHS(=O) 1-2 -R 4b , C 6~10 Aryl group or C 1~9 heteroaryl groups, etc., where R 4a and R 4b All have the definitions set forth in the present invention.

[0015] In addition, unless otherwise specified, the expressions "each... independently", "... is each, independently", and "... independently, is" used in the present invention can be used interchangeably, and all should be understood in a broad sense, and may indicate that in different groups, specific options represented by the same symbol do not affect each other, or may indicate that in the same group, specific options represented by the same symbol do not affect each other.

[0016] In various parts of this specification, substituents of the compounds disclosed herein are disclosed in radical classes or ranges. In particular, the invention includes each independent subcombination of each member of these radical classes and ranges. For example, the term "C 1~6 "Alkyl group" refers specifically to methyl, ethyl, C3 alkyl groups, C4 alkyl groups, C5 alkyl groups, and C6 alkyl groups, each of which is disclosed independently.

[0017] In each section of the present invention, linking substituents are described. When a linking group is clearly required for a structure, the Markush variable recited for said group should be understood as the linking group. For example, when a linking group is required for the structure and the Markush group definition for said variable recites "alkyl group" or "aryl group", said "alkyl group" or "aryl group" should be understood to represent the linking alkylene group or arylene group, respectively.

[0018] The term "alkyl group" or "alkyl group" as used herein refers to a saturated, linear or branched, monovalent hydrocarbon group containing 1 to 30 carbon atoms, where the alkyl group may be optionally substituted with one or more of the substituents described herein. Unless otherwise specified, the alkyl group contains 1 to 30 carbon atoms. Furthermore, unless otherwise specified, the alkyl group contains 1 to 22 carbon atoms. In one embodiment, the alkyl group contains 1 to 12 carbon atoms, in another embodiment, the alkyl group contains 1 to 6 carbon atoms, in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms, and in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms. The alkyl group may be optionally substituted with one or more of the substituents described herein.

[0019] Examples of alkyl groups are methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -CH(CH3)CH2CH3), (CH3)3), n-pentyl group (-CH2CH2CH2CH2CH3), 2-pentyl group (-CH(CH3)CH2CH2CH3), 3-pentyl group (-CH(CH2CH3)2), 2-methyl-2-butyl group (-C(CH3)2CH2CH3), 3-methyl-2-butyl group (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl group (-CH2CH2CH(CH3)2), 2-methyl-1-butyl group (-CH 2CH(CH3)CH2CH3), n-hexyl group (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl group (-CH(CH3)CH2CH2CH2CH2CH3), 3-hexyl group (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl group (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl group (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl Examples of such groups include, but are not limited to, the following: (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl group (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl group (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl group (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl group (-CH(CH3)C(CH3)3), n-heptyl group, n-octyl group, and the like.

[0020] The term "alkenyl group" refers to a linear or branched monovalent hydrocarbon group containing from 2 to 30 carbon atoms and having at least one site of unsaturation, i.e., one carbon-carbon sp 2It has double bonds and may be in the "cis" and "trans" configurations, or the "E" and "Z" configurations. In one embodiment, an alkenyl group contains 2-30 carbon atoms, in one embodiment, an alkenyl group contains 2-22 carbon atoms, in one embodiment, an alkenyl group contains 2-8 carbon atoms, in another embodiment, an alkenyl group contains 2-6 carbon atoms, and in yet another embodiment, an alkenyl group contains 2-4 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl groups (-CH=CH2), allyl groups (-CH2CH=CH2), and the like. The alkenyl groups may be optionally substituted with one or more substituents described herein.

[0021] The term "alkynyl group" refers to a linear or branched monovalent hydrocarbon group containing 2 to 30 carbon atoms and having at least one site of unsaturation, i.e., one carbon-carbon sp triple bond. In one embodiment, an alkynyl group contains 2 to 30 carbon atoms, in one embodiment, an alkynyl group contains 2 to 22 carbon atoms, in one embodiment, an alkynyl group contains 2 to 8 carbon atoms, in another embodiment, an alkynyl group contains 2 to 6 carbon atoms, and in yet another embodiment, an alkynyl group contains 2 to 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl groups (-C≡CH), propargyl groups (-CH2C≡CH), 1-propynyl groups (-C≡C-CH3), and the like. The alkynyl groups may be optionally substituted with one or more substituents described herein.

[0022] The term "aliphatic" or "aliphatic group" as used herein refers to a straight-chain (i.e., unbranched) or branched-chain, substituted or unsubstituted, fully saturated or with one or more degrees of unsaturation, hydrocarbon chain. Unless otherwise specified, an aliphatic group contains 1-30 carbon atoms, in some embodiments, an aliphatic group contains 1-20 carbon atoms, in some embodiments, an aliphatic group contains 1-10 carbon atoms, in some embodiments, an aliphatic group contains 1-8 carbon atoms, in some embodiments, an aliphatic group contains 1-6 carbon atoms, in some embodiments, an aliphatic group contains 1-4 carbon atoms, and in some embodiments, an aliphatic group contains 1-3 carbon atoms. Suitable aliphatic groups include, but are not limited to, straight-chain or branched-chain, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups, where said alkyl, alkenyl, or alkynyl groups are defined in the present description. Examples of aliphatic or aliphatic groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, hexyl, isobutyl, sec-butyl, ethenyl, propenyl, butenyl, ethynyl groups, and the like.

[0023] The term "cycloalkyl group" as used herein, unless otherwise specified, refers to a monovalent saturated or partially unsaturated (but not aromatic) monocyclic or polycyclic hydrocarbon. In some embodiments, the cycloalkyl group may be a bridged or unbridged, spirocyclic or non-spirocyclic, and / or fused or non-fused bicyclic group. In some embodiments, the cycloalkyl group contains 3 to 10 carbon atoms, i.e., C3 to C6. 10 In some embodiments, the cycloalkyl group is a cycloalkyl group having 3 to 15 (C 3~15 ), 3~10(C 3~10 ), or 3 to 7 (C 3~7) carbon atoms. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is bicyclic. In some embodiments, the cycloalkyl group is tricyclic. In some embodiments, the cycloalkyl group is fully saturated. In some embodiments, the cycloalkyl group is partially saturated. In some embodiments, the cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a bicyclo[2.1.1]hexyl group, a bicyclo[2.2.1]heptyl group, a decahydronaphthyl group, or an adamantyl group. When a cycloalkyl group is substituted, it may be substituted independently in any ring, i.e., in any aromatic or non-aromatic ring contained in the cycloalkyl group, by one or more of the substituents described herein.

[0024] The terms "heterocyclyl group" and "heterocycle" may be used interchangeably herein, and unless otherwise stated, refer to a monovalent, monocyclic non-aromatic and / or polycyclic ring system containing at least one non-aromatic ring, wherein one or more (in some embodiments, 1, 2, 3, or 4) of the atoms of said non-aromatic monocycle are selected from the group consisting of O, S(O), and / or aryl. 0~2 and N, and the remaining ring atoms are all carbon atoms, and one or more (in some embodiments, 1, 2, 3, or 4) of the ring atoms of the polycyclic ring system are selected from O, S(O), 0~2and N, and the remaining ring atoms are all carbon atoms. In some embodiments, the heterocycle contains one or two heteroatoms, and each of the heteroatoms is a nitrogen atom. In some embodiments, the heterocyclyl group is polycyclic and contains one heteroatom in a non-aromatic ring, or one heteroatom in an aromatic ring, or two heteroatoms in an aromatic ring, or two heteroatoms, one in the aromatic ring and the other in the non-aromatic ring. In some embodiments, the heterocyclyl group has 3-20, 3-15, 3-10, 3-8, 4-7, or 5-6 ring atoms. In some embodiments, the heterocyclyl group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system. In some embodiments, the heterocyclyl group may be a bridged or non-bridged, spirocyclic or non-spirocyclic, and / or fused or non-fused bicyclic group. One or more of the nitrogen and sulfur atoms may be optionally oxidized, one or more of the nitrogen atoms may be optionally quaternized, and one or more of the carbon atoms may be optionally [ka] Some rings may be partially or fully saturated or aromatic, with the proviso that the heterocycle is not fully aromatic. The monocyclic and polycyclic heterocycles may be linked to the main structure at any heteroatom or carbon atom that results in a stable compound. The polycyclic heterocyclyl group may be linked to the main structure by any of its rings, including any aromatic or non-aromatic ring, whether or not said ring contains a heteroatom. In some embodiments, the heterocyclyl group is a "heterocycloalkyl group" which is 1) a saturated or partially unsaturated (but not aromatic) monovalent monocyclic group containing at least one cycloheteroatom as defined in the present invention, or 2) a saturated or partially unsaturated (but not aromatic) monovalent bicyclic or tricyclic group, at least one ring of which contains at least one heteroatom as defined in the present invention. When heterocyclyl and heterocycloalkyl groups are substituted, they may be substituted at any ring, i.e., at any aromatic or non-aromatic ring contained within the heterocyclyl and heterocycloalkyl groups. In some embodiments, such heterocyclyl groups include oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl group, dithiocyclopentyl group, tetrahydropyranyl group, dihydropyranyl group, 2H-pyranyl group, 4H-pyranyl group, tetrahydrothiopyranyl group, piperidinyl group, morpholinyl group, thiomorpholinyl group, piperazinyl group, dioxanyl group, dithianyl group, thioxanyl group, homopiperazinyl group, homopiperidinyl group, oxepanyl group, thiepanyl group, oxazepinyl group, diazepanyl group, thiazepinyl group, benzodioxanyl group, benzodioxole group, benzofuranonyl group, benzopyranonyl group, benzopyra nyl group, dihydrobenzofuryl group, benzotetrahydrothienyl group, benzothiopyranyl group, benzoxazinyl group, β-carbolinyl group, benzodihydropyranyl group, chromonyl group, cinnolinyl group, coumarinyl group, decahydroquinolinyl group, decahydroisoquinolinyl group, dihydrobenzisothiazinyl group, dihydrobenzisoxazinyl group, dihydrofuryl group, dihydroisoindolyl group, dihydropyranyl group, dihydropyrazolyl group, dihydropyrazinyl group, dihydropyridinyl group, dihydropyrimidinyl group, dihydropyrrolyl group, dihydropyrazole group, dihydropyrazinyl group, dihydropyridinyl group, dihydropyrimidinyl group, dihydropyrrolyl group, dihydropyrazole group, dihydropyrazinyl group, dihydropyridinyl group, dihydropyrimidinyl group, dihydropyrazole ... xolanyl group, 1,4-dithiopyranyl group, furanonyl group, imidazolidinyl group, 2,4-dioxo-imidazolidinyl group, imidazolinyl group, indolinyl group, 2-oxo-indolinyl group, isobenzotetrahydrofuryl group, isobenzotetrahydrothienyl group, isobenzodihydropyranyl group, isocoumarinyl group, isodihydroindolyl group (isoindolinyl group), 1-oxo-isodihydroindolyl group, 1,3-dioxo-isodihydroindolyl group, isothiazolidinyl group, isoxazolidinyl group, 3-oxo-isoxazolidinyl group nyl group, morpholinyl group, 3,5-dioxo-morpholinyl group, octahydroindolyl group, octahydroisoindolyl group, 1-oxo-octahydroisoindolyl group, 1,3-dioxo-hexahydroisoindolyl group, oxazolidinonyl group, oxazolidinyl group, oxiranyl group, piperazinyl group, 2,6-dioxo-piperazinyl group, piperidinyl group, 2,6-dioxo-piperidinyl group, 4-piperidonyl group, 2-oxopyrrolidinyl group, 2,5-dioxopyrrolidinyl group, quinuclidinyl group, tetrahydroisoquinolinyl group, 3,Examples of heterocyclyl groups in which the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidonyl, 3,5-dioxopiperidinyl, and pyrimidindionyl. Examples of heterocyclyl groups in which the sulfur atom is oxidized include, but are not limited to, sulfolanyl, and 1,1-dioxothiomorpholinyl. The heterocyclyl group may be optionally substituted with one or more of the substituents described herein.

[0025] In one embodiment, the heterocyclyl group is a heterocyclyl group of 3-8 atoms, which refers to a saturated or partially unsaturated monocyclic ring containing 3-8 ring atoms, at least one ring atom of which is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise stated, the heterocyclyl group of 3-8 atoms may be carbon-based or nitrogen-based, and the -CH2- group may be optionally replaced by -C(=O)-. The sulfur atom of the ring may be optionally oxidized to the S-oxide. The nitrogen atom of the ring may be optionally oxidized to the N-oxide. Examples of heterocyclyl groups consisting of 3 to 8 atoms are azetidinyl group, oxetanyl group, thietanyl group, pyrrolidinyl group, 2-pyrrolinyl group, 3-pyrrolinyl group, pyrazolinyl group, pyrazolidinyl group, imidazolinyl group, imidazolidinyl group, tetrahydrofuryl group, dihydrofuryl group, tetrahydrothienyl group, dihydrothienyl group, 1,3-dioxocyclopentyl group, dithiocyclopentyl group, tetrahydrofuryl group, dihydrothien ... Examples of heterocyclyl groups in which the -CH2- group of the heterocyclyl group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidonyl, 3,5-dioxopiperidinyl, and pyrimidinedioneyl groups. Examples of heterocyclyl groups in which the sulfur atom of the heterocyclyl group is oxidized include, but are not limited to, sulfolanyl and 1,1-dioxothiomorpholinyl groups. The heterocyclyl group of 3 to 8 atoms may be optionally substituted with one or more substituents described herein.

[0026] In one embodiment, the heterocyclyl group is a heterocyclyl group of 3-6 atoms, which refers to a saturated or partially unsaturated monocyclic ring containing 3-6 ring atoms, at least one ring atom of which is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise specified, the heterocyclyl group of 3-6 atoms may be carbon-based or nitrogen-based, and the -CH2- group may be optionally replaced by -C(=O)-. The sulfur atom of the ring may be optionally oxidized to an S-oxide. The nitrogen atom of the ring may be optionally oxidized to an N-oxide. The heterocyclyl group of 3-6 atoms may be optionally substituted by one or more of the substituents described in the present invention.

[0027] In another embodiment, the heterocyclyl group is a 5-6 atom heterocyclyl group, which refers to a saturated or partially unsaturated monocyclic ring containing 5-6 ring atoms, at least one ring atom of which is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise stated, the 5-6 atom heterocyclyl group may be carbon-based or nitrogen-based, and the -CH2- group may be optionally replaced by -C(=O)-. The ring sulfur atom may be optionally oxidized to the S-oxide. The ring nitrogen atom may be optionally oxidized to the N-oxide. Examples of heterocyclyl groups consisting of 5 to 6 atoms are pyrrolidinyl group, 2-pyrrolinyl group, 3-pyrrolinyl group, pyrazolinyl group, pyrazolidinyl group, imidazolinyl group, imidazolidinyl group, tetrahydrofuryl group, dihydrofuryl group, tetrahydrothienyl group, dihydrothienyl group, 1,3-dioxocyclopentyl group, dithiocyclopentyl group, 2-oxopyrrolidinyl group, oxo-1,3-thiazolidinyl group, sulfuryl group, and the like. The heterocyclyl groups of 5-6 atoms include, but are not limited to, folanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, 2-piperidonyl, 3,5-dioxopiperidinyl, and pyrimidindionyl, 1,1-dioxothiomorpholinyl. The heterocyclyl groups of 5-6 atoms may be optionally substituted with one or more of the substituents described herein.

[0028] The term "aryl group" as used herein means, unless otherwise specified, a monovalent C6-C 14It refers to a carbocyclic ring system, where the aromatic ring system is monocyclic, bicyclic, or tricyclic. The aryl group may be linked to the main structure by any of its rings, i.e., any aromatic or non-aromatic ring. In some embodiments, the aryl group is a phenyl group, a naphthyl group, a bicyclo[4.2.0]octo-1,3,5-trienyl group, an indanyl group, a fluorenyl group, or a tetrahydronaphthyl group. When the aryl group is substituted, it may be substituted in any of its rings, i.e., any aromatic or non-aromatic ring contained in the aryl group. In some or any one of the embodiments, the aryl group is a phenyl group, a naphthyl group, a tetrahydronaphthyl group, a fluorenyl group, or an indanyl group. The aryl group may be optionally substituted independently by one or more of the substituents described in the present invention.

[0029] The term "heteroaryl group," as used herein, unless otherwise specified, refers to a monovalent monocyclic or polycyclic aromatic group, wherein said at least one (and in some embodiments 1, 2, 3, or 4) ring atom(s) is / are not O, S(O) or NH(O) in said ring. 0~2and N. The heteroaryl group may be linked to the remainder of the molecule by any atom in the ring system, provided that the valence rules are met. In some embodiments, each ring of the heteroaryl group may contain 1 or 2 O atoms, 1 or 2 S atoms, and / or 1-4 N atoms, or a combination thereof, provided that the total number of heteroatoms in each ring is 4 or less, and each ring contains at least 1 carbon atom. In some embodiments, the heteroaryl group has 5-20, 5-15, or 5-10 ring atoms. When a heteroaryl group is substituted, it may be substituted in any ring. In some embodiments, monocyclic heteroaryl groups include, but are not limited to, furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl groups. In some embodiments, bicyclic heteroaryl groups include, but are not limited to, benzofuryl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridinyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuryl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridinyl, pyrrolopyridinyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl, and thienopyridinyl groups. In some embodiments, tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzoindolyl, carbazolyl, dibenzofuryl, perimidinyl, phenanthrolinyl, phenanthridinyl, and phenazinyl groups.In some or any one embodiments, the heteroaryl group is a phenylene group, a naphthylene group, a pyridinylene group, a pyrimidinylene group, a pyrazinylene group, a pyridazinylene group, a thiazolylene group, a benzothiazolyl group, a benzo[d]isothiazolyl group, an imidazo[1,2-a]pyridinyl group, a quinolinyl group, a 1H-indolyl group, a pyrrolo[1,2-b]pyridazinyl group, a benzofuryl group, a benzo [b] thienyl, 1H-indazolyl, benzo[d]isoxazolyl, quinazolinyl, 1H-pyrrolo[3,2-c]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, or pyrazolo[1,5-a]pyridinyl, each of which is optionally substituted by one, two, three or four groups as defined throughout the specification.

[0030] "Cycloalkylaliphatic," "heterocyclylaliphatic," "arylaliphatic," and "heteroarylaliphatic" refer to aliphatic groups substituted with cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, respectively, where cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, and aliphatic groups all have the definitions set forth herein.

[0031] As used herein, the term "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are known in the art as described in S. M. Berge et al., describe soluble salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19. Salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts (e.g., hydrochloride, hydrobromide, phosphate, sulfate, perchlorate) formed by reacting with amino groups, and organic acid salts (e.g., acetate, oxalate, maleate, tartrate, citrate, succinate, malonate) or obtained by other methods (e.g., ion exchange methods) described in the literature. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydrogenphosphate, and the like. Salts obtained by reaction with a suitable base include alkali metal salts, alkaline earth metal salts, ammonium salts and N-butyl salts. +(C1-C4 alkyl)4 salts. The present invention also contemplates quaternary ammonium salts formed from any compound containing an N group. Water or oil soluble or dispersible salts may be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, and the like. Pharmaceutically acceptable salts further include amine cations formed from suitable non-toxic ammonium salts, quaternary ammonium salts, and counterions, such as, for example, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C salts, etc. 1~8 Sulfonates and aromatic sulfonates.

[0032] The term "solvate" in the present invention refers to a combination formed by one or more solvent molecules and the compound of the present invention. The solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid and aminoethanol. The term "hydrate" refers to a combination formed by the solvent molecule water.

[0033] When the solvent is water, the term "hydrate" can be used.In some embodiments, one compound molecule of the present invention can be combined with one water molecule, for example, monohydrate, in some embodiments, one compound molecule of the present invention can be combined with one or more water molecules, for example, dihydrate, in some embodiments, one compound molecule of the present invention can be combined with less than one water molecule, for example, hemihydrate.It should be noted that the hydrate described in the present invention retains the bioavailability of the compound in non-hydrate form.

[0034] The present invention provides a tetrahydronaphthalene compound, a pharmaceutical composition comprising said compound, and a method for using said compound or composition in the manufacture of a drug for preventing and / or treating diseases of the central nervous system, particularly Parkinson's disease, restless legs syndrome or depression. In particular, said drug is a long-acting drug. The compound of the present invention has a high melting point and low water solubility, and can be used to prepare an excellent suspension formulation, with a slow dissolution rate and the effect of lasting for several weeks after a single administration.

[0035] In one aspect of the present invention, there is provided a novel tetrahydronaphthalene compound having the structure shown in formula (I), or a stereoisomer, solvate, or pharma- ceutically acceptable salt thereof: [ka] (In the formula, X is absent or -C(R 1 )(R 2 )-and Y is absent or is O; Z is absent or C 1~15 is an alkylene group, W is -C(=O)NH- or -NHC(=O)-; R 1 and R 2 are each independently H, D, F, Cl, OH, -CN, or C 1~4 is an alkyl group, R is C 1~30 Alkyl group, C 1~30 Heteroalkyl groups, C 2~30 Alkenyl group, C 2~30 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl C 1~10 aliphatic, C 2~10 Heterocyclyl group, C 2~10 Heterocyclyl C 1~10 Aliphatic, aryl, aryl C 1~10 Aliphatic, Heteroaryl, Heteroaryl C 1~10 Aliphatic, cholane-based fatty chain, -R 3a -C(=O)NH-R3b , or -R 3a -NHC(=O)-R 3b and R 3a is C 1~24 Alkylene group, C 2~10 Alkenylene group, arylene group, -C 1~10 Aliphatic-aryl- or -aryl-C 1~10 Aliphatic - R 3b , H, C 1~22 Alkyl group, C 2~10 Alkenyl group, aryl group, or aryl C 1~10 It is aliphatic, However, R 1 , R 2 , R, R 3a and R 3b wherein each of the alkyl, alkylene, heteroalkyl, alkenyl, alkenylene, alkynyl, cycloalkyl, heterocyclyl, cycloalkylaliphatic, heterocyclylaliphatic, aryl, arylene, arylaliphatic, heteroaryl, heteroarylaliphatic, -aliphatic-aryl-, -aryl-aliphatic- and cholane-based aliphatic chains independently optionally includes H, D, oxo (=O), thio (=S), F, Cl, Br, -OH, -CN, an amine group, -C(=O)NH-R 4a , -NHC(=O)-R 4a , -S(=O) 1-2 NH-R 4b , -NHS(=O) 1-2 -R 4b , C 1~6 Alkyl group, C 1~6 Alkoxy group, carboxy group, C 3~6 Cycloalkyl groups, C 6~10 Aryl groups and C 1~9 heteroaryl groups, and each R 4a and R 4b are each independently H or C 1~6 It is an alkyl group.

[0036] In some embodiments, there is provided a compound according to the present invention having the structure shown in formula (II), or a stereoisomer, solvate, or pharma- ceutically acceptable salt thereof. [ka] (In the formula, m is an integer of 1 to 5.)

[0037] In some embodiments, X is absent and Y is absent.

[0038] In some embodiments, R 1 and R 2 are each independently H, D, F, Cl, OH, -CN, a methyl group, or an ethyl group.

[0039] In some embodiments, R is C 1~30 Alkyl group, C 2~30 Alkenyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl C 1~6 aliphatic, C 2~7 Heterocyclyl group, C 2~7 Heterocyclyl C 1~6 aliphatic, C 6~10 Aryl group, C 6~10 Aryl C 1~6 aliphatic, C 1~9 Heteroaryl groups, C 1~9 Heteroaryl C 1~6 Aliphatic, cholane-based fatty chain, -R 3a -C(=O)NH-R 3b , or -R 3a -NHC(=O)-R 3b and However, the above C 1~30 Alkyl group, C 2~30 Alkenyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl C 1~6 aliphatic, C 2~7 Heterocyclyl group, C 2~7 Heterocyclyl C 1~6 aliphatic, C 6~10 Aryl group, C 6~10 Aryl C1~6 aliphatic, C 1~9 Heteroaryl groups, C 1~9 Heteroaryl C 1~6 Aliphatic, cholane-based fatty chain, -R 3a -C(=O)NH-R 3b and -R 3a -NHC(=O)-R 3b are independently optionally selected from H, D, oxo (=O), thio (=S), fluorine, chlorine, Br, -OH, -CN, an amine group, -C(=O)NH-R 4a , -NHC(=O)-R 4a , -S(=O) 1-2 NH-R 4b , -NHS(=O) 1-2 -R 4b , carboxy group, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 3~6 Cycloalkyl groups, C 6~10 Aryl groups and C 1~9 The heteroaryl group is substituted with 1, 2, 3 or 4 substituents independently selected from the heteroaryl group.

[0040] In some embodiments, R is C 1~22 Alkyl group, C 2~22 Alkenyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl C 1~6 aliphatic, C 2~7 Heterocyclyl group, C 2~7 Heterocyclyl C 1~6 aliphatic, C 6~10 Aryl group, C 6~10 Aryl C 1~6 aliphatic, C 1~9 Heteroaryl groups, C 1~9 Heteroaryl C 1~6 Aliphatic, cholane-based fatty chain, -R 3a -C(=O)NH-R 3b , or -R 3a -NHC(=O)-R 3b and However, the above C 1~22 Alkyl group, C 2~22 Alkenyl group, C 3~10 Cycloalkyl groups, C3~10 Cycloalkyl C 1~6 aliphatic, C 2~7 Heterocyclyl group, C 2~7 Heterocyclyl C 1~6 aliphatic, C 6~10 Aryl group, C 6~10 Aryl C 1~6 aliphatic, C 1~9 Heteroaryl groups, C 1~9 Heteroaryl C 1~6 Aliphatic, cholane-based fatty chain, -R 3a -C(=O)NH-R 3b and -R 3a -NHC(=O)-R 3b are independently optionally selected from H, D, oxo (=O), thio (=S), F, Cl, Br, -OH, -CN, an amine group, -C(=O)NH-R 4a , -NHC(=O)-R 4a , -S(=O) 1-2 NH-R 4b , -NHS(=O) 1-2 -R 4b , carboxy group, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 3~6 Cycloalkyl groups, C 6~10 Aryl groups and C 1~9 The heteroaryl group is substituted with 1, 2, 3 or 4 substituents independently selected from the heteroaryl group.

[0041] In some embodiments, R is C 1~22 Alkyl group, C 2~22 Alkenyl group, C 2~7 Heterocyclyl C 1~6 Aliphatic, -R 3a -C(=O)NH-R 3b , -R 3a -NHC(=O)-R 3b , or C 6~10 Aryl C 1~6 It is aliphatic, However, the above C 1~22 Alkyl group, C 2~22 Alkenyl group, C 2~7 Heterocyclyl C 1~6 Aliphatic, -R 3a-C(=O)NH-R 3b , -R 3a -NHC(=O)-R 3b and C 6~10 Aryl C 1~6 Aliphatic groups are independently optionally selected from H, D, oxo (=O), thio (=S), fluorine, chlorine, Br, -OH, -CN, an amine group, -C(=O)NH-R 4a , -NHC(=O)-R 4a , -S(=O) 1-2 NH-R 4b , -NHS(=O) 1-2 -R 4b , carboxy group, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 3~6 Cycloalkyl groups, C 6~10 Aryl groups and C 1~9 The heteroaryl group is substituted with 1, 2, 3 or 4 substituents independently selected from the heteroaryl group.

[0042] In some embodiments, R is C 5~20 Alkyl group, C 2~20 Alkenyl group, C 3~6 Cycloalkyl groups, C 3~6 Cycloalkyl C 1~6 aliphatic, C 2~7 Heterocyclyl group, C 2~7 Heterocyclyl C 1~6 aliphatic, C 6~10 Aryl group, C 6~10 Aryl C 1~6 aliphatic, C 1~9 Heteroaryl groups, C 1~9 Heteroaryl C 1~6 Aliphatic, cholane-based fatty chain, -R 3a -C(=O)NH-R 3b , or -R 3a -NHC(=O)-R 3b and However, the above C 5~20 Alkyl group, C 2~20 Alkenyl group, C 3~6 Cycloalkyl groups, C 3~6 Cycloalkyl C 1~6 aliphatic, C 2~7 Heterocyclyl group, C2~7 Heterocyclyl C 1~6 aliphatic, C 6~10 Aryl group, C 6~10 Aryl C 1~6 aliphatic, C 1~9 Heteroaryl groups, C 1~9 Heteroaryl C 1~6 Aliphatic, cholane-based fatty chain, -R 3a -C(=O)NH-R 3b and -R 3a -NHC(=O)-R 3b are independently optionally selected from H, D, oxo (=O), thio (=S), F, Cl, Br, -OH, -CN, an amine group, -C(=O)NH-R 4a , -NHC(=O)-R 4a , -S(=O) 1-2 NH-R 4b , -NHS(=O) 1-2 -R 4b , carboxy group, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 3~6 Cycloalkyl groups, C 6~10 Aryl groups and C 1~9 The heteroaryl group is substituted with 1, 2, 3 or 4 substituents independently selected from the heteroaryl group.

[0043] In some embodiments, R 3a is C 1~20 Alkylene group, C 2~6 Alkenylene group, C 6~10 Arylene group, -C 1~6 Aliphatic-C 6~10 Aryl- or -C 6~10 Aryl C 1~6 Aliphatic and R 3b , H, C 1~19 Alkyl group, C 2~6 Alkenyl group, C 6~10 Aryl group, or C 6~10 Aryl C 1~6 aliphatic, provided that each of said C 1~19 Alkyl group, C 1~20 Alkylene group, C 2~6 Alkenyl group, C 2~6 Alkenylene group, C 6~10Aryl group, C 6~10 Arylene group, -C 1~6 Aliphatic-C 6~10 Aryl-, -C 6~10 Aryl C 1~6 Aliphatic- and C 6~10 Aryl C 1~6 Aliphatic is independently any of the following: H, D, oxo (=O), thio (=O), F, Cl, Br, -OH, -CN, an amine group, -C(=O)NH-R 4a , -NHC(=O)-R 4a , -S(=O) 1-2 NH-R 4b , -NHS(=O) 1-2 -R 4b , carboxy group, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 3~6 Cycloalkyl groups, C 6~10 Aryl groups and C 1~9 The heteroaryl group is substituted with 1, 2, 3, or 4 substituents independently selected from the heteroaryl group.

[0044] In some embodiments, each R 4a and R 4b are each independently H or C 1~3 It is an alkyl group.

[0045] In some embodiments, the compound is selected from the following: or a stereoisomer, solvate, or pharma- ceutically acceptable salt thereof: [ka] (In the formula, m and m' are each independently an integer of 1 to 5, n is an integer of 7 to 20, n' is an integer of 2 to 20, and R 3b is H or C 1~18 is an alkyl group.

[0046] In some embodiments, R 3b is H or C 1~12 In another embodiment, R 3b is H or C 1~10 It is an alkyl group.

[0047] In some embodiments, the compound is any compound selected from the following: or a stereoisomer, solvate, or pharma- ceutically acceptable salt thereof: [ka] [ka] [ka] [ka]

[0048] In another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound according to the present invention or a stereoisomer, solvate, or pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient, carrier, or diluent.

[0049] In another aspect of the present invention, there is provided the use of a compound according to the present invention or a stereoisomer, solvate, or pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to the present invention, in the manufacture of a medicament for the prevention and / or treatment of a disease of the central nervous system.

[0050] In some embodiments, the disease of the central nervous system is Parkinson's disease, restless legs syndrome, or depression.

[0051] In some embodiments, the drug is a long-acting drug.

[0052] Pharmaceutical Compositions, Formulations, and Uses When used as a drug, the compound of the present invention is generally administered in the form of a pharmaceutical composition.The composition can be prepared in a manner well known in the pharmaceutical art, and comprises at least one compound according to the present invention of formula I or formula II.Generally, the compound of the present invention is administered in a pharmacologic effective amount.The amount of the compound of the present invention that is actually administered is generally determined by a physician based on the relevant circumstances, including the pathology to be treated, the route of administration selected, the specific compound of the present invention to be administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0053] The present invention provides a pharmaceutical composition comprising the compound of the present invention and a pharma- ceutically acceptable carrier. The pharmaceutical composition can be prepared as a formulation suitable for a particular route of administration (e.g., oral administration, parenteral administration, rectal administration, etc.). The pharmaceutical composition of the present invention can also be prepared in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories) or liquid form (including, but not limited to, solutions, suspensions, or emulsions). The pharmaceutical composition can be subjected to conventional pharmaceutical operations (e.g., sterilization), and / or may contain conventional inert diluents, lubricants or buffers, and auxiliary substances (e.g., preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.).

[0054] As liquid compositions for oral administration, pharma- ceutically acceptable solutions, suspensions, emulsions, syrups, and elixirs containing inert diluents (e.g., water or liquid paraffin) can be used. These compositions may further contain substances other than diluents, and in some embodiments, contain wetting agents, sweeteners, or flavoring agents.

[0055] Compositions for parenteral administration may be emulsions or sterile solutions. In some embodiments, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, or injectable organic esters may be used as solvents or carriers, and in some embodiments, ethyl oleate may be used as solvents or carriers. These compositions may further include adjuvants, especially wetting agents, isotonic agents, emulsifiers, dispersants, and stabilizers. They may be sterilized in several ways, and in some embodiments, they are sterilized by irradiation or heat, using a bacteriological filter. They may also be manufactured in the form of sterile solid compositions, which can be dissolved in sterile water or any other injectable sterile medium at the time of use.

[0056] In some embodiments, the compositions provided by the present invention are pharmaceutical compositions or single unit dosage forms. The pharmaceutical compositions and single unit dosage forms provided by the present invention contain a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., a compound provided by the present invention or other prophylactic or therapeutic agents) and one or more typical pharmaceutically acceptable carriers or excipients. In the present invention and the mode for carrying out the invention, the term "pharmaceutically acceptable" refers to a drug approved by a federal or state government regulatory agency or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, particularly humans. The term "carrier" includes a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), additive, or vehicle with which the therapeutic agent is administered. Such drug carriers may be sterile liquids (e.g., water and oils), including petroleum, animal oils, vegetable oils, or synthetic, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. When the pharmaceutical composition is administered intravenously, water can be used as a carrier. Saline solutions, aqueous glucose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in "Remington: The Science and Practice of Pharmacy, Pharmaceutical Press, 22nd Ed., September 15, 2012".

[0057] Typical pharmaceutical compositions and dosage forms include one or more additives. Suitable additives are well known to those skilled in the art of pharmacy, and in some embodiments, suitable additives include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, nonfat dry milk, glycerol, propylene, glycol, water, ethanol, etc. Whether a particular additive should be included in a pharmaceutical composition or dosage form depends on various factors well known in the art, including, but not limited to, the manner in which the dosage form is to be administered to a subject and the particular active ingredients in the dosage form. If necessary, the composition or single unit dosage form may also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

[0058] For an individual of about 50-70 kg, the pharmaceutical composition or combination product of the present invention may be a unit dose of about 1-1000 mg of active ingredient, or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or about 1-50 mg of active ingredient. The therapeutically effective amount of the compound, pharmaceutical composition or combination product thereof depends on the species, weight, age and health condition of the individual, the condition or disease being treated or its severity. A physician, clinician or veterinarian can readily determine the effective amount of each active ingredient required to prevent, treat or inhibit the progression of the disease or condition.

[0059] The dosage characteristics can be verified by in vitro and in vivo tests using suitable mammals, such as mice, rats, dogs, monkeys, or isolated organs, tissues, and products thereof. The compounds of the present invention can be used in vitro in the form of a solution, such as an aqueous solution, and in vivo in the form of a suspension or aqueous solution, enterally, parenterally (preferably intravenously). The dosage range outside the body is between about 10-3 molar and 10-9 molar. The therapeutically effective amount inside the body is determined by the route of administration and is in the range of about 0.1-500 mg / kg or about 1-100 mg / kg.

[0060] The compounds of the present invention may be administered simultaneously with, prior to or subsequent to, one or more other therapeutic components, each of which may be administered by the same or different route of administration as the other component, or both may be incorporated into a single pharmaceutical composition and administered together.

[0061] In another aspect of the present invention, there is provided a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for medical use.In a mode for carrying out the invention, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for preventing and / or treating a disease of the central nervous system in a mammal, in particular Parkinson's disease, restless legs syndrome or depression. [Brief description of the drawings]

[0062] [Figure 1] FIG. 1 shows a distribution diagram of the blood drug concentration of the active compound at each time point after intramuscular injection of a suspension of the compound of the present invention into rats. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0063] In the following, examples are given to illustrate the present invention, but it should be understood that the present invention is not limited to these examples, which are merely provided as methods for carrying out the present invention.

[0064] In general, the compounds of the present invention can be obtained by the methods described in the present invention, and unless further specified, the definitions of the substituents are as shown in formula I or formula II. The following reaction schemes and examples are intended to further illustrate the contents of the present invention.

[0065] Those skilled in the art will understand that the chemical reactions described in this invention are suitable for preparing many other compounds of the invention, and all other methods for preparing the compounds of the invention are considered to be within the scope of this invention. For example, the synthesis of those untested compounds of the invention can be carried out by those skilled in the art in a modified manner, such as by properly protecting interfering groups, using other reagents than those described in this invention, or making regular modifications to some of the reaction conditions. Also, the reactions disclosed in this invention or known reaction conditions are generally considered to be suitable for preparing other compounds of the invention.

[0066] In the examples described below, all temperatures are in degrees Celsius unless otherwise stated. Reagents are purchased from suppliers such as Aldrich Chemical Company, Arco Chemical Company, Energy-chemical Company, Shanghai Shaoyuan Company, J&K Chemical Company, Aladdin Chemical Company, Meryer Chemical Company, TCI Chemical Company, Xiya Reagent Company, Bidepharm Company, Macklin Company, Alfa Chemical Company, and none of them are further purified when used unless otherwise stated. Common reagents are purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Factory, Wuhan Xin Huayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyang Chemical Factory.

[0067] Anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether are obtained by refluxing and drying over metallic sodium. Anhydrous dichloromethane and chloroform are obtained by refluxing and drying over calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide are dried over anhydrous sodium sulfate before use.

[0068] The reactions that follow are generally carried out under a positive pressure of nitrogen or argon or with dry tubing in addition to anhydrous solvents (unless otherwise stated), all reaction vials contain appropriate rubber stoppers, and substrates are injected via syringe. All glassware was pre-dried.

[0069] A silica gel column is used as the column. Silica gel (300-400 mesh) is purchased from Qingdao Ocean Chemical Factory.

[0070] 1 1 H NMR spectra are recorded using a Bruker 400 MHz or 500 MHz nuclear magnetic resonance spectrometer. 1 H NMR spectra were recorded in CDCl3, DMSO-d6, CD3OD, or acetone-d6 (in ppm) and referenced to TMS (0 ppm) or chloroform (7.26 ppm). When multiplets appear, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are given in Hertz (Hz).

[0071] The measurement conditions for low-resolution mass spectrometry (MS) data were as follows: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1 × 30 mm, 3.5 μm, 6 min, flow rate 0.6 mL / min. Mobile phase: 5% to 95% ((CH3CN containing 0.1% formic acid) in (HO containing 0.1% formic acid)), using electrospray ionization (ESI), 210 nm / 254 nm, UV detection.

[0072] Pure compounds are analyzed using an Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column model: NOVASEP 50 / 80mm DAC) with UV detection at 210nm / 254nm.

[0073] (Example) Example 1: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 2-stearamidoacetate [ka] Rotigotine (1 g, 3.17 mmol), octanamidoacetic acid (0.70 g, 3.49 mmol, 1.1 eq), DMAP (39 mg, 0.32 mmol, 0.1 eq), triethylamine (0.48 g, 4.75 mmol, 1.5 eq) and THF (15 mL) were added to a 50 mL one-neck flask, and EDCI (0.73 g, 3.80 mmol, 1.2 eq) was added while stirring the mixture, and the mixture was stirred at 70 °C overnight, and TLC showed that the reaction of the raw materials was completed. It was filtered, the filter cake was washed with THF, the filtrate was combined and concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 60: 40) to obtain compound 1 as a white solid powder (0.95 g, 60% yield). 1 H NMR(500MHz,CDCl3)δ 7.16~7.11(m,2H),7.11(d,J=7.2Hz,1H),6.94~6.90(m,1H),6.84(d,J=8.0Hz,1H) ,6.81(d,J=2.8Hz,1H),5.97(t,J=5.2Hz,1H),4.32(d,J=5.2Hz,2H),2.96~2.89(m, 4H),2.81~2.74(m,4H),2.53~2.47(m,3H),2.27(t,J=8.0Hz,2H),2.03(m,1H),1.73 ~1.61(m,2H),1.59(m,1H),1.47(q,J=6.8Hz,2H),1.35~1.23(m,28H),0.88(m,6H). MS(m / z):639.23[M+H] + .

[0074] Example 2: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 2-aracamide acetate [ka] Following the procedure of Example 1, but substituting arachidinoacetic acid (1.1 eq) for octanamidoacetic acid, compound 2 was prepared as a white solid powder (2.30 g, 64.0% yield). 1 H NMR(500MHz,CDCl3)δ 7.15~7.11(m,2H),7.11(d,J=7.2Hz,1H),6.93~6.91(m,1H),6.84(d,J=8.0Hz,1H ),6.81(d,J=2.8Hz,1H),5.97(t,J=5.2Hz,1H),4.32(d,J=5.2Hz,2H),2.97~2.89( m,4H),2.82~2.73(m,4H),2.54~2.47(m,3H),2.27(t,J=8.0Hz,2H),2.03(m,1H), 1.72~1.62(m,2H),1.59(m,1H),1.47(q,J=6.8Hz,2H),1.25(m,32H),0.88(m,6H). MS(m / z):667.71[M+H] + .

[0075] Example 3: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 4-palmitamidobutyric acid ester [ka] Following the procedure of Example 1, but substituting 4-palmitamidobutyric acid (1.1 eq) for octanamidoacetic acid, compound 3 was prepared as a white solid powder (0.53 g, 26% yield) MS (m / z): 639.15 [M+H] + .

[0076] Example 4: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 4-stearamidobutyric acid ester [ka] Following the procedure of Example 1, but substituting 4-stearamidobutyric acid (1.1 eq) for octane amide acetic acid, compound 4 was prepared as a white solid powder (0.77 g, 47.3% yield). 1 H NMR(400MHz,CDCl3)δ 7.14~7.10(m,2H),6.98(d,J=7.6Hz,1H),6.93~6.91(dd,J=4.2Hz,3.2Hz,1H),6.82(d,J=3.6 Hz,1H),6.81(s,1H),5.65(br,1H),3.41~3.36(dd,J=12.8Hz,6.8Hz,2H),2.97~2.89(m,4H), 2.84~2.76(m,4H),2.63(t,J=7.2Hz,2H),2.56~2.46(m,3H),2.16(t,J=8.0Hz,2H),2.03(m,1 H),2.00~1.93(m,2H),1.64~1.59(m,3H),1.54~1.47(m,2H),1.25(m,28H),0.92~0.86(m,6H). MS(m / z):667.59[M+H] + .

[0077] Example 5: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 4-aracamidobutyric acid ester [ka] Following the procedure of Example 1, but substituting 4-arachidobutyric acid (1.1 eq) for octane amide acetic acid, compound 5 was prepared as a white solid powder (1.80 g, 40.8% yield). 1H NMR(500MHz,CDCl3)δ 7.12(m,2H),6.98(m,1H),6.92(m,1H),6.81(m,2H),5.65(s,1H),3.78(m,2H),2.98~2.88(m,4H),2.82~2.76(m,4H) ), 2.62 (m, 2H), 2.54 (m, 3H), 2.16 (m, 2H), 2.03 (m, 1H), 1.97~1.96 (m, 2H), 1.61 (m, 5H), 1.25 (m, 32H), 0.89 (m, 6H). MS(m / z):696.58[M+H] + .

[0078] Example 6: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(2-(4-acetylaminophenyl)acetyl)glycine ester [ka] Following the procedure of Example 1, but substituting 2-(4-acetylaminophenyl)acetyl)glycine (1.1 eq) for octanamidoacetic acid, compound 6 was prepared (1.30 g, 75% yield). MS (m / z): 548.15 [M+H] + .

[0079] Example 7: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 4-(2-(4-acetylaminophenyl)acetylamino)butyric acid ester [ka] Following the procedure of Example 1, but substituting 4-(2-(4-acetylaminophenyl)acetylamino)butyric acid (1.1 eq) for octanamidoacetic acid, compound 7 was prepared (0.60 g, 33% yield). MS (m / z): 576.31 [M+H] + .

[0080] Example 8: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 2-cinnamamide acetate [ka] Following the procedure of Example 1, but substituting cinnamamide acetic acid (1.1 eq) for octanamide acetic acid, compound 8 was prepared (1.30 g, 82% yield). MS (m / z): 503.10 [M+H] + .

[0081] Example 9: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 4-cinnamamide butyric acid ester [ka] Following the procedure of Example 1, but substituting cinnamamide butyric acid (1.1 eq) for octanamide acetic acid, compound 9 was prepared (0.59 g, 35% yield). MS (m / z): 531.20 [M+H] + .

[0082] Example 10: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 2-phenylacetamide acetic acid ester [ka] Following the procedure of Example 1, but substituting phenylacetamidoacetic acid (1.1 eq) for octanamidoacetic acid, compound 10 was prepared (1.23 g, 79% yield). MS (m / z): 491.08 [M+H] + .

[0083] Example 11: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 4-phenylacetamidobutyric acid ester [ka] Following the procedure of Example 1, but substituting phenylacetamidobutyric acid (1.1 eq) for octanamidoacetic acid, compound 11 was prepared (0.5 g, 30% yield). MS (m / z): 519.13 [M+H] + .

[0084] Example 12: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 2-phenylpropionamidoacetate [ka] Following the procedure of Example 1, but substituting phenylpropionamidoacetic acid (1.1 eq) for octanamidoacetic acid, compound 12 was prepared (1.18 g, 74% yield). MS (m / z): 505.10 [M+H] + .

[0085] Example 13: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 4-phenylpropionamidobutyric acid ester [ka] Following the procedure of Example 1, but substituting phenylpropionamidobutyric acid (1.1 eq) for octanamidoacetic acid, compound 13 was prepared (0.47 g, 28% yield). MS (m / z): 533.17 [M+H] + .

[0086] Example 14: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(4-aracamidobenzoyl)glycine ester [ka] Following the procedure of Example 1, substituting p-arachidombenzamidoacetic acid (1.1 eq) for octanamidoacetic acid, compound 14 was prepared as a white solid powder (0.31 g, 13% yield).1 H NMR(500MHz,CDCl3)δ 7.80(d,J=8.5Hz,2H),7.62(d,J=8.5Hz,2H),7.33(m,1H),7.16~7.11(m,2H),7.01(d,J= 7.5Hz,1H),6.92(t,J=5.0Hz,1H),6.88(d,J=7.5Hz,1H),6.82(s,1H),6.68(br,1H),4.5 0(d,J=5.0Hz,2H),2.98(m,4H),2.85~2.83(m,4H),2.56~2.54(m,3H),2.37(t,J=7.5Hz, 2H), 2.08(m, 1H), 1.74~1.69(m, 2H), 1.59~1.42(m, 3H), 1.25(m, 32H), 0.90~0.84(m, 6H). MS(m / z):786.56[M+H] + .

[0087] Example 15: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 2-p-stearamide benzamide acetate [ka] Following the procedure of Example 1, substituting p-stearamidobenzamidoacetic acid (1.1 eq) for octanamidoacetic acid, compound 15 was prepared as a white solid powder (0.18 g, 12.5% ​​yield). 1 H NMR(500MHz,CDCl3)δ 7.80(d,J=8.5Hz,2H),7.62(d,J=8.5Hz,2H),7.33(m,1H),7.15~7.12(m,2H),7.01(d,J= 7.5Hz,1H),6.92(t,J=5.0Hz,1H),6.88(d,J=7.5Hz,1H),6.82(s,1H),6.69(br,1H),4.5 0(d,J=5.0Hz,2H),2.98(m,4H),2.85~2.83(m,4H),2.56~2.54(m,3H),2.37(t,J=7.5Hz, 2H), 2.08(m, 1H), 1.75~1.70(m, 2H), 1.58~1.43(m, 3H), 1.25(m, 28H), 0.91~0.86(m, 6H). MS(m / z):758.76[M+H]+ .

[0088] Example 16: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 2-p-palmitamidobenzamidoacetate [ka] Following the procedure of Example 1, but substituting p-palmitamidobenzamidoacetic acid (1.1 eq) for octanamidoacetic acid, compound 16 was prepared as a white solid powder (0.36 g, 15% yield). MS (m / z): 730.49 [M+H] + .

[0089] Example 17: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 2-p-myristamidobenzamidoacetate [ka] Following the procedure of Example 1, but substituting p-myristamidobenzamidoacetic acid (1.1 eq) for octanamidoacetic acid, compound 17 was prepared as a white solid powder (0.28 g, 14.3% yield). MS (m / z): 702.47 [M+H] + .

[0090] Example 18: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 4-p-myristamide benzamide butyric acid ester [ka] Following the procedure of Example 1, but substituting 4-p-myristamidobenzamidobutyric acid (1.1 eq) for octanamidoacetic acid, compound 18 was prepared as a white solid powder (0.12 g, 11% yield). MS (m / z): 688.53 [M+H] + .

[0091] Example 19: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 4-p-palmitamidobenzamidobutyric acid ester [ka] Following the procedure of Example 1, but substituting 4-p-palmitamidobenzamidobutyric acid (1.1 eq) for octanamidoacetic acid, compound 19 was prepared as a white solid powder (0.15 g, 12% yield). MS (m / z): 716.41 [M+H] + .

[0092] Example 20: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 4-p-stearamide benzamide butyric acid ester [ka] Following the procedure of Example 1, but substituting 4-p-stearamidobenzamidobutyric acid (1.1 eq) for octanamidoacetic acid, compound 20 was prepared as a white solid powder (0.25 g, 12.5% ​​yield). MS (m / z): 744.51 [M+H] + .

[0093] Example 21: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 4-p-aracamide benzamide butyric acid ester [ka] Following the procedure of Example 1, but substituting 4-p-arachidomedobenzamidbutyric acid (1.61 g, 3.49 mmol, 1.1 eq) for octanamidoacetic acid, compound 21 was prepared as a white solid powder (0.18 g, 13% yield) MS (m / z): 772.53 [M+H] + .

[0094] Example 22: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(4-palmitamidobutyryl)glycine ester [ka] Rotigotine (0.6 g, 1.91 mmol), (4-palmitamidobutyryl)glycine (0.91 mg, 2.29 mmol, 1.10 eq), DMAP (23.2 mg, 0.19 mmol, 0.10 eq), triethylamine (0.39 g, 3.81 mmol, 2.0 eq) and THF (6 mL) were added to a 50 mL one-neck flask, and EDCI (0.55 g, 2.86 mmol, 1.2 eq) and HOBT (25.7 mg, 0.19 mmol, 0.10 eq) were added while stirring the mixture, and the mixture was stirred at 70 °C overnight, and TLC showed that the reaction of the raw materials was completed. It was filtered, the filter cake was washed with THF, the filtrate was combined and concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain compound 22 as a white solid powder (0.27 g, yield 20.4%). 1 H NMR(500MHz,CDCl3)δ 7.15(s,1H),7.13~7.10(m,2H),6.99(d,J=7.5Hz,1H),6.93~6.91(mr,1H),6.84(d,J=8.0Hz,1H ),6.81(br,1H),5.83(br,1H),4.30(d,J=5.5Hz,2H),3.39~3.36(dd,J=12.5Hz,6.0Hz,2H),2.9 6~2.88(m,4H),2.83~2.73(m,4H),2.54~2.49(m,3H),2.31(t,J=6.0Hz,2H),2.17(t,J=7.5Hz,2 H),2.03(br,1H),1.86~1.83(m,2H),1.61~1.58(m,5H),1.28~1.25(m,24H),0.91~0.86(m,6H). MS(m / z):696.58[M+H] + .

[0095] Example 23: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(4-stearamidobutyryl)glycine ester [ka] Following the procedure of Example 22, substituting (4-palmitamidobutyryl)glycine (1.1 eq) for (4-stearamidobutyryl)glycine, compound 23 was prepared as a white solid powder (0.60 g, 43.6% yield). 1 H NMR(500MHz,CDCl3)δ 7.13(m,3H),7.00(d,J=3.0Hz,1H),6.92(s,1H),6.85~6.83(m,2H),5.83( br,1H),4.30(d,J=5.5Hz,2H),3.40~3.36(m,2H),2.97(m,4H),2.83(m,4H) ,2.54(m,3H),2.31(t,J=6.5Hz,2H),2.17(t,J=7.5Hz,2H),2.04(m,1H),1. 91~1.82(m,2H),1.62~1.58(m,5H),1.28~1.25(m,28H),0.90~0.86(m,6H). MS(m / z):724.66[M+H] + .

[0096] Example 24: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(4-aracamidobutyryl)glycine ester [ka] Following the procedure of Example 22, substituting (4-palmitamidobutyryl)glycine (1.1 eq) for (4-arachimidobutyryl)glycine, compound 24 was prepared as a white solid powder (0.78 g, 65.4% yield). 1H NMR(500MHz,CDCl3)δ 7.12(m,2H),6.99(d,J=7.5Hz,1H),6.92(m,1H),6.85(d,J=7.5Hz,1H),6.82(br,1H),5 .85(br,1H),4.30(d,J=5.5Hz,2H),3.39~3.36(m,2H),2.99~2.97(m,4H),2.85~2.82(m ,4H),2.53(m,3H),2.31(t,J=6.5Hz,2H),2.17(t,J=8.0Hz,2H),2.03(m,1H),1.87~1.8 3(m,2H),1.64~1.59(m,3H),1.60(m,3H),1.50(m,2H),1.25(m,32H),0.93~0.86(m,6H). MS(m / z):752.65[M+H] + .

[0097] Example 25: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(18-amino-18-oxostearoyl)glycine ester [ka] Rotigotine (0.4 g, 1.14 mmol), (18-amino-18-oxostearoyl)glycine (0.56 g, 1.35 mmol, 1.10 eq), N,N-diisopropylethylamine (0.44 g, 3.41 mmol, 3.0 eq) and CH3CN (8 mL) were added to a 50 mL single-neck flask, and EDCI (0.33 g, 1.71 mmol, 1.5 eq) and HOBT (30.7 mg, 0.23 mmol, 0.20 eq) were added while stirring the mixture, and the mixture was stirred at 80 °C overnight, and TLC showed that the reaction of the raw materials was complete. After filtration, the filter cake was washed with water, and then the filter cake was dissolved in dichloromethane to filter out the insoluble matter. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate=1:1) to obtain compound 25 as a white solid powder (0.04 g, yield 5.3%). 1H NMR(500MHz,DMSO-d6)δ 8.40(br,1H),7.28(d,J=4.5Hz,1H),7.19(br,1H),7.11(t,J=4.5Hz,1H),6.99(d,J=3 .0Hz,1H),6.87(s,1H),6.81(d,J=8.0Hz,1H),6.65(br,1H),4.06(d,J=5.5Hz,2H),2.9 2~2.81(m,4H),2.76~2.71(m,4H),2.50~2.36(m,3H),2.13(t,J=7.0Hz,2H),2.01(t,J= 7.0Hz, 2H), 1.90 (m, 1H), 1.50~1.38 (m, 7H), 1.22~1.19 (m, 24H), 0.82 (t, J=7.0Hz, 3H). MS(m / z):668.64[M+H] + .

[0098] Example 26: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(16-amino-16-oxopalmitoyl)glycine ester [ka] Following the procedure of Example 25, substituting (16-amino-16-oxopalmitoyl)glycine (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 26 was prepared as a white solid powder (0.2 g, 55% yield). 1H NMR(500MHz,DMSO-d6)δ 8.40(br,1H),7.29(d,J=4.0Hz,1H),7.20(br,1H),7.13(t,J=7.5Hz,1H),7.01(d,J=3.0Hz, 1H),6.93(s,1H),6.88(s,1H),6.83(d,J=8.0Hz,1H),6.66(br,1H),4.08(d,J=5.5Hz,2H),2. 92~2.82(m,4H),2.76~2.67(m,4H),2.50~2.37(m,3H),2.15(t,J=7.0Hz,2H),2.01(t,J=7.0H z,2H),1.92(d,J=13.5Hz,1H),1.54~1.38(m,7H),1.23~1.20(m,20H),0.85(t,J=7.0Hz,3H). MS(m / z):640.56[M+H] + .

[0099] Example 27: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(14-amino-14-oxomyristoyl)glycine ester [ka] Following the procedure of Example 25, substituting (14-amino-14-oxomyristoyl)glycine (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 27 was prepared as a white solid powder (1.0 g, 57.5% yield). 1H NMR(500MHz,DMSO-d6)δ 8.40(br,1H),7.28(d,J=5.5Hz,1H),7.20(br,1H),7.12(t,J=7.5Hz,1H),7.01(d,J=7.5Hz,1H),6.92 (dd,J=5.5Hz,3.5Hz,1H),6.87(d,J=3.0Hz,1H),6.82(d,J=8.0Hz,1H),6.66(br,1H),4.07(d,J=6.0H z,2H),2.92~2.82(m,4H),2.76~2.67(m,4H),2.48(m,2H),2.44~2.37(m,1H),2.14(t,J=7.0Hz,2H),2 .00(t,J=7.5Hz,2H),1.92~1.90(m,1H),1.52~1.35(m,7H),1.23~1.20(m,16H),0.84(t,J=7.5Hz,3H). MS(m / z):612.45[M+H] + .

[0100] Example 28: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(20-(ethylamino)-20-oxoarachidonoyl)glycine ester [ka] Following the procedure of Example 25, substituting (20-(ethylamino)-20-oxoarachidonoyl)glycine (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 28 was prepared as a white solid powder (0.38 g, 52% yield) MS (m / z): 724.55 [M+H] + .

[0101] Example 29: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(19-(ethylamino)-19-oxononadecanoyl)glycine ester [ka] Following the procedure of Example 25, substituting (18-amino-18-oxostearoyl)glycine with (19-(ethylamino)-19-oxonadecanoyl)glycine (1.1 eq) to prepare compound 29 as a white solid powder (0.25 g, 50% yield) MS (m / z): 710.52 [M+H] + .

[0102] Example 30: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(18-(ethylamino)-18-oxostearoyl)glycine ester [ka] Following the procedure of Example 25, but substituting 16-ethylamino-16-oxostearamidoacetic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 30 was prepared as a white solid powder (1.27 g, 60% yield) MS (m / z): 696.53 [M+H] + .

[0103] Example 31: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(17-(ethylamino)-17-oxoheptadecanoyl)glycine ester [ka] Following the procedure of Example 25, substituting (17-(ethylamino)-17-oxoheptadecanoyl)glycine (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 31 was prepared as a white solid powder (0.26 g, 62% yield) MS (m / z): 682.46 [M+H] + .

[0104] Example 32: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(16-(ethylamino)-16-oxopalmitoyl)glycine ester [ka] Following the procedure of Example 25, substituting (16-(ethylamino)-16-oxopalmitoyl)glycine (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 32 was prepared as a white solid powder (0.48 g, 73.8% yield). 1 H NMR(500MHz,DMSO-d6)δ 8.40(br,1H),7.71(br,1H),7.28(d,J=5.0Hz,1H),7.12(t,J=7.5Hz,1H),7.01(d,J=3.0Hz,1H),6 .92(s,1H),6.87(s,1H),6.83(d,J=8.0Hz,1H),4.07(d,J=5.0Hz,2H),3.05(t,J=6.5Hz,2H),2.91 ~2.82(m,4H),2.75~2.63(m,4H),2.50~2.37(m,3H),2.14(t,J=7.0Hz,2H),2.01(t,J=7.0Hz,2H), 1.90(br,1H),1.50~1.38(m,7H),1.23~1.20(m,20H),0.98(t,J=7.0Hz,3H),0.84(t,J=7.0Hz,3H). MS(m / z):668.60[M+H] + .

[0105] Example 33: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(15-(ethylamino)-15-oxopentadecanoyl)glycine ester [ka] Following the procedure of Example 25, substituting (15-(ethylamino)-15-oxopentadecanoyl)glycine (1.1 eq) for octanoyl(18-amino-18-oxostearoyl)glycine, compound 33 was prepared as a white solid powder (0.42 g, 70% yield) MS (m / z): 654.45 [M+H] + .

[0106] Example 34: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(14-(ethylamino)-14-oxomyristoyl)glycine ester [ka] Following the procedure of Example 25, substituting (14-(ethylamino)-14-oxomyristyl)glycine (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 34 was prepared as a white solid powder (0.37 g, 65% yield). 1 H NMR(500MHz,DMSO-d6)δ 8.41(br,1H),7.72(m,1H),7.28(d,J=5.0Hz,1H),7.12(t,J=7.5Hz,1H),7.01(d,J=3.0Hz,1H),6 .92(s,1H),6.87(s,1H),6.83(d,J=8.0Hz,1H),4.07(d,J=5.0Hz,2H),3.05(t,J=6.5Hz,2H),2.92 ~2.81(m,4H),2.75~2.62(m,4H),2.51~2.35(m,3H),2.14(t,J=7.0Hz,2H),2.01(t,J=7.0Hz,2H), 1.90(m,1H),1.50~1.38(m,7H),1.23~1.18(m,16H),0.98(t,J=7.0Hz,3H),0.84(t,J=7.0Hz,3H). MS(m / z):640.46[M+H] + .

[0107] Example 35: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(16-(propylamino)-16-oxopalmitoyl)glycine ester [ka] Following the procedure of Example 25, substituting (16-(propylamino)-16-oxopalmitoyl)glycine (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 35 was prepared as a white solid powder (0.62 g, 64% yield).1 H NMR(500MHz,CDCl3)δ 7.13~7.12(m,2H),7.01(d,J=7.5Hz,1H),6.92(t,J=4.0Hz,1H),6.82(d,J=7.0Hz, 1H),6.82(s,1H),6.02(br,1H),5.42(m,1H),4.31(d,J=5.5Hz,2H),3.21(dd,J=8.5 Hz,7.0Hz,2H),2.96(m,4H),2.82(m,4H),2.54(m,3H),2.27(t,J=7.5Hz,2H),2.15 (t,J=7.5Hz,2H),2.03(m,1H),1.67~1.48(m,9H),1.31~1.24(m,20H),0.92(m,6H). MS(m / z):682.67[M+H] + .

[0108] Example 36: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(15-(propylamino)-15-oxopentadecanoyl)glycine ester [ka] Following the procedure of Example 25, but substituting 15-propylamino-15-oxopentadecane amide acetic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 36 was prepared as a white solid powder (0.34 g, 62% yield) MS (m / z): 668.60 [M+H] + .

[0109] Example 37: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(14-(propylamino)-14-oxomyristoyl)glycine ester [ka] Following the procedure of Example 25, substituting 14-propylamino-14-oxomyristamide acetic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 37 was prepared as a white solid powder (0.42 g, 73% yield). 1 H NMR(500MHz,DMSO-d6)7.14~7.11(m,2H),7.01(d,J=7.5Hz,1H),6.92(t,J=4.0Hz,1H),6. 82(d,J=7.0Hz,1H),6.82(s,1H),6.02(br,1H),5.42(br,1H),4.31(d,J=5.5Hz,2H),3.21( dd,J=8.5Hz,7.0Hz,2H),2.96(m,4H),2.82(m,4H),2.54(m,3H),2.27(t,J=7.5Hz,2H),2.1 5(t,J=7.5Hz,2H),2.03(m,1H),1.67~1.47(m,9H),1.30~1.23(m,16H),0.95~0.83(m,6H). MS(m / z):654.46[M+H] + .

[0110] Example 38: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(13-(propylamino)-13-oxotridecanoyl)glycine ester [ka] Following the procedure of Example 25, but substituting 13-propylamino-13-oxotridecanamidoacetic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 38 was prepared as a white solid powder (0.18 g, 60% yield) MS (m / z): 640.43 [M+H] + .

[0111] Example 39: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(12-(propylamino)-12-oxolauroyl)glycine ester [ka] Following the procedure of Example 25, but substituting 12-propylamino-12-oxolauramidoacetic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 39 was prepared as a white solid powder (0.20 g, 65% yield) MS (m / z): 626.40 [M+H] + .

[0112] Example 40: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(15-(butylamino)-15-oxopentadecanoyl)glycine ester [ka] Following the procedure of Example 25, but substituting 15-butylamino-15-oxopentadecane amide acetic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 40 was prepared as a white solid powder (0.26 g, 67% yield) MS (m / z): 696.50 [M+H] + .

[0113] Example 41: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(14-(butylamino)-14-oxomyristoyl)glycine ester [ka] Following the procedure of Example 25, substituting (14-(butylamino)-14-oxomyristyl)glycine (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 41 was prepared as a white solid powder (0.45 g, 70% yield). 1H NMR(500MHz,DMSO-d6)δ 7.15~7.10(m,2H),6.98(d,J=7.5Hz,1H),6.94~6.91(m,1H),6.84(d,J=8.0Hz,1H),6.81(d,J=2.5 Hz,1H),6.07(br,1H),5.41(s,1H),4.31(d,J=5.5Hz,2H),3.24(q,J=6.5Hz,2H),2.83~2.74(m,4H) ),2.55~2.47(m,3H),2.26(t,J=7.5Hz,2H),2.14(t,J=8.0Hz,2H),2.03(m,1H),1.67~1.66(m,1H) ,1.61~1.55(m,4H),1.50~1.46(m,4H),1.36~1.32(m,2H),1.38~1.23(m,16H),0.94~0.85(m,6H). MS(m / z):668.52[M+H] + .

[0114] Example 42: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(13-(butylamino)-13-oxotridecanoyl)glycine ester [ka] Following the procedure of Example 25, but substituting 13-butylamino-13-oxotridecanamidoacetic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 42 was prepared as a white solid powder (0.19 g, 64% yield) MS (m / z): 654.47 [M+H] + .

[0115] Example 43: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(12-(butylamino)-12-oxolauroyl)glycine ester [ka] Following the procedure of Example 25, substituting 12-butylamino-12-oxolauramidoacetic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 43 was prepared as a white solid powder (1.50 g, 82.5% yield). 1 H NMR(500MHz,CDCl3)δ 7.14~7.11(m,2H),7.00(d,J=7.5Hz,1H),6.93~6.91(m,1H),6.84(d,J=8.0Hz,1H),6.81(d,J=2. 5Hz,1H),6.07(br,1H),5.41(s,1H),4.31(d,J=5.5Hz,2H),3.24(q,J=6.5Hz,2H),2.83~2.74(m, 4H),2.55~2.47(m,3H),2.26(t,J=7.5Hz,2H),2.14(t,J=8.0Hz,2H),2.03(br,1H),1.67~1.66(m ,1H),1.61~1.55(m,4H),1.50~1.46(m,4H),1.36~1.32(m,2H),1.26(m,12H),0.93~0.88(m,6H). MS(m / z):640.72[M+H] + .

[0116] Example 44: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(12-(hexylamino)-12-oxolauroyl)glycine ester [ka] Following the procedure of Example 25, substituting 12-hexylamino-12-oxolauramidoacetic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 44 was prepared as a white solid powder (0.90 g, 41% yield). 1H NMR(500MHz,CDCl3)δ 7.17~7.11(m,2H),7.02(d,J=7.6Hz,1H),6.97~6.92(m,1H),6.86(d,J=7.9Hz,1H),6.83(d,J= 3.4Hz,1H),6.15(t,J=5.3Hz,1H),5.48(t,J=5.9Hz,1H),4.33(d,J=5.3Hz,2H),3.25(q,J=6.7H z,2H),3.03~2.74(m,8H),2.62~2.47(m,3H),2.28(t,J=7.6Hz,2H),2.16(t,J=7.6Hz,2H),2.09 ~2.03(m,1H),1.70~1.56(m,5H),1.51(q,J=7.8Hz,4H),1.37~1.24(m,18H),0.93~0.88(m,6H). MS(m / z):668.92[M+H] + .

[0117] Example 45: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(10-(butylamino)-10-oxodecanoyl)glycine ester [ka] Following the procedure of Example 25, substituting 10-butylamino-10-oxodecanamidoacetic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 45 was prepared as a white solid powder (0.18 g, 52% yield) MS (m / z): 612.40 [M+H] + .

[0118] Example 46: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(16-(methylamino)-16-oxopalmitoyl)glycine ester [ka] Following the procedure of Example 25, substituting 16-methylamino-16-oxopalmitamidoacetic acid (1.29 g, 3.49 mmol, 1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 46 was prepared as a white solid powder (0.7 g, 75.4% yield). 1 H NMR(500MHz,DMSO-d6)δ 8.40(t,J=6.0Hz,1H),7.66(br,1H),7.28(dd,J=5.0Hz,1.0Hz,1H),7.12(t,J=7.5Hz,1H),7.00(d,J=7.5 Hz,1H),6.93~6.91(m,1H),6.87(d,J=3.0Hz,1H),6.82(d,J=8.0Hz,1H),4.07(d,J=6.0Hz,2H),2.91~2.8 2(m,4H),2.76~2.67(m,4H),2.57(d,J=4.5Hz,3H),2.48(m,2H),2.43~2.36(m,1H),2.14(t,J=7.5Hz,2H) ,2.01(t,J=7.0Hz,2H),1.92~1.90(m,1H),1.51~1.36(m,7H),1.22~1.19(m,20H),0.84(t,J=7.0Hz,3H). MS(m / z):654.54[M+H] + .

[0119] Example 47: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(14-(methylamino)-14-oxopalmitoyl)glycine ester [ka] Following the procedure of Example 25, substituting 14-methylamino-14-oxopalmitamidoacetic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 47 was prepared as a white solid powder (1.2 g, 67.5% yield). 1H NMR(500MHz,DMSO-d6)δ 8.41(t,J=5.5Hz,1H),7.67(br,1H),7.29(d,J=4.5Hz,1H),7.13(t,J=8.0Hz,1H),7.01(d,J=7.5Hz,1H),6.9 2(dd,J=5.5Hz,3.5Hz,1H),6.88(d,J=2.5Hz,1H),6.82(d,J=8.0Hz,1H),6.66(br,1H),4.07(d,J=5.5Hz,2H), 2.92~2.83(m,4H),2.73~2.71(m,4H),2.54(d,J=4.5Hz,3H),2.49(m,2H),2.44~2.37(m,1H),2.15(t,J=7.5Hz ,2H),2.02(t,J=7.0Hz,2H),1.93~1.91(m,1H),1.51~1.40(m,7H),1.24~1.20(m,16H),0.85(t,J=7.5Hz,3H). MS(m / z):626.41[M+H] + .

[0120] Example 48: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(12-(methylamino)-12-oxolauroyl)glycine ester [ka] Following the procedure of Example 25, substituting 12-methylamino-12-oxolauramidoacetic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 48 was prepared as a white solid powder (1.0 g, 58.9% yield). 1H NMR(500MHz,DMSO-d6)δ 8.40(t,J=6.0Hz,1H),7.66(s,1H),7.29(d,J=5.5Hz,1H),7.12(t,J=7.5Hz,1H),7.01(d,J=7.5Hz,1H),6 .92(dd,J=5.5Hz,3.5Hz,1H),6.87(d,J=3.0Hz,1H),6.82(d,J=7.5Hz,1H),4.07(d,J=6.0Hz,2H),2.92~2. 82(m,4H),2.76~2.71(m,4H),2.53(d,J=4.5Hz,3H),2.49(m,2H),2.43~2.37(m,1H),2.14(t,J=7.5Hz,2H ),2.01(t,J=7.5Hz,2H),1.90(m,1H),1.50~1.38(m,7H),1.23(s,4H),1.19(s,8H),0.84(t,J=7.5Hz,3H). MS(m / z):598.43[M+H] + .

[0121] Example 49: (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl(4-(hexadecylamino)-4-oxobutyryl)glycine ester [ka] Following the procedure of Example 25, substituting 4-hexadecylamino-4-oxobutyramidoacetic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 49 was prepared as a white solid powder (0.27 g, 45.5% yield). 1H NMR(500MHz,DMSO-d6)δ 8.46(br,1H),7.78(s,1H),7.29(d,J=4.5Hz,1H),7.13(t,J=8.0Hz,1H),7.01(d,J=7.5Hz,1H),6 .93(s,1H),6.88(s,1H),6.83(d,J=8.0Hz,1H),4.08(d,J=5.0Hz,2H),3.00~2.99(m,2H),2.91~2. 82(m,4H),2.77~2.64(m,4H),2.50(s,2H),2.40~2.39(m,3H),2.31(t,J=7.0Hz,2H),1.91(m,1H), 1.51~1.48(m,1H),1.41(dd,J=14.0Hz,7.0Hz,2H),1.35(m,2H),1.23(s,26H),0.86~0.85(m,6H). MS(m / z):696.58[M+H] + .

[0122] Example 50: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(20-(ethylamino)-20-oxoaracamide)propionic acid ester [ka] Following the procedure of Example 25, but substituting 3-((20-ethylamino)-20-oxoaracamido)propionic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 50 was prepared as a white solid powder (0.23 g, 41% yield) MS (m / z): 738.56 [M+H] + .

[0123] Example 51: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(19-(ethylamino)-19-oxononadecanamide)propionic acid ester [ka] Following the procedure of Example 25, but substituting 3-((19-ethylamino)-19-oxononadecanamido)propionic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 51 was prepared as a nearly white solid powder (0.31 g, 44% yield) MS (m / z): 724.35 [M+H] + .

[0124] Example 52: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(18-(ethylamino)-18-oxostearamide)propionic acid ester [ka] Following the procedure of Example 25, but substituting 3-((18-ethylamino)-18-oxostearamido)propionic acid (1.29 g, 3.49 mmol, 1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 52 was prepared as a nearly white solid powder (0.25 g, 60% yield) MS (m / z): 710.39 [M+H] + .

[0125] Example 53: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(17-(ethylamino)-17-oxoheptadecanamido)propionic acid ester [ka] Following the procedure of Example 25, but substituting 3-((17-ethylamino)-17-oxoheptadecanamido)propionic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 53 was prepared as a nearly white solid powder (0.28 g, 65% yield) MS (m / z): 696.42 [M+H] + .

[0126] Example 54: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(16-(ethylamino)-16-oxopalmitamido)propionate [ka] Following the method of Example 25, substituting 3-(16-(ethylamino)-16-oxopalmitamido)propionic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 54 was prepared (2.5 g, 87.5% yield). 1 H NMR(500MHz,CDCl3)δ 7.14~7.11(m,2H),7.00(d,J=7.5Hz,1H),6.93~6.91(m,1H),6.83~6.81(m,2H),6.06(b r,1H),5.39(br,1H),3.62(q,J=6.0Hz,2H),3.31~3.26(m,2H),2.93~2.89(m,4H),2.83 ~2.74(m,6H),2.55~2.45(m,3H),2.17~2.12(m,4H),2.03~2.00(m,1H),1.63~1.56(m,5 H),1.51~1.47(m,2H),1.28~1.24(m,20H),1.13(t,J=7.5Hz,3H),0.89(t,J=7.0Hz,3H). MS(m / z):682.98[M+H] + .

[0127] Example 55: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(15-(ethylamino)-15-oxopentadecane amide)propionic acid ester [ka] Following the procedure of Example 25, but substituting 3-(15-(ethylamino)-15-oxopentadecaneamido)propionic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 55 was prepared as a white solid powder (0.28 g, 63% yield) MS (m / z): 668.60 [M+H]+ .

[0128] Example 56: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(14-(ethylamino)-14-oxomyristamide)propionate [ka] Following the procedure of Example 25, substituting 3-(14-(ethylamino)-14-oxomyristamide)propionic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 56 was prepared as a white solid powder (1.0 g, 74% yield). 1 H NMR(500MHz,DMSO-d6)δ 7.14~7.10(m,2H),7.00(d,J=7.5Hz,1H),6.93~6.90(m,1H),6.83~6.81(m,2H),6.06(b r,1H),5.39(br,1H),3.62(q,J=6.0Hz,2H),3.31~3.26(m,2H),2.90~2.89(m,4H),2.83 ~2.74(m,6H),2.55~2.45(m,3H),2.17~2.10(m,4H),2.03~2.00(m,1H),1.62~1.56(m,5 H),1.50~1.46(m,2H),1.28~1.24(m,16H),1.13(t,J=7.5Hz,3H),0.89(t,J=7.0Hz,3H). MS(m / z):654.43[M+H] + .

[0129] Example 57: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(13-(ethylamino)-13-oxotridecanamide)propionic acid ester [ka] Following the procedure of Example 25, but substituting 3-(13-(ethylamino)-13-oxotridecanamido)propionic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 57 was prepared as a white solid powder (0.18 g, 63% yield) MS (m / z): 640.38 [M+H] + .

[0130] Example 58: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(12-(ethylamino)-12-oxolauramido)propionic acid ester [ka] Following the procedure of Example 25, substituting 3-(12-(ethylamino)-12-oxolauramido)propionic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 58 was prepared as a white solid powder (0.8 g, 70% yield). 1 H NMR(500MHz,DMSO-d6)δ 7.16~7.09(m,2H),7.01(d,J=7.5Hz,1H),6.93~6.90(m,1H),6.84~6.81(m,2H),6.06(b r,1H),5.39(br,1H),3.62(q,J=6.0Hz,2H),3.31~3.26(m,2H),2.91~2.89(m,4H),2.83 ~2.74(m,6H),2.55~2.45(m,3H),2.18~2.09(m,4H),2.03~2.01(m,1H),1.62~1.56(m,5 H),1.51~1.45(m,2H),1.28~1.23(m,12H),1.13(t,J=7.5Hz,3H),0.89(t,J=7.0Hz,3H). MS(m / z):626.40[M+H] + .

[0131] Example 59: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(16-(propylamino)-16-oxopalmitamido)propionic acid ester [ka] Following the procedure of Example 25, substituting 3-(16-(propylamino)-16-oxopalmitamido)propionic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 59 was prepared as a white solid powder (0.8 g, 74% yield). 1 H NMR (500MHz, DMSO-d6) δ 7.14~7.10(m,2H),7.01(d,J=7.5Hz,1H),6.93~6.90(m,1H),6.84~6.81(m ,2H),6.06(br,1H),5.39(br,1H),3.62(q,J=6.0Hz,2H),3.31~3.26(m,2H) ,2.91~2.89(m,4H),2.83~2.74(m,6H),2.55~2.45(m,3H),2.18~2.09(m,4 H), 2.02(m, 1H), 1.68~1.47(m, 9H), 1.30~1.24(m, 20H), 0.93~0.85(m, 6H). MS(m / z):696.48[M+H] + .

[0132] Example 60: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(15-(propylamino)-15-oxopentadecane amide)propionic acid ester [ka] Following the procedure of Example 25, but substituting 3-(15-(propylamino)-15-oxopentadecaneamido)propionic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 60 was prepared as a nearly white solid (0.13 g, 51% yield) MS (m / z): 682.38 [M+H] + .

[0133] Example 61: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(14-(propylamino)-14-oxomyristamide)propionate [ka] Following the procedure of Example 25, but substituting 3-(14-(propylamino)-14-oxomyristamide)propionic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 61 was prepared as a nearly white solid (0.39 g, 67% yield) MS (m / z): 668.33 [M+H] + .

[0134] Example 62: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(13-(propylamino)-13-oxotridecanamide)propionic acid ester [ka] Following the procedure of Example 25, but substituting 3-(13-(propylamino)-13-oxotridecanamido)propionic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 62 was prepared as a nearly white solid (0.31 g, 63% yield) MS (m / z): 654.45 [M+H] + .

[0135] Example 63: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(12-(propylamino)-12-oxolauramido)propionic acid ester [ka] Following the procedure of Example 25, substituting 3-(12-(propylamino)-12-oxolauramido)propionic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 63 was prepared as a nearly white solid (0.87 g, 72% yield). 1 H NMR (500MHz, DMSO-d6) δ 7.13~7.09(m,2H),7.01(d,J=7.5Hz,1H),6.93~6.91(m,1H),6.83~6.80(m ,2H),6.06(br,1H),5.39(br,1H),3.62(q,J=6.0Hz,2H),3.33~3.25(m,2H) ,2.91~2.89(m,4H),2.84~2.75(m,6H),2.54~2.43(m,3H),2.17~2.08(m,4 H), 2.02(m, 1H), 1.70~1.48(m, 9H), 1.30~1.24(m, 12H), 0.93~0.85(m, 6H). MS(m / z):640.47[M+H] + .

[0136] Example 64: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(17-(propylamino)-17-oxoheptadecanamido)propionic acid ester [ka] Following the procedure of Example 25, but substituting 3-(17-(propylamino)-17-oxoheptadecanamido)propionic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 64 was prepared as a nearly white solid (0.13 g, 43% yield) MS (m / z): 710.52 [M+H] + .

[0137] Example 65: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(18-(propylamino)-18-oxostearamide)propionic acid ester [ka] Following the procedure of Example 25, but substituting 3-(18-(propylamino)-18-oxostearamido)propionic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 65 was prepared as a nearly white solid (0.31 g, 67% yield) MS (m / z): 724.43 [M+H] + .

[0138] Example 66: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(16-(butylamino)-16-oxopalmitamido)propionic acid ester [ka] Following the procedure of Example 25, substituting 3-(16-(butylamino)-16-oxopalmitamido)propionic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 66 was prepared as a nearly white solid (0.67 g, 76% yield). 1 H NMR(500MHz,DMSO-d6)δ 7.16~7.10(m,2H),6.99(d,J=7.5Hz,1H),6.93~6.91(m,1H),6.84~6.80(m,2H),6.10(t, J=6.0Hz,1H),5.42(br,1H),3.61(q,J=6.0Hz,2H),3.23(q,J=6.5Hz,2H),3.01~2.88(m,4 H),2.83~2.72(m,6H),2.56~2.46(m,3H),2.18~2.11(m,4H),2.03(m,1H),1.67(m,1H),1 .61(m,5H),1.51~1.43(m,4H),1.37~1.31(m,2H),1.27~1.24(m,20H),0.95~0.86(m,6H). MS(m / z):710.42[M+H] + .

[0139] Example 67: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(15-(butylamino)-15-oxopentadecane amide)propionic acid ester [ka] Following the procedure of Example 25, substituting 3-(15-(butylamino)-15-oxopentadecaneamido)propionic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 67 was prepared as a white solid (0.23 g, 57% yield) MS (m / z): 696.40 [M+H] + .

[0140] Example 68: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(14-(butylamino)-14-oxomyristamide)propionic acid ester [ka] Following the procedure of Example 25, but substituting 3-(14-(butylamino)-14-oxomyristamide)propionic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 68 was prepared as a nearly white solid (0.8 g, 69% yield) MS (m / z): 682.47 [M+H] + .

[0141] Example 69: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(13-(butylamino)-13-oxotridecanamide)propionic acid ester [ka] Following the procedure of Example 25, but substituting 3-(13-(butylamino)-13-oxotridecanamido)propionic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 69 was prepared as a nearly white solid (0.37 g, 71% yield) MS (m / z): 668.43 [M+H] + .

[0142] Example 70: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(12-(butylamino)-12-oxolauramido)propionic acid ester [ka] Following the method of Example 25, substituting 3-(12-(butylamino)-12-oxolauramido)propionic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 70 was prepared (1.53 g, 82.4% yield). 1 H NMR(500MHz,CDCl3)δ 7.14~7.11(m,2H),6.99(d,J=7.5Hz,1H),6.93~6.91(m,1H),6.83~6.81(m,2H),6.10(t,J= 6.0Hz,1H),5.42(s,1H),3.61(q,J=6.0Hz,2H),3.23(q,J=6.5Hz,2H),2.96~2.89(m,4H),2 .83~2.74(m,6H),2.56~2.46(m,3H),2.17~2.12(m,4H),2.03(br,1H),1.67~1.66(m,1H),1 .61(br,5H),1.50~1.44(m,4H),1.36~1.31(m,2H),1.27~1.26(m,12H),0.93~0.88(m,6H). MS(m / z):654.69[M+H] + .

[0143] Example 71: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(13-(pentylamino)-13-oxotridecanamide)propionic acid ester [ka] Following the procedure of Example 25, but substituting 3-(13-(pentylamino)-13-oxotridecanamido)propionic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 71 was prepared as a nearly white solid (0.16 g, 55% yield) MS (m / z): 682.50 [M+H] + .

[0144] Example 72: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(12-(hexylamino)-12-oxolauramido)propionic acid ester [ka] Following the method of Example 25, substituting 3-(12-(hexylamino)-12-oxolauramido)propionic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 72 was prepared (0.96 g, 42% yield). 1 H NMR(500MHz,CDCl3)δ 7.13(t,J=7.6Hz,2H),7.00(d,J=7.7Hz,1H),6.94~6.89(m,1H),6.82(t,J=5.4Hz,2H),6 .15(t,J=6.2Hz,1H),5.49(t,J=6.0Hz,1H),3.61(q,J=6.2Hz,2H),3.23(q,J=6.7Hz,2H) ,3.05~2.71(m,10H),2.61~2.43(m,3H),2.15(dt,J=12.3,7.6Hz,4H),2.05~2.02(m,1H) ,1.66~1.55(m,5H),1.49(dt,J=13.4,7.0Hz,4H),1.35~1.17(m,18H),0.94~0.82(m,6H). MS(m / z):682.58[M+H] + .

[0145] Example 73: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(11-(heptylamino)-11-oxoundecanamide)propionic acid ester [ka] Following the procedure of Example 25, substituting 3-(11-(heptylamino)-11-oxoundecanamido)propionic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 73 was prepared as a nearly white solid (0.21 g, 58% yield) MS (m / z): 682.52 [M+H] + .

[0146] Example 74: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(10-(hexylamino)-10-oxodecanamido)propionic acid ester [ka] Following the procedure of Example 25, but substituting 3-(10-(hexylamino)-10-oxodecanamido)propionic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 74 was prepared as a nearly white solid powder (0.29 g, 63% yield) MS (m / z): 654.31 [M+H] + .

[0147] Example 75: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(8-(hexylamino)-8-oxooctane amide)propionic acid ester [ka] Following the procedure of Example 25, but substituting 3-(8-(hexylamino)-8-oxooctaneamido)propionic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 75 was prepared as a nearly white solid powder (0.33 g, 72% yield) MS (m / z): 626.47 [M+H] + .

[0148] Example 76: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(12-(tert-butylamino)-12-oxolauramido)propionic acid ester [ka] Following the procedure of Example 25, substituting 3-(12-(tert-butylamino)-12-oxolauramido)propionic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 76 was prepared as a white solid (2.12 g, 89.8% yield). 1 H NMR(500MHz,CDCl3)δ 7.14~7.11(m,2H),6.99(d,J=8.0Hz,1H),6.92~6.91(m,1H),6.83~6.81(br,2H),6.10(t,J=6.0Hz,1H),5.24(s,1H),3.61(q,J=6.0Hz,2H) ,2.97~2.83(m,4H),2.02(br,1H),1.73(br,1H),1.62~1.56(m,4H),1.52~1.46(m,2H),1.33(s,9H),1.26(br,12H),0.89(t,J=7.5Hz,3H). MS(m / z):655.35[M+H] + .

[0149] Example 77: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(16-(methylamino)-16-oxopalmitamido)propionate [ka] Following the procedure of Example 25, substituting 3-(16-(methylamino)-16-oxopalmitamido)propionic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 77 was prepared (1.60 g, 56.3% yield). 1 H NMR(500MHz,CDCl3)δ 7.14~7.11(m,2H),6.99(d,J=7.5Hz,1H),6.93~6.91(m,1H),6.83~6.81(m,2H),6. 07(t,J=6.0Hz,1H),5.45(br,1H),3.63~3.60(m,2H),3.31~3.26(m,2H),2.99~2.89 (m,3H),2.84~2.74(m,8H),2.57~2.48(m,3H),2.17~2.14(m,4H),2.04~2.00(m,1H ),1.63~1.58(m,5H),1.52~1.47(m,2H),1.28~1.24(m,22H),0.89(t,J=7.5Hz,3H). MS(m / z):668.69[M+H] + .

[0150] Example 78: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(16-(methylamino)-16-oxopalmitamido)propionate [ka] Following the procedure of Example 25, substituting 3-(16-(methylamino)-16-oxopalmitamido)propionic acid (1.1 eq) for (18-amino-18-oxostearoyl)glycine, compound 78 was prepared as a white solid powder (1.20 g, 69% yield). 1H NMR(500MHz,DMSO-d6)δ 10.31(s,1H),8.08(d,J=9.0Hz,2H),7.81(d,J=8.5Hz,2H),7.67(s,1H),7.32(br,2H) ,7.20(t,J=7.5Hz,1H),7.08(d,J=7.5Hz,1H),7.01(d,J=7.5Hz,3H),6.94(br,2H),2. 95~2.76(m,8H),2.55(d,J=9.5Hz,3H),2.37(t,J=7.5Hz,3H),2.03(t,J=7.5Hz,2H),1 .61(t,J=7.0Hz,2H),1.47(t,J=7.0Hz,2H),1.30~1.25(m,12H),0.87(t,J=6.5Hz,3H). MS(m / z):660.46[M+H] + .

[0151] Example 79: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(16-(methylamino)-16-oxopalmitamido)propionate [ka] Rotigotine (2.0g, 5.68mmol), Boc-glycine (1.04g, 5.966mmol, 1.05eq), triethylamine (1.73g, 17.05mmol, 3.0eq), THF (20.0mL) were added to a 100mL single-neck flask, and EDCI (1.64g, 8.52mmol, 1.5eq) and HOBT (0.15g, 1.14mmol, 0.2eq) were added under stirring, and the mixture was reacted at room temperature for 3 hours. When LCMS showed that the reaction of the raw material was complete, water and ethyl acetate were added, and the mixture was separated. The aqueous phase was extracted twice with ethyl acetate, and the organic phase was combined and concentrated under reduced pressure. The residue was dissolved by adding dichloromethane (20.0mL). Then, trifluoroacetic acid (5.0mL) was added and reacted at room temperature for 2 hours. When TLC showed that the reaction of the raw materials was completed, the reaction solution was concentrated under reduced pressure, and the residue was added with tetrahydrofuran (20.0mL) to dissolve it. Then, DIPEA (2.53g, 19.60mmol, 4.0eq) and (2.06g, 5.88mmol, 1.2eq) were added and reacted at room temperature for 2 hours. When TLC showed that the reaction of the raw materials was completed, water and ethyl acetate were added and separated. The aqueous phase was extracted twice with ethyl acetate. The organic phase was combined, concentrated under reduced pressure, and subjected to column chromatography to obtain compound 79 as a pale yellow oil (0.88g, total yield 24.2%). 1 H NMR(500MHz,DMSO-d6)δ 7.28(dd,J=5.0Hz,1.5Hz,1H),7.12(t,J=8.0Hz,1H),6.99(d,J=7.5Hz,1H),6.93~6.91(m,2H),6.87 ~6.86(m,1H),6.82(d,J=8.0Hz,1H),6.28(t,J=5.5Hz,1H),6.19(t,J=5.5Hz,1H),4.02(d,J=6.5Hz,2 H),2.99(q,J=1.5Hz,2H),2.90(t,J=7.0Hz,2H),2.85~2.81(m,2H),2.76~2.60(m,4H),2.44~2.38(m, 1H), 1.92~1.90(m,1H),1.50~1.46(m,1H),1.42~1.34(m,4H),1.24~1.22(m,20H),0.86~0.82(m,6H). MS(m / z):584.59[M+H] + .

[0152] Example 80: (R)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(16-(methylamino)-16-oxopalmitamido)propionic acid ester [ka] Following the procedure of Example 1, substituting 3-(16-(methylamino)-16-oxopalmitamido)propionic acid (1.1 eq) for octanamidoacetic acid, compound 80 was prepared as a pale yellow oil (0.25 g, 66.7% yield). 1 H NMR(500MHz,CDCl3)δ 7.21(s,1H),7.12~7.10(br,2H),6.98(d,J=7.5Hz,1H),6.93~6.91(br,1H),6.85(d,J=8.0Hz,1 H),6.81(s,1H),5.88(s,1H),4.29(d,J=5.5Hz,2H),3.39~3.36(dd,J=12.0Hz,6.0Hz,2H),2.98~ 2.89(br,4H),2.84~2.82(br,4H),2.55~2.49(br,3H),2.31(t,J=6.0Hz,2H),2.17(t,J=7.5Hz,2 H),2.04(br,1H),1.87~1.83(m,2H),1.63~1.60(br,5H),1.29~1.27(br,8H),0.91~0.86(m,6H). MS(m / z):584.44[M+H] + .

[0153] Example 81: Determination of the physical and chemical properties of the compounds of the present invention An appropriate amount of the test compound of the present invention was placed in an aluminum crucible, and DSC was measured, and the results are shown in Table 1. The test results show that all of the compounds of the present invention have high melting points, which can meet the needs of producing long-acting drugs by the grinding method.

[0154] Equipment model: NETZSCH DSC3500 Heating rate: 10.0K / min Atmosphere: N2 [Table 1-1] [Table 1-2]

[0155] Example 82: Preparation of samples for pharmacokinetic experiments The compound of the present invention was accurately weighed and placed in a 20mL vial, and then blank matrix solution and zirconia balls were added and vortex polished. After polishing, the suspension sample was transferred and adjusted to a constant volume with blank matrix solution, and dispensed into a 7mL vial to prepare a suspension of about 20mg / mL. The content was measured and then used in a rat pharmacokinetic experiment.

[0156] Example 83: In vivo pharmacokinetic study of the compounds of the present invention in rats The suspensions of Examples 15, 24, 27, 32 and 54 prepared by the method of Example 82 were intramuscularly injected into SD rats at a dose of 9 mg / kg (rotigotine equivalent), three rats each. Whole blood was collected at 1 hour, 4 hours, 8 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 168 hours, 216 hours, 264 hours, 312 hours and 360 hours at 0.3 mL / time, and K2EDTA / heparin was added as an anticoagulant and BNPP was added as a stabilizer. The blood was centrifuged within 30 minutes to extract and detect the plasma. The results are shown in Table 2 and Figure 1. [Table 2]

[0157] Tests have shown that the compounds of the present invention are sustained and slowly released in the body, and have a fast onset and long duration of action.

[0158] In summary, the compounds of the present invention have low water solubility, high melting point, excellent suspension formulations can be prepared, rapid efficacy, long duration of action, and bright prospects for clinical application.

[0159] All publications, patents, and patent applications referenced in this specification are incorporated herein by reference to the same extent as if each publication, patent, or patent application was specifically and individually stated to be incorporated by reference. Although the claimed technical features are described based on various examples / embodiments, those skilled in the art will appreciate that various modifications / alterations, substitutions, deletions, and changes / variations can be made without departing from the spirit of the invention. Therefore, it is intended that the scope of the claimed technical features be limited only by the appended claims, or equivalents thereof.

Claims

1. A compound having the structure shown in formula (II), or a stereoisomer, solvate, or pharma- ceutically acceptable salt thereof. 【Chemistry 87】 (In the formula, X does not exist, Y does not exist, R is -R ３ａ -C(=O)NH-R ３ｂ , or -R ３ａ -NHC(=O)-R ３ｂ and R ３ａ is C １～２４ an alkylene group or an arylene group, R ３ｂ is H or C １～２２ is an alkyl group, m is 1 or 2).

2. R ３ａ is C １～２０ Alkylene group, or C ６～１０ The compound of claim 1 which is an arylene group.

3. 2. The compound of claim 1 selected from the following: and stereoisomers, solvates, or pharma- ceutically acceptable salts thereof. 【Chemistry 88】 (wherein m is 1 or 2, m' is an integer from 1 to 5, n is an integer from 7 to 20, n' is an integer from 2 to 20, and R ３ｂ is H or C １～１８ It is an alkyl group.

4. 2. The compound of claim 1 selected from the following: and stereoisomers, solvates, or pharma- ceutically acceptable salts thereof. 【Chemistry 89-2】 【Chemistry 89-3】 【Chemistry 89-4】

5. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4, or a stereoisomer or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient, carrier or diluent.

6. The compound according to claim 5, which is used as a drug for preventing and / or treating diseases of the central nervous system. A pharmaceutical composition comprising:

7. The pharmaceutical composition of claim 6, wherein the drug is a long-acting drug.

8. The pharmaceutical composition according to claim 6, wherein the central nervous system disease is Parkinson's disease, restless legs syndrome or depression.

9. 5. The compound according to any one of claims 1 to 4, or a stereoisomer, solvate or pharma- ceutical acceptable salt thereof, for use in a drug for preventing and / or treating a disease of the central nervous system.

10. 10. The compound of claim 9, or a stereoisomer, solvate or pharma- ceutically acceptable salt thereof, wherein the drug is a long-acting drug.

11. 10. The compound according to claim 9, or a stereoisomer, solvate or pharma- ceutically acceptable salt thereof, wherein the central nervous system disease is Parkinson's disease, restless legs syndrome or depression.

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