TETRAHYDRONAPHTHALENE COMPOUNDS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF

Abstract

A novel tetrahydronaphthalene compound is provided, or a stereoisomer, a solvate, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the compound, and a use of the compound or the composition for preparing a medicament in prevention and/or treatment of a central nervous system disease, wherein the compound has a structure of formula (I),

##STR00001##

wherein each of X, Y, Z, W and R is defined as described in the present disclosure.

Claims

1. A compound, having a structure of formula (I), or a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof: ##STR00108## wherein, X is absent, or X is —C(R.sup.1)(R.sup.2)—; Y is absent, or Y is 0; Z is absent, or Z is C.sub.1-15 alkylene; W is —C(═O)NH—, or —NHC(═O)—; each of R.sup.1 and R.sup.2 is independently H, D, F, Cl, OH, —CN, or C.sub.1-4 alkyl; R is C.sub.1-30 alkyl, C.sub.1-30 heteroalkyl, C.sub.2-30 alkenyl, C.sub.2-30 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-10 aliphatic, C.sub.2-10 heterocyclyl, C.sub.2-10 heterocyclyl-C.sub.1-10 aliphatic, aryl, aryl-C.sub.1-10 aliphatic, heteroaryl, heteroaryl-C.sub.1-10 aliphatic, cholane aliphatic group, —R.sup.3a—C(═O)NH—R.sup.3b, or —R.sup.3a—NHC(═O)—R.sup.3b; R.sup.3a is C.sub.1-24 alkylene, C.sub.2-10 alkenylene, arylene, —C.sub.1-10 aliphatic-aryl-, or -aryl-C.sub.1-10 aliphatic-; R.sup.3b is H, C.sub.1-22 alkyl, C.sub.2-10 alkenyl, aryl, or aryl-C.sub.1-10 aliphatic; each of the alkyl, alkylene, heteroalkyl, alkenyl, alkenylene, alkynyl, cycloalkyl, heterocyclyl, cycloalkyl aliphatic, heterocyclyl aliphatic, aryl, arylene, aryl aliphatic, heteroaryl, heteroaryl aliphatic, -aliphatic-aryl-, -aryl-aliphatic-, cholane aliphatic group of R.sup.1, R.sup.2, R, R.sup.3a, and R.sup.3b is independently substituted with 1, 2, 3, or 4 substituents independently selected from H, D, oxo (═O), thio (═S), F, Cl, Br, —OH, —CN, amino, —C(═O)NH—R.sup.4a, —NHC(═O)—R.sup.4a, —S(═O).sub.1-2NH—R.sup.4b, —NHS(═O).sub.1-2—R.sup.4b, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, carboxyl, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl, and C.sub.1-9 heteroaryl; and each of R.sup.4a and R.sup.4b is independently H, or C.sub.1-6 alkyl.

2. The compound of claim 1, wherein the compound has a structure of formula (II): ##STR00109## or a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof, wherein, m is an integer from 1 to 5.

3. The compound of claim 1, wherein X is absent; and Y is absent.

4. The compound of claim 1, wherein each of R.sup.1 and R.sup.2 is independently H, D, F, Cl, OH, —CN, methyl, or ethyl.

5. The compound of claim 1, wherein R is C.sub.1-22 alkyl, C.sub.2-22 alkenyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-6 aliphatic, C.sub.2-7 heterocyclyl, C.sub.2-7 heterocyclyl-C.sub.1-6 aliphatic, C.sub.6-10 aryl, C.sub.6-10 aryl-C.sub.1-6 aliphatic, C.sub.1-9 heteroaryl, C.sub.1-9 heteroaryl-C.sub.1-6 aliphatic, cholane aliphatic group, —R.sup.3a—C(═O)NH—R.sup.3b, or —R.sup.3a—NHC(═O)—R.sup.3b; wherein, each of C.sub.1-22 alkyl, C.sub.2-22 alkenyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-6 aliphatic, C.sub.2-7 heterocyclyl, C.sub.2-7 heterocyclyl-C.sub.1-6 aliphatic, C.sub.6-10 aryl, C.sub.6-10 aryl-C.sub.1-6 aliphatic, C.sub.1-9 heteroaryl, C.sub.1-9 heteroaryl-C.sub.1-6 aliphatic, cholane aliphatic group, —R.sup.3a—C(═O)NH—R.sup.3b, or —R.sup.3a—NHC(═O)—R.sup.3b is independently substituted with 1, 2, 3, or 4 substituents independently selected from H, D, oxo (═O), thio (═S), F, Cl, Br, —OH, —CN, amino, —C(═O)NH—R.sup.4a, —NHC(═O)—R.sup.4a, —S(═O).sub.1-2NH—R.sup.4b, —NHS(═O).sub.1-2—R.sup.4b, carboxyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl, or C.sub.1-9 heteroaryl.

6. The compound of claim 1, wherein R is C.sub.5-20 alkyl, C.sub.2-20 alkenyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 aliphatic, C.sub.2-7 heterocyclyl, C.sub.2-7 heterocyclyl-C.sub.1-6 aliphatic, C.sub.6-10 aryl, C.sub.6-10 aryl-C.sub.1-6 aliphatic, C.sub.1-9 heteroaryl, C.sub.1-9 heteroaryl-C.sub.1-6 aliphatic, cholane aliphatic group, —.sup.3a—C(═O)NH—R.sup.3b, or —R.sup.3a—NHC(═O)—R.sup.3b; wherein, each of C.sub.5-20 alkyl, C.sub.2-20 alkenyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 aliphatic, C.sub.2-7 heterocyclyl, C.sub.2-7 heterocyclyl-C.sub.1-6 aliphatic, C.sub.6-10 aryl, C.sub.6-10 aryl-C.sub.1-6 aliphatic, C.sub.1-9 heteroaryl, C.sub.1-9 heteroaryl-C.sub.1-6 aliphatic, cholane aliphatic group, —R.sup.3a—C(═O)NH—R.sup.3b, or —R.sup.3a—NHC(═O)—R.sup.3b is independently substituted with 1, 2, 3, or 4 substituents independently selected from H, D, oxo (═O), thio (═S), F, Cl, Br, —OH, —CN, amino, —C(═O)NH—R.sup.4a, —NHC(═O)—R.sup.4a, —S(═O).sub.1-2NH—R.sup.4b, —NHS(═O).sub.1-2—R.sup.4b, carboxyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl, or C.sub.1-9 heteroaryl.

7. The compound of claim 1, wherein R.sup.3a is C.sub.1-20 alkylene, C.sub.2-6 alkenylene, C.sub.6-10 arylene, —C.sub.1-6 aliphatic-C.sub.6-10 aryl-, or —C.sub.6-10 aryl-C.sub.1-6 aliphatic-; and R.sup.3b is H, C.sub.1-19 alkyl, C.sub.2-6 alkenyl, C.sub.6-10 aryl, or C.sub.6-10 aryl-C.sub.1-6 aliphatic-; wherein, each of C.sub.1-19 alkyl, C.sub.1-20 alkylene, C.sub.2-6 alkenyl, C.sub.2-6 alkenylene, C.sub.6-10 aryl, C.sub.6-10 arylene, —C.sub.1-6 aliphatic-C.sub.6-10 aryl-, —C.sub.6-10 aryl-C.sub.1-6 aliphatic-, or —C.sub.6-10 aryl-C.sub.1-6 aliphatic- is independently substituted with 1, 2, 3, or 4 substituents independently selected from H, D, oxo (═O), thio (═S), F, Cl, Br, —OH, —CN, amino, —C(═O)NH—R.sup.4a, —NHC(═O)—R.sup.4a, —S(═O).sub.1-2NH—R.sup.4b, —NHS(═O).sub.1-2—R.sup.4b, carboxyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl, or C.sub.1-9 heteroaryl.

8. The compound of claim 1, wherein the compound is selected from any one of the following structures: ##STR00110## ##STR00111## ##STR00112## or a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof; wherein, each of m and m′ is independently an integer from 1 to 5; n is an integer from 7 to n′ is an integer from 2 to 20; and R a b is H, or C.sub.1-18 alkyl.

9. The compound of claim 1, wherein the compound is a compound selected from any one of the following compounds: ##STR00113## ##STR00114## ##STR00115## ##STR00116## ##STR00117## ##STR00118## ##STR00119## ##STR00120## ##STR00121## ##STR00122## ##STR00123## ##STR00124## ##STR00125## ##STR00126## ##STR00127## ##STR00128## ##STR00129## ##STR00130## ##STR00131## ##STR00132## or a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof

10. A pharmaceutical composition, comprising the compound, or the stereoisomer, the solvate, or a pharmaceutically acceptable salt thereof of claim 1, and a pharmaceutically acceptable excipient, a carrier, or a diluent.

11. A method of preventing or treating a central nervous system disease in a mammal in need thereof, comprising administering at least one of the compound or a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof of claim 1, or administering a pharmaceutical composition comprising the compound or a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.

12. The method of claim 11, wherein the medicament is a long-acting drug.

13. The method of claim 11, wherein the central nervous system disease comprises Parkinson's disease, Restless Legs Syndrome, or depression.

14. The compound of claim 2, wherein X is absent; and Y is absent.

15. The compound of claim 2, wherein each of R.sup.1 and R.sup.2 is independently H, D, F, Cl, OH, —CN, methyl, or ethyl.

16. The compound of claim 2, wherein R is C.sub.1-22 alkyl, C.sub.2-22 alkenyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-6 aliphatic, C.sub.2-7 heterocyclyl, C.sub.2-7 heterocyclyl-C.sub.1-6 aliphatic, C.sub.6-10 aryl, C.sub.6-10 aryl-C.sub.1-6 aliphatic, C.sub.1-9 heteroaryl, C.sub.1-9 heteroaryl-C.sub.1-6 aliphatic, cholane aliphatic group, —R.sup.3a—C(═O)NH—R.sup.3b, or —R.sup.3a—NHC(═O)—R.sup.3b; wherein, each of C.sub.1-22 alkyl, C.sub.2-22 alkenyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-6 aliphatic, C.sub.2-7 heterocyclyl, C.sub.2-7 heterocyclyl-C.sub.1-6 aliphatic, C.sub.6-10 aryl, C.sub.6-10 aryl-C.sub.1-6 aliphatic, C.sub.1-9 heteroaryl, C.sub.1-9 heteroaryl-C.sub.1-6 aliphatic, cholane aliphatic group, —R.sup.3a—C(═O)NH—R.sup.3b, or —R.sup.3a—NHC(═O)—R 3b is independently substituted with 1, 2, 3, or 4 substituents independently selected from H, D, oxo (═O), thio (═S), F, Cl, Br, —OH, —CN, amino, —C(═O)NH—R.sup.4a, —NHC(═O)—R.sup.4a, —S(═O).sub.1-2NH—R.sup.4b, —NHS(═O).sub.1-2—R.sup.4b, carboxyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl, or C.sub.1-9 heteroaryl.

17. The compound of claim 2, wherein R is C.sub.5-20 alkyl, C.sub.2-20 alkenyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 aliphatic, C.sub.2-7 heterocyclyl, C.sub.2-7 heterocyclyl-C.sub.1-6 aliphatic, C.sub.6-10 aryl, C.sub.6-10 aryl-C.sub.1-6 aliphatic, C.sub.1-9 heteroaryl, C.sub.1-9 heteroaryl-C.sub.1-6 aliphatic, cholane aliphatic group, —R.sup.3a—C(═O)NH—R.sup.3b, or —R.sup.3a—NHC(═O)—R.sup.3b; wherein, each of C.sub.5-20 alkyl, C.sub.2-20 alkenyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 aliphatic, C.sub.2-7 heterocyclyl, C.sub.2-7 heterocyclyl-C.sub.1-6 aliphatic, C.sub.6-10 aryl, C.sub.6-10 aryl-C.sub.1-6 aliphatic, C.sub.1-9heteroaryl, C.sub.1-9heteroaryl-C.sub.1-6 aliphatic, cholane aliphatic group, —R.sup.3a—C(═O)NH—R.sup.3b, or —R.sup.3a—NHC(═O)—R.sup.3b is independently substituted with 1, 2, 3, or 4 substituents independently selected from H, D, oxo (═O), thio (═S), F, Cl, Br, —OH, —CN, amino, —C(═O)NH—R.sup.4a, —NHC(═O)—R.sup.4a, —S(═O).sub.1-2NH—R.sup.4b, —NHS(═O).sub.1-2—R.sup.4b, carboxyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl, or C.sub.1-9 heteroaryl.

18. The compound of claim 2, wherein R.sup.3a is C.sub.1-20 alkylene, C.sub.2-6 alkenylene, C.sub.6-10 arylene, —C.sub.1-6 aliphatic-C.sub.6-10 aryl-, or —C.sub.6-10 aryl-C.sub.1-6 aliphatic-; and R.sup.3b is H, C.sub.1-19 alkyl, C.sub.2-6 alkenyl, C.sub.6-10 aryl, or C.sub.6-10 aryl-C.sub.1-6 aliphatic-; wherein, each of C.sub.1-19 alkyl, C.sub.1-20 alkylene, C.sub.2-6 alkenyl, C.sub.2-6 alkenylene, C.sub.6-10 aryl, C.sub.6-10 arylene, —C.sub.1-6 aliphatic-C.sub.6-10 aryl-, —C.sub.6-11) aryl-C.sub.1-6 aliphatic-, or —C.sub.6-11) aryl-C.sub.1-6 aliphatic- is independently substituted with 1, 2, 3, or 4 substituents independently selected from H, D, oxo (═O), thio (═S), F, Cl, Br, —OH, —CN, amino, —C(═O)NH—R.sup.4a, —NHC(═O)—R.sup.4a, —S(═O).sub.1-2NH—R.sup.4b, —NHS(═O).sub.1-2—R.sup.4b, carboxyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl, or C.sub.1-9 heteroaryl.

19. The compound of claim 2, wherein the compound is a compound selected from any one of the following compounds: ##STR00133## ##STR00134## ##STR00135## ##STR00136## ##STR00137## ##STR00138## ##STR00139## ##STR00140## ##STR00141## ##STR00142## ##STR00143## ##STR00144## ##STR00145## ##STR00146## ##STR00147## ##STR00148## ##STR00149## ##STR00150## ##STR00151## ##STR00152## or a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition, comprising the compound, or the stereoisomer, the solvate, or a pharmaceutically acceptable salt thereof of claim 2, and a pharmaceutically acceptable excipient, a carrier, or a diluent.

Description

BRIEF DESCRIPTION Some of the embodiments will be described in detail, with reference to the following figure, wherein like designations denote like members, wherein:

[0086] FIG. 1 depicts a distribution diagram of blood concentration of active compounds at different time points after the mouse is intramuscularly injected with the compound suspension of the present disclosure.

DETAILED DESCRIPTION

[0087] In order to describe the present disclosure, embodiments are listed hereinafter. It should be understood that the present disclosure is not limited to the embodiments, and only provides methods for practicing the present disclosure.

[0088] In general, unless otherwise stated, the compound of the present disclosure can be prepared by the method described herein, wherein the substituents are defined as shown in formula I, or II. The following reaction schemes and embodiments are used to further illustrate the content of the present disclosure.

[0089] It should be recognized by one skilled in the conventional art that the chemical reactions described in the present disclosure can be used to appropriately prepare many other compounds of the present disclosure, and other methods for preparing the compounds are considered to be within the scope of the present disclosure. For embodiment, the synthesis of non-exemplary compounds according to the present disclosure may be successfully prepared by one skilled in the conventional art through modifying methods, such as appropriate protection of interfering groups, by using other well-known reagents in addition to those described in the present disclosure, or regularly modifying some reaction conditions. In addition, the reaction disclosed in the present disclosure or well-known reaction conditions are also recognized to be applicable for the preparation of other compounds of the present disclosure.

[0090] In the embodiments described hereinafter, unless otherwise indicated, all the temperatures are set to degree centigrade. The reagents are commercially available from commercial 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 and Alfa Chemical Company, and are used without further purifying, unless otherwise indicated. General reagents are purchased from Shantou Xilong Chemical Co., Ltd, Guangdong Guanghua Sci-Tech Co., Ltd., Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemicals Co., Ltd., Tianjin Fuchen Chemical Reagent Factory, Wuhan Xinhuayuan Science and Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyang Chemical Factory.

[0091] Anhydrous tetrahydrofuran, dioxane, methylbenzene, and diethyl ether are obtained by refluxing and drying with metallic sodium. Anhydrous dichloromethane and chloroform are obtained by refluxing and drying with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide are dried with anhydrous sodium sulfate before use.

[0092] The following reactions generally perform under a positive pressure of nitrogen gas or argon gas or with a drying tube on anhydrous solvent (unless otherwise indicated). Reaction flasks are plugged with suitable rubber plugs, and substrates are injected by a syringe. Glasswares are all dried.

[0093] Chromatographic column uses silica gel. The silica gel (300 to 400 meshes) is purchased from Qingdao Haiyang Chemical Factory.

[0094] .sup.1H NMR spectrum is recorded by Bruker 400 MHz or 500 MHz nuclear magnetic resonance spectrometer. .sup.1NMR spectrum uses CDCl.sub.3, DMSO-d.sub.6, CD.sub.3OD, or acetone-d.sub.6 as solvent (in ppm), and uses TMS (0 ppm) or chloroform (7.26 ppm) as reference. When multiplicities are present, the following abbreviations are used: s (singlet), d (double), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are used in Hz.

[0095] The measurement conditions of low-resolution mass spectrometer (MS) data are: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1×30 mm, 3.5 microns, 6 min, flow rate: 0.6 mL/min. The mobile phase: 5%-95% (the ratio of (0.1% formic acid in CH.sub.3CN) to (0.1% formic acid in H.sub.2O)), being ionized by electrospray ionization (ESI), and detected by UV at 210 nm/254 nm.

[0096] Pure compounds are prepared by Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column model: NOVASEP 50/80 mm DAC) and are detected by UV at 210 nm/254 nm.

Embodiments

Embodiment 1 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 2-stearamido acetate

[0097] ##STR00014##

[0098] Rotigotine (1 g, 3.17 mmol), octadecanamide acetic 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 single-neck flask. The mixture was stirred while EDCI (0.73 g, 3.80 mmol, 1.2 eq) was added, and then the mixture was stirred overnight at 70° C. TLC showed that the raw materials were completely reacted. The mixture was filtered, and a filter cake was washed by THF, 3 0 and then the filtrate was combined and concentrated under reduced pressure, to obtain residues, which were purified through column chromatography (petroleum ether/ethyl acetate=60/40), and finally a white solid powder, Compound 1 (0.95 g, yield: 60%) was obtained. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.16-7.11(m, 2H), 7.11 (d, J=7.2 Hz, 1H), 6.94-6.90 (m, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.81 (d, J=2.8 Hz, 1H), 5.97 (t, J=5.2 Hz, 1H), 4.32 (d, J=5.2 Hz, 2H), 2.96-2.89 (m, 4H), 2.81-2.74 (m, 4H), 2.53-2.47 (m, 3H), 2.27 (t, J=8.0 Hz, 2H), 2.03(m, 1H), 1.73-1.61 (m, 2H), 1.59 (m, 1H), 1.47 (q, J=6.8 Hz, 2H), 1.35-1.23 (m, 28H), 0.88(m, 6H). MS(m/z): 639.23 [M+H].sup.+.

Embodiment 2 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 2-icosanamido acetate

[0099] ##STR00015##

[0100] Referring to the method of Embodiment 1, icosanamido acetic acid (1.1 eq) was used to replace octadecanamide acetic acid, so that a white solid powder, Compound 2 (2.30 g, yield: 64.0%) was prepared. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.15-7.11 (m, 2H), 7.11 (d, J=7.2 Hz, 1H), 6.93-6.91 (m, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.81 (d, J=2.8 Hz, 1H), 5.97 (t, J=5.2 Hz, 1H), 4.32 (d, J=5.2 Hz, 2H), 2.97-2.89 (m, 4H), 2.82- 2.73 (m, 4H), 2.54-2.47(m, 3H), 2.27 (t, J=8.0 Hz, 2H), 2.03 (m, 1H), 1.72-1.62 (m, 2H), 1.59 (m, 1H), 1.47 (q, J=6.8 Hz, 2H), 1.25 (m, 32H), 0.88 (m, 6H). MS(m/z): 667.71 [M+H].sup.+.

Embodiment 3 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 4-palmitamido butanoate

[0101] ##STR00016##

[0102] Referring to the method of Embodiment 1, 4-palmitamido butyric acid (1.1 eq) was used to replace octadecanamide acetic acid, so that a white solid powder, Compound 3 (0.53 g, yield: 26%) was prepared. MS(m/z): 639.15 [M+H].sup.+.

Embodiment 4 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 4-stearamido butanoate

[0103] ##STR00017##

[0104] Referring to the method of Embodiment 1, 4-stearamido butyric acid (1.1 eq) was used to replace octadecanamide acetic acid, so that a white solid powder, Compound 4 (0.77 g, yield: 47.3%) was prepared. .sup.1H H NMR (400 MHz, CDCl.sub.3) δ 7.14-7.10 (m, 2H), 6.98 (d, J=7.6 Hz, 1H), 6.93-6.91 (dd, J=4.2 Hz, 3.2 Hz, 1H), 6.82 (d, J=3.6 Hz, 1H), 6.81 (s, 1H), 5.65 (br, 1H), 3.41-3.36 (dd, J=12.8 Hz, 6.8 Hz, 2H), 2.97-2.89 (m, 4H), 2.84-2.76 (m, 4H), 2.63 (t, J=7.2 Hz, 2H), 2.56-2.46 (m, 3H), 2.16 (t, J=8.0 Hz, 2H), 2.03 (m, 1H), 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].sup.+.

Embodiment 5 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 4-icosanamido butanoate

[0105] ##STR00018##

[0106] Referring to the method of Embodiment 1, 4-icosanamido butyric acid (1.1 eq) was used to replace octadecanamide acetic acid, so that a while solid powder, Compound 5 (1.80 g, yield: 40.8%) was prepared. .sup.1H NMR (500 MHz, CDCl.sub.3) 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].sup.+.

Embodiment 6 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (2-(4-acetamidophenyl)acetyl) glycinate

[0107] ##STR00019##

[0108] Referring to the method of Embodiment 1, 2-(4-acetamidophenyl)acetyl) glycine (1.1 eq) was used to replace octadecanamide acetic acid, so that Compound 6 (1.30 g, yield: 75%) was prepared. MS (m/z): 548.15 [M+H].sup.+.

Embodiment 7 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 4-(2-(4-acetamidophenyl)acetamido) butanoate

[0109] ##STR00020##

[0110] Referring to the method of Embodiment 1, 4-(2-(4-acetamidophenyl)acetamido) butyric acid (1.1 eq) was used to replace octadecanamide acetic acid, so that Compound 7 (0.60 g, yield: 33%) was prepared. MS(m/z): 576.31 [M+H].sup.+.

Embodiment 8 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl cinnamamido acetate

[0111] ##STR00021##

[0112] Referring to the method of Embodiment 1, cinnamamino acetic acid (1.1 eq) was used to replace octadecanamide acetic acid, so that Compound 8 (1.30 g, yield: 82%) was prepared. MS(m/z): 503.10 [M+H].sup.+.

Embodiment 9 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 4-(cinnamamido) butanoate

[0113] ##STR00022##

[0114] Referring to the method of Embodiment 1,4-cinnamamido butyric acid (1.1 eq) was used to replace octadecanamide acetic acid, so that Compound 9 (0.59 g, yield: 35%) was prepared. MS(m/z): 531.20 [M+H].sup.+.

Embodiment 10 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 2-(phenylacetamido) acetate

[0115] ##STR00023##

[0116] Referring to the method of Embodiment 1, 2-(phenylacetamido) acetic acid (1.1 eq) was used to replace octadecanamide acetic acid, so that Compound 10 (1.23 g, yield: 79%) was prepared. MS (m/z): 491.08 [M+H].sup.+.

Embodiment 11 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 4-(2-phenylacetamido) butanoate

[0117] ##STR00024##

[0118] Referring to the method of Embodiment 1, 4-(2-phenylacetamido) butyric acid (1.1 eq) was used to replace octadecanamide acetic acid, so that Compound 11 (0.5 g, yield: 30%) was prepared. MS(m/z): 519.13 [M+H].sup.+.

Embodiment 12 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (3-phenylpropanylamido) acetate

[0119] ##STR00025##

[0120] Referring to the method of Embodiment 1, (3-phenylpropanylamido) acetic acid (1.1 eq) was used to replace octadecanamide acetic acid, so that Compound 12 (1.18 g, yield: 74%) was prepared. MS(m/z): 505.10 [M+H].sup.+.

Embodiment 13 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 4-(3-phenylpropanylamido) butanoate

[0121] ##STR00026##

[0122] Referring to the method of Embodiment 1, 4-(3-phenylacetamido) butyric acid (1.1 eq) was used to replace octadecanamide acetic acid, so that Compound 13 (0.47 g, yield: 28%) was prepared. MS(m/z): 533.17 [M+H].sup.+.

Embodiment 14 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (4-icosanamidobenzoyl) glycinate

[0123] ##STR00027##

[0124] Referring to the method of Embodiment 1, (4-icosanamidobenzoyl) glycine (1.1 eq) was used to replace octadecanamide acetic acid, so that Compound 14 (0.31 g, yield: 13%) was prepared. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.80 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.33 (m, 1H), 7.16-7.11 (m, 2H), 7.01 (d, J=7.5 Hz, 1H), 6.92 (t, J=5.0 Hz, 1H), 6.88 (d, J=7.5 Hz, 1H), 6.82 (s, 1H), 6.68 (br, 1H), 4.50 (d, J=5.0 Hz, 2H), 2.98 (m, 4H), 2.85-2.83 (m, 4H), 2.56-2.54 (m, 3H), 2.37 (t, J=7.5 Hz, 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].sup.+.

Embodiment 15 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (4-stearamidobenzoyl) glycinate

[0125] ##STR00028##

[0126] Referring to the method of Embodiment 1, (4-stearamidobenzoyl) glycine (1.1 eq) was used to replace octadecanamide acetic acid, so that a white solid powder, Compound 15 (0.18 g, yield: 12.5%) was prepared. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.80 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.33 (m, 1H), 7.15-7.12 (m, 2H), 7.01 (d, J=7.5 Hz, 1H), 6.92 (t, J=5.0 Hz, 1H), 6.88 (d, J=7.5 Hz, 1H), 6.82 (s, 1H), 6.69 (br, 1H), 4.50 (d, J=5.0 Hz, 2H), 2.98 (m, 4H), 2.85-2.83 (m, 4H), 2.56-2.54 (m, 3H), 2.37 (t, J=7.5 Hz, 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].sup.+.

Embodiment 16 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (4-palmitamidobenzoyl) glycinate

[0127] ##STR00029##

[0128] Referring to the method of Embodiment 1, (4-palmitamidobenzoyl) glycine (1.1 eq) was used to replace octadecanamide acetic acid, so that a white solid powder, Compound 16 (0.36 g, yield: 15%) was prepared. MS(m/z): 730.49 [M+H].sup.+.

Embodiment 17 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (4-tetradecanamidobenzyol) glycinate

[0129] ##STR00030##

[0130] Referring to the method of Embodiment 1, (4-tetradecanamidobenzoyl) glycine (1.1 eq) was used to replace octadecanamide acetic acid, so that a white solid powder, Compound 17 (0.28 g, yield: 14.3%) was prepared. MS(m/z): 702.47 [M+H].sup.+.

Embodiment 18 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 4-(4-tetradecanamidobenzamido) butanoate

[0131] ##STR00031##

[0132] Referring to the method of Embodiment 1, 4-(4-tetradecanamidobenzamido) butyric acid (1.1 eq) was used to replace octadecanamide acetic acid, so that a white solid powder, Compound 18 (0.12 g, yield: 11%) was prepared. MS(m/z): 730.65 [M+H].sup.+.

Embodiment 19 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 4-(4-palmitoylamidobenzamido) butanoate

[0133] ##STR00032##

[0134] Referring to the method of Embodiment 1, 4-(4-palmitoylamidobenzamido) butyric acid (1.1 eq) was used to replace octadecanamide acetic acid, so that a white solid powder, Compound 19 (0.15 g, yield: 12%) was prepared. MS(m/z): 758.57 [M+H].sup.+.

Embodiment 20 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 4-(4-stearamidobenzamido) butanoate

[0135] ##STR00033##

[0136] Referring to the method of Embodiment 1, 4-(4-stearamidobenzamido) butyric acid (1.1 eq) was used to replace octadecanamide acetic acid, so that a white solid powder, Compound 20 (0.25 g, yield: 12.5%) was prepared. MS(m/z): 788.53 [M+H].sup.+.

Embodiment 21 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 4-(4-icosanoylbenzamido) butanoate

[0137] ##STR00034##

[0138] Referring to the method of Embodiment 1, 4-(4-icosanoylbenzamido) butyric acid (1.61 g, 3.49 mmol, 1.1 eq) was used to replace octadecanamide acetic acid, so that a white solid powder, Compound 21 (0.18 g, yield: 13%) was prepared. MS(m/z): 814.64 [M+H].sup.+.

Embodiment 22 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (4-palmitamidobutanoyl) glycinate

[0139] ##STR00035##

[0140] Rotigotine (0.6 g, 1.91 mmol), (4-palmitamidobutanoyl) glycine (0.91 g, 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 single-neck flask. The mixture was stirred while EDCI (0.55 g, 2.86 mmol, 1.2 eq) and HOBT (25.7 mg, 0.19 mmol, 0.10 eq) were added, and then the mixture was stirred overnight at 70° C. TLC showed that the raw materials were completely reacted. The mixture was filtered, and filter cake was washed by THF, and then the filtrate was combined and concentrated under reduced pressure, to obtain residues, which were purified through column chromatography (petroleum ether/ethyl acetate=2/1), and finally a white solid powder, Compound 22 (0.27 g, yield: 20.4%) was obtained. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.15 (s, 1H), 7.13-7.10 (m, 2H), 6.99 (d, J=7.5 Hz, 1H), 6.93-6.91 (mr, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.81 (br, 1H), 5.83 (br, 1H), 4.30 (d, J=5.5 Hz, 2H), 3.39-3.36 (dd, J=12.5 Hz, 6.0 Hz, 2H), 2.96-2.88 (m, 4H), 2.83-2.73 (m, 4H), 2.54-2.49 (m, 3H), 2.31 (t, J=6.0 Hz, 2H), 2.17 (t, J=7.5 Hz, 2H), 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]

Embodiment 23 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (4-stearamidobutanoyl) glycinate

[0141] ##STR00036##

[0142] Referring to the method of Embodiment 22, (4-stearamidobutanoyl) glycine (1.1 eq) was used to replace (4-palmitamidobutanoyl) glycine, so that a white solid powder, Compound 23 (0.60 g, yield: 43.6%) was prepared. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.13 (m, 3H), 7.00 (d, J=3.0 Hz, 1H), 6.92 (s, 1H), 6.85-6.83 (m, 2H), 5.83 (br, 1H), 4.30 (d, J=5.5 Hz, 2H), 3.40-3.36 (m, 2H), 2.97 (m, 4H), 2.83 (m, 4H), 2.54 (m, 3H), 2.31 (t, J=6.5 Hz, 2H), 2.17 (t, J=7.5 Hz, 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].sup.+.

Embodiment 24 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (4-icosanoamidobutanoyl) glycinate

[0143] ##STR00037##

[0144] Referring to the method of Embodiment 22, (4-icosanamidobutanoyl) glycine (1.1 eq) was used to replace (4-palmitamidobutanoyl) glycine, so that a white solid powder, Compound 24 (0.78 g, yield: 65.4%) was prepared. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.12 (m, 2H), 6.99 (d, J=7.5 Hz, 1H), 6.92 (m, 1H), 6.85 (d, J=7.5Hz, 1H), 6.82 (br, 1H), 5.85 (br, 1H), 4.30 (d, J=5.5 Hz, 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=6.5 Hz, 2H), 2.17 (t, J=8.0 Hz, 2H), 2.03 (m, 1H), 1.87-1.83 (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].sup.+.

Embodiment 25 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (18-amino-18-oxooctadecanoyl) glycinate

[0145] ##STR00038##

[0146] Rotigotine (0.4 g, 1.14 mmol), (18-amino-18-oxooctadecanoyl) glycine (0.56 g, 1.35 mmol, 1.10 eq), N, N-diisopropylethylamine (0.44 g, 3.41 mmol, 3.0 eq), CH3CN (8 mL) were added to a 50 mL single-neck flask. The mixture was stirred while EDCI (0.33 g, 1.71 mmol, 1.5 eq) and HOBT (30.7 mg, 0.23 mmol, 0.20 eq) was added and then the mixture was stirred overnight at 80° C., TLC showed that the raw materials were completely reacted. The mixture was filtered, and filter cake was washed by THF, and then the filtrate was combined and concentrated under reduced pressure, to obtain residues, which were purified through column chromatography (petroleum ether:ethyl acetate=1:1), and finally a while solid powder, Compound 25 (0.04 g, yield: 5.3%) was obtained. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.40 (br, 1H), 7.28 (d, J=4.5 Hz, 1H), 7.19 (br, 1H), 7.11 (t, J=4.5 Hz, 1H), 6.99 (d, J=3.0 Hz, 1H), 6.87 (s, 1H), 6.81 (d, J=8.0 Hz, 1H), 6.65 (br, 1H), 4.06 (d, J=5.5 Hz, 2H), 2.92-2.81 (m, 4H), 2.76-2.71 (m, 4H), 2.50-2.36 (m, 3H), 2.13 (t, J=7.0 Hz, 2H), 2.01 (t, J=7.0 Hz, 2H), 1.90 (m, 1H), 1.50-1.38 (m, 7H), 1.22-1.19 (m, 24H), 0.82 (t, J=7.0 Hz, 3H). MS(m/z): 668.64 [M+H].sup.+.

Embodiment 26 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (16-amino-16-oxohexadecanoyl) glycinate

[0147] ##STR00039##

[0148] Referring to the method of Embodiment 25, (16-amino-16-oxooctadecanoyl) glycine (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 26 (0.2 g, yield: 55%) was prepared. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.40 (br, 1H), 7.29 (d, J=4.0 Hz, 1H), 7.20 (br, 1H), 7.13 (t, J=7.5 Hz, 1H), 7.01 (d, J=3.0 Hz, 1H), 6.93 (s, 1H), 6.88 (s, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.66 (br, 1H), 4.08 (d, J=5.5 Hz, 2H), 2.92-2.82 (m, 4H), 2.76-2.67 (m, 4H), 2.50-2.37 (m, 3H), 2.15 (t, J=7.0 Hz, 2H), 2.01 (t, J=7.0 Hz, 2H), 1.92 (d, J=13.5 Hz, 1H), 1.54-1.38 (m, 7H), 1.23-1.20 (m, 20H), 0.85 (t, J=7.0 Hz, 3H). MS(m/z): 640.56 [M+H].sup.+.

Embodiment 27 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (14-amino-14-oxotetradecanoyl) glycinate

[0149] ##STR00040##

[0150] Referring to the method of Embodiment 25, (14-amino-14-oxotetradecanoyl) glycine (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 27 (1.0 g, yield: 57.5%) was prepared. .sup.1NMR (500 MHz, DMSO-d.sub.6) 68.40 (br, 1H), 7.28(d, J=5.5 Hz, 1H), 7.20 (br, 1H), 7.12 (t, J=7.5 Hz, 1H), 7.01 (d, J=7.5 Hz, 1H), 6.92 (dd, J=5.5 Hz, 3.5 Hz, 1H), 6.87 (d, J=3.0 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 6.66 (br, 1H), 4.07 (d, J=6.0 Hz, 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=7.0 Hz, 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=7.5 Hz, 3H). MS(m/z): 612.45 [M+H].sup.+.

Embodiment 28 (S)-6-(propyl(2-(thiophen-2-yl) ethyl) amino)-5,6,7,8-tetrahydronaphthalen-1-yl (20-(ethylamino)-20-oxoicosanoyl) glycinate

[0151] ##STR00041##

[0152] Referring to the method of Embodiment 25, (20-(ethylamino)-20-oxoicosanoyl) glycine (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 28 (0.38 g, yield: 52%) was prepared. MS(m/z): 724.55 [M+H].sup.+.

Embodiment 29 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (19-(ethylamino)-19-oxononadecanoyl) glycinate

[0153] ##STR00042##

[0154] Referring to the method of Embodiment 25, (19-(ethylamino)-19-oxononadecanoyl) glycine (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 29 (0.25 g, yield: 50%) was prepared. MS(m/z): 710.52 [M+H].sup.+.

Embodiment 30 (S)-6-(propyl (2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (18-(ethylamino)-18-oxooctadecanoyl) glycinate

[0155] ##STR00043##

[0156] Referring to the method of Embodiment 25, (18-(ethylamino)-18-oxooctadecanoyl) glycine (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 30 (1.27 g, yield: 60%) was prepared. MS(m/z): 696.53 [M+H].sup.+.

Embodiment 31 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (17-(ethylamino)-17-oxoheptadecanoyl) glycinate

[0157] ##STR00044##

[0158] Referring to the method of Embodiment 25, (17-(ethylamino)-17-oxoheptadecanoyl) glycine (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 31 (0.26 g, yield: 62%) was prepared. MS(m/z): 682.46 [M+H].sup.+.

Embodiment 32 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (16-(ethylamino)-16-oxohexadecanoyl) glycinate

[0159] ##STR00045##

[0160] Referring to the method of Embodiment 25, (16-(ethylamino)-16-oxohexadecanoyl) glycine (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 32 (0.48 g, yield: 73.8%) was prepared. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.40 (br, 1H), 7.71 (br, 1H), 7.28 (d, J=5.0 Hz, 1H), 7.12 (t, J=7.5 Hz, 1H), 7.01 (d, J=3.0 Hz, 1H), 6.92 (s, 1H), 6.87 (s, 1H), 6.83 (d, J=8.0 Hz, 1H), 4.07 (d, J=5.0 Hz, 2H), 3.05 (t, J=6.5 Hz, 2H), 2.91-2.82 (m, 4H), 2.75-2.63 (m, 4H), 2.50-2.37 (m, 3H), 2.14 (t, J=7.0 Hz, 2H), 2.01 (t, J=7.0 Hz, 2H), 1.90 (br, 1H), 1.50-1.38 (m, 7H), 1.23-1.20 (m, 20H), 0.98 (t, J=7.0 Hz, 3H), (t, J=7.0 Hz, 3H). MS(m/z): 668.60 [M+H].sup.+.

Embodiment 33 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (15-(ethylamino)-15-oxopentadecanoyl) glycinate

[0161] ##STR00046##

[0162] Referring to the method of Embodiment 25, (15-(ethylamino)-15-oxopentadecanoyl) glycine (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 33 (0.42 g, yield: 70%) was prepared. MS(m/z): 654.45 [M+H].sup.+.

Embodiment 34 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (14-(ethylamino)-14-oxotetradecanoyl) glycinate

[0163] ##STR00047##

[0164] Referring to the method of Embodiment 25, (14-(ethylamino)-14-oxotetradecanoyl) glycine (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 34 (0.37 g, yield: 65%) was prepared. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.41 (br, 1H), 7.72 (m, 1H), 7.28 (d, J=5.0 Hz, 1H), 7.12 (t, J=7.5 Hz, 1H), 7.01 (d, J=3.0 Hz, 1H), 6.92 (s, 1H), 6.87 (s, 1H), 6.83 (d, J=8.0 Hz, 1H), 4.07 (d, J=5.0 Hz, 2H), 3.05 (t, J=6.5 Hz, 2H), 2.92-2.81 (m, 4H), 2.75-2.62 (m, 4H), 2.51-2.35 (m, 3H), 2.14 (t, J=7.0 Hz, 2H), 2.01 (t, J=7.0 Hz, 2H), 1.90 (m, 1H), 1.50-1.38 (m, 7H), 1.23-1.18 (m, 16H), 0.98 (t, J=7.0 Hz, 3H), (t, J=7.0 Hz, 3H). MS(m/z): 640.46 [M+H].sup.+.

Embodiment 35 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (16-(propylamino)-16-oxohexadecanoyl) glycinate

[0165] ##STR00048##

[0166] Referring to the method of Embodiment 25, (16-(propylamino)-16-oxohexadecanoyl) glycine (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 35 (0.62 g, yield: 64%) was prepared. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.13-7.12 (m, 2H), 7.01 (d, J=7.5 Hz, 1H), 6.92 (t, J=4.0 Hz, 1H), 6.82 (d, J=7.0 Hz, 1H), 6.82 (s, 1H), 6.02 (br, 1H), 5.42 (m, 1H), 4.31 (d, J=5.5 Hz, 2H), 3.21 (dd, J=8.5 Hz, 7.0 Hz, 2H), 2.96 (m, 4H), 2.82 (m, 4H), 2.54 (m, 3H), 2.27 (t, J=7.5 Hz, 2H), 2.15 (t, J=7.5 Hz, 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].sup.+.

Embodiment 36 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (15-(propylamino)-15-oxopentadecanoyl) glycinate

[0167] ##STR00049##

[0168] Referring to the method of Embodiment 25, (15-(propylamino)-15-oxopentadecanoyl) glycine (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 36 (0.34 g, yield: 62%) was prepared. MS(m/z): 668.60 [M+H].sup.+.

Embodiment 37 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (14-(propylamino)-14-oxotetradecanoyl) glycinate

[0169] ##STR00050##

[0170] Referring to the method of Embodiment 25, (14-(propylamino)-14-oxopentadecanoyl) glycine (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 37 (0.42 g, yield: 73%) was prepared. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.14-7.11 (m, 2H), 7.01 (d, J=7.5 Hz, 1H), 6.92 (t, J=4.0 Hz, 1H), 6.82(d, J=7.0 Hz, 1H), 6.82 (s, 1H), 6.02 (br, 1H), 5.42 (br, 1H), 4.31 (d, J=5.5 Hz, 2H), 3.21 (dd, J=8.5 Hz, 7.0 Hz, 2H), 2.96 (m, 4H), 2.82 (m, 4H), 2.54 (m, 3H), 2.27 (t, J=7.5 Hz, 2H), 2.15 (t, J=7.5 Hz, 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].sup.+.

Embodiment 38 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (13-(propylamino)-13-oxotridecanoyl) glycinate

[0171] ##STR00051##

[0172] Referring to the method of Embodiment 25, (13-(propylamino)-13-oxotridecanoyl) glycine (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 38 (0.18 g, yield: 60%) was prepared. MS(m/z): 640.43 [M+H].sup.+.

Embodiment 39 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (12-(propylamino)-12-oxododecanoyl) glycinate

[0173] ##STR00052##

[0174] Referring to the method of Embodiment 25, (12-(propylamino)-12-oxododecanoyl) glycine (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 39 (0.20 g, yield: 65%) was prepared. MS(m/z): 626.40 [M+H].sup.+.

Embodiment 40 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (15 -(butylamino)-15-oxopentadecanoyl) glycinate

[0175] ##STR00053##

[0176] Referring to the method of Embodiment 25, (15-(butylamino)-15-oxopentadecanoyl) glycine (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 40 (0.26 g, yield: 67%) was prepared. MS(m/z): 682.6 [M+H].sup.+.

Embodiment 41 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (14-(butylamino)-14-oxotetradecanoyl) glycinate

[0177] ##STR00054##

[0178] Referring to the method of Embodiment 25, (14-(butylamino)-14-oxotetradecanoyl) glycine (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 41 (0.45 g, yield: 70%) was prepared. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.15-7.10 (m, 2H), 6.98 (d, J=7.5 Hz, 1H), 6.94-6.91 (m, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.81 (d, J=2.5 Hz, 1H), 6.07 (br, 1H), 5.41 (s, 1H), 4.31 (d, J=5.5 Hz, 2H), 3.24 (q, J=6.5 Hz, 2H), 2.83-2.74 (m, 4H), 2.55-2.47 (m, 3H), 2.26 (t, J=7.5 Hz, 2H), 2.14 (t, J=8.0 Hz, 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].sup.+.

Embodiment 42 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (13-(butylamino)-13-oxotridecanoyl) glycinate

[0179] ##STR00055##

[0180] Referring to the method of Embodiment 25, (13-(butylamino)-13-oxotridecanoyl) glycine (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 42 (0.19 g, yield: 64%) was prepared. MS(m/z): 654.47 [M+H].sup.+.

Embodiment 43 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (12-(butylamino)-12-oxododecanoyl) glycinate

[0181] ##STR00056##

[0182] Referring to the method of Embodiment 25, (12-(butylamino)-12-oxododecanoyl) glycine (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 43 (1.50 g, yield: 82.5%) was prepared. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.14-7.11 (m, 2H), 7.00 (d, J=7.5 Hz, 1H), 6.93-6.91 (m, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.81 (d, J=2.5 Hz, 1H), 6.07 (br, 1H), 5.41 (s, 1H), 4.31 (d, J=5.5 Hz, 2H), 3.24 (q, J=6.5 Hz, 2H), 2.83-2.74 (m, 4H), 2.55-2.47 (m, 3H), 2.26 (t, J=7.5 Hz, 2H), 2.14 (t, J=8.0 Hz, 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].sup.+.

Embodiment 44 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (12-(hexylamino)-12-oxododecanoyl) glycinate

[0183] ##STR00057##

[0184] Referring to the method of Embodiment 25, (12-(hexylamino)-12-oxododecanoyl) glycine (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 44 (0.90 g, yield: 41%) was prepared. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.17-7.11 (m, 2H), 7.02 (d, J=7.6 Hz, 1H), 6.97-6.92 (m, 1H), 6.86 (d, J=7.9 Hz, 1H), 6.83 (d, J=3.4 Hz, 1H), 6.15 (t, J=5.3 Hz, 1H), 5.48 (t, J=5.9 Hz, 1H), 4.33 (d, J=5.3 Hz, 2H), 3.25 (q, J=6.7 Hz, 2H), 3.03-2.74 (m, 8H), 2.62-2.47 (m, 3H), 2.28 (t, J=7.6 Hz, 2H), 2.16 (t, J=7.6 Hz, 2H), 2.09-2.03 (m, 1H), 1.70-1.56 (m, 5H), 1.51 (q, J=7.8 Hz, 4H), 1.37-1.24 (m, 18H), 0.93-0.88 (m, 6H). MS(m/z): 668.92 [M+H].sup.+.

Embodiment 45 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (10-(butylamino)-10-oxodecanoyl) glycinate

[0185] ##STR00058##

[0186] Referring to the method of Embodiment 25, (10-(butylamino)-10-oxodecanoyl) glycine (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 45 (0.18 g, yield: 52%) was prepared. MS(m/z): 612.40 [M+H].sup.+.

Embodiment 46 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (16-(methylamino)-16-oxohexadecanoyl) glycinate

[0187] ##STR00059##

[0188] Referring to the method of Embodiment 25, (16-(methylamino)-16-oxohexadecanoyl) glycine (1.29g, 3.49mmol, 1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 46 (0.7 g, yield: 75.4%) was prepared. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ8.40 (t, J=6.0 Hz, 1H), 7.66 (br, 1H), 7.28 (dd, J=5.0 Hz, 1.0 Hz, 1H), 7.12 (t, J=7.5Hz, 1H), 7.00 (d, J=7.5Hz, 1H), 6.93-6.91 (m, 1H), 6.87 (d, J=3.0 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 4.07 (d, J=6.0 Hz, 2H), 2.91-2.82 (m, 4H), 2.76-2.67 (m, 4H), 2.57 (d, J=4.5 Hz, 3H), 2.48 (m, 2H), 2.43-2.36 (m, 1H), 2.14 (t, J=7.5 Hz, 2H), 2.01 (t, J=7.0 Hz, 2H), 1.92-1.90 (m, 1H), 1.51-1.36 (m, 7H), 1.22-1.19 (m, 20H), 0.84 (t, J=7.0 Hz, 3H). MS(m/z): 654.54 [M+H].sup.+.

Embodiment 47 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (14-(methylamino)-14-oxotetradecanoyl) glycinate

[0189] ##STR00060##

[0190] Referring to the method of Embodiment 25, (14-(methylamino)-14-oxotetradecanoyl) glycine (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 47 (1.2 g, yield: 67.5%) was prepared. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ8.41 (t, J=5.5 Hz, 1H), 7.67 (br, 1H), 7.29 (d, J=4.5 Hz, 1H), 7.13 (t, J=8.0 Hz, 1H), 7.01 (d, J=7.5 Hz, 1H), 6.92 (dd, J=5.5 Hz, 3.5 Hz, 1H), 6.88 (d, J=2.5 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 6.66 (br, 1H), 4.07 (d, J=5.5 Hz, 2H), 2.92-2.83 (m, 4H), 2.73-2.71 (m, 4H), 2.54 (d, J=4.5 Hz, 3H), 2.49 (m, 2H), 2.44-2.37 (m,1H), 2.15 (t, J=7.5 Hz, 2H), 2.02 (t, J=7.0 Hz, 2H), 1.93-1.91 (m, 1H), 1.51 -1.40 (m, 7H), 1.24-1.20 (m, 16H), 0.85 (t, J=7.5 Hz, 3H). MS(m/z): 626.41 [M+H].sup.+.

Embodiment 48 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (12-(methylamino)-12-oxododecanoyl) glycinate

[0191] ##STR00061##

[0192] Referring to the method of Embodiment 25, (12-(methylamino)-12-oxododecanoyl) glycine (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 48 (1.0 g, yield: 58.9%) was prepared. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ8.40 (t, J=6.0 Hz, 1H), 7.66 (s, 1H), 7.29 (d, J=5.5 Hz, 1H), 7.12 (t, J=7.5 Hz, 1H), 7.01 (d, J=7.5 Hz, 1H), 6.92 (dd, J=5.5 Hz, 3.5 Hz, 1H), 6.87 (d, J=3.0 Hz, 1H), 6.82 (d, J=7.5 Hz, 1H), 4.07 (d, J=6.0 Hz, 2H), 2.92-2.82 (m, 4H), 2.76-2.71 (m, 4H), 2.53 (d, J=4.5 Hz, 3H), 2.49 (m, 2H), 2.43-2.37 (m, 1H), 2.14 (t, J=7.5 Hz, 2H), 2.01 (t, J=7.5 Hz, 2H), 1.90 (m, 1H), 1.50-1.38 (m, 7H), 1.23 (s, 4H), 1.19(s, 8H), 0.84 (t, J=7.5 Hz, 3H). MS(m/z): 598.43 [M+H].sup.+.

Embodiment 49 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (4-(hexadecylamino)-4-oxobutanoyl) glycinate

[0193] ##STR00062##

[0194] Referring to the method of Embodiment 25, (4-(hexadecylamino)-4-oxobutanoyl) glycine (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 49 (0.27 g, yield: 45.5%) was prepared. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.46 (br, 1H), 7.78 (s, 1H), 7.29 (d, J=4.5 Hz, 1H), 7.13 (t, J=8.0 Hz, 1H), 7.01 (d, J=7.5 Hz, 1H), 6.93 (s, 1H), 6.88 (s, 1H), 6.83 (d, J=8.0 Hz, 1H), 4.08 (d, J=5.0 Hz, 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=7.0 Hz, 2H), 1.91 (m, 1H), 1.51-1.48 (m, 1H), 1.41 (dd, J=14.0 Hz, 7.0 Hz, 2H), 1.35 (m, 2H), 1.23 (s, 26H), 0.86-0.85 (m, 6H). MS(m/z): 696.58 [M+H].sup.+.

Embodiment 50 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(20-(ethylamino)-20-oxoicosanamido) propanoate

[0195] ##STR00063##

[0196] Referring to the method of Embodiment 25, 3-(20-(ethylamino)-20-oxoicosanamido) propanoic acid (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 50 (0.23 g, yield: 41%) was prepared. MS(m/z): 738.56 [M+H].sup.+.

Embodiment 51 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(19-(ethylamino)-19-oxononadecanamido) propanoate

[0197] ##STR00064##

[0198] Referring to the method of Embodiment 25, 3-(19-(ethylamino)-19-oxononadecanami do) propanoic acid (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 51 (0.31 g, yield: 44%) was prepared. MS(m/z): 724.35 [M+H].sup.+.

Embodiment 52 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(18-(ethylamino)-18-oxooctadecanamido) propanoate

[0199] ##STR00065##

[0200] Referring to the method of Embodiment 25, 3-(18-(ethylamino)-18-oxooctadecanami do) propanoic acid (1.29g, 3.49mmol, 1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 52 (0.25 g, yield: 60%) was prepared. MS(m/z): 710.39 [M+H].sup.+.

Embodiment 53 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(17-(ethylamino)-17-oxoheptadecanamido) propanoate

[0201] ##STR00066##

[0202] Referring to the method of Embodiment 25, 3-(17-(ethylamino)-17-oxoheptadecanamido) propanoic acid (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 53 (0.28 g, yield: 65%) was prepared. MS(m/z): 696.42 [M+H].sup.+.

Embodiment 54 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(16-(ethylamino)-16-oxohexadecanamido) propanoate

[0203] ##STR00067##

[0204] Referring to the method of Embodiment 25, 3-(16-(ethylamino)-16-oxohexadecanamido) propanoic acid (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that Compound 54 (2.5 g, yield: 87.5%) was prepared. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.14-7.11 (m, 2H), 7.00 (d, J=7.5 Hz, 1H), 6.93-6.91 (m, 1H), 6.83-6.81 (m, 2H), 6.06 (br, 1H), 5.39 (br, 1H), 3.62 (q, J=6.0 Hz, 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, 5H), 1.51-1.47 (m, 2H), 1.28-1.24 (m, 20H), 1.13 (t, J=7.5 Hz, 3H), J=7.0 Hz, 3H). MS(m/z): 682.98 [M+H].sup.+.

Embodiment 55 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(15-(ethylamino)-15-oxopentadecanamido) propanoate

[0205] ##STR00068##

[0206] Referring to the method of Embodiment 25, 3-(15-(ethylamino)-15-oxopentadecanamido) propanoic acid (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 55 (0.28 g, yield: 63%) was prepared. MS(m/z): 668.60 [M+H].sup.+.

Embodiment 56 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(14-(ethylamino)-14-oxotetradecanamido) propanoate

[0207] ##STR00069##

[0208] Referring to the method of Embodiment 25, 3-(14-(ethylamino)-14-oxotetradecanamido) propanoic acid (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 56 (1.0 g, yield: 74%) was prepared. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.14-7.10 (m, 2H), 7.00(d, J=7.5 Hz, 1H), 6.93-6.90 (m, 1H), 6.83-6.81 (m, 2H), 6.06 (br, 1H), 5.39 (br, 1H), 3.62 (q, J=6.0 Hz, 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, 5H), 1.50-1.46 (m, 2H), 1.28-1.24 (m, 16H), 1.13 (t, J=7.5 Hz, 3H), 0.89 (t, J=7.0 Hz, 3H). MS(m/z): 654.43 [M+H].sup.+.

Embodiment 57 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(13-(ethylamino)-13-oxotridecanamido) propanoate

[0209] ##STR00070##

[0210] Referring to the method of Embodiment 25, 3-(13-(ethylamino)-13-oxotridecanamido) propanoic acid (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 57 (0.18 g, yield: 63%) was prepared. MS(m/z): 640.38 [M+H].sup.+.

Embodiment 58 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(12-(ethylamino)-12-oxododecanamido) propanoate

[0211] ##STR00071##

[0212] Referring to the method of Embodiment 25, 3-(12-(ethylamino)-12-oxododecanamido) propanoic acid (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 58 (0.8 g, yield: 70%) was prepared. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.16-7.09 (m, 2H), 7.01 (d, J=7.5 Hz, 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=6.0 Hz, 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, 5H), 1.51-1.45 (m, 2H), 1.28-1.23 (m, 12H), 1.13 (t, J=7.5 Hz, 3H), 0.89 (t, J=7.0 Hz, 3H). MS(m/z): 626.40 [M+H].sup.+.

Embodiment 59 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(16-(propylamino)-16-oxohexadecanamido) propanoate

[0213] ##STR00072##

[0214] Referring to the method of Embodiment 25, 3-(16-(propylamino)-16-oxohexadecanamido) propanoic acid (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 59 (0.8 g, yield: 74%) was prepared. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.14-7.10 (m, 2H), 7.01 (d, J=7.5 Hz, 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=6.0 Hz, 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), 2.02 (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].sup.+.

Embodiment 60 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(15-(propylamino)-15-oxopentadecanamido) propanoate

[0215] ##STR00073##

[0216] Referring to the method of Embodiment 25, 3-(15-(propylamino)-15-oxopentadecanamido) propanoic acid (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that an off-white solid powder, Compound 60 (0.13 g, yield: 51%) was prepared. MS(m/z): 682.38 [M+H].sup.+.

Embodiment 61 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(14-(propylamino)-14-oxotetradecanamido) propanoate

[0217] ##STR00074##

[0218] Referring to the method of Embodiment 25, 3-(14-(propylamino)-14-oxotetradecanamido) propanoic acid (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that an off-white solid powder, Compound 61 (0.39 g, yield: 67%) was prepared. MS(m/z): 668.33 [M+H].sup.+.

Embodiment 62 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(13-(propylamino)-13-oxotridecanamido) propanoate

[0219] ##STR00075##

[0220] Referring to the method of Embodiment 25, 3-(13-(propylamino)-13-oxotridecanamido) propanoic acid (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that an off-white solid powder, Compound 62 (0.31 g, yield: 63%) was prepared. MS(m/z): 654.45 [M+H].sup.+.

Embodiment 63 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(12-(propylamino)-12-oxododecanamido) propanoate

[0221] ##STR00076##

[0222] Referring to the method of Embodiment 25, 3-(12-(propylamino)-12-oxododecanamido) propanoic acid (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that an off-white solid powder, Compound 63 (0.87 g, yield: 72%) was prepared. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.13-7.09 (m, 2H), 7.01 (d, J=7.5 Hz, 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=6.0 Hz, 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, 4H), 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].sup.+.

Embodiment 64 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(17-(propylamino)-17-oxoheptadecanamido) propanoate

[0223] ##STR00077##

[0224] Referring to the method of Embodiment 25, 3-(17-(propylamino)-17-oxoheptadecanamido) propanoic acid (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that an off-white solid powder, Compound 64 (0.13 g, yield: 43%) was prepared. MS(m/z): 710.52 [M+H].sup.+.

Embodiment 65 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(18-(propylamino)-18-oxooctadecanamido) propanoate

[0225] ##STR00078##

[0226] Referring to the method of Embodiment 25, 3-(18-(propylamino)-18-oxooctadecanamido) propanoic acid (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that an off-white solid powder, Compound 65 (0.31 g, yield: 67%) was prepared. MS(m/z): 724.43 [M+H].sup.+.

Embodiment 66 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(16-(butylamino)-16-oxohexadecanamido) propanoate

[0227] ##STR00079##

[0228] Referring to the method of Embodiment 25, 3-(16-(butylamino)-16-oxohexadecanamido) propanoic acid (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that an off-white solid powder, Compound 66 (0.67 g, yield: 76%) was prepared. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.16-7.10 (m, 2H), 6.99 (d, J=7.5 Hz, 1H), 6.93-6.91 (m, 1H), 6.84-6.80 (m, 2H), 6.10 (t, J=6.0 Hz, 1H), 5.42 (br, 1H), 3.61 (q, J=6.0 Hz, 2H), 3.23 (q, J=6.5 Hz, 2H), 3.01-2.88 (m, 4H), 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, 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].sup.+.

Embodiment 67 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(15-(butylamino)-15-oxopentadecanamido) propanoate

[0229] ##STR00080##

[0230] Referring to the method of Embodiment 25, 3-(15-(butylamino)-15-oxopentadecanamido) propanoic acid (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 67 (0.23 g, yield: 57%) was prepared. MS(m/z): 696.40 [M+H].sup.+.

Embodiment 68 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(14-(butylamino)-14-oxotetradecanamido) propanoate

[0231] ##STR00081##

[0232] Referring to the method of Embodiment 25, 3-(14-(butylamino)-14-oxotetradecanamido) propanoic acid (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that an off-white solid powder, Compound 68 (0.8 g, yield: 69%) was prepared. MS(m/z): 682.47 [M+H].sup.+.

Embodiment 69 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(13-(butylamino)-13-oxotridecanamido) propanoate

[0233] ##STR00082##

[0234] Referring to the method of Embodiment 25, 3-(13-(butylamino)-13-oxotridecanamido) propanoic acid (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that an off-white solid powder, Compound 69 (0.37 g, yield: 71%) was prepared. MS(m/z): 668.43 [M+H].sup.+.

Embodiment 70 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(12-(butylamino)-12-oxododecanamido) propanoate

[0235] ##STR00083##

[0236] Referring to the method of Embodiment 25, 3-(12-(butylamino)-12-oxododecanamido) propanoic acid (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that Compound 70 (1.53 g, yield: 82.4%) was prepared. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.14-7.11 (m, 2H), 6.99 (d, J=7.5 Hz, 1H), 6.93-6.91 (m, 1H), 6.83-6.81 (m, 2H), 6.10 (t, J=6.0 Hz, 1H), 5.42 (s, 1H), 3.61 (q, J=6.0 Hz, 2H), 3.23 (q, J=6.5 Hz, 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].sup.+.

Embodiment 71 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(13-(pentylamino)-13-oxotridecanamido) propanoate

[0237] ##STR00084##

[0238] Referring to the method of Embodiment 25, 3-(13-(butylamino)-13-oxotridecanamido) propanoic acid (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that an off-white solid powder, Compound 71 (0.16 g, yield: 55%) was prepared. MS(m/z): 682.50 [M+H].sup.+.

Embodiment 72 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(12-(hexylamino)-12-oxododecanamido) propanoate

[0239] ##STR00085##

[0240] Referring to the method of Embodiment 25, 3-(12-(hexylamino)-12-oxododecanamido) propanoic acid (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that Compound 72 (0.96 g, yield: 42%) was prepared. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.13 (t, J=7.6 Hz, 2H), 7.00 (d, J=7.7 Hz, 1H), 6.94-6.89 (m, 1H), 6.82 (t, J=5.4 Hz, 2H), 6.15 (t, J=6.2 Hz, 1H), 5.49 (t, J=6.0 Hz, 1H), 3.61 (q, J=6.2 Hz, 2H), 3.23 (q, J=6.7 Hz, 2H), 3.05 -2.71 (m, 10H), 2.61-2.43 (m, 3H), 2.15 (dt, J=12.3, 7.6 Hz, 4H), 2.05-2.02 (m, 1H), 1.66 -1.55 (m, 5H), 1.49 (dt, J=13.4, 7.0 Hz, 4H), 1.35-1.17 (m, 18H), 0.94-0.82 (m, 6H). MS(m/z): 682.58 [M+H].sup.+.

Embodiment 73 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(11-(heptylamino)-11-oxoundecanamido) propanoate

[0241] ##STR00086##

[0242] Referring to the method of Embodiment 25, 3-(11-(heptylamino)-11-oxoundecanamido) propanoic acid (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that an off-white solid powder, Compound 73 (0.21 g, yield: 58%) was prepared. MS(m/z): 682.52 [M+H].sup.+.

Embodiment 74 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(10-(hexylamino)-10-oxodecylamido) propanoate

[0243] ##STR00087##

[0244] Referring to the method of Embodiment 25, 3-(10-(hexylamino)-10-hexylamido) propanoic acid (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that an off-white solid powder, Compound 74 (0.29 g, yield: 63%) was prepared. MS(m/z): 654.31 [M+H].sup.+.

Embodiment 75 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(8-(hexylamino)-8-oxooctanamido) propanoate

[0245] ##STR00088##

[0246] Referring to the method of Embodiment 25, 3-(8-(hexylamino)-8-oxooctanamido) propanoic acid (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that an off-white solid powder, Compound 75 (0.33 g, yield: 72%) was prepared. MS(m/z): 626.47 [M+H].sup.+.

Embodiment 76 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(12-(tertbutylamino)-12-oxododecanamido) propanoate

[0247] ##STR00089##

[0248] Referring to the method of Embodiment 25, 3-(12-(tertbutylamino)-12-oxododecanamido) propanoic acid (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 76 (2.12 g, yield: 89.8%) was prepared. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.14-7.11 (m, 2H), 6.99 (d, J=8.0 Hz, 1H), 6.92-6.91 (m, 1H), 6.83-6.81 (br, 2H), 6.10 (t, J=6.0 Hz, 1H), 5.24 (s, 1H), 3.61 (q, J=6.0 Hz, 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=7.5 Hz, 3H). MS(m/z): 655.35 [M+H].sup.+.

Embodiment 77 (S)-6-(propyl(2-(thiophen-2-yl) ethyl) amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3-(16-(methylamino)-16-oxohexadecanamido) propanoate

[0249] ##STR00090##

[0250] Referring to the method of Embodiment 25, 3-(16-(methylamino)-16-oxohexadecanamido) propanoic acid (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that Compound 77 (1.60 g, yield: 56.3%) was prepared. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.14-7.11 (m, 2H), 6.99 (d, J=7.5 Hz, 1H), 6.93-6.91 (m, 1H), 6.83-6.81 (m, 2H), 6.07 (t, J=6.0 Hz, 1H), 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=7.5 Hz, 3H). MS(m/z): 668.69 [M+H].sup.+.

Embodiment 78 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl 3 -(12-(ethyl amino)-12-oxododecanoyl) glycinate

[0251] ##STR00091##

[0252] Referring to the method of Embodiment 25, 2-(12-(ethylamino)-12-oxododecanoyl) glycine (1.1 eq) was used to replace (18-amino-18-oxooctadecanoyl) glycine, so that a white solid powder, Compound 78 (1.20 g, yield: 69%) was prepared. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 10.31 (s, 1H), 8.08 (d, J=9.0 Hz, 2H), 7.81 (d, J=8.5 Hz, 2H), 7.67 (s, 1H), 7.32 (br, 2H), J=7.5 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 7.01 (d, J=7.5 Hz, 3H), 6.94 (br, 2H), 2.95-2.76 (m, 8H), 2.55 (d, J=9.5 Hz, 3H), 2.37 (t, J=7.5 Hz, 3H), J=7.5 Hz, 2H), 1.61 (t, J=7.0 Hz, 2H), 1.47 (t, J=7.0 Hz, 2H), 1.30-1.25 (m, 12H), 0.87 (t, J=6.5 Hz, 3H). MS(m/z): 612.46 [M+H].sup.+.

Embodiment 79 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (dodecylcarbamoyl) glycinate

[0253] ##STR00092##

[0254] Rotigotine (2.0 g, 5.68 mmol), Boc-glycine (1.04 g, 5.966 mmol, 1.05 eq), triethylamine (1.73 g, 17.05 mmol, 3.0 eq), THF (20.0 mL) were added to a 100 mL single-neck flask. The mixture was stirred while EDCI (1.64 g, 8.52 mmol, 1.5 eq) and HOBT (0.15 g, 1.14 mmol, 0.20 eq) were added and the mixture was reacted for three hours at room temperature. LCMS showed that the raw materials were completely reacted. Subsequently, water and ethyl acetate were added to separate the mixture, the aqueous phase was extracted by ethyl aetate twice, and the organic phase was combined and concentrated under reduced pressure, to obtain residues. Dichloromethane (20.0 mL) was added to the residues to dissolve them, and then trifluoroacetic acid (5.0 mL) was added. The mixture was reacted for two hours at room temperature, and TLC showed that the raw materials were completely reacted. The reaction mixture was concentrated under reduced pressure, to obtain residues. Tetrahydrofuran (20.0 mL) was added to the residues to dissolve them, and then DIPEA (2.53 g, 19.60 mmol, 4.0 eq) and 4-nitrophenyldodecylcarbamate (2.06 g, 5.88 mmol, 1.2 eq) were added. The mixture was reacted for two hours at room temperature, and TLC showed that the raw materials were completely reacted. Water and ethyl acetate were further added to separate the aqueous phase and organic phase, the aqueous phase as extracted by ethyl aetate twice, and the organic phase was combined, concentrated under reduced pressure, purified through a column chromatography, to obtain Compound 79 (0.88 g, yield: 24.2%), a light yellow oily product. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ7.28 (dd, J=5.0 Hz, 1.5 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.99 (d, J=7.5 Hz, 1H), 6.93-6.91 (m, 2H), 6.87-6.86 (m, 1H), 6.82 (d, J=8.0 Hz, 1H), 6.28 (t, J=5.5 Hz, 1H), 6.19 (t, J=5.5 Hz, 1H), 4.02 (d, J=6.5 Hz, 2H), 2.99 (q, J=1.5 Hz, 2H), 2.90 (t, J=7.0 Hz, 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].sup.+.

Embodiment 80 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl (4-octanamidobutanoyl) glycinate

[0255] ##STR00093##

[0256] Referring to the method of Embodiment 1, (4-octanamidobutanoyl) glycine (1.1 eq) was used to replace octanonamido acetic acid, so that a light yellow oily product, Compound 80 (0.25 g, yield: 66.7%) was prepared. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.21 (s, 1H), 7.12-7.10 (br, 2H), 6.98 (d, J=7.5 Hz, 1H), 6.93-6.91 (br, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.81 (s, 1H), 5.88 (s, 1H), 4.29 (d, J=5.5 Hz, 2H), 3.39-3.36 (dd, J=12.0 Hz, 6.0 Hz, 2H), 2.98-2.89 (br, 4H), 2.84-2.82 (br, 4H), 2.55-2.49 (br, 3H), 2.31 (t, J=6.0 Hz, 2H), 2.17 (t, J=7.5 Hz, 2H), 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].sup.+.

Embodiment 81 Assay for Testing Physical and Chemical Properties of the Compounds of the Present Disclosure

[0257] The compounds of the present disclosure to be tested were taken in a proper amount and filled in an aluminum crucible for testing DSC. The test results were shown in Table 1. The test results indicated that the compounds of the present disclosure had higher melting points, which met the requirements of grinding method to prepare a long-acting drug. [0258] Instrument Model: NETZSCH DSC 3500 [0259] Heating rate: 10.0 K/min [0260] Atmosphere: N.sub.2

TABLE-US-00001 TABLE 1 DSC Test results of melting points of the compounds of the present disclosure Melting points/ Embodiments Structural formula ° C. 15 [00094] 116.8 24 [00095] 92.5 27 [00096] 97.4 32 [00097] 112.3 43 [00098] 101.1 44 [00099] 88.5 47 [00100] 102.8 54 [00101] 113.7 70 [00102] 101.2 72 [00103] 92.8 76 [00104] 70.6 78 [00105] 105.1 79 [00106] <25 80 [00107] <25

Embodiment 82 Preparation of Drugs Used in Pharmacokinetics Experiment

[0261] The compounds of the present disclosure were precisely weighed in a proper amount and placed in a 20 ml vial, a blank matrix solution and a zirconia grinding ball were added to grind by vortex. After grinding, the suspension sample was transferred, and the blank matrix solution was used for diluting the suspension sample to final volume, and the suspension sample was packaged into 7 ml vials to prepare about a 20 mg/ml suspension. After the quantitative analysis was determined, the suspension was used for the pharmacokinetics experiment in the mouse.

Embodiment 83 Pharmacokinetics Experiment of the Compounds of the Present Disclosure in Mouse

[0262] Suspensions of Embodiments 15, 24, 27, 32 and 54 were prepared according to the method of Embodiment 82 and were taken at a dose of 9 mg/kg(calculated according to Rotigotine), and each of the above-mentioned compound suspensions was intramuscularly administrated for three SD mice, and whole blood samples were taken in 1 h, 4 h, 8 h, 24 h, 48 h, 72 h, 96 h, 120 h, 168 h, 216, 264 h, 312 h, and 360 h after administration, with 0.3ml/time point. K2EDT/heparin sodium were added to the whole blood samples for anticoagulation, and a BNPP stabilizer was further added, and then each whole blood sample was centrifuged to obtain plasma in 30min. The results were shown in Table 2 and FIG. 1:

TABLE-US-00002 TABLE 2 The blood concentrations (ng/ml) of the active compounds at different time points after the intramuscular injection of the compound suspensions of the present disclosure in mouse Embodi- Embodi- Embodi- Embodi- Embodi- TIME ment ment ment ment ment (h) 24 15 32 54 27 1 2.73 1.75 0.363 0.288 0.889 4 2.55 2.12 1.38 1.26 3.9 8 3.35 1.89 2.92 2.53 9.52 24 2.67 0.652 2.15 2.31 6.79 48 1.89 0.533 2.16 2.02 4.6 72 2.17 0.646 1.94 1.51 3.3 96 2.6 0.504 2.33 1.57 3.35 120 2.94 1.1 2.68 1.86 3.7 168 2.46 1.85 2.77 2.29 1.75 216 1.99 3.1 2.6 2.76 1.01 264 0.741 1.98 1.54 1.83 0.212 312 0.919 1.56 1.03 1.33 0.0935 360 0.314 0.822 0.619 0.906 0

[0263] The experiment indicated that the compounds of the present disclosure can sustainably and slowly release in vivo and have short onset time and long effect time.

[0264] In conclusion, the compounds of the present disclosure have a low solubility, higher melting point and can be prepared into a suspension preparation with short onset time and long effect time, and therefore they have a better clinical application prospect.

[0265] Although the present invention has been disclosed in the form of embodiments and variations thereon, it will be understood that numerous additional modifications and variations could be made thereto without departing from the scope of the invention.

[0266] For the sake of clarity, it is to be understood that the use of ‘a’ or ‘an’ throughout this application does not exclude a plurality, and ‘comprising’ does not exclude other steps or elements.