A 1,2,3,4-tetrahydroisoquinoline-thiophene derivative and a preparation method thereof

Abstract

The invention discloses a 1,2,3,4-tetrahydroisoquinoline-thiophene derivative and a preparation method thereof. The tetrahydroisoquinoline nitrogen atom is connected to an alkyl, aryl or heterocyclic aryl substituent through a chain (including an alkyl, carbonyl, thioether and amide bond). Biological activity tests show that this type of compound has the activity of antagonizing dopamine (D2 receptor) receptors. This type of compound can be used as a pharmaceutical active ingredient for the treatment of diseases related to the D2 receptor.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical synthesis intermediates, and in particular to a 1,2,3,4-tetrahydroisoquinoline-thiophene derivative and a preparation method thereof. Background Art

[0002] 1,2,3,4-Tetrahydroisoquinoline derivatives are an important class of drug synthesis intermediates, and they themselves also have multiple pharmacological activities. Current Biology Vol 24 117–123, January 20, 2014 reported that a compound extracted from traditional Chinese medicine, berberine (as shown in structure II), has significant anti-analgesic activity. J.Med.Chem.2000,43,1878-1885 found that 1,2,3,4-tetrahydroisoquinoline derivatives with similar structures (as shown in structure III) have selective D3 antagonism, exhibit significant antispasmodic activity, and also have mild analgesic activity. Subsequently, J.Med.Chem.2019,62,4755-4771 also reported 1,2,3,4-tetrahydroisoquinoline derivatives (as shown in structure IV) with selective D2 partial agonism. The above studies show that derivatives of 1,2,3,4-tetrahydroisoquinoline skeleton can selectively act on D receptors, and their performance is closely related to the connecting chain and the connecting group.

[0003]

[0004] It can be seen from existing literature reports that many 1,2,3,4-tetrahydroisoquinoline derivatives functionalized by nitrogen atoms have ethyl groups as their connecting chains, and the types of connecting groups are relatively limited, and there are few studies on their biological target activities. Therefore, the present invention focuses on using 1,2,3,4-tetrahydroisoquinoline as the basic skeleton to study the length and type of nitrogen atom connecting chains (mainly the number of carbons in the connecting chains and the use of carbonyl, amide and ether bonds to replace carbon) and the types of connecting groups (mainly thiophene and its derivatives). Summary of the invention

[0005] One of the purposes of the present invention is to provide a novel 1,2,3,4-tetrahydroisoquinoline derivative and a preparation method thereof, which is suitable for treating diseases associated with D2 receptors (mainly including drug abuse, restless legs syndrome, schizophrenia, Parkinson's disease and depression, etc.).

[0006] To achieve the above object, the present invention provides a 1,2,3,4-tetrahydroisoquinoline-thiophene derivative, and a pharmaceutically acceptable salt, solvate, hydrate or crystal form thereof, the general formula of which is as follows:

[0007]

[0008] in,

[0009] R 1 -H, -OH, halogen, -NO 2 、-CN、-C 1-5 Alkyl, -OC 1-5 Any one, any two or any three groups of the alkoxy group are monosubstituted, disubstituted or trisubstituted at the 5, 6, 7 or 8 position of the tetrahydroisoquinoline group;

[0010] R 2 -H, -OH, halogen, -NO 2 、-CN、-C 1-3 Alkyl, -OC 1-3 Alkoxy, substituted or unsubstituted phenyl, any or any disubstituted on the thiophene group;

[0011] X is a chemical bond, sulfur, oxygen, nitrogen, carbonyl, amide, or ester group;

[0012] n is an integer between 0 and 5.

[0013] In some embodiments, R 1 is a mono-, di- or tri-substituted group at the 5, 6, 7 or 8 position of the tetrahydroisoquinoline group, and these groups include -H, -OH, -Br, -Cl, -F, -NO 2 , -CN, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, isopentyl, tert-butyl, methoxy, ethoxy, propoxy, butoxy, isopropoxy, and isobutoxy, or any combination of one, two, or three thereof.

[0014] Preferably, these groups include -H, -OH, -Br, -Cl, -F, -NO 2 , methyl, ethyl, methoxy, ethoxy.

[0015] More preferably, R 1 is a mono- or di-substituted group at the 6- or 7-position of the tetrahydroisoquinoline group, including -H, -OH, -Br, -Cl, -NO 2 , methyl, methoxy or any combination of two thereof. More preferably, R 1 Substituted tetrahydroisoquinolines are:

[0016]

[0017] In some embodiments, R 2 -H, -OH, halogen, -NO 2 、-CN、-C 1-3 Alkyl, -OC 1-3Alkoxy, substituted or unsubstituted phenyl (substituted phenyl is substituted by methoxy, ethoxy, halogen, alkoxyformyl at the ortho, meta, or para position, or any one or two of them), any one or any one of them on the thiophene group. 2 is -H, -OH, -Br, -Cl, -F, -NO 2 , -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, substituted or unsubstituted phenyl (substituted phenyl is substituted by methoxy, ethoxy, halogen, alkoxyformyl at the ortho, meta, or para position, any or any disubstituted on the thiophene group. Furthermore, R 2 is -H, -OH, -Br, -Cl, -F, -NO 2 , -CN, methyl, ethyl, methoxy, ethoxy, substituted or unsubstituted phenyl (substituted phenyl is substituted by methoxy, ethoxy, halogen, ethoxycarbonyl in the ortho, meta, or para position at any or any two positions), any or any two substitutions on the thiophene group.

[0018] Preferably, R 2 Substituted thiophene groups are:

[0019]

[0020] In some embodiments, X is a chemical bond, sulfur, oxygen, nitrogen, carbonyl, amide, or ester. Preferably, X is a chemical bond, sulfur, or -NH-CO-.

[0021] In some embodiments, n is an integer between 0 and 5. Preferably, n is 0, 1, 2, or 3.

[0022] The above compounds include free bases, salts with pharmaceutically acceptable acids, hydrates, solvates and various crystals. When the compound is in the form of diastereoisomers, it includes a diastereoisomer mixture and individual diastereoisomer monomers; when the compound is in the form of enantiomers, it includes an enantiomeric mixture and individual enantiomer monomers.

[0023] The above compounds can be salified with pharmaceutically acceptable acids, including HCl, HBr, citric acid, fumaric acid, succinic acid, sulfuric acid, formic acid, and acetic acid.

[0024] In the compounds according to the invention, the term "alkyl" preferably stands for a straight-chain or branched hydrocarbon radical having 1 to 5 carbon atoms.

[0025] The term "phenyl" refers to -C 6 H 5 , where the benzene ring may have one or more substituents.

[0026] The term "alkoxy" refers to a straight or branched chain alkyl-OC having 1 to 5 carbon atoms and bonded via an oxygen atom. 1-5 .

[0027] The term "alkoxycarbonyl" denotes -OCOR, wherein R is alkyl as defined above.

[0028] Another object of the present invention is to provide a composition consisting of the compound of the present invention and pharmaceutically acceptable excipients or other active compounds.

[0029] The present invention also relates to a pharmaceutical composition comprising one or more of the above-mentioned 1,2,3,4-tetrahydroisoquinoline-thiophene derivatives. In other words, the compounds according to the present invention can be used as pharmaceutically active substances, in particular as D2 receptor antagonists.

[0030] They can be used for the preparation of pharmaceutical preparations containing at least one compound described according to the invention.

[0031] The free alkali of the compound of the present invention or the salt generated with pharmaceutically acceptable acid can be made into suitable galenic dosage forms according to acceptable pharmaceutical operation procedures, such as oral, injection, spray administration composition, etc. The pharmaceutical composition according to the present invention comprises an effective amount of the compound of the present invention, and a suitable pharmaceutically acceptable carrier or diluent, which are well known in the art. The carrier can be any inert raw material, organic or inorganic, suitable for enteral, percutaneous or parenteral administration, such as water, gelatin, gum arabic, lactose, microcrystalline fiber starch, calcium hydrogen phosphate, magnesium stearate, talcum, colloidal silicon dioxide, etc. The composition can also contain other pharmaceutically active agents, and conventional additives, such as stabilizers, wetting agents, emulsifiers, flavoring agents, buffers, etc.

[0032] The composition according to the present invention can be prepared into solid or liquid dosage forms for oral administration, such as tablets, capsules, powders, syrups; prepared into sterile solutions, suspensions or emulsions for parenteral administration; prepared into dry powder preparations, sterile solutions, suspensions or emulsions for spray administration.

[0033] Another object of the present invention is to provide the use of the compounds of the present invention in the preparation of a medicament for treating and / or preventing one or more diseases or disorders mediated by D2 receptors. As mentioned above, the compounds or compositions of the present invention can be used to treat diseases associated with D2 receptor antagonism including drug abuse, restless legs syndrome, schizophrenia, Parkinson's disease and depression. The dosage of the specific compound will vary depending on its potency, the mode of administration, the age and weight of the patient, and the severity of the condition being treated.

[0034] Another object of the present invention is to provide a method for preparing the 1,2,3,4-tetrahydroisoquinoline-thiophene derivative. The raw materials required for the method are widely available, the operation is simple and easy, and it is easy to scale up.

[0035] The present invention further relates to a method for preparing the above-mentioned compound. According to the conditions disclosed in the present invention, experienced researchers can easily prepare the compound shown in general formula I. In particular, according to the present invention, the following method is provided:

[0036] (1), when Y is a halogen, such as -Cl, -Br or -I, the specific steps are:

[0037]

[0038] Weigh S-1 (1.0mmol) and S-2 (1.0-2.0mmol) and dissolve them in 10-100ml DMF. Add potassium carbonate (1.0-2.0mmol) and stir, then continue to add potassium iodide (1.0-2.0mmol). Heat to 70°C for 8h and monitor by LC-MS. After the reaction is completed, the reaction solution is cooled to room temperature and quenched by adding water (10-100ml). The mixture is extracted 3 times with 10ml of dichloromethane, the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated to remove the solvent. The residue is separated and purified by silica column chromatography to obtain the target product I.

[0039] (2) When S-3 is aldehyde thiophene, the specific steps are:

[0040]

[0041] S-1 (1.0 mmol) and S-3 (0.5 mmol) were added to 15 ml of DMF and stirred to dissolve. Acetic acid (0.09 ml, 1.5 mmol) was added, and the temperature was raised to 50 °C and stirred for 24 h. After the reaction was completed, the temperature was lowered to room temperature. DMF was concentrated and methanol was added to dissolve. NaBH was added in batches. 4 (0.06 g, 1.5 mmol), LC-MS detection, after the reaction is completed, the methanol is concentrated, water is added, and the mixture is extracted with dichloromethane. The organic phase is washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and chromatographed on a sand column to obtain the target product I.

[0042] Among them, the substituent R 1 , R 2 , X, and n are defined the same as before.

[0043] The advantages of the present invention are: the present invention provides a novel 1,2,3,4-tetrahydroisoquinoline-thiophene derivative, which controls the length and type of the connecting chain (mainly the number of carbons in the connecting chain and the replacement of carbons with carbonyl, amide and thioether bonds) and the type of connecting group (mainly thiophene as the skeleton). Biological activity tests show that this type of compound has D2 receptor antagonist activity, and when there are thioether bonds, amides and carbonyls in the connecting chain and the connecting group is thiophene and its derivatives, the antagonist activity can be significantly enhanced. This type of compound can be used as a pharmaceutical active ingredient for drug abuse, restless legs syndrome, schizophrenia, Parkinson's disease, depression and other diseases.

[0044] The 1,2,3,4-tetrahydroisoquinoline derivatives and pharmaceutical compositions thereof (at least comprising one or more active compounds represented by general formula I) of the present invention are preferably used in combination with a pharmaceutical carrier, and if necessary, can also be used in combination with other pharmaceutical active ingredients. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] The drawings described herein are used to provide further understanding of the present invention and constitute a part of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0046] Figure 1 It is a dose curve diagram showing the effect of the compound I-8 of the present invention on the calcium flux fluorescence signal (RFU) of dopamine. DETAILED DESCRIPTION

[0047] The following will describe the implementation methods of the present invention in detail with reference to the accompanying drawings and embodiments, so that the implementation process of how the present invention applies technical means to solve technical problems and achieve technical effects can be fully understood and implemented accordingly.

[0048] It should be understood that when used in this specification and the appended claims, the terms "include" and "comprises" indicate the presence of described features, integers, steps, operations, elements and / or components, but do not exclude the presence or addition of one or more other features, integers, steps, operations, elements, components and / or combinations thereof.

[0049] It should also be understood that the terms used in this description of the embodiments of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the embodiments of the present invention. As used in the description of the embodiments of the present invention and the appended claims, unless the context clearly indicates otherwise, the singular forms of "a", "an" and "the" are intended to include plural forms.

[0050] By referring to similar literature reports or the specific examples shown below, experienced researchers can easily select appropriate reaction conditions for the chemical reactions. The necessary raw materials for such reactions can be purchased or prepared by themselves according to conventional methods.

[0051] The present invention provides a 1,2,3,4-tetrahydroisoquinoline-thiophene derivative, the general formula of which is as follows:

[0052]

[0053] According to the present invention, preferred compounds I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-12, I-13, I-14, I-15, I-16, I -17, I-18, I-19, I-20, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, as follows:

[0054] 2-(2-(Thien-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-1)

[0055] 7-Bromo-2-(2-(thiophen-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-2)

[0056] 7-Chloro-2-(2-(thiophen-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-3)

[0057] 7-Nitro-2-(2-(thiophen-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-4)

[0058] 7-Methyl-2-(2-(thiophen-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-5)

[0059] 6-Methoxy-2-(2-(thiophen-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-6)

[0060] 6,7-Dimethoxy-2-(2-(thiophen-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-7)

[0061] 6-Hydroxy-7-methoxy-2-(2-(thiophen-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-8)

[0062] 2-(2-(Thien-3-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-9)

[0063] 7-Bromo-2-(2-(thiophen-3-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-10)

[0064] 7-Chloro-2-(2-(thiophen-3-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-11)

[0065] 7-Nitro-2-(2-(thiophen-3-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-12)

[0066] 7-Methyl-2-(2-(thiophen-3-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-13)

[0067] 6-Methoxy-2-(2-(thiophen-3-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-14)

[0068] 6,7-Dimethoxy-2-(2-(thiophen-3-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-15)

[0069] 6-Hydroxy-7-methoxy-2-(2-(5-(4-methoxyphenyl)thiophen-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-16)

[0070] 6-Hydroxy-7-methoxy-2-(2-(5-nitro-thiophen-2-yl)-ethyl)-1,2,3,4-tetrahydroisoquinoline (I-17)

[0071] 6-Hydroxy-7-methoxy-2-(2-(5-(2-methoxyphenyl)thiophen-2-yl)-ethyl)-1,2,3,4-tetrahydroisoquinoline (I-18)

[0072] 6-Hydroxy-7-methoxy-2-(2-(5-phenylthiophen-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-19)

[0073] 6-Hydroxy-7-methoxy-2-(2-(5-(3-methoxyphenyl)thiophen-2-yl)-ethyl)-1,2,3,4-tetrahydroisoquinoline (I-20)

[0074] 6-Hydroxy-7-methoxy-2-(2-(5-(2-fluoro-3-methoxyphenyl)thiophen-2-yl)-ethyl)-1,2,3,4-tetrahydroisoquinoline (I-21)

[0075] 6-Hydroxy-7-methoxy-2-(2-(5-(3-ethoxycarbonylphenyl)thiophen-2-yl)-ethyl)-1,2,3,4-tetrahydroisoquinoline (I-22)

[0076] 2-((5-Bromo-thiophen-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (I-23)

[0077] 6-Hydroxy-7-methoxy-2-((5-bromo-thiophen-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (I-24)

[0078] 6-Hydroxy-7-methoxy-2-((5-(2-methoxyphenyl)thiophen-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (I-25)

[0079] 6-Hydroxy-7-methoxy-2-((5-(3-methoxyphenyl)thiophen-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (I-26)

[0080] 6-Hydroxy-7-methoxy-2-((5-phenylthiophen-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (I-27)

[0081] 2-(3-(Thiophene-2-carboxamido)-propyl)-1,2,3,4-tetrahydroisoquinoline (I-28)

[0082] 6-Hydroxy-7-methoxy-2-(N-propyl 2-carboxamidothiophene)-1,2,3,4-tetrahydroisoquinoline (I-29)

[0083] 2-(3-(Thiophene-2-mercapto)propyl)-1,2,3,4-tetrahydroisoquinoline (I-30)

[0084] 6-Hydroxy-7-methoxy-2-(3-(thiophene-2-thio)propyl)-1,2,3,4-tetrahydroisoquinoline (I-31)

[0085] In this embodiment, hydrates, solvates and various crystals of general formula I and pharmaceutically acceptable salts thereof.

[0086] The present invention also provides a pharmaceutical composition of 1,2,3,4-tetrahydroisoquinoline-thiophene derivatives for use in the preparation of a pharmaceutical composition for treating or preventing diseases associated with D2 receptor antagonism. The pharmaceutical composition comprises physiologically suitable excipients, carriers, diluents and at least one free base, physiologically suitable acid-generated salt, hydrate and solvate or crystal of a diaryl vinyl cyclic amine derivative; the acid comprises an inorganic acid and an organic acid, and the pharmaceutical composition comprises at least one active substance described in general formula I.

[0087] The present invention also reports a method for preparing the above-mentioned 1,2,3,4-tetrahydroisoquinoline-thiophene derivative, wherein compound S-1 reacts with S-2 or S-3 to generate compound I of the general formula:

[0088] (1) When Y is a halogen, such as -Cl, -Br or -I, the specific steps are:

[0089]

[0090] Weigh S-1 (1.0mmol) and S-2 (1.0-2.0mmol) and dissolve them in 10-100ml DMF. Add potassium carbonate (1.0-2.0mmol) and stir, then continue to add potassium iodide (1.0-2.0mmol). Heat to 70°C for 8h and monitor by LC-MS. After the reaction is completed, the reaction solution is cooled to room temperature and quenched by adding water (10-100ml). The mixture is extracted 3 times with 10ml of dichloromethane, the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated to remove the solvent. The residue is separated and purified by silica column chromatography to obtain the target product I.

[0091] (2) When S-3 is aldehyde thiophene, the specific steps are:

[0092]

[0093] S-1 (1.0 mmol) and S-3 (0.5 mmol) were added to 15 ml of DMF and stirred to dissolve. Acetic acid (0.09 ml, 1.5 mmol) was added, and the temperature was raised to 50 °C and stirred for 24 h. After the reaction was completed, the temperature was lowered to room temperature. DMF was concentrated and methanol was added to dissolve. NaBH was added in batches. 4 (0.06 g, 1.5 mmol), LC-MS detection, after the reaction is completed, the methanol is concentrated, water is added, and the mixture is extracted with dichloromethane. The organic phase is washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and chromatographed on a sand column to obtain the target product I.

[0094] Among them, R 1 , R 2 , X, Y and n are as defined above.

[0095] According to the present invention, the compound shown in general formula I or the salt generated with physiologically acceptable acid can be prepared into suitable galenic dosage forms according to acceptable pharmaceutical operation processes, such as oral, injection, nasal spray administration, etc. The pharmaceutical composition according to the present invention comprises the compound shown in general formula I, and compatible pharmaceutically acceptable carrier materials or diluents, which are well known in the art. The carrier can be any inert material, organic or inorganic, suitable for enteral, percutaneous or parenteral administration, such as water, gelatin, gum arabic, lactose, microcrystalline cellulose starch, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talc, colloidal silicon dioxide, etc. The composition can also include other pharmaceutically active agents, and conventional additives, such as stabilizers, wetting agents, emulsifiers, flavoring agents, buffers, etc.

[0096] The composition according to the present invention can be prepared into solid or liquid dosage forms for oral administration, such as tablets, capsules, powders, syrups, elixirs, etc., and sterile solutions, suspensions or emulsions for parenteral administration.

[0097] The compounds and pharmaceutical compositions according to the present invention can be used for the treatment of drug abuse, restless legs syndrome, schizophrenia, Parkinson's disease and depression, as well as other diseases associated with antagonizing D2 receptors. According to common sense, the dosage of a specific compound will vary depending on its potency, the mode of administration, the age and weight of the patient, and the severity of the condition being treated.

[0098] The following non-limiting examples and pharmacological experiments will further illustrate the present invention.

[0099] Experimental Section

[0100] General approach

[0101] All compounds 1 H-NMR spectra were collected on a Brucker AVANCE III 400 MHz instrument, and tetraethylsilane (TMS) was used as the internal standard.

[0102] Liquid chromatography-mass spectrometry (LC-MS) analyses were performed on a Waters Alliance e2695-ZQ 2000 system and m / z values ​​are reported.

[0103] Unless otherwise noted, all solvents were used as received. All ratios of mixed solvents are by volume (v / v). All temperatures are in degrees Celsius (°C).

[0104] The following non-limiting examples and pharmacological experiments will further illustrate the present invention.

[0105] Example 1

[0106] 2-(2-(Thien-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-1)

[0107] According to the steps described in Synthesis Method 1, 1,2,3,4-tetrahydroisoquinoline and 2-(2-chloroethyl)thiophene were used as raw materials to obtain the target product I-1 with a yield of 93%. MS (m / z): 244.37 [M+H] + . 1 H NMR (400 MHz, CDCl 3), δ: 7.14-7.09(m,4H),7.04-7.02(m,1H),6.94-6.92(m,1H),6.87-6.86(m ,1H),3.73(s,2H),3.15-3,12(m,2H),2.95-2,92(m,2H),2.86-2.80(m,4H).

[0108] Example 2

[0109] 7-Bromo-2-(2-(thiophen-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-2)

[0110] According to the steps described in Synthesis Method 1, 7-bromo-1,2,3,4-tetrahydroisoquinoline and 2-(2-chloroethyl)thiophene were used as raw materials to obtain the target product in a yellow oily form with a yield of 91%. MS (m / z): 323.26 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ), δ: 7.24-7.23(m,1H),7.18-7.16(m,1H),7.14-7.13(m,1H),6.99-6.97(m,1H),6.9 3-6.92(m,1H),6.86-6.85(m,1H),3.68(s,2H),3.13-3.10(m,2H),2.88-2.79(m,6H).

[0111] Example 3

[0112] 7-Chloro-2-(2-(thiophen-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-3)

[0113] According to the steps described in Synthesis Method 1, 7-chloro-1,2,3,4-tetrahydroisoquinoline and 3-chloroethylthiophene are used as raw materials to obtain a yellow oily product of 7-chloro-2-(2-thienylethyl)-1,2,3,4-tetrahydroisoquinoline with a yield of 90%. MS (m / z): 278.81 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ), δ: 7.30-7.29(m,1H),7.16-7.12(m,3H),6.94-6.91(m,2H),3.63(s,2H),3.07-3.03(m,2H),2.80-2.78(m,2H),2.74-2.72(m,4H).

[0114] Example 4

[0115] 7-Nitro-2-(2-(thiophen-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-4)

[0116] According to the steps described in Synthesis Method 1, 7-nitro-1,2,3,4-tetrahydroisoquinoline and 2-(2-chloroethyl)thiophene were used as raw materials to obtain the target product as a brown solid with a yield of 88%. MS (m / z): 377.47 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ), δ: 8.03-8.00(m,1H),7.96-7.95(m,1H),7.29-7.27(m,1H),6.97-6.95(m,1H),6.89-6.88(m ,1H),6.86-6.85(m,1H),3.81(s,2H),3.17-3.14(m,2H),3.05-3.02(m,2H),2.91-2.86(m,4H).

[0117] Example 5

[0118] 7-Methyl-2-(2-(thiophen-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-5)

[0119] According to the steps described in Synthesis Method 1, 7-methyl-1,2,3,4-tetrahydroisoquinoline and 2-(2-chloroethyl)thiophene are used as raw materials to obtain a yellow oily product with a yield of 93%. MS (m / z): 258.39 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ), δ: 7.16-7.14(m,1H),7.03-7.01(m,1H),6.99-6.94(m,2H),6.89-6.87(m,2H),3 .71(s,2H),3.17-3.13(m,2H),2.92-2.90(m,2H),2.87-2.80(m,4H),2.31(s,3H).

[0120] Example 6

[0121] 6-Methoxy-2-(2-(thiophen-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-6)

[0122] According to the steps described in Synthesis Method 1, 6-methoxy-1,2,3,4-tetrahydroisoquinoline and 2-chloroethylthiophene were used as raw materials to obtain a yellow oily product with a yield of 92%. MS (m / z): 274.39 [M+H] + . 1H NMR (400 MHz, CDCl 3 ), δ: 7.16-7.15(m,1H),6.99-6.94(m,2H),6.88-6.87(m,1H),6.74-6.71(m,1H),6.67-6.66 (m,1H),3.80(s,1H),3.69(s,2H),3.17-3.13(m,2H),2.95-2.92(m,2H),2.87-2.80(m,4H).

[0123] Example 7

[0124] 6,7-Dimethoxy-2-(2-(thiophen-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-7)

[0125] According to the steps described in Synthesis Method 1, 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-(2-chloroethyl)thiophene were used as raw materials to obtain a yellow solid product with a yield of 89%. MS (m / z): 304.42 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ), δ: 7.14-7.13(m,1H),6.94-6.92(m,1H),6.87-6.86(m,1H),6.61(s,1H),6.53(s ,1H),3.85(s,3H),3.84(s,3H),3.65(s,2H),3.15-3.11(m,2H),2.85-2.80(m,6H).

[0126] Example 8

[0127] 6-Hydroxy-7-methoxy-2-(2-(thiophen-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-8)

[0128] According to the steps described in Synthesis Method 1, 6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline and 2-(2-chloroethyl)thiophene were used as raw materials to obtain the target product with a yield of 53%. MS (m / z): 290.39 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ), δ: 7.16-7.15(m,1H),6.97-6.94(m,1H),6.89-6.88(m,1H),6.68(s,1H),6.54(s ,1H),5.55(s,1H),3.87(s,2H),3.66(s,2H),3.17-3.13(m,2H),2.87-2.78(m,6H).

[0129] Example 9

[0130] 2-(2-(Thien-3-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-9)

[0131] According to the steps described in Synthesis Method 1, 1,2,3,4-tetrahydroisoquinoline and 3-(2-chloroethyl)thiophene were used as raw materials to obtain a yellow oily product with a yield of 71%. MS (m / z): 244.37 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ), δ: 7.48-7.46(m,1H),7.27-7.26(m,1H),7.14-7.12(m,3H),7.09-7.08(m,2H),3.65(s,2H),2.91-2.83(m,4H),2.76-2.72(m,4H).

[0132] Example 10

[0133] 7-Bromo-2-(2-(thiophen-3-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-10)

[0134] According to the steps described in Synthesis Method 1, 7-bromo-1,2,3,4-tetrahydroisoquinoline and 3-(2-chloroethyl)thiophene are used as raw materials to obtain a yellow oily product with a yield of 80%. MS (m / z): 323.26 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ), δ: 7.45-7.43(m,1H),7.30-7.28(m,2H),7.23-7.22(m,1H),7.08-7.04(m ,2H),3.62(s,2H),2.86-2.83(m,2H),2.78-2,75(m,2H),2.72-2.68(m,4H).

[0135] Embodiment 11

[0136] 7-Chloro-2-(2-(thiophen-3-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-11)

[0137] According to the steps described in Synthesis Method 1, 7-chloro-1,2,3,4-tetrahydroisoquinoline and 3-(2-chloroethyl)thiophene are used as raw materials to obtain a yellow oily product with a yield of 90%. MS (m / z): 278.81 [M+H] + . 1H NMR (400 MHz, DMSO-d 6 ), δ: 7.45-7.43(m,1H),7.23(s,1H),7.18-7.12(m,3H),7.05-7.04(m,1H) ),3.62(s,2H),2.87-2.83(m,2H),2.78-2.77(m,2H),2.72-2.68(m,4H).

[0138] Example 12

[0139] 7-Nitro-2-(2-(thiophen-3-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-12)

[0140] According to the steps described in Synthesis Method 1, 7-nitro-1,2,3,4-tetrahydroisoquinoline and 3-(2-chloroethyl)thiophene were used as raw materials to obtain a brown solid product with a yield of 86%. MS (m / z): 289.37 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ), δ: 7.99-7.96(m,2H),7.45-7.43(m,1H),7.40-7.37(m,1H),7.23-7.22(m,1H),7.0 6-7.04(m,1H),3.74(s,2H),2.96-2.91(m,2H),2.89-2,85(m,2H),2.77-2.72(m,4H).

[0141] Example 13

[0142] 7-Methyl-2-(2-(thiophen-3-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-13)

[0143] According to the steps described in Synthesis Method 1, 7-methyl-1,2,3,4-tetrahydroisoquinoline and 3-(2-chloroethyl)thiophene were used as raw materials to obtain a yellow oily product with a yield of 87%. MS (m / z): 258.39 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ), δ: 7.48-7.46(m,1H),7.26-7.25(m,1H),7.09-7.07(m,1H),7.01-6.99(m,1H),7.01-6.99(m,1H) ),6.96-6.94(m,1H),6.88(s,1H),3.60(s,2H),2.90-2.86(m,2H),2.78-2.70(m,6H),2.26(s,3H).

[0144] Embodiment 14

[0145] 6-Methoxy-2-(2-(thiophen-3-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-14)

[0146] According to the steps described in Synthesis Method 1, 6-methoxy-1,2,3,4-tetrahydroisoquinoline and 3-(2-chloroethyl)thiophene are used as raw materials to obtain a yellow oily product with a yield of 85%. MS (m / z): 274.39 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ), δ: 7.45-7.42(m,1H),7.22(s,1H),7.05-7.04(m,1H),6.97-6.95(m,1H),6.70-6.66(m ,2H),3.71(s,3H),3.54(s,2H),2.86-2.83(m,2H),2.80-2.77(m,2H),2.70-2.77(m,4H).

[0147] Embodiment 15

[0148] 6,7-Dimethoxy-2-(2-(thiophen-3-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-15)

[0149] According to the steps described in Synthesis Method 1, 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 3-(2-chloroethyl)thiophene were used as raw materials to obtain a yellow solid product with a yield of 83%. MS (m / z): 304.42 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ), δ: 7.45-7.43(m,1H),7.23-7.22(m,1H),7.05-7.04(m,1H),6.66(s,1H),6.63(s ,1H),3.70(s,3H),3.69(s,3H),3.53(s,2H),2.86-2.82(m,2H),2.74-2.66(m,6H).

[0150] Example 16

[0151]

[0152] 16.1 2-(2-Hydroxyethyl)-5-(4-methoxyphenyl)thiophene

[0153] 5-Bromo-2-thiopheneethanol (0.6 g, 3.0 mmol) and 4-methoxyphenylboronic acid (0.66 g, 4.5 mmol) were dissolved in dioxane (30 ml) and water (6 ml), and Pd(PPh 3 ) 2 Cl 2 (0.18g, 0.024mmol) and potassium carbonate (0.90g, 6.6mmol), nitrogen replacement for 5min, heating to 80℃, stirring for 18h, TLC detection, after the reaction is completed, heating to 70℃ for 8h, LC-MS monitoring, after the reaction is completed. Add 1N hydrochloric acid to quench, concentrate to remove dioxane, add ethyl acetate and water to extract, dry and concentrate, sand column chromatography to obtain 0.51g of white solid, yield 74%. MS (m / z): 235.31 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ), δ: 7.52-7.50(m,2H),7.07-7.06(m,1H),6.93-6.91(m,2H),6.84-6.83(m,1H),3.92-3.89(m,2H),3.85(s,3H), 3.10-3.07(m,2H).

[0154] 16.2 2-(2-Chloroethyl)-5-(4-methoxyphenyl)thiophene

[0155] 2-(5-(4-methoxyphenyl))thiopheneethanol (0.37 g, 2.0 mmol) was dissolved in DCM (15 ml), TEA (0.14 ml, 2.0 mmol) was added, cooled in an ice-water bath, and SOCl was added dropwise. 2 (0.15ml, 4.0mmol) 5ml DCM solution, dropwise addition, heating to reflux and stirring for 2h, TLC detection, complete reaction, stirring for 6h, SM1 reaction completed and potassium carbonate (0.90g, 6.6mmol), nitrogen replacement for 5min, heating to 80℃, stirring for 18h, TLC detection, after the reaction is completed, water is added to quench, liquid separation extraction, washing with saturated sodium chloride, drying and concentration with anhydrous sodium sulfate, sand column chromatography to obtain 0.34g of light yellow oil, yield 68%. MS (m / z): 253.76 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ), δ: 7.52-7.50(m,2H),7.07-7.06(m,1H),6.94-6.92(m,2H),6.85-6.84(m,1H),3.85(s,3H),3.79-3.75(m,2H),3.30-3.27(m,2H).

[0156] 16.3 6-Hydroxy-7-methoxy-2-(2-(5-(4-methoxyphenyl)thiophen-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-16)

[0157] According to the steps described in Synthesis Method 1, 6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline and 2-(2-chloroethyl)-5-(4-methoxyphenyl)thiophene are used as raw materials to obtain a yellow oily product with a yield of 50%. MS (m / z): 396.52 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ), δ: 7.50-7.48(m,2H),7.03-7.02(m,1H),6.92-6.90(m,2H),6.81-6.80(m,1H),6.69(s,1H) ), 6.53(s,1H), 3.86(s,3H), 3.84(s,3H), 3.68(s,2H), 3.15-3.11(m,2H), 2.89-2.82(m,6H).

[0158] Embodiment 17

[0159] 6-Hydroxy-7-methoxy-2-(2-(5-nitro-thiophen-2-yl)-ethyl)-1,2,3,4-tetrahydroisoquinoline (I-17)

[0160] According to the steps described in Synthesis Method 1, 6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline and 2-chloroethyl-5-nitrothiophene were used as raw materials to obtain a brown solid product with a yield of 40%. MS (m / z): 335.39 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ), δ: 7.79-7.78(m,1H),6.84-6.83(m,1H),6.71(s,1H),6.53(s,1H),3.87(s,3H),3.67(s,2H),3.13-3.10(m,2H),2.86-2.82(m,6H).

[0161] Embodiment 18

[0162] 6-Hydroxy-7-methoxy-2-(2-(5-(2-methoxyphenyl)thiophen-2-yl)-ethyl)-1,2,3,4-tetrahydroisoquinoline (I-18)

[0163] According to the steps described in Synthesis Method 1, 6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline and 2-(2-chloroethyl)-5-(2-methoxyphenyl)thiophene were used as raw materials to obtain a brown solid product with a yield of 42%. MS (m / z): 396.52 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ), δ: 7.61-7.59(m,1H),7.34-7.22(m,1H),7.25-7.24(m,1H),7.01-6.97(m,2H),6.87-6.86(m,1H),6 .69(s,1H), 6.53(s,1H), 3.93(s,3H), 3.86(s,3H), 3.76(s,2H), 3.23-3.20(m,2H), 2.98-2.90(m,6H).

[0164] Embodiment 19

[0165] 6-Hydroxy-7-methoxy-2-(2-(5-phenylthiophen-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-19)

[0166] According to the steps described in Synthesis Method 1, 6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline and 2-chloroethyl-5-(2-methoxyphenyl)thiophene were used as raw materials to obtain a brown solid product with a yield of 42%. MS (m / z): 366.49 [M+H] + . 1 HNMR (400 MHz, CDCl 3 ), δ: 7.61-7.59(m,1H),7.34-7.22(m,1H),7.25-7.24(m,1H),7.01-6.97(m,2H),6.87-6.86(m,1H),6 .69(s,1H), 6.53(s,1H), 3.93(s,3H), 3.86(s,3H), 3.76(s,2H), 3.23-3.20(m,2H), 2.98-2.90(m,6H).

[0167] Embodiment 20

[0168] 6-Hydroxy-7-methoxy-2-(2-(5-(3-methoxyphenyl)thiophen-2-yl)-ethyl)-1,2,3,4-tetrahydroisoquinoline (I-20)

[0169] According to the steps described in Synthesis Method 1, 6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline and 2-(2-chloroethyl)-5-(3-methoxyphenyl)thiophene were used as raw materials to obtain a yellow solid product with a yield of 39%. MS (m / z): 396.52 [M+H]+. 1 H NMR (400 MHz, CDCl 3 ), δ: 7.31-7.27(m,1H),7.19-7.15(m,2H),7.12-7.11(m,1H),6.84-6.81(m,2H),6.69(s,1H ), 6.54(s,1H), 3.87(s,3H), 3.87(s,3H), 3.68(s,2H), 3.16-3.12(m,2H), 2.89-2.82(m,6H).

[0170] Embodiment 21

[0171] 6-Hydroxy-7-methoxy-2-(2-(5-(2-fluoro-3-methoxyphenyl)thiophen-2-yl)-ethyl)-1,2,3,4-tetrahydroisoquinoline (I-21)

[0172] According to the steps described in Synthesis Method 1, 6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline and 2-(2-chloroethyl)-5-(2-fluoro-3-methoxyphenyl)thiophene were used as raw materials to obtain a yellow solid product with a yield of 37%. MS (m / z): 414.51 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ), δ: 7.34-7.32(m,1H),7.19-7.15(m,2H),7.09-7.05(m,1H),6.90-6.86(m,2H),6.69(s,1H ), 6.54(s,1H), 3.94(s,3H), 3.87(s,3H), 3.69(s,2H), 3.18-3.14(m,2H), 2.91-2.83(m,6H).

[0173] Embodiment 22

[0174] 6-Hydroxy-7-methoxy-2-(2-(5-(3-ethoxycarbonylphenyl)thiophen-2-yl)-ethyl)-1,2,3,4-tetrahydroisoquinoline (I-22)

[0175] According to the steps described in Synthesis Method 1, 6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline and 2-(2-chloroethyl)-5-(3-ethoxycarbonylphenyl)thiophene were used as raw materials to obtain a yellow solid product with a yield of 37%. MS (m / z): 438.55 [M+H] +. 1 H NMR (400 MHz, CDCl 3 ), δ: 8.25-8.24(m,1H),7.94-7.92(m,1H),7.75-7.73(m,1H),7.46-7.42(m,1H),7.24-7.23(m,1H),6.87-6.86(m,1H),6.70(s,1H) ), 6.54(s,1H), 4.45-4.40(m,2H), 3.87(s,3H), 3.87(s,3H), 3.69(s,2H), 3.18-3.14(m,2H), 2.90-2.83(m,6H), 1.45-1.42(m,3H).

[0176] Embodiment 23

[0177] 2-((5-Bromo-thiophen-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (I-23)

[0178] According to the steps described in Synthesis Method 2, 1,2,3,4-tetrahydroisoquinoline and 2-formyl-5-bromo-thiophene are used as raw materials to obtain a yellow solid product with a yield of 48%. MS (m / z): 309.24 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ), δ: 7.17-7.11(m,3H),7.03-7.01(m,1H),6.93-6.92(m,1H), 6.75-6.74 (m,1H), 3.85(s,2H), 3.72(s,2H), 2.94-2.91(m,2H), 2.83-2.80(m,2H).

[0179] Embodiment 24

[0180] 6-Hydroxy-7-methoxy-2-((5-bromo-thiophen-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (I-24)

[0181] According to the steps described in Synthesis Method 2, 6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline and 2-formyl-5-bromo-thiophene are used as raw materials to obtain the target product with a yield of 50%. MS (m / z): 355.26 [M+H] + . 1HNMR (400 MHz, CDCl 3 ), δ: 7.29(s,1H),6.93-6.92(m,1H),6.75-6.73(m,1H),6.68(s,1H),6.50(s,1H),3.85(s,3H),3.82(s,2H),3.61(s,2H),2.80-2.77(m,4H).

[0182] Embodiment 25

[0183] 6-Hydroxy-7-methoxy-2-((5-(2-methoxyphenyl)thiophen-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (I-25)

[0184] According to the steps described in Synthesis Method 2, 6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline and 2-formyl-5-(2-methoxyphenyl)-thiophene are used as raw materials to obtain a yellow solid product of 6-hydroxy-7-methoxy-2-(5-(2-methoxyphenyl)thienyl)-1,2,3,4-tetrahydroisoquinoline with a yield of 54%. MS (m / z): 382.49 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ), δ: 8.66(s,1H),7.69-7.66(m,1H),7.44-7.43(m,1H),7.28-7.26(m,1H),7.13-7.11(m,1H),7.02-6.98 (m,2H), 6.56(s,1H), 6.50(s,1H), 3.88(s,3H), 3.82(s,2H), 3.68(s,3H), 3.48(s,2H), 2.73-2.64(m,4H).

[0185] Embodiment 26

[0186] 6-Hydroxy-7-methoxy-2-((5-(3-methoxyphenyl)thiophen-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (I-26)

[0187] According to the steps described in Synthesis Method 2, 6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline and 2-formyl-5-(3-methoxyphenyl)-thiophene were used as raw materials to obtain a yellow solid product with a yield of 52%. MS (m / z): 382.49 [M+H] + . 1 HNMR (400 MHz, DMSO-d 6), δ: 8.67(s,1H),7.39-7.38(m,1H),7.33-7.29(m,1H),7.20-7.18(m,1H),7.14-7.13(m,1H),7.02-7.01(m,1H), 6 .88-6.86(m,1H), 6.57(s,1H), 6.50(s,1H), 3.82(s,2H), 3.80(s,3H), 3.68(s,3H), 3.50(s,2H), 2.71-2.65(m,4H).

[0188] Embodiment 27

[0189] 6-Hydroxy-7-methoxy-2-((5-phenylthiophen-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (I-27)

[0190]

[0191] According to the steps described in Synthesis Method 2, 6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline and 2-formyl-5-phenyl-thiophene are used as raw materials to obtain a yellow solid product with a yield of 52%. MS (m / z): 352.46 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ), δ: 7.62-7.60(m,2H),7.40-7.36(m,2H),7.30-7.27(m,1H), 7.21-7.20(m,1H), 6.97-6.96(m,1H) , 6.69(s,1H), 6.51(s,1H), 5.49(s,1H), 3.91(s,2H), 3.84(s,3H), 3.67(s,2H), 2.86-2.82(m,4H).

[0192] Embodiment 28

[0193] 28.1 N-(3-Bromopropyl)thiophene-2-carboxamide

[0194] After dissolving thiophene-2-carboxylic acid (1.8 g, 10.0 mmol) in DCM (50 ml), add thionyl chloride (2.20 ml, 30.0 mmol), raise to reflux and stir for 4 h, concentrate to remove DCM, add 3-bromopropylamine hydrobromide (2.60 g, 20.0 mmol) and triethylamine (3.5 ml, 25.0 mmol) in 10 ml DCM, stir at room temperature for 1 h, LC-MS detection reaction is complete, add water and saturated sodium chloride to wash, dry over anhydrous sodium sulfate, concentrate and chromatograph on a sand column to obtain 1.50 g of colorless oil, yield 60.5%. MS (m / z): 249.14 [M+H] +

[0195] 28.2 2-(3-(Thiophene-2-carboxamido)-propyl)-1,2,3,4-tetrahydroisoquinoline (I-28)

[0196] According to the steps described in Synthesis Method 1, 1,2,3,4-tetrahydroisoquinoline and N-(3-bromopropyl)thiophene-2-carboxamide were used as raw materials to obtain a brown solid product of 2-(N-propyl 2-carboxamidethiophene)-1,2,3,4-tetrahydroisoquinoline with a yield of 48%. MS (m / z): 301.42 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ), δ: 8.60(s,1H), 7.27-7.26(m,1H), 7.22-7.20(m,1H), 7.17-7.14(m,2H), 7.06-7.04(m,1H), 6.90-6.89(m,1H), 6.68-6 .66(m,1H), 3.73(s,2H), 3.64-3.60(m,2H), 2.99-2.96(m,2H), 2.86-2.83(m,2H), 2.81-2.78(m,2H), 1.91-1.88(m,2H).

[0197] Embodiment 29

[0198] 6-Hydroxy-7-methoxy-2-(N-propyl 2-carboxamidothiophene)-1,2,3,4-tetrahydroisoquinoline (I-29)

[0199] According to the steps described in Synthesis Method 1, 6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline and N-(3-bromopropyl)thiophene-2-carboxamide were used as raw materials to obtain the target product with a yield of 51%. MS (m / z): 347.44 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6), δ: 8.65(s,1H), 8.56-8.54(m,1H), 7.72-7.71(m,1H), 7.66-7.65(m,1H), 7.10-7.08(m,1H), 6.58(s,1H), 6.4 9(s,1H), 3.70(s,3H), 3.44(s,2H), 3.29-3.27(m,2H), 2.64-2.60(m,4H), 2.48-2.47(m,2H), 1.77-1.74(m,2H).

[0200] Embodiment 30

[0201] 30.1 2-((3-Chloropropyl)mercapto)thiophene

[0202] After dissolving 2-mercaptothiophene (0.35 g, 3.0 mmol) and 1-bromo-3-chloropropane in DMF (20 ml), potassium carbonate (0.83 g, 6.0 mmol) was added, and the temperature was raised to 75°C and stirred for 18 h. LC-MS detected that the reaction was complete. EA and water were added for extraction, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated by sand column chromatography to obtain 0.42 g of a yellow oil with a yield of 73.7%.

[0203] 30.2 2-(3-(Thiophene-2-mercapto)propyl)-1,2,3,4-tetrahydroisoquinoline (I-30)

[0204] According to the steps described in Synthesis Method 1, 1,2,3,4-tetrahydroisoquinoline and 2-((3-chloropropyl)mercapto)thiophene were used as raw materials to obtain the target product with a yield of 59%. MS (m / z): 290.45 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ), δ: 7.37-7.35(m,1H),7.16-7.10(m,4H),7.04-6.99(m,2H), 3.62(s,2H), 2.93-2.89(m,4H), 2.74-2.71(m,2H), 2.65-2.62(m,2H), 1.96-1.89(m,2H).

[0205] Embodiment 31

[0206] 6-Hydroxy-7-methoxy-2-(3-(thiophene-2-thio)propyl)-1,2,3,4-tetrahydroisoquinoline (I-31)

[0207] According to the steps described in Synthesis Method 1, 6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline and 2-((3-chloropropyl)mercapto)thiophene were used as raw materials to obtain the target product with a yield of 46%. MS (m / z): 336.48 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ), δ: 7.36-7.35(m,1H),7.15-7.14(m,1H),7.01-6.98(m,1H), 6.66(s,1H), 6.50(s,1H), 5.53(s,1H), 3.86(s,3 H), 3.54(s,2H), 2.92-2.88(m,2H), 2.80-2.77(m,2H), 2.70-2.67(m,2H), 2.63-2.59(m,2H), 1.95-1.87(m,2H).

[0208] Activity test example:

[0209] The present invention relates to the antagonistic activity of compounds on dopamine receptors, especially dopamine receptor 2 (D2), which is mainly evaluated by detecting calcium flow fluorescence signal (RFU) by real-time fluorescence detection and analysis system (FLIPR) at the cell level. All detections are carried out on the FLIPR platform, wherein the target model of dopamine receptor D2 is a HEK293 cell model with stably transfected D2 receptors, and the selected probe molecule is dopamine. The probe molecule dopamine and all compounds are dissolved in DMSO.

[0210] Activity Test Example 1: Using the HEK293 cell model stably transfected with D2 receptor, the antagonistic effect of some compounds of the present invention on dopamine receptor D2 subtype was preliminarily evaluated in vitro.

[0211] Experimental plan: First, HEK293-D2 cells in the logarithmic growth phase were cultured at 80×10 3The cells were inoculated at a density of 100 μL / well in a 96-well plate coated with poly-D-lysine (PDL), with the inoculation volume of each well being 100 μL (culture medium: composition: DMEM + 10% fetal bovine serum (FBS) (v / v)). The inoculated cell plate was cultured in a cell culture incubator for 20 to 24 hours until the cell growth confluence reached about 95%, and then an activity assay was performed. The culture medium was removed from the cultured cells and 100 μL fluorescent dye solution (Calcium-6) was added to each well and incubated at 37°C for 1 hour; the dye solution was removed and 100 μL Amaranth (0.5 mg / mL) was added to each well and incubated at room temperature for 5 minutes; each compound was added to a 96-well plate inoculated with HEK293-D2 cells, and the concentrations of each compound were 100 μM, 33.33 μM, 11.11 μM, 3.70 μM, 1.23 μM, 0.41 μM, 0.14 μM, and 0.01 μM in drug plate A, with 3 replicates for each concentration; 20 nM (EC 100 ) was added to plate B, and the FLIPR instrument was used to automatically add samples to drug plates A and B, 50 μL per well, and calcium flow fluorescence signal (RFU) was detected at wavelengths of 520 nm and 488 nm. The test results are shown in Figure 1 As shown in Figure 2, compound I-8 can antagonize the fluorescence signal of dopamine in a dose-dependent manner, and the curve is a single-phase "S" type. Its IC 50 The value was 0.31±0.12 μM, indicating that compound I-8 has antagonistic activity against D2.

[0212] Experimental results: Through activity detection, it was found that the test compound of the present invention can antagonize the calcium flow fluorescence response signal (RFU) of dopamine in a dose-dependent manner and the dose curve is "S" shaped (see Figure 1 ), indicating that the compounds tested in the present invention have a dose-dependent antagonistic effect on D2 receptors. The corresponding IC 50 The values ​​are shown in Table 1. According to the structure and IC 50 The results showed that this type of compound has the following structure-activity rule at D2 receptor: when the thiophene group is combined with tetrahydroisoquinoline with -CH 2 CH 2-connected, the thienyl group was substituted at the ortho or meta position, which had no significant effect on the activity of the compound, such as I-1 (3.12±0.79μM) and I-9 (3.31±1.61μM); when the tetrahydroisoquinoline group was substituted by halogen or nitro, the activity generally decreased, such as I-2, I-3, I-4, I-10, I-11, I-12, and when it was substituted by alkoxy, the activity of the compound remained basically unchanged, such as I-6, I-7, I-14, I-15, but when the tetrahydroisoquinoline was substituted by 6-hydroxy-7-methoxy, the activity was significantly improved, I-8 (0.31±0.12), which was equivalent to the positive control molecule Haloperidol. Subsequently, the effect of modification on the thienyl group on the activity was investigated, and it was found that when phenyl or o-methoxyphenyl was coupled to thiophene, the activity of the obtained compounds I-18 and I-19 could remain equivalent to I-8, and other substitutions led to varying degrees of decrease in activity. When the length of the connecting chain between thiophene and tetrahydroisoquinoline groups is shortened to -CH 2 When an amide or thioether bond is introduced between the thiophene and tetrahydroisoquinoline groups, the activity of the resulting compounds I-28-I-31 also decreases.

[0213] Table 1. Antagonistic activity of the compounds of the present invention on D2 receptors (IC 50 ).

[0214]

[0215]

[0216]

[0217]

[0218] The embodiments described in the present invention may be combined, and such combinations are contemplated and still fall within the scope of protection of the present invention.

[0219] The above description is only for the best embodiment of the present invention, but it should not be understood as limiting the claims. The present invention is not limited to the above embodiments, and its specific structure is allowed to be changed. All changes made within the scope of protection of the independent claims of the present invention are within the scope of protection of the present invention.

Claims

1. A 1,2,3,4-tetrahydroisoquinoline-thiophene derivative, characterized in that: The derivatives are: 2-(2-(Thien-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-1) 7-Chloro-2-(2-(thiophen-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-3) 7-Methyl-2-(2-(thiophen-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-5) 6-Methoxy-2-(2-(thiophen-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-6) 6-Hydroxy-7-methoxy-2-(2-(thiophen-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-8) 2-(2-(Thien-3-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-9) 7-Bromo-2-(2-(thiophen-3-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-10) 7-Chloro-2-(2-(thiophen-3-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-11) 7-Nitro-2-(2-(thiophen-3-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-12) 7-Methyl-2-(2-(thiophen-3-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-13) 6-Methoxy-2-(2-(thien-3-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-14) 6,7-Dimethoxy-2-(2-(thiophen-3-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-15) 6-Hydroxy-7-methoxy-2-(2-(5-nitro-thiophen-2-yl)-ethyl)-1,2,3,4-tetrahydroisoquinoline (I-17) 6-Hydroxy-7-methoxy-2-(2-(5-(2-methoxyphenyl)thiophen-2-yl)-ethyl)-1,2,3,4-tetrahydroisoquinoline (I-18) 6-Hydroxy-7-methoxy-2-(2-(5-phenylthiophen-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-19) 6-Hydroxy-7-methoxy-2-(2-(5-(3-methoxyphenyl)thiophen-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline (I-20) 6-Hydroxy-7-methoxy-2-(2-(5-(2-fluoro-3-methoxyphenyl)thiophen-2-yl)-ethyl)-1,2,3,4-tetrahydroisoquinoline (I-21) 6-Hydroxy-7-methoxy-2-((5-bromo-thiophen-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (I-24) 2-(3-(Thiophene-2-mercapto)propyl)-1,2,3,4-tetrahydroisoquinoline (I-30) 6-Hydroxy-7-methoxy-2-(3-(thiophene-2-mercapto)propyl)-1,2,3,4-tetrahydroisoquinoline (I-31).

2. A compound of 1,2,3,4-tetrahydroisoquinoline-thiophene derivatives according to claim 1 or a pharmaceutically acceptable acid salt thereof, wherein the acid is selected from HCl, HBr, citric acid, fumaric acid, succinic acid, sulfuric acid, formic acid, and acetic acid.

3. A pharmaceutical composition, characterized in that include: One or two compounds according to claim 2 or pharmaceutically acceptable acid salts thereof, and pharmaceutically acceptable excipients, carriers, diluents or other active ingredients.

4. Use of the 1,2,3,4-tetrahydroisoquinoline-thiophene derivative according to claim 1 in the preparation of a drug for treating or preventing diseases associated with D2 receptor antagonism.

5. The use according to claim 4, characterized in that: Such disorders include substance abuse, restless legs syndrome, schizophrenia, Parkinson's disease and depression.

Images