Thiophene derivative, preparation method and application thereof, and Mu opioid receptor agonist

Abstract

The invention relates to the technical field of drug synthesis, in particular to a thiophene derivative, a preparation method and application thereof and a Mu opioid receptor agonist. The thiophene derivative is selected from compounds shown in the following structural formula, wherein R1 is phenyl or C1-C5 unsubstituted alkyl substituted phenyl; and R2 is any one of substituted phenyl, 4-to 7-membered oxacycloalkyl, benzo 4-to 7-membered oxacycloalkyl and naphthyl. The thiophene derivative can be used as an MOR agonist, can effectively inhibit the concentration change of cAMP in cells so as to relieve pain, and can be used as an analgesic drug.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, in particular to thiophene derivatives, preparation methods and applications thereof, and Mu opioid receptor agonists. Background Art

[0002] As the clinical first-line drug, opioids hold an irreplaceable position in the management of acute pain, chronic non-cancer pain, and pain associated with malignant tumors. However, with the expansion of their clinical application, the abuse of these drugs has become a global public health challenge. For example, fentanyl, a potent narcotic analgesic, is a Mu opioid receptor (MOR) agonist that induces analgesia and euphoria. The variability in potency among fentanyl analogs also poses a significant risk to public health, particularly for some derivatives such as carfentanil, which is estimated to be approximately 10,000 times more potent than morphine. Consequently, many researchers are deeply exploring the molecular mechanisms of opioid receptor drugs and are committed to finding more novel alternative analgesics with lower addictive potential and fewer side effects, which remain irreplaceable in controlling severe pain.

[0003] In view of this, the present invention is proposed. Summary of the Invention

[0004] The present invention aims to provide thiophene derivatives, preparation methods and uses thereof, and Mu opioid receptor agonists. The present invention provides a novel thiophene derivative that can act as a MOR agonist, effectively inhibiting changes in intracellular cAMP concentration, thereby helping to relieve pain and serving as an analgesic.

[0005] The present invention is achieved in that:

[0006] In the first aspect, the present invention provides a thiophene derivative selected from the compounds represented by the following structural formula Wherein, R1 is phenyl or C1-C5 unsubstituted alkyl substituted phenyl; R2 is any one of substituted phenyl, 4-membered to 7-membered oxygen-containing heterocycloalkyl, benzo 4-membered to 7-membered oxygen-containing heterocycloalkyl and naphthyl.

[0007] In a second aspect, the present invention provides a method for preparing the thiophene derivatives described in the aforementioned embodiment, comprising: synthesizing according to the following synthetic route:

[0008]

[0009] R is hydrogen or C1-C5 unsubstituted alkyl.

[0010] In a third aspect, the present invention provides a Mu opioid receptor agonist, which includes the thiophene derivatives described in the aforementioned embodiments.

[0011] In a fourth aspect, the present invention provides a use of the thiophene derivatives described in the aforementioned embodiment in the preparation of analgesics.

[0012] The present invention has the following beneficial effects: The embodiment of the present invention provides a new thiophene derivative, which can have a good inhibitory effect on the intracellular cAMP concentration, can be used to relieve pain, and then used as an analgesic. DETAILED DESCRIPTION

[0013] To make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are described clearly and completely below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer are used. Where the manufacturer of the reagents or instruments is not specified, all are conventional products that can be purchased commercially.

[0014] In a first aspect, embodiments of the present invention provide thiophene derivatives selected from compounds represented by the following structural formulas:

[0015] Wherein, R1 is phenyl or C1-C5 unsubstituted alkyl substituted phenyl; R2 is any one of substituted phenyl, 4-membered to 7-membered oxygen-containing heterocycloalkyl, benzo 4-membered to 7-membered oxygen-containing heterocycloalkyl and naphthyl.

[0016] That is, the structural formula of the thiophene derivative is as follows: That is, R is hydrogen or C1-C5 unsubstituted alkyl; R2 is any one of substituted phenyl, 4-membered to 7-membered oxygen-containing heterocycloalkyl, benzo 4-membered to 7-membered oxygen-containing heterocycloalkyl and naphthyl.

[0017] Preferably, R1 is phenyl or C1-C3 unsubstituted alkyl substituted phenyl, that is, R is hydrogen or C1-C3 unsubstituted alkyl. For example, C1-C3 unsubstituted alkyl includes but is not limited to methyl, ethyl, n-propyl, isopropyl and n-butyl unsubstituted alkyl.

[0018] When R1 is a C1-C5 unsubstituted alkyl substituted phenyl group, the C1-C5 unsubstituted alkyl group is located at the meta position of the phenyl group.

[0019] The substituent of the substituted phenyl group in R2 is selected from any one of halogen, hydroxy, C1-C3 alkoxy and C1-C5 unsubstituted alkyl.

[0020] Among them, halogen is chlorine, bromine and iodine.

[0021] The C1-C3 alkoxy group includes methoxy, ethoxy, propoxy and the like.

[0022] The C1-C5 unsubstituted alkyl group includes unsubstituted alkyl groups such as methyl, ethyl, n-propyl, isopropyl and n-butyl.

[0023] Furthermore, R1 is phenyl, that is, when R is hydrogen, R2 is any one of substituted phenyl, 4-membered to 7-membered oxygen-containing heterocycloalkyl, benzo 4-membered to 7-membered oxygen-containing heterocycloalkyl and naphthyl, and the substituent of the substituted phenyl is any one of hydroxyl, fluorine and C1-C3 alkoxy.

[0024] More preferably, R1 is phenyl, that is, when R is hydrogen, R2 is a substituted phenyl, and the substituent is halogen, most preferably fluorine. In other words, the number of fluorine atoms in the fluorine-substituted phenyl is 1-3, preferably 2-3, and most preferably 2.

[0025] When there is one fluorine atom, it is located at the para position, and when there are three fluorine atoms, it is a bis-trifluoro atom.

[0026] When R1 is phenyl, that is, R is hydrogen, and R2 is a C1-C3 alkoxy group substituted with phenyl, the number of the C1-C3 alkoxy groups is 2-3, and most preferably 2. The C1-C3 alkoxy group is located at the meta position.

[0027] R1 is a C1-C5 unsubstituted alkyl substituted phenyl, that is, when R is a C1-C5 unsubstituted alkyl, R2 is a monofluoro substituted phenyl.

[0028] The 4-membered to 7-membered oxygen-containing heterocycloalkyl group is a 7-membered oxygen-containing heterocycloalkyl group, including but not limited to oxetane, oxolane, oxhexane and oxepane.

[0029] The benzo 4-membered to 7-membered oxygen-containing heterocycloalkyl group is a benzo 4-membered to 7-membered oxygen-containing heterocycloalkyl group.

[0030] Furthermore, the thiophene derivative is selected from any one of the following compounds formed by R1 and R2:

[0031]

[0032]

[0033] It should be noted that the numbers described above are the selections of R1 and R2 of the corresponding compounds.

[0034] Furthermore, the preparation method of thiophene derivatives comprises:

[0035] The synthesis was carried out according to the following synthesis route:

[0036]

[0037] R is hydrogen or C1-C5 unsubstituted alkyl.

[0038] Specifically, the operation of step a includes: mixing the M1 compound with a benzyl chloride reagent to perform a benzylation reaction;

[0039] The operation of step b comprises: mixing the M2 compound with a strong base to carry out an ester hydrolysis reaction;

[0040] The operation of step c comprises: performing an amide condensation reaction on the M3 compound and the corresponding amino group.

[0041] The overall reaction process is as follows: methyl 3-amino-5-phenylthiophene-2-carboxylate (M1) reacts with a benzyl chloride reagent (M2) in the presence of N,N-dimethylformamide (DMF), potassium iodide (KI), and triethylamine to produce the corresponding benzyl chloride. M2 is hydrolyzed in the presence of a strong base (such as sodium methoxide) to yield the corresponding carboxylic acid. Compound M3 is then mixed with O-benzotriazole-N,N,N,N-tetramethyluronium tetrafluoroborate (TBTU) and N,N-diisopropylethylamine (DIPEA) to undergo an amide condensation reaction with the corresponding amine to synthesize the corresponding amide M4.

[0042] After each step of the reaction, post-treatment is required to obtain a compound with higher purity. The post-treatment methods include pH adjustment, rotary evaporation, drying, and extraction, etc., which will not be described in detail in the embodiments of the present invention.

[0043] The thiophene derivatives provided in the embodiments of the present invention have a good inhibitory effect on intracellular cAMP concentration. Therefore, the thiophene derivatives can be used to prepare MOR agonists. Therefore, in a third aspect, the present invention provides a Mu opioid receptor agonist, which includes the thiophene derivatives described in the above embodiments.

[0044] The thiophene compounds provided in the embodiments of the present invention have a good pain relief effect, and therefore, they can be used in the preparation of analgesic drugs.

[0045] The features and performance of the present invention are further described in detail below with reference to the embodiments.

[0046] Example 1

[0047] An embodiment of the present invention provides a thiophene derivative (denoted as A1), the structural formula of which is shown below:

[0048] Among them, R1 is R2 is

[0049] The present invention provides a method for preparing a thiophene derivative, comprising: synthesizing according to the following synthesis path:

[0050]

[0051] R2 is R is hydrogen.

[0052] The specific steps are as follows:

[0053] Synthesis of M2 compound:

[0054] 6 g of methyl 3-amino-5-phenylthiophene-2-carboxylate (M1) (1 equivalent) and benzyl chloride (approximately 82.3 mmol, 3.2 equivalents) were dissolved in 15 ml of DMF. 3.93 g of potassium iodide (0.92 equivalents) and 4.7 mL of triethylamine (1.3 equivalents) were added, and the mixture was stirred at 90°C. The reaction progress was monitored in real time by thin-layer chromatography (TLC), using a 3:1 v / v mixture of petroleum ether and ethyl acetate as the developing solvent. After approximately 6 hours of reaction time, complete conversion was confirmed. Extraction was performed using a two-phase system of water and ethyl acetate. The organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate, and the organic solvent was removed by rotary evaporation. The crude product was transferred to a 12 g silica gel column using a dry loading technique and purified using a fully automated flash chromatography system using a petroleum ether-ethyl acetate (4:1, v / v) elution system. After the target product was confirmed by TLC spot plate, the product-containing fractions were collected and distilled under reduced pressure to obtain a light yellow solid intermediate with an isolation yield of about 80%. The obtained product was sealed and stored at -20°C for future use.

[0055] Synthesis of M3 compound:

[0056] 6 g of methyl 3-(benzylamino)-5-phenylthiophene-2-carboxylate (M2) (1 equivalent) and 2.94 g of sodium methoxide (2.93 equivalents) were dissolved in 18 mL of a tetrahydrofuran / methanol / water mixture (3:2:1) and stirred at 90°C. The reaction was monitored by TLC using a 1:1 dichloromethane:methanol ratio as the developing solvent. The reaction was complete after approximately 12 hours. After completion, the reaction was quenched by adding a large amount of water. A solid precipitated and the mixture was allowed to stand overnight. Vacuum filtration was performed to obtain the filtrate. A small amount of NaOH solution was added to adjust the pH. Then, dilute HCl solution was continuously added dropwise to the filtrate to acidify the solution, stirring the mixture dropwise until a yellow-green solid precipitated. Vacuum filtration afforded the yellow-green crystalline intermediate in an isolated yield of 87% (mass fraction). The product was sealed and stored at -20°C until further use.

[0057] Synthesis of M4 compound:

[0058] 800 mg of 3-(Benzylamino)-5-phenylthiophene-2-carboxylic acid (M3) (1 equivalent) was dissolved in 3 ml of DMF. 1.66 g of TBTU (2 equivalents) and 1.3 mL of DIPEA (3 equivalents) were added, followed by benzylamine (3.1 mmol, 1.2 equivalents) and stirring at room temperature. The reaction progress was monitored by TLC using a petroleum ether-ethyl acetate (3:1, v / v) solvent mixture. After confirming complete conversion after approximately 6 hours of reaction, the product was extracted using a two-phase system of water and ethyl acetate. The organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate, and then the organic solvent was removed by rotary evaporation. The reaction mixture was then transferred to a 4 g silica gel column by dry loading and purified using a petroleum ether-ethyl acetate (93:7, v / v) elution system on an automated flash chromatography system. The reaction product spot was detected by TLC control, and the collected product was then dried by rotary evaporation to obtain a yellow-green crystalline intermediate with an isolated yield of 15%. The product was sealed and stored in a low-temperature storage environment at -20°C.

[0059] Example 2-35

[0060] Examples 2-35 respectively provide a thiophene derivative (marked as A2-A35 in sequence) and a preparation method thereof. The preparation method refers to the preparation method of the thiophene derivative provided in Example 1, with the only difference being that the raw materials are different and some reaction conditions are different. However, the reaction conditions are also within the scope specified in the embodiments of the present invention and will not be described in detail here.

[0061] The structural formulas of the thiophene derivatives (A1-A35) prepared in Examples 1-35 are as follows: Among them, R1 and R2 are selected as follows:

[0062]

[0063]

[0064] Characterization

[0065] The thiophene derivatives of Examples 1-35, i.e. A1-A35, were characterized, and the characterization data are as follows:

[0066] Example 1 - Compound A1

[0067] Purity>95%. Yellow solid, 47 mg, yield 17%. 1H NMR(400MHz,DMSO-d6)δ8.21(t,J=6.0Hz,1H),7.84(t,J=6.3Hz,1H),7.68-7.61(m,2H),7 .46-7.24(m,9H),7.14(t,J=8.9Hz,2H),4.53(d,J=6.4Hz,2H),4.36(d,J=6.0Hz,2H).13C NMR(151MHz,DMSO-d6)δ165.03,155.42,144.76,140.59,136.92,133.61,129.75,129.69,129.27, 128.99,127.70,127.45,125.92,115.45,115.31,114.69,100.73,48.53,42.01.HRMS(ESI):calcd forC 25 H 21 FN2OS:416.1359; found:417.1431.

[0068] Example 2 - Compound A2

[0069] Purity>95%. Yellow solid, 94 mg, yield 12%. 1 H NMR (400MHz, DMSO-d6) δ8.23(t,J=6.1Hz,1H),7.83(t,J=6.5Hz,1H),7.65(dd,J=7. 2,1.7Hz,2H),7.50-7.21(m,11H),4.53(d,J=6.3Hz,2H),4.36(d,J=6.0Hz,2H).13C NMR(151MHz,DMSO-d6)δ165.06,155.46,144.82,140.57,139.79,133.59,131.66,129.69,129.62, 129.29,128.99,128.64,127.70,127.45,125.93,114.69,100.63,48.51,42.09.HRMS(ESI):calcd for C 25 H 21 ClN2OS:432.1063; found:433.1135.

[0070] Example 3 - Compound A3

[0071] Purity>95%. Yellow solid, 62 mg, yield 17%. 1H NMR (400MHz, DMSO-d6) δ8.05(t,J=5.3Hz,1H),7.83(t,J=6.5Hz,1H),7.62(dd,J=7.3,1.7Hz,2 H),7.46-7.25(m,9H),7.07(t,J=7.9Hz,2H),4.52(d,J=6.4Hz,2H),4.44(d,J=5.2Hz,2H).13C NMR(151MHz,DMSO-d6)δ165.06,155.51,144.89,143.66,140.59,133.57,130.93,130.46,129.98,129.69, 129.31,128.99,127.68,127.44,126.87,125.94,122.05,114.72,100.54,48.49,42.20.HRMS(ESI):calcd for C 25 H 21 BrN2OS:476.0558; found:477.0632.

[0072] Example 4 - Compound A4

[0073] Purity>95%. Yellow solid, 133 mg, yield 28%. 1 H NMR(400MHz,DMSO-d6)δ8.19(t,J=6.0Hz,1H),7.83(t,J=6.3Hz,1H),7.70-7.6 0(m,2H),7.47-7.15(m,11H),4.53(d,J=6.3Hz,2H),4.43(d,J=5.8Hz,2H).13C NMR(151MHz,DMSO-d6)δ165.04,155.44,144.80,140.63,140.57,137.43,133.59,130.18,129.69 ,129.29,129.00,127.70,127.45,125.93,114.69,100.63,92.72,48.51,42.26.HRMS(ESI):calcd for C 25 H 21 IN2OS:524.0419; found:525.0492.

[0074] Example 5 - Compound A5

[0075] Purity>95%. Yellow solid, 37 mg, yield 11%. 1H NMR(400MHz, DMSO-d6)δ8.15(t,J=6.0Hz,1H),7.84(t,J=6.5Hz,1H),7.69-7.61(m,2 H),7.44-7.12(m,11H),4.53(d,J=6.4Hz,2H),4.33(d,J=5.9Hz,2H),2.27(s,3H).13C NMR(151MHz,DMSO-d6)δ165.01,155.32,144.73,140.55,137.63,136.15,133.56,129.68,129.28,129 .23,129.00,127.74,127.68,127.46,125.91,114.61,100.92,48.53,42.38,21.15.HRMS(ESI):calcd forC 26 H 24 N2OS:412.1609; found:413.1686.

[0076] Example 6 - Compound A6

[0077] Purity>95%. Yellow solid, 93 mg, yield 17%. 1 H NMR(400MHz, DMSO-d6)δ8.17(s,1H),7.85(t,J=6.5Hz,1H),7.64(d,J=7.3Hz,2H), 7.45-7.04(m,11H),4.53(d,J=6.4Hz,2H),4.35(d,J=6.0Hz,2H),2.29(s,3H).13C NMR(151MHz,DMSO-d6)δ164.99,155.35,144.67,140.66,140.62,137.69,133.63,129.68,129.25,128.98,128 .61,128.35,127.73,127.69,127.43,125.92,124.88,114.70,100.91,48.53,42.61,21.57.HRMS(ESI):calcd forC 26 H 24 N2OS:412.1609; found:413.1688.

[0078] Example 7 - Compound A7

[0079] Purity>95%. Yellow solid, 83 mg, yield 14%. 1H NMR(400MHz,DMSO-d6)δ8.26(t,J=6.0Hz,1H),7.82(t,J=6.4Hz,1H),7.70-7.6 3(m,2H),7.49-7.18(m,10H),4.53(d,J=6.4Hz,2H),4.35(d,J=5.9Hz,2H).13C NMR(151MHz,DMSO-d6)δ165.12,155.51,144.89,140.59,133.60,130.65,130.60,129.68,129.29,128.98,127.68,1 27.44,125.95,123.71,123.69,114.70,114.42,114.27,113.92,113.78,100.66,48.53,42.28.HRMS(ESI):calcdfor C 25 H 21 FN2OS:416.1359; found:417.1434.

[0080] Example 8 - Compound A8

[0081] Purity>95%. Yellow solid, 77 mg, yield 21%. 1 H NMR(400MHz, DMSO-d6)δ8.05(t,J=5.2Hz,1H),7.83(t,J=6.5Hz,1H),7.67-7.5 9(m,2H),7.49-7.10(m,11H),4.52(d,J=6.4Hz,2H),4.39(d,J=5.1Hz,2H).13C NMR(151MHz,DMSO-d6)δ165.07,155.50,144.89,143.39,140.59,133.57,133.40,130.62,129.69,129.31, 128.99,127.68,127.55,127.44,127.07,126.45,125.94,114.72,100.56,48.49,42.23.HRMS(ESI):calcd forC 25 H 21 ClN2OS:432.1063; found:433.1137.

[0082] Example 9 - Compound A9

[0083] Purity>95%. Yellow solid, 98 mg, yield 27%. 1H NMR (400MHz, DMSO-d6) δ8.23(t,J=5.9Hz,1H),7.85(t,J=6.4Hz,1H),7.65(d,J= 7.6Hz,2H),7.53-7.27(m,11H),4.53(d,J=6.3Hz,2H),4.35(d,J=5.9Hz,2H).13C NMR(151MHz,DMSO-d6)δ165.07,155.46,144.83,140.57,140.22,133.60,131.56,130.00,129.69, 129.29,129.00,127.70,127.45,125.93,120.11,114.69,100.63,48.52,42.16.HRMS(ESI):calcd for C 25 H 21 BrN2OS:476.0558; found:477.0630.

[0084] Example 10 - Compound A10

[0085] Purity>95%. Yellow solid, 63 mg, yield 15%. 1 H NMR (400MHz, DMSO-d6) δ8.11(t,J=5.7Hz,1H),7.85(t,J=6.4Hz,1H),7.68-7.61(m,2H),7.56(d,J=1.6Hz, 1H),7.45-7.25(m,7H),6.39(dd,J=3.2,1.9Hz,1H),6.23(d,J=3.2Hz,1H),4.53(d,J=6.4Hz,2H),4.37(d,J =5.7Hz,2H).13CNMR(151MHz,DMSO-d6)δ164.90,155.49,153.51,144.86,142.26,140.60,133.60,129.68, 129.27,128.99,127.69,127.44,125.92,114.62,110.95,107.14,100.66,48.51,36.04.HRMS(ESI):calcd for C 23 H 20 N2O2S:388.1245; found:389.1323.

[0086] Example 11 - Compound A11

[0087] Purity>95%. Yellow solid, 82 mg, yield 19%. 1H NMR (600MHz, DMSO-d6) δ9.27(s,1H),8.09(t,J=6.2Hz,1H),7.91(t,J=6.4Hz,1H),7.66(d,J=7.7Hz,2H),7. 45-7.28(m,7H),7.17(d,J=8.1Hz,2H),6.80-6.73(m,2H),4.56(d,J=6.4Hz,2H),4.32(d,J=6.0Hz,2H).13C NMR(151MHz,DMSO-d6)δ164.92,156.67,155.29,144.58,140.63,133.66,130.94,129.67,129.21, 129.15,128.99,127.70,127.44,125.91,115.46,114.68,101.09,48.57,42.20.HRMS(ESI):calcd for C25H 22 N2O2S:414.1402; found:415.1478.

[0088] Example 12 - Compound A12

[0089] Purity>95%. Yellow solid, 74 mg, yield 18%. 1 H NMR (400MHz, DMSO-d6) δ8.11(t,J=6.1Hz,1H),7.85(t,J=6.4Hz,1H),7.68-7.60(m,2H),7.46-7. 24(m,8H),6.95-6.84(m,2H),4.53(d,J=6.4Hz,2H),4.31(d,J=5.9Hz,2H),3.73(d,J=4.8Hz,6H). 13 C NMR(151MHz,DMSO-d6)δ164.97,155.33,149.13,148.25,144.64,140.64,133.64,133.23,129.67,129.23,128.98 ,127.67,127.43,125.91,120.02,114.69,112.30,112.15,101.02,56.11,55.97,48.54,42.46.HRMS(ESI):calcd for C 27 H 26 N2O3S:458.1664; found:459.1740.

[0090] Example 13 - Compound A13

[0091] Purity>95%. Yellow solid, 134 mg, yield 29%. 1 H NMR (400MHz, DMSO-d6) δ8.17-8.11(m,1H),7.84(d,J=6.6Hz,1H),7.64(d,J=8.0Hz,2H),7.52- 7.25(m,9H),6.87(d,J=7.5Hz,1H),5.98(s,2H),4.53(d,J=6.3Hz,2H),4.28(d,J=6.0Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ164.95,155.37,147.67,146.45,144.69,140.62,134.67,133.63,129.84,129.67,129.24,129.05,128.98,127.68,127 .43,126.69,125.91,125.68,120.99,120.35,114.69,113.95,109.79,108.51,108.43,101.27,100.88,48.53,48.36,42.48.HRMS(ESI):calcd for C 26 H 22 N2O3S:442.1351; found:443.1423.

[0092] Example 14 - Compound A14

[0093] Purity>95%. Yellow solid, 162 mg, yield 27%. 1 H NMR (400MHz, DMSO-d6) δ8.05(t,J=5.3Hz,1H),7.83(t,J=6.5Hz,1H),7.62(dd,J=7.3,1.7Hz,2H),7.44- 7.34(m,6H),7.25(d,J=4.4Hz,2H),7.07(t,J=7.9Hz,2H),4.52(d,J=6.4Hz,2H),4.44(d,J=5.2Hz,2H). 13C NMR(151MHz,DMSO-d6)δ164.81,160.92,155.44,144.80,140.64,133.61,129.99,129.66,129.24,128.97,127 .68,127.42,125.88,115.26,114.52,111.98,111.94,111.84,111.81,100.60,48.48,31.49.HRMS(ESI):calcd for C 25 H 20 F2N2OS:434.1264; found:435.1342.

[0094] Example 15 - Compound A15

[0095] Purity>95%. Yellow solid, 221 mg, yield 32%. 1 H NMR (600MHz, DMSO-d6) δ8.25(t,J=6.0Hz,1H),7.87(t,J=6.4Hz,1H),7.67(dd,J=8.2,1.4Hz,2H),7. 46-7.33(m,8H),7.28-7.22(m,1H),7.20-7.14(m,1H),4.55(d,J=6.4Hz,2H),4.39(d,J=6.0Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ165.10,155.53,144.93,140.57,138.60,133.57,129.68,129.30,128.98,127.68,127.44, 125.94,124.42,124.40,124.38,117.72,117.61,116.72,116.61,114.68,100.54,48.51,41.85.HRMS(ESI):calcd for C 25 H 20 F2N2OS:434.1264; found:435.1341.

[0096] Example 16 - Compound A16

[0097] Purity>95%. Yellow solid, 49 mg, yield 13%. 1H NMR(600MHz, DMSO-d6)δ8.23(t,J=5.9Hz,1H),7.86(t,J=6.5Hz,1H),7.71-7.64(m,2H),7.46-7.32(m,6H),7.24 (ddd,J=14.2,6.3,3.7Hz,2H),7.15(tdd,J=12.6,6.9,3.5Hz,2H),4.55(d,J=6.4Hz,2H),4.45(d,J=5.8Hz,2H). 13 CNMR(151MHz,DMSO-d6)δ165.20,157.87,155.62,145.09,140.57,133.56,129.68,129.33,128.97,127.67,127.43,125.96,117.16 ,117.11,117.00,116.94,116.07,116.04,115.91,115.47,115.41,115.31,115.25,114.67,100.39,48.49,36.36.HRMS(ESI):calcd for C 25 H 20 F2N2OS:434.1264; found:435.1339.

[0098] Example 17 - Compound A17

[0099] Purity>95%. Yellow solid, 48 mg, yield 19%. 1 H NMR (400MHz, DMSO-d6) δ8.26(t,J=6.0Hz,1H),7.83(t,J=6.6Hz,1H),7.66(d,J=7.4Hz,2H),7.47-7.32( m, 6H), 7.25 (t, J = 6.8Hz, 1H), 7.06 (dd, J = 41.0, 8.5Hz, 3H), 4.53 (d, J = 6.4Hz, 2H), 4.39 (d, J = 5.9Hz, 2H). 13 C NMR(151MHz,DMSO-d6)δ165.15,163.71,155.60,145.70,145.02,140.58,133.56,129.69,129.33,128.97,127.67, 127.44,125.96,114.72,110.68,110.65,110.54,110.51,102.51,102.34,100.42,48.49,42.16.HRMS(ESI):calcd for C 25 H20 F2N2OS:434.1264; found:435.1341.

[0100] Example 18 - Compound A18

[0101] Purity>95%. Yellow solid, 45 mg, yield 18%. 1 H NMR(600MHz,DMSO-d6)δ8.19(t,J=5.9Hz,1H),7.87(t,J=6.4Hz,1H),7.71-7.64(m,2H ),7.46-7.27(m,9H),7.21-7.14(m,2H),4.55(d,J=6.4Hz,2H),4.47(d,J=5.8Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ165.16,155.50,144.90,140.58,133.60,129.82,129.79,129.69,129.29,129.11,129.05,128 .99,127.69,127.44,125.94,124.75,124.73,115.53,115.39,114.66,100.62,48.51,36.36,36.33.HRMS(ESI):calcd for C 25 H 21 FN2OS:416.1359; found:417.1436.

[0102] Example 19 - Compound A19

[0103] Purity>95%. Yellow solid, 73 mg, yield 21%. 1 H NMR (600MHz, DMSO-d6) δ8.05(t,J=5.3Hz,1H),7.85(t,J=6.4Hz,1H),7.67-7.61(m,2H),7.45-7. 35(m,5H),7.26(d,J=6.5Hz,2H),7.20-7.13(m,2H),4.54(d,J=6.4Hz,2H),4.42(d,J=5.2Hz,2H). 13C NMR(151MHz,DMSO-d6)δ164.82,162.65,155.47,144.83,140.64,133.60,129.66,129.25,128.97, 127.68,127.42,125.88,114.54,101.04,100.86,100.67,100.46,48.46,31.23.HRMS(ESI):calcd for C 25 H 19 F3N2OS:452.1170; found:453.1248.

[0104] Example 20 - Compound A20

[0105] Purity>95%. Yellow solid, 47 mg, yield 17%. 1 H NMR (600MHz, DMSO-d6) δ8.19(t,J=5.9Hz,1H),7.86(t,J=6.6Hz,1H),7.67(d,J=7.6Hz,2H ),7.46-7.20(m,9H),7.07(t,J=8.8Hz,1H),4.55(d,J=6.3Hz,2H),4.43(d,J=5.6Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ165.14,155.53,144.94,140.57,133.59,131.19,131.15,129.68,129.29,128.98,127 .69,127.44,125.94,123.66,114.65,111.78,111.66,103.98,103.81,100.50,48.50,36.00.HRMS(ESI):calcd for C 25 H 20 F2N2OS:434.1264; found:435.1340.

[0106] Example 21 - Compound A21

[0107] Purity>95%. Yellow solid, 73 mg, yield 19%. 1H NMR (400MHz, DMSO-d6) δ8.25(t,J=6.0Hz,1H),7.85(t,J=6.4Hz,1H),7.66(dd,J=7.6,1.8H z,2H),7.45-7.25(m,7H),7.15-7.03(m,2H),4.53(d,J=6.4Hz,2H),4.40(d,J=6.0Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ165.16,155.63,145.08,140.56,138.33,133.55,129.68,129.33,128.97,127.6 7,127.44,125.95,114.68,112.11,112.08,112.00,111.97,100.35,48.49,41.86.HRMS(ESI):calcdfor C 25 H 19 F3N2OS:452.1170; found:453.1249.

[0108] Example 22 - Compound A22

[0109] Purity>95%. Yellow solid, 75 mg, yield 20%. 1 H NMR(600MHz,DMSO-d6)δ8.32(t,J=6.1Hz,1H),7.89(dt,J=9.1,3.4Hz,4H),7.81(s,1H),7.54-7 .44(m,5H),7.40-7.30(m,6H),7.27-7.19(m,1H),4.60(d,J=6.0Hz,2H),4.55(d,J=6.4Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ165.12,155.44,144.76,140.61,138.37,133.64,133.41,132.59,129.69,129.26,128.99,128.31, 128.03,128.02,127.70,127.43,126.62,126.54,126.04,125.93,125.84,114.72,100.87,48.54,42.91.HRMS(ESI):calcd for C 29 H 24 N2OS:448.1609; found:449.1684.

[0110] Example 23 - Compound A23

[0111] Purity>95%. Yellow solid, 83 mg, yield 21%. 1H NMR (400MHz, DMSO-d6) δ8.20(d,J=7.0Hz,1H),7.79(d,J=7.8Hz,1H),7.65(d,J=7.5H z,2H),7.45-7.06(m,10H),4.48(d,J=6.3Hz,2H),4.36(d,J=6.0Hz,2H),2.29(s,3H). 13 C NMR(151MHz,DMSO-d6)δ165.04,155.46,144.77,140.45,138.08,133.62,129.74,129.68,129.26,128.90,1 28.35,128.14,125.93,124.80,115.45,115.31,114.67,100.67,48.58,42.01,21.55.HRMS(ESI):calcdfor C 26 H 23 FN2OS:430.1515; found:431.1591.

[0112] Example 24 - Compound A24

[0113] Purity>95%. Yellow solid, 82 mg, yield 21%. 1 H NMR (400MHz, DMSO-d6) δ8.23(t,J=5.7Hz,1H),7.79(t,J=6.4Hz,1H),7.65(d,J=7.6H z,2H),7.48-7.06(m,10H),4.48(d,J=6.3Hz,2H),4.36(d,J=6.0Hz,2H),2.28(s,3H). 13 C NMR(151MHz,DMSO-d6)δ165.09,155.50,144.84,140.43,139.79,138.08,133.62,131.67,129.68,129.61,129 .28,128.90,128.64,128.35,128.15,125.94,124.80,114.66,100.59,48.59,42.10,21.55.HRMS(ESI):calcd for C 26 H 23 ClN2OS:446.1220; found:447.1294.

[0114] Example 25 - Compound A25

[0115] Purity>95%. Yellow solid, 72 mg, yield 16%. 1 H NMR (400MHz, DMSO-d6) δ8.25 (s, 1H), 7.80 (s, 1H), 7.66 (d, J = 7.4Hz, 2H), 7. 50-7.07(m,10H),4.48(d,J=6.3Hz,2H),4.37(d,J=5.7Hz,2H),2.29(s,3H). 13 C NMR (151MHz, DMSO-d6) δ165.07,155.54,144.90,143.66,140.45,138.07,133.59,130.92,130.45,129.98,129.69,129. 31,128.90,128.34,128.13,126.86,125.96,124.78,122.05,114.69,100.46,48.54,42.19,21.57.HRMS(ESI):calcdfor C 26 H 23 BrN2OS:490.0714; found:491.0788.

[0116] Example 26 - Compound A26

[0117] Purity>95%. Yellow solid, 69 mg, yield 16%. 1 H NMR(400MHz, DMSO-d6)δ8.24(t,J=6.0Hz,1H),7.80(t,J=6.4Hz,1H),7.69-7.62(m, 2H),7.48-7.05(m,10H),4.49(d,J=6.3Hz,2H),4.40(d,J=6.0Hz,2H),2.28(s,3H). 13 C NMR(151MHz,DMSO-d6)δ165.11,155.53,144.88,140.45,138.08,133.60,130.65,130.59,129.69,129.29,128.89,128.33,128 .13,125.95,124.78,123.70,123.68,114.69,114.39,114.25,113.91,113.77,100.56,48.56,42.26,21.54.HRMS(ESI):calcd for C 26 H 23FN2OS:430.1515; found:431.1591.

[0118] Example 27 - Compound A27

[0119] Purity>95%. Yellow solid, 152 mg, yield 26%. 1 H NMR(400MHz, DMSO-d6)δ8.18(t,J=5.8Hz,1H),7.79(t,J=6.3Hz,1H),7.68-7.62(m, 2H),7.47-7.06(m,10H),4.48(d,J=6.3Hz,2H),4.43(d,J=5.8Hz,2H),2.29(s,3H). 13 C NMR(151MHz,DMSO-d6)δ165.16,155.53,144.90,140.44,138.08,133.61,129.80,129.77,129.69,129.29,129.10,129.05,128.89 ,128.35,128.14,125.95,124.80,124.74,124.71,115.52,115.38,114.64,100.54,48.56,36.35,36.32,21.55.HRMS(ESI):calcd for C 26 H 23 FN2OS:430.1515; found:431.1593.

[0120] Example 28 - Compound A28

[0121] Purity>95%. Yellow solid, 47 mg, yield 17%. 1 H NMR (400MHz, DMSO-d6) δ8.25(d,J=6.3Hz,1H),7.69(t,J=8.0Hz,2H),7.49-7.10(m,11H),4.51(d,J=6.1Hz,2H),4.37(d,J=5.8Hz,2H),2.34(s,3H). 13C NMR(151MHz,DMSO-d6)δ165.14,155.60,144.91,139.77,138.10,136.36,133.61,131.66,130.70,129.68,129 .60,129.30,128.64,127.75,127.54,126.41,125.97,114.69,100.51,46.90,42.06,19.10.HRMS(ESI):calcd for C 26 H 23 ClN2OS:446.1220; found:447.1293.

[0122] Example 29 - Compound A29

[0123] Purity>95%. Yellow solid, 114 mg, yield 21%. 1 H NMR (400MHz, DMSO-d6) δ8.26(s,1H),7.74-7.63(m,2H),7.52-7.10(m,11H),5.76(s,1H),4.51(d,J=6.0Hz,2H),4.37(d,J=6.1Hz,2H),2.34(s,3H). 13 C NMR(151MHz,DMSO-d6)δ160.01,153.96,137.12,136.15,132.51,130.92,130 .84,130.74,130.70,130.44,129.97,129.85,129.67,129.31,127.73,127.6 1,127.53,127.08,126.85,126.73,126.47,126.40,125.98,125.71,120.34, 114.71,113.93,109.79,46.89,46.78,42.17,19.15,19.10.HRMS(ESI):calcd for C 26 H 23 BrN2OS:490.0714; found:491.0781.

[0124] Example 30 - Compound A30

[0125] Purity>95%. Yellow solid, 122 mg, yield 22%. 1H NMR (400MHz, DMSO-d6) δ8.17 (s, 1H), 7.69 (dd, J = 15.6, 6.5Hz, 3H), 7.50-7.08 (m,11H),4.58-4.43(m,2H),4.34(d,J=5.9Hz,2H),2.34(s,3H),2.26(s,3H). 13 CNMR(151MHz,DMSO-d6)δ165.07,155.49,144.74,138.14,137.68,136.36,136.09,133.66,130.69,129.66,12 9.22,127.76,127.74,127.53,126.40,125.96,114.69,100.82,46.93,42.39,21.17,19.10.HRMS(ESI):calcd forC 27 H 26 N2OS:426.1766; found:427.1843.

[0126] Example 31 - Compound A31

[0127] Purity>95%. Yellow solid, 47 mg, yield 17%. 1 H NMR(400MHz,DMSO-d6)δ8.17(d,J=6.7Hz,1H),7.70(dd,J=21.9,7.1Hz,2H),7.48-7 .02(m,11H),4.51(d,J=6.1Hz,2H),4.35(d,J=5.9Hz,2H),2.35(s,3H),2.29(s,3H). 13 C NMR(151MHz,DMSO-d6)δ165.07,155.50,144.77,140.63,138.14,137.69,136.37,133.65,130.69,129.66,129.25,128.60 ,128.34,127.77,127.73,127.53,126.39,125.96,124.86,114.70,100.79,46.93,42.59,21.56,19.10.HRMS(ESI):calcd for C 27 H 26 N2OS:426.1766; found:427.1844.

[0128] Example 32 - Compound A32

[0129] Purity>95%. Yellow solid, 43 mg, yield 15%. 1 H NMR (400MHz, DMSO-d6) δ8.25 (s, 1H), 7.73-7.65 (m, 2H), 7.50-7.03 (m, 11H), 4.51 (d, J = 6.1Hz, 2H), 4.39 (d, J = 5.9Hz, 2H), 2.34 (s, 3H). 13 C NMR (151MHz, DMSO-d6) δ165.18,155.64,144.97,138.11,136.35,133.61,130.69,130.65,130.60,129.68,129.31,127.74,127. 53,126.39,125.98,123.69,123.67,114.71,114.39,114.24,113.91,113.78,100.50,46.90,42.24,19.09.HRMS(ESI):calcdfor C 26 H 23 FN2OS:430.1515; found:431.1591.

[0130] Example 33 - Compound A33

[0131] Purity>95%. Yellow solid, 45 mg, yield 16%. 1 H NMR (400MHz, DMSO-d6) δ8.25(t,J=6.0Hz,1H),7.73-7.66(m,2H),7.48-7.14(m,11H),4.51(d,J=6.2Hz,2H),4.38(d,J=5.9Hz,2H),2.34(s,3H). 13 C NMR(151MHz,DMSO-d6)δ165.16,155.66,145.00,143.36,138.10,136.35,133.59,133.41,130.69,130.60,129.67 ,129.31,127.74,127.53,127.07,126.43,126.39,125.98,114.71,100.45,46.90,42.21,19.09.HRMS(ESI):calcd forC 26 H 23 ClN2OS:446.1220; found:447.1292.

[0132] Example 34 - Compound A34

[0133] Purity>95%. Yellow solid, 43 mg, yield 15%. 1 H NMR (400MHz, DMSO-d6) δ8.27-8.11(m,1H),7.68-7.15(m,13H),4.49(d,J=6.1Hz,2H),4.33(d,J=5.8Hz,2H),2.33(s,3H). 13 CNMR(151MHz,DMSO-d6)δ165.14,155.59,144.94,140.23,138.10,136.36,133.60,131.98,131.54,130.68,130.45,130.0 1,129.67,129.29,127.73,127.53,126.40,125.97,120.09,114.68,100.56,47.45,46.91,42.12,19.11.HRMS(ESI):calcd for C 26 H 23 BrN2OS:490.0714; found:491.0782.

[0134] Example 35 - Compound A35

[0135] Purity>95%. Yellow solid, 47 mg, yield 17%. 1 H NMR (400MHz, DMSO-d6) δ8.19(t,J=5.9Hz,1H),7.71-7.67(m,2H),7.49-7.16(m,11H),4.51(d,J=6.1Hz,2H),4.44(d,J=5.8Hz,2H),2.34(s,3H). 13 C NMR(151MHz,DMSO-d6)δ165.24,155.65,145.00,138.10,136.36,133.62,130.69,129.79,129.76,129.67,129.30,129.10,129.05 ,127.74,127.53,126.40,125.98,124.74,124.72,115.53,115.39,114.66,100.48,46.90,36.36,36.32,19.10.HRMS(ESI):calcd for C 26 H 23 FN2OS:430.1515; found:431.1595.

[0136] Experimental Example 1

[0137] The enzyme-linked immunosorbent assay (ELISA) method was used to detect the in vitro anti-tumor activity of the thiophene derivatives (A1-A35) provided in the examples of the present invention.

[0138] The results are shown in Table 1.

[0139] Table 1 IC values ​​of 35 compounds measured by competitive ELISA 50 value

[0140]

[0141]

[0142] As shown in Table 1, the thiophene derivatives provided by the embodiments of the present invention can produce good analgesic effects.

[0143] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. A thiophene derivative, characterized in that: It is selected from the compounds shown in the following structural formula Wherein, R1 is phenyl or C1-C5 unsubstituted alkyl substituted phenyl; R2 is any one of substituted phenyl, 4-membered to 7-membered oxygen-containing heterocycloalkyl, benzo 4-membered to 7-membered oxygen-containing heterocycloalkyl and naphthyl.

2. The thiophene derivative according to claim 1, characterized in that R1 is phenyl or C1-C3 unsubstituted alkyl substituted phenyl.

3. The thiophene derivative according to claim 1, characterized in that The substituent of the substituted phenyl group in R2 is selected from any one of halogen, hydroxy, C1-C3 alkoxy and C1-C5 unsubstituted alkyl.

4. The thiophene derivative according to claim 1, characterized in that When R1 is phenyl, R2 is any one of substituted phenyl, 4-membered to 7-membered oxygen-containing heterocycloalkyl, benzo 4-membered to 7-membered oxygen-containing heterocycloalkyl and naphthyl, and the substituent of the substituted phenyl is any one of hydroxyl, fluorine and C1-C3 alkoxy.

5. The thiophene derivative according to claim 4, characterized in that When R1 is a phenyl group and R2 is a fluorine-substituted phenyl group, the number of fluorine groups is 1-3; preferably, the number of fluorine groups is 2-3.

6. The thiophene derivative according to claim 4, characterized in that When R1 is a phenyl group and R2 is a C1-C3 alkoxy-substituted phenyl group, the number of the C1-C3 alkoxy groups is 2-3; The C1-C3 alkoxy group is located at the meta position.

7. The thiophene derivative according to any one of claims 1 to 6, characterized in that: The thiophene derivative is selected from any one of the following compounds formed by R1 and R2:

8. A method for preparing the thiophene derivatives according to claim 1, characterized in that: include: The synthesis was carried out according to the following synthesis route: R is hydrogen or C1-C5 unsubstituted alkyl.

9. A Mu opioid receptor agonist, characterized in that It includes the thiophene derivatives according to claim 1.

10. Use of the thiophene derivative according to claim 1 in the preparation of analgesics.

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