1-thienyl-β-carboline-based IDO1 and TDO dual inhibitor and medical use thereof

Abstract

Disclosed in the present invention is a 1-thienyl-β-carboline-based IDO1 and TDO dual inhibitor, selected from a 1-thienyl-β-carboline derivative having a structure as represented by formula I or a pharmaceutically acceptable salt thereof. R1 is hydrogen, fluorine, chlorine or bromine, R2 is hydrogen, methyl or trifluoromethyl, R3 is methyl, and R4 is C1-C4 linear or branched alkyl. Disclosed in the present invention is a use of the 1-thienyl-β-carboline derivative or the pharmaceutically acceptable salt thereof in the preparation of a IDO1 and TDO dual inhibitor. Disclosed in the present invention is a use of the 1-thienyl-β-carboline derivative or the pharmaceutically acceptable salt thereof in the preparation of a medicament for treating IDO1- and TDO-mediated diseases. The IDO1- and TDO-mediated diseases are central nervous system diseases associated with IDO1- and TDO-mediated tryptophan-kynurenine metabolic pathway abnormalities, specifically including depression, anxiety, Parkinson's disease and Alzheimer's disease.

Description

1-Thienyl-β-carboline dual inhibitors of IDO1 and TDO and their pharmaceutical uses Technical Field

[0001] This invention belongs to the pharmaceutical field and relates to the use of 1-thienyl-β-carboline derivatives or pharmaceutically acceptable salts thereof as dual inhibitors of indoleamine-2,3-dioxygenase 1 (IDO1) and tryptophan-2,3-dioxygenase (TDO). Background Technology

[0002] Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting more than 1% of the population aged 65 and older (Weintraub D, et al. Nat Rev Dis Primers. 2021, 7(1):47). PD is a multifactorial and heterogeneous disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra striatum, clinically manifesting as both motor and nonmotor symptoms. Compared to the main motor symptoms such as rigidity, bradykinesia, and resting tremor, nonmotor symptoms such as sleep disturbances, depression, anxiety, and constipation are often overlooked and not effectively treated in the early stages of PD (Mondal AC, et al. Ageing Res Rev. 2023, 85:101840). In the clinical presentation of patients with advanced PD, these nonmotor symptoms dominate, leading to severe disability, decreased quality of life, and shortened life expectancy (Schapira AH, Lancet Neurol. 2006, 5(3):235). Depression is one of the most common and disabling nonmotor symptoms in all stages of Parkinson's disease (PD), affecting approximately 38% of PD patients (Cong S, Neurosci Biobehav Rev. 2022, 141:104749); among them, about 14% suffer from major depressive disorder. Currently, clinical drugs acting on the dopamine pathway, such as levodopa, dopamine receptor agonists, and monoamine oxidase B inhibitors, are mainly used to alleviate motor symptoms in PD patients, but their efficacy on nonmotor symptoms is limited. Therefore, there is an urgent clinical need to develop new treatment methods that can effectively alleviate motor symptoms of PD and improve some nonmotor symptoms, especially depression.

[0003] The kynurenine pathway is the main pathway for tryptophan metabolism in mammals, producing a series of active metabolites involved in inflammatory immune responses and neurotransmission, such as kynurenine, 3-hydroxykynurenine, and quinolinic acid (Li L, Cell Metab. 2023, 35(8):1304). Imbalance in the tryptophan-kynurenine metabolic pathway is closely related to the pathogenesis of various brain diseases, especially depression and Parkinson's disease (PD). Clinical studies have shown that in patients with depression and PD, the activities of indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO), the first rate-limiting enzymes in the kynurenine pathway, are upregulated, leading to an increased kynurenine / tryptophan ratio in peripheral blood and cerebrospinal fluid. Elevated levels of the free radical precursor 3-hydroxykynurenine and the excitatory toxin quinolinic acid have also been observed in the putamen, prefrontal cortex, and substantia nigra pars compacta of PD patients. It is noteworthy that TDO is primarily expressed in the liver and is responsible for regulating systemic tryptophan levels; while IDO1 can be activated by pro-inflammatory cytokines and is highly expressed in extrahepatic tissues, leading to decreased serotonin levels and increased kynurenine levels (Eynde BJ, Front Mol Biosci. 2022, 9:897929). Therefore, inhibiting the activity of IDO1 and TDO may provide a novel treatment strategy for patients with Parkinson's disease and comorbid depression.

[0004] Currently, most IDO1 and TDO inhibitors are undergoing evaluation for antitumor activity, but some studies have noted their therapeutic potential for central nervous system diseases (Opitz CA, Nat Rev Drug Discov. 2019, 18(5):379). For example, the IDO1 inhibitor 1-MT and the TDO inhibitor LM10 have been shown to effectively alleviate inflammation and stress-induced depressive-like behavior in mice (Dantzer R, Mol Psychiatry. 2009, 14(5):511; Wang S, J Ethnopharmacol. 2023, 317:116714). Li et al. reported a novel dual IDO1 / TDO inhibitor, 1H-indazole-4-amine, which showed anti-PD activity in an MPTP-induced mouse model (Li GB, J Med Chem. 2021, 64(12):8303). Andreasson et al. demonstrated the efficacy of a brain-penetrating IDO1 inhibitor (PF-06840003) in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (PD) (Andreasson KI, Science. 2024, 385(6711):eabm6131). In conclusion, given the therapeutic potential of IDO1 and TDO inhibitors in central nervous system diseases such as PD, depression, and Alzheimer's disease, there remains a high demand for novel and effective IDO1 and TDO inhibitors. Summary of the Invention

[0005] The technical problem to be solved by this invention is to provide a novel 1-thienyl-β-carboline derivative or a pharmaceutically acceptable salt thereof, a method for its preparation, and its use as a dual inhibitor of indoleamine-2,3-dioxygenase 1 (IDO1) and tryptophan-2,3-dioxygenase (TDO). The compounds of this invention can be used to treat central nervous system disorders involving abnormalities in the IDO1 and TDO-mediated tryptophan-kynurenine metabolic pathway, including depression, anxiety disorders, Parkinson's disease, and Alzheimer's disease.

[0006] 1-Thienyl-β-carbamoline derivatives or pharmaceutically acceptable salts thereof with structures as shown in formula (I):

[0007] Among them, R 1 For hydrogen, fluorine, chlorine, or bromine, R 2 R is hydrogen, methyl, or trifluoromethyl. 3 For methyl, R 4 It is a C1-C4 straight-chain or branched alkyl group.

[0008] Furthermore, R 1 When R is hydrogen, fluorine, chlorine or bromine 2 For hydrogen, R 3 For methyl, R 4 It can be methyl, ethyl, propyl, or butyl;

[0009] R 1 When it is hydrogen, R 2 It is methyl or trifluoromethyl, R 3 For methyl, R 4 It can be methyl, ethyl, propyl or butyl.

[0010] Furthermore, a 1-thienyl-β-carbamoline derivative or a pharmaceutically acceptable salt thereof, as shown in general formula (I), is characterized by: R 1 For hydrogen or fluorine, R 2 It is hydrogen or methyl; R 3 Methyl; R 4 It can be methyl, ethyl, propyl or butyl.

[0011] Going further, R 1 For hydrogen or fluorine, R 2 For hydrogen or methyl, R 3 For methyl, R 4 It is methyl, ethyl, propyl, or butyl; but does not include: R 1 For hydrogen, R 2 For methyl, R 3 For methyl, R 4 Methyl, ethyl; R 1It is fluorine, R 2 For hydrogen, R 3 For methyl, R 4 It is propyl.

[0012] Specifically, the 1-thienyl-β-carboline derivatives mentioned above are selected from the following compounds:

[0013] The compound codes used in the following pharmacological experiments are equivalent to the compounds corresponding to the codes listed here.

[0014] The pharmaceutically acceptable salts of the 1-thienyl-β-carboline derivatives are salts formed by the 1-thienyl-β-carboline derivatives with inorganic or organic acids.

[0015] Pharmaceutically acceptable salts of the aforementioned 1-thienyl-β-carboline derivatives can be synthesized by conventional chemical methods. Generally, they are prepared by reacting free 1-thienyl-β-carboline derivatives with an equisical or excess amount of an acid (inorganic or organic) in a suitable solvent or solvent combination.

[0016] Another object of the present invention is to provide a method for preparing the aforementioned 1-thienyl-β-carboline derivative, the synthetic route of which is as follows:

[0017] Among them, R 1 R 2 R 3 and R 4 The definition is as stated above;

[0018] This includes: Compound II and Compound III undergo a Pictet-Spengler reaction to obtain Compound IV, and Compound IV is further dehydrogenated and aromatized to obtain a 1-thienyl-β-carboline derivative as shown in Formula I.

[0019] Specifically, the following steps are included:

[0020] Step (1), Pictet-Spengler reaction: using dichloromethane as the reaction solvent and trifluoroacetic acid as the catalyst, under the action of the catalyst, compound II and compound III undergo Pictet-Spengler reaction to generate compound IV;

[0021] Step (2), Dehydrogenation aromatization reaction: Using N,N-dimethylformamide as the reaction solvent and 10% Pd / C as the catalyst, compound IV undergoes a dehydrogenation aromatization reaction to generate 1-thienyl-β-carboline derivatives as shown in Formula I.

[0022] In step (1), the molar ratio of compound II to compound III is 1:1 to 1.5:1, preferably 1.2:1.

[0023] The molar ratio of the catalyst to compound II is 4:1 to 1:1, preferably 2.5:1.

[0024] The Pictet-Spengler reaction was carried out at room temperature.

[0025] After the reaction was completed, the pH of the reaction solution was adjusted to 7-8 with sodium bicarbonate aqueous solution, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried with anhydrous Na2SO4, and the solvent was evaporated under reduced pressure to obtain compound IV.

[0026] In step (2), the mass ratio of the 10% Pd / C to compound IV is 1:5.5 to 1:6.

[0027] The reaction temperature for the dehydrogenation aromatization reaction is 120–160°C, preferably 140°C.

[0028] After the reaction was completed, the mixture was filtered, and the filtrate was collected. The filtrate was concentrated by vacuum distillation to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography with petroleum ether / ethyl acetate volume ratio of 5 / 1 to 2 / 1 as the eluent to obtain the 1-thienyl-β-carboline derivative shown in Formula I.

[0029] Another object of the present invention is to provide the use of the aforementioned 1-thienyl-β-carboline derivatives or pharmaceutically acceptable salts thereof in the preparation of IDO1 and / or TDO inhibitors.

[0030] Another object of the present invention is to provide the use of the aforementioned 1-thienyl-β-carboline derivatives or pharmaceutically acceptable salts thereof in the preparation of dual inhibitors of IDO1 and TDO.

[0031] Another object of the present invention is to provide the use of the aforementioned 1-thienyl-β-carboline derivatives or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating IDO1 and TDO-mediated diseases.

[0032] The diseases mediated by IDO1 and TDO are central nervous system diseases caused by abnormalities in the IDO1 and TDO-mediated tryptophan-kynurenine metabolic pathway, specifically depression, anxiety, Parkinson's disease, and Alzheimer's disease.

[0033] Another object of the present invention is to provide a pharmaceutical composition wherein the 1-thienyl-β-carbamoline derivative or a pharmaceutically acceptable salt thereof is used as the active ingredient or the main active ingredient, and is prepared into a pharmaceutically acceptable dosage form with a pharmaceutically acceptable carrier.

[0034] The dosage forms mentioned are tablets, capsules, powders, pellets, suspensions, or nasal sprays. Attached Figure Description

[0035] Figure 1 shows the percentage of time zebrafish spent moving in the open field after treatment with compound I-1 in Example 14; compared with the model control group, *p<0.05, ***p<0.001.

[0036] Figure 2 shows the total distance traveled by zebrafish after treatment with compound I-1 in Example 14; where, compared with the model control group, **p<0.01, ***p<0.001.

[0037] Figure 3 shows the movement speed of zebrafish treated with compound I-1 in Example 14; where, compared with the model control group, **p<0.01, ***p<0.001.

[0038] Figure 4 shows the 5-HT content in zebrafish after treatment with compound I-1 in Example 14; compared with the model control group, **p<0.01, ***p<0.001.

[0039] Figure 5 shows the DA content in zebrafish after treatment with compound I-1 in Example 14; where, compared with the model control group, *p<0.05, **p<0.01.

[0040] Figure 6 is a concentration-mortality curve of compound I-1 in Example 15. Detailed Implementation

[0041] To further illustrate the technical solution of the present invention, a series of embodiments are given below. These embodiments enable those skilled in the art to fully understand the present invention, but should not be considered as limiting the scope of the present invention.

[0042] Example 1

[0043] Preparation of 1-(2,5-dimethylthiophene-3-yl)-9H-pyrido[3,4-b]indole (compound I-1)

[0044] Pictet-Spengler reaction: In a 100 mL round-bottom flask, indoleethylamine (compound 1) (429 mg, 2.68 mmol) was dissolved in 20 mL of dichloromethane. 2,5-Dimethylthiophene-3-carboxaldehyde (compound 2) (313 mg, 2.23 mmol) was added, and the mixture was stirred at room temperature for 10 min. Then, trifluoroacetic acid (0.5 mL) was added, and the reaction mixture was stirred overnight at room temperature. At this point, the starting material disappeared as determined by TLC. The pH of the reaction mixture was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (20 mL × 3), and the organic layers were combined. The organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, and the solvent was evaporated under reduced pressure to give a pale yellow solid (compound 3, 478.63 mg, yield 76%).

[0045] Dehydroaromatization reaction: Compound 3 (479 mg, 1.69 mmol) was added to a 100 mL round-bottom flask and dissolved in 10 mL of N,N-dimethylformamide. 10% Pd / C (80 mg) was added while stirring at room temperature. The reaction mixture was heated to 140 °C and reacted for 12 h. At this point, the starting material disappeared as determined by TLC. The mixture was filtered, and the filtrate was collected and concentrated by vacuum distillation to obtain a yellow crude product. The crude product was then purified by normal-phase silica gel column chromatography (eluent: petroleum ether / ethyl acetate, volume ratio = 5 / 1 to 2 / 1) to obtain a pale yellow solid (compound I-1, 268 mg, yield 57%). 1 H NMR (400MHz, DMSO-d6) δ11.16(s,1H),8.35(d,J=5.3Hz,1H),8.19(d,J=7.9Hz,1H),8.02(d,J=5.1Hz,1H),7.57( d,J=8.2Hz,1H),7.49(t,J=7.6Hz,1H),7.20(t,J=7.5Hz,1H),7.00(s,1H),2.46(s,3H),2.38(s,3H); MS(ESI)m / z 279.1[M+H] + .

[0046] Example 2

[0047] Preparation of 1-(2,5-dimethylthiophene-3-yl)-6-fluoro-9H-pyrido[3,4-b]indole (compound I-2)

[0048] Following the preparation method of compound I-1, indoleethylamine in Example 1 was replaced with an equimolar amount of 5-fluoroindoleethylamine, and a pale yellow solid (compound I-2, 271 mg, two-step yield 41%) was obtained by Pictet-Spengler reaction and dehydrogenation aromatization reaction. 1H NMR (400MHz, DMSO-d6) δ11.18(s,1H),8.36(d,J=5.3Hz,1H),8.19(d,J=7.9Hz,1H),8.03(d,J=5.1Hz, 1H),7.56(d,J=8.2Hz,1H),7.49(t,J=7.6Hz,1H),7.02(s,1H),2.46(s,3H),2.38(s,3H); MS(ESI)m / z 297.1[M+H] + .

[0049] Example 3

[0050] Preparation of 1-(2,5-dimethylthiophene-3-yl)-7-methyl-9H-pyrido[3,4-b]indole (compound I-3)

[0051] Following the preparation method of compound I-1, indoleethylamine in Example 1 was replaced with an equimolar amount of 6-methylindoleethylamine, and a pale yellow solid (compound I-3, 306 mg, two-step yield 47%) was obtained by Pictet-Spengler reaction and dehydrogenation aromatization reaction. 1 H NMR (400MHz, DMSO-d6) δ11.15(s,1H),8.35(d,J=5.3Hz,1H),8.16(d,J=7.9Hz,1H),8.00(d,J=5.1Hz,1 H),7.56(d,J=8.2Hz,1H),7.28(s,1H),7.10(s,1H),2.44(s,3H),2.37(s,3H),2.28(s,3H); MS(ESI)m / z 293.1[M+H] + .

[0052] Example 4

[0053] Preparation of 4-bromo-5-methylthiophene-2-carboxaldehyde (compound 5)

[0054] In a 100 mL round-bottom flask, 5-methyl-2-thiophenecarboxaldehyde (compound 4, 2 g, 15.8 mmol) was dissolved in 15 mL of DMF. N-bromosuccinimide (4 g, 22 mmol) and FeCl3 (0.1 g, 0.62 mmol) were slowly added in portions with stirring. The reaction mixture was stirred overnight at room temperature. At this point, the starting material disappeared as determined by TLC. The mixture was extracted with ethyl acetate (30 mL × 3), and the organic layers were combined. The organic layers were washed with saturated brine, dried over anhydrous Na2SO4, and precipitated at 0 °C as pale yellow, transparent crystals (compound 5, 2.5 g, 78% yield). 1H NMR (400MHz, CDCl3) δ9.76 (s, 1H), 7.57 (s, 1H), 2.47 (s, 3H); MS (ESI) m / z 206.9 [M+H] + .

[0055] Preparation of 1-(4-bromo-5-methylthiophen-2-yl)ethanol-1-ol (compound 6)

[0056] In a 100 mL round-bottom flask, 4-bromo-5-methylthiophene-2-carboxaldehyde (compound 5, 1 g, 4.9 mmol) was dissolved in 10 mL of THF. Under a nitrogen atmosphere, a THF solution of methyl magnesium chloride (2.0 M, 2.5 mL, 5 mmol) was slowly added while stirring at -78 °C. The reaction mixture was stirred at room temperature for 1 h. At this point, the starting material disappeared as determined by TLC. The reaction mixture was quenched by adding 1 N HCl. The mixture was extracted with ethyl acetate (20 mL × 3), and the organic layers were combined. The organic layers were washed successively with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure to obtain a yellow oily crude product. The crude product was purified by normal-phase silica gel column chromatography (eluent: pure petroleum ether) to obtain a pale yellow oily substance (compound 6, 0.98 g, yield 90%). 1 H NMR (400MHz, CDCl3) δ6.73 (s, 1H), 4.68-4.65 (t, J = 6.7Hz, 1H), 2.35 (s, 3H), 1.52-1.48 (t, J = 7.4Hz, 3H); MS (ESI) m / z 223.0 [M+H] + .

[0057] Preparation of 5-ethyl-2-methylthiophene-3-carboxaldehyde (compound 7)

[0058] In a 100 mL round-bottom flask, 1-(4-bromo-5-methylthiophen-2-yl)ethanol-1-ol (compound 6, 0.75 g, 3.4 mmol) was dissolved in 10 mL of dichloromethane. Triethylsilane (2.5 mL) and trifluoroacetic acid (2.5 mL) were slowly added in portions with stirring. The reaction mixture was stirred at room temperature for 2 h. At this time, the starting material disappeared as determined by TLC. The mixture was extracted with dichloromethane (10 mL × 3), and the organic layers were combined. The organic layers were washed with saturated sodium bicarbonate aqueous solution and saturated brine, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain a pale yellow oily crude product. The above-mentioned pale yellow oily crude product was added to a 100 mL double-necked flask and dissolved in 10 mL of THF. Under a nitrogen atmosphere, n-butyllithium hexane solution (1.6 M, 3 mL, 4.8 mmol) was slowly added while stirring at -78 °C. The mixture was stirred for 0.5 h, and anhydrous DMF (2.5 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 1 h, at which point the starting material disappeared as determined by TLC. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic layers were combined. The organic layers were washed with saturated brine and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain a yellow oily crude product, which was then purified by normal-phase silica gel column chromatography (eluent: pure petroleum ether) to obtain a pale yellow oily substance (compound 7, 131 mg, two-step yield 25%). 1 H NMR (400MHz, CDCl3) δ9.93 (s, 1H), 7.01 (s, 1H), 2.70 (s, 3H), 2.68-2.66 (t, J = 8Hz, 2H), 1.55-1.51 (t, J = 7.3Hz, 3H); MS (ESI) m / z 155.1 [M+H] + .

[0059] Preparation of 1-(5-ethyl-2-methylthiophen-3-yl)-9H-pyrido[3,4-b]indole (compound I-4)

[0060] Following the preparation method of compound I-1, 2,5-dimethylthiophene-3-carboxaldehyde in Example 1 was replaced with an equimolar amount of 5-ethyl-2-methylthiophene-3-carboxaldehyde. After Pictet-Spengler reaction and dehydrogenation aromatization reaction, a pale yellow solid (compound I-4, 254 mg, two-step yield 39%) was obtained. 1H NMR (400MHz, CDCl3) δ8.62(s,1H),8.47(d,J=5.3Hz,1H),8.16(d,J=7.9Hz,1H),7.90(d,J=5.2Hz,1H),7.50(t,J=7.7Hz,1H), 7.42(d,J=8.3Hz,1H),7.27(t,J=8.0Hz,1H),6.95(s,1H),2.64(t,J=7.5Hz,2H),2.46(s,3H),1.32-1.27(m,3H); MS(ESI)m / z 293.1[M+H] + .

[0061] Example 5

[0062] Preparation of 1-(5-ethyl-2-methylthiophen-3-yl)-6-fluoro-9H-pyrido[3,4-b]indole (compound I-5)

[0063] Following the preparation method of compound I-1, indoleethylamine and 2,5-dimethylthiophen-3-carboxaldehyde in Example 1 were replaced with equimolar amounts of 5-fluoroindoleethylamine and 5-ethyl-2-methylthiophen-3-carboxaldehyde, respectively. After Pictet-Spengler reaction and dehydrogenation aromatization reaction, a pale yellow solid (compound I-5, 284 mg, two-step yield 41%) was obtained. 1 H NMR (400MHz, CDCl3) δ8.62(s,1H),8.47(d,J=5.3Hz,1H),8.16(d,J=7.9Hz,1H),7.95(d,J=5.2Hz,1H),7.54(t,J= 7.7Hz, 1H), 7.48 (d, J = 8.3Hz, 1H), 6.95 (s, 1H), 2.65 (t, J = 7.5Hz, 2H), 2.47 (s, 3H), 1.38-1.30 (m, 3H); MS (ESI) m / z 311.1[M+H] + .

[0064] Example 6

[0065] Preparation of 1-(5-ethyl-2-methylthiophen-3-yl)-7-methyl-9H-pyrido[3,4-b]indole (compound I-6)

[0066] Following the preparation method of compound I-1, indoleethylamine and 2,5-dimethylthiophen-3-carboxaldehyde in Example 1 were replaced with equimolar amounts of 6-methylindoleethylamine and 5-ethyl-2-methylthiophen-3-carboxaldehyde, respectively. After Pictet-Spengler reaction and dehydrogenation aromatization reaction, a pale yellow solid (compound I-6, 273 mg, two-step yield 40%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ11.10(s,1H),8.33(d,J=5.3Hz,1H),8.12(d,J=7.9Hz,1H),7.94(d,J=5.3Hz,1H),7.56(d,J= 8.2Hz,1H),7.28(s,1H),7.08(s,1H),2.58(t,J=7.4Hz,2H),2.44(s,3H),2.37(s,3H),1.20-1.14(m,3H); MS(ESI)m / z 307.1[M+H] + .

[0067] Example 7

[0068] Preparation of 2-methyl-5-propyl-3-thiophenecarboxaldehyde (compound 8)

[0069] Following the preparation method of compound 7, 5-methyl-2-thiophenecarboxaldehyde (compound 4) was used as the starting material, and only an equimolar amount (based on ethyl magnesium chloride) of ethyl magnesium chloride THF solution was used to replace the methyl magnesium chloride THF solution to obtain a pale yellow oily substance (compound 8, 143 mg, yield 25%). 1 H NMR (400MHz, CDCl3) δ9.93 (s, 1H), 7.01 (s, 1H), 2.70 (s, 3H), 2.68-2.66 (t, J= 8Hz, 2H), 1.70-1.62 (q, J=7.4Hz, 2H), 0.97-0.93 (t, J=7.3Hz, 3H); MS (ESI) m / z 169.1[M+H] + .

[0070] Preparation of 1-(2-methyl-5-propylthiophen-3-yl)-9H-pyrido[3,4-b]indole (compound I-7)

[0071] Following the preparation method of compound I-1, 2,5-dimethylthiophene-3-carboxaldehyde in Example 1 was replaced with an equimolar amount of 2-methyl-5-propyl-3-thiophenecarboxaldehyde. After Pictet-Spengler reaction and dehydrogenation aromatization reaction, a pale yellow oil (compound I-7, 171 mg, two-step yield 25%) was obtained.1 H NMR (400MHz, CDCl3) δ8.62(s,1H),8.47(d,J=5.3Hz,1H),8.13(d,J=7.9Hz,1H),7.88(d,J=5.2Hz,1H),7.50(t,J=7.7Hz,1H),7.42(d,J =8.2Hz,1H),7.27(t,J=8.1Hz,1H),6.95(s,1H),2.73(t,J=7.6Hz,2H),2.46(s,3H),1.72-1.63(m,2H),1.00-0.94(m,3H); MS(ESI)m / z 307.1[M+H] + .

[0072] Example 8

[0073] Preparation of 1-(2-methyl-5-propylthiophen-3-yl)-6-fluoro-9H-pyrido[3,4-b]indole (compound I-8)

[0074] Following the preparation method of compound I-1, indoleethylamine and 2,5-dimethylthiophen-3-carboxaldehyde in Example 1 were replaced with equimolar amounts of 5-fluoroindoleethylamine and 2-methyl-5-propyl-3-thiophenecarboxaldehyde, respectively. After Pictet-Spengler reaction and dehydrogenation aromatization reaction, a pale yellow solid (compound I-8, 253 mg, two-step yield 35%) was obtained. 1 H NMR (400MHz, CDCl3) δ8.67(s,1H),8.35(d,J=5.3Hz,1H),8.16(d,J=7.9Hz,1H),8.00(d,J=5.1Hz,1H),7.56(d,J=8.2Hz,1H), 7.28(s,1H),7.10(s,1H),6.96(s,1H),2.75(t,J=7.6Hz,2H),2.50(s,3H),1.76-1.67(m,2H),1.04-0.98(m,3H); MS(ESI)m / z 325.1[M+H] + .

[0075] Example 9

[0076] Preparation of 1-(2-methyl-5-propylthiophen-3-yl)-7-methyl-9H-pyrido[3,4-b]indole (compound I-9)

[0077] Following the preparation method of compound I-1, indoleethylamine and 2,5-dimethylthiophen-3-carboxaldehyde in Example 1 were replaced with equimolar amounts of 6-methylindoleethylamine and 2-methyl-5-propyl-3-thiophenecarboxaldehyde, respectively. After Pictet-Spengler reaction and dehydrogenation aromatization reaction, a pale yellow oil (compound I-9, 236 mg, two-step yield 33%) was obtained. 1 H NMR (400MHz, CDCl3) δ8.62(s,1H),8.42(d,J=5.3Hz,1H),8.10(d,J=7.9Hz,1H),7.82(d,J=5.2Hz,1H),7.42(t,J=7.7Hz,1H ),7.24(t,J=8.1Hz,1H),6.90(s,1H),2.73(t,J=7.6Hz,2H),2.46(s,3H),1.72-1.63(m,2H),1.00-0.94(m,3H); MS(ESI)m / z 321.1[M+H] + .

[0078] Example 10

[0079] Preparation of 5-butyl-2-methylthiophene-3-carboxaldehyde (compound 9)

[0080] Following the preparation method of compound 7, 5-methyl-2-thiophenecarboxaldehyde (compound 4) was used as the starting material, and only an equimolar amount (based on n-propyl magnesium chloride) of n-propyl magnesium chloride THF solution was used to replace the methyl magnesium chloride THF solution to obtain a pale yellow oily substance (compound 9, 180 mg, yield 29%). 1 H NMR(400MHz, CDCl3)δ9.93(s,1H),7.01(s,1H),2.71-2.66(m,5H),1.66-1.59(m,2H),1.33-1.30(m,2H),0.90-0.86(m,3H); MS(ESI)m / z183.1[M+H] + .

[0081] Preparation of 1-(5-butyl-2-methylthiophene-3-yl)-9H-pyrido[3,4-b]indole (compound I-10)

[0082] Following the preparation method of compound I-1, 2,5-dimethylthiophene-3-carboxaldehyde in Example 1 was replaced with an equimolar amount of 5-butyl-2-methylthiophene-3-carboxaldehyde. After Pictet-Spengler reaction and dehydrogenation aromatization reaction, a pale yellow oil (compound I-10, 214 mg, two-step yield 30%) was obtained.1 H NMR (400MHz, CDCl3) δ8.62(s,1H),8.47(d,J=5.3Hz,1H),8.13(d,J=7.9Hz,1H),7.88(d,J=5.2Hz,1H),7.50(t,J=7.7Hz,1H),7.42(d,J=8.2Hz,1H ),7.27(t,J=8.1Hz,1H),6.95(s,1H),2.73(t,J=7.6Hz,2H),2.46(s,3H) ,1.72-1.63(m,2H),1.46-1.38(m,2H),0.90(t,J=6.8Hz,3H);MS(ESI)m / z 321.1[M+H] + .

[0083] Example 11

[0084] Preparation of 1-(5-butyl-2-methylthiophene-3-yl)-6-fluoro-9H-pyrido[3,4-b]indole (compound I-11)

[0085] Following the preparation method of compound I-1, indoleethylamine and 2,5-dimethylthiophen-3-carboxaldehyde in Example 1 were replaced with equimolar amounts of 5-fluoroindoleethylamine and 5-butyl-2-methylthiophen-3-carboxaldehyde, respectively. After Pictet-Spengler reaction and dehydrogenation aromatization reaction, a pale yellow oil (compound I-11, 279 mg, two-step yield 37%) was obtained. 1 H NMR (400MHz, CDCl3) δ8.67(s,1H),8.35(d,J=5.3Hz,1H),8.16(d,J=7.9Hz,1H),8.00(d,J=5.1Hz,1H),7.56(d,J=8.2Hz,1H),7.28(s,1H ),7.10(s,1H),6.96(s,1H),2.75(t,J=7.6Hz,2H),2.50(s,3H),1.76-1.67(m,2H),1.48-1.40(m,2H),0.90(t,J=6.8Hz,3H); MS(ESI)m / z 339.1[M+H] + .

[0086] Example 12

[0087] Preparation of 1-(5-butyl-2-methylthiophen-3-yl)-7-methyl-9H-pyrido[3,4-b]indole (compound I-12)

[0088] Following the preparation method of compound I-1, indoleethylamine and 2,5-dimethylthiophen-3-carboxaldehyde in Example 1 were replaced with equimolar amounts of 6-methylindoleethylamine and 5-butyl-2-methylthiophen-3-carboxaldehyde, respectively. After Pictet-Spengler reaction and dehydrogenation aromatization reaction, a pale yellow oil (compound I-12, 261 mg, two-step yield 35%) was obtained. 1 H NMR (400MHz, CDCl3) δ8.62(s,1H),8.42(d,J=5.3Hz,1H),8.10(d,J=7.9Hz,1H),7.82(d,J=5.2Hz,1H),7.42(t,J=7.7Hz,1H),7.24(t,J =8.1Hz,1H),6.90(s,1H),2.73(t,J=7.6Hz,2H),2.46(s,3H),1.72-1.63(m,2H),1.42-1.33(m,2H),0.90(t,J=6.8Hz,3H); MS(ESI)m / z 335.2[M+H] + .

[0089] Example 13

[0090] In vitro assay and analysis of the inhibitory activities of recombinant human IDO1 and TDO enzymes

[0091] Instruments, consumables and reagents: Microplate reader (Bio-Tekb, model: SYNERGYb H1), 96-well plate (Nest Biotech), human recombinant IDO1 and TDO enzymes (TopScience), human catalase (Sigma), L-tryptophan (Sigma), potassium phosphate (Sangon Biotech Co., Ltd.), methylene blue (Shanghai Maclean Biotechnology Co., Ltd.), ascorbic acid (Sangon Biotech Co., Ltd.), and other reagents were all of analytical grade.

[0092] Test compounds: Compounds I-1 to I-12, positive control drugs PF-06840003 and 680C91. The test compounds were sequentially diluted to eight concentrations (1:3 ratio) using potassium phosphate buffer containing 5% DMSO to obtain a series of test compound solutions. These solutions were then used for in vitro testing of the inhibitory activity of recombinant human IDO1 and TDO enzymes.

[0093] Experimental procedure:

[0094] Prepare a 96-well plate and set up a blank control, a negative control, and a test control, with two replicates for each control. Except for the incubation process, all subsequent operations should be performed at 0°C. Prepare the standard reaction solution (100 μL): containing potassium phosphate buffer (50 mM, pH 6.5), ascorbic acid (20 mM), catalase (0.2 mg / mL), methylene blue (3.5 μM), and recombinant human IDO1 (40 nM). For the test control: add 10 μL of the test compound (0.01–100 μM, 5% DMSO) and 10 μL of L-tryptophan (900 μM, pH 6.5, potassium phosphate buffer) to each well of the 96-well plate, and mix three times. For the blank control: add 20 μL of the standard reaction solution to each well. For the negative control: add 10 μL of the standard reaction solution and 10 μL of L-tryptophan (900 μM, pH 6.5, potassium phosphate buffer) to each well. The reaction mixture was incubated at 37°C for 180 min, and the ultraviolet absorption signal was detected.

[0095] Prepare a 96-well plate and set up a blank control, a negative control, and a test control, with two replicates for each group. Except for the incubation process, all subsequent operations should be performed at 0°C. Prepare the standard reaction solution (100 μL): containing potassium phosphate buffer (100 mM, pH 6.5), ascorbic acid (20 mM), catalase (200 μg / mL), methylene blue (20 μM), and recombinant human TDO (50 nM). For the test control: add 10 μL of the test compound (0.01–100 μM, 5% DMSO) and 10 μL of L-tryptophan (200 μM, pH 6.5, potassium phosphate buffer) to each well of the 96-well plate, and mix three times. For the blank control: add 20 μL of the standard reaction solution to each well. For the negative control: add 10 μL of the standard reaction solution and 10 μL of L-tryptophan (200 μM, pH 6.5, potassium phosphate buffer) to each well. The reaction mixture was incubated at 37°C for 75 min, and the ultraviolet absorption signal was detected.

[0096] Enzyme activity was determined by measuring the increase in optical density at 321 nm due to the formation of N-formylkynurenine. Inhibition rate = [(negative group - test group) / (negative group - blank group)] × 100. Dose-response curves were fitted using Graph Pad Prism software, and the IC50 of the analyte inhibiting IDO1 and TDO enzymes was calculated. 50 Value; repeated at least twice at different time points.

[0097] Experimental results:

[0098] The results, shown in Table 1, indicate that the compounds of this invention significantly inhibit the activities of both recombinant human IDO1 and TDO enzymes. Among them, compound I-1 exhibited the best inhibitory effect on both IDO1 and TDO enzyme activities (IDO1:IC). 50 =0.33μM, TDO:IC 50= 1.78 μM). In addition, the IC 50 value of the IDO1 enzyme inhibitory activity of the positive control drug PF-06840003 measured by the detection method of this embodiment is 0.37 μM, while the IC 50 value of the TDO enzyme inhibitory activity of 680C91 is 0.56 μM, both of which are comparable to the literature values. Thus, the test results of the in vitro human recombinant IDO1 and TDO enzyme inhibitory activities of the present invention are reliable.

[0099] The structure-activity relationship study by the inventors shows that: when R of compounds I-1, I-4, I-7, I-10 is adjusted to chlorine or bromine, the compound activity is maintained; when R of compounds I-2, I-5, I-8, I-11 is adjusted to methyl, the compound activity is maintained.

[0100] Table 1. Analysis results of the inhibitory activities of the compounds of the present invention against human IDO1 and TDO enzymes

[0101] Example 14

[0102] Pharmacodynamic evaluation of compound I-1 in improving the motor ability and depressive symptoms of zebrafish in a Parkinson's disease with depression model [[ID=,24]]

[0103] Experimental animals: Zebrafish were all raised in fish culture water at 28 °C (water quality: 200 mg of instant sea salt was added to every 1 L of reverse osmosis water, the conductivity was 450 - 550 μS / cm; pH was 6.5 - 8.5; hardness was 50 - 100 mg / L, calculated as CaCO3). The license number for the use of experimental animals is: SYXK(Zhe)2022 - 0004, and the feeding management meets the requirements of international AAALAC accreditation (accreditation number: 001458), and the IACUC ethical review number: IACUC - 2024 - 9085 - 01.

[0104] ​​​​Instruments, consumables, and reagents: Dissecting microscope (OLYMPUS, model: SZX7), CCD camera (Shanghai Tusen Vision Technology Co., Ltd., model: VertA1), precision electronic balance (OHAUS, model: CP214); 6-well plates (Zhejiang Beilanbo Biotechnology Co., Ltd.), 24-well plates (Nest Biotech), 96-well plates (Nest Biotech), behavior analyzer (ViewPoint, model: Zebra Lab 3.11), multi-functional microplate reader (TECAN, model: SPARK); LPS (Sigma, batch number: 1001164401), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP; Shanghai Aladdin Biochemical Technology Co., Ltd., batch number: J2210583), dimethyl sulfoxide (DMSO; Sigma), Zebrafish 5-HT Elisa Kit (Shanghai Enzyme-Link Biotechnology Co., Ltd., batch number: 202403), Zebrafish DA Elisa Kit (Shanghai Enzyme-Link Biotechnology Co., Ltd., batch number: 202403).

[0105] Sample preparation information: Compound I-1, solvent: water. Positive control drug: Nomiphene maleate (hereinafter referred to as Nomiphene; Sigma, batch number: 029M4053V), solvent: water.

[0106] Detection methods and results:

[0107] (1) Determination of maximum detectable concentration (MTC)

[0108] Wild-type AB strain zebrafish, 4 days post-fertilization (4 dpf), were randomly selected and placed in 6-well plates. Each well (experimental group) contained 30 zebrafish. Samples were administered in water (concentrations shown in Table 2). A normal control group and a model control group were also included. Each well contained 3 mL of sample. Except for the normal control group, the model control group and all experimental groups received an injection of LPS (50.0 ng / zebrafish) into the yolk sac and were also administered MPTP in water (final concentration 25 μM) to establish a zebrafish model of Parkinson's disease with depression. After treatment at 28℃ for 48 h, the MTC of the samples in the model zebrafish was measured.

[0109] The results are shown in Table 2. The MTC value of compound I-1 in improving the zebrafish model of Parkinson's disease with depression was 0.244 μg / mL.

[0110] Table 2. Results of the efficacy concentration exploratory experiments for compound I-1 (n=30)

[0111] (2) Pharmacological evaluation of compound I-1 in improving depressive symptoms

[0112] Wild-type AB strain zebrafish (4 dpf) were randomly selected and placed in 6-well plates, with 30 zebrafish treated in each well (experimental group). Samples (concentrations shown in Table 3) were administered in water, along with a positive control of nomiphenecin at a concentration of 1.50 μg / mL. A normal control group and a model control group were also included, with a volume of 3 mL per well. Except for the normal control group, both the experimental and model control groups received an injection of LPS (50.0 ng / zebrafish) into the yolk sac and were administered MPTP (25 μM) in water to establish a zebrafish model of Parkinson's disease with depression. After treatment at 28℃ for 48 h, 10 zebrafish from each group were randomly selected and placed in 24-well plates, one zebrafish per well, with a volume of 1 mL per well. The proportion of light field movement time in the zebrafish was measured using a behavioral analyzer to evaluate the efficacy of the samples in improving depressive symptoms in the zebrafish model of Parkinson's disease with depression. Statistical results are expressed as mean ± SE. Statistical analysis was performed using SPSS 26.0 software; p < 0.05 indicated statistical significance.

[0113] The results are detailed in Table 3 and Figure 1. Compound I-1 can improve the depressive symptoms of a zebrafish model of Parkinson's disease with depression, specifically by increasing the proportion of light field movement time in zebrafish.

[0114] Table 3. Pharmacological evaluation results of compound I-1 in improving depressive symptoms (n=10) Note: Compared with the model control group, *p<0.05, ***p<0.001.

[0115] (3) Evaluation of the efficacy of compound I-1 in improving motor function in Parkinson's disease

[0116] Wild-type AB strain zebrafish (4 dpf) were randomly selected and placed in 6-well plates, with 30 zebrafish treated in each well (experimental group). Samples (concentrations shown in Table 4) were administered in water, along with a positive control of nomiphenecin at a concentration of 1.50 μg / mL. A normal control group and a model control group were also included, with a volume of 3 mL per well. Except for the normal control group, both the experimental and model control groups received an injection of LPS (50.0 ng / zebrafish) into the yolk sac and were administered MPTP (25 μM) in water to establish a zebrafish model of Parkinson's disease accompanied by depression. After treatment at 28℃ for 48 h, 10 zebrafish from each group were randomly selected and placed in 96-well plates, one zebrafish per well, with a volume of 200 μL per well. The total distance and speed of movement of the zebrafish over 1 h were measured using a behavioral analyzer. Statistical analysis of these indicators was used to evaluate the efficacy of the samples in improving motor function in patients with Parkinson's disease. Statistical results are expressed as mean ± SE. Statistical analysis was performed using SPSS 26.0 software, and p < 0.05 indicated that the difference was statistically significant.

[0117] The results are detailed in Table 4, Figure 2 and Figure 3. Compound I-1 can improve the motor symptoms of Parkinson's disease, specifically by increasing the total distance and speed of movement in zebrafish.

[0118] Table 4. Pharmacodynamic evaluation results of compound I-1 in improving motor symptoms of Parkinson's disease (n=10) Note: Compared with the model control group, **p<0.01, ***p<0.001.

[0119] (4) Evaluation of the efficacy of compound I-1 in improving the levels of 5-hydroxytryptamine (5-HT) and dopamine (DA) in zebrafish

[0120] Wild-type AB strain zebrafish (4 dpf) were randomly selected and placed in 6-well plates, with 30 zebrafish treated in each well (experimental group). Samples (concentrations shown in Table 5) were administered in water, along with a positive control of nomiphenecin at a concentration of 1.50 μg / mL. A normal control group and a model control group were also included, with a volume of 3 mL per well. Except for the normal control group, both the experimental and model control groups received LPS (50.0 ng / zebrafish) injected into the yolk sac and MPTP (25 μM) in water to establish a zebrafish model of Parkinson's disease with depression. After treatment at 28℃ for 48 h, data were collected using a multi-mode microplate reader according to the 5-HT and DA kit instructions. The 5-HT and DA levels in each experimental group were analyzed, and the statistical analysis results were used to evaluate the efficacy of the samples in improving 5-HT and DA levels in zebrafish. Statistical results are expressed as mean ± SE. Statistical analysis was performed using SPSS 26.0 software; p < 0.05 indicated statistical significance.

[0121] The results are detailed in Table 5, Figure 4 and Figure 5. Compound I-1 has the effect of improving the depressive symptoms associated with Parkinson's disease, specifically by increasing the content of 5-HT and DA in zebrafish.

[0122] Table 5. Efficacy evaluation results of compound I-1 in improving 5-HT and DA levels in zebrafish (n=3) Note: Compared with the model control group, *p<0.05, **p<0.01, ***p<0.001.

[0123] Example 15

[0124] Acute toxicity evaluation of compound I-1

[0125] Experimental animals: Zebrafish were all raised in fish-raising water at 28 °C (Water quality: 200 mg of instant sea salt was added to every 1 L of reverse osmosis water, with a conductivity of 450 - 550 μS / cm; pH of 6.5 - 8.5; hardness of 50 - 100 mg / L, calculated as CaCO3). The license number for the use of experimental animals is: SYXK(Zhe)2022 - 0004, and the feeding management meets the requirements of international AAALAC accreditation (accreditation number: 001458), and the IACUC ethical review number is: IACUC - 2024 - 10185 - 01.

[0126] Instruments, consumables and reagents: Dissecting microscope (OLYMPUS, model: SZX7), CCD camera (Shanghai Tusen Vision Technology Co., Ltd., model: VertA1, China), precision electronic balance (OHAUS, model: CP214); 6-well plates (Zhejiang Beranbo Biotechnology Co., Ltd.); Methyl cellulose (Shanghai Aladdin Biochemical Technology Co., Ltd., batch number: C2004046), Dimethyl sulfoxide (DMSO; Sigma).

[0127] Sample preparation information: Compound I - 1, with water as the solvent.

[0128] Detection methods and results: <(

[0129] (1) Determination of 10% lethal concentration (LC 10 ) and maximum non - lethal concentration (MNLC)

[0130] Wild - type AB strain zebrafish at 2 days post - fertilization (2 dpf) were randomly selected and placed in 6 - well plates, with thirty zebrafish in each well (experimental group). The samples were administered by water solution (concentrations are shown in Table 6), and a normal control group was set up simultaneously, with a volume of 3 mL per well. They were treated at 28 °C for 72 h, and the number of dead zebrafish in each experimental group was counted daily and removed in a timely manner. The best "concentration - mortality" effect curve was plotted using Origin 8.0 statistical software, and the LC 10 and MNLC of the samples on zebrafish were calculated.

[0131] The results are shown in Table 6 and Figure 6. The MNLC of Compound I - 1 on the acute toxicity of zebrafish is 1.93 μg / mL, and the LC 10 is 1.98 μg / mL.

[0132] Table 6. "Concentration - mortality" results after treatment with Compound I - 1 (n = 30)

[0133] (2) Acute toxicity evaluation

[0134] Wild-type AB strain zebrafish (2 dpf) were randomly selected and placed in 6-well plates, with 30 zebrafish treated in each well (experimental group). Samples were administered in water solution (concentrations shown in Table 7), and a normal control group was also included. The volume per well was 3 mL. Treatment was carried out at 28℃ for 72 h. The number of dead zebrafish in each experimental group was counted daily and removed promptly. After the experiment, the reactions of the zebrafish's heart, circulatory system, hemorrhage and thrombosis, brain, lower jaw, eyes, liver, kidneys, intestines, trunk / tail / notochord, muscles / segments, body coloration, and body length were observed and recorded under a dissecting microscope. Photographs of typical toxic organs were collected. The acute toxicity of the samples to zebrafish was evaluated based on the incidence of toxicity in each organ, and the toxic target organs were identified.

[0135] The results are detailed in Table 7. Within the effective concentration range (<0.244 μg / mL), compound I-1 does not produce any toxicity.

[0136] Table 7. Statistics on the incidence of acute toxicity in samples (n=30) Note: "-" indicates that no obvious abnormalities were observed.

Claims

1. A 1-thienyl-β-carbamoline derivative or a pharmaceutically acceptable salt thereof, as shown in Formula I: in, R 1 For hydrogen, fluorine, chlorine, or bromine, R 2 It is hydrogen, methyl, or trifluoromethyl, R 3 For methyl, R 4 It is a C1-C4 straight-chain or branched alkyl group.

2. The 1-thienyl-β-carbamoline derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R 1 For hydrogen, fluorine, chlorine, or bromine, R 2 For hydrogen, R 3 For methyl, R 4 It is methyl, ethyl, propyl, or butyl; or R 1 For hydrogen, R 2 It is methyl or trifluoromethyl, R 3 For methyl, R 4 It can be methyl, ethyl, propyl or butyl.

3. The 1-thienyl-β-carbamoline derivative or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that: R 1 For hydrogen or fluorine, R 2 For hydrogen or methyl, R 3 For methyl, R 4 It can be methyl, ethyl, propyl or butyl. 4.1-Thienyl-β-carbamoline derivatives or pharmaceutically acceptable salts thereof, characterized in that: The 1-thienyl-β-carboline derivatives mentioned above are selected from the following compounds:

5. A method for preparing the 1-thienyl-β-carbamoline derivative according to claim 1, characterized in that: The synthesis route is as follows: Among them, R 1 R 2 R 3 and R 4 The definition is as described in claim 1; This includes: Compound II and Compound III undergo a Pictet-Spengler reaction to obtain Compound IV, and Compound IV is further dehydrogenated and aromatized to obtain a 1-thienyl-β-carboline derivative as shown in Formula I.

6. The method for preparing 1-thienyl-β-carbamoline derivatives according to claim 5, characterized in that: Includes the following steps: Step (1), Pictet-Spengler reaction: using dichloromethane as the reaction solvent and trifluoroacetic acid as the catalyst, compound II and compound III undergo a Pictet-Spengler reaction to generate compound IV under the action of the catalyst; wherein, the molar ratio of compound II to compound III is 1:1 to 1.5:1, preferably 1.2:1; the molar ratio of the catalyst to compound II is 4:1 to 1:1, preferably 2.5:1; Step (2), Dehydrogenation aromatization reaction: Using N,N-dimethylformamide as the reaction solvent and 10% Pd / C as the catalyst, compound IV undergoes a dehydrogenation aromatization reaction to generate 1-thienyl-β-carbamoline derivatives as shown in Formula I; wherein, the mass ratio of 10% Pd / C to compound IV is 1:5.5 to 1:

6.

7. Use of the 1-thienyl-β-carboline derivative or a pharmaceutically acceptable salt thereof as described in any one of claims 1-4 in the preparation of IDO1 and / or TDO inhibitors; preferably, use of the 1-thienyl-β-carboline derivative or a pharmaceutically acceptable salt thereof as described in any one of claims 1-4 in the preparation of dual IDO1 and TDO inhibitors.

8. Use of the 1-thienyl-β-carbamoline derivative or a pharmaceutically acceptable salt thereof as described in any one of claims 1-4 in the preparation of a medicament for treating IDO1 and TDO-mediated diseases.

9. The use according to claim 8, characterized in that: The diseases mediated by IDO1 and TDO are central nervous system diseases caused by abnormalities in the IDO1 and TDO-mediated tryptophan-kynurenine metabolic pathway, preferably depression, anxiety, Parkinson's disease, or Alzheimer's disease.

10. A pharmaceutical composition, characterized in that: The pharmaceutical composition comprises, as an active ingredient or main active ingredient, a 1-thienyl-β-carbamoline derivative or a pharmaceutically acceptable salt thereof as described in any one of claims 1-4, and is prepared into a pharmaceutically acceptable dosage form with a pharmaceutically acceptable carrier.

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