1-thienyl-beta-carboline IDO1 and TDO dual inhibitor and medical application thereof

Abstract

The invention discloses a 1-thienyl-beta-carboline IDO1 and TDO dual inhibitor, which is selected from 1-thienyl-beta-carboline derivatives or pharmaceutically acceptable salts thereof as shown in a formula I, R1 is hydrogen, fluorine, chlorine or bromine, R2 is hydrogen, methyl or trifluoromethyl, R3 is methyl, and R4 is C1-C4 straight chain or branched chain alkyl. The invention further discloses application of the 1-thienyl-beta-carboline derivative or the pharmaceutically acceptable salt of the 1-thienyl-beta-carboline derivative in preparation of an IDO1 and TDO dual inhibitor. The invention further discloses application of the 1-thienyl-beta-carboline derivative or the pharmaceutically acceptable salt of the 1-thienyl-beta-carboline derivative in preparation of a medicine for treating IDO1 and TDO mediated diseases. The IDO1 and TDO mediated diseases are central nervous system diseases with IDO1 and TDO mediated tryptophan-kynurenine metabolic pathway abnormality, and specifically, the IDO1 and TDO mediated central nervous system diseases comprise depression, anxiety disorder, Parkinson's disease and Alzheimer's disease. # imgabs0 #

Description

Technical Field

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

[0002] Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting more than 1% of the elderly population over 65 years old (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 and striatum, and clinically manifests as motor and non-motor symptoms. Compared with the main motor symptoms such as rigidity, bradykinesia and resting tremor, non-motor symptoms such as sleep disorders, depression, anxiety and constipation are often ignored and not effectively treated in the early stages of PD (Mondal AC, et al. Ageing Res Rev. 2023, 85: 101840). In the clinical manifestations of patients with advanced PD, the above non-motor 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 non-motor symptoms at all stages of the PD process, affecting about 38% of PD patients (Cong S, Neurosci Biobehav Rev. 2022, 141: 104749); among them, patients with severe depression account for about 14%. At present, clinical drugs that act on the dopamine pathway, such as levodopa, dopamine receptor agonists, and monoamine oxidase B inhibitors, are mainly used to relieve the motor symptoms of PD patients, but have limited efficacy on non-motor symptoms. Therefore, there is an urgent need to develop new treatments that can effectively relieve the motor symptoms of PD and improve some non-motor 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, quinolinic acid, etc. (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 PD. Clinical studies have shown that in patients with depression and PD, the activity of indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO), the first rate-limiting enzyme of the kynurenine pathway, is upregulated, leading to an increase in the kynurenine / tryptophan ratio in peripheral blood and cerebrospinal fluid. Elevated levels of free radical precursor 3-hydroxykynurenine and excitotoxin quinolinic acid were also observed in the putamen, prefrontal cortex, and substantia nigra compacta of PD patients. It is worth noting that TDO is mainly expressed in the liver and is responsible for regulating tryptophan levels throughout the body; while IDO1 can be activated by proinflammatory 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 new treatment strategy for patients with PD and depression.

[0004] Currently, most IDO1 and TDO inhibitors are being evaluated for anti-tumor 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 new dual IDO1 / TDO inhibitor 1H-indazole-4-amine, which exhibited anti-PD effects in MPTP-induced mouse models (Li GB, J Med Chem. 2021, 64(12): 8303). Andreasson et al. demonstrated the effectiveness of a brain-penetrating IDO1 inhibitor (PF-06840003) against neurodegenerative diseases such as Alzheimer's disease and PD dementia (Andreasson KI, Science. 2024, 385(6711):eabm6131). In summary, given the therapeutic potential of IDO1 and TDO inhibitors in central nervous system diseases such as PD, depression, and Alzheimer's disease, the discovery of new and effective IDO1 and TDO inhibitors is still highly demanded. Summary of the invention

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

[0006] 1-thienyl-β-carboline derivatives or pharmaceutically acceptable salts thereof having a structure as shown in formula (I):

[0007]

[0008] Among them, R 1 is hydrogen, fluorine, chlorine or bromine, R 2 is hydrogen, methyl or trifluoromethyl, R 3 is methyl, R 4 It is a C1~C4 straight chain or branched chain alkyl.

[0009] Furthermore, R 1 When R is hydrogen, fluorine, chlorine or bromine, 2 is hydrogen, R 3 is methyl, R 4 is methyl, ethyl, propyl or butyl;

[0010] R 1 When it is hydrogen, R 2 is methyl or trifluoromethyl, R 3 is methyl, R 4 It is methyl, ethyl, propyl or butyl.

[0011] Furthermore, a 1-thienyl-β-carboline derivative or a pharmaceutically acceptable salt thereof having the general formula (I) is characterized in that: R 1 is hydrogen or fluorine, R 2 is hydrogen or methyl; R 3 is methyl; R 4 It is methyl, ethyl, propyl or butyl.

[0012] Furthermore, R 1 is hydrogen or fluorine, R 2 is hydrogen or methyl, R 3 is methyl, R 4 is methyl, ethyl, propyl or butyl; but does not include: R 1 is hydrogen, R 2 is methyl, R 3 is methyl, R 4is methyl or ethyl; R 1 is fluorine, R 2 is hydrogen, R 3 is methyl, R 4 It is propyl.

[0013] Specifically, the 1-thienyl-β-carboline derivatives are selected from the following compounds:

[0014]

[0015] The compound codes involved in the following pharmacological experiments are equivalent to the compounds corresponding to the codes herein.

[0016] The pharmaceutically acceptable salt of the 1-thienyl-β-carboline derivative is a salt formed by the 1-thienyl-β-carboline derivative and an inorganic acid or an organic acid.

[0017] The pharmaceutically acceptable salt of the 1-thienyl-β-carboline derivative can be synthesized by general chemical methods. Generally, it is prepared by reacting a free 1-thienyl-β-carboline derivative with an equal chemical equivalent or excess acid (inorganic acid or organic acid) in a suitable solvent or solvent combination.

[0018] Another object of the present invention is to provide a method for preparing the 1-thienyl-β-carboline derivatives, the synthetic route of which is as follows:

[0019]

[0020] Among them, R 1 , R 2 , R 3 and R 4 The definition of is as mentioned above;

[0021] The method comprises: compound II and compound III are subjected to Pictet-Spengler reaction to obtain compound IV, and compound IV is further subjected to dehydrogenation aromatization to obtain 1-thienyl-β-carboline derivatives shown in formula I.

[0022] The specific steps include:

[0023] Step (1), Pictet-Spengler reaction: using dichloromethane as a reaction solvent and trifluoroacetic acid as a catalyst, compound II and compound III undergo a Pictet-Spengler reaction under the action of the catalyst to generate compound IV;

[0024] Step (2), dehydrogenation aromatization reaction: using N,N-dimethylformamide as a reaction solvent and 10% Pd / C as a catalyst, compound IV undergoes a dehydrogenation aromatization reaction to produce a 1-thienyl-β-carboline derivative shown in formula I.

[0025] In step (1), the molar ratio of compound II to compound III is 1:1 to 1.5:1, preferably 1.2:1.

[0026] The molar ratio of the catalyst to compound II is 4:1 to 1:1, preferably 2.5:1.

[0027] The reaction temperature of the Pictet-Spengler reaction is room temperature.

[0028] After the reaction, the pH of the reaction solution was adjusted to 7-8 with sodium bicarbonate aqueous solution, extracted with ethyl acetate, and the organic layers were combined, washed with saturated brine, dried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure to obtain compound IV.

[0029] In step (2), the mass ratio of the 10% Pd / C to compound IV is 1:5.5 to 1:6.

[0030] The reaction temperature of the dehydrogenation aromatization reaction is 120-160°C, preferably 140°C.

[0031] After the reaction is completed, the reaction is filtered and the filtrate is collected. The filtrate is concentrated by distillation under reduced pressure to obtain a crude product. The crude product is chromatographed on a normal phase silica gel column using petroleum ether / ethyl acetate in a volume ratio of 5 / 1 to 2 / 1 as an eluent to purify the 1-thienyl-β-carboline derivatives shown in formula I.

[0032] Another object of the present invention is to provide the use of the 1-thienyl-β-carboline derivatives or pharmaceutically acceptable salts thereof in the preparation of IDO1 and / or TDO inhibitors.

[0033] Another object of the present invention is to provide the use of the 1-thienyl-β-carboline derivatives or pharmaceutically acceptable salts thereof in the preparation of dual inhibitors of IDO1 and TDO.

[0034] Another object of the present invention is to provide the use of the 1-thienyl-β-carboline derivatives or pharmaceutically acceptable salts thereof in the preparation of drugs for treating IDO1 and TDO-mediated diseases.

[0035] The IDO1 and TDO-mediated diseases are central nervous system diseases with abnormal tryptophan-kynurenine metabolic pathways mediated by IDO1 and TDO, specifically depression, anxiety, Parkinson's disease, and Alzheimer's disease.

[0036] Another object of the present invention is to provide a pharmaceutical composition, wherein the pharmaceutical composition comprises the 1-thienyl-β-carboline derivative or a pharmaceutically acceptable salt thereof as an effective ingredient or a main effective ingredient and a pharmaceutically acceptable carrier to prepare a pharmaceutically acceptable dosage form.

[0037] The dosage form is tablet, capsule, powder, pill, suspension or nasal spray. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 The percentage of time spent moving in the bright field by zebrafish after treatment with compound I-1 in Example 14; compared with the model control group, *p<0.05, ***p<0.001.

[0039] Figure 2 is the total movement distance of zebrafish after treatment with compound I-1 in Example 14; wherein, compared with the model control group, **p<0.01, ***p<0.001.

[0040] Figure 3 is the movement speed of zebrafish after treatment with compound I-1 in Example 14; compared with the model control group, **p<0.01, ***p<0.001. .

[0041] Figure 4 The 5-HT content in zebrafish treated with compound I-1 in Example 14; compared with the model control group, **p<0.01, ***p<0.001.

[0042] Figure 5 DA content in zebrafish after treatment with compound I-1 in Example 14; compared with the model control group, *p<0.05, **p<0.01.

[0043] Figure 6 This is the “concentration-mortality” curve of compound I-1 in Example 15. DETAILED DESCRIPTION

[0044] In order to further illustrate the technical solution of the present invention, a series of embodiments are given below. These embodiments can 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.

[0045] Example 1

[0046] Preparation of 1-(2,5-dimethylthiophen-3-yl)-9H-pyrido[3,4-b]indole (Compound I-1)

[0047]

[0048] 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, and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was stirred at room temperature overnight, and the raw material disappeared by TLC determination. The pH of the reaction solution was adjusted to 8 with saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate (20 mL × 3), and the organic layers were combined, washed with saturated brine, dried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure to obtain a light yellow solid (compound 3, 478.63 mg, yield 76%).

[0049] Dehydrogenation aromatization reaction: In a 100 mL round-bottom flask, compound 3 (479 mg, 1.69 mmol) was added and dissolved with 10 mL of N,N-dimethylformamide. At room temperature, 10% Pd / C (80 mg) was added while stirring. The reaction mixture was heated to 140 ° C for 12 h. At this time, the raw material disappeared as determined by TLC. The product was filtered and the filtrate was collected and concentrated by vacuum distillation to give a yellow crude product, which was then purified by normal phase silica gel column chromatography (eluent: petroleum ether / ethyl acetate volume ratio = 5 / 1 to 2 / 1) to give a light 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] + .

[0050] Example 2

[0051] Preparation of 1-(2,5-dimethylthiophen-3-yl)-6-fluoro-9H-pyrido[3,4-b]indole (Compound I-2)

[0052]

[0053] Referring to the preparation method of compound I-1, only an equal molar amount of 5-fluoroindoleethylamine was used to replace the indoleethylamine in Example 1. After Pictet-Spengler reaction and dehydrogenation aromatization reaction, a light yellow solid (compound I-2, 271 mg, two-step yield 41%) was obtained. 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] + .

[0054] Example 3

[0055] Preparation of 1-(2,5-dimethylthiophen-3-yl)-7-methyl-9H-pyrido[3,4-b]indole (Compound I-3)

[0056]

[0057] Referring to the preparation method of compound I-1, only an equal molar amount of 6-methylindoleethylamine was used to replace the indoleethylamine in Example 1. After Pictet-Spengler reaction and dehydrogenation aromatization reaction, a light yellow solid (compound I-3, 306 mg, two-step yield 47%) was obtained. 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] + .

[0058] Example 4

[0059]

[0060] Preparation of 4-bromo-5-methylthiophene-2-carbaldehyde (Compound 5)

[0061] In a 100mL round-bottom flask, 5-methyl-2-thiophenecarboxaldehyde (compound 4, 2g, 15.8mmol) was dissolved in 15mL DMF, and N-bromosuccinimide (4g, 22mmol) and FeCl3 (0.1g, 0.62mmol) were slowly added in batches under stirring. The reaction mixture was stirred at room temperature overnight, at which time the raw material disappeared as determined by TLC, and extracted with ethyl acetate (30mL×3), the organic layers were combined, washed with saturated brine, dried over anhydrous Na2SO4, and pale yellow transparent crystals (compound 5, 2.5g, yield 78%) were precipitated at 0°C. 1 H NMR (400MHz, CDCl3) δ9.76 (s, 1H), 7.57 (s, 1H), 2.47 (s, 3H); MS (ESI) m / z 206.9 [M+H] + .

[0062] Preparation of 1-(4-bromo-5-methylthiophen-2-yl)ethan-1-ol (Compound 6)

[0063] 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 THF. Under a nitrogen atmosphere, a THF solution of methylmagnesium chloride (2.0 M, 2.5 mL, 5 mmol) was slowly added at -78 °C with stirring; the reaction mixture was stirred at room temperature for 1 h, at which time the starting material disappeared as determined by TLC. 1N HCl was added to the reaction mixture to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with saturated sodium bicarbonate solution and saturated brine in turn, 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 light yellow oily substance (compound 6, 0.98 g, yield 90%). 1 HNMR (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] + .

[0064] Preparation of 5-ethyl-2-methylthiophene-3-carbaldehyde (Compound 7)

[0065] In a 100 mL round-bottom flask, 1-(4-bromo-5-methylthiophen-2-yl)ethan-1-ol (Compound 6, 0.75 g, 3.4 mmol) was dissolved in 10 mL of dichloromethane, and triethylsilane (2.5 mL) and trifluoroacetic acid (2.5 mL) were slowly added in batches under stirring; the reaction mixture was stirred at room temperature for 2 h, at which time the raw material disappeared as determined by TLC, and the mixture was extracted with dichloromethane (10 mL × 3), the organic layers were combined, washed with saturated aqueous sodium bicarbonate 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 into a 100 mL double-necked flask, dissolved with 10 mL of THF, and under a nitrogen atmosphere, n-butyl lithium hexane solution (1.6 M, 3 mL, 4.8 mmol) was slowly added with 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 time the raw material disappeared as determined by TLC. The mixture was extracted with ethyl acetate (15 mL×3), the organic layers were combined, 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 chromatography (eluent: pure petroleum ether) to obtain a pale yellow oil (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] + .

[0066] Preparation of 1-(5-ethyl-2-methylthiophen-3-yl)-9H-pyrido[3,4-b]indole (Compound I-4)

[0067]

[0068] Referring to the preparation method of compound I-1, only an equal molar amount of 5-ethyl-2-methylthiophene-3-carboxaldehyde was used to replace the 2,5-dimethylthiophene-3-carboxaldehyde in Example 1. After Pictet-Spengler reaction and dehydrogenation aromatization reaction, a light yellow solid was obtained (compound I-4, 254 mg, two-step yield 39%). 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] + .

[0069] Example 5

[0070] Preparation of 1-(5-ethyl-2-methylthiophen-3-yl)-6-fluoro-9H-pyrido[3,4-b]indole (Compound I-5)

[0071]

[0072] Referring to the preparation method of compound I-1, only 5-fluoroindoleethylamine and 5-ethyl-2-methylthiophene-3-carboxaldehyde were used to replace the indoleethylamine and 2,5-dimethylthiophene-3-carboxaldehyde in Example 1 respectively. After Pictet-Spengler reaction and dehydrogenation aromatization reaction, a light yellow solid was obtained (compound I-5, 284 mg, two-step yield 41%). 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] + .

[0073] Example 6

[0074] Preparation of 1-(5-ethyl-2-methylthiophen-3-yl)-7-methyl-9H-pyrido[3,4-b]indole (Compound I-6)

[0075]

[0076] Referring to the preparation method of compound I-1, only 6-methylindoleethylamine and 5-ethyl-2-methylthiophene-3-carboxaldehyde were used to replace the indoleethylamine and 2,5-dimethylthiophene-3-carboxaldehyde in Example 1 respectively. After Pictet-Spengler reaction and dehydrogenation aromatization reaction, a light yellow solid was obtained (compound I-6, 273 mg, two-step yield 40%). 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] + .

[0077] Example 7

[0078] Preparation of 2-methyl-5-propyl-3-thiophenecarboxaldehyde (Compound 8)

[0079]

[0080] Referring to the preparation method of compound 7, 5-methyl-2-thiophenecarboxaldehyde (compound 4) was used as the starting material, and only the methylmagnesium chloride THF solution was replaced by an equimolar amount (based on ethylmagnesium chloride) of ethylmagnesium chloride THF solution to obtain a light yellow oil (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] + .

[0081] Preparation of 1-(2-methyl-5-propylthiophen-3-yl)-9H-pyrido[3,4-b]indole (Compound I-7)

[0082]

[0083] Referring to the preparation method of compound I-1, only an equal molar amount of 2-methyl-5-propyl-3-thiophenecarboxaldehyde was used to replace the 2,5-dimethylthiophene-3-carboxaldehyde in Example 1. After Pictet-Spengler reaction and dehydrogenation aromatization reaction, a light yellow oil was obtained (compound I-7, 171 mg, two-step yield 25%). 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] + .

[0084] Example 8

[0085] Preparation of 1-(2-methyl-5-propylthiophen-3-yl)-6-fluoro-9H-pyrido[3,4-b]indole (Compound I-8)

[0086]

[0087] Referring to the preparation method of compound I-1, only 5-fluoroindoleethylamine and 2-methyl-5-propyl-3-thiophenecarboxaldehyde were used to replace the indoleethylamine and 2,5-dimethylthiophene-3-carboxaldehyde in Example 1 respectively. After Pictet-Spengler reaction and dehydrogenation aromatization reaction, a light yellow solid was obtained (compound I-8, 253 mg, two-step yield 35%). 1 HNMR (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] + .

[0088] Example 9

[0089] Preparation of 1-(2-methyl-5-propylthiophen-3-yl)-7-methyl-9H-pyrido[3,4-b]indole (Compound I-9)

[0090]

[0091] Referring to the preparation method of compound I-1, only 6-methylindoleethylamine and 2-methyl-5-propyl-3-thiophenecarboxaldehyde were used to replace the indoleethylamine and 2,5-dimethylthiophene-3-carboxaldehyde in Example 1 respectively. After Pictet-Spengler reaction and dehydrogenation aromatization reaction, a light yellow oil was obtained (compound I-9, 236 mg, two-step yield 33%). 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] + .

[0092] Example 10

[0093] Preparation of 5-butyl-2-methylthiophene-3-carbaldehyde (Compound 9)

[0094]

[0095] Referring to 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-propylmagnesium chloride) of n-propylmagnesium chloride THF solution was used to replace the methylmagnesium chloride THF solution to obtain a light yellow oil (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] + .

[0096] Preparation of 1-(5-butyl-2-methylthiophen-3-yl)-9H-pyrido[3,4-b]indole (Compound I-10)

[0097]

[0098] Referring to the preparation method of compound I-1, only an equal molar amount of 5-butyl-2-methylthiophene-3-carboxaldehyde was used to replace the 2,5-dimethylthiophene-3-carboxaldehyde in Example 1. After Pictet-Spengler reaction and dehydrogenation aromatization reaction, a light yellow oil was obtained (compound I-10, 214 mg, two-step yield 30%). 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] + .

[0099] Embodiment 11

[0100] Preparation of 1-(5-butyl-2-methylthiophen-3-yl)-6-fluoro-9H-pyrido[3,4-b]indole (Compound I-11)

[0101]

[0102] Referring to the preparation method of compound I-1, only 5-fluoroindoleethylamine and 5-butyl-2-methylthiophene-3-carboxaldehyde were used to replace the indoleethylamine and 2,5-dimethylthiophene-3-carboxaldehyde in Example 1 respectively. After Pictet-Spengler reaction and dehydrogenation aromatization reaction, a light yellow oil was obtained (compound I-11, 279 mg, two-step yield 37%). 1H 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] + .

[0103] Example 12

[0104] Preparation of 1-(5-butyl-2-methylthiophen-3-yl)-7-methyl-9H-pyrido[3,4-b]indole (Compound I-12)

[0105]

[0106] Referring to the preparation method of compound I-1, only 6-methylindoleethylamine and 5-butyl-2-methylthiophene-3-carboxaldehyde were used to replace the indoleethylamine and 2,5-dimethylthiophene-3-carboxaldehyde in Example 1 respectively. After Pictet-Spengler reaction and dehydrogenation aromatization reaction, a light yellow oil was obtained (compound I-12, 261 mg, two-step yield 35%). 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] + .

[0107] Embodiment 13

[0108] In vitro assay for the inhibitory activity of human recombinant IDO1 and TDO enzymes

[0109] Instruments, consumables and reagents: microplate reader (Bio-Tekb, model: SYNERGYb H1), 96-well plate (NestBiotech), human recombinant IDO1 and TDO enzymes (TopScience), human catalase (Sigma), L-tryptophan (Sigma), potassium phosphate (Sangon Biotechnology Co., Ltd.), methylene blue (Shanghai MacLean Biochemical Technology Co., Ltd.), ascorbic acid (Sangon Biotechnology Co., Ltd.), and other reagents were of analytical grade.

[0110] Test compounds: Compounds I-1 to I-12, positive control drugs PF-06840003, 680C91. The test compounds were diluted in 8 concentrations (diluted in a 1:3 ratio) with potassium phosphate buffer containing 5% DMSO to obtain a series of concentrations of test compound solutions for in vitro human recombinant IDO1 and TDO enzyme inhibition activity tests.

[0111] Experimental steps:

[0112] Take a 96-well plate and set up a blank group, a negative group and a test group, with 2 replicates in each group. Except for the incubation process, all the following operations were performed at 0°C. Prepare a 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 human recombinant IDO1 (40 nM). Test group: 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) were added to the 96-well plate and mixed 3 times; blank group: 20 μL of standard reaction solution was added to each well; negative group: 10 μL of standard reaction and 10 μL of L-tryptophan (900 μM, pH 6.5 potassium phosphate buffer) were added to each well. The reaction mixture was incubated at 37°C for 180 min, and the UV absorption signal was detected.

[0113] Take a 96-well plate and set up a blank group, a negative group and a test group, with 2 replicates in each group. Except for the incubation process, all the following operations were performed at 0°C. Prepare a 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 human recombinant TDO (50 nM). Test group: 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) were added to the 96-well plate and mixed 3 times; blank group: 20 μL of standard reaction solution was added to each well; negative group: 10 μL of standard reaction and 10 μL of L-tryptophan (200 μM, pH 6.5 potassium phosphate buffer) were added to each well. The reaction mixture was incubated at 37°C for 75 min, and the UV absorption signal was detected.

[0114] The activity of the enzyme 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. The dose-effect curve was fitted using Graph Pad Prism software to calculate the IC of the test compound to inhibit IDO1 and TDO enzymes. 50 Values; repeated at least twice at different time points

[0115] Experimental results:

[0116] The results are shown in Table 1, indicating that the compounds of the present invention have significant inhibitory effects on the activities of human recombinant IDO1 and TDO enzymes. Among them, compound I-1 has the best inhibitory effect on IDO1 and TDO enzymes (IDO1: IC 50 =0.33μM, TDO:IC 50 =1.78 μM). In addition, the IDO1 enzyme inhibitory activity of the positive control drug PF-06840003 was measured using the detection method of this example. 50 The value was 0.37 μM, while the IC of 680C91 for TDO enzyme inhibition activity was 50 The value is 0.56 μM, which is comparable to the literature value. Therefore, it can be seen that the test results of the in vitro human recombinant IDO1 and TDO enzyme inhibitory activity of the present invention are reliable.

[0117] The inventor's structure-activity relationship study showed that: adjusting the R 1 is chlorine or bromine, the activity of the compound is maintained; adjust the R of compounds I-2, I-5, I-8, and I-11 2 The compound remains active.

[0118] Table 1. Analysis results of the inhibitory activity of the compounds of the present invention on human IDO1 and TDO enzymes

[0119]

[0120]

[0121] Embodiment 14

[0122] Pharmacodynamic evaluation of compound I-1 in improving motor ability and depressive symptoms in zebrafish model of Parkinson's disease with depression

[0123] Experimental animals: Zebrafish were kept in fish farming water at 28°C (water quality: 200 mg of instant sea salt was added to every 1L of reverse osmosis water, conductivity was 450-550 μS / cm; pH was 6.5-8.5; hardness was 50-100 mg / L, calculated as CaCO3). The experimental animal use license number is: SYXK (Zhejiang) 2022-0004, and the feeding and management complies with the requirements of the international AAALAC certification (certification number: 001458), and the IACUC ethics review number is: IACUC-2024-9085-01.

[0124] 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 plate (Zhejiang Bellanbo Biotechnology Co., Ltd.), 24-well plate (Nest Biotech), 96-well plate (Nest Biotech), behavior analyzer (ViewPoint, model Zebra Lab 3.11), multifunctional 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 ELISA Biotechnology Co., Ltd., batch number: 202403), Zebrafish DA Elisa Kit (Shanghai ELISA Biotechnology Co., Ltd., batch number: 202403).

[0125] Sample preparation information: Compound I-1, solvent is water. Positive control drug is Nomifensine maleate (hereinafter referred to as Nomifensine; Sigma, batch number: 029M4053V), solvent is water.

[0126] Testing methods and results:

[0127] (1) Maximum detectable concentration (MTC) determination

[0128] Wild-type AB strain zebrafish at 4 days post-fertilization (4dpf) were randomly selected in a 6-well plate, and 30 zebrafish were treated in each well (experimental group), and samples (concentrations are shown in Table 2) were given in water. At the same time, a normal control group and a model control group were set up, and the volume of each well was 3mL. In addition to the normal control group, the model control group and each experimental group were injected with LPS (50.0ng / fish) in the yolk sac, and MPTP (final concentration 25μM) was given in water to establish a zebrafish model of Parkinson's disease with depression. After treatment at 28℃ for 48h, the MTC of the sample on the model zebrafish was determined.

[0129] The results are shown in Table 2. The MTC value of compound I-1 in improving the zebrafish model of Parkinson's disease associated with depression was 0.244 μg / mL.

[0130] Table 2. Results of the drug efficacy concentration exploration experiment of compound I-1 (n=30)

[0131]

[0132] (2) Evaluation of the efficacy of compound I-1 in improving depressive symptoms

[0133] 4dpf wild-type AB strain zebrafish were randomly selected in a 6-well plate, and 30 zebrafish were treated in each well (experimental group). The samples were given water-soluble (concentrations are shown in Table 3), and the positive control nomifensine concentration was 1.50μg / mL. At the same time, a normal control group and a model control group were set up, and the volume of each well was 3mL. In addition to the normal control group, the experimental group and the model control group were injected with LPS (50.0ng / fish) in the yolk sac, and MPTP (25μM) was given water-soluble to establish a zebrafish model of Parkinson's disease with depression. After 48h of treatment at 28℃, 10 zebrafish were randomly selected from each group and placed in a 24-well plate, 1 fish per well, and the volume of each well was 1mL. The proportion of zebrafish bright field movement time was measured by a behavioral analyzer to evaluate the efficacy of the samples in improving the depressive symptoms of the zebrafish model of Parkinson's disease with depression. The statistical results were expressed as mean±SE. SPSS26.0 software was used for statistical analysis, and p<0.05 indicated that the difference was statistically significant.

[0134] The results are shown in Table 3 and Figure 1 Compound I-1 can improve the depressive symptoms of the zebrafish model of Parkinson's disease with depression, specifically by increasing the proportion of bright field movement time of zebrafish.

[0135] Table 3. Results of the evaluation of the efficacy of compound I-1 in improving depressive symptoms (n=10)

[0136]

[0137]

[0138] Note: Compared with the model control group, *p<0.05, ***p<0.001.

[0139] (3) Evaluation of the efficacy of compound I-1 in improving motor function in Parkinson's disease

[0140] 4dpf wild-type AB strain zebrafish were randomly selected in a 6-well plate, and 30 zebrafish were treated in each well (experimental group). The samples were given water-soluble (concentrations are shown in Table 4), and the positive control nomifensine concentration was 1.50μg / mL. At the same time, a normal control group and a model control group were set up, and the volume of each well was 3mL. In addition to the normal control group, the experimental group and the model control group were injected with LPS (50.0ng / fish) in the yolk sac, and MPTP (25μM) was given water-soluble to establish a zebrafish model of Parkinson's disease with depression. After 48h of treatment at 28℃, 10 zebrafish were randomly selected from each group and placed in a 96-well plate, 1 fish per well, and the volume of each well was 200μL. The total movement distance and movement speed of zebrafish for 1h were detected by a behavioral analyzer, and the statistical analysis results of this index were used to evaluate the efficacy of the sample in improving the motor ability of Parkinson's disease. The statistical analysis results are expressed as mean±SE. SPSS26.0 software was used for statistical analysis, and p<0.05 indicated that the difference was statistically significant.

[0141] The results are shown 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 movement distance and movement speed of zebrafish.

[0142] Table 4. Results of the evaluation of the efficacy of compound I-1 in improving motor symptoms of Parkinson's disease (n=10)

[0143]

[0144] Note: Compared with the model control group, **p<0.01, ***p<0.001.

[0145] (4) Evaluation of the efficacy of compound I-1 in improving 5-hydroxytryptamine (5-HT) and dopamine (DA) levels in zebrafish

[0146] 4dpf wild-type AB strain zebrafish were randomly selected in a 6-well plate, and 30 zebrafish were treated in each well (experimental group). The samples were given water-soluble (concentrations are shown in Table 5), and the positive control nomifensine concentration was 1.50μg / mL. At the same time, a normal control group and a model control group were set up, and the volume of each well was 3mL. In addition to the normal control group, the experimental group and the model control group were injected with LPS (50.0ng / fish) in the yolk sac, and MPTP (25μM) was given water-soluble to establish a zebrafish model of Parkinson's disease with depression. After 48h of treatment at 28℃, the 5-HT and DA kit instructions were followed, and the data were collected using a multifunctional microplate reader to analyze the 5-HT and DA content of zebrafish in each experimental group. The statistical analysis results of this index were used to evaluate the efficacy of the sample in improving the 5-HT and DA levels in zebrafish. The statistical analysis results were expressed as mean±SE. SPSS26.0 software was used for statistical analysis, and p<0.05 indicated that the difference was statistically significant.

[0147] The results are shown in Table 5. Figure 4 and Figure 5 Compound I-1 has the effect of improving the depression symptoms associated with Parkinson's disease, specifically by increasing the levels of 5-HT and DA in zebrafish.

[0148] Table 5. Results of the efficacy evaluation of compound I-1 in improving 5-HT and DA levels in zebrafish (n=3)

[0149]

[0150] Note: Compared with the model control group, *p<0.05, **p<0.01, ***p<0.001.

[0151] Embodiment 15

[0152] Acute toxicity evaluation of compound I-1

[0153] Experimental animals: Zebrafish were kept in fish farming water at 28°C (water quality: 200 mg of instant sea salt was added to every 1L of reverse osmosis water, conductivity was 450-550 μS / cm; pH was 6.5-8.5; hardness was 50-100 mg / L, calculated as CaCO3). The experimental animal use license number is: SYXK (Zhejiang) 2022-0004, and the feeding and management complies with the requirements of the international AAALAC certification (certification number: 001458), and the IACUC ethics review number is: IACUC-2024-10185-01.

[0154] 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 plate (Zhejiang Bellambo Biotechnology Co., Ltd.); methylcellulose (Shanghai Aladdin Biochemical Technology Co., Ltd., batch number: C2004046), dimethyl sulfoxide (DMSO; Sigma).

[0155] Sample preparation information: Compound I-1, solvent is water.

[0156] Testing methods and results:

[0157] (1) 10% lethal concentration (LC 10 ) and maximum non-lethal concentration (MNLC) determination

[0158] Wild-type AB strain zebrafish 2 days post-fertilization (2dpf) were randomly selected in a 6-well plate, and 30 zebrafish were treated in each well (experimental group). The samples were dissolved in water (concentrations are shown in Table 6), and a normal control group was set up at the same time, with a volume of 3mL per well. The treatment was carried out at 28℃ for 72h, and the number of zebrafish deaths in each experimental group was counted every day and removed in time. The optimal "concentration-mortality" effect curve was drawn using Origin 8.0 statistical software, and the LC of the samples on zebrafish was calculated. 10 and MNLC.

[0159] The results are shown in Table 6 and Figure 6 The acute toxicity of compound I-1 to zebrafish was MNLC1.93μg / mL, and the LC 10 It is 1.98μg / mL.

[0160] Table 6. "Concentration-mortality" results after treatment with compound I-1 (n=30)

[0161]

[0162] (2) Acute toxicity evaluation

[0163] 2dpf wild-type AB strain zebrafish were randomly selected in a 6-well plate, and 30 zebrafish were treated in each well (experimental group). The samples were dissolved in water (concentrations are shown in Table 7), and a normal control group was set up at the same time, with a capacity of 3mL per well. The zebrafish were treated at 28℃ for 72h, and the number of zebrafish deaths in each experimental group was counted every day and removed in time. After the experiment, the zebrafish heart, circulatory system, bleeding and thrombosis, brain, mandible, eyes, liver, kidney, intestine, trunk / tail / notochord, muscle / somite, body coloration, body length and other reactions were observed and recorded under a dissecting microscope, and photos of typical toxic organs were collected. The acute toxicity of the samples to zebrafish was evaluated by the toxicity incidence of each organ, and the toxic target organs were identified.

[0164] The results are shown in Table 7. Within the effective concentration range (<0.244 μg / mL), compound I-1 did not produce any toxicity.

[0165] Table 7. Statistical table of acute toxicity incidence of samples (n=30)

[0166]

[0167]

[0168] Note: “-” indicates no obvious abnormality.

Claims

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

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

3. The 1-thienyl-β-carboline derivative or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that: R 1 is hydrogen or fluorine, R 2 is hydrogen or methyl, R 3 is methyl, R 4 It is methyl, ethyl, propyl or butyl.

4. 1-Thienyl-β-carboline derivatives or pharmaceutically acceptable salts thereof, characterized in that: The 1-thienyl-β-carboline derivatives are selected from the following compounds:

5. A method for preparing the 1-thienyl-β-carboline derivatives according to claim 1, characterized in that: The synthetic route is as follows: Among them, R 1 , R 2 , R 3 and R 4 The definition of is as in claim 1; The method comprises: compound II and compound III are subjected to Pictet-Spengler reaction to obtain compound IV, and compound IV is further subjected to dehydrogenation aromatization to obtain 1-thienyl-β-carboline derivatives shown in formula I.

6. The method for preparing 1-thienyl-β-carboline derivatives according to claim 5, characterized in that: The following steps are involved: Step (1), Pictet-Spengler reaction: using dichloromethane as a reaction solvent and trifluoroacetic acid as a catalyst, compound II and compound III undergo a Pictet-Spengler reaction under the action of the catalyst to generate compound IV; 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 a reaction solvent and 10% Pd / C as a catalyst, compound IV undergoes a dehydrogenation aromatization reaction to produce a 1-thienyl-β-carboline derivative shown in formula I; wherein the mass ratio of the 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 according to any one of claims 1 to 4 in the preparation of an IDO1 and / or TDO inhibitor; preferably, use of the 1-thienyl-β-carboline derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 in the preparation of an IDO1 and TDO dual inhibitor.

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

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

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

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