Carbazole derivatives as modulators of dopamine d2 / 3 receptors

Abstract

This invention discloses carbazole derivatives as dopamine D2 / 3 receptor modulators, as shown in formula (I), wherein the definitions of each substituent are detailed in the specification. Furthermore, this invention also discloses a method for preparing the compound and pharmaceutical compositions comprising it. The carbazole derivatives of this invention possess pharmacological effects of regulating dopamine D2 / 3 receptors and pharmacodynamic effects such as cognitive protection.

Description

Technical Field

[0001] This article relates to medicinal chemistry techniques, particularly carbazole derivatives as dopamine D2 / 3 receptor modulators, their preparation methods, pharmaceutical compositions, and uses. Background Technology

[0002] Schizophrenia is a complex and diverse group of mental illnesses characterized by severe disturbances in thinking, emotion, cognition, and behavior; it typically develops slowly or subacutely during young adulthood. Clinically, it generally presents in three aspects: positive symptoms, negative symptoms, and cognitive deficits. Positive symptoms refer to abnormalities or hyperactivity of mental function, including hallucinations, delusions, thought disorders, and loss of control over speech and behavior. Negative symptoms refer to decline or absence of mental function, including lack of motivation, emotional blunting, social withdrawal, and lack of willpower. Cognitive deficits mainly include difficulty concentrating, executive function, and work impairment. Globally, the overall lifetime prevalence of schizophrenia is 3.8-8.4 per 1,000. Most patients experience a chronic course of illness, and once diagnosed, the condition is prone to migration or relapse, leading to significant decline in mental function. Simultaneously, the quality of life for schizophrenia patients is significantly impaired, with unemployment rates as high as 80-90% and average life expectancy reduced by 10-20 years. More than half of patients eventually develop mental disability, placing a tremendous burden on patients, their families, and society. The causes of schizophrenia are not yet fully understood, but genetic factors may account for approximately 80%. Currently available antipsychotic drugs fall into two main categories: typical antipsychotic drugs and atypical antipsychotic drugs.

[0003] The common pharmacological action of typical antipsychotics is as D2 receptor antagonists, blocking the action of D2 receptors before and after the synapse of dopamine neurons, thereby reducing the function of the dopamine nervous system. Their therapeutic effects are mainly on the dopamine neurotransmitter pathways in the limbic lobe and midbrain cortex. The differences between the various types of typical antipsychotics are only the different sites of action and receptor subtype selectivity.

[0004] Typical antipsychotics are highly effective for the positive symptoms of schizophrenia, but the main problem is their inability to significantly improve patients' cognitive symptoms. Furthermore, because typical antipsychotics are non-selective for D2 receptors on dorsal striatal neurons (related to motor function) and ventral striatal neurons (related to limbic system function), they inevitably cause extrapyramidal side-effects (EPS) along with their therapeutic effects. These include acute dystonia, akathisia, rigidity, and tremors, as well as tardive dyskinesia, primarily manifesting as repetitive involuntary movements of the lips, face, legs, or trunk. Despite this, the importance of first-generation typical antipsychotics cannot be ignored, especially in treating patients resistant to atypical antipsychotics.

[0005] Clozapine not only demonstrated good clinical efficacy but also avoided extrapyramidal adverse reactions, proving for the first time that the therapeutic effect of antipsychotics can be completely separated from their adverse reactions. Because these drugs produce fewer or no extrapyramidal adverse reactions at therapeutic doses and are effective for both negative and cognitive symptoms, their mechanism of action differs significantly from traditional typical antipsychotics. Therefore, they are defined as "atypical antipsychotics" in contrast to typical antipsychotics. Atypical antipsychotics are a class of drugs effective for both positive and negative symptoms of psychosis, improving cognitive function, effective for diseases refractory to typical antipsychotics, and with fewer extrapyramidal adverse reactions and elevated prolactin levels. Following clozapine, new atypical antipsychotics have continued to emerge, with risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, zolpidem, amisulpride, and serindole becoming representative drugs in current clinical treatment. Unlike typical antipsychotics, atypical antipsychotics exhibit diverse pharmacological characteristics. Their chemical structures are either similar to or quite similar to clozapine (e.g., olanzapine, quetiapine, and zotiprine) or completely different (e.g., risperidone, ziprasidone, and serindole), but most possess the key characteristic of "atypicality," namely, 5-HT. 2A Selective D2 / D3 receptor antagonists exhibit a high ratio of D2 receptor blockade (except for amisulpride and aripiprazole) and a more pronounced effect on neurochemical activity in the limbic and frontal cortex, while having a very weak effect on the striatum. Amisulpride is a representative selective D2 / D3 receptor antagonist, a benzamide derivative that replaces sulpiride, and has highly selective D2 / D3 receptor antagonism. Because amisulpride produces fewer extrapyramidal adverse reactions, it is classified as an atypical antipsychotic. Aripiprazole has a completely different mechanism of action from other antipsychotics; it targets both D2 / 3 / 4 receptors and 5-HT. 1A Partial agonist of the receptor, and also 5-HT 2A / 2C Receptor antagonists. Although the exact mechanism of action of aripiprazole remains controversial, one thing is clear: single selective D2 receptor partial agonists are not very effective in treating schizophrenia. Only when D2 receptor partial agonists also target other receptors (such as 5-HT receptors and other subtypes of DA receptors) can they produce more satisfactory therapeutic effects. Most atypical antipsychotics have high affinity for 5-HT receptors. 2A Receptor antagonism, therefore using 5-HT 2A New drugs or compounds targeting receptors have emerged, and new drugs or compounds with different receptor selectivities have been developed, including ritanserin, M100907, and iriserin (SR46349B). Clinical studies have shown that although 5-HT... 2A / D2 type atypical antipsychotics and 5-HT 2A The receptor has a much stronger affinity than D2R, but it only antagonizes 5-HT. 2A The effect of receptors alone cannot achieve satisfactory therapeutic results; the regulation of D2R is indispensable.

[0006] In 2015, the FDA approved caliprazine, a D2 / 3R partial agonist with D3R selectivity (6-8 times), for the treatment of schizophrenia, mania, and type I bipolar disorder with mixed mania. Caliprazine demonstrated safe and effective treatment with fewer extrapyramidal reactions. Caliprazine has strong binding affinity for both D2R and D3R, but its selectivity for D3R is not good. Although there are currently no selective D3R modulators on the market, numerous studies have demonstrated that targeting D3R while avoiding D2R could be beneficial for the treatment of mental illnesses, especially schizophrenia. Therefore, the discovery and research of selective D3R modulators is essential.

[0007] To date, although selective D3R modulators have entered phase III clinical trials as antipsychotic drugs, the following bottlenecks remain based on existing experimental results: (1) The selectivity of existing candidate drugs for D3R and D2R is not high enough, resulting in insufficient improvement of negative symptoms and cognitive function in schizophrenia, and the extrapyramidal side effects are still relatively severe; (2) Low bioavailability; (3) Insufficient stability to hepatic drug-metabolizing enzymes, especially to primate hepatic drug-metabolizing enzymes, with a short half-life; (4) Low blood-brain barrier permeability or excretion as a substrate of P-glycoprotein in the blood-brain barrier; (5) Blocking hERG potassium ion channels, posing a risk of arrhythmia. Therefore, there is an urgent need to develop new highly selective and highly active D3R modulators to further confirm and improve the therapeutic effect of D3R on schizophrenia, so as to obtain antipsychotic drugs with good therapeutic effects and low side effects. Summary of the Invention

[0008] The following is an overview of the subject matter described in detail herein. This overview is not intended to limit the scope of the claims.

[0009] On the one hand, this application provides carbazole derivatives as modulators of dopamine D2, dopamine D3, or dopamine D2 and D3 receptors, said carbazole derivatives as shown in formula (I), or pharmaceutically acceptable salts, solvates, prodrugs, or stereoisomers thereof:

[0010]

[0011] In equation (I), one of Y1 and Y2 is -CH2-, while the other is -N(R3)-; R3 is -(CH2). n-A-R4, where n is an integer from 3 to 6, and A is non-existent (or a single bond), O, N(R5)C(O) or N(R5)C(O)O;

[0012] R1 is hydrogen or an unsubstituted C1-C6 alkyl group;

[0013] R2 is hydrogen, hydroxyl, halogen, unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl, unsubstituted C1-C6 alkoxy, or substituted C1-C6 alkoxy; the substituted C1-C6 alkyl or the substituted C1-C6 alkoxy refers to being substituted by a substituent of group M.

[0014] R4 is hydrogen, an unsubstituted C1-C8 alkyl group, a substituted C1-C8 alkyl group, an unsubstituted aromatic group, a substituted aromatic group, an unsubstituted heteroaryl group, or a substituted heteroaryl group; wherein the substituted C1-C8 alkyl group, the substituted aromatic group, or the substituted heteroaryl group refers to a group substituted by a substituent of group L.

[0015] R5 is hydrogen or an unsubstituted C1-C6 alkyl group;

[0016] The substituents in group M are selected from one or more of the following groups: halogen, nitro, cyano, hydroxyl, and C1-C6 alkoxy;

[0017] The L group of substituents is selected from one or more of the following groups: halogen, nitro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylacyl, carbamoyl, phenyl, pyridyl, pyrimidinyl, substituted phenyl, substituted pyridyl, substituted pyrimidinyl, and C1-C6 alkoxy; wherein the substituted phenyl, substituted pyridyl, or substituted pyrimidinyl is substituted by one or more of the following groups: halogen, nitro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkylacyl, and C1-C6 alkoxy.

[0018] Secondly, this application provides a method for preparing the above-mentioned carbazole derivatives, or pharmaceutically acceptable salts, solvates, prodrugs, or stereoisomers thereof, wherein the preparation method includes the following steps:

[0019]

[0020] Compound of formula (I-1) and X-(CH2) n The -A-R4 reaction yields compound (I);

[0021] In equation (I-1), one of Z1 and Z2 is -CH2-, and the other is -N(H)-; R1 and R2 are defined in the same way as in equation (I);

[0022] X-(CH2) nIn -A-R4, X is a leaving group; n, A, and R4 are defined as in formula (I).

[0023] Thirdly, this application provides pharmaceutical compositions comprising the above-mentioned carbazole derivatives, or pharmaceutically acceptable salts, solvates, prodrugs, or stereoisomers thereof.

[0024] Fourthly, this application provides the use of the above-mentioned carbazole derivatives, or pharmaceutically acceptable salts, solvates, prodrugs or stereoisomers thereof, or pharmaceutical compositions thereof, including but not limited to dopamine D2, dopamine D3 or dopamine D2 and D3 receptor modulators, for purposes including but not limited to antipsychotics.

[0025] In an embodiment of the first aspect, this application provides a carbazole derivative as shown in formula (I), or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof:

[0026]

[0027] In equation (I), one of Y1 and Y2 is -CH2-, while the other is -N(R3)-; R3 is -(CH2). n -A-R4, where n is an integer from 3 to 6, and A is non-existent (or a single bond), O, N(R5)C(O) or N(R5)C(O)O;

[0028] R1 is hydrogen or an unsubstituted C1-C6 alkyl group;

[0029] R2 is hydrogen, hydroxyl, halogen, unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl, unsubstituted C1-C6 alkoxy, or substituted C1-C6 alkoxy; the substituted C1-C6 alkyl or the substituted C1-C6 alkoxy refers to being substituted by a substituent of group M.

[0030] R4 is hydrogen, an unsubstituted C1-C8 alkyl group, a substituted C1-C8 alkyl group, an unsubstituted aromatic group, a substituted aromatic group, an unsubstituted heteroaryl group, or a substituted heteroaryl group; wherein the substituted C1-C8 alkyl group, the substituted aromatic group, or the substituted heteroaryl group refers to a group substituted by a substituent of group L.

[0031] R5 is hydrogen or an unsubstituted C1-C6 alkyl group;

[0032] The substituents in group M are selected from one or more of the following groups: halogen, nitro, cyano, hydroxyl, and C1-C6 alkoxy;

[0033] The L group of substituents is selected from one or more of the following groups: halogen, nitro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylacyl, carbamoyl, phenyl, pyridyl, pyrimidinyl, substituted phenyl, and C1-C6 alkoxy; wherein the substituted phenyl is substituted by one or more of the following groups: halogen, nitro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkylacyl, and C1-C6 alkoxy.

[0034] In some embodiments of the first aspect, in formula (I), R1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

[0035] In some embodiments of the first aspect, in formula (I), R1 is hydrogen, methyl or ethyl.

[0036] In some embodiments of the first aspect, in formula (I), R2 is hydrogen, hydroxyl, halogen, unsubstituted C1-C6 alkyl, halo-C1-C6 alkyl, unsubstituted C1-C6 alkoxy or halo-C1-C6 alkoxy.

[0037] In some embodiments of the first aspect, in formula (I), R2 is hydrogen, hydroxyl, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, or trifluoromethoxy.

[0038] In some embodiments of the first aspect, in formula (I), R2 is hydrogen, hydroxyl, fluorine, chlorine, methoxy, or trifluoromethoxy.

[0039] In some embodiments of the first aspect, in formula (I), R4 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, unsubstituted phenyl, substituted phenyl, unsubstituted heteroaryl, or substituted heteroaryl; wherein the substituted phenyl or substituted heteroaryl refers to a substance substituted by a substituent of group L;

[0040] The L group of substituents is selected from one or more of the following groups: halogen, nitro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylacyl, carbamoyl, phenyl, pyridyl, pyrimidinyl, substituted phenyl and C1-C6 alkoxy; here, the substituted phenyl is substituted by one or more of the following groups: halogen, nitro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkylacyl and C1-C6 alkoxy;

[0041] The unsubstituted heteroaryl group or the substituted heteroaryl group is: thienyl, furanyl, pyrroleyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, triazole, pyridyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, inzolyl, inazinyl, benzofuranyl, benzimidazolyl, benzimidazolone, benzopyrazolyl, benzooxazolyl, benzothiazolyl, quinolinyl, quinolinone, imidazopyrazinyl, benzopyranyl, benzopyranone, benzodihydropyranone, or carbazoleyl.

[0042] In some embodiments of the first aspect, in formula (I), Y1 is -CH2- and Y2 is -N(R3)-.

[0043] In some embodiments of the first aspect, in formula (I), Y1 is -N(R3)- and Y2 is -CH2-.

[0044] In some embodiments of the first aspect, in formula (I), Y1 is -CH2-, and Y2 is -N(R3)-; R3 is -(CH2). n -A-R4, n is an integer from 3 to 6, A is absent (or a single bond), O, N(R5)C(O) or N(R5)C(O)O; R5 is hydrogen; R4 is hydrogen, unsubstituted C1-C8 alkyl, unsubstituted phenyl, substituted phenyl, unsubstituted heteroaryl, or substituted heteroaryl; here, the substituted phenyl or substituted heteroaryl refers to being substituted by a substituent of group L;

[0045] The L group of substituents is selected from one or more of the following groups: halogen, nitro, cyano, hydroxy C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylacyl, carbamoyl, phenyl, pyridyl, pyrimidinyl, substituted phenyl, substituted pyridyl, substituted pyrimidinyl, and C1-C6 alkoxy; wherein the substituted phenyl, substituted pyridyl, or substituted pyrimidinyl is substituted by one or more of the following groups: halogen, nitro, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkylacyl, and C1-C6 alkoxy.

[0046] In some embodiments of the first aspect, in formula (I), Y1 is -N(R3)-, and Y2 is -CH2-; R3 is -(CH2). n -A-R4, n is an integer from 3 to 6, A is absent (or a single bond), O, N(R5)C(O) or N(R5)C(O)O; R5 is hydrogen; R4 is hydrogen, unsubstituted C1-C8 alkyl, unsubstituted phenyl, substituted phenyl, unsubstituted heteroaryl, or substituted heteroaryl; the substituted phenyl or substituted heteroaryl refers to being substituted by a substituent of group L;

[0047] The L group of substituents is selected from one or more of the following groups: halogen, nitro, cyano, hydroxy C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylacyl, carbamoyl, phenyl, pyridyl, pyrimidinyl, substituted phenyl, substituted pyridyl, substituted pyrimidinyl, and C1-C6 alkoxy; wherein the substituted phenyl, substituted pyridyl, or substituted pyrimidinyl is substituted by one or more of the following groups: halogen, nitro, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkylacyl, and C1-C6 alkoxy.

[0048] In some embodiments of the first aspect, in formula (I), Y1 is -CH2-, and Y2 is -N(R3)-; R3 is -(CH2). n -A-R4, where n is an integer from 3 to 6, A represents non-existent (or a single bond), and R4 represents hydrogen.

[0049] In some embodiments of the first aspect, in formula (I), Y1 is -N(R3)-, and Y2 is -CH2-; R3 is -(CH2). n -A-R4, where n is an integer from 3 to 6, A represents non-existent (or a single bond), and R4 represents hydrogen.

[0050] In some embodiments of the first aspect, in formula (I), Y1 is -CH2-, and Y2 is -N(R3)-; R3 is -(CH2). n -A-R4, where n is an integer from 3 to 6, A is N(R5)C(O)O; R5 is hydrogen; R4 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl, or n-octyl.

[0051] In some embodiments of the first aspect, in formula (I), Y1 is -N(R3)-, and Y2 is -CH2-; R3 is -(CH2). n -A-R4, where n is an integer from 3 to 6, A is N(R5)C(O)O; R5 is hydrogen; R4 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl, or n-octyl.

[0052] In some embodiments of the first aspect, in formula (I), Y1 is -CH2-, and Y2 is -N(R3)-; R3 is -(CH2). n -A-R4, where n is an integer from 3 to 6, A is O or N(R5)C(O); R5 is hydrogen; and R4 is one of the following groups optionally substituted with L group substituents:

[0053] Phenyl, thiophene, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, triazole, pyridyl, pyranyl, pyrimidinyl, pyrazinyl, indoleyl, isoindoleyl, indazoleyl, inrazinyl, benzofuranyl, benzimidazolyl, benzimidazolone, benzopyrazolyl, benzooxazolyl, benzothiazolyl, quinolinyl, quinolinone, imidazopyrazinyl, benzopyranyl, benzopyranone, benzodihydropyranone, or carbazoleyl;

[0054] The L group of substituents is selected from one or more of the following groups: halogen, nitro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylacyl, carbamoyl, phenyl, pyridyl, pyrimidinyl, substituted phenyl, substituted pyridyl, substituted pyrimidinyl, and C1-C6 alkoxy; wherein the substituted phenyl, substituted pyridyl, or substituted pyrimidinyl is substituted by one or more of the following groups: halogen, nitro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkylacyl, and C1-C6 alkoxy.

[0055] In some embodiments of the first aspect, in formula (I), Y1 is -N(R3)-, and Y2 is -CH2-; R3 is -(CH2). n -A-R4, where n is an integer from 3 to 6, A is O or N(R5)C(O); R5 is hydrogen; and R4 is one of the following groups optionally substituted with L group substituents:

[0056] Phenyl, thiophene, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, triazole, pyridyl, pyranyl, pyrimidinyl, pyrazinyl, indoleyl, isoindoleyl, indazoleyl, inrazinyl, benzofuranyl, benzimidazolyl, benzimidazolone, benzopyrazolyl, benzooxazolyl, benzothiazolyl, quinolinyl, quinolinone, imidazopyrazinyl, benzopyranyl, benzopyranone, benzodihydropyranone, or carbazoleyl;

[0057] The L group of substituents is selected from one or more of the following groups: halogen, nitro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylacyl, carbamoyl, phenyl, pyridyl, pyrimidinyl, substituted phenyl, substituted pyridyl, substituted pyrimidinyl, and C1-C6 alkoxy; wherein the substituted phenyl, substituted pyridyl, or substituted pyrimidinyl is substituted by one or more of the following groups: halogen, nitro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkylacyl, and C1-C6 alkoxy.

[0058] In some embodiments of the first aspect, this application provides the following compounds or their pharmaceutically acceptable salts, solvates, prodrugs, or stereoisomers:

[0059] 2-Propyl-2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indole (CL-04);

[0060] 5-Methyl-2-propyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (CL-08);

[0061] 5-Ethyl-2-propyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (CL-12);

[0062] 8-Hydroxy-2-propyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (CL-13);

[0063] 8-Methoxy-2-propyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (CL-16);

[0064] 8-Trifluoromethoxy-2-propyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (CL-17);

[0065] 8-Fluoro-2-propyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (CL-18);

[0066] 8-Chloro-2-propyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (CL-19);

[0067] (4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)amine carbonyl tert-butyl ester (CL-20);

[0068] (4-(5-ethyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butyl)amine carbonyl tert-butyl ester (CL-21);

[0069] N-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butyl)-1H-indol-2-carboxamide (CL-22);

[0070] 6-Chloro-N-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butyl)imidazo[1,2-b]pyridazin-2-carboxamide (CL-23);

[0071] N-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butyl)-4-(pyridin-3-yl)benzamide (CL-24);

[0072] N-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butyl)quinoline-3-carboxamide (CL-25);

[0073] N-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butyl)-9H-carbazole-3-carboxamide (CL-26);

[0074] N-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-carboxamide (CL-27);

[0075] N-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butyl)-1H-benzo[d]imidazol-5-carboxamide (CL-28);

[0076] N-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butyl)-1H-benzo[d]imidazol-2-carboxamide (CL-29);

[0077] N-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butyl)quinoline-4-carboxamide (CL-30);

[0078] N-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butyl)-[1,1'-biphenyl]-4-carboxamide (CL-31);

[0079] N-(4-(5-ethyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butyl)-1H-indol-2-carboxamide (CL-32);

[0080] (4-(9-methyl-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)butyl)amine carbonyl tert-butyl ester (CL-34);

[0081] N-(4-(9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)-1H-indol-2-carboxamide (CL-35);

[0082] N-(4-(9-ethyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)-1H-indol-2-carboxamide (CL-38);

[0083] N-(4-(9-ethyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)-9H-carbazole-3-carboxamide (CL-39);

[0084] N-(4-(9-ethyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)-[1,1'-biphenyl]-4-carboxamide (CL-40);

[0085] 2-(4-((1H-indol-5-yl)oxy)butyl)-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (CL-41);

[0086] 7-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butoxy)-3,4-dihydroquinoline-2(1H)-one (CL-42);

[0087] 7-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butoxy)-2H-benzopyran-2-one (CL-43);

[0088] 5-Methyl-2-(4-(quinoline-7-oxy)butyl)-1,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (CL-44);

[0089] 6-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butoxy)quinoline-2(1H)-one (CL-45);

[0090] 7-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butoxy)quinoline-2(1H)-one (CL-46);

[0091] 2-(4-((1H-indazol-6-yl)oxy)butyl)-5-methyl-1,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (CL-47);

[0092] 6-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butoxy)benzo[d]thiazole (CL-48);

[0093] 5-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butoxy)benzo[d]thiazole (CL-49);

[0094] 5-Methyl-2-(4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)tetrabutyl)-1,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (C-L50);

[0095] 5-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butoxy)1,3-dihydro-2H-benzo[d]imidazol-2-one (CL-51);

[0096] 4-Methyl-7-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butoxy)-2H-benzopyran-2-one (CL-52);

[0097] 2-(4-((1H-indol-5-yl)oxy)butyl)-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (CL-53);

[0098] 9-Methyl-2-(4-(quinoline-7-oxy)butyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (CL-54);

[0099] 6-(4-(9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)quinoline-2(1H)-one (CL-55);

[0100] 7-(4-(9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)-2H-benzopyran-2-one (CL-56);

[0101] N-(4-(9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)-1H-benzo[d]indol-6-carboxamide (CL-57);

[0102] N-(4-(9-ethyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)-1H-benzo[d]imidazolium-6-carboxamide (CL-58);

[0103] N-(4-(9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)-4-(pyridin-3-yl)benzamide (CL-59);

[0104] N-(4-(9-ethyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)-4-(pyridin-3-yl)benzamide (CL-60);

[0105] N-(4-(9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazolium-5-carboxamide (CL-61); and

[0106] N-(4-(9-ethyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-carboxamide (CL-62).

[0107] In the second aspect of the implementation, this application provides a method for preparing the above-mentioned carbazole derivatives, the method comprising:

[0108]

[0109] Compound of formula (I-1) and X-(CH2) n The -A-R4 reaction yields compound (I);

[0110] In equation (I-1), one of Z1 and Z2 is -CH2-, and the other is -N(H)-; R1 and R2 are defined in the same way as in equation (I);

[0111] X-(CH2) n In -A-R4, X is a leaving group, such as a bromine, chlorine, or sulfonate group; n, A, and R4 are defined in the same way as in formula (I).

[0112] In some embodiments of the second aspect, the preparation method provided in this application is carried out in the presence of a catalyst, such as potassium iodide and potassium carbonate.

[0113] In some embodiments of the second aspect, the carbazole derivatives of this application can be prepared using the following methods:

[0114] Synthesis Scheme 1:

[0115]

[0116] Reagents and conditions: (a) AcOH, benzenesulfonic acid monohydrate, 118℃, 5h.

[0117] Synthesis Scheme 2:

[0118]

[0119] Reagents and conditions: (a) AcOH, HCl, rt, 5h; (b) (4-bromobutyl)amine carbonyl tert-butyl ester, K2CO3, TBAI, DMF, rt, 10h; (c) CF3COOH, CH2Cl2, 2h; (d) aromatic acid, EDCI, DMAP, CH2Cl2, rt, 2h.

[0120] Synthesis Scheme 3:

[0121]

[0122] Reagents and conditions: (a) (Boc)₂O, CH₂Cl₂, rt, 4h; (b) Iodoformane or iodoethane, NaH, THF, 0℃, 12h; (c) Trifluoroacetic acid, CH₂Cl₂, 2h; (d) (4-bromobutyl)amine carbonyl tert-butyl ester, K₂CO₃, KI, DMF, 65℃, 10h; (e) Arylformic acid, EDCI, DMAP, CH₂Cl₂, 4h.

[0123] Synthesis scheme 4:

[0124]

[0125] Reagents and conditions: (a) glacial acetic acid, HCl, rt, 5h; (b) 4-bromobutoxy aromatic compound, KI, K2CO3, DMF, 65℃, 12h.

[0126] Synthesis Scheme 5:

[0127]

[0128] Reagents and conditions: (a) 4-bromobutoxy aromatic compound, KI, K2CO3, DMF, 65℃.

[0129] In some embodiments of the third aspect, this application provides pharmaceutical compositions comprising the above-mentioned carbazole derivatives. The pharmaceutical compositions provided in this application may be in the form of oral or non-gastrointestinal administration, and the dosage may be 0.1-5000 mg / time / day.

[0130] In some embodiments of the fourth aspect, this application provides the use of the above-mentioned novel carbazole derivatives or pharmaceutical compositions thereof as receptor modulators of dopamine D2, dopamine D3, or dopamine D2 and D3, said use including but not limited to: antipsychotics, etc.

[0131] Other features and advantages of this application will be set forth in the following description, and will be apparent in part from the description, or may be learned by practicing the application. Other advantages of this application can be realized and obtained by means of the solutions described in the description and the accompanying drawings. Attached Figure Description

[0132] The accompanying drawings are used to provide an understanding of the technical solutions of this application and constitute a part of the specification. They are used together with the embodiments of this application to explain the technical solutions of this application and do not constitute a limitation on the technical solutions of this application.

[0133] Figure 1 This study investigated the inhibitory effects of single concentrations of compounds CL-22 and CL-29 on MK-801-induced increases in spontaneous activity in mice. N = 4–8, Mean ± SEM. *P < 0.05, **P < 0.01, ****P < 0.0001, compared with the MK group; ### P < 0.001, compared with the Vehicle group. One-way multilevel ANOVA, Newman-Keuls Multiple Comparison Test;

[0134] Figure 2 This study investigated the inhibitory effects of single concentrations of compounds CL-24, CL-26, and CL-27 on MK-801-induced increases in spontaneous activity in mice. N = 4–8, Mean ± SEM. *P < 0.05, **P < 0.01, ****P < 0.0001, compared with the MK group; ### P < 0.001, compared with the Vehicle group. One-way multilevel ANOVA, Newman-Keuls Multiple Comparison Test;

[0135] Figure 3 The compound CL-22 of this application was used to inhibit MK-801-induced hyperactivity in mice at three concentration gradients of 3 mg / kg, 10 mg / kg, and 30 mg / kg.

[0136] Figure 4 The compound CL-29 of this application was used to inhibit MK-801-induced hyperactivity in mice at three concentration gradients of 3 mg / kg, 10 mg / kg, and 30 mg / kg.

[0137] Figure 5 The compound CL-29 of this application was shown to inhibit APO-induced climbing behavior in mice at three concentration gradients of 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg, and 30 mg / kg.

[0138] Figure 6 The compound CL-29 of this application was used to increase the forced swimming time of mice at three concentration gradients of 3 mg / kg, 10 mg / kg, and 30 mg / kg.

[0139] Figure 7 The compound CL-29 of this application was used to reduce the immobility time of mouse tail suspension at three concentration gradients of 3 mg / kg, 10 mg / kg, and 30 mg / kg.

[0140] Figure 8 The study investigated the restorative effect of compound CL-29 of this application on novelty recognition disorder induced by MK-801 at three concentration gradients of 3 mg / kg, 10 mg / kg, and 30 mg / kg. Detailed Implementation

[0141] To make the objectives, technical solutions, and advantages of this application clearer, the embodiments of the present invention will be described in detail below. It should be noted that, unless otherwise specified, the embodiments and features described in these embodiments can be arbitrarily combined with each other.

[0142] In this invention, the abbreviations are:

[0143] Me methyl

[0144] Et Ethyl

[0145] Acetyl group

[0146] Boc tert-butyloxycarbonyl

[0147] PE petroleum ether

[0148] DMF dimethyl amide

[0149] THF Tetrahydrofuran

[0150] TBAI Tetrabutylammonium Iodide

[0151] DMAP 4-Dimethylaminopyridine

[0152] EDCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide

[0153] rt room temperature

[0154] IC 50 Half-inhibition level

[0155] DIPEA (diisopropylethylamine)

[0156] HATU 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate

[0157] MeOH (methanol)

[0158] FBS Fetal Bovine Serum

[0159] PBS phosphate buffer

[0160] ATP adenosine triphosphate

[0161] Tris-aminobutyritin

[0162] GTP (Guanine Triphosphate)

[0163] EGTA (ethylene glycol bis(2-aminoethyl ether)tetraacetic acid)

[0164] HEPES 4-Hydroxyethylpiperazine ethanesulfonic acid

[0165] NMR data were measured using a Bruker Avance III 400 NMR spectrometer with TMS (tertramethyl silance) as the internal standard; NMR data were processed using mesrelab Research SL software (Ver. 6.1.0); high-resolution mass spectrometry data (ESI-TOF) were measured using a Bruker Apex IV FTMS Fourier transform ion cyclotron mass spectrometer; thin-layer chromatography silica gel plates (Shanghai Shangbang Industrial Co., Ltd.); column chromatography silica gel (200-300 mesh, Shanghai Shangbang Industrial Co., Ltd.).

[0166] Unless otherwise stated, all solvents, raw materials and reagents are commercially available analytical grade.

[0167] Synthesis Experiment Section

[0168] General Synthesis Method 1:

[0169] Dissolve 1.0 mmol of phenylhydrazine hydrochloride, 1.5 mmol of N-n-propyl-4-piperidinone, or 4-dipropylaminocyclohexanone with different substituents in 30 mL of anhydrous acetic acid. Then add a catalytic amount of benzenesulfonic acid monohydrate, stir, and heat to reflux for 5 h. After the reaction is complete, cool to room temperature and add 50 mL of ethyl acetate, resulting in precipitation. Filter the precipitate, and wash the residue three times with ethyl acetate. Purify by silica gel column chromatography using dichloromethane / methanol / ammonia as the mobile phase to obtain the final product.

[0170] Example 1

[0171] Synthesis of 2-propyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (CL-04)

[0172]

[0173] The synthesis method is the same as General Method 1, using phenylhydrazine hydrochloride and N-n-propyl-4-piperidinone as starting materials. A white solid is obtained. Yield: 69%. 1 H NMR (400MHz, CDCl3) δ8.03 (s, 1H), 7.43 (d,J=7.3Hz,1H),7.27(d,J=7.3Hz,1H),7.17–7.05(m,2H),3.75(d,J=1.7H z,2H),2.94–2.80(m,4H),2.67–2.59(m,2H),1.71(dt,J=15.3,7.5Hz,2H), 1.00(t,J=7.4Hz,3H). 13 C NMR (101MHz, CDCl3) δ 136.11, 132.15, 126.24, 121.10, 119.23, 117.49, 110.58, 108.71, 60.16, 50.75, 49.56, 23.74, 20.70, 12.05. MS (ESI) calculated C 14 H 19 N2,[M+H]+m / z 215.3, measured value 215.3.

[0174] Example 2

[0175] Synthesis of 5-methyl-2-propyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (CL-08)

[0176]

[0177] The synthesis method is the same as General Method 1, using compound 1-methyl-1-phenylhydrazine hydrochloride and N-n-propyl-4-piperidinone as starting materials. A white solid is obtained. Yield: 69%. 1 H NMR (400MHz, CDCl3) δ7.44(dt, J=7.7,1.0Hz,1H),7.29(d,J=8.1Hz,2H),7.23–7.14(m,1H),7.14–7.05(m, 1H),3.76(d,J=1.7Hz,2H),3.65(s,3H),3.00–2.91(m,2H),2.88(dd,J=7. 0,5.2Hz,2H),2.67–2.58(m,2H),1.71(h,J=7.4Hz,2H),1.06–0.97(m,3H). 13C NMR (101MHz, CDCl3) δ 137.09, 133.92, 125.72, 120.58, 118.75, 117.53, 108.66, 107.80, 77.37, 77.26, 77.05, 76.74, 60.10, 50.84, 49.72, 29.07, 22.83, 20.84, 12.06. MS (ESI) calculated C 15 H 21 N2,[M+H]+m / z 229.3, measured value 229.3.

[0178] Example 3

[0179] Synthesis of 5-ethyl-2-propyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (CL-12)

[0180]

[0181] The synthesis method is the same as General Method 1, using compound 1-ethyl-1-phenylhydrazine hydrochloride and N-n-propyl-4-piperidinone as starting materials. A white solid is obtained. Yield: 74%. 1 H NMR (400MHz, CDCl3) δ7.46 (dt, J=7.8, 1.0Hz, 1H), 7.32 (dt, J=8.2, 1.0Hz, 1H), 7.19 (ddd, J=8.1, 7.0, 1.3Hz, 1H),7.10(ddd,J=8.0,7.0,1.1Hz,1H),4.11(q,J=7.2Hz,2H),3.77(t,J=1. 7Hz,2H),2.99–2.92(m,2H),2.89(t,J=6.1Hz,2H),2.68–2.60(m,2H),1.73 (dq,J=14.9,7.4Hz,2H),1.36(t,J=7.2Hz,3H),1.03(t,J=7.4Hz,3H). 13 C NMR (101MHz, CDCl3) δ 135.99, 133.14, 125.94, 120.53, 118.67, 117.63, 108.76, 107.90, 77.40, 77.09, 76.77, 60.23, 50.88, 49.79, 37.57, 22.88, 20.83, 15.51, 12.08. MS (ESI) calculated C 16 H 23 N2, [M+H] + m / z 243.4, measured value 243.4.

[0182] Example 4

[0183] Synthesis of 8-hydroxy-2-propyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (CL-13)

[0184]

[0185] The synthesis method is the same as General Method 1, using compound 4-hydroxyphenylhydrazine hydrochloride and N-n-propyl-4-piperidinone as starting materials. A white solid is obtained. Yield: 47%. 1 H NMR (400MHz, DMSO-d6) δ10.38 (s,1H),8.51(s,1H),7.03(d,J=8.5Hz,1H),6.61(d,J=2.3Hz,1H),6.50(dd,J =8.5,2.3Hz,1H),3.46(s,2H),2.73(s,4H),2.50–2.42(m,2H),1.56(h,J=7.4Hz,2H),0.91(t,J=7.3Hz,3H). 13 C NMR (101MHz, DMSO-d6) δ 150.59, 133.76, 130.84, 126.76, 111.40, 110.35, 106.92, 101.92, 59.99, 50.96, 49.87, 40.62, 40.41, 40.20, 39.99, 39.78, 39.58, 39.37, 24.17, 20.59, 12.35. MS (ESI) calculated C 14 H 19 N₂O, [M+H] + m / z 231.3, measured value 231.3.

[0186] Example 5

[0187] Synthesis of 8-methoxy-2-propyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (CL-16)

[0188]

[0189] The synthesis method is the same as General Method 1, using compound 4-methoxyphenylhydrazine hydrochloride and N-n-propyl-4-piperidinone as starting materials. A white solid is obtained. Yield: 74%. 1H NMR (400MHz, DMSO-d6) δ11.07 (s,1H),10.88(s,1H),7.24(d,J=8.7Hz,1H),7.00(d,J=2.4Hz,1H),6.73(dd, J=8.8,2.5Hz,1H),4.54(s,1H),4.22(s,1H),3.75(s,3H),3.70(s,1H),3.36(s ,5H),3.19(d,J=8.7Hz,3H),3.03(s,1H),1.85(p,J=7.8Hz,2H),0.96(t,J=7.4 Hz,3H). 13 C NMR (101MHz, DMSO-d6) δ 153.78, 131.59, 131.32, 125.71, 112.29, 111.47, 101.77, 100.28, 56.82, 55.79, 49.70, 48.43, 20.76, 17.65, 11.47. MS (ESI) calculated C 15 H 21 N₂O, [M+H] + m / z 245.3, measured value 245.3.

[0190] Example 6

[0191] Synthesis of 8-trifluoromethoxy-2-propyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (CL-17)

[0192]

[0193] The synthesis method is the same as General Method 1, using compound 4-trifluoromethoxyphenylhydrazine hydrochloride and N-n-propyl-4-piperidinone as starting materials. A white solid is obtained. Yield: 56%. 1 H NMR(400MHz,DMSO-d6) δ11.57(s,1H),10.97(s,1H),7.51(t,J=1.7Hz,1H),7.44(d,J=8.8Hz,1H), 7.11–7.03(m,1H),4.63(d,J=14.4Hz,1H),4.34–4.15(m,1H),3.72(s,1H), 3.44(s,1H),3.27–3.00(m,4H),1.92–1.80(m,2H),0.96(t,J=7.4Hz,3H). 13C NMR (101MHz, DMSO-d6) δ 135.09, 133.46, 125.44, 115.28, 112.66, 110.63, 102.69, 56.82, 49.54, 48.06, 40.61, 40.40, 40.19, 39.98, 39.77, 39.57, 39.36, 20.70, 17.62, 11.44. MS (ESI) calculated C 15 H 18 F3N2O,[M+H] + m / z 299.31, measured value 299.31.

[0194] Example 7

[0195] Synthesis of 8-fluoro-2-propyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (CL-18)

[0196]

[0197] The synthesis method is the same as General Method 1, using compound 4-fluorophenylhydrazine hydrochloride and N-n-propyl-4-piperidinone as starting materials. A white solid is obtained. Yield: 47%. 1 H NMR (400MHz, CDCl3) δ8.11 (s, 1H), 7.15(dd,J=8.8,4.3Hz,1H),7.06(dd,J=9.5,2.5Hz,1H),6.85(td,J=9.1,2 .5Hz,1H),3.70(t,J=1.7Hz,2H),2.90(t,J=6.0Hz,2H),2.86–2.78(m,2H), 2.68–2.59(m,2H),1.70(h,J=7.4Hz,2H),1.00(t,J=7.4Hz,3H). 13 C NMR (101MHz, CDCl3) δ 158.92, 156.59, 134.14, 132.56, 126.54 (d), 111.05 (d), 109.19, 108.93, 102.79, 102.55, 60.13, 50.65, 49.43, 23.78, 20.60, 12.00. MS (ESI) calculated C 14 H 18 FN2,[M+H] + m / z 233.30, measured value 233.30.

[0198] Example 8

[0199] Synthesis of 8-chloro-2-propyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (CL-19)

[0200]

[0201] The synthesis method is the same as General Method 1, using compound 4-chlorophenylhydrazine hydrochloride and N-n-propyl-4-piperidinone as starting materials. A white solid is obtained. Yield: 77%. 1 H NMR (400MHz, CDCl3) δ8.80 (s, 1H), 7.36(d,J=1.9Hz,1H),7.08–6.97(m,2H),3.70(t,J=1.6Hz,2H),3.20(s,1H) ,2.85(t,J=5.8Hz,2H),2.65(ddd,J=10.5,8.1,5.5Hz,4H),1.87(t,J=5.8Hz, 1H),1.76–1.63(m,2H),0.99(t,J=7.3Hz,3H).13C NMR (101MHz, CDCl3) δ 134.51, 133.78, 127.10, 124.78, 121.17, 116.91, 111.61, 107.77, 60.14, 50.75, 49.22, 23.40, 20.40, 12.00. MS (ESI) calculated C 14 H 18 ClN2,[M+H] + m / z 249.75, measured value 249.75.

[0202] Example 9

[0203] Synthesis of 5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole

[0204]

[0205] 0.10 mol of 1-methyl-1-phenylhydrazine and 0.11 mol of 4-piperidinone were dissolved in 30 mL of anhydrous acetic acid, followed by the addition of 2 mL of hydrochloric acid. The mixture was stirred for 5 h. After the reaction was complete, the solvent was removed by rotary evaporation, and the pH was adjusted to weakly alkaline with saturated sodium bicarbonate solution. The product was washed three times with 30 mL of dichloromethane, and the organic layers were combined. The target product was purified by silica gel column chromatography using a mobile phase of dichloromethane / methanol / ammonia (25:1:0.1) to obtain a white solid. Yield: 83%. 1H NMR(400MHz,DMSO-d6)δ9.84(s,1H),7.47(dd, J=14.2,8.1Hz,2H),7.17(ddd,J=8.2,7.0,1.2Hz,1H),7.05(ddd,J=7.9,7.1, 1.0Hz,1H),4.27(t,J=4.6Hz,2H),3.65(s,3H),3.48–3.40(m,2H),3.07(t,J= 6.1Hz,2H). 13 C NMR (101MHz, DMSO-d) 6 )δ137.07,132.52,124.93,121.74, 119.55,118.18,109.95,101.93,41.05,40.16,29.59,19.42.HRMS(ESI) calculated value C 12 H 14 N2, [M+H] + m / z 186.26, measured value 186.26.

[0206] Example 10

[0207] Synthesis of (4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)amine carbonyl tert-butyl ester (CL-20)

[0208]

[0209] 2.0 mmol of 5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole was added to 30 mL of dry DMF. 2.2 mmol of 4-bromo-n-butylamine carbonyl tert-butyl ester, 2.5 mmol of K₂CO₃, and 2.0 mmol of TBAI were added under stirring at room temperature, and the reaction mixture was stirred for 10 h. After the reaction was complete, the solvent was evaporated to dryness, and the reaction mixture was washed three times with dichloromethane and water. The organic layers were combined, and the mixture was purified by silica gel column chromatography using dichloromethane / methanol / ammonia (25:1:0.1) as the mobile phase, yielding a white solid. The yield was 67%. 1H NMR (400MHz, CDCl3) δ7.43 (dt, J=7.8, 1.0Hz, 1H), 7.29 –7.24(m,1H),7.18(ddd,J=8.2,7.0,1.2Hz,1H),7.09(ddd,J=8.0,7.0,1.1Hz ,1H),5.15(s,1H),3.74(d,J=1.6Hz,2H),3.63(s,3H),3.18(q,J=6.4Hz,2H), 2.93(dd,J=6.3,3.9Hz,2H), 2.87(dd,J=8.5,3.7Hz,2H), 2.66(t,J=7.2Hz,2H), 1.70(ddd,J=14.3,8.1,5.9Hz,2H), 1.60(p,J=6.9Hz,2H). 13 C NMR (101 MHz, CDCl3) δ 156.10, 137.08, 133.78, 125.62, 120.67, 118.82, 117.50, 108.69, 107.43, 78.85, 57.39, 50.82, 49.60, 40.50, 29.08, 28.45 (3C), 27.92, 24.95, 22.68. HRMS (ESI) calculated C 21 H 31 N3O2, [M+H] + m / z 357.50, measured value 357.50.

[0210] Example 11

[0211] Synthesis of (4-(5-ethyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butyl)amine carbonyl tert-butyl ester (CL-21)

[0212]

[0213] 2.0 mmol of 5-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole was added to 30 mL of dry DMF. 2.2 mmol of 4-bromo-n-butylamine carbonyl tert-butyl ester, 2.5 mmol of K₂CO₃, and 2.0 mmol of TBAI were added with stirring at room temperature, and the reaction mixture was stirred for 10 h. After the reaction was complete, the solvent was evaporated to dryness, and the reaction mixture was washed three times with dichloromethane and water. The organic layers were combined and purified by silica gel column chromatography using dichloromethane / methanol / ammonia (25:1:0.1) as the mobile phase, yielding a white solid. The yield was 61%. 1 H NMR (400MHz, CDCl3) δ7.44(dd,J=7.7,1.1Hz,1H),7.30(d,J=8.2Hz,1H),7.18(ddd,J=8.3,7.0,1.2Hz,1H),7.09(td,J=7.4,7.0,1.0 Hz,1H),5.09(s,1H),4.09(q,J=7.2Hz,2H),3.77(d,J=1.6Hz,2H),3.18(q, J=6.5Hz,2H),2.96(dd,J=6.2,4.2Hz,2H),2.92–2.86(m,2H),2.69(t,J=7.3 Hz,2H),1.72(ddd,J=14.6,8.3,6.1Hz,2H),1.60(p,J=7.0Hz,2H),1.47(s,9H),1.35(t,J=7.2Hz,3H). 13 C NMR (101MHz, CDCl3) δ 156.10, 135.97, 132.87, 125.76, 120.68, 118.79, 117.61, 108.82, 107.23, 78.90, 57.36, 50.81, 49.60, 40.43, 37.61, 28.47 (3C), 27.92, 24.79, 22.55, 15.52. HRMS (ESI) calculated C 22 H 33 N3O2, [M+H] + m / z 371.53, measured value 371.53.

[0214] General Synthesis Method Two:

[0215] Dissolve 1.0 mmol of compound CL-20 or CL-21 in 20 mL of dry dichloromethane, add 1 mL of trifluoroacetic acid, and stir at room temperature for 2 h. After the reaction is complete, evaporate the reaction solvent and unreacted trifluoroacetic acid to dryness, then redissolve in 30 mL of dichloromethane, add 1.0 mmol of EDCI·HCl and a catalytic amount of DMAP, stir for 20 min, add the corresponding arethane, and continue stirring for 2 h. After the reaction is complete, wash the reaction system three times with 30 mL of water, evaporate the organic layer to dryness, and purify by silica gel column chromatography using dichloromethane / methanol / ammonia (15–25:1:0.1) as the mobile phase to obtain the corresponding final product.

[0216] Example 12

[0217] Synthesis of N-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butyl)-1H-indol-2-carboxamide (CL-22)

[0218]

[0219] The synthesis method is the same as General Method 2, using compound (4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)amine carbonyl tert-butyl ester and indol-2-carboxylic acid as starting materials. A white solid was obtained. Yield: 56%. 1 H NMR (400MHz, CDCl3) δ9.21 (s, 1H), 7.92 (s, 1H), 7.45 (dt, J = 7.8, 1.0Hz,1H),7.33(dt,J=8.4,1.0Hz,2H),7.31–7.23(m,2H),7.17(dddd,J=20 .9,7.9,6.9,1.1Hz,2H),6.96(ddd,J=8.0,7.0,1.0Hz,1H),6.72(d,J=8.1Hz, 1H),6.41–6.35(m,1H),3.87(s,2H),3.56(s,5H),3.00(t,J=5.7Hz,2H),2 .90(t,J=6.1Hz,2H),2.79(t,J=6.1Hz,2H),1.85(dh,J=12.1,6.7Hz,4H). 13C NMR (101MHz, CDCl3) δ 161.76, 137.26, 136.03, 133.70, 130.98, 127.65, 125.46, 123.98, 122.00, 121.04, 120.07, 119.23, 117.74, 111.59, 109.00, 107.00, 102.05, 57.07, 50.76, 49.75, 39.55, 29.12, 27.45, 25.26, 22.53. HRMS (ESI) calculated C 25 H 28 N4O, [M+H] + m / z 400.53, measured value 400.53.

[0220] Example 13

[0221] Synthesis of 6-chloro-N-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butyl)imidazo[1,2-b]pyridazin-2-carboxamide (CL-23)

[0222]

[0223] The synthesis method is the same as General Method 2, using compound (4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)amine carbonyl tert-butyl ester and 6-chloroimidozolo[1,2-b]pyridazin-2-carboxylic acid as starting materials. A white solid was obtained. Yield: 58%. 1 H NMR(400MHz, CDCl3)δ8.42(s,1H),7.67(s,1H), 7.62(d,J=9.5Hz,1H),7.39(d,J=7.8Hz,1H),7.27(d,J=8.2Hz,3H),7.22–7 .13(m,1H),7.11–7.02(m,2H),3.75(s,2H),3.63(s,3H),3.57(q,J=6.4Hz, 2H), 2.94 (t, J=5.5Hz, 2H), 2.88 (d, J=5.6Hz, 2H), 2.75–2.67 (m, 2H), 1.83– 1.77 (m, 4H). 13C NMR (101MHz, CDCl3) δ 161.80, 147.96, 140.59, 137.05, 136.78, 133.86, 127.39, 125.66, 120.71, 120.61, 120.46, 118.80, 118.39, 117.53, 108.69, 57.32, 50.55, 49.92, 39.19, 29.09, 27.52, 25.13, 22.75. HRMS (ESI) calculated C 23 H 25 ClN6O,[M+H] + m / z 436.94, measured value 436.94.

[0224] Example 14

[0225] Synthesis of N-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butyl)-4-(pyridin-3-yl)benzamide (CL-24)

[0226]

[0227] The synthesis method is the same as General Method 2, using compound (4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)amine carbonyl tert-butyl ester and 4-(pyridin-3-yl)benzoic acid as starting materials. A white solid was obtained. Yield: 71%. 1 H NMR(400MHz, CDCl3)δ8.64–8.58(m,2H),8.36(s,1H), 7.65–7.60(m,2H),7.58(dt,J=8.0,2.0Hz,1H),7.40(dd,J=7.7,1.1Hz,1H), 7.34(ddd,J=7.9,4.8,0.9Hz,1H),7.22–7.15(m,2H),7.09(ddd,J=8.0,4.8, 3.3Hz,1H),6.99–6.89(m,2H),3.78(d,J=1.7Hz,2H),3.55(q,J=5.3Hz,2H),3 .51(s,3H),2.94(t,J=5.7Hz,2H),2.84–2.73(m,4H),1.86(dd,J=6.2,3.1Hz, 4H). 13C NMR (101MHz, CDCl3) δ 166.80, 148.86, 148.14, 139.71, 137.14, 135.25, 134.24, 133.94, 133.75, 127.55 (2C), 126.44 (2C), 125.52, 123.42, 120.97, 119.12, 117.65, 108.83, 107.54, 57.33, 51.13, 49.36, 40.12, 29.07, 27.53, 25.67, 22.68. MS (ESI) calculated C 28 H 31 N4O, [M+H] + m / z 438.58, measured value 438.58.

[0228] Example 15

[0229] Synthesis of N-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butyl)quinoline-3-carboxamide (CL-25)

[0230]

[0231] The synthesis method is the same as General Method 2, using compound (4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)amine carbonyl tert-butyl ester and quinoline-3-carboxylic acid as starting materials. A white solid is obtained. Yield: 69%. 1 H NMR (400MHz, CDCl3) δ8.93 (t, J = 4.9Hz, 1H), 8.27 (s, 1H), 8.09 (dd,J=8.5,1.4Hz,1H),7.97(dd,J=8.5,1.2Hz,1H),7.62(ddd,J=8.4,6.8,1. 4Hz,1H),7.44(ddd,J=8.3,6.8,1.3Hz,1H),7.28(d,J=7.9Hz,1H),7.19(dd,J =3.4,1.1Hz,2H),7.08(ddd,J=7.9,4.9,3.2Hz,1H),7.01(d,J=4.3Hz,1H) ,3.65–3.49(m,4H),3.27(s,3H),2.70(t,J=5.8Hz,2H),2.66–2.60(m,2H), 2.24(t,J=5.7Hz,2H),1.90–1.79(m,4H). 13C NMR (101MHz, CDCl3) δ 167.39, 149.39, 148.15, 142.31, 136.86, 132.83, 129.55, 129.46, 127.06, 125.22, 125.07, 124.40, 120.93, 118.91, 118.12, 117.27, 108.92, 106.55, 58.06, 50.46, 49.74, 40.28, 28.76, 27.95, 25.58, 22.03. HRMS (ESI) calculated C 26 H 28 N4O, [M+H] + m / z 412.54, measured value 412.54.

[0232] Example 16

[0233] Synthesis of N-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butyl)-9H-carbazole-3-carboxamide (CL-26)

[0234]

[0235] The synthesis method is the same as General Method 2, using compound (4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)amine carbonyl tert-butyl ester and 9H-carbazole-3-carboxylic acid as starting materials. A white solid was obtained. Yield: 46%. 1 H NMR(400MHz,DMSO-d6)δ11.52(s,1H),8.68(s,1H),8.45(t, J=5.7Hz,1H),8.14(d,J=7.8Hz,1H),7.93(d,J=8.5Hz,1H),7.51(dd,J=14.9,8.3Hz,2H),7.43(t,J=7.6Hz,1H),7.35(t,J=7.9Hz,2H),7.21(t,J=7.4 Hz,1H),7.07(t,J=7.6Hz,1H),6.95(t,J=7.4Hz,1H),3.63(d,J=20.3Hz, 5H),3.38(d,J=5.6Hz,2H),2.97–2.75(m,4H),2.66(s,2H),1.77–1.55(m, 4H). 13C NMR (101MHz, DMSO-d6) δ 167.24, 141.74, 140.78, 137.04, 134.73, 126.44, 125.76, 125.52 (2C), 123.02, 122.34, 120.65, 120.62, 120.15 (2C), 119.59, 118.84, 117.60, 111.74, 110.72, 109.52, 57.45, 55.39, 50.84, 49.67, 29.36, 27.74, 24.88, 22.70. MS (ESI) calculated C 29 H 31 N4O, [M+H] + m / z 450.59, measured value 450.59.

[0236] Example 17

[0237] Synthesis of N-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazolium-5-carboxamide (CL-27)

[0238]

[0239] The synthesis method is the same as General Method II, using compound (4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)amine carbonyl tert-butyl ester and 2-oxo-2,3-dihydro-1H-benzo[d]imidazolium-5-carboxylic acid as starting materials. A white solid was obtained. Yield: 58%. 1H NMR (400MHz, DMSO-d6) δ10.91– 10.84(m,2H),10.75(s,1H),8.46(t,J=5.7Hz,1H),7.55(dd,J=8.2,1.6Hz, 1H),7.50–7.43(m,3H),7.17(ddd,J=8.4,7.1,1.2Hz,1H),7.06(ddd,J=7.8 ,7.0,1.0Hz,1H),6.96(d,J=8.1Hz,1H),4.61(d,J=13.9Hz,1H),4.28(dd,J= 14.3,7.3Hz,1H),3.80(d,J=12.2Hz,1H),3.67(s,3H),3.47(dq,J=13.8,7.5 Hz,1H),3.30(t,J=6.5Hz,4H),3.16(s,1H),3.10–2.95(m,1H),2.73(d,J=5.1 Hz,1H),1.88(p,J=7.8Hz,2H),1.61(p,J=7.2Hz,2H). 13 C NMR (101MHz, DMSO-d6) δ 166.80, 156.00, 137.34, 132.61, 132.23, 129.88, 127.52, 124.78, 121.86, 120.84, 119.69, 118.06, 110.08, 108.13, 108.05, 101.48, 54.81, 49.46, 48.43, 42.49, 29.71, 26.93, 21.72, 19.58. HRMS (ESI) calculated C 24 H 27 N5O2,[M+H] + m / z 417.51, measured value 417.51.

[0240] Example 18

[0241] Synthesis of N-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butyl)-1H-benzo[d]imidazolium-5-carboxamide (CL-28)

[0242]

[0243] The synthesis method is the same as General Method 2, using compound (4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)amine carbonyl tert-butyl ester and 1H-benzo[d]imidazolium-5-carboxylic acid as starting materials. A white solid was obtained. Yield: 66%. 1H NMR(400MHz, CDCl3)δ8.15(s,1H),7.74(s,1H),7.67 (s,1H),7.59(dd,J=8.4,1.6Hz,1H),7.42(d,J=7.8Hz,1H),7.36–7.21(m,3H ),7.13(ddd,J=7.9,5.1,2.9Hz,1H),5.32(s,1H),3.81(s,2H),3.54(q,J=5.5 Hz,2H),3.44(s,3H),2.94(t,J=5.8Hz,2H),2.76(dq,J=6.3,2.9Hz,4H),1.83 (td,J=12.2,6.0Hz,4H). 13 C NMR (101MHz, CDCl3) δ 168.18, 142.52, 137.03, 135.83, 133.99, 129.35, 125.32, 121.71, 121.03, 120.55, 119.23, 117.57, 116.89, 112.55, 109.12, 106.95, 57.43, 50.65, 49.68, 40.13, 29.03, 27.70, 25.31, 22.35. MS (ESI) Calculated C 24 H 28 N5O, [M+H] + m / z 401.51, measured value 401.51.

[0244] Example 19

[0245] Synthesis of N-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butyl)-1H-benzo[d]imidazolium-2-carboxamide (CL-29)

[0246]

[0247] The synthesis method is the same as General Method 2, using compound (4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)amine carbonyl tert-butyl ester and 1H-benzo[d]imidazolium-2-carboxylic acid as starting materials. A white solid was obtained. Yield: 52%. 1H NMR (400MHz, CDCl3) δ8.09 (d, J=7.0Hz, 1H), 7.76 (s, 1H), 7.56 (s, 1H), 7.44–7.39 (m, 1H), 7.35 (dd, J=6.5, 2.9Hz, 2H), 7.28–7.23 (m,1H),7.17(ddd,J=8.2,7.0,1.2Hz,1H),7.07(ddd,J=8.0,7.0,1.1Hz,1H),5 .32(s,1H),3.77(d,J=1.7Hz,2H),3.65(q,J=6.2Hz,2H),3.60(s,3H),2.95(t, J=5.7Hz,2H),2.88(t,J=5.7Hz,2H),2.77–2.67(m,2H),1.83(p,J=3.4Hz, 4H). 13 C NMR (101MHz, CDCl3) δ 159.48, 145.14, 137.06, 134.28, 133.83, 125.63, 124.80, 120.63 (2C), 118.81 (2C), 117.53 (2C), 108.67 (2C), 107.44, 57.26, 50.84, 49.69, 39.67, 29.05, 27.44, 25.07, 22.65. HRMS (ESI) calculated C 24 H 27 N5O, [M+H] + m / z 401.51, measured value 401.51.

[0248] Example 20

[0249] Synthesis of N-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butyl)quinoline-4-carboxamide (CL-30)

[0250]

[0251] The synthesis method is the same as General Method 2, using compound (4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)amine carbonyl tert-butyl ester and quinoline-4-carboxylic acid as starting materials. A white solid was obtained. Yield: 76%. 1H NMR (400MHz, CDCl3) δ8.93 (s, 1H), 8.29 (d, J = 4.3Hz, 1H), 8.11 (dd,J=8.5,1.3Hz,1H),7.99(dd,J=8.5,1.2Hz,1H),7.64(ddd,J=8.4,6.8,1. 4Hz,1H),7.46(ddd,J=8.3,6.8,1.3Hz,1H),7.28(dt,J=7.8,1.0Hz,1H),7.23– 7.18(m,2H),7.08(ddd,J=7.9,4.5,3.5Hz,1H),7.05(d,J=4.3Hz,1H),3.63–3 .54(m,4H),3.28(s,3H),2.70(dt,J=18.3,5.5Hz,4H),2.24(t,J=5.7Hz,2H), 1.88(qd,J=6.2,3.9,3.3Hz,4H). 13 C NMR (101MHz, CDCl3) δ 167.40, 149.42, 148.21, 142.31, 136.88, 132.74, 129.55, 129.52, 127.07, 125.22, 125.04, 124.42, 120.99, 118.95, 118.12, 117.27, 108.93, 106.45, 58.07, 50.51, 49.74, 40.30, 28.77, 27.99, 25.61, 21.98. HRMS (ESI) calculated C 26 H 28 N4O, [M+H] + m / z 412.54, measured value 412.54.

[0252] Example 21

[0253] Synthesis of N-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butyl)-[1,1'-biphenyl]-4-carboxamide (CL-31)

[0254]

[0255] The synthesis method is the same as General Method 2, using compound (4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)amine carbonyl tert-butyl ester and [1,1'-biphenyl]-4-carboxylic acid as starting materials. A white solid was obtained. Yield: 69%. 1H NMR (400MHz, CDCl3) δ8.04 (t, J = 5.1Hz, 1H), 7.69–7.61 (m, 2H),7.48–7.33(m,6H),7.26–7.15(m,2H),7.15–7.07(m,3H),3.79(d,J=1.7 Hz,2H),3.55(q,J=5.6Hz,2H),3.51(s,3H),2.93(t,J=5.7Hz,2H),2.84–2.72 (m,4H),1.84(qd,J=7.1,5.8,3.5Hz,4H). 13 CNMR (101MHz, CDCl3) δ 167.19, 143.25, 139.77, 137.16, 133.75, 133.21, 128.74 (2C), 127.78, 127.41 (2C), 127.07 (2C), 126.56 (2C), 125.57, 120.88, 119.06, 117.63, 108.89, 107.41, 57.38, 50.81, 49.71, 40.08, 29.05, 27.56, 25.50, 22.62. HRMS (ESI) calculated value C 29 H 31 N3O, [M+H] + m / z 437.59, measured value 437.59.

[0256] Example 22

[0257] Synthesis of N-(4-(5-ethyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butyl)-1H-indol-2-carboxamide (CL-32)

[0258]

[0259] The synthesis method is the same as General Method 2, using compound (4-(5-ethyl-1,3,4,5-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)amine carbonyl tert-butyl ester and indol-2-carboxylic acid as starting materials. A white solid is obtained. Yield: 77%. 1H NMR (400MHz, CDCl3) δ9.54 (s, 1H), 8.03 (t, J = 5.4Hz, 1H), 7.45 (d, J=7.8Hz,1H),7.34(dd,J=8.3,4.6Hz,2H),7.28–7.23(m,1H),7.22–7.09(m, 2H),6.93(ddd,J=8.0,6.8,1.0Hz,1H),6.66(d,J=8.0Hz,1H),6.38(d,J=2.1 Hz,1H),4.01(q,J=7.2Hz,2H),3.87(d,J=1.6Hz,2H),3.58(q,J=5.6Hz,2H),2.99(t,J=5.7Hz,2H),2.93–2.85(m,2H),2.79(t,J=6.1Hz,2H),1.93– 1.77(m,4H),1.17(t,J=7.2Hz,3H). 13 C NMR (101MHz, CDCl3) δ 161.72, 136.14, 136.00, 132.94, 130.92, 127.71, 125.64, 123.93, 121.99, 120.99, 120.01, 119.16, 117.84, 111.53, 109.11, 107.10, 102.02, 57.15, 50.86, 49.66, 39.50, 37.64, 27.57, 25.32, 22.52, 15.27. HRMS (ESI) calculated C 26 H 30 N4O, [M+H] + m / z 414.55, measured value 414.55.

[0260] Example 23

[0261] Synthesis of 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carbonyl tert-butyl ester

[0262]

[0263] 0.10 mol of 2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole and 0.15 mol of ditert-butyl dicarbonate were dissolved in 100 mL of dichloromethane, and the mixture was stirred at room temperature for 4 h. After the reaction was complete, the solvent was removed by rotary evaporation, and the reaction mixture was washed with ethyl acetate and water. The organic layers were combined. The mixture was purified by silica gel column chromatography using petroleum ether / ethyl acetate (3:1) as the mobile phase, yielding a white solid. Yield: 96%. 1H NMR (400MHz, CDCl3) δ7.51(d,J=7.7Hz,1H),7.34(d,J=7.9Hz,1H),7.22–7.09 (m,2H),4.68(s,2H),3.80(t,J=5.6Hz,2H),2.83(t,J=5.7Hz,2H),1.55(s,9H). 13 C NMR (101MHz, CDCl3) δ 136.23, 130.62, 127.08, 121.68, 119.51, 117.94, 117.89, 110.81, 80.09, 77.32, 77.00, 76.68, 42.47, 28.51, 21.36. HRMS (ESI) calculated C 16 H 20 N₂O₂, [M+H] + m / z 272.35, measured value 272.35.

[0264] Example 24

[0265] Synthesis of 9-methyl-1,3,4,9-tetrahydro-2H-pyridine[3,4-b]-indole-2-carbonyl tert-butyl ester

[0266]

[0267] 50 mmol of compound 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carbonyl tert-butyl ester was dissolved in 50 mL of dry tetrahydrofuran. 60% NaH (60 mmol) was added at 0 °C, and the mixture was stirred and activated for 30 min. Then, 55 mmol of iodomethane was added, and the reaction was allowed to proceed overnight. After the reaction was complete, 1 mL of water was added to remove unreacted NaH and iodomethane. The solvent was removed by rotary evaporation. The mixture was extracted three times with ethyl acetate and water; the organic layers were combined and dried to give a white solid. Yield: 94%. 1 H NMR (400MHz, CDCl3) δ7.54(d,J=7.8Hz,1H),7.35–7.29(m,1H),7.27–7.21(m,1H),7.16(t,J=7 .5Hz,1H),4.68(s,2H),3.87–3.76(m,2H),3.65(s,3H),2.86(t,J=5.7Hz, 2H),1.59(s,9H). 13C NMR (101MHz, CDCl3) δ155.30,137.15,132.20,126.59, 121.21,119.11,117.99,108.75,107.54,80.12,50.72,41.02,29.29,28.54,21.45.

[0268] Example 25

[0269] Synthesis of 9-ethyl-1,3,4,9-tetrahydro-2H-pyridine[3,4-b]-indole-2-carbonyl tert-butyl ester

[0270]

[0271] 50 mmol of compound 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carbonyl tert-butyl ester was dissolved in 50 mL of dry tetrahydrofuran. 60% NaH (60 mmol) was added at 0 °C, and the mixture was stirred and activated for 30 min. Then, 55 mmol of iodoethane was added, and the reaction was allowed to proceed overnight. After the reaction was complete, 1 mL of water was added to remove unreacted NaH and iodoethane. The solvent was removed by rotary evaporation. The mixture was extracted three times with ethyl acetate and water; the organic layers were combined and dried to give a white solid. Yield: 96%. 1 H NMR (400MHz, CDCl3) δ7.56(d,J=7.8Hz,1H),7.36(d,J=8.1Hz,1H),7.30–7.21(m,1H),7.17(t,J =7.4Hz,1H),4.71(s,2H),4.11(q,J=7.2Hz,2H),3.83(t,J=5.7Hz,2H),2.88 (t,J=5.8Hz,2H),1.60(d,J=1.9Hz,9H),1.42(t,J=7.2Hz,3H). 13 C NMR (101MHz, CDCl3) δ155.31,136.05,131.42,126.83,121.20,119.06,118.12, 108.89,107.65,80.10,42.55,40.95,37.97,28.55,21.54,15.45.

[0272] Example 26

[0273] Synthesis of (4-(9-methyl-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)butyl)amine carbonyl tert-butyl ester (CL-34)

[0274]

[0275] 50 mmol of 9-methyl-1,3,4,9-tetrahydro-2H-pyridine[3,4-b]indole-2-carbonyl tert-butyl ester was dissolved in 15 mL of dichloromethane. 5 mL of trifluoroacetic acid was added with stirring, and the mixture was stirred at room temperature for 5 h. After the reaction was complete, the solvent was removed by rotary evaporation, and the solution was dissolved in 30 mL of dry DMF. K₂CO₃ (150 mmol), 4-bromo-n-butylamine carbonyl tert-butyl ester (55 mmol), and potassium iodide (50 mmol) were added under heating at 65 °C, and the mixture was stirred for 10 h. The solvent was removed by rotary evaporation, and the reaction mixture was washed three times with dichloromethane and water. The organic layers were combined, and the mixture was purified by silica gel column chromatography using dichloromethane / methanol / ammonia (25:1:0.1) as the mobile phase, yielding a white solid. Yield: 76%. 1 H NMR (400 MHz, CDCl3) δ7.52–7.45(m,1H),7.30–7.25(m,1H),7.18(ddd,J=8.2,7.0, 1.2Hz,1H),7.09(ddd,J=8.0,6.9,1.1Hz,1H),5.02(s,1H),3.73(s,2H),3.6 1(s,3H),3.18(q,J=6.5Hz,2H),2.88(d,J=3.0Hz,4H),2.69(t,J=7.2Hz,2H), 1.73–1.68(m,2H),1.61(p,J=6.6Hz,2H),1.46(d,J=3.4Hz,9H). 13 C NMR (101MHz, CDCl3) δ 156.09, 137.18, 132.97, 126.69, 120.84, 118.84, 117.96, 108.63, 107.35, 57.40, 50.97, 49.55, 29.19, 28.44 (3C), 27.92, 24.73, 21.29, 19.80, 13.75. HRMS (ESI) calculated C 21 H 31 N3O2, [M+H] + m / z 357.50, measured value 357.50.

[0276] Example 27

[0277] Synthesis of (4-(9-ethyl-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)butyl)amine carbonyl tert-butyl ester

[0278]

[0279] 50 mmol of 9-ethyl-1,3,4,9-tetrahydro-2H-pyridine[3,4-b]indole-2-carbonyl tert-butyl ester was dissolved in 15 mL of dichloromethane. 5 mL of trifluoroacetic acid was added with stirring, and the mixture was stirred at room temperature for 5 h. After the reaction was complete, the solvent was removed by rotary evaporation, and the solution was dissolved in 30 mL of dry DMF. K₂CO₃ (150 mmol), 4-bromo-n-butylamine carbonyl tert-butyl ester (55 mmol), and potassium iodide (50 mmol) were added under heating at 65 °C, and the mixture was stirred for 10 h. The solvent was removed by rotary evaporation, and the reaction mixture was washed three times with dichloromethane and water. The organic layers were combined, and the mixture was purified by silica gel column chromatography using dichloromethane / methanol / ammonia (25:1:0.1) as the mobile phase, yielding a white solid. Yield: 71%. 1 H NMR (400 MHz, CDCl3) δ7.52(d,J=7.8Hz,1H),7.31(d,J=8.2Hz,1H),7.20(t,J=7.6 Hz,1H),7.11(t,J=7.4Hz,1H),5.17(s,1H),4.06(q,J=7.2Hz,2H),3.74(s,2 H),3.19(q,J=6.5Hz,2H),2.90(s,4H),2.70(t,J=7.3Hz,2H),1.72(p,J=7.2 Hz, 2H), 1.61 (q, J = 7.1Hz, 2H), 1.47 (s, 9H), 1.35 (t, J = 7.2Hz, 3H). 13 C NMR (101MHz, CDCl3) δ156.15,136.07,132.15,126.91,120.84,118.81,118.10, 108.79,107.38,78.90,57.37,50.92,49.53,40.45,37.75,28.49,27.97,24.70,21.29,15.58.

[0280] General Synthesis Method 3:

[0281] Compound (4-(9-methyl-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]-indol-2-yl)butyl)amine carbonyl tert-butyl ester or (4-(9-ethyl-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]-indol-2-yl)butyl)amine carbonyl tert-butyl ester (1 mmol) was dissolved in 20 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 4 h. After the reaction was completed, the reaction solvent and unreacted trifluoroacetic acid were removed by rotary evaporation. The mixture was redissolved in 20 mL of DMF, and 1 mmol of EDCI and a catalytic amount of DMAP were added. The mixture was stirred for 20 min, and then indol-2-carboxylic acid was added. The mixture was stirred overnight. After the reaction was completed, the reaction solvent was removed by rotary evaporation, and the mixture was purified by silica gel column chromatography using dichloromethane / methanol / ammonia as the mobile phase to obtain the final product.

[0282] Example 28

[0283] Synthesis of N-(4-(9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)-1H-indol-2-carboxamide (CL-35)

[0284]

[0285] The synthesis method is the same as general method three, using compound (4-(9-methyl-1,3,4,9-tetrahydro-2H-pyridine[3,4-b]indol-2-yl)butyl)amine carbonyl tert-butyl ester and indol-2-carboxylic acid as raw materials to obtain a white solid. Yield: 87%. 1 H NMR (400MHz, CDCl3) δ10.25 (s, 1H), 7.82 (t, J = 5.3Hz, 1H), 7.56 (d,J=7.9Hz,1H),7.49–7.27(m,3H),7.27–7.22(m,1H),7.22–7.11(m,1H), 7.02(d,J=4.1Hz,2H),6.41(d,J=2.0Hz,1H),3.66(s,2H),3.60(q,J=5.7Hz, 2H), 3.42 (s, 3H), 2.99–2.86 (m, 4H), 2.72 (q, J=4.5, 3.1Hz, 2H), 1.91–1.79 (m, 4H). 13C NMR (101MHz, CDCl3) δ 162.06, 137.30, 136.43, 133.02, 131.15, 127.60, 126.65, 123.99, 121.94, 121.10, 120.16, 119.06, 118.16, 111.92, 108.91, 107.53, 102.00, 56.68, 50.40, 50.01, 39.59, 32.10, 26.80, 25.14, 21.61. HRMS (ESI) calculated C 25 H 28 N4O, [M+H] + m / z 400.53, measured value 400.53.

[0286] Example 29

[0287] Synthesis of N-(4-(9-ethyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)-1H-indol-2-carboxamide (CL-38)

[0288]

[0289] The synthesis method is the same as general method three, using compound (4-(9-ethyl-1,3,4,9-tetrahydro-2H-pyridine[3,4-b]indol-2-yl)butyl)amine carbonyl tert-butyl ester and indol-2-carboxylic acid as raw materials to obtain a white solid. Yield: 89%. 1 H NMR (400MHz, CDCl3) δ9.36 (s, 1H), 7.70 (d, J = 5.6Hz, 1H), 7.55 (dt,J=7.8,1.0Hz,1H),7.35(ddd,J=8.2,2.3,1.0Hz,2H),7.23(dddd,J=20.1, 8.2,7.0,1.2Hz,2H),7.15(ddd,J=7.9,7.0,1.0Hz,1H),6.98(ddd,J=8.0,6.9, 1.0Hz,1H),6.89(dd,J=8.0,1.1Hz,1H),6.35(dd,J=2.2,1.0Hz,1H),3.92( q,J=7.2Hz,2H),3.70(d,J=1.5Hz,2H),3.58(q,J=5.8Hz,2H),3.00–2.88(m, 4H),2.79–2.72(m,2H),1.92–1.81(m,4H),1.18(t,J=7.2Hz,3H). 13C NMR (101MHz, CDCl3) δ 161.70, 136.20, 135.99, 132.32, 130.99, 127.70, 126.80, 124.07, 122.03, 121.04, 120.19, 118.99, 118.26, 111.57, 108.97, 107.61, 101.78, 56.75, 50.48, 50.04, 39.43, 37.69, 26.92, 25.18, 21.67, 15.29. HRMS (ESI) calculated C 26 H 30 N4O, [M+H] + m / z 414.55, measured value 414.55.

[0290] Example 30

[0291] Synthesis of N-(4-(9-ethyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)-9H-carbazole-3-carboxamide (CL-39)

[0292]

[0293] The synthesis method is the same as general method three, using compound (4-(9-ethyl-1,3,4,9-tetrahydro-2H-pyridine[3,4-b]indol-2-yl)butyl)amine carbonyl tert-butyl ester and 9H-carbazole-3-carboxylic acid as raw materials to obtain a white solid. Yield: 70%. 1 HNMR (600MHz, CDCl3) δ8.75 (s, 1H), 8.55 (d, J = 1.7Hz, 1H), 8.00 (d, J=7.8Hz,1H),7.64(dd,J=8.5,1.8Hz,1H),7.49(d,J=7.8Hz,1H),7.48–7.36(m,3H),7.25(d,J=8.1Hz,1H),7.21(tdd,J=8.1,3.1,1.4Hz,2H),7.15– 7.09(m,1H),6.92(d,J=8.4Hz,1H),5.32(s,1H),3.83(q,J=7.2Hz,2H),3.62 (s,2H),3.59(q,J=5.9Hz,2H),2.86(s,4H),2.72–2.67(m,2H),1.86–1.78(m, 4H),1.17(t,J=7.2Hz,3H). 13C NMR (151MHz, CDCl3) δ 168.72, 141.35, 140.13, 136.06, 132.41, 126.89, 126.29, 125.87, 124.46, 123.18, 123.00, 120.81, 120.50, 119.85, 119.78, 118.80, 118.14, 110.95, 110.19, 108.74, 107.43, 57.08, 50.42, 49.93, 40.15, 37.58, 27.24, 25.17, 21.46, 15.36. HRMS (ESI) calculated C 30 H 32 N4O, [M+H] + m / z 464.61, measured value 464.61.

[0294] Example 31

[0295] Synthesis of N-(4-(9-ethyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)-[1,1'-biphenyl]-4-carboxamide (CL-40)

[0296]

[0297] The synthesis method is the same as General Method 3, using compound (4-(9-ethyl-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)butyl)amine carbonyl tert-butyl ester and [1,1'-biphenyl]-4-carboxylic acid as raw materials to obtain a white solid. Yield: 90%. 1 H NMR (400MHz, CDCl3) δ7.90 (t, J=5.1Hz, 1H), 7.72–7.66 (m, 2H), 7.55 (d, J=7.7Hz, 1H), 7.48–7.34 (m, 5H), 7.27–7.18 (m, 4H), 7.14 (ddd, J=8.0,6.5,1.7Hz,1H),3.88(q,J=7.2Hz,2H),3.63(s,2H),3.56(q,J=5.6Hz, 2H), 2.90 (td, J=9.2, 7.4, 4.3Hz, 4H), 2.77–2.69 (m, 2H), 1.85 (h, J=3.8, 3.1Hz, 4H), 1.16 (t, J=7.2Hz, 3H). 13C NMR (101MHz, CDCl3) δ 167.29, 143.33, 139.70, 136.10, 133.34, 132.38, 128.78, 127.81, 127.41, 127.00, 126.85, 126.62, 120.96, 118.96, 118.17, 108.86, 107.53, 56.90, 50.39, 50.03, 39.83, 37.62, 26.93, 25.28, 21.72, 15.37. HRMS (ESI) calculated C 30 H 33 N3O, [M+H] + m / z 451.61, measured value 451.61.

[0298] General Synthesis Method Four:

[0299] Dissolve the corresponding phenolic compound (0.01 mol) in acetonitrile, add potassium carbonate (0.02 mol) and 1,4-dibromobutane (0.02 mol), heat to 52 °C, and react for 12 h. After rotary evaporation to dryness, separate and purify by silica gel column chromatography. Mobile phase: petroleum ether / ethyl acetate (5:1).

[0300] Example 32

[0301] Synthesis of 5-(4-bromobutoxy)-1H-indole

[0302]

[0303] The synthesis method is the same as General Method 4, using 5-hydroxyindole and 1,4-dibromobutane as starting materials. A white solid is obtained. Yield: 76%. 1 H NMR (400MHz, CDCl3) δ8.04 (s, 1H), 7.28 (d, J = 8.8Hz, 1H), 7.20 (d, J = 2.4Hz, 1H), 7.17 (t, J = 2.8Hz, 1H), 6.95 (dd, J = 8.8, 2.4Hz, 1H),6.56–6.55(m,1H),4.09(t,J=6.1Hz,2H),3.55(t,J=6.7Hz,2H),2.21–2.07(m,2H),2.04–1.98(m,2H). 13 C NMR (101MHz, CDCl3) δ153.42,131.15, 128.37,125.15,112.87,111.89,103.65,102.33,67.81,33.88,29.72,28.20.

[0304] Example 33

[0305] Synthesis of 7-(4-bromobutoxy)-3,4-dihydroquinoline-2(1H)-one

[0306]

[0307] The synthesis method is the same as General Method 4, using 3,4-dihydro-7-hydroxy-2(1H)-quinolinone and 1,4-dibromobutane as starting materials. A white oily liquid is obtained. Yield: 68%. 1 H NMR (400MHz, CDCl3) δ9.95 (s, 1H), 7.01 (d, J = 8.2Hz, 1H), 6.49 (dd, J = 8.2, 2.5Hz, 1H), 6.45 (d, J = 2.5Hz, 1H), 3.92(t,J=6.1Hz,2H),3.45(t,J=6.6Hz,2H),2.91–2.82(m,2H),2.65–2.57(m,2H),2.05–1.98(m,2H),1.91–1.84(m,2H). 13 C NMR (101MHz, CDCl3) δ 172.92, 158.48, 138.41, 128.54, 115.76, 108.74, 102.37, 66.98, 33.59, 31.03, 29.46, 27.89, 24.53.

[0308] Example 34

[0309] Synthesis of 7-(4-bromobutoxy)-2H-benzopyran-2-one

[0310]

[0311] The synthesis method is the same as General Method 4, using 7-hydroxy-2H-benzopyran-2-one and 1,4-dibromobutane as starting materials. A white solid is obtained. Yield: 66%. 1 H NMR (400MHz, CDCl3) δ7.58 (d, J=9.5Hz, 1H),7.31(d,J=8.6Hz,1H),6.76(dd,J=8.7,2.4Hz,1H),6.68(d,J=2.4Hz,1H),6.15(d,J=9.6Hz,1H),3.98(t,J=6.0Hz,2H),3.44(t,J=6.5Hz,2H), 2.06–1.96(m,2H),1.96–1.86(m,2H). 13C NMR (101MHz, CDCl3) δ162.01, 161.03, 155.75, 143.47, 128.85, 112.92, 112.71, 112.50, 101.28, 67.52, 33.40, 29.29, 27.62.

[0312] Example 35

[0313] Synthesis of 7-(4-bromobutoxy)quinoline

[0314]

[0315] The synthesis method is the same as General Method 4, using 7-hydroxyquinoline and 1,4-dibromobutane as starting materials. A white solid is obtained. Yield: 58%. 1 H NMR(400MHz,DMSO-d6)δ8.82–8.80(m,1H),8.23(d,J =7.7Hz,1H),7.84(d,J=8.9Hz,1H),7.40(d,J=2.0Hz,1H),7.34(dd,J=8.1,4 .2Hz,1H),7.23(dd,J=8.9,2.5Hz,1H),4.14(t,J=6.2Hz,2H),3.60(t,J=6.6 Hz,2H),2.02–1.95(m,2H),1.94–1.83(m,2H). 13 C NMR (101MHz, DMSO-d6) δ159.82,151.02,149.92,136.02,129.61,123.50,119.86,119.60,108.38,67.38,35.18,29.58,27.75.

[0316] Example 36

[0317] Synthesis of 6-(4-bromobutoxy)-2(1H)-quinolinone

[0318]

[0319] The synthesis method is the same as General Method 4, using 6-hydroxy-2(1H)-quinolinone and 1,4-dibromobutane as starting materials. A white solid is obtained. Yield: 60%. 1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),7.82(d, J=9.5Hz,1H),7.27–7.18(m,2H),7.14(dd,J=8.9,2.8Hz,1H),6.49(d,J=9 .5Hz,1H),4.01(t,J=6.2Hz,2H),3.61(t,J=6.6Hz,2H),2.03–1.92(m,2H), 1.88–1.81(m,2H). 13 C NMR (101MHz, DMSO-d6) δ161.98,153.78,140.22, 133.81,122.76,120.32,120.13,116.81,110.65,67.48,35.27,29.56,27.86.

[0320] Example 37

[0321] Synthesis of 7-(4-bromobutoxy)-2-quinolone

[0322]

[0323] The synthesis method is the same as General Method 4, using 7-hydroxy-2-quinolone and 1,4-dibromobutane as starting materials. A white solid is obtained. Yield: 63%. 1 H NMR (400MHz, DMSO-d6) δ11.60 (s, 1H), 7.78 (d, J= 9.5Hz,1H),7.53(d,J=8.4Hz,1H),6.81–6.74(m,2H),6.30(d,J=9.4Hz,1H) ,4.03(t,J=6.2Hz,2H),3.59(t,J=6.6Hz,2H),2.04–1.93(m,2H),1.92–1.79 (m,2H). 13 C NMR (101MHz, DMSO-d6) δ162.73,160.77,141.10,140.43, 129.68,119.00,113.82,111.18,99.15,67.33,35.17,29.50,27.78.

[0324] Example 38

[0325] Synthesis of 6-(4-bromobutoxy)-1H-indazole

[0326]

[0327] The synthesis method is the same as General Method 4, using 6-hydroxyindazole and 1,4-dibromobutane as starting materials. A white solid is obtained. Yield: 70%.1 H NMR (400MHz, CDCl3) δ10.27(s,1H),8.02(s,1H),7.67– 7.60(m,1H),6.84(d,J=7.7Hz,2H),4.05(t,J=6.0Hz,2H),3.52(t,J=6.5Hz,2H),2.15–2.07(m,2H),2.05–1.97(m,2H). 13 C NMR (101MHz, CDCl3) δ 158.97, 141.40, 134.76, 121.63, 118.02, 113.46, 91.50, 67.13, 33.42, 29.49, 27.82.

[0328] Example 39

[0329] Synthesis of 6-(4-bromobutoxy)benzo[d]thiazole

[0330]

[0331] The synthesis method is the same as General Method 4, using 6-hydroxybenzothiazole and 1,4-dibromobutane as starting materials. A white solid is obtained. Yield: 70%. 1 H NMR (400MHz, CDCl3) δ8.83 (s, 1H), 8.01 (d, J = 8.9 Hz,1H),7.38(d,J=2.4Hz,1H),7.11(dd,J=9.1,2.5Hz,1H),4.06(t,J=6.0Hz,2H),3.51(t,J=6.5Hz,2H),2.14–2.07(m,2H),2.02–1.96(m,2H). 13 C NMR (101MHz, CDCl3) δ157.28,151.45,147.90,135.11,124.02,116.15,104.80, 67.52,33.38,29.43,27.87.

[0332] Example 40

[0333] Synthesis of 5-(4-bromobutyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0334]

[0335] 10 mmol of compound 5-hydroxy-1H-benzo[d]imidazol-2(3H)-one was dissolved in acetonitrile, and potassium carbonate (20 mmol) and 1,4-dibromobutane (30 mmol) were added. The mixture was heated to 52 °C and reacted for 12 h. The reaction system was washed with water to precipitate a white solid, which was filtered, washed, and dried to give compound 5-(4-bromobutyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one, which was then directly used for subsequent reactions.

[0336] Example 41

[0337] Synthesis of 5-(4-bromobutoxy)benzo[d]thiazole

[0338]

[0339] The synthesis method is the same as General Method 4, using 5-hydroxybenzothiazole and 1,4-dibromobutane as starting materials. A white solid is obtained. Yield: 73%. 1 H NMR (400MHz, CDCl3) δ8.96 (s, 1H), 7.78 (d, J = 8.8 Hz,1H),7.58(d,J=2.5Hz,1H),7.07(dd,J=8.8,2.5Hz,1H),4.06(t,J=6.0Hz,2H),3.49(t,J=6.6Hz,2H),2.12–2.04(m,2H),2.04–1.94(m,2H). 13 C NMR (101MHz, CDCl3) δ158.22,155.02,154.63,125.62,122.07,116.35,106.44, 67.30,33.47,29.50,27.85.

[0340] Example 42

[0341] Synthesis of 5-(4-bromobutoxy)-1-methyl-1H-benzo[d]imidazole

[0342]

[0343] The synthesis method is the same as General Method 4, using 5-hydroxy-1-methyl-1H-benzis[d]imidazole and 1,4-dibromobutane as starting materials. A white solid is obtained. Yield: 75%. 1H NMR (400MHz, CDCl3) δ7.77 (s, 1H), 7.24 –7.22(m,2H),6.93(dd,J=8.9,2.3Hz,1H),4.02(t,J=6.1Hz,2H),3.77(s,3H),3.48(t,J=6.7Hz,2H),2.11–2.04(m,2H),1.98–1.91(m,2H). 13 C NMR (101 MHz, CDCl3) δ155.30,144.51,143.74,129.35,113.53,109.71,103.26,67.56, 33.54,31.10,29.59,27.98.

[0344] Example 43

[0345] Synthesis of 7-(4-bromobutoxy)-4-methyl-2H-benzopyran-2-one

[0346]

[0347] The synthesis method is the same as General Method 4, using 7-hydroxy-4-methyl-2H-benzopyran-2-one and 1,4-dibromobutane as starting materials. A white solid is obtained. Yield: 75%. 1 H NMR (400MHz, CDCl3) δ7.49 (d, J= 8.8Hz,1H),6.85(dd,J=8.8,2.5Hz,1H),6.78(d,J=2.5Hz,1H),6.12(d,J=1.5Hz,1H),4.06(t,J=6.0Hz,2H),3.50(t,J=6.5Hz,2H),2.39(d,J=1.2Hz, 3H),2.15–2.02(m,2H),2.04–1.93(m,2H). 13 CNMR(101MHz, CDCl3)δ 161.88,161.22,155.25,152.53,125.56,113.61,112.50,111.95,101.37,67.48,33.22,29.32,27.67,18.66.

[0348] General Synthesis Method Five:

[0349] 2 mmol of 5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and the corresponding 4-bromobutoxybenzene derivative (2.2 mmol) were dissolved in DMF. Potassium iodide (3 mmol) and potassium carbonate (4 mmol) were added, and the mixture was heated to 65 °C and reacted overnight. The reaction mixture was washed with dichloromethane and water three times with 30 mL of dichloromethane. The organic layers were combined, the solvent was removed by rotary evaporation, and the mixture was purified by silica gel column chromatography using a mobile phase of dichloromethane / methanol / ammonia (15–25:1:0.1).

[0350] Example 44

[0351] Synthesis of 2-(4-((1H-indol-5-yl)oxy)butyl)-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (CL-41)

[0352]

[0353] The synthesis method is the same as General Method 5, using compounds 5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and 5-(4-bromobutoxy)-1H-indole as starting materials. A white solid is obtained. Yield: 86%. 1 H NMR (400MHz, CDCl3) δ8.51(s,1H),7.50(d,J=7.7Hz,1H),7.32(d,J=8.1Hz, 1H),7.27–7.20(m,2H),7.19–7.13(m,2H),7.11(t,J=2.8Hz,1H),6.90(dd,J =8.8,2.4Hz,1H),4.13–4.10(m,2H),3.85(s,2H),3.63(s,3H),3.01(t,J=5 .7Hz,2H),2.89(t,J=5.8Hz,2H),2.80(t,J=7.0Hz,2H),1.97–1.94(m,4H). 13 C NMR (101MHz, CDCl3) δ 153.49, 137.17, 133.83, 131.15, 128.36, 125.69, 125.04, 120.78, 118.94, 117.64, 112.83, 111.78, 108.82, 107.40, 103.59, 102.13, 68.61, 57.66, 50.73, 49.76, 29.11, 27.58, 24.22, 22.64. HRMS (ESI) calculated C 24 H 28 N3O, [M+H] +m / z 347.2232, measured value 347.2227.

[0354] Example 45

[0355] Synthesis of 7-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butoxy)-3,4-dihydroquinoline-2(1H)-one (CL-42)

[0356]

[0357] The synthesis method is the same as General Method 5, using compound 5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and compound 7-(4-bromobutoxy)-3,4-dihydroquinoline-2(1H)-one as starting materials. A white solid is obtained. Yield: 82%. 1 HNMR (400MHz, CDCl3) δ9.11 (s, 1H), 7.45 (d, J = 7.7Hz, 1H), 7.28 (d,J=8.2Hz,1H),7.21–7.17(m,1H),7.13–7.07(m,1H),7.04(d,J=8.3Hz, 1H),6.55(dd,J=8.3,2.5Hz,1H),6.42(d,J=2.4Hz,1H),4.02–3.96(m,2H), 3.79(s,2H),3.64(s,3H),2.97(t,J=5.6Hz,2H),2.92–2.87(m,4H),2.74(t,J=6.9Hz,2H),2.66–2.62(m,2H),1.91–1.81(m,4H). 13 C NMR (101MHz, CDCl3) δ 172.32, 158.72, 138.30, 137.11, 133.80, 128.57, 125.65, 120.70, 118.85, 117.54, 115.65, 108.84, 108.73, 107.50, 102.32, 67.93, 57.49, 50.77, 49.70, 31.12, 29.10, 27.25, 24.59, 24.07, 22.72. HRMS (ESI) calculated C 25 H 30 N3O2, [M+H] + m / z 404.2338, measured value 404.2332.

[0358] Example 46

[0359] Synthesis of 7-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butoxy)-2H-benzopyran-2-one (CL-43)

[0360]

[0361] The synthesis method is the same as General Method 5, using compound 5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and compound 7-(4-bromobutoxy)-2H-benzopyran-2-one as starting materials. A white solid is obtained. Yield: 85%. 1 H NMR (400MHz, CDCl3) δ7.58 (d, J = 9.4Hz, 1H), 7.43 (d, J = 7.7Hz, 1H),7.32(d,J=8.6Hz,1H),7.27(d,J=8.6Hz,1H),7.20–7.16(m,1H),7.11– 7.07(m,1H),6.85(dd,J=8.5,2.4Hz,1H),6.81(d,J=2.4Hz,1H),6.23(d,J= 9.4Hz,1H),4.09(t,J=6.2Hz,2H),3.76(s,2H),3.62(s,3H),2.94(t,J=5.6H z,2H),2.87(t,J=5.3Hz,2H),2.73(t,J=7.1Hz,2H),1.98–1.91(m,2H),1.90– 1.81(m,2H). 13 C NMR (101MHz, CDCl3) δ 162.35, 161.25, 155.90, 143.49, 137.10, 133.87, 128.78, 125.66, 120.65, 118.82, 117.50, 112.94, 112.85, 112.42, 108.74, 107.60, 101.35, 68.42, 57.47, 50.86, 49.75, 29.09, 27.03, 24.04, 22.85. HRMS (ESI) calculated C 25 H 27 N₂O₃, [M+H] + m / z 403.2022, measured value 403.2017.

[0362] Example 47

[0363] Synthesis of 5-methyl-2-(4-(quinoline-7-oxy)butyl)-1,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (CL-44)

[0364]

[0365] The synthesis method is the same as General Method 5, using compound 5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and compound 7-(4-bromobutoxy)quinoline as starting materials. A white solid is obtained. Yield: 77%. 1 H NMR (400MHz, CDCl3)δ8.85(dd,J=4.4,1.8Hz,1H),8.10–8.07(m,1H),7.71(d,J =8.9Hz,1H),7.45–7.43(m,2H),7.29(d,J=4.2Hz,1H),7.28–7.26(m,1H),7 .24(dd,J=8.9,2.5Hz,1H),7.20–7.16(m,1H),7.11–7.07(m,1H),4.21(t,J =6.2Hz,2H),3.78(t,J=1.6Hz,2H),3.64(s,3H),2.96(t,J=5.5Hz,2H),2.91 –2.84(m,2H),2.79–2.71(m,2H),2.05–1.95(m,2H),1.95–1.86(m,2H). 13 C NMR (101MHz, CDCl3) δ 160.11, 150.54, 150.04, 137.09, 135.63, 133.87, 128.75, 125.69, 123.47, 120.61, 120.11, 118.88, 118.78, 117.54, 108.66, 108.02, 107.73, 67.98, 57.56, 50.83, 49.77, 29.06, 27.11, 24.26, 22.86. HRMS (ESI) calculated C 25 H 27 N₂O₃, [M+H] + m / z 386.2232, measured value 386.2227.

[0366] Example 48

[0367] Synthesis of 6-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butoxy)quinoline-2(1H)-one (CL-45)

[0368]

[0369] The synthesis method is the same as General Method 5, using compound 5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and compound 6-(4-bromobutoxy)-2(1H)-quinolinone as starting materials. A white solid is obtained. Yield: 83%. 1 H NMR (400MHz, CDCl3) δ12.89 (s, 1H), 7.69 (d, J=9.5Hz, 1H), 7.42 (t, J= 8.7Hz,2H),7.28(d,J=8.1Hz,1H),7.22–7.15(m,2H),7.13–7.06(m,1H),7 .00(d,J=2.7Hz,1H),6.72(d,J=9.5Hz,1H),4.08(t,J=6.0Hz,2H),3.79(s, 2H),3.63(s,3H),2.97(t,J=5.7Hz,2H),2.88(d,J=5.7Hz,2H),2.75(t,J=7.0Hz,2H),1.99–1.82(m,4H). 13 C NMR (101MHz, CDCl3) δ 164.27, 154.63, 140.52, 137.09, 133.78, 133.13, 125.63, 121.61, 120.71 (2C), 120.50, 118.86, 117.51 ​​(2C), 109.62, 108.72, 107.52, 68.27, 57.41, 50.72, 49.77, 29.08, 27.20, 24.05, 22.76. HRMS (ESI) calculated C 25 H 28 N3O2, [M+H] + m / z 402.2182, measured value 402.2178.

[0370] Example 49

[0371] Synthesis of 7-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butoxy)quinoline-2(1H)-one (CL-46)

[0372]

[0373] The synthesis method is the same as General Method 5, using compound 5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and compound 7-(4-bromobutoxy)-2-quinolone as starting materials. A white solid is obtained. Yield: 76%. 1H NMR (400MHz, CDCl3) δ12.63 (s, 1H), 7.73 (d, J = 9.4Hz, 1H), 7.45–7.42 (m, 2H),7.28(d,J=8.3Hz,1H),7.21–7.14(m,1H),7.12–7.06(m,1H),6.88(d,J =2.4Hz,1H),6.83(dd,J=8.7,2.3Hz,1H),6.57(d,J=9.4Hz,1H),4.12(t,J=5.9Hz,2H),3.79(s,2H ),3.63(s,3H),2.97(t,J=5.7Hz,2H),2.90–2.87(m,2H),2.75(t,J=7.0Hz,2H),1.97–1.83(m,4H). 13 C NMR (101MHz, CDCl3) δ 165.12, 161.44, 140.83, 140.47, 137.10, 133.84, 128.97, 125.66, 120.65, 118.82, 117.87, 117.54, 114.16, 112.70, 108.70, 107.60, 99.02, 68.16, 57.52, 50.79, 49.73, 29.08, 27.17, 24.07, 22.80. HRMS (ESI) calculated C 25 H 28 N3O2, [M+H] + m / z 402.2182, measured value 402.2177.

[0374] Example 50

[0375] Synthesis of 2-(4-((1H-indazol-6-yl)oxy)butyl)-5-methyl-1,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (CL-47)

[0376]

[0377] The synthesis method is the same as General Method 5, using compound 5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and compound 6-(4-bromobutoxy)-1H-indazole as starting materials. A white solid is obtained. Yield: 88%. 1H NMR (400MHz, CDCl3) δ10.60(s,1H),7.96(s,1H),7.59(d,J=8.8Hz,1H),7.45(d, J=7.8Hz,1H),7.29(d,J=8.3Hz,1H),7.24–7.17(m,1H),7.14–7.08(m,1H),6 .82(dd,J=8.8,2.1Hz,1H),6.74(s,1H),4.00–3.93(m,2H),3.85(s,2H),3.62 (s,3H),3.02(t,J=5.7Hz,2H),2.89(t,J=5.8Hz,2H),2.79(t,J=6.7Hz,2H),1.91–1.88(m,4H). 13 C NMR (101MHz, CDCl3) δ 159.00, 141.44, 137.13, 134.67, 133.70, 125.54, 121.41, 120.88, 119.00, 117.87, 117.54, 113.53, 108.83, 107.16, 91.44, 67.85, 57.29, 50.63, 49.67, 29.12, 27.03, 23.84, 22.52. HRMS (ESI) Calculated C 23 H 27 N4O, [M+H] + m / z 375.2185, measured value 375.2180.

[0378] Example 51

[0379] Synthesis of 6-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butoxy)benzo[d]thiazole (CL-48)

[0380]

[0381] The synthesis method is the same as General Method 5, using compound 5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and compound 6-(4-bromobutoxy)benzo[d]thiazole as starting materials. A white solid was obtained. Yield: 85%. 1H NMR(400MHz, CDCl3)δ8.83(s,1H),8.02(d,J=8.9Hz,1H),7.48–7.40 (m,2H),7.28(d,J=8.1Hz,1H),7.23–7.11(m,2H),7.14–7.05(m,2H),4.12(t, J=6.0Hz,2H),3.81(s,2H),3.64(s,3H),3.02–2.95(m,2H),2.90(d,J=4.9Hz,2H),2.77(t,J=7.1Hz,2H),2.00–1.86(m,4H). 13 CNMR (101MHz, CDCl3) δ 157.51, 151.40, 147.81, 137.12, 135.14, 133.80, 125.66, 123.96, 120.72, 118.87, 117.54, 116.30, 108.77, 107.44, 104.82, 68.42, 57.44, 50.74, 49.75, 29.09, 27.24, 24.09, 22.71. HRMS (ESI) calculated value C 23 H 26 N3OS,[M+H] + m / z 392.1797, measured value 392.1794.

[0382] Example 52

[0383] Synthesis of 5-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butoxy)benzo[d]thiazole (CL-49)

[0384]

[0385] The synthesis method is the same as General Method 5, using compound 5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and compound 5-(4-bromobutoxy)benzo[d]thiazole as starting materials. A white solid was obtained. Yield: 77%. 1H NMR (400MHz, CDCl3) δ8.99 (s, 1H), 7.81 (d, J = 8.8Hz, 1H), 7.64 (d, J = 2.4Hz, 1H), 7.43 (d, J = 7.8Hz, 1H), 7.28 (d, J = 8.1Hz, 2H), 7.20–7.16 (m, 1H), 7.14–7.11(m,2H),7.11–7.07(m,2H),4.15(t,J=6.1Hz,2H),3.79(d,J=1.7H z,2H),3.64(s,3H),2.97(t,J=5.6Hz,2H),2.92–2.84(m,2H),2.79–2.71(m, 2H),2.01–1.94(m,2H),1.93–1.85(m,2H). 13 C NMR (101MHz, CDCl3) δ 158.48, 154.83, 154.69, 137.10, 133.80, 125.67, 125.45, 121.98, 120.65, 118.81, 117.53, 116.50, 108.67, 107.60, 106.55, 68.23, 57.51, 50.78, 49.73, 29.06, 27.21, 24.19, 22.77. HRMS (ESI) calculated C 23 H 26 N3OS,[M+H] + m / z 392.1797, measured value 392.1793.

[0386] Example 53

[0387] Synthesis of 5-methyl-2-(4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)butyl)-1,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (C-L50)

[0388]

[0389] The synthesis method is the same as General Method 5, using compound 5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and compound 5-(4-bromobutoxy)-1-methyl-1H-benzo[d]imidazole as starting materials. A white solid was obtained. Yield: 88%. 1HNMR (400MHz, CDCl3) δ7.92 (s, 1H), 7.38 (d, J = 7.8Hz, 1H), 7.31 (s,1H),7.24(t,J=8.1Hz,2H),7.18(t,J=7.6Hz,1H),7.08(t,J=7.4Hz,1H),6 .95(d,J=7.7Hz,1H),4.11(s,2H),4.02(t,J=6.1Hz,2H),3.75(s,3H),3.58(s, 3H),3.27(t,J=5.9Hz,2H),3.10–2.93(m,4H),2.08–2.01(m,2H),1.91–1.84 (m,2H). 13 C NMR (101MHz, CDCl3) δ 155.55, 143.86, 143.68, 137.25, 132.01, 129.14, 125.11, 121.45, 119.38, 117.55, 113.89, 110.05, 109.01, 103.73, 102.99, 68.05, 55.89, 49.92, 48.98, 31.29, 29.26, 26.91, 22.74, 20.67. HRMS (ESI) calculated C 24 H 29 N4O, [M+H] + m / z 389.2341, measured value 389.2339.

[0390] Example 54

[0391] Synthesis of 5-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butoxy)-1,3-dihydro-2H-benzo[d]imidazol-2-one (CL-51)

[0392]

[0393] The synthesis method is the same as General Method 5, using compound 5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and compound 5-(4-bromobutyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one as starting materials. A white solid is obtained. Yield: 85%. 1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),10.39(s,1H),7.38– 7.30(m,2H),7.11–7.03(m,1H),7.00–6.93(m,1H),6.80(d,J=8.2Hz,1H),6. 53(d,J=8.5Hz,2H),3.93(t,J=6.0Hz,2H),3.59(s,3H),3.57(s,2H),2.77(s, 4H),2.57(t,J=6.7Hz,2H),1.78–1.65(m,4H). 13 C NMR (101MHz, DMSO-d6) δ 156.15, 154.18, 137.04, 134.79, 130.97, 125.58, 124.03, 120.59, 118.83, 117.59, 109.49, 109.18, 107.48, 107.35, 96.51, 68.39, 57.39, 50.78, 49.70, 29.31, 27.23, 23.95, 22.78. HRMS (ESI) calculated C 23 H 27 N4O2,[M+H] + m / z 391.2134, measured value 391.2130.

[0394] Example 55

[0395] Synthesis of 4-methyl-7-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)butoxy)-2H-benzopyran-2-one (CL-52)

[0396]

[0397] The synthesis method is the same as General Method 5, using compound 5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and compound 7-(4-bromobutoxy)-4-methyl-2H-benzopyran-2-one as starting materials. A white solid is obtained. Yield: 82%. 1HNMR (400MHz, CDCl3) δ7.44 (dd, J=11.0, 8.3Hz, 2H), 7.28– 7.23(m,1H),7.21–7.14(m,1H),7.11–7.04(m,1H),6.87(dd,J=8.8,2.5Hz, 1H),6.81(d,J=2.5Hz,1H),6.12(s,1H),4.10(t,J=6.1Hz,2H),3.76(s,2H), 3.62(s,3H),2.95(t,J=5.7Hz,2H),2.88(d,J=5.7Hz,2H),2.73(t,J=7.2Hz,2H),2.37(s,3H),1.99–1.91(m,2H),1.91–1.82(m,2H). 13 C NMR (101MHz, CDCl3) δ 162.15, 161.34, 155.27, 152.63, 137.08, 133.83, 125.63, 125.51, 120.66, 118.80, 117.49, 113.43, 112.63, 111.78, 108.72, 107.54, 101.36, 68.35, 57.45, 50.85, 49.72, 29.09, 27.05, 23.99, 22.81, 18.65. HRMS (ESI) calculated C 26 H 29 N₂O₃, [M+H] + m / z 417.2178, measured value 417.2177.

[0398] Example 56

[0399] Synthesis of 2-(4-((1H-indol-5-yl)oxy)butyl)-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (CL-53)

[0400]

[0401] 2 mmol of 9-methyl-1,3,4,9-tetrahydro-2H-pyridine[3,4-b]indole-2-carbonyl tert-butyl ester was dissolved in 15 mL of dichloromethane. 5 mL of trifluoroacetic acid was added with stirring, and the reaction was carried out at room temperature for 5 h. After the reaction was complete, the solvent was removed by rotary evaporation, and the solution was dissolved in 30 mL of dry DMF. Potassium carbonate (4 mmol), potassium iodide (3 mmol), and 5-(4-bromobutoxy)-1H-indole (2.2 mmol) were added under heating at 65 °C, and the reaction was stirred for 10 h. The solvent was removed by rotary evaporation, and the reaction system was washed three times with dichloromethane (30 mL each time). The organic layers were combined, and the solution was purified by silica gel column chromatography using dichloromethane / methanol / ammonia (25:1:0.1) as the mobile phase, yielding a white solid. Yield: 86%. 1 H NMR(400MHz, DMSO-d6)δ10.90(s,1H),7.39–7.34(m,2H),7.28(d,J=8.2Hz,2H),7.07(d,J =8.1Hz,2H),6.98(t,J=7.4Hz,1H),6.75(dd,J=8.8,2.4Hz,1H),6.32(s,1H),3 .99(t,J=5.7Hz,2H),3.64(s,2H),3.57(s,3H),2.74(d,J=5.5Hz,2H),2.69(d, J=4.1Hz,2H),2.62(t,J=6.3Hz,2H),1.84–1.69(m,4H). 13 C NMR (101MHz, DMSO-d6) δ 153.02, 137.15, 134.63, 131.52, 128.51, 126.67, 126.13, 120.69, 118.82, 117.91, 112.37, 112.13, 109.47, 106.83, 103.26, 101.25, 68.23, 57.57, 51.04, 49.42, 29.36, 27.34, 23.89, 21.78. HRMS (ESI) calculated C 24 H 28 N3O, [M+H] + m / z 374.2232, measured value 374.2230.

[0402] Example 57

[0403] Synthesis of 9-methyl-2-(4-(quinoline-7-oxy)butyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (CL-54)

[0404]

[0405] 2 mmol of 9-methyl-1,3,4,9-tetrahydro-2H-pyridine[3,4-b]indole-2-carbonyl tert-butyl ester was dissolved in 15 mL of dichloromethane. 5 mL of trifluoroacetic acid was added with stirring, and the reaction was carried out at room temperature for 5 h. After the reaction was complete, the solvent was removed by rotary evaporation, and the solution was dissolved in 30 mL of dry DMF. Potassium carbonate (4 mmol), potassium iodide (3 mmol), and 7-(4-bromobutoxy)quinoline (2.2 mmol) were added under heating at 65 °C, and the reaction was stirred for 10 h. The solvent was removed by rotary evaporation, and the reaction system was washed three times with dichloromethane (30 mL each time). The organic layers were combined, and the solution was purified by silica gel column chromatography using dichloromethane / methanol / ammonia (25:1:0.1) as the mobile phase, yielding a white solid. Yield: 78%. 1 H NMR(400MHz, CDCl3)δ8.88–8.82(m,1H),8.04(d,J=8.1Hz,1H),7.69(d,J=8.9Hz,1H), 7.52(d,J=7.7Hz,1H),7.47(d,J=2.5Hz,1H),7.30–7.17(m,4H),7.12(t,J=7 .4Hz,1H),4.21(t,J=6.1Hz,2H),3.72(s,2H),3.58(s,3H),2.88(s,4H),2.75 (t,J=7.3Hz,2H),2.03–1.96(m,2H),1.94–1.87(m,2H). 13 CNMR (101MHz, CDCl3) δ 160.09, 150.58, 150.02, 137.17, 135.67, 133.40, 128.83, 126.80, 123.49, 120.78, 120.06, 118.95, 118.83, 117.99, 108.65, 108.02, 107.42, 67.94, 57.64, 51.04, 49.72, 29.14, 27.06, 24.13, 21.57. HRMS (ESI) calculated value C 25 H 28 N3O, [M+H] + m / z 386.2232, measured value 386.2226.

[0406] Example 58

[0407] Synthesis of 6-(4-(9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)quinoline-2(1H)-one (CL-55)

[0408]

[0409] 2 mmol of 9-methyl-1,3,4,9-tetrahydro-2H-pyridine[3,4-b]indole-2-carbonyl tert-butyl ester was dissolved in 15 mL of dichloromethane. 5 mL of trifluoroacetic acid was added with stirring, and the mixture was stirred at room temperature for 5 h. After the reaction was complete, the solvent was removed by rotary evaporation, and the solution was dissolved in 30 mL of dry DMF. Potassium carbonate (4 mmol), potassium iodide (3 mmol), and 6-(4-bromobutoxy)-2(1H)-quinolinone (2.2 mmol) were added under heating at 65 °C, and the mixture was stirred for 10 h. The solvent was removed by rotary evaporation, and the reaction mixture was washed with dichloromethane and water. The washings were repeated three times with 30 mL of dichloromethane. The combined organic layers were purified by silica gel column chromatography using dichloromethane / methanol / ammonia (25:1:0.1) as the mobile phase, yielding a white solid. Yield: 78%. 1 H NMR (400MHz, DMSO-d6)δ11.62(s,1H),7.76(d,J=9.5Hz,1H),7.42–7.33(m, 2H),7.25–7.19(m,2H),7.16–7.13(m,1H),7.07(t,J=7.6Hz,1H),6.97(t,J= 7.4Hz,1H),6.44(d,J=9.5Hz,1H),4.04(t,J=6.3Hz,2H),3.65(s,2H),3.58(s,3H),2.76–2.74(m,2H),2.69–2.62(m,4H),1.83–1.69(m,4H). 13 C NMR (101 MHz, DMSO-d6) δ 161.96, 153.91, 140.21, 137.13, 134.57, 133.73, 126.64, 122.69, 120.70, 120.37, 120.15, 118.82, 117.90, 116.80, 110.54, 109.47, 106.81, 68.20, 57.37, 50.97, 49.41, 29.38, 26.99, 23.67, 21.75. HRMS (ESI) calculated C 25 H 28 N3O2, [M+H] + m / z 402.2182, measured value 402.2184.

[0410] Example 59

[0411] Synthesis of 7-(4-(9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)-2H-benzopyran-2-one (CL-56)

[0412]

[0413] 2 mmol of 9-methyl-1,3,4,9-tetrahydro-2H-pyridine[3,4-b]indole-2-carbonyl tert-butyl ester was dissolved in 15 mL of dichloromethane. 5 mL of trifluoroacetic acid was added with stirring, and the reaction was carried out at room temperature for 5 h. After the reaction was complete, the solvent was removed by rotary evaporation, and the solution was dissolved in 30 mL of dry DMF. Potassium carbonate (4 mmol), potassium iodide (3 mmol), and 7-(4-bromobutoxy)-2H-benzopyran-2-one (2.2 mmol) were added under heating at 65 °C, and the reaction was stirred for 10 h. The solvent was removed by rotary evaporation, and the reaction system was washed three times with dichloromethane (30 mL each time). The organic layers were combined, and the solution was purified by silica gel column chromatography using dichloromethane / methanol / ammonia (25:1:0.1) as the mobile phase, yielding a white solid. Yield: 67%. 1 H NMR (400MHz, CDCl3) δ7.59(d,J=9.4Hz,1H),7.49(d,J=7.8Hz,1H),7.34(d,J= 8.5Hz,1H),7.27(d,J=8.1Hz,1H),7.19(t,J=7.5Hz,1H),7.10(t,J=7.4Hz,1 H),6.88–6.79(m,2H),6.23(d,J=9.5Hz,1H),4.09(t,J=6.1Hz,2H),3.73(s, 2H),3.61(s,3H),2.91–2.86(m,4H),2.75(t,J=7.2Hz,2H),1.98–1.91(m,2H),1.90–1.83(m,2H). 13 C NMR (101MHz, CDCl3) δ 162.31, 161.26, 155.89, 143.46, 137.15, 133.31, 128.77, 126.74, 120.81, 118.84, 117.96, 112.92, 112.89, 112.45, 108.65, 107.39, 101.37, 68.36, 57.52, 51.00, 49.71, 29.17, 27.00, 23.91, 21.52. HRMS (ESI) calculated C 25 H 27 N₂O₃, [M+H] + m / z 403.2022, measured value 403.2016.

[0414] Example 60

[0415] Synthesis of N-(4-(9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)-1H-benzo[d]indol-6-carboxamide (CL-57)

[0416]

[0417] 1 mmol of compound (4-(9-methyl-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)butyl)amine carbonyl tert-butyl ester) was dissolved in 20 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 4 h. After the reaction was complete, the reaction solvent and unreacted trifluoroacetic acid were removed by rotary evaporation. The mixture was redissolved in 20 mL of DMF, and 1 mmol of EDCI and a catalytic amount of DMAP were added. The mixture was stirred for 20 min, and then 1H-benzimidazole-6-carboxylic acid was added. The mixture was stirred overnight. After the reaction was complete, the reaction solvent was removed by rotary evaporation, and the mixture was purified by silica gel column chromatography using dichloromethane / methanol / ammonia as the mobile phase, yielding a white solid. Yield: 62%. 1 H NMR (400MHz, CD3OD) δ8.26 (s, 1H), 8.18 (s, 1H), 7.77 (dd, J = 8.5, 1.8Hz,1H),7.61(dd,J=8.5,3.3Hz,1H),7.42–7.33(m,1H),7.24(d,J=8.4H z,1H),7.10(t,J=7.5Hz,1H),7.00(t,J=7.4Hz,1H),3.69(s,2H),3.49(d,J= 7.5Hz,5H),2.90–2.75(m,4H),2.70(t,J=7.2Hz,2H),1.79–1.67(m,4H). 13 C NMR (101MHz, CD3OD) δ 169.15, 143.26, 141.36, 137.38, 135.68, 132.02, 129.16, 126.43, 121.66, 120.65, 118.48, 117.35, 113.23, 108.38, 107.93, 106.40, 57.20, 50.53, 48.95, 39.47, 31.17, 27.09, 23.83, 20.56. HRMS (ESI) calculated C 24 H 28 N5O, [M+H] + m / z 402.2294, measured value 402.2290.

[0418] Example 61

[0419] Synthesis of N-(4-(9-ethyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)-1H-benzo[d]imidazolium-6-carboxamide (CL-58)

[0420]

[0421] 1 mmol of compound (4-(9-ethyl-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)butyl)amine carbonyl tert-butyl ester) was dissolved in 20 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 4 h. After the reaction was complete, the reaction solvent and unreacted trifluoroacetic acid were removed by rotary evaporation. The mixture was redissolved in 20 mL of DMF, and 1 mmol of EDCI and a catalytic amount of DMAP were added. The mixture was stirred for 20 min, and then 1H-benzimidazole-6-carboxylic acid was added. The mixture was stirred overnight. After the reaction was complete, the reaction solvent was removed by rotary evaporation, and the mixture was purified by silica gel column chromatography using dichloromethane / methanol / ammonia (15:1:0.1) as the mobile phase to give a white solid. Yield: 55%. 1 H NMR (400MHz, CDCl3) δ7.99 (t, J=5.8Hz, 1H), 7.88–7.81 (m,1H),7.80(s,1H),7.54–7.48(m,2H),7.30–7.27(m,1H),7.25–7.15(m,2 H),7.11(t,J=7.3Hz,1H),3.83–3.78(m,2H),3.60(s,2H),3.52(d,J=5.7Hz, 2H),2.87(s,3H),2.68(d,J=6.2Hz,2H),1.78(d,J=6.4Hz,4H),1.05(t,J=6.9Hz,3H),0.93–0.83(m,1H). 13 C NMR (101MHz, CDCl3) δ 168.57, 155.07, 142.77, 136.04, 132.28, 129.35, 126.59, 121.43, 121.10, 119.04, 118.09, 116.24, 113.30, 109.01, 107.26, 106.62, 56.82, 50.13, 49.99, 39.95, 37.61, 27.04, 25.02, 21.45, 15.15. HRMS (ESI) calculated C 25 H 30 N5O, [M+H] + m / z 416.2450, measured value 416.2442.

[0422] Example 62

[0423] Synthesis of N-(4-(9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)-4-(pyridin-3-yl)benzamide (CL-59)

[0424]

[0425] 1 mmol of compound (4-(9-methyl-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)butyl)amine carbonyl tert-butyl ester) was dissolved in 20 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 4 h. After the reaction was complete, the reaction solvent and unreacted trifluoroacetic acid were removed by rotary evaporation. The mixture was redissolved in 20 mL of DMF, and 1 mmol of EDCI and a catalytic amount of DMAP were added. The mixture was stirred for 20 min, and then 4-(pyridin-3-yl)-benzoic acid was added. The mixture was stirred overnight. After the reaction was complete, the reaction solvent was removed by rotary evaporation, and the mixture was purified by silica gel column chromatography using dichloromethane / methanol / ammonia (20:1:0.1) as the mobile phase, yielding a white solid. Yield: 68%. 1 H NMR (400MHz, CD3OD) δ8.80–8.79(m,1H),8.57–8.55(m,1H),8.08–8.04(m,1H),7.90(d,J=8.3Hz,2H),7.65–7.62(m,2H),7.53 (dd,J=8.0,4.9Hz,1H),7.41(d,J=7.5Hz,1H),7.29–6.97(m,3H),3.71(d,J= 6.6Hz,2H),3.55(d,J=11.3Hz,4H),3.49(t,J=6.3Hz,2H),2.88(d,J=4.8Hz, 2H),2.84(d,J=5.7Hz,2H),2.73(d,J=7.5Hz,2H),1.85–1.72(m,5H). 13 C NMR (101MHz, CD3OD) δ 168.03, 147.98, 147.00, 139.94, 137.34, 135.88, 135.10, 134.11, 132.60, 127.75 (2C), 126.65 (2C), 124.09, 120.57, 118.47, 117.37, 113.24, 108.36, 106.61, 57.18, 50.33, 49.19, 48.08, 39.49, 33.97, 31.20, 27.01, 24.14, 20.83. HRMS (ESI) calculated C 28 H 30 N4O, [M+H] +m / z 439.2494, measured value 439.2493.

[0426] Example 63

[0427] Synthesis of N-(4-(9-ethyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)-4-(pyridin-3-yl)benzamide (CL-60)

[0428]

[0429] 1 mmol of compound (4-(9-ethyl-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)butyl)amine carbonyl tert-butyl ester) was dissolved in 20 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 4 h. After the reaction was complete, the reaction solvent and unreacted trifluoroacetic acid were removed by rotary evaporation. The mixture was redissolved in 20 mL of DMF, and 1 mmol of EDCI and a catalytic amount of DMAP were added. The mixture was stirred for 20 min, and then 4-(pyridin-3-yl)-benzoic acid was added. The mixture was stirred overnight. After the reaction was complete, the reaction solvent was removed by rotary evaporation, and the mixture was purified by silica gel column chromatography using dichloromethane / methanol / ammonia (20:1:0.1) as the mobile phase to give a white solid. Yield: 75%. 1 H NMR (400MHz, CD3OD) δ8.72 (d, J=2.5Hz, 1H), 8.49 (dd, J=4.9,1.6Hz,1H),7.93–7.83(m,3H),7.52(d,J=7.9Hz,2H),7.44–7.34(m ,2H),7.22(d,J=8.2Hz,1H),7.08(t,J=7.6Hz,1H),6.99(t,J=7.4Hz,1H), 3.95–3.90(m,2H),3.62(s,2H),3.50–3.42(m,2H),2.75(t,J=4.3Hz,4H), 2.62(d,J=7.1Hz,2H),1.80–1.65(m,4H),1.14(t,J=7.1Hz,3H). 13C NMR (101MHz, CD3OD) δ 167.93, 148.00, 147.01, 139.89, 136.17, 135.78, 135.04, 134.09, 131.80, 127.79 (2C), 126.79, 126.64 (2C), 124.09, 120.63, 118.50, 117.58, 108.58, 106.78, 57.16, 50.34, 49.28, 39.51, 37.12, 27.04, 24.14, 20.89, 14.44. HRMS (ESI) calculated C 29 H 33 N4O, [M+H] + m / z 453.2650, measured value 453.2654.

[0430] Example 64

[0431] Synthesis of N-(4-(9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazolium-5-carboxamide (CL-61)

[0432]

[0433] 1 mmol of compound (4-(9-methyl-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)butyl)amine carbonyl tert-butyl ester) was dissolved in 20 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 4 h. After the reaction was complete, the reaction solvent and unreacted trifluoroacetic acid were removed by rotary evaporation. The mixture was redissolved in 20 mL of DMF, and 1 mmol of EDCI and a catalytic amount of DMAP were added. The mixture was stirred for 20 min, and then 2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid was added. The mixture was stirred overnight. After the reaction was complete, the reaction solvent was removed by rotary evaporation, and the mixture was purified by silica gel column chromatography using dichloromethane / methanol / ammonia (20:1:0.1) as the mobile phase, yielding a white solid. Yield: 49%. 1 H NMR(400MHz,CD3OD)δ7.58–7.49(m,2H), 7.39(d,J=8.1Hz,1H),7.35–7.25(m,1H),7.25–6.95(m,3H),3.70(d,J=4. 9Hz,2H),3.56(d,J=8.4Hz,3H),3.45(t,J=6.4Hz,2H),2.95–2.76(m,4H), 2.70(t,J=7.3Hz,2H),1.80–1.68(m,4H). 13C NMR (101MHz, CD3OD) δ 168.89, 156.79, 137.39, 132.50, 132.25, 129.44, 127.81, 126.52, 120.63, 120.54, 118.39, 117.26, 113.15, 108.27, 108.14, 106.55, 57.34, 50.56, 49.10, 39.46, 31.11, 27.13, 24.04, 20.75. HRMS (ESI) calculated C 24 H 28 N5O2,[M+H] + m / z 418.2243, measured value 418.2241.

[0434] Example 65

[0435] Synthesis of N-(4-(9-ethyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazolium-5-carboxamide (CL-62)

[0436]

[0437] 1 mmol of compound (4-(9-ethyl-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)butyl)amine carbonyl tert-butyl ester) was dissolved in 20 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 4 h. After the reaction was complete, the reaction solvent and unreacted trifluoroacetic acid were removed by rotary evaporation. The mixture was redissolved in 20 mL of DMF, and 1 mmol of EDCI and a catalytic amount of DMAP were added. The mixture was stirred for 20 min, and then 2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid was added. The mixture was stirred overnight. After the reaction was complete, the reaction solvent was removed by rotary evaporation, and the mixture was purified by silica gel column chromatography using dichloromethane / methanol / ammonia (20:1:0.1) as the mobile phase, yielding a white solid. Yield: 53%. 1 H NMR (400MHz, DMSO-d6) δ10.86(d,J=10.6Hz, 2H),8.36(t,J=5.6Hz,1H),7.53(d,J=8.2Hz,1H),7.47(s,1H),7.37–7.34(m, 2H),7.05(t,J=7.6Hz,1H),6.96(t,J=7.9Hz,2H),4.05–4.00(m,2H),3.63( s,2H),3.32–3.28(m,2H),2.83–2.53(m,6H),1.60(s,4H),1.18(t,J=7.1Hz, 3H). 13C NMR (101MHz, DMSO-d6) δ 166.66, 156.04, 136.03, 133.69, 132.51, 129.87, 127.75, 126.84, 120.80, 120.76, 118.80, 118.02, 109.48, 108.12, 108.05, 106.94, 57.49, 50.98, 49.35, 39.62, 37.52, 27.61, 24.70, 21.69, 15.79. HRMS (ESI) Calculated C 25 H 30 N5O2,[M+H] + m / z 432.2400, measured value 432.2393.

[0438] Experimental Example 1

[0439] Radioligand competitive binding experiment

[0440] Radiolabeled ligands (agonists or antagonists) are incubated with tissues, cells, or preparations containing receptors to allow the receptors and ligands to fully bind and form receptor-ligand complexes. After the reaction is terminated, unbound labels are removed by filtration or centrifugation, and the radioactivity in the filter membrane or precipitate is measured to calculate the amount of receptors bound to the ligands.

[0441] When radioligands interact with receptor preparations (tissue or cell preparations containing receptors), there are two binding modes: one is specific binding between the ligand and the receptor, characterized by high affinity and saturation due to the limited number of receptors; the other is binding between the ligand and non-receptor molecules in the receptor preparation, called non-specific binding, characterized by low affinity but numerous binding sites and less saturation. When studying specific receptors using radioligands, it is essential to reduce non-specific binding. A common method is to prepare total binding tubes and non-specific binding tubes; the difference between the two counts represents the amount of specific binding. Total binding tube: The radioligand is reacted with the receptor preparation to remove free radioligands, and the count of bound radioligands is measured (including both specific and non-specific bindings, called total binding). Non-specific binding tube: A large amount (typically 500-1000 times) of unlabeled specific ligands is mixed with labeled radioligands and then reacted together with the receptor preparation. Because the ratio of unlabeled to labeled ligands is significantly different, the receptor is almost entirely saturated with unlabeled ligands, and the labeled ligands can only bind to non-specific binding sites in the tissue preparation. Therefore, the amount of labeled ligand binding measured reflects the amount of non-specific binding. The specific binding count can be obtained by subtracting the count of non-specific binding tubes from the total number of binding tubes.

[0442] D2 receptor binding experiment

[0443] Preparation of homogenate: Weigh 1.191g HEPES and 101.6mg MgCl2, add purified water to a total volume of 250mL, and adjust the pH to 7.4. The final concentrations are HEPES 20mM and MgCl2 2mM, respectively.

[0444] Preparation of receptor membrane: CHO-D2 cells were taken out of the -80℃ freezer and thawed naturally. They were centrifuged at 3000g for 5 min, and the precipitate was added to the homogenate. The mixture was vortexed and centrifuged at 50000g at 4℃ for 12 min. The supernatant was discarded, and the precipitate was washed again with buffer. The centrifugation was repeated three times, and the supernatant was discarded. The precipitate was stored at -80℃ for later use.

[0445] Receptor competition binding assay: The prepared membrane was first homogenized to form a suspension at 8 mg / mL. 100 μL of the membrane preparation was added to each reaction tube. 100 μL of homogenate was added to the total binding tube (TB), and 100 μL of Haloperidol (final concentration 1.0 × 10⁻⁶) was added to the nonspecific binding tube (NB). -5 M), 100 μL of the test compound (initial activity screening test 1.0 × 10⁻⁶) was added to each test compound binding tube (CB). -5 M represents the inhibition rate of the compound against the labeled ligand at a single concentration, repeated 2-3 times; K represents the inhibition rate of the compound against the labeled ligand at a single concentration. i For the assay, eight concentrations of each test compound were prepared, with a concentration gradient of 1.0 × 10⁻⁶. -5 M was diluted fivefold sequentially, and each concentration of each compound was tested in duplicate 2-3 times. Radioactive ligands were added to each reaction tube. 3 10 μL of H-Spiperone was added to a final concentration of 1.176 nM. Each reaction tube was incubated at 37°C for 25 min. After the reaction was complete, the bound ligands were rapidly filtered under reduced pressure. Whatman test paper GF / C plates were pre-soaked in 0.5% PEI for at least 1 h. After filtration, the filter membrane was dried at 60°C, a base membrane was attached, and 45 μL of scintillation solution was added. The membrane was sealed and allowed to stand overnight. The scintillation counter was used to count the scintillation.

[0446] The sum and constant are denoted as TB, the nonspecific binding constant as NSB, and the compound binding constant as CB. The formula for calculating the inhibition rate of the compound is as follows:

[0447] Inhibition rate (I%) = (TB - CB) / (TB - NSB) × 100%

[0448] D3 receptor binding assay

[0449] Preparation of homogenate: Weigh 50.8 mg MgCl2 and add 50 mM Tris-HCl buffer to a total volume of 250 mL, adjusting the pH to 7.4. The final concentration should be 1 mM MgCl2.

[0450] Preparation of receptor membrane: CHO-D3 cells were taken out of the -80℃ freezer and thawed naturally. They were centrifuged at 2000g for 10min, and the precipitate was added to the homogenate. The mixture was vortexed and centrifuged at 45000g at 4℃ for 15min. The supernatant was discarded, and the precipitate was washed again with buffer. The centrifugation was repeated three times. After centrifugation, the supernatant was discarded, and the precipitate was stored at -80℃ for later use.

[0451] Receptor competition binding assay: The prepared membrane was first homogenized to form a suspension at 8 mg / mL. 100 μL of the membrane preparation was added to each reaction tube. 100 μL of solution B was added to the total binding tube (TB), and 10 μM Haloperidol (final concentration 1.0 × 10⁻⁶) was added to the nonspecific binding tube (NB). -5 M) 100 μL, each test compound binding tube (CB) contains 100 μL of the test compound (initial activity screening test 1.0 × 10⁻⁶). -5 M represents the inhibition rate of the compound against the labeled ligand at a single concentration, repeated 2-3 times; K represents the inhibition rate of the compound against the labeled ligand at a single concentration. i For the assay, eight concentrations of each test compound were prepared, with a concentration gradient of 1.0 × 10⁻⁶. -5 M was diluted fivefold sequentially, and each concentration of each compound was tested in duplicate 2-3 times. Radioactive ligands were added to each reaction tube. 3 10 μL of H-Spiperone was added to a final concentration of 1.176 nM. Each reaction tube was incubated at 27°C for 30 min. After the reaction was complete, the bound ligands were rapidly filtered under reduced pressure. Whatman test strips for GF / B were saturated with 0.5% PEI solution 1 h in advance, thoroughly washed with ice-cold Tris buffer, filtered, and the filter membrane was dried at 60°C. After attaching the base membrane, 45 μL of scintillation solution was added, the membrane was sealed, and allowed to stand overnight. The scintillation counter was used for counting.

[0452]

[0453]

[0454]

[0455]

[0456] Experimental Example 2

[0457] Effects of compounds on the MK-801-induced high-activity model

[0458] MK-801 is an NMDA receptor (N-methyl-D-aspartic acid receptor, NMDAR) blocker. Subcutaneous injection of 0.3 mg / kg MK-801 significantly increased the distance mice moved within 1 hour compared to the control group (p < 0.05). Intraperitoneal injection and gavage administration of 1 mg / kg cariprazine (CRP) significantly inhibited the above-mentioned behavioral excitatory effects induced by MK-801. This indicates that the model has been successfully established. Using this model, the inhibitory effects of compounds CL-22, CL-24, CL-26, CL-27, and CL-29 at 30 mg / kg via intraperitoneal injection on MK-induced hyperactivity were investigated. Figure 1 As shown in Figure 2, compounds CL-22 and CL-29 were found to exhibit good inhibitory effects.

[0459] Further research will be conducted on compounds CL-22 and CL-29, which showed good efficacy at single concentrations; three concentration gradients of 3 mg / kg, 10 mg / kg, and 30 mg / kg will be established, such as... Figure 3 The results showed that compound CL-22 significantly inhibited MK-801-induced hyperactivity in mice at 30 mg / kg and 10 mg / kg, but showed no inhibitory effect at a lower concentration of 3 mg / kg, exhibiting a generally good dose-dependent effect; while... Figure 4 As shown, compound CL-29 exhibited good dose-dependent inhibitory effects at all three concentrations.

[0460] Experimental Example 3

[0461] Effects of compounds on apomorphine (APO)-induced climbing activity

[0462] APO is a dopamine receptor agonist. Subcutaneous injection of 1 mg / kg APO can induce climbing-like behavior in mice. The inhibitory effect of compound CL-29 at different concentrations on APO-induced climbing behavior in mice was investigated by intraperitoneal injection. The results showed (e.g.) Figure 5 Compound CL-29 exhibited good dose-dependent inhibitory effects, showing significant inhibitory effects at three doses: 3 mg / kg, 10 mg / kg, and 30 mg / kg.

[0463] Test Example 4

[0464] Effect of compounds on immobility time during forced swimming in mice

[0465] In a mouse forced swimming model (e.g.) Figure 6Administering duloxetine (DLX) at 15 mg / kg for three consecutive days significantly reduced the immobility time in mice (P<0.001). CL-29, administered at a higher dose of 30 mg / kg for three consecutive administrations, also shortened the immobility time in mice, showing a significant difference compared to the solvent control group (P<0.005). However, the 3 mg / kg and 10 mg / kg groups did not show any difference compared to the solvent control group. Regarding the effect on the swimming immobility latency, neither duloxetine at 15 mg / kg nor any of the three doses of CL-29 showed a difference compared to the solvent group, possibly due to the insensitivity of the swimming model.

[0466] Experimental Example 5

[0467] Effect of compound CL-29 on immobility time of mouse tail suspension

[0468] In the mouse tail suspension model (e.g.) Figure 7 Administering duloxetine (DLX) at 15 mg / kg for three consecutive days significantly reduced the immobility time of suspended tails in mice (P<0.0001). CL-29, administered at a higher dose of 30 mg / kg three times consecutively, significantly shortened the immobility time in mice, showing a significant difference compared to the solvent control group (P<0.001). The 10 mg / kg group also showed some effect (P<0.05), but the 3 mg / kg group did not show any difference compared to the solvent control group. Regarding the effect on the immobility latency of suspended tails, duloxetine at 15 mg / kg administered three times consecutively prolonged the immobility latency. CL-29 only showed a significant effect at the highest dose of 30 mg / kg (P<0.05), while the other two lower dose groups did not show any effect in prolonging the latency.

[0469] Experimental Example 6

[0470] Effects of compound CL-29 on MK-801-induced neo-object recognition disorder

[0471] The study found no significant difference in the total exploration time and exploration index between mice during the learning period when exploring two identical objects (e.g., Figure 8 Where A represents the total exploration time for each group and B represents the exploration index for two identical objects. During the test period, intraperitoneal injection of MK-801 (0.2 mg / kg) in the MK group significantly increased the activity and total exploration time of mice; the positive control drug risperidone effectively reduced the activity and total exploration time of mice; similarly, the CL-29 30 mg / kg group also significantly inhibited the exploration time of mice, restoring it to the same level as the blank control, while the 10 mg / kg and 3 mg / kg groups showed no significant difference compared to the model group.

[0472] During the testing period, the blank group showed a stronger interest in new objects and a higher recognition index. After intraperitoneal injection of MK-801 (0.2 mg / kg) into the MK group, the mice's recognition memory was disrupted, and there was no difference in the recognition of new and old objects. The recognition index was significantly reduced, which was significantly different from the solvent control group (P<0.001). The RPD group did not show any difference from the model group, and it did not show any recovery effect on the cognitive decline induced by MK-801. CL-29 only showed a certain protective effect on cognition in the 30 mg / kg administration group (P<0.05).

[0473] While the embodiments disclosed in this application are as described above, the content is merely for the purpose of facilitating understanding of this application and is not intended to limit this application. Any person skilled in the art to which this application pertains may make any modifications and changes in the form and details of the implementation without departing from the spirit and scope disclosed in this application; however, the scope of protection of this application shall still be determined by the scope defined in the appended claims.

Claims

1. A carbazole derivative, said carbazole derivative as shown in formula (I), or a pharmaceutically acceptable salt thereof: In equation (I), one of Y1 and Y2 is -CH2-, while the other is -N(R3)-; R3 is -(CH2) n -A-R4, n is an integer from 3 to 6, A is O, N(R5)C(O) or N(R5)C(O)O; R5 is hydrogen or an unsubstituted C1-C6 alkyl group; R1 is an unsubstituted C1-C6 alkyl group; R2 is hydrogen; When A is N(R5)C(O)O, R4 is an unsubstituted C1-C8 alkyl group; When A is O or N(R5)C(O), R4 is a phenyl-substituted phenyl, a pyridyl-substituted phenyl, an unsubstituted heteroaryl, or a substituted heteroaryl; the substituted heteroaryl refers to one substituted by a substituent of group L. The L group of substituents is selected from one or more of the following groups: halogens, C1-C6 alkyl groups; The unsubstituted heteroaryl group or the substituted heteroaryl group is: thienyl, furanyl, pyrroleyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, triazole, pyridyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, inzolyl, inazinyl, benzofuranyl, benzimidazolyl, benzimidazolone, benzopyrazolyl, benzooxazolyl, benzothiazolyl, quinolinyl, quinolinone, imidazopyrazinyl, benzopyranyl, benzopyranone, benzodihydropyranone, or carbazoleyl.

2. The carbazole derivative according to claim 1, wherein, In formula (I), R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

3. The carbazole derivative according to claim 2, wherein, In formula (I), R1 is methyl or ethyl.

4. The carbazole derivative according to claim 1, wherein, In formula (I), when A is N(R5)C(O)O, R4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl, or n-octyl. When A is O or N(R5)C(O), R4 is a phenyl-substituted phenyl, a pyridyl-substituted phenyl, an unsubstituted heteroaryl, or a substituted heteroaryl; the substituted heteroaryl refers to one substituted by a substituent of group L. The L group of substituents is selected from one or more of the following groups: halogens, C1-C6 alkyl groups; The unsubstituted heteroaryl group or the substituted heteroaryl group is: thienyl, furanyl, pyrroleyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, triazole, pyridyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, inzolyl, inazinyl, benzofuranyl, benzimidazolyl, benzimidazolone, benzopyrazolyl, benzooxazolyl, benzothiazolyl, quinolinyl, quinolinone, imidazopyrazinyl, benzopyranyl, benzopyranone, benzodihydropyranone, or carbazoleyl.

5. The carbazole derivative according to claim 1, wherein, In equation (I), Y1 is -CH2-, while Y2 is -N(R3)-; R3 is -(CH2). n -A-R4, where n is an integer from 3 to 6, A is O, N(R5)C(O) or N(R5)C(O)O; R5 is hydrogen; When A is N(R5)C(O)O, R4 is an unsubstituted C1-C8 alkyl group; When A is O or N(R5)C(O), R4 is a phenyl-substituted phenyl, a pyridyl-substituted phenyl, an unsubstituted heteroaryl, or a substituted heteroaryl; here, the substituted heteroaryl refers to one substituted by a substituent of group L. The L group of substituents is selected from one or more of the following groups: halogens, C1-C6 alkyl groups.

6. The carbazole derivative according to claim 1, wherein, In equation (I), Y1 is -N(R3)-, and Y2 is -CH2-; R3 is -(CH2). n -A-R4, where n is an integer from 3 to 6, A is O, N(R5)C(O) or N(R5)C(O)O; R5 is hydrogen; When A is N(R5)C(O)O, R4 is an unsubstituted C1-C8 alkyl group; When A is O or N(R5)C(O), R4 is a phenyl-substituted phenyl, a pyridyl-substituted phenyl, an unsubstituted heteroaryl, or a substituted heteroaryl; here, the substituted heteroaryl refers to one substituted by a substituent of group L. The L group of substituents is selected from one or more of the following groups: halogens, C1-C6 alkyl groups.

7. The carbazole derivative according to any one of claims 1 to 5, wherein, In equation (I), Y1 is -CH2-, while Y2 is -N(R3)-; R3 is -(CH2). n -A-R4, where n is an integer from 3 to 6, A is N(R5)C(O)O; R5 is hydrogen; and R4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl, or n-octyl.

8. The carbazole derivative according to any one of claims 1 to 4 and 6, wherein, In equation (I), Y1 is -N(R3)-, and Y2 is -CH2-; R3 is -(CH2). n -A-R4, where n is an integer from 3 to 6, A is N(R5)C(O)O; R5 is hydrogen; and R4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl, or n-octyl.

9. The carbazole derivative according to any one of claims 1 to 5, wherein, In equation (I), Y1 is -CH2-, while Y2 is -N(R3)-; R3 is -(CH2). n -A-R4, where n is an integer from 3 to 6, A is O or N(R5)C(O); R5 is hydrogen; R4 is a phenyl-substituted phenyl, a pyridyl-substituted phenyl, or one of the following groups optionally substituted by a group of L substituents: Thiophene, furanyl, pyrrole, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, triazole, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, inzolyl, inazinyl, benzofuranyl, benzimidazolyl, benzimidazolone, benzopyrazolyl, benzooxazolyl, benzothiazolyl, quinolinyl, quinolinone, imidazopyridazinyl, benzopyranyl, benzopyranone, benzodihydropyranone, or carbazoleyl; The L group of substituents is selected from one or more of the following groups: halogens, C1-C6 alkyl groups.

10. The carbazole derivative according to any one of claims 1 to 4 and 6, wherein, In equation (I), Y1 is -N(R3)-, and Y2 is -CH2-; R3 is -(CH2). n -A-R4, where n is an integer from 3 to 6, A is O or N(R5)C(O); R5 is hydrogen; R4 is a phenyl-substituted phenyl, a pyridyl-substituted phenyl, or one of the following groups optionally substituted by a group of L substituents: Thiophene, furanyl, pyrrole, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, triazole, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, inzolyl, inazinyl, benzofuranyl, benzimidazolyl, benzimidazolone, benzopyrazolyl, benzooxazolyl, benzothiazolyl, quinolinyl, quinolinone, imidazopyridazinyl, benzopyranyl, benzopyranone, benzodihydropyranone, or carbazoleyl; The L group of substituents is selected from one or more of the following groups: halogens, C1-C6 alkyl groups.

11. A compound, or a pharmaceutically acceptable salt thereof, selected from one of the following compounds: (4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[3,4-) b Indole-2-yl)butyl)amine carbonyl tert-butyl ester; (4-(5-ethyl-1,3,4,5-tetrahydro-2) H -pyrido[4,3- b Indole-2-yl)butyl)amine carbonyl tert-butyl ester; N-(4-(5-methyl-1,3,4,5-tetrahydro-2-) H -pyrido[4,3- b Indole-2-yl)butyl)-1 H -Indole-2-carboxamide; 6-Chloro-N-(4-(5-methyl-1,3,4,5-tetrahydro-2-) H -pyrido[4,3- b [Indole-2-yl)butyl)imidazo[1,2-] b ]pyridazine-2-carboxamide; N-(4-(5-methyl-1,3,4,5-tetrahydro-2-) H -pyrido[4,3- b Indole-2-yl)butyl)-4-(pyridin-3-yl)benzamide; N-(4-(5-methyl-1,3,4,5-tetrahydro-2-) H -pyrido[4,3- b Indole-2-yl)butyl)quinoline-3-carboxamide; N-(4-(5-methyl-1,3,4,5-tetrahydro-2-) H -pyrido[4,3- b Indole-2-yl)butyl)-9 H -Carbazole-3-formamide; N-(4-(5-methyl-1,3,4,5-tetrahydro-2-) H -pyrido[4,3- b Indole-2-yl)butyl)-2-oxo-2,3-dihydro-1 H -benzo[ d Imidazole-5-carboxamide; N-(4-(5-methyl-1,3,4,5-tetrahydro-2-) H -pyrido[4,3- b Indole-2-yl)butyl)-1 H -benzo[ d Imidazole-5-carboxamide; N-(4-(5-methyl-1,3,4,5-tetrahydro-2-) H -pyrido[4,3- b Indole-2-yl)butyl)-1 H -benzo[ d Imidazole-2-carboxamide; N-(4-(5-methyl-1,3,4,5-tetrahydro-2-) H -pyrido[4,3- b Indole-2-yl)butyl)quinoline-4-carboxamide; N-(4-(5-methyl-1,3,4,5-tetrahydro-2-) H -pyrido[4,3- b Indole-2-yl)butyl)-[1,1'-biphenyl]-4-carboxamide; N-(4-(5-ethyl-1,3,4,5-tetrahydro-2-) H -pyrido[4,3- b Indole-2-yl)butyl)-1 H -Indole-2-carboxamide; (4-(9-methyl-1,3,4,9-tetrahydro-2H-pyridine[3,4- b Indo-2-yl)butyl)amine carbonyl tert-butyl ester; N-(4-(9-methyl-1,3,4,9-tetrahydro-2-) H -pyrido[3,4- b Indole-2-yl)butyl)-1 H -Indole-2-carboxamide; N-(4-(9-ethyl-1,3,4,9-tetrahydro-2-) H -pyrido[3,4- b Indole-2-yl)butyl)-1 H -Indole-2-carboxamide; N-(4-(9-ethyl-1,3,4,9-tetrahydro-2-) H -pyrido[3,4- b Indole-2-yl)butyl)-9 H -Carbazole-3-formamide; N-(4-(9-ethyl-1,3,4,9-tetrahydro-2-) H -pyrido[3,4- b Indole-2-yl)butyl)-[1,1'-biphenyl]-4-carboxamide; 2-(4-((1 H -indol-5-yl)oxy)butyl)-5-methyl-2,3,4,5-tetrahydro-1 H -pyrido[4,3- b Indole; 7-(4-(5-methyl-1,3,4,5-tetrahydro-2-) H -pyrido[4,3- b Indole-2-yl)butoxy)-3,4-dihydroquinoline-2(1 H )-ketone; 7-(4-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-) b Indole-2-yl)butoxy)-2 H -Benzopyran-2-one; 5-Methyl-2-(4-(quinoline-7-oxy)butyl)-1,3,4,5-tetrahydro-1 H -pyrido[4,3- b Indole; 6-(4-(5-methyl-1,3,4,5-tetrahydro-2-) H -pyrido[4,3- b Indole-2-yl)butoxy)quinoline-2(1 H )-ketone; 7-(4-(5-methyl-1,3,4,5-tetrahydro-2-) H -pyrido[4,3- b Indole-2-yl)butoxy)quinoline-2(1 H )-ketone; 2-(4-((1 H -Indazole-6-yl)oxy)butyl)-5-methyl-1,3,4,5-tetrahydro-1 H -pyrido[4,3- b Indole; 6-(4-(5-methyl-1,3,4,5-tetrahydro-2-) H -pyrido[4,3- b Indole-2-yl)butoxy)benzo[ d ]Thiazole; 5-(4-(5-methyl-1,3,4,5-tetrahydro-2-) H -pyrido[4,3- b Indole-2-yl)butoxy)benzo[ d ]Thiazole; 5-Methyl-2-(4-((1-Methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)tetrabutyl)-1,3,4,5-tetrahydro-1 H -pyrido[4,3- b Indole; 5-(4-(5-methyl-1,3,4,5-tetrahydro-2-) H -pyrido[4,3- b Indole-2-yl)butoxy)1,3-dihydro-2 H -benzo[ d Imidazol-2-one; 4-Methyl-7-(4-(5-methyl-1,3,4,5-tetrahydro-2-) H -pyrido[4,3- b Indole-2-yl)butoxy)-2 H -Benzopyran-2-one; 2-(4-((1 H -indol-5-yl)oxy)butyl)-9-methyl-2,3,4,9-tetrahydro-1 H -pyrido[3,4- b Indole; 9-Methyl-2-(4-(quinoline-7-oxy)butyl)-2,3,4,9-tetrahydro-1 H -pyrido[3,4- b Indole; 6-(4-(9-methyl-1,3,4,9-tetrahydro-2-) H -pyrido[3,4- b Indole-2-yl)butyl)quinoline-2(1 H )-ketone; 7-(4-(9-methyl-1,3,4,9-tetrahydro-2-) H -pyrido[3,4- b Indole-2-yl)butyl)-2 H -Benzopyran-2-one; N-(4-(9-methyl-1,3,4,9-tetrahydro-2-) H -pyrido[3,4- b Indole-2-yl)butyl)-1 H -benzo[ d Indole-6-carboxamide; N-(4-(9-ethyl-1,3,4,9-tetrahydro-2-) H -pyrido[3,4- b Indole-2-yl)butyl)-1 H -benzo[ d Imidazole-6-carboxamide; N-(4-(9-methyl-1,3,4,9-tetrahydro-2-) H -pyrido[3,4- b Indole-2-yl)butyl)-4-(pyridin-3-yl)benzamide; N-(4-(9-ethyl-1,3,4,9-tetrahydro-2-) H -pyrido[3,4- b Indole-2-yl)butyl)-4-(pyridin-3-yl)benzamide; N-(4-(9-methyl-1,3,4,9-tetrahydro-2-) H -pyrido[3,4- b Indole-2-yl)butyl)-2-oxo-2,3-dihydro-1 H -benzo[ d Imidazole-5-carboxamide; and N-(4-(9-ethyl-1,3,4,9-tetrahydro-2-) H -pyrido[3,4- b Indole-2-yl)butyl)-2-oxo-2,3-dihydro-1 H -benzo[ d Imidazole-5-carboxamide.

12. The method for preparing carbazole derivatives according to claim 1, comprising the following steps: Compound of formula (I-1) and X-(CH2) n The -A-R4 reaction yields compound (I); In formula (I-1), one of Z1 and Z2 is -CH2-, and the other is -N(H)-; R1 and R2 are defined as in formula (I) of claim 1. X-(CH2) n In -A-R4, X is a leaving group; n, A, and R4 are defined as in formula (I) of claim 1.

13. A pharmaceutical composition comprising any carbazole derivative according to any one of claims 1 to 11.

14. Use of any carbazole derivative of claim 1 to 11 or the pharmaceutical composition of claim 13 in the preparation of dopamine D2, dopamine D3 or receptor modulators of dopamine D2 and D3.

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