Indazole CB1 bias agonist as well as preparation and application thereof

Abstract

The invention discloses an indazole CB1 biased agonist as well as preparation and application thereof. The indazole CB1 biased agonist has a structure as shown in a general formula I. The invention further discloses a preparation method of the indazole CB1 biased agonist. Experiments prove that the compound can activate CB1 protein and can be used for treating mental diseases such as addiction and depression and diseases such as cancer, obesity, analgesia, diabetes, tumors, cardiovascular and cerebrovascular diseases, rheumatoid, asthma, liver diseases and multiple sclerosis.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug molecule design, and in particular relates to an indazole CB1 biased agonist, its preparation and application. Background Art

[0002] G protein-coupled receptors (GPCRs) belong to a family of membrane proteins. They are composed of seven α-helices that penetrate the plasma membrane, with the C-terminus located inside the membrane and the N-terminus located outside. Currently, sales of drugs targeting GPCRs account for approximately 27% of the global pharmaceutical market share. Cannabinoid receptors belong to the A family of GPCRs. GPCR ligands include the endogenous ligands anandamide (AEA), N-arachidonic acid-dopamine (NADA), and 2-arachidonic acid glycerol (2-AG), as well as the plant-derived ligand 19-tetrahydrocannabinol (THC) and synthetic cannabinoid ligands.

[0003] Cannabinoid receptors (CBs) are potential therapeutic targets for a variety of diseases, primarily including cannabinoid type I (CB1) and type II (CB2) receptors. Human CB1, composed of 472 amino acids, is primarily found in the hippocampus, cortex, basal ganglia, and cerebellum, making it the most abundant GPCR in the central nervous system. CB1 antagonists can be used to treat obesity and liver fibrosis. Rimonabant, the first clinically approved CB1 antagonist, was launched in the European Union in 2006 as a novel weight-loss drug. However, it was withdrawn from the market in 2008 due to its potential for causing serious psychiatric adverse reactions, including depression, anxiety, and even suicide. Therefore, current research is limited to peripherally restricted CB1 antagonists.

[0004] CB1 agonists have potential value in treating conditions such as pain, inflammation, and neuropsychiatric disorders. Existing research has focused on selectivity for the two cannabinoid receptor subtypes rather than specific signaling pathways. However, studies have shown that signaling pathway bias is closely associated with mitigating side effects. Upon receptor activation by a biased ligand, CB1 and CB2 tend to recruit either downstream G protein signaling or β-arrestin signaling, a phenomenon known as biased agonism. GPCRs adopt diverse conformations upon ligand binding. Biased agonists selectively stabilize a subset of receptor conformations, specifically activating downstream signaling pathways and thus reducing adverse effects. AEF0117 is an allosteric modulator targeting the CB1 receptor. It has been reported that AEF0117 does not affect ligand-activated G protein signaling, but rather antagonizes the role of CB1 in β-arrestin-mediated pERK1 / 2 signaling. Animal studies have shown that AEF0117 can alleviate the addictive side effect of marijuana. Currently, research on cannabinoid receptor bias is still at the basic stage. Given that biased ligands may have huge therapeutic advantages, drugs with biased activation of cannabinoid receptors are worthy of vigorous development. Summary of the Invention

[0005] The purpose of the present invention is to provide a novel CB1 biased agonist and its optical isomers or pharmaceutically acceptable salts that have not been reported in the literature.

[0006] The present invention also provides a use of the above compound or its stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt in preparing a drug for treating diseases, disorders or conditions that benefit from CB1-biased agonist molecules.

[0007] To achieve the above objectives, the present invention provides a compound having a structure shown in Formula I:

[0008]

[0009] or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt or prodrug thereof;

[0010] in:

[0011] Cyc1 is selected from: cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0012] R1 is selected from hydrogen, halogen, nitro, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 1a 、-C(O)R 1a 、-OC(O)R 1a 、-OS(O)2R 1a 、-C(O)OR 1a 、-NR 1a C(O)R 1b 、-NR 1a C(O)OR 1b 、-NR 1a C(O)NR 1b R 1c 、-NR 1b R 1c 、-C(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-NR 1a S(O)2R 1b 、-SO2NR 1b R 1c 、-S(O)(NR 1a )R 1b or -S(O) r R 1awherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more groups selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -OR 1a 、-C(O)R 1a 、-OC(O)R 1a 、-OS(O)2R 1a 、-C(O)OR 1a 、-NR 1a C(O)R 1b 、-NR 1a C(O)OR 1b 、-NR 1a C(O)NR 1b R 1c 、-NR 1b R 1c 、-C(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-NR 1a S(O)2R 1b 、-S(O)2NR 1b R 1c 、-S(O)(NR 1a )R 1b or -S(O) r R 1a substituted by a substituent;

[0013] Or two adjacent R1 together with the atoms to which they are attached form a 5-12 membered carbocyclic ring or a 5-12 membered heterocyclic ring, wherein the 5-12 membered heterocyclic ring contains one or more N, O or S(O)r, and the 5-12 membered carbocyclic ring or heterocyclic ring is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -OR 1a 、-C(O)R 1a 、-OC(O)R 1a 、-NR 1b R 1c 、-C(O)NR 1b R 1c 、-S(O) r R 1a 、-S(O)2NR 1b R 1c or -NR 1b C(O)R 1c substituted by a substituent;

[0014] R 1ais selected from hydrogen, alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -OR 1aa 、-C(O)R 1aa 、-C(O)OR 1aa 、-OC(O)R 1aa 、-NR 1bb R 1cc 、-C(O)NR 1bb R 2cc 、-S(O)2NR 1bb R 1cc or -NR 1aa C(O)R 1cc substituted by a substituent;

[0015] R 1b and R 1c Each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -OR 1aa 、-C(O)R 1aa 、-C(O)OR 1aa 、-OC(O)R 1aa 、-NR 1bb R 1cc 、-C(O)NR 1bb R 1cc 、-S(O)2NR 1bb R 1cc or -NR 1aa C(O)R 1cc substituted by a substituent;

[0016] Or, R 1b and R 1c Together with the atoms to which they are attached, they form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more N, O or S(O)r, and the 4-8 membered heterocyclic group is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -OR 1aa 、-C(O)R 1aa 、-C(O)OR 1aa 、-OC(O)R 1aa 、-NR 1bb R 1cc 、-C(O)NR1bb R 1cc 、-S(O)2NR 1bb R 1cc or -NR 1aa C(O)R 1bb substituted by a substituent;

[0017] R 1aa 、R 1bb and R 1cc are each independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from hydrogen, hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl or carboxylate;

[0018] R2 is selected from hydrogen, halogen, nitro, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 2a 、-C(O)R 2a 、-OC(O)R 2a 、-OS(O)2R 2a 、-C(O)OR 2a 、-NR 2a C(O)R 2b 、-NR 2a C(O)OR 2b 、-NR 2a C(O)NR 2b R 2c 、-NR 2b R 2c 、-C(O)NR 2b R 2c 、-NR 2a S(O)2NR 2b R 2c 、-NR 2a S(O)2R 2b 、-S(O)2NR 2b R 2c 、-S(O)(NR 2a )R 2b or -S(O) r R 2a wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more groups selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -OR 2a 、-C(O)R 2a 、-OC(O)R 2a 、-OS(O)2R 2a、-C(O)OR 2a 、-NR 2a C(O)R 2b 、-NR 2a C(O)OR 2b 、-NR 2a C(O)NR 2b R 2c 、-NR 2b R 2c 、-C(O)NR 2b R 2c 、-NR 2a S(O)2NR 2b R 2c 、-NR 2a S(O)2R 2b 、-S(O)2NR 2b R 2c 、-S(O)(NR 2a )R 2b or -S(O) r R 2a substituted by a substituent;

[0019] Or two adjacent R2 together with the atoms to which they are attached form a 5-12 membered carbocyclic or heterocyclic ring, wherein the 5-12 membered heterocyclic ring contains one or more N, O or S(O)r, and the 5-12 membered carbocyclic or heterocyclic ring is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -OR 2a 、-C(O)R 2a 、-C(O)R 2a 、-OC(O)R 2a 、-NR 2b R 2c 、-C(O)NR 2b R 2c 、-S(O)2NR 2b R 2c or -NR 2b C(O)R 2c substituted by a substituent;

[0020] R 2a is selected from hydrogen, alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -OR 2aa 、-C(O)R 2aa 、-C(O)OR 2aa 、-OC(O)R 2aa、-NR 2bb R 2cc 、-C(O)NR 2bb R 2cc 、-S(O)2NR 2bb R 2cc or -NR 2aa C(O)R 2bb substituted by a substituent;

[0021] R 2b and R 2c Each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -OR 2aa 、-C(O)R 2aa 、-C(O)OR 2aa 、-OC(O)R 2aa 、-NR 2bb R 2cc 、-C(O)NR 2bb R 2cc 、-S(O)2NR 2bb R 2cc or -NR 2aa C(O)R 2bb substituted by a substituent;

[0022] Or, R 2b and R 2c Together with the atoms to which they are attached, they form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more N, O or S(O)r, and the 4-8 membered heterocyclic group is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -OR 2aa 、-C(O)R 2aa 、-C(O)OR 2aa 、-OC(O)R 2aa 、-NR 2bb R 2cc 、-C(O)NR 2bb R 2cc 、-S(O)2NR 2bb R 2cc or -NR 2aa C(O)R 2bb substituted by a substituent;

[0023] R 2aa 、R 2bb and R 2ccare each independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from hydrogen, hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl or carboxylate;

[0024] n and m are each independently selected from: 0, 1, 2, 3, 4;

[0025] R3 is independently selected at each occurrence from the group consisting of hydrogen, halogen, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 3a 、-C(O)R 3a 、-OC(O)R 3a 、-OS(O)2R 3a 、-C(O)OR 3a 、-NR 3a C(O)R 3b 、-NR 3a C(O)OR 3b 、-NR 3a C(O)NR 3b R 3c 、-NR 3b R 3c 、-C(O)NR 3b R 3c 、-NR 3a SO2NR 3b R 3c 、-NR 3a SO2R 3b 、-SO2NR 3b R 3c or -S(O) r R 3a wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more groups selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -OR 3a 、-C(O)R 3a 、-OC(O)R 3a 、-OS(O)2R 3a 、-C(O)OR 3a 、-NR 3a C(O)R 3b 、-NR 3a C(O)OR 3b 、-NR 3a C(O)NR 3b R 3c 、-NR 3b R3c 、-C(O)NR 3b R 3c 、-NR 3a S(O)2NR 3b R 3c 、-NR 3a S(O)2R 3b 、-S(O)2NR 3b R 3c 、-S(O)(NR 3a )R 3b or -S(O) r R 3a substituted by a substituent;

[0026] Alternatively, two R3 together with the atoms to which they are attached form a 3-12 membered carbocyclic ring or a 3-12 membered heterocyclic ring, wherein the 3-12 membered heterocyclic ring contains one or more N, O or S(O)r, and the 3-12 membered carbocyclic ring or heterocyclic ring is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -OR 3a 、-C(O)R 3a 、-C(O)OR 3b 、-OC(O)R 3a 、-NR 3b R 3c 、-C(O)NR 3b R 3c 、-S(O)2NR 3b R 3c or -NR 3a C(O)R 3b substituted by a substituent;

[0027] R 3a is selected from hydrogen, alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -OR 3aa 、-C(O)R 3aa 、-C(O)OR 3aa 、-OC(O)R 3aa 、-NR 3bb R 3cc 、-C(O)NR 3bb R 3cc 、-S(O)2NR 3bb R 3cc or -NR 3aa C(O)R 3bb substituted by a substituent;

[0028] R 3b and R 3c Each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -OR 3aa 、-C(O)R 3aa 、-C(O)OR 3aa 、-OC(O)R 3aa 、-NR 3bb R 3cc 、-C(O)NR 3bb R 3cc 、-S(O)2NR 3bb R 3cc or -NR 3aa C(O)R 3bb substituted by a substituent;

[0029] Or, R 3b and R 3c Together with the atoms to which they are attached, they form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more N, O or S(O)r, and the 4-8 membered heterocyclic group is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -OR 3aa 、-C(O)R 3aa 、-C(O)OR 3aa 、-OC(O)R 3aa 、-NR 3bb R 3cc 、-C(O)NR 3bb R 3cc 、-S(O)2NR 3bb R 3cc or -NR 3aa C(O)R 3bb substituted by a substituent;

[0030] R 3aa 、R 3bb and R 3cc are each independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from hydrogen, hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl or carboxylate;

[0031] p is selected from: 0, 1, 2, 3, 4;

[0032] oSelect from: 1, 2, 3, 4, 5, 6;

[0033] R4 is selected from: -C(O)OR 4a 、-C(O)NR 4b R 4c ;

[0034] R 4a is selected from hydrogen, alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -OR 4A 、-C(O)R 4A 、-OC(O)R 4A 、-OS(O)2R 4A 、-C(O)OR 4A 、-NR 4A C(O)R 4B 、-NR 4A C(O)OR 4B 、-NR 4A C(O)NR 4B R 4C 、-NR 4B R 4C 、-C(O)NR 4B R 4C 、-NR 4A S(O)2NR 4B R 4C 、-NR 4A S(O)2R 4B 、-S(O)2NR 4B R 4C 、-S(O)(NR 4A )R 4B or -S(O) r R 4A substituted by a substituent;

[0035] R 4b and R 4c Each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -OR 4A 、-C(O)R 4A 、-C(O)OR 4B 、-OC(O)R4B 、-NR 4B R 4C 、-C(O)NR 4B R 4C 、-S(O)2NR 4B R 4C or -NR 4A C(O)R 4C substituted by a substituent;

[0036] Or, R 4b and R 4c Together with the atoms to which they are attached, they form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more N, O or S(O)r, and the 4-8 membered heterocyclic group is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -OR 4A 、-C(O)R 4A 、-C(O)OR 4A 、-OC(O)R 4A 、-NR 4B R 4C 、-C(O)NR 4B R 4C 、-SO2NR 4B R 4C or -NR 4A C(O)R 4B substituted by a substituent;

[0037] R 4A is selected from hydrogen, alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -OR 4AA 、-C(O)R 4AA 、-C(O)OR 4AA 、-OC(O)R 4AA 、-NR 4BB R 4CC 、-C(O)NR 4BB R 4CC 、-SO2NR 4BB R 4CC or -NR 4AA C(O)R 4BB substituted by a substituent;

[0038] R 4B and R 4CEach independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -OR 4AA 、-C(O)R 4AA 、-C(O)OR 4AA 、-OC(O)R 4AA 、-NR 4BB R 4CC 、-C(O)NR 4BB R 4CC 、-S(O)2NR 4BB R 4CC or -NR 4AA C(O)R 4BB substituted by a substituent;

[0039] Or, R 4B and R 4C Together with the atoms to which they are attached, they form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more N, O or S(O)r, and the 4-8 membered heterocyclic group is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -OR 4AA 、-C(O)R 4AA 、-C(O)OR 4AA 、-OC(O)R 4AA 、-NR 4BB R 4CC 、-C(O)NR 4BB R 4CC 、-S(O)2NR 4BB R 4CC or -NR 4BB C(O)R 4CC substituted by a substituent;

[0040] R 4AA 、R 4BB and R 4CC are each independently selected from hydrogen, alkyl, amino, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from hydrogen, hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl or carboxylate;

[0041] R5 and R6 are each independently selected from: hydrogen, halogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl may be further substituted by one or more selected from hydrogen, alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -OR 5a 、-C(O)R 5a 、-OC(O)R 5a 、-OS(O)2R 5a 、-C(O)OR 5a 、-NR 5a C(O)R 5b 、-NR 5a C(O)OR 5b 、-NR 5a C(O)NR 5b R 5c 、-NR 5b R 5c 、-C(O)NR 5b R 5c 、-NR 5a S(O)2NR 5b R 5c 、-NR 5a S(O)2R 5b 、-S(O)2NR 5b R 5c 、-S(O)(NR 5a )R 5b or -S(O) r R 5a substituted by a substituent;

[0042] Alternatively, R5 and R6 together with the atoms to which they are attached form a 3-8 membered carbocyclic ring or a 3-8 membered heterocyclic ring, wherein the 3-8 membered heterocyclic ring contains one or more N, O or S(O)r, and the 3-8 membered carbocyclic ring or heterocyclic ring is optionally further substituted with one or more selected from hydrogen, hydroxy, halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -OR 5a 、-C(O)R 5a 、-C(O)OR 5a 、-OC(O)R 5a 、-NR 5b R 5c 、-C(O)NR 5b R 5c 、-S(O)2R 5a 、-S(O)2NR 5b R 5c or -NR 5a C(O)R 5b substituted by a substituent;

[0043] R 5a is selected from hydrogen, alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -OR 5aa 、-C(O)R 5aa 、-C(O)OR 5aa 、-OC(O)R 5aa 、-NR 5bb R 5cc 、-C(O)NR 5bb R 5cc 、-S(O)2NR 5bb R 5cc or -NR 5aa C(O)R 5bb substituted by a substituent;

[0044] R 5b and R 5c Each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -OR 5aa 、-C(O)R 5aa 、-C(O)OR 5aa 、-OC(O)R 5aa 、-NR 5bb R 5cc 、-C(O)NR 5bb R 5cc 、-S(O)2NR 5bb R 5cc or -NR 5aa C(O)R 5bb substituted by a substituent;

[0045] Or, R 5b and R 5c Together with the atoms to which they are attached, they form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more N, O or S(O)r, and the 4-8 membered heterocyclic group is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -OR 5aa 、-C(O)R 5aa 、-C(O)OR 5aa 、-OC(O)R 5aa 、-NR 5bb R 5cc、-C(O)NR 5bb R 5cc 、-S(O)2NR 5bb R 5cc or -NR 5aa C(O)R 5bb substituted by a substituent;

[0046] R 5aa 、R 5bb and R 5cc are each independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from hydrogen, hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl or carboxylate;

[0047] R7 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, aryl, heteroaryl may be further substituted by one or more radicals selected from the group consisting of hydrogen, alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -OR 7a 、-C(O)R 7a 、-OC(O)R 7a 、-OS(O)2R 7a 、-C(O)OR 7a 、-NR 7a C(O)R 7b 、-NR 7a C(O)OR 7b 、-NR 7a C(O)NR 7b R 7c 、-NR 7b R 7c 、-C(O)NR 7b R 7c 、-NR 7a S(O)2NR 7b R 7c 、-NR 7a S(O)2R 7b 、-S(O)2NR 7b R 7c 、-S(O)(NR 7a )R 7b or -S(O) r R 7a substituted by a substituent;

[0048] R 7ais selected from hydrogen, alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -OR 7aa 、-C(O)R 7aa 、-C(O)OR 7aa 、-OC(O)R 7aa 、-NR 7bb R 7cc 、-C(O)NR 7bb R 7cc 、-S(O)2NR 7bb R 7cc or -NR 7aa C(O)R 7bb substituted by a substituent;

[0049] R 7b and R 7c Each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -OR 7aa 、-C(O)R 7aa 、-C(O)OR 7aa 、-OC(O)R 7aa 、-NR 7bb R 7cc 、-C(O)NR 7bb R 7cc 、-S(O)2NR 7bb R 7cc or -NR 7aa C(O)R 7bb substituted by a substituent;

[0050] Or, R 7b and R 7c Together with the atoms to which they are attached, they form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more N, O or S(O)r, and the 4-8 membered heterocyclic group is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -OR 7aa 、-C(O)R 7aa 、-C(O)OR 7aa 、-OC(O)R 7aa 、-NR 7bb R 7cc 、-C(O)NR 7bb R7cc 、-S(O)2NR 7bb R 7cc or -NR 7aa C(O)R 7bb substituted by a substituent;

[0051] R 7aa 、R 7bb and R 7cc are each independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from hydrogen, hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl or carboxylate;

[0052] r is selected from 0, 1 or 2;

[0053] X is selected from: O, S.

[0054] In other preferred embodiments of the present disclosure, according to the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, the Cyc1 is selected from: C6-C10 aryl, 5-10 membered heteroaryl.

[0055] As further preferred, the Cyc1 is selected from:

[0056]

[0057] Wherein, X1, X2, X3, X4, and X5 are each independently selected from N, C, or CH, provided that the valence theory is satisfied (the resulting compound is chemically possible); for example, when any of X1, X2, X3, X4, and X5 has a non-H substituent, it is C. If no substituent is present, it may be CH or N.

[0058] As further preferred, the Cyc1 is selected from:

[0059]

[0060] Or the Cyc1 is selected from:

[0061]

[0062] Or the Cyc1 is selected from:

[0063]

[0064] As a more specific preference, the Cyc1 is selected from a benzene ring or a pyridine ring, and is further selected from:

[0065] Rx is selected from the group consisting of: hydrogen, C1-C3 alkyl, 3-6 cycloalkyl.

[0066] Preferably, R1 is independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, halogen, nitro, cyano, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, C6-C10 aryl, 5-10 heteroaryl, -OR 1a 、-SR 1a 、-C(O)R 1a 、-OC(O)R 1a 、-C(O)OR 1a 、-NR 1a C(O)R 1b 、-NR 1a C(O)OR 1b 、-NR 1a C(O)NR 1b R 1c 、-NR 1b R 1c 、-C(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-NR 1a S(O)2R 1b 、-S(O)2NR 1b R 1c 、-S(O)(NR 1a )R 1b or -S(O)2R 1a wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more groups selected from hydrogen, C1-C8 alkyl, halogen, nitro, cyano, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, =O, -OR 1a 、-C(O)R 1a 、-OC(O)R 1a 、-C(O)OR 1a 、-NR 1a C(O)R 1b 、-NR 1a C(O)OR 1b 、-NR 1a C(O)NR 1b R 1c 、-NR 1b R 1c 、-C(O)NR 1b R 1c 、-NR 1a S(O)2NR 1bR 1c 、-NR 1a S(O)2R 1b 、-S(O)2NR 1b R 1c 、-S(O)(NR 1a )R 1b or -S(O)2R 1a substituted by a substituent;

[0067] Or two adjacent R1s independently form a 5-12 membered carbocyclic ring or a 5-12 membered heterocyclic ring together with the atoms to which they are attached, wherein the 5-12 membered heterocyclic ring contains one or more N, O or S(O)r, and the 5-12 membered carbocyclic ring or the 5-12 membered heterocyclic ring is optionally further substituted by one or more selected from hydrogen, C1-C8 alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocyclic ring, C6-C10 aryl, 5-10 membered heteroaryl, =O, -OR 1a 、-C(O)R 1a 、-C(O)R 1a 、-OC(O)R 1a 、-NR 1b R 1c 、-C(O)NR 1b R 1c 、-S(O)2NR 1b R 1c or -NR 1a C(O)R 1b substituted by a substituent.

[0068] As further preferred, R1 is selected from: hydrogen, C1-C5 alkyl, 3-6 membered cycloalkyl, halogen, nitro, cyano, C6-C10 aryl, 5-10 membered heteroaryl, -OR 1a 、-OC(O)R 1a 、-NR 1b R 1c 、-NR 1a C(O)R 1b 、-C(O)R 1a 、-C(O)NR 1b R 1c 、-NR 1a SO2R 1b 、-C(O)OR 1a wherein the alkyl, cycloalkyl, aryl, heteroaryl are optionally further substituted by one or more selected from hydrogen, C1-C5 alkyl, halogen, -OR 1a 、-C(O)R 1a 、-OC(O)R 1a 、-C(O)OR 1a 、-NR 1a C(O)R1b 、-NR 1b R 1c 、-C(O)NR 1b R 1c 、-NR 1a SO2R 1b substituted by a substituent.

[0069] As further preferred, R1 is selected from: hydrogen, C1-C3 alkyl, 3-6 membered cycloalkyl, halogen (preferably F, Cl, Br), nitro, cyano, C6-C10 aryl, 5-10 membered heteroaryl, -OR 1a 、-OC(O)R 1a 、-NR 1b R 1c 、-NR 1a C(O)R 1b 、-C(O)R 1a 、-C(O)NR 1b R 1c 、-NR 1a SO2R 1b 、-C(O)OR 1a wherein the alkyl, cycloalkyl, aryl, heteroaryl are optionally further substituted by one or more selected from hydrogen, C1-C5 alkyl, halogen, -OR 1a 、-C(O)R 1a 、-OC(O)R 1a 、-C(O)OR 1a 、-NR 1a C(O)R 1b 、-NR 1b R 1c 、-C(O)NR 1b R 1c 、-NR 1a SO2R 1b substituted by a substituent.

[0070] As a specific preference, R1 is selected from: hydrogen, C1-C3 alkyl (such as methyl, ethyl or propyl), halogenated C1-C3 alkyl (such as trifluoro or difluoro substituted methyl, ethyl, propyl, etc.), F, Cl, C1-C3 alkoxy, 3-6 membered cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), nitro, cyano, phenyl, pyridyl, -OC(O)R 1a 、-NR 1b R 1c 、-NR 1a C(O)R 1b 、-C(O)R 1a 、-C(O)NR 1b R 1c 、-NR 1aSO2R 1b 、-C(O)OR 1a More specifically, F, trifluoromethyl, methyl, Cl, and H are preferred.

[0071] Preferably, R2 is independently selected from the group consisting of hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, halogen, nitro, cyano, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, C6-C10 aryl, 5-10 heteroaryl, -OR 2a 、-SR 2a 、-C(O)R 2a 、-OC(O)R 2a 、-C(O)OR 2a 、-NR 2a C(O)R 2b 、-NR 2a C(O)OR 2b 、-NR 2a C(O)NR 2b R 2c 、-NR 2b R 2c 、-C(O)NR 2b R 2c 、-NR 2a S(O)2NR 2b R 2c 、-NR 2a S(O)2R 2b 、-S(O)2NR 2b R 2c 、-S(O)(NR 2a )R 2b or -S(O)2R 2a wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more groups selected from hydrogen, C1-C8 alkyl, halogen, nitro, cyano, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, =O, -OR 2a 、-C(O)R 2a 、-OC(O)R 2a 、-C(O)OR 2a 、-NR 2a C(O)R 2b 、-NR 2a C(O)OR 2b 、-NR 2a C(O)NR 2b R 2c 、-NR 2b R 2c 、-C(O)NR 2b R 2c 、-NR2a S(O)2NR 2b R 2c 、-NR 2a S(O)2R 2b 、-S(O)2NR 2b R 2c 、-S(O)(NR 2a )R 2b or -S(O)2R 2a substituted by a substituent;

[0072] Or two adjacent R2 are independently formed together with the atoms to which they are attached to form a 5-12 membered carbocyclic ring or a 5-12 membered heterocyclic ring, wherein the 5-12 membered heterocyclic ring contains one or more N or O, and the 5-12 membered carbocyclic ring or the 5-12 membered heterocyclic ring is optionally further substituted by one or more selected from hydrogen, C1-C8 alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocyclic ring, C6-C10 aryl, 5-10 membered heteroaryl, =O, -OR 2a 、-C(O)R 2a 、-C(O)R 2a 、-OC(O)R 2a 、-NR 2b R 2c 、-C(O)NR 2b R 2c 、-S(O)2NR 2b R 2c or -NR 2a C(O)R 2c substituted by a substituent.

[0073] As further preferred, R2 is selected from: hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, halogen, nitro, cyano, -OR 2a 、-OC(O)R 2a 、-NR 2b R 2c 、-NR 2a C(O)R 2b 、-C(O)R 2a 、-C(O)NR 2b R 2c 、-NR 2a S(O)2R 2b 、-C(O)OR 2a .

[0074] As a specific preference, R2 is selected from: hydrogen, Br, Cl, F, C1-C3 alkyl (methyl, ethyl or propyl, etc.), C1-C3 haloalkyl, nitro, cyano, -OR 1a 、-OC(O)R 2a 、-NR 2bR 2c 、-NR 2a C(O)R 2b 、-C(O)R 2a 、-C(O)NR 2b R 2c 、-NR 2a SO2R 2b 、-C(O)OR 2a More specifically, R2 is selected from H, Br, Cl, F, trifluoromethyl, trifluoromethoxy, and methyl.

[0075] Preferably, R3 is independently selected at each occurrence from the group consisting of hydrogen, halogen, cyano, oxo, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, -OR 3a 、-C(O)R 3a 、-OC(O)R 3a 、-C(O)OR 3a 、-NR 3a C(O)R 3b 、-NR 3a C(O)OR 3b 、-NR 3b R 3c or -C(O)NR 3b R 3c wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more groups selected from hydrogen, C1-C8 alkyl, halogen, nitro, cyano, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, =O, -OR 3a 、-SR 3a 、-C(O)R 3a 、-C(O)OR 3a 、-NR 3a C(O)R 3b 、-NR 3a C(O)OR 3b 、-S(O)2R 3a 、-NR 3b R 3c or -C(O)NR 3b R 3c substituted by a substituent;

[0076] Alternatively, two R3 together with the atoms to which they are attached form a 3-12 membered carbocyclic ring or a 3-12 membered heterocyclic ring, wherein the 3-12 membered heterocyclic ring contains one or more N, O or S(O)2, and the 3-12 membered carbocyclic ring or heterocyclic ring is optionally further substituted by one or more selected from hydrogen, hydroxyl, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic ring, C6-C10 aryl, 5-10 membered heteroaryl, =O, -C(O)R 3a 、-C(O)OR 3a 、-OC(O)R 3a 、-NR 3b R 3c 、-C(O)NR 3b R 3c , or -NR 3b C(O)R 3c substituted by a substituent.

[0077] As further preferred, R3 is selected from the group consisting of hydrogen, cyano, halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, C2-C4 alkenyl, C2-C4 alkynyl, benzene ring, 5-10 membered aromatic heterogroup, and the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, benzene ring or aromatic heterogroup is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro and cyano;

[0078] Or two R3 together with the atoms to which they are attached form a 3-12 membered carbocyclic ring or a 3-12 membered heterocyclic ring, wherein the 3-12 membered heterocyclic ring contains one or more N or O, and the 3-12 membered carbocyclic ring or heterocyclic ring is optionally further substituted by one or more substituents selected from halogen, hydroxyl, and amino.

[0079] As a specific preference, the R3 is selected from H, C1-C3 alkyl, C2-C4 alkenyl, F, Cl, C1-C3 alkoxy, etc. More specifically, the R3 is selected from H, chloroethyl, vinyl, hydroxymethyl, hydroxyl, benzene ring, fluoromethyl, carbonyl, methoxy, cyano; or two R3 and one carbon group to which they are connected form a 3-membered carbocyclic ring / 5-membered carbocyclic ring; two R3 and three carbon groups to which they are connected form a 5-membered carbocyclic ring, etc.

[0080] Preferably, R5 and R6 are each independently selected from: hydrogen, halogen, C1-C4 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, and the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, C1-C4 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, =O, -OR 5a、-C(O)R 5a 、-C(O)OR 5a 、-OC(O)R 5a 、-NR 5b R 5c 、-C(O)NR 5b R 5c 、-S(O)2NR 5b R 5c or -NR 5a C(O)R 5b substituted by a substituent;

[0081] Alternatively, R5 and R6 together with the atoms to which they are attached form a 3-8 membered carbocyclic ring or a 3-8 membered heterocyclic ring, wherein the 3-8 membered heterocyclic ring contains one or more N or O, and the 3-8 membered carbocyclic ring or heterocyclic ring is optionally further substituted with one or more selected from hydrogen, halogen, nitro, cyano, C1-C8 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic ring, C6-C10 aryl, 5-10 membered heteroaryl, =O, -OR 5a 、-C(O)R 5a 、-SO2R 5a 、-C(O)OR 5a 、-OC(O)R 5a 、-NR 5b R 5c 、-C(O)NR 5b R 5c 、-S(O)2NR 5b R 5c or -NR 5a C(O)R 5b substituted by a substituent.

[0082] Preferably, R5 and R6 are each independently selected from: hydrogen, halogen, C1-C3 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocyclyl, phenyl, and the alkyl, cycloalkyl, heterocyclyl, phenyl are optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, C1-C4 alkyl, -OR 5a 、-NR 5b R 5c or -NR 5a C(O)R 5b substituted by a substituent;

[0083] Alternatively, R5 and R6 together with the atoms to which they are attached form a 3-6 membered carbocyclic ring or a 4-8 membered heterocyclic ring, wherein the 4-8 membered heterocyclic ring contains one N or O, and the carbocyclic ring or heterocyclic ring is optionally further substituted with one or more selected from hydrogen, C1-C4 alkyl, 3-6 membered cycloalkyl, -OR 5a 、-C(O)R 5a 、-S(O)2R5a 、-C(O)OR 5a 、-OC(O)R 5a 、-NR 5b R 5c 、-C(O)NR 5b R 5c 、-S(O)2NR 5b R 5c or -NR 5a C(O)R 5b substituted by a substituent.

[0084] As a specific preference, said R5 and R6 are selected from: hydrogen; or a cyclopropyl group formed by said R5 and R6 together with the atoms to which they are connected.

[0085] R7 is selected from the group consisting of hydrogen, C1-C3 alkyl, and 3-6 membered cycloalkyl. Preferably, R7 is selected from the group consisting of hydrogen, C1-C3 alkyl, and further selected from H.

[0086] In other preferred embodiments of the present application, according to the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, wherein R 1a is selected from hydrogen, C1-C8 alkyl, C2-C8 alkynyl, C2-C8 alkenyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl, wherein said alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, C1-C8 alkyl, halogen, nitro, cyano, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl, =O, -OR 1aa 、-C(O)R 1aa 、-C(O)OR 1aa 、-OC(O)R 1aa 、-NR 1bb R 1cc 、-C(O)NR 1bb R 1cc 、-S(O)2NR 1bb R 1cc or -NR 1aa C(O)R 1bb substituted by a substituent;

[0087] R 1b and R 1cEach is independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, C1-C8 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, =O, -OR 1aa 、-C(O)R 1aa 、-C(O)OR 1aa 、-OC(O)R 1aa 、-NR 1bb R 1cc 、-C(O)NR 1bb R 1cc 、-S(O)2NR 1bb R 1cc or -NR 1aa C(O)R 1bb substituted by a substituent;

[0088] Or, R 1b and R 1c Together with the atoms to which they are attached, they form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more N or O, and the 4-8 membered heterocyclic group is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, C1-C8 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl, =O, -OR 1aa 、-C(O)R 1aa 、-C(O)OR 1aa 、-OC(O)R 1aa 、-NR 1bb R 1cc 、-C(O)NR 1bb R 1cc 、-S(O)2NR 1bb R 1cc or -NR 1aa C(O)R 1bb substituted by a substituent;

[0089] R 1aa 、R 1bb and R 1cceach independently selected from hydrogen, C1-C8 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from hydrogen, hydroxy, halogen, nitro, amino, cyano, C1-C8 alkyl, C1-C8 alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, carboxyl or C1-C8 carboxylate;

[0090] R 2a is selected from hydrogen, C1-C8 alkyl, C2-C8 alkynyl, C2-C8 alkenyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, wherein said alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, C1-C8 alkyl, halogen, nitro, cyano, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, =O, -OR 2aa 、-C(O)R 2aa 、-C(O)OR 2aa 、-OC(O)R 2aa 、-NR 2bb R 2cc 、-C(O)NR 2bb R 2cc 、-S(O)2NR 2bb R 2cc or -NR 2aa C(O)R 2bb substituted by a substituent;

[0091] R 2b and R 2c Each is independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, C1-C8 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, =O, -OR 2aa 、-C(O)R 2aa 、-C(O)OR 2aa 、-OC(O)R 2aa 、-NR 2bb R 2cc 、-C(O)NR 2bb R 2cc 、-S(O)2NR 2bb R 2cc or -NR2aa C(O)R 2bb substituted by a substituent;

[0092] Or, R 2b and R 2c Together with the atoms to which they are attached, they form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more N or O, and the 4-8 membered heterocyclic group is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, C1-C8 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl, =O, -OR 2aa 、-C(O)R 2aa 、-C(O)OR 2aa 、-OC(O)R 2aa 、-NR 2bb R 2cc 、-C(O)NR 2bb R 2cc 、-S(O)2NR 2bb R 2cc or -NR 2aa C(O)R 2bb substituted by a substituent;

[0093] R 2aa 、R 2bb and R 2cc each independently selected from hydrogen, C1-C8 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from hydrogen, hydroxy, halogen, nitro, amino, cyano, C1-C8 alkyl, C1-C8 alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, carboxyl or C1-C8 carboxylate;

[0094] R 3a is selected from hydrogen, C1-C8 alkyl, C2-C8 alkynyl, C2-C8 alkenyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl, wherein said alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, C1-C8 alkyl, halogen, nitro, cyano, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, =O, -OR 3aa 、-C(O)R 3aa 、-C(O)OR 3aa 、-OC(O)R 3aa 、-NR 3bb R 3cc、-C(O)NR 3bb R 3cc 、-SO2NR 3bb R 3cc or -NR 3aa C(O)R 3bb substituted by a substituent;

[0095] R 3b and R 3c Each is independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, C1-C8 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, =O, -OR 3aa 、-C(O)R 3aa 、-C(O)OR 3aa 、-OC(O)R 3aa 、-NR 3bb R 3cc 、-C(O)NR 3bb R 3cc 、-S(O)2NR 3bb R 3cc or -NR 3aa C(O)R 3bb substituted by a substituent;

[0096] Or, R 3b and R 3c Together with the atoms to which they are attached, they form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more N or O, and the 4-8 membered heterocyclic group is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, C1-C8 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl, =O, -OR 3aa 、-C(O)R 3aa 、-C(O)OR 3aa 、-OC(O)R 3aa 、-NR 3bb R 3cc 、-C(O)NR 3bb R 3cc 、-S(O)2NR 3bb R 3cc or -NR 3aa C(O)R 3bb substituted by a substituent;

[0097] R 3aa 、R3bb and R 3cc each independently selected from hydrogen, C1-C8 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from hydrogen, hydroxy, halogen, nitro, amino, cyano, C1-C8 alkyl, C1-C8 alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, carboxyl or C1-C8 carboxylate;

[0098] R4 is selected from: -C(O)OR 4a 、-C(O)NR 4b R 4c ;

[0099] R 4a is selected from the group consisting of: hydrogen, C1-C8 alkyl, C2-C8 alkynyl, C2-C8 alkenyl, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl, wherein said alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, C1-C8 alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, =O, -OR 4A 、-C(O)R 4A 、-OC(O)R 4A 、-OS(O)2R 4A 、-C(O)OR 4A 、-NR 4A C(O)R 4B 、-NR 4A C(O)OR 4B 、-NR 4A C(O)NR 4B R 4C 、-NR 4B R 4C 、-C(O)NR 4B R 4C 、-NR 4A S(O)2NR 4B R 4C 、-NR 4A S(O)2R 4B 、-S(O)2NR 4B R 4C 、-S(O)(NR 4A )R 4B or -S(O)2R 4A substituted by a substituent;

[0100] R 4band R 4c Each is independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, C1-C8 alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, =O, -OR 4A 、-C(O)R 4A 、-C(O)OR 4A 、-OC(O)R 4A 、-NR 4B R 4C 、-C(O)NR 4B R 4C 、-S(O)2NR 4B R 4C or -NR 4A C(O)R 4B substituted by a substituent;

[0101] Or, R 4b and R 4c Together with the atoms to which they are attached, they form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more N, O or S(O)2, and the 4-8 membered heterocyclic group is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, C1-C8 alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl, =O, -OR 4A 、-C(O)R 4A 、-C(O)OR 4A 、-OC(O)R 4A 、-NR 4B R 4C 、-C(O)NR 4B R 4C 、-S(O)2NR 4B R 4C or -NR 4A C(O)R 4B substituted by a substituent;

[0102] R 4Ais selected from hydrogen, C1-C8 alkyl, C2-C8 alkynyl, C2-C8 alkenyl, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl, wherein said alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, =O, -OR 4AA 、-C(O)R 4AA 、-C(O)OR 4AA 、-OC(O)R 4AA 、-NR 4BB R 4CC 、-C(O)NR 4BB R 4CC 、-S(O)2NR 4BB R 4CC or -NR 4AA C(O)R 4BB substituted by a substituent;

[0103] R 4B and R 4C Each is independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkynyl, C2-C8 alkenyl, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, =O, -OR 4AA 、-C(O)R 5A 、-C(O)OR 4AA 、-OC(O)R 4AA 、-NR 4BB R 4CC 、-C(O)NR 4BB R 4CC 、-S(O)2NR 4BB R 4CC or -NR 4AA C(O)R 4BB substituted by a substituent;

[0104] Or, R 4B and R 4C Together with the atoms to which they are attached, they form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more N or O, and the 4-8 membered heterocyclic group is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, 3-8 membered cycloalkyl, 4-8 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl, =O, -OR4AA 、-C(O)R 4AA 、-C(O)OR 4AA 、-OC(O)R 4AA 、-NR 4BB R 4CC 、-C(O)NR 4BB R 4CC 、-SO2NR 4BB R 4CC or -NR 4AA C(O)R 4BB substituted by a substituent;

[0105] R 4AA 、R 4BB and R 4CC Each is independently selected from hydrogen, C1-C8 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl, 5-10 heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from hydrogen, hydroxy, halogen, nitro, amino, cyano, C1-C8 alkyl, C1-C8 alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, aryl, heteroaryl, carboxyl or carboxylate.

[0106] As a specific preference, the R4 is selected from methoxyl, ethoxyl, propoxyl, butoxyl, pentoxyl, methylaminol, ethylaminol, alanyl,

[0107] wait.

[0108] More preferably, the R4 is selected from methoxyacyl, ethoxyacyl, propoxyacyl, butoxyacyl, pentoxyacyl,

[0109] R 5a is selected from hydrogen, C1-C8 alkyl, C2-C8 alkynyl, C2-C8 alkenyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl, wherein said alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, C1-C8 alkyl, halogen, nitro, cyano, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, =O, -OR 5aa 、-C(O)R 5aa 、-C(O)OR 5aa 、-OC(O)R 5aa 、-NR 5bb R 5cc 、-C(O)NR 5bb R5cc 、-S(O)2NR 5bb R 5cc or -NR 5aa C(O)R 5bb substituted by a substituent.

[0110] R 5b and R 5c Each is independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, C1-C8 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, =O, -OR 5aa 、-C(O)R 5aa 、-C(O)OR 5aa 、-OC(O)R 5aa 、-NR 5bb R 5cc 、-C(O)NR 5bb R 5cc 、-S(O)2NR 5bb R 5cc or -NR 5aa C(O)R 5bb substituted by a substituent;

[0111] Or, R 5b and R 5c Together with the atoms to which they are attached, they form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more N or O, and the 4-8 membered heterocyclic group is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, C1-C8 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl, =O, -OR 5aa 、-C(O)R 5aa 、-C(O)OR 5aa 、-OC(O)R 5aa 、-NR 5bb R 5cc 、-C(O)NR 5bb R 5cc 、-S(O)2NR 5bb R 5cc or -NR 5aa C(O)R 5bb substituted by a substituent;

[0112] R 5aa 、R 5bb and R5cc Each is independently selected from hydrogen, C1-C8 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from hydrogen, hydroxy, halogen, nitro, amino, cyano, C1-C8 alkyl, C1-C8 alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, carboxyl or C1-C8 carboxylate.

[0113] In other preferred embodiments of the present disclosure, the compounds have structures shown in Formula IIa to IIc:

[0114]

[0115] or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt or prodrug thereof.

[0116] R1, R2, R3, R4, R5, R6, R7, m, n, and o are as defined in the above embodiments;

[0117] p is selected from: 0, 1, 2;

[0118] middle:

[0119] X1, X2, X3, X4, X5 are each independently selected from N or C, provided that the valence theory is satisfied (the resulting compound is chemically possible);

[0120] Ring B is selected from: a benzene ring or a 5-6 membered heteroaryl ring;

[0121] Ring C is selected from: none, 6-membered aryl or heteroaryl;

[0122] is selected from the following fragments, and the fused ring may be arbitrarily substituted by n R1:

[0123]

[0124] Selected from the following fragments, and the fragment can be arbitrarily substituted by n R1:

[0125]

[0126] Rx is selected from the group consisting of: hydrogen, C1-C3 alkyl, 3-6 cycloalkyl.

[0127] As a preferred embodiment, the compound of the present invention is characterized by having the structure shown in the general formula IIIa to IIIh:

[0128]

[0129] or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt or prodrug thereof.

[0130] Further as a preferred embodiment, the compounds of the present invention are characterized by having the structure of the general formula IIIa to IIId:

[0131]

[0132] or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt or prodrug thereof;

[0133] R3, R4, m, n, p, o, R 1a 、R 1b 、R 1c 、R 2a 、R 2b 、R 2c As defined in any of the above technical solutions;

[0134] R1 is selected from the group consisting of: hydrogen, C1-C5 alkyl, 3-6 membered cycloalkyl, halogen, nitro, cyano, C6-C10 aryl, 5-10 membered heteroaryl, -OR 1a 、-OC(O)R 1a 、-NR 1b R 1c 、-NR 1a C(O)R 1b 、-C(O)R 1a 、-C(O)NR 1b R 1c 、-NR 1a S(O)2R 1b 、-C(O)OR 1a wherein the alkyl, cycloalkyl, aryl, heteroaryl are optionally further substituted by one or more selected from hydrogen, C1-C5 alkyl, halogen, -OR 1a 、-C(O)R 1a 、-OC(O)R 1a 、-C(O)OR 1a 、-NR 1a C(O)R 1b 、-NR 1b R 1c 、-C(O)NR 1b R 1c 、-NR 1a SO2R 1b substituted by a substituent;

[0135] R2 is selected from: hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, halogen, nitro, cyano, -OR 2a、-OC(O)R 2a 、-NR 2b R 2c 、-NR 2a C(O)R 2b 、-C(O)R 2a 、-C(O)NR 2b R 2c 、-NR 2a S(O)2R 2b 、-C(O)OR 2a ;

[0136] R5 and R6 are each independently selected from: hydrogen, halogen, C1-C3 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocyclyl, phenyl, and the alkyl, cycloalkyl, heterocyclyl, phenyl are optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, C1-C4 alkyl, -OR 5a 、-NR 5b R 5c or -NR 5a C(O)R 5b substituted by a substituent;

[0137] Alternatively, R5 and R6 together with the atoms to which they are attached form a 3-6 membered carbocyclic ring or a 4-8 membered heterocyclic ring, wherein the 4-8 membered heterocyclic ring contains one N or O, and the carbocyclic ring or heterocyclic ring is optionally further substituted with one or more selected from hydrogen, C1-C4 alkyl, 3-6 membered cycloalkyl, -OR 5a 、-C(O)R 5a 、-S(O)2R 5a 、-C(O)OR 5a 、-OC(O)R 5a 、-NR 5b R 5c 、-C(O)NR 5b R 5c 、-S(O)2NR 5b R 5c or -NR 5a C(O)R 5b substituted by a substituent;

[0138] R 5a is selected from hydrogen, C1-C4 alkyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl, wherein said alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, C1-C4 alkyl, halogen, nitro, cyano, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl, =O, -OR 5aa 、-C(O)R 5aa、-C(O)OR 5aa 、-OC(O)R 5aa 、-NR 5bb R 5cc 、-C(O)NR 5bb R 5cc 、-S(O)2NR 5bb R 5cc or -NR 5aa C(O)R 5bb substituted by a substituent;

[0139] R 5b and R 5c Each is independently selected from hydrogen, C1-C8 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, C1-C8 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, =O, -OR 5aa 、-C(O)R 5aa 、-C(O)OR 5aa 、-OC(O)R 5aa 、-NR 5bb R 5cc 、-C(O)NR 5bb R 5cc 、-S(O)2NR 5bb R 5cc or -NR 5aa C(O)R 5bb substituted by a substituent;

[0140] Or, R 5b and R 5c Together with the atoms to which they are attached, they form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more N or O, and the 4-8 membered heterocyclic group is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, C1-C8 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl, =O, -OR 5aa 、-C(O)R 5aa 、-C(O)OR 5aa 、-OC(O)R 5aa 、-NR 5bb R 5cc 、-C(O)NR 5bb R 5cc 、-S(O)2NR 5bb R 5cc or -NR 5aa C(O)R5cc substituted by a substituent;

[0141] R 5aa 、R 5bb and R 5cc each independently selected from hydrogen, C1-C3 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from hydrogen, hydroxy, halogen, nitro, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, carboxyl or C1-C8 carboxylate;

[0142] R7 is selected from the group consisting of: hydrogen, C1-C3 alkyl.

[0143] Further as a preferred embodiment, The fragments may be selected from, but not limited to, the following structures:

[0144]

[0145] R3 is selected from the group consisting of hydrogen, cyano, halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, C2-C4 alkenyl, C2-C4 alkynyl, benzene ring, and 5-10 membered aromatic heterogroup, and the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, benzene ring, or aromatic heterogroup is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, and cyano;

[0146] p is selected from: 0, 1, 2;

[0147] Or two R3 together with the atoms to which they are attached form a 3-12 membered carbocyclic ring or a 3-12 membered heterocyclic ring, wherein the 3-12 membered heterocyclic ring contains one or more N, O or S(O)2, and the 3-12 membered carbocyclic ring or heterocyclic ring is optionally further substituted by one or more substituents selected from halogen, hydroxyl, and amino.

[0148] R4 is selected from: -C(O)OR 4a 、-C(O)NR 4b R 4c ;

[0149] R 4ais selected from hydrogen, C1-C5 alkyl, C2-C5 alkynyl, C2-C5 alkenyl, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl, wherein said alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, C1-C3 alkyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl, =O, -OR 4A 、-C(O)R 4A 、-OC(O)R 4A 、-OS(O)2R 4A 、-C(O)OR 4A 、-NR 4A C(O)R 4B 、-NR 4A C(O)OR 4B 、-NR 4A C(O)NR 4B R 4C 、-NR 4B R 4C 、-C(O)NR 4B R 4C 、-NR 4A SO2NR 4B R 4C 、-NR 4A SO2R 4B 、-SO2NR 4B R 4C 、-S(O)(NR 4A )R 4B or -S(O) r R 4A substituted by a substituent;

[0150] R 4b and R 4c Each is independently selected from hydrogen, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, C1-C3 alkyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl, =O, -OR 4A 、-C(O)R 4A 、-C(O)OR 4B 、-OC(O)R 4B 、-NR 4B R 4C 、-C(O)NR 4B R 4C、-SO2NR 4B R 4C or -NR 4A C(O)R 4C substituted by a substituent;

[0151] Or, R 4b and R 4c Together with the atoms to which they are attached, they form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more N, O or S(O)2, and the 4-8 membered heterocyclic group is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, C1-C3 alkyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl, =O, -OR 4A 、-C(O)R 4A 、-C(O)OR 4A 、-OC(O)R 4A 、-NR 4B R 4C 、-C(O)NR 4B R 4C 、-SO2NR 4B R 4C or -NR 4A C(O)R 4B substituted by a substituent;

[0152] R 4A is selected from hydrogen, C1-C3 alkyl, C2-C5 alkynyl, C2-C5 alkenyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl;

[0153] R 4B and R 4C Each is independently selected from hydrogen, C1-C3 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl;

[0154] Or, R 4B and R 4C Together with the atoms to which they are attached, they form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more N or O.

[0155] Further as a preferred solution, Selected from the following excerpts:

[0156]

[0157] As a further preferred embodiment, the structure shown in formula IVa or IVb is

[0158]

[0159] or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt or prodrug thereof;

[0160] in:

[0161] R1 is selected from hydrogen, C1-C5 alkyl, 3-6 membered cycloalkyl, halogen, nitro, cyano, C6-C10 aryl, 5-10 membered heteroaryl, C1-C3 alkoxy; wherein the alkyl, cycloalkyl, aryl, heteroaryl are optionally further substituted with one or more substituents selected from hydrogen, C1-C5 alkyl, and halogen; preferably, R1 is selected from hydrogen, C1-C5 alkyl, 3-6 membered cycloalkyl, halogen, nitro, cyano, C1-C3 alkoxy; wherein the alkyl and cycloalkyl are optionally further substituted with one or more substituents selected from hydrogen, C1-C5 alkyl, and halogen; specifically preferably, R1 is selected from F, Cl, methyl, and trifluoromethyl;

[0162] R2 is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, halogen, nitro, cyano, C1-C4 alkoxy, wherein the alkyl, haloalkyl, alkoxy is optionally further substituted with one or more substituents selected from hydrogen, C1-C5 alkyl, halogen; preferably, R2 is selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, halogen, C1-C3 alkoxy, C1-C3 haloalkoxy; specifically preferably, R2 is selected from hydrogen, bromine, chlorine, fluorine, methyl, cyano;

[0163] o is selected from: 1, 2, 3, 4, 5; as a preferred embodiment, o is selected from 1, 2;

[0164] p is selected from: 0, 1, 2; as a preferred embodiment, p is selected from 0, 1;

[0165] As a preferred option The fragments may be selected from the following structures:

[0166]

[0167] R3 is selected from C1-C3 alkyl, C1-C3 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, halogen, cyano, oxo, hydroxyl, C1-C3 hydroxyalkyl; or, two R3 together with the atoms to which they are attached form a 3-5 membered carbocyclic ring or a 3-5 membered heterocyclic ring, wherein the heterocyclic ring contains one or more N, O or S(O)2, and the carbocyclic ring or heterocyclic ring is optionally further substituted with one or more substituents selected from hydrogen, hydroxyl, halogen, cyano, and C1-C4 alkyl; as a specific preference, R3 is selected from F, methyl, and vinyl;

[0168] m and n are each independently selected from: 0, 1, 2;

[0169] R4 is selected from: -C(O)OR 4a 、-C(O)NR 4b R 4c ;

[0170] R 4a is selected from hydrogen, C1-C5 alkyl, C2-C5 alkynyl, C2-C5 alkenyl, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl, wherein said alkyl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, C1-C3 alkyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl, =O, -OR 4A 、-C(O)R 4A 、-NR 4B R 4C As a preferred embodiment, R 4a Selected from methyl, ethyl, propyl, isopropyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, isopentenyl, trifluoroethyl;

[0171] R 4b and R 4c Each is independently selected from hydrogen, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, 3-6-membered cycloalkyl, 4-8-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl is optionally further substituted with one or more substituents selected from hydrogen, halogen, nitro, cyano, C1-C3 alkyl, 3-6-membered cycloalkyl, 4-8-membered heterocyclyl; or, R 4b and R 4c Together with the atoms to which they are attached, they form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more N, O or S(O)2, and the 4-8 membered heterocyclic group is optionally further substituted by one or more selected from hydrogen, halogen, nitro, cyano, C1-C3 alkyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl, =O, -OR 4A 、-NR 4B R 4C , substituted by a substituent; as a preferred embodiment,

[0172] R 4A is selected from hydrogen, C1-C3 alkyl, C2-C5 alkynyl, C2-C5 alkenyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl;

[0173] R 4B and R 4CEach is independently selected from hydrogen, C1-C3 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl;

[0174] Or, R 4B and R 4C Together with the atoms to which they are attached, they form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more N or O;

[0175] As a specific preference, the R4 is selected from methoxyl, ethoxyl, propoxyl, butoxyl, pentoxyl, methylaminol, ethylaminol, alanyl,

[0176] wait;

[0177] More preferably, the R4 is selected from methoxyacyl, ethoxyacyl, propoxyacyl, butoxyacyl, pentoxyacyl,

[0178] R5 and R6 are each independently selected from: hydrogen, halogen, C1-C3 alkyl, phenyl, and the alkyl and phenyl are optionally further substituted by one or more substituents selected from hydrogen, halogen, nitro, and cyano; as a specific preferred embodiment, R5 and R6 are each independently selected from hydrogen and methyl.

[0179] As a preferred embodiment, the compound of the present invention is characterized by being selected from one or more of the following compounds:

[0180]

[0181]

[0182]

[0183]

[0184] or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

[0185] Terminology

[0186] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art. Unless otherwise indicated, all patent documents, public disclosures, and other materials referenced herein are incorporated by reference in their entirety. If multiple definitions of the same term are used herein, the definition in this section shall prevail.

[0187] It should be understood that the foregoing general description and the following detailed description are merely exemplary and explanatory and are not restrictive to any claims. In the present invention, unless otherwise stated, the singular includes the plural. It should be noted that in the specification and the appended claims, unless otherwise stated, singular forms such as "one", "an", "this", include plural references. It should also be noted that, unless otherwise stated, "or" represents "and / or". In addition, similar terms such as "including", "comprising" are not restrictive. "Substituted" means that a hydrogen atom is replaced by a substituent. It should be noted that the substituents on a particular atom are limited by their valence. In the definition section, "Ci-Cj" refers to a range including a starting point and an end point, where i and j are integers representing the number of carbon atoms. For example, C1-C5, C3-C6, C3-C10, etc.

[0188] The term "alkyl" as used in the present invention refers to a straight-chain or branched saturated monovalent hydrocarbon group containing 1 to 8 carbon atoms, including but not limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-hexyl, 2-hexyl, etc. The alkyl group may be substituted with one or more substituents. In the case of multiple substitutions, the substituents may be the same or different. The substituents are independently D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, amino, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylate, acyl, amide, methylsulfone, alkylamide, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 hydroxyalkyl, C1-C8 alkylamino, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, halogenated C1-C8 hydroxyalkyl, halogenated C1-C8 alkylamino, C3-C12 cycloalkyl, halogenated C3-C12 cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, hydroxyalkylamide, sulfonamide, C6-C12 aryl, C5-C14 heteroaryl, or C3-C12 heterocyclyl.

[0189] As used herein, the terms "alkenyl" and "olefin" refer to straight or branched hydrocarbon chain groups containing at least one C=C double bond, including but not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, and the like. Alkenyl groups may be substituted with one or more substituents, which may be the same or different when multiple substituents are present; the substituents are independently D, alkyl, haloalkyl, alkoxy, alkylamino, haloalkoxy, hydroxyalkyl, halohydroxyalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, halogen, cyano, nitro, or amino.

[0190] The term "alkynyl" as used herein refers to a straight or branched hydrocarbon chain group containing at least one C≡C triple bond, including but not limited to C2-C8 alkynyl, C2-C6 alkynyl, and the like, including but not limited to ethynyl, propynyl, 1-butynyl, 2-butynyl, pentynyl, and hexynyl. Alkynyl groups may be substituted with one or more substituents, which may be the same or different when multiple substituents are present; the substituents are independently D, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halohydroxyalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxy, halogen, cyano, nitro, or amino.

[0191] The term "halogen" as used herein refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine or bromine.

[0192] The term "halogenated" as used in the present invention refers to substitution by halogen on the same atom or on different atoms, and the substitution may be one or more times, such as disubstituted or trisubstituted.

[0193] The term "cycloalkyl" as used in the present invention refers to a non-aromatic monovalent hydrocarbon group having 3 to 12 carbon atoms, which is a monocyclic or polycyclic ring (two monocyclic rings are connected by a chemical bond or are bridged, spirocyclic or fused), and one or more chemical bonds may be double bonds or triple bonds. It includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, octahydro, decahydro, bicyclo[1.1.0]butanyl, bicyclo[2.1.0]pentanyl, bicyclo[2.2.0]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.2.0]octanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[4.1.1]octanyl, bicyclo[3.2.1]octanyl, bicyclo[3. alkyl, spiro[2.5]octyl, spiro[2.6]wannah alkyl, spiro[3.5]wannah alkyl, spiro[3.4]octyl, spiro[3.3]heptyl, spiro[4.5]decyl, spiro[4.4]alkyl, and the like. The cycloalkyl group may be substituted with one or more substituents. In the case of multiple substitutions, the substituents may be the same or different. The substituents are independently D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, amino, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylate, acyl, amide, methylsulfonyl, alkylamide, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 hydroxyalkyl, C1-C8 alkylamino, halo-substituted C1-C8 alkyl, halo-substituted C1-C8 alkoxy, halo-substituted C1-C8 hydroxyalkyl, halo-substituted C1-C8 alkylamino, C3-C12 cycloalkyl, halo-substituted C3-C12 cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, hydroxyalkylamide, sulfonamide, C6-C12 aryl, C5-C14 heteroaryl, or C3-C12 heterocyclyl.

[0194] As used herein, the terms "heterocyclyl" and "heterocycloalkyl" refer to non-aromatic monocyclic or polycyclic rings (two monocyclic rings are chemically bonded, bridged, spirocyclic, or fused) having 3 to 12 ring atoms, having one or more heteroatoms selected from N, O, and S, and one or more chemical bonds may be double or triple bonds. Heterocyclyl groups include, but are not limited to, piperidinyl, piperazinyl, morpholinyl, dihydrofuranyl, tetrahydrofuranyl, oxirane, aziridine, oxetanyl, and azetidinyl. The heterocyclic group may be substituted by one or more substituents. In the case of multiple substitutions, the substituents may be the same or different. The substituents are independently D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, amino, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylate, acyl, amide, methylsulfonyl, alkylamide, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 hydroxyalkyl, C1-C8 alkylamino, halo-substituted C1-C8 alkyl, halo-substituted C1-C8 alkoxy, halo-substituted C1-C8 hydroxyalkyl, halo-substituted C1-C8 alkylamino, C3-C12 cycloalkyl, halo-substituted C3-C12 cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, hydroxyalkylamide, sulfonamide, C6-C12 aryl, C5-C14 heteroaryl, or C3-C12 heterocyclic group.

[0195] The terms "aryl" and "aromatic ring" used in the present invention refer to an all-carbon monocyclic or fused polycyclic group having 6 to 12 carbon atoms (one of the fused rings may be partially saturated), including but not limited to a benzene ring, a naphthalene ring, an anthracene ring, an indene ring, a dihydroindenyl (indanyl), etc. The aryl group may be unsubstituted or substituted, and may be monosubstituted (e.g., ortho, meta, or para), disubstituted, or trisubstituted, and in the case of polysubstitution, the substituents may be the same or different. The substituents are independently D (deuterium), halogen, cyano, nitro, hydroxyl, amino, aminoalkyl, alkenyl, alkynyl, carboxyl, acyl, amide, alkylamide, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 hydroxyalkyl, C1-C8 alkylamino, halosubstituted C1-C8 alkyl, halosubstituted C1-C8 alkoxy, halosubstituted C1-C8 hydroxyalkyl, halosubstituted C1-C8 alkylamino, C3-C12 cycloalkyl, halosubstituted C3-C12 cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, hydroxyalkylamide, sulfonamide, C6-C12 aryl, C5-C14 heteroaryl, or C3-C12 heterocyclyl.

[0196] As used herein, the terms "aromatic heterocycle" and "heteroaryl" refer to monocyclic or fused polycyclic groups having 5 to 14 ring atoms (one of the fused rings may be partially saturated), which corresponds to one or more carbon atoms in the aforementioned "aryl" being replaced by heteroatoms such as N, O, or S. The heteroaromatic ring may be monocyclic or bicyclic, i.e., formed by the fusion of two rings. Heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl, oxazolyl, imidazolyl, indazole, dihydroindazole, and benzimidazole. The heteroaryl group may be unsubstituted, monosubstituted or polysubstituted. In the case of polysubstituted groups, the substituents may be the same or different. The substituents are independently D (deuterium), halogen, cyano, nitro, amino, aminoalkyl, hydroxyl, carboxyl, carboxylate, acyl, amide, alkylamide, alkoxycarbonyl, alkylthio, alkylsulfonyl, hydroxyalkylamide, sulfonamide, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 alkylamino, halosubstituted C1-C8 alkyl, halosubstituted C1-C8 hydroxyalkyl, halosubstituted C1-C8 alkoxy, halosubstituted C1-C8 alkylamino, C3-C12 cycloalkyl, halosubstituted C3-C12 cycloalkyl, C3-C12 heterocyclyl, C6-C12 aryl, or C5-C14 heteroaryl.

[0197] The term "alkoxy" as used herein refers to alkyl-O-, wherein alkyl is as defined above. Examples of "alkoxy" as used herein include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and tert-butoxy. "Alkoxy" also includes substituted alkoxy groups, the substituents of which may be D, halogen, oxo, amino, hydroxyl, cyano, nitro, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 alkylamino, halo-C1-C8 alkyl, halo-C1-C8 hydroxyalkyl, halo-C1-C8 alkoxy, halo-C1-C8 alkylamino, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C6-C12 aryl, or C5-C14 heteroaryl.

[0198] The term "haloalkyl" as used herein refers to a straight or branched chain alkyl group substituted with a halogen (preferably fluorine, chlorine, bromine, or iodine), wherein "alkyl" is as defined above. Examples of "haloalkyl" as used herein include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, tetrafluoroethyl, pentafluoroethyl, 1,1,1-trifluoroprop-2-yl, and the like. "Haloalkyl" may be substituted one or more times with a halogen.

[0199] The term "alkylamino" as used herein refers to an alkyl-NH- group, wherein the alkyl group is as defined above. Examples of "alkylamino" as used herein include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, and the like. "Alkylamino" also includes substituted alkylamino groups, the substituents of which may be D, halogen, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amide, sulfonamide, spiroalkyl, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 alkylamino, halo-C1-C8 alkyl, halo-C1-C8 hydroxyalkyl, halo-C1-C8 alkoxy, halo-C1-C8 alkylamino, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C6-C12 aryl, or C5-C14 heteroaryl. The substituents may be substituted on the alkyl group or on the N group.

[0200] The term "aminoalkyl" as used herein refers to NH2-alkyl-, wherein alkyl is as defined above. Examples of "aminoalkyl" as used herein include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, and the like. "Aminoalkyl" also includes substituted aminoalkyl groups, the substituents of which may be D, halogen, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amide, sulfonamide, spiroalkyl, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 alkylamino, halo-C1-C8 alkyl, halo-C1-C8 hydroxyalkyl, halo-C1-C8 alkoxy, halo-C1-C8 alkylamino, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C6-C12 aryl, C5-C14 heteroaryl, and the substituents may be substituted on the alkyl or on the N.

[0201] The term "hydroxyalkyl" as used in the present invention refers to -alkyl-OH, wherein alkyl is as defined above. Examples of "alkyl" used in the present invention include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, and the like. "Hydroxyalkyl also includes substituted hydroxyalkyl, whose substituents may be D, halogen, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amide, sulfonamide, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 alkylamino, halo-substituted C1-C8 alkyl, halo-substituted C1-C8 hydroxyalkyl, halo-substituted C1-C8 alkoxy, halo-substituted C1-C8 alkylamino, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C6-C12 aryl, C5-C14 heteroaryl.

[0202] As used herein, the term "haloalkyl" refers to a straight or branched chain alkyl group in which one or more hydrogen atoms are replaced by one or more halogen atoms (preferably fluorine, chlorine, iodine, or iodine), wherein alkyl is as defined above. Examples of "haloalkyl" as used herein include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloroethyl, tetrafluoroethyl, pentafluoroethyl, 1,1,1-trifluoroprop-2-yl, and the like.

[0203] The -S(O)2-, -C(O)-, -S(O)(NR)- and other expressions used in the present invention represent sulfonyl, carbonyl and sulfenimino groups, respectively.

[0204] Salts of the compounds of the present invention can be prepared using methods well known to those skilled in the art. Acid addition salts include, but are not limited to, salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphonic acid, and salts derived from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. The present invention relates to the preparation of the present invention and the preparation of the present invention.Therefore, these salts include but are not limited to sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, iodate, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberic acid, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartaric acid and mesylate, also comprising amino acid whose salt is as arginate, gluconate, galacturonate etc.Acid addition salts can be prepared by making the free alkali form contact with sufficient amount of required acid in a conventional manner.Free alkali form can be regenerated by making the salt form contact with alkali, and separating this free alkali in a conventional manner.

[0205] The base addition salts are formed with metals or amines, such as hydroxides of alkali metals and alkaline earth metals, or with organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Examples of suitable amines include, but are not limited to, N, dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1,2-diamine), N-methylglucamine, and procaine. Base addition salts can be prepared by contacting the free acid form with a sufficient amount of the desired base in a conventional manner to form a salt. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner.

[0206] The stereoisomers of the present invention include enantiomers, diastereomers and geometric isomers. Some compounds of the present invention have cycloalkyl groups that may be substituted on more than one carbon atom. In this case, all geometric forms, including cis and trans forms, and mixtures thereof, are within the scope of the present invention.

[0207] The compounds described herein include compounds in which certain atoms have been replaced by isotopes. Isotopes refer to atoms with the same atomic number but different atomic masses. For example, isotopes of hydrogen include deuterium and tritium. One or more atoms in the atoms comprising the compounds described herein may be replaced by natural or unnatural isotopes. For example, in some embodiments, hydrogen atoms may be replaced by one or more deuterium atoms. Methods for synthesizing compounds containing isotopic atoms are known in the art.

[0208] The present invention provides a pharmaceutical formulation comprising at least one active ingredient, wherein the active ingredient is one or more of the compounds described in any of the above technical solutions. The pharmaceutical formulation comprises at least one active ingredient and one or more pharmaceutically acceptable carriers or excipients. The active ingredient can be any one or more of the CB1 agonist compounds of the present invention, optical isomers of the compounds, pharmaceutically acceptable salts of the compounds or optical isomers thereof, or solvates of the compounds or optical isomers thereof.

[0209] The carrier includes conventional diluents, excipients, fillers, adhesives, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants, etc. in the pharmaceutical field, and flavoring agents, sweeteners, etc. may also be added if necessary.

[0210] The medicine of the present invention can be prepared into various forms such as tablets, powders, granules, capsules, oral solutions and injections. The medicines in the above dosage forms can be prepared according to conventional methods in the pharmaceutical field.

[0211] A second object of the present invention is to provide a pharmaceutical composition comprising one or more of the compounds described in any of the above technical solutions. The pharmaceutical composition of the present invention may be composed of one or more of the compounds described in any of the above technical solutions together with other compounds, or may be composed of one or more of the compounds described in any of the above technical solutions.

[0212] In another aspect, the present invention provides the use of compounds of Formula I to Formula III disclosed herein, or their stereoisomers, or mixtures of stereoisomers, or pharmaceutically acceptable salts thereof, in treating diseases, disorders, or conditions that benefit from activating CB-1.

[0213] In a further preferred embodiment, the present invention provides a method for activating CB1 in a subject in need thereof by administering a composition comprising a therapeutically effective amount of at least one compound, wherein the compound has the structural formulae I to III. In some embodiments, the compounds of the structural formulae I to III can be used to treat psychiatric disorders such as addiction and depression, as well as cancer, obesity, analgesia, diabetes, tumors, cardiovascular and cerebrovascular diseases, rheumatoid arthritis, asthma, liver disease, multiple sclerosis, and other diseases.

[0214] The inventors of the present invention have confirmed through experiments that the compound of the present invention can activate CB1 protein.

[0215] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0216] The solvent used in the present invention is commercially available. BRIEF DESCRIPTION OF THE DRAWINGS

[0217] Figure 1 : Effects of compound 1 (LZD503) on the recruitment of β-arrestin1 or the dissociation of Gαi-Gγ in wild-type CB1 receptors. The BRET curve shows that compound 1 (LZD503) prefers to recruit G protein.

[0218] Figure 2 : The mechanical pain test results of compound 1 (LZD503) showed that the mechanical pain test results showed that 2.0 mg / kg compound 1 (LZD503) and 0.1 mg / kg positive molecule MDMB-Fubinaca had similar analgesic effects.

[0219] Figure 3 : Hot plate test results of compound 1 (LZD503). The hot plate test results showed that 2.0 mg / kg compound 1 (LZD503) had a significant analgesic effect compared with the blank control.

[0220] Figure 4 : The results of the rotarod test of compound 1 (LZD503) showed that 2.0 mg / kg of compound 1 (LZD503) significantly improved the problem of reduced motor ability in mice.

[0221] Figure 5 : The body temperature measurement results of compound 1 (LZD503) showed that LZD503 significantly increased body temperature at 120 minutes, and could significantly improve the problem of hypothermia in mice.

[0222] Figure 6 : Conditioned place preference experiment of compound 1 (LZD503) showed that morphine is rewarding, Fub is aversive to a certain extent, and compound 1 (LZD503) is neither rewarding nor aversive.

[0223] Figure 7: PK data of the compound after intraperitoneal injection in mice (plasma and brain drug exposure) showed that compound 1 (LZD503) has the ability to penetrate the brain. DETAILED DESCRIPTION

[0224]

[0225] Synthesis Operation

[0226] First step: 1H-indazole-3-carboxylic acid methyl ester (776.7 mg, 4.4 mmol) was dissolved in 25 mL of anhydrous tetrahydrofuran. Sodium hydride (317.4 mg, 13.2 mmol) was added to the system in portions under ice-cooling conditions. The mixture was stirred for 30 min, and then 4-fluorobenzyl bromide 1-1 (1.0 g, 5.3 mmol) was added. The mixture was allowed to react at room temperature overnight. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Compound 1-2 (1.1 g, 3.9 mmol) was obtained by column chromatography. ESI-MS (M+H) + =285.11.

[0227] Step 2: Dissolve intermediate 1-2 (1.1 g, 3.9 mmol) in 20 mL of tetrahydrofuran, add water (20 ml) and NaOH (619.1 mg, 15.5 mmol) sequentially, and react at 60°C overnight. After the reaction, adjust the pH to 4-5 with 6N HCl, extract three times with DCM, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 1-3 (1.0 g, 3.7 mmol). ESI-MS (M+H) + =271.10.

[0228] Step 3: Dissolve intermediate 1-3 (1.0 mg, 3.7 mmol) in 25 ml of DMF, and add O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.8 g, 7.4 mmol) and N,N-diisopropylethylamine (1.9 g, 14.8 mmol) sequentially to the system. Stir at room temperature for 30 min, then add 1-aminocyclopropylcarboxylic acid methyl ester (directly purchased from the market, 639.0 mg, 5.6 mmol), and react at room temperature overnight. After the reaction is completed, water is added to quench the reaction, and the mixture is extracted with DCM three times. The organic phases are combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Compound 1, i.e., LZD503, is obtained by column chromatography. Compound 1 is represented by LZD503 in the accompanying drawings (1.2 g, 3.3 mmol). 1H NMR(500MHz,Chloroform-d)δ8.39(dt,J=8.1,1.1Hz,1H),7.50(s,1H),7.41–7.36(m,1H),7.35–7.27(m,2H),7 .18(dd,J=8.6,5.3Hz,2H),7.03–6.98(m,2H),5.56(s,2H),3.71(s,3H),1.72–1.68(m,2H),1.38–1.34(m,2H). ESI-MS(M+H) + =368.1.

[0229] The synthesis methods of the following compounds are the same as those of compound 1

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238] Active biological evaluation

[0239] Test 1: Bioluminescence Energy Resonance Transfer Experiment

[0240] Bioluminescence resonance energy transfer (BRET) assays were used to assess cannabinoid receptor type 1 (CB1) recruitment of β-arrestin 1 and the ability of CB1 to recruit Gi. Human embryonic kidney (HEK293T) cells were seeded in six-well plates and grown to 80% confluency before transfection. For β-arrestin 1 recruitment assays, HEK293T cells were co-transfected with human CB1 tagged with a C-terminal RLuc8 tag and β-arrestin 1 tagged with an N-terminal Venus tag at a 1:6 ratio using lipofectamine. For Gi recruitment assays, the RLuc8 tag was inserted into the helical domain of the Gαi subunit (between the αA and αB helices) and linked by a 15-amino acid flexible segment. The Venus tag was fused N-terminally to the Gγ2 subunit (carrying the C68S mutation) and linked by a 15-amino acid flexible segment. HEK293T cells were co-transfected with human CB1, Gαi-RLuc8, Venus-Gγ2, and Gβ1 in a ratio of 3:1:2:2. Six hours after transfection, the transfected cells were placed on a 96-well plate treated with a cell adhesion reagent. The next day, the cells were washed with D-PBS buffer to remove complete culture medium, and then 45 μL of detection buffer (1xHBSS, 20 mM HEPES, 0.1% (w / v) BSA, pH 7.5) was added to each well and incubated at 37°C for 30 minutes. After incubation, 45 μL of 10 μM coelenterazine H (diluted in detection buffer) was added to each well and incubated at room temperature for 10 minutes to allow substrate diffusion. Subsequently, the fluorescence value of each well at 475 nm and the fluorescence value of eYFP at 535 nm were measured using a TECAN microplate reader. The eYFP / RLuc ratio of each well was used as the baseline. MDMB-Fubinaca (10 μL) was added at a gradient concentration and incubated at room temperature for 3-5 minutes before the second measurement. The ratio of the second measurement was divided by the baseline and analyzed in GraphPad Prism 9. The processed data were normalized to 100% of the maximum activation window of the positive control CB1 agonist MDMB-Fubinaca and analyzed using the nonlinear regression "log (agonist) vs. response" in GraphPad Prism 9. MDMB-Fubinaca (structure shown below) served as the positive control.

[0241] Table 1 shows the effects of the compounds on the recruitment of β-arrestin1 or the dissociation of Gαi-Gγ in wild-type CB1 receptors. The examples in this application all exhibit certain biased agonist properties.

[0242] like Figure 1 The BRET curves show that compound 1 (LZD503) preferentially recruits G protein.

[0243]

[0244] MDMB-Fubinaca (hereinafter referred to as "Fub")

[0245] Table 1 Effects of compounds on recruitment of β-arrestin1 or dissociation of Gαi-Gγ in wild-type CB1 receptors investigated using bioluminescence resonance energy transfer

[0246]

[0247]

[0248] in:

[0249] Gi: pEC 50 :pEC 50 >6:A;pEC 50 ≤6: B;

[0250] Gi Span±SEMa,b,c(%FUB): 80<%FUB≤100: A; 40<%FUB≤80: B; %FUB≤40:C;

[0251] β-arrestin1: pEC 50 :pEC 50 >8: A; 5 <pEC 50 ≤8: B; pEC 50 ≤5: C;

[0252] β-arrestin1 Span±SEMa,b,c(%FUB): 80<%FUB≤100%: A; 40<%FUB≤80%: B; %FUB≤40:C;

[0253] The bias factor is calculated using the following formula:

[0254]

[0255] Among them, P1 indicates Gi protein dissociation; P2 indicates β-arrestin recruitment; Bias factor greater than 0 indicates Gi bias, and Bias factor less than 0 indicates β-arrestin bias.

[0256] MDMB-Fubinaca (Fub) is a balanced ligand with strong ability to recruit both Gi and β-arrestin. Exclusively G indicates that the ligand is completely biased towards Gi.

[0257] Test 2: Mechanical pain measurement (Von Frey Test)

[0258] Several mice were divided into three groups: a control group, a group injected with 0.1 mg / kg of Fub, and a group injected with 2.0 mg / kg of LZD503. After the injection of the drugs, the mice were placed in a box to adapt for 1 hour, and then a series of calibrated fibers were used to vertically poke the hind paws of the mice, applying enough force to bend the fibers. Rapid hind paw movements (contraction or flinching) were regarded as pain responses. Paw lifting due to normal motor behavior was ignored. If there was no contraction response to the selected fiber, the next fiber with greater force would be applied. If there was paw contraction, the next weaker stimulus was selected. Finally, the formula 50% g threshold = (10 [Xf+kδ] ) / 10,000 to calculate the pain threshold (Withdraw Threshold (g)). X f is the last fiber stress value in logarithmic units, k is the k value corresponding to the sequence of 6 consecutive positive and negative reactions in the test, and δ is the average difference in stress between adjacent fiber filaments in logarithmic units.

[0259] like Figure 2 The results of mechanical pain assay showed that 2.0 mg / kg compound 1 (LZD503) and 0.1 mg / kg positive molecule MDMB-Fubinaca had similar analgesic effects.

[0260] Test 3: Hot Plate Experiment

[0261] The animals were placed on a heated plate at 52 degrees Celsius. The plate was surrounded by four layers of plexiglass and a lid, preventing them from escaping. Several mice were divided into three groups: a control group, a group receiving an intraperitoneal injection of 0.1 mg / kg of Fub, and a group receiving an intraperitoneal injection of 2.0 mg / kg of LZD503. The time it took for the mice to lift their hind paws was measured from the time they were placed on the hot plate. The mice were removed from the hot plate after 30 seconds. MPE (%) = [(post-dose - pre-dose) / (termination time - pre-dose)] × 100. In the formula, pre-dose and post-dose both refer to the reaction latency. The post-dose reaction latency refers to the reaction latency in the experiment after the animal receives the drug injection, and the termination time refers to the time after the drug administration when the animal fails to react to the heat and the test is terminated.

[0262] like Figure 3 The hot plate assay results shown above showed that 2.0 mg / kg of compound 1 (LZD503) had a significant analgesic effect compared to the blank control.

[0263] Test 4: Rotarod test

[0264] The rotarod test is used to assess the motor coordination and balance of rodents. The animals must maintain balance on a rotating rod. Several mice were divided into three groups: a control group, a group injected with 0.1 mg / kg of Fub intraperitoneally, and a group injected with 2.0 mg / kg of LZD503 intraperitoneally. The instrument recorded the time required for the animals to fall off a rod rotating at different speeds or continuously accelerating (e.g., from 4 rpm to 40 rpm), the speed of the rod when falling (terminal speed), and the distance the animals traveled.

[0265] like Figure 4 As shown, the results of the rotarod test showed that 2.0 mg / kg of compound 1 (LZD503) significantly improved the problem of decreased motor ability in mice.

[0266] Test 5: Body temperature measurement

[0267] Several mice were divided into three groups: control group, group injected with 0.1 mg / kg Fub intraperitoneally, and group injected with 2.0 mg / kg LZD503 intraperitoneally. Rectal temperature was recorded using a mouse rectal thermometer 30 and 60 minutes after intraperitoneal injection of the compound.

[0268] like Figure 5 As shown, the body temperature test results showed that LZD503 significantly restored body temperature at 120 minutes, and could significantly improve the problem of hypothermia in mice.

[0269] Test 6: Conditioned Place Preference Experiment

[0270] To determine whether the compounds induce psychological dependence, we used a conditioned place preference paradigm. Mice were first habituated to the three-compartment apparatus twice, and their time spent in each compartment was recorded for 30 minutes each time (referred to as pretest time). This was followed by two days of conditioning training, during which mice received either a negative vehicle control or compound injection and were then confined to one of the compartments for 30 minutes 30 minutes later. On day 5 (test day), mice were allowed to move freely between the three compartments of the testing apparatus, and their preference for each compartment was recorded for 30 minutes each time. To calculate the conditioned place preference score, the time spent in each compartment on the pretest day was subtracted from the time spent in each compartment on the test day (CPP score = test - pretest).

[0271] like Figure 6 As shown, the conditioned place preference experiment showed that morphine was rewarding, Fub was aversive to a certain extent, and compound 1 (LZD503) was neither rewarding nor aversive.

[0272] Test 7, mouse absorption test

[0273] After intraperitoneal administration of 2 mg / kg, blood and brain samples were collected at 5, 15, 30, 1, 2, 4, 6, 8, and 24 hours. 0.3 mL of whole blood was collected, centrifuged, and 0.1 mL of plasma was analyzed by LC-MS. Brain tissue was homogenized and analyzed by LC-MS.

[0274] After intravenous administration of 1 mg / kg, blood and brain tissue samples were collected at 5, 15, 30, 1, 2, 4, 6, 8, and 24 hours. 0.3 mL of whole blood was collected, centrifuged, and 0.1 mL of plasma was collected for analysis by LC-MS. Brain tissue was homogenized and analyzed by LC-MS, and PK parameters such as Cmax and AUC0-t were analyzed using PKSolver.

[0275] like Figure 7 The results in Table 2 show that compound 1 (LZD503) has the ability to penetrate the brain.

[0276] Table 2 Pharmacokinetics of Compound Fub and LZD503 (Intraperitoneal Administration)

[0277]

[0278] Test 8. Rat absorption experiment

[0279] The drug was administered intraperitoneally at 2 mg / kg. Blood and brain samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. 0.3 mL of whole blood was collected, centrifuged, and 0.1 mL of plasma was analyzed by LC-MS. Brain tissue was homogenized and analyzed by LC-MS.

[0280] After intravenous administration of 1 mg / kg, blood and brain tissue samples were collected at 5, 15, 30, 1, 2, 4, 6, 8, and 24 hours. 0.3 mL of whole blood was collected, centrifuged, and 0.1 mL of plasma was collected for analysis by LC-MS. Brain tissue was homogenized and analyzed by LC-MS.

[0281] The results showed that compound 1 (LZD503) has the ability to penetrate the brain.

Claims

1. A compound, characterized in that It has the structure shown in general formula I: or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt or prodrug thereof; in: Cyc1 is selected from: C6-C10 aryl, 5-10 membered heteroaryl; n R1 are each independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, halogen, and cyano; wherein the alkyl is optionally further substituted with one or more halogens; m R2 are each independently selected from hydrogen, C1-C8 alkyl, -OR 2a , halogen; wherein the alkyl group is optionally further substituted by one or more halogens; R 2a is selected from C1-C8 alkyl, wherein the alkyl is optionally further substituted with one or more halogens; R3 is independently selected at each occurrence from the group consisting of: hydrogen, halogen, cyano, oxo, C1-C8 alkyl, -OR 3a , C2-C8 alkenyl, C6-C10 aryl; wherein the alkyl group is optionally further substituted with one or more halogen, -OR 3a replaced by; R 3a is selected from hydrogen, C1-C8 alkyl; wherein the alkyl is optionally further substituted by one or more halogens; Alternatively, two R3 together with the atoms to which they are attached form a 3-12 membered carbocyclic ring or a 3-12 membered heterocyclic ring, wherein the 3-12 membered heterocyclic ring contains one or more N, O or S(O)2, and the 3-12 membered carbocyclic ring or heterocyclic ring is optionally further substituted with one or more selected from hydrogen, hydroxyl, and halogen; R4 is selected from: -C(O)OR 4a 、-C(O)NR 4b R 4c ; R 4a Selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, 3-8 membered cycloalkyl; wherein the alkyl and alkenyl are optionally further substituted with one or more halogens and C1-C8 alkyl; R 4b and R 4c Each is independently selected from hydrogen, C1-C8 alkyl, 3-8 membered cycloalkyl; Or, R 4b and R 4c Together with the atoms to which they are attached, they form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more N, O or S(O)2, and the 4-8 membered heterocyclic group is optionally further substituted with one or more 4-8 membered heterocyclic groups selected from hydrogen, C1-C8 alkyl, 4-8 membered heterocyclic group, C1-C3 alkyl, -NR 4B R 4C replaced by R 4B and R 4C Each independently selected from hydrogen, C1-C8 alkyl; R5 and R6 are each independently selected from: hydrogen, C1-C4 alkyl; Alternatively, R5 and R6 together with the atoms to which they are attached form a 3-8 membered carbocyclic ring or a 3-8 membered heterocyclic ring, wherein the 3-8 membered heterocyclic ring contains one or more N or O; R7 is selected from the group consisting of: hydrogen, C1-C3 alkyl, 3-6 membered cycloalkyl; n and m are each independently selected from: 0, 1, 2, 3, 4; p is selected from: 0, 1, 2, 3, 4; oSelect from: 1, 2, 3, 4, 5, 6; X is selected from: O, S.

2. The compound according to claim 1, characterized in that It has the structure shown in the general formula IIa: or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt or prodrug thereof; R1, R2, R3, R4, R5, R6, R7, m, n, o are as defined in claim 1; p is selected from: 0, 1, 2; X1, X2, X3, X4, and X5 are each independently selected from N, C, or CH, provided that the valence theory is satisfied.

3. The compound according to claim 2, characterized in that It has a structure shown in one of the general formulas IIIa to IIId: or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt or prodrug thereof; R3, R4, p, o, m, n are as defined in claim 2; R1 is selected from the group consisting of: hydrogen, C1-C5 alkyl, halogen, and cyano; wherein the alkyl group is optionally further substituted with one or more groups selected from hydrogen and halogen; R2 is selected from: hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, halogen, -OR 2a ; R 2a Selected from hydrogen, C1-C8 alkyl, wherein the alkyl is optionally further substituted with one or more halogens; R5 and R6 are each independently selected from: hydrogen, C1-C3 alkyl; Alternatively, R5 and R6 together with the atoms to which they are attached form a 3-6 membered carbon ring; R7 is selected from the group consisting of: hydrogen, C1-C3 alkyl.

4. The compound according to claim 3, characterized in that Excerpts from: R3 is selected from the group consisting of: hydrogen, cyano, halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C2-C4 alkenyl, and benzene ring; or two R3 together with the atoms to which they are attached form a 3-12 membered carbocyclic ring; R4 is selected from: -C(O)OR 4a 、-C(O)NR 4b R 4c ; R 4a Selected from hydrogen, C1-C5 alkyl, C2-C5 alkenyl, 3-8 membered cycloalkyl; wherein the alkyl is optionally further substituted with one or more halogens; R 4b and R 4c Each is independently selected from hydrogen, C1-C5 alkyl, 3-6 membered cycloalkyl; Or, R 4b and R 4c Together with the atoms to which they are attached, they form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more N, O or S(O)2, and the 4-8 membered heterocyclic group is optionally further substituted with one or more 4-8 membered heterocyclic groups selected from hydrogen, 4-8 membered heterocyclic groups, C1-C3 alkyl groups, -NR 4B R 4C replaced by; R 4B and R 4C Each is independently selected from hydrogen, C1-C3 alkyl.

5. The compound according to claim 3 or 4, characterized in that It has the structure shown in general formula IVa or IVb: or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt or prodrug thereof; in: R1 is selected from the group consisting of: hydrogen, C1-C5 alkyl, halogen, cyano, C1-C5 haloalkyl; R2 is selected from the group consisting of: hydrogen, C1-C5 alkyl, C1-C5 haloalkyl, halogen, C1-C5 alkoxy, C1-C5 haloalkoxy; R3 is selected from the group consisting of: H, C1-C3 alkyl, C1-C3 haloalkyl, C2-C4 alkenyl, C1-C3 alkoxy, halogen, cyano, oxo, hydroxy, C1-C3 hydroxyalkyl; Alternatively, two R3 together with the atoms to which they are attached form a 3-5 membered carbocyclic ring; m and n are each independently selected from: 0, 1, 2; R4 is selected from: -C(O)OR 4a 、-C(O)NR 4b R 4c ; R 4a Selected from C1-C5 alkyl, C2-C5 alkenyl, 3-8 membered cycloalkyl, C1-C5 haloalkyl, C1-C3 alkyl substituted C2-C5 alkenyl; R 4b and R 4c Each is independently selected from hydrogen, C1-C5 alkyl, 3-6 membered cycloalkyl; Or, R 4b and R 4c Together with the atoms to which they are attached, they form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more N, O or S(O)2, and the 4-8 membered heterocyclic group is optionally further substituted with one or more 4-8 membered heterocyclic groups selected from hydrogen, 4-8 membered heterocyclic groups, C1-C3 alkyl groups, -NR 4B R 4C replaced by; R 4B and R 4C Each is independently selected from hydrogen, C1-C3 alkyl; R5 and R6 are each independently selected from: hydrogen, C1-C3 alkyl; or, R5 and R6 together with the atoms to which they are attached form a 3-5 membered carbocyclic ring; oSelect from: 1, 2, 3, 4, 5; p is selected from: 0, 1, 2.

6. The compound according to claim 5, characterized in that R1 is selected from the group consisting of: hydrogen, C1-C3 alkyl, halogen, cyano, C1-C3 haloalkyl; R2 is selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, halogen, C1-C3 haloalkoxy; The fragments may be selected from the following structures: R3 is selected from H, C1-C3 alkyl, C1-C3 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, halogen, cyano, oxo, hydroxy, C1-C3 hydroxyalkyl; p is selected from 0, 1, 2; R4, R5, and R6 are as defined in claim 5.

7. The compound according to claim 1, characterized in that One or more selected from the following compounds: or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition, characterized in that Comprising one or more of the compounds according to any one of claims 1 to 7.

9. Use of a compound according to any one of claims 1 to 7 in the preparation of a medicament for treating a disease, disorder or condition that benefits from CB1 biased activation, alone or in combination with other drugs, wherein the disease comprises one or more of a psychiatric disease, a metabolic disease, and an autoimmune disease.

10. The use according to claim 9, characterized in that The mental-related diseases include one or more of analgesia, addiction, depression, anxiety, and schizophrenia; the metabolic diseases include one or more of obesity, diabetes, rheumatoid arthritis, asthma, and liver disease; and the autoimmune diseases include one or more of multiple sclerosis or cancer.

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