A nitrogen-containing heterocyclic compound, a pharmaceutically acceptable salt thereof, and a preparation method and application thereof

Abstract

The application discloses a nitrogen-containing heterocyclic compound, a pharmaceutically acceptable salt thereof, and a preparation method and application thereof. The application provides a compound shown in formula I or a pharmaceutically acceptable salt thereof. The compound of the application can be used as a muscarinic receptor positive allosteric modulator, and the compound of the application can be used for treating M receptor-mediated (or M receptor-related) diseases.

Description

Technical Field

[0001] This invention relates to a nitrogen-containing heterocyclic compound, its pharmaceutically acceptable salt, its preparation method, and its application. Background Technology

[0002] Muscarinic receptors (M receptors) are G protein-coupled receptors and a type of acetylcholine receptor. There are five subtypes of M receptors. M1, M3, and M5 are coupled to Gq protein, activating phospholipase C and increasing intracellular calcium levels. M2 and M4 are coupled to Gi protein, inhibiting adenylate cyclase and decreasing cAMP levels. M1 receptors are distributed in the central nervous system, digestive tract, and lymphatic tissues. As the major subtype of M receptors, it can simultaneously regulate cellular excitatory and cholinergic transmission. M4 receptors are mainly located in the cortex, hippocampus, and striatum, playing an important role in controlling dopamine release and motor activity, but do not regulate important peripheral physiological functions (Neuropharmacology 2018, 136, 362).

[0003] M receptor agonists have been extensively studied by numerous research institutions and pharmaceutical companies for the treatment of mental illnesses. For example, the M1 / M4 receptor agonist zanmexilin underwent a phase II clinical trial in the 1990s for the treatment of Alzheimer's disease. While treatment with this drug improved patients' cognitive function, it also caused significant peripheral and gastrointestinal toxicity. KarXT, composed of zanmexilin and the M1 receptor antagonist troxetine, is a drug developed by Karuna for the treatment of schizophrenia. The latest phase II clinical study showed that compared to the placebo group, the KarXT treatment group had a significant improvement in the Positive and Negative Syndrome Scale (PANSS) score, meeting the primary endpoint, but peripheral cholinergic side effects still existed (N Engl J Med 2021, 384, 717).

[0004] M-receptor positive allosteric modulators (PAMs) have become a research hotspot in the field of mental illness in recent years. In a genetic mouse model of schizophrenia, the M1 receptor positive allosteric modulator TAK-071 significantly improved deficits in memory, cognition, social skills, and sensorimotor gating (Neurosci Lett 2021, 764, 136240), and a phase II clinical trial for its use in treating Parkinson's syndrome is underway. Another M1 receptor positive allosteric modulator, MK-7622, ​​is undergoing a phase II clinical trial to evaluate its efficacy in treating Alzheimer's disease (ACSMed Chem Lett 2018, 9, 652). In schizophrenia patients recruited for a clinical Ib trial, the M4 receptor positive allosteric modulator CVL-231, developed by Cerevel, significantly reduced patients' total PANSS score. Common adverse reactions were similar to those in the placebo group, and no extrapyramidal adverse reactions were reported. Compared to traditional M receptor orosteric agonists, orosteric modulators have lower potential risks in both the peripheral and central nervous systems, and may produce fewer toxic side effects while maintaining efficacy. Therefore, acting on the orosteric regulatory pocket is a new direction for targeting M receptors in the treatment of mental illnesses. Orosteric modulators of M receptors with good drug-like properties, in vivo efficacy, and safety have significant development value and market potential. Summary of the Invention

[0005] This invention provides a nitrogen-containing heterocyclic compound, its pharmaceutically acceptable salt, its preparation method, and its applications. The compound of this invention can act as a positive allosteric modulator of muscarinic receptors. The compound of this invention can treat M receptor-mediated (or M receptor-related) diseases.

[0006] This invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof:

[0007]

[0008] in, for

[0009] m is a natural number from 0 to 3;

[0010] n is a natural number from 0 to 3; m and n are not both 0;

[0011] k is a natural number between 0 and 3;

[0012] X1, X2, X3, X4, and X5 are independently -CR 1 -、N、O、S、 Or chemical bonds;

[0013] RN-1 It is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, or a 3- to 7-membered cycloalkyl group, wherein the C1-C6 alkyl and C1-C6 alkoxy groups are optionally independently surrounded by one, two, three, or four R groups. N-2 replace;

[0014] Each R N-2 Halogens are independent of each other;

[0015] Y and Z are independently carbonyl (CO) and - (CR) groups. 2 R 3 ) r - or chemical bond; r is a natural number from 0 to 5;

[0016] Each W can be independently carbonyl (CO), -O-, or -(CR) 4 R 5 )-、-NR 6 -or chemical bonds;

[0017] Each R 1 Independently, it is hydrogen, halogen, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or -NR. 1-1 R 1-2 The C1-C6 alkylthio group, C1-C6 alkyl group, and C1-C6 alkoxy group are optionally independently bounded by one, two, three, or four R groups. a Replace; or two Rs 1 It forms 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl with the atoms attached to it;

[0018] Each R a Independently halogen, cyano, hydroxyl, C1-C3 alkyl, C1-C6 alkoxy, or -NR 1-4 R 1-5 Or, two Rs a It forms 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl with the atoms it is attached to;

[0019] R 1-1 and R 1-2 Independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl group is optionally independently formed by one, two, three or four R atoms. b Replace; or, R 1-1 and R 1-2 The atoms bonded to it form 3- to 7-membered heterocyclic alkyl groups, wherein the 3- to 7-membered heterocyclic alkyl groups are arbitrarily bound by 1, 2, 3, or 4 R atoms. b-2 replace;

[0020] Each R bIndependently halogen, cyano, hydroxyl, C1-C6 alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, C1-C3 alkyl, and NR 1-1-1 R 1-2-1 In this context, the 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, and C1-C3 alkyl groups are optionally independently bound by one, two, three, or four R groups. b-1 replace;

[0021] Each R b-1 It can be independently a halogen, hydroxyl, or cyano group;

[0022] Each R b-2 It can be halogen, C1-C6 alkyl, or cyano independently;

[0023] R 1-4 and R 1-5 Independently hydrogen or C1-C3 alkyl, wherein the C1-C3 alkyl group is optionally independently formed by one, two, three or four R atoms. 1-4-1 Replace; or, R 1-4 and R 1-5 The atoms attached to it form 3- to 7-membered heterocyclic alkyl groups;

[0024] R 1-1-1 and R 1-2-1 Independently hydrogen or C1-C3 alkyl, wherein the C1-C3 alkyl group is optionally independently formed by one, two, three or four R atoms. 1-1-1-1 replace;

[0025] Each R 1-4-1 and R 1-1-1-1 It can be independently a halogen, hydroxyl, or cyano group;

[0026] R 2 and R 3 Independently hydrogen, halogen, cyano, hydroxyl, C1-C6 alkoxy, or NR 2-1 R 2-2 Or R 2 and R 3 The atoms attached to it form 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl;

[0027] R 2-1 and R 2-2 Independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl group is optionally independently formed by one, two, three or four R atoms. d Replace; or, R 2-1 and R 2-2 The atoms attached to it form 3- to 7-membered heterocyclic alkyl groups;

[0028] Each R dIt can be independently a halogen, cyano, hydroxyl, C1-C6 alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or C1-C3 alkyl;

[0029] R 4 R 5 and R 6 Independently hydrogen, halogen, cyano, hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, or NR 4-1 R 4-2 The C1-C6 alkyl group is optionally independently bound by one, two, three, or four R atoms. e replace;

[0030] Each R e Independently halogen, cyano, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, or -NR 4-4 R 4-5 ;

[0031] R 4-1 and R 4-2 Independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl group is optionally independently formed by one, two, three or four R atoms. f Replace; or, R 4-1 and R 4-2 The atoms attached to it form 3- to 7-membered heterocyclic alkyl groups;

[0032] Each R f Independently, it is a halogen, cyano, hydroxyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, C1-C3 alkyl, C1-C3 alkoxy, or -NR. 4-1-1 R 4-2-1 ;

[0033] R 4-4 and R 4-5 Independently hydrogen or C1-C3 alkyl; or R 4 and R 5 The atoms attached to it form 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl;

[0034] R 4-1-1 and R 4-2- Independently hydrogen or C1-C3 alkyl;

[0035] L is

[0036] t is a natural number between 0 and 3;

[0037] u is a natural number from 0 to 3;

[0038] E is a carbonyl group. -NHCO-, or chemical bonds;

[0039] F is a carbonyl group. -O-, -NH- or chemical bonds;

[0040] R 8 and R 9 Independently hydrogen, halogen, cyano, hydroxyl, or C1-C6 alkyl, wherein the C1-C6 alkyl group is optionally independently surrounded by one, two, three, or four R groups. g Replace; or R 8 and R 9 The atoms attached to it form 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl;

[0041] Each R g It can be independently a halogen, cyano, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxy group;

[0042] B is a 3-7 membered cycloalkyl, a 4-6 membered heterocycloalkyl, a 6-10 membered aryl, or a 5-12 membered heteroaryl; wherein the 3-7 membered cycloalkyl, 4-6 membered heterocycloalkyl, 6-10 membered aryl, and 5-12 membered heteroaryl are optionally independently bounded by one, two, or three Rs. i replace;

[0043] Each R i Independently, it is hydrogen, halogen, hydroxyl, C1-C3 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, cyano, -NR 11-1 R 11-2 -OR 11-3 or -SR 11-4 ; wherein the C1-C3 alkyl group is optionally independently bound by one, two, three or four R groups. i-1 Substitution, or, R on two of the same atom i It forms a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl with the atoms attached to it; or, two adjacent R atoms form a cycloalkyl or heterocycloalkyl or heterocycloalkyl or heterocycloalkyl. i The atoms attached thereto form 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl (wherein, the 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl forms a fused ring with B);

[0044] Each R i-1 It is independently a C1-C3 alkyl, halogen, cyano or hydroxyl group;

[0045] R 11-1 and R 11-2 Independently hydrogen, C1-C3 alkyl, 3- to 7-membered cycloalkyl, or 3- to 7-membered heterocycloalkyl; or, R 11-1 and R 11-2 The atoms connected to it form 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl;

[0046] R 11-3 and R 11-4It is independently a C1-C3 alkyl, a 3- to 7-membered cycloalkyl, or a 3- to 7-membered heterocycloalkyl;

[0047] R 11-1 R 11-2 R 11-3 and R 11-4 In this context, the C1-C3 alkyl, 3-7 membered cycloalkyl, and 3-7 membered heterocycloalkyl are optionally independently bound by one, two, or three R atoms. i-2 replace;

[0048] Each R i-2 It is independently a C1-C3 alkyl, a 3-7 membered cycloalkyl, a 3-7 membered heterocycloalkyl, a halogen, a cyano or a hydroxyl group;

[0049] D is hydrogen, halogen, cyano, hydroxyl, C1-C6 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, or 5-12 membered heteroaryl; wherein the C1-C6 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-12 membered heteroaryl are optionally independently surrounded by one, two, or three Rs. j replace;

[0050] Each R j Independently hydrogen, halogen, cyano, hydroxyl, C1-C3 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, -NR 12-1 R 12-2 -OR 12-3 or -SR 12-4 The C1-C3 alkyl, 3-7 membered cycloalkyl, and 3-7 membered heterocycloalkyl groups are optionally independently and independently associated with one, two, or three R groups. k replace;

[0051] R 12-1 R 12-2 R 12-3 and R 12-4 Independently, it is hydrogen, C1-C3 alkyl, 3-7 membered cycloalkyl, or 3-7 membered heterocycloalkyl; wherein, the C1-C3 alkyl, 3-7 membered cycloalkyl, and 3-7 membered heterocycloalkyl are optionally independently surrounded by one, two, or three R. k-1 Replace; or, R 12-1 With R 12-2 It forms 3- to 7-membered heterocyclic alkyl groups with the atoms attached to it;

[0052] Each R k It can be independently a halogen, cyano, hydroxyl, C1-C3 alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl;

[0053] Each R k-1It can be independently a halogen, cyano, hydroxyl, C1-C3 alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl;

[0054] When A is X1, X2, and X3 are CR 1 When the compound represented by Formula I satisfies any of the following conditions:

[0055] (1) E is -NHCO- or a chemical bond, and F is -O-, -NH- or a chemical bond.

[0056] (2) E is a carbonyl group, and F is -NH-.

[0057] (3) L is -(CH2)-, -(CH2)2-,

[0058] (4) When E or F is a carbonyl group, B is a 4-7 membered cycloalkyl group, a 6-10 membered aryl group, a 5-12 membered heteroaryl group, or is surrounded by 1, 2, or 3 R groups. i Substituted 4- to 6-membered heterocyclic alkyl groups, wherein the R atoms on the same atom are... i It forms a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl with the atoms attached to it; or, two adjacent R atoms form a cycloalkyl or heterocycloalkyl or heterocycloalkyl or heterocycloalkyl. i The atoms attached thereto form 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl (wherein, the 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl forms a fused ring with B); wherein the 4- to 7-membered cycloalkyl, 6- to 10-membered aryl and 5- to 12-membered heteroaryl groups are optionally independently bonded by one, two or three R atoms. i replace,

[0059] (5) for

[0060] When A is At that time, X1, X2, and X4 contain one or two heteroatoms;

[0061] When A is When L is a carbonyl group, u is a natural number from 1 to 3, and B is a 4- to 6-membered heterocyclic alkyl group, wherein the 4- to 6-membered heterocyclic alkyl group is optionally independently surrounded by one, two, or three R groups. i replace;

[0062] In the 3-7 membered heterocyclic alkyl, 4-6 membered heterocyclic alkyl and 5-12 membered heteroaryl groups, the heteroatom is one or more of N, O and S, and the number of heteroatoms is 1 to 5.

[0063] In one embodiment, certain groups in the compound represented by Formula I or its pharmaceutically acceptable salt have the following definitions, and the definitions of groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in one embodiment", "in some embodiments", "in one embodiment" or "in one preferred embodiment").

[0064] In one of the schemes,

[0065]

[0066] in, for

[0067] m is a natural number from 0 to 3;

[0068] n is a natural number from 0 to 3; m and n are not both 0;

[0069] k is a natural number between 0 and 3;

[0070] X1, X2, X3, X4, and X5 are independently -CR 1 -、N、O、S、 Or chemical bonds;

[0071] R N-1 It is hydrogen or C1-C6 alkyl, C1-C6 alkoxy or 3- to 7-membered cycloalkyl, wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally independently surrounded by 1, 2, 3 or 4 R. N-2 replace;

[0072] Each R N-2 Halogens are independent of each other;

[0073] Y and Z are independently carbonyl (CO) and - (CR) groups. 2 R 3 ) r - or chemical bond; r is a natural number from 0 to 5;

[0074] Each W can be independently carbonyl (CO), -O-, or -(CR) 4 R 5 )-、-NR 6 -or chemical bonds;

[0075] Each R 1 Independently hydrogen, halogen, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or -NR 1-1 R 1-2 The C1-C6 alkyl and C1-C6 alkoxy groups are optionally independently bounded by one, two, three, or four R groups. a Replace; or two Rs 1It forms 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl with the atoms attached to it;

[0076] Each R a Independently halogen, cyano, hydroxyl, C1-C3 alkyl, C1-C6 alkoxy, or -NR 1-4 R 1-5 Or, two Rs a And the atoms bonded to it form 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl; R 1-1 and R 1-2 Independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl group is optionally independently formed by one, two, three or four R atoms. b Replace; or, R 1-1 and R 1-2 The atoms attached to it form 3- to 7-membered heterocyclic alkyl groups;

[0077] Each R b Independently halogen, cyano, hydroxyl, C1-C6 alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, C1-C3 alkyl, and NR 1-1-1 R 1-2-1 In this context, the 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, and C1-C3 alkyl groups are optionally independently bound by one, two, three, or four R groups. b-1 replace;

[0078] Each R b-1 It can be independently a halogen, hydroxyl, or cyano group;

[0079] R 1-4 and R 1-5 Independently hydrogen or C1-C3 alkyl, wherein the C1-C3 alkyl group is optionally independently formed by one, two, three or four R atoms. 1-4-1 Replace; or, R 1-4 and R 1-5 The atoms attached to it form 3- to 7-membered heterocyclic alkyl groups;

[0080] R 1-1-1 and R 1-2-1 Independently hydrogen or C1-C3 alkyl, wherein the C1-C3 alkyl group is optionally independently formed by one, two, three or four R atoms. 1-1-1-1 replace;

[0081] Each R 1-4-1 and R 1-1-1-1 It can be independently a halogen, hydroxyl, or cyano group;

[0082] R 2 and R 3 Independently hydrogen, halogen, cyano, hydroxyl, C1-C6 alkoxy, or NR 2-1 R2-2 Or R 2 and R 3 The atoms attached to it form 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl;

[0083] R 2-1 and R 2-2 Independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl group is optionally independently formed by one, two, three or four R atoms. d Replace; or, R 2-1 and R 2-2 The atoms attached to it form 3- to 7-membered heterocyclic alkyl groups;

[0084] Each R d It can be independently a halogen, cyano, hydroxyl, C1-C6 alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or C1-C3 alkyl;

[0085] R 4 R 5 and R 6 Independently hydrogen, halogen, cyano, hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, or NR 4-1 R 4-2 The C1-C6 alkyl group is optionally independently bound by one, two, three, or four R atoms. e replace;

[0086] Each R e Independently halogen, cyano, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, or -NR 4-4 R 4-5 ;

[0087] R 4-1 and R 4-2 Independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl group is optionally independently formed by one, two, three or four R atoms. f Replace; or, R 4-1 and R 4-2 The atoms attached to it form 3- to 7-membered heterocyclic alkyl groups;

[0088] Each R f Independently, it is a halogen, cyano, hydroxyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, C1-C3 alkyl, C1-C3 alkoxy, or -NR. 4-1-1 R 4-2-1 ;

[0089] R 4-4 and R 4-5 Independently hydrogen or C1-C3 alkyl; or R 4 and R 5The atoms attached to it form 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl;

[0090] R 4-1-1 and R 4-2- Independently hydrogen or C1-C3 alkyl;

[0091] L is

[0092] t is a natural number between 0 and 3;

[0093] u is a natural number from 0 to 3;

[0094] E can be a carbonyl group, -NHCO-, or a chemical bond;

[0095] F can be a carbonyl group, -O-, -NH-, or a chemical bond;

[0096] R 8 and R 9 Independently hydrogen, halogen, cyano, hydroxyl, or C1-C6 alkyl, wherein the C1-C6 alkyl group is optionally independently surrounded by one, two, three, or four R groups. g Replace; or R 8 and R 9 The atoms attached to it form 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl;

[0097] Each R g It can be independently a halogen, cyano, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxy group;

[0098] B is a 3-7 membered cycloalkyl, a 4-6 membered heterocycloalkyl, a 6-10 membered aryl, or a 5-12 membered heteroaryl; wherein the 3-7 membered cycloalkyl, 4-6 membered heterocycloalkyl, 6-10 membered aryl, and 5-12 membered heteroaryl are optionally independently bounded by one, two, or three Rs. i replace;

[0099] Each R i Independently, it is hydrogen, halogen, hydroxyl, C1-C3 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, cyano, -NR 11-1 R 11-2 -OR 11-3 or -SR 11-4 ; wherein the C1-C3 alkyl group is optionally independently bound by one, two, three or four R groups. i-1 Substitution, or, R on two of the same atom i It forms a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl with the atoms attached to it; or, two adjacent R atoms form a cycloalkyl or heterocycloalkyl or heterocycloalkyl or heterocycloalkyl. i The atoms attached thereto form 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl (wherein, the 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl forms a fused ring with B);

[0100] Each R i-1 It is independently a C1-C3 alkyl, halogen, cyano or hydroxyl group;

[0101] R 11-1 and R 11-2 Independently hydrogen, C1-C3 alkyl, 3- to 7-membered cycloalkyl, or 3- to 7-membered heterocycloalkyl; or, R 11-1 and R 11-2 The atoms connected to it form 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl;

[0102] R 11-3 and R 11-4 It is independently a C1-C3 alkyl, a 3- to 7-membered cycloalkyl, or a 3- to 7-membered heterocycloalkyl;

[0103] R 11-1 R 11-2 R 11-3 and R 11-4 In this context, the C1-C3 alkyl, 3-7 membered cycloalkyl, and 3-7 membered heterocycloalkyl are optionally independently bound by one, two, or three R atoms. i-2 replace;

[0104] Each R i-2 It is independently a C1-C3 alkyl, a 3-7 membered cycloalkyl, a 3-7 membered heterocycloalkyl, a halogen, a cyano or a hydroxyl group;

[0105] D is hydrogen, halogen, cyano, hydroxyl, C1-C6 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, or 5-12 membered heteroaryl; wherein the C1-C6 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-12 membered heteroaryl are optionally independently surrounded by one, two, or three Rs. j replace;

[0106] Each R j Independently hydrogen, halogen, cyano, hydroxyl, C1-C3 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, -NR 12-1 R 12-2 -OR 12-3 or -SR 12-4 The C1-C3 alkyl, 3-7 membered cycloalkyl, and 3-7 membered heterocycloalkyl groups are optionally independently and independently associated with one, two, or three R groups. k replace;

[0107] R 12-1 R 12-2 R 12-3 and R 12-4Independently, it is hydrogen, C1-C3 alkyl, 3-7 membered cycloalkyl, or 3-7 membered heterocycloalkyl; wherein, the C1-C3 alkyl, 3-7 membered cycloalkyl, and 3-7 membered heterocycloalkyl are optionally independently surrounded by one, two, or three R. k-1 Replace; or, R 12-1 With R 12-2 It forms 3- to 7-membered heterocyclic alkyl groups with the atoms attached to it;

[0108] Each R k It can be independently a halogen, cyano, hydroxyl, C1-C3 alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl;

[0109] Each R k-1 It can be independently a halogen, cyano, hydroxyl, C1-C3 alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl;

[0110] When A is X1, X2, and X3 are CR 1 When the compound represented by Formula I satisfies any of the following conditions:

[0111] (1) E is -NHCO- or a chemical bond, and F is -O-, -NH- or a chemical bond.

[0112] (2) E is a carbonyl group, and F is -NH-.

[0113] (3) L is -(CH2)-, -(CH2)2-,

[0114] (4) When E or F is a carbonyl group, B is a 4-7 membered cycloalkyl group, a 6-10 membered aryl group, a 5-12 membered heteroaryl group, or is surrounded by 1, 2, or 3 R groups. i Substituted 4- to 6-membered heterocyclic alkyl groups, wherein the R atoms on the same atom are... i It forms a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl with the atoms attached to it; or, two adjacent R atoms form a cycloalkyl or heterocycloalkyl or heterocycloalkyl or heterocycloalkyl. i The atoms attached thereto form 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl (wherein, the 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl forms a fused ring with B); wherein the 4- to 7-membered cycloalkyl, 6- to 10-membered aryl and 5- to 12-membered heteroaryl groups are optionally independently bonded by one, two or three R atoms. i replace,

[0115] (5) for

[0116] When A is At that time, X1, X2, and X4 contain one or two heteroatoms;

[0117] When A is When L is a carbonyl group, u is a natural number from 1 to 3, and B is a 4- to 6-membered heterocyclic alkyl group, wherein the 4- to 6-membered heterocyclic alkyl group is optionally independently surrounded by one, two, or three R groups. i replace;

[0118] In the 3-7 membered heterocyclic alkyl, 4-6 membered heterocyclic alkyl, and 5-12 membered heteroaryl groups, the heteroatom is N, O, or S, and the number of heteroatoms is 1 to 5; or, in the 3-7 membered heterocyclic alkyl, 4-6 membered heterocyclic alkyl, and 5-12 membered heteroaryl groups, the heteroatom is one or more of N, O, and S, and the number of heteroatoms is 1 to 5.

[0119] In one scheme, m is preferably a natural number from 0 to 3, such as 0, 1, 2 or 3, or even 1, 2 or 3.

[0120] In a certain scheme, n is preferably a natural number from 1 to 3, such as 1, 2 or 3, or 1 or 2.

[0121] In one particular scheme, n is 1.

[0122] In a certain scheme, when X1 is N, X2, X3, and X4 are -CR 1 When -, Y and Z are independently -(CH2)-, m and n are 2, R j It is trifluoromethyl.

[0123] In one of the schemes, for

[0124] In one of the schemes, for

[0125] In one particular scheme, m is 1.

[0126] In a certain scheme, k is preferably a natural number from 0 to 3, such as 0, 1, 2 or 3, or 1, 2 or 3.

[0127] In a certain scheme, r is preferably a natural number from 0 to 5, such as 0, 1, 2, 3, 4 or 5, or 1 or 2.

[0128] In one particular scheme, r is 1.

[0129] In one scheme, r is a natural number between 0 and 3, such as 1 or 2.

[0130] In one of the schemes, R N-1 It is a C1-C6 alkyl group.

[0131] In one of the schemes, R N-1 It is hydrogen, C1-C6 alkyl, or 3-7 membered cycloalkyl.

[0132] In a certain scheme, each W is independently -(CR) 4 R 5 )-、-O-、-NR 6 - or chemical bonds.

[0133] In a certain scheme, each W is independently -(CR) 4 R 5 )-、-NR 6 - or chemical bonds.

[0134] In one scheme, Y and Z are independently carbonyl (CO) or -(CR) groups. 2 R 3 ) r -

[0135] In a certain scheme, Y and Z are independently -(CR) 2 R 3 ) r -

[0136] In a certain scheme, each R 1 Independently hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or -NR 1-1 R 1-2 .

[0137] In a certain scheme, each R 1 Independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio or -NR 1-1 R 1-2 .

[0138] In a certain scheme, each R 1 Independently, it is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, or -NR. 1-1 R 1-2 For example, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio or -NR 1-1 R 1-2 .

[0139] In a certain scheme, each R 1 Independently hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or -NR 1-1 R 1-2 The C1-C6 alkylthio group, C1-C6 alkyl group, and C1-C6 alkoxy group are optionally independently bounded by one, two, three, or four R groups. a replace.

[0140] In a certain scheme, each R 1 Independently hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or -NR 1-1 R 1-2 .

[0141] In a certain scheme, each R 1 It is independently a C1-C6 alkyl group.

[0142] In a certain scheme, each R 1 It is independently C1-C6 alkyl or C1-C6 alkoxy.

[0143] In one of the schemes, R 1-1 and R 1-2 Independently hydrogen or C1-C6 alkyl; or, R 1-1 and R 1-2 The atoms bonded to it form 3- to 7-membered heterocyclic alkyl groups; for example, R 1-1 and R 1-2 The atoms attached to it form 3- to 7-membered heterocyclic alkyl groups.

[0144] In a certain scheme, X1 and X3 are independently N; X4 and X2 are independently -CR 1 - At that time, each R 1 It is independently a C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, 3- to 7-membered heterocyclic alkyl or -NR 1-1 R 1-2 .

[0145] In a certain scheme, when X2 is independently -CR 1 - At that time, R 1 (X2) is a C1-C6 alkyl or C1-C6 alkoxy group.

[0146] In a certain scheme, when D is a pyrimidine group, each R 1 It can be halogenated or 3- to 7-membered cycloalkyl.

[0147] In a certain scheme, X2 and X3 are independently N; X4 and X1 are independently -CR 1 - At that time, each R 1 It is independently a C1-C6 alkyl or a 3- to 7-membered heterocyclic alkyl.

[0148] In a certain scheme, each R a Independently hydroxyl, C1-C3 alkoxy or NR 1-4 R 1-5 .

[0149] In a certain scheme, each R aIndependently halogen, hydroxyl, C1-C6 alkoxy or -NR 1-4 R 1-5 For example, each R a Independently hydroxyl, C1-C6 alkoxy or -NR 1-4 R 1-5 For example, hydroxyl groups.

[0150] In a certain scheme, each R b Independently hydroxyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, C1-C3 alkyl, C1-C3 alkoxy or NR 1-1-1 R 1-2-1 .

[0151] In a certain scheme, each R b Independently hydroxyl, 3- to 7-membered cycloalkyl, or C1-C3 alkyl, for example, each R b It can be independently a hydroxyl group or a 3- to 7-membered cycloalkyl group.

[0152] In a certain scheme, each R b It is independently a 3- to 7-membered cycloalkyl group.

[0153] In one of the schemes, R b-1 Independently, it is a hydroxyl group.

[0154] In a certain scheme, each R b-1 Independently, it is a hydroxyl group.

[0155] In a certain scheme, each R b-2 It is independently a halogen or a C1-C6 alkyl group.

[0156] In one of the schemes, R 1-4 and R 1-5 It is independently a C1-C3 alkyl group.

[0157] In a certain scheme, each R 1-4-1 Halogens are independent of each other.

[0158] In one of the schemes, R 1-4-1 It is a halogen.

[0159] In one of the schemes, R 2 and R 3 Independently hydrogen or NR 2-1 R 2-2 .

[0160] In one of the schemes, R 2 and R 3 It is hydrogen independently.

[0161] In one of the schemes, R 2-1 and R 2-2 It is independently hydrogen or C1-C6 alkyl, such as hydrogen.

[0162] In one of the schemes, R 4 R 5 and R 6 It is hydrogen independently.

[0163] In one of the schemes, R 4 R 5 and R 6 Independently hydrogen or NR 4-1 R 4-2 .

[0164] In one of the schemes, R 4-1 and R 4-2 It is hydrogen independently.

[0165] In one of the schemes, R e For -NR 4-4 R 4-5 .

[0166] In one of the schemes, R 4-4 and R 4-5 It is independently hydrogen or C1-C3 alkyl.

[0167] In one scheme, E is a carbonyl group, -NHCO- or chemical bonds.

[0168] In one scheme, E is a carbonyl group or a chemical bond.

[0169] In one particular scheme, E represents a carbonyl group.

[0170] In one particular scheme, t is 0.

[0171] In one scheme, F is -NH-, -O-, or a chemical bond.

[0172] In one scheme, F is a carbonyl group, -O-, -NH- or chemical bonds.

[0173] In one scheme, F represents a chemical bond.

[0174] In one of the schemes, R 8 and R 9 Independently hydrogen or C1-C6 alkyl; or R 8 and R 9 The atoms attached to it form 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl.

[0175] In one of the schemes, R 8 and R 9 Independently hydrogen or C1-C6 alkyl, or R 8 and R 9 The atoms attached to it form 3- to 7-membered cycloalkyl groups.

[0176] In one of the schemes, R 8 and R 9 Independently C1-C6 alkyl; or R 8 and R 9 The atoms attached to it form 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl.

[0177] In one embodiment, B is a 4-6 membered heterocyclic alkyl group, a 6-10 membered aryl group, or a 5-12 membered heterocyclic aryl group, wherein the 5-12 membered heterocyclic aryl group, the 6-10 membered aryl group, and the 4-6 membered heterocyclic alkyl group are optionally independently bounded by one, two, or three R groups. i replace.

[0178] In one embodiment, B is a 4- to 6-membered heterocyclic alkyl group or a 5- to 12-membered heteroaryl group, wherein the 5- to 12-membered heteroaryl group and the 4- to 6-membered heterocyclic alkyl group are optionally independently bound by one, two, or three R groups. i replace.

[0179] In one embodiment, B is a 4- to 6-membered heterocyclic alkyl group, wherein the 4- to 6-membered heterocyclic alkyl group is optionally independently bound by one, two, or three R groups. i replace;

[0180] In one embodiment, when B is a 6-10 aryl or a 5-12 heteroaryl, D is hydrogen, halogen, cyano, hydroxyl, C1-C6 alkyl, 3-7 cycloalkyl, or 3-7 heterocycloalkyl, wherein the C1-C6 alkyl, 3-7 cycloalkyl, or 3-7 heterocycloalkyl is optionally independently bound by one, two, or three R. j Substitution; preferably, D is hydrogen or C1-C6 alkyl.

[0181] In a certain scheme, X2 and X3 are independently N; X4 and X1 are independently -CR 1 - When B is an azahexacyclic butyl group (e.g. ).

[0182] In a certain scheme, when X1 and X3 (or X2 and X4) are -CR 1 -, R 1 When it is a C1-C6 alkyl group, each R j Independently for -OR 12 -3 or -SR 12-4 .

[0183] In one of the schemes, R i It is hydrogen, halogen, hydroxyl, or C1-C3 alkyl; or, two Rs i It forms 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl with the atoms attached to it.

[0184] In a certain scheme, each Ri Independently hydrogen, halogen, hydroxyl, or C1-C3 alkyl; or, two Rs i And the atoms attached thereto form 3- to 7-membered cycloalkyl groups, for example, R i It is hydrogen or a C1-C3 alkyl group, for example, a C1-C3 alkyl group. In one embodiment, R... i It is hydrogen.

[0185] In one embodiment, D is hydrogen, a C1-C6 alkyl group, or a 5- to 12-membered heteroaryl group; wherein the C1-C6 alkyl group and the 5- to 12-membered heteroaryl group are optionally independently bound by one, two, or three R groups. j replace.

[0186] In one embodiment, D is hydrogen, a 3- to 7-membered cycloalkyl group, a C1- to C6 alkyl group, or a 5- to 6-membered heteroaryl group, wherein the C1- to C6 alkyl group and the 5- to 6-membered heteroaryl group are optionally independently bound by one, two, or three R groups. j replace.

[0187] In one embodiment, D is a 5- to 12-membered heteroaryl group; wherein the 5- to 12-membered heteroaryl group is optionally and independently coupled to one, two, or three R groups. j replace.

[0188] In one embodiment, D is a 5-6 member heteroaryl group; wherein the 5-6 member heteroaryl group is optionally and independently coupled to one, two, or three R groups. j replace.

[0189] In a certain scheme, X2 and X3 are independently N; X4 and X1 are independently -CR 1 - When D is a 6-membered heteroaryl group (e.g. ); wherein the 6-membered heteroaryl group is optionally and independently constitutively bound by 1, 2 or 3 R groups. j replace.

[0190] In one embodiment, when D is a five-membered heteroaryl group, the five-membered heteroaryl group is... Each R 1 It is independently C1-C6 alkyl or C1-C6 alkoxy.

[0191] In one of the schemes, R j Halogen, C1-C3 alkyl, OR 12-3 or SR 12-4 .

[0192] In a certain scheme, each R j Independently C1-C3 alkyl, OR 12-3 or SR 12-4 The C1-C3 alkyl group is optionally independently and independently surrounded by one, two, or three R atoms. k Instead, preferably, each R jindependently for OR 12-3 or SR 12-4 .

[0193] In a certain scheme, each R j Independently halogen, C1-C3 alkyl, OR 12-3 or SR 12-4 .

[0194] In a certain scheme, each R j Independently hydrogen, halogen, C1-C3 alkyl, 3- to 7-membered cycloalkyl, -OR 12-3 or -SR 12-4 .

[0195] In a certain scheme, each R j Independently hydrogen, halogen, C1-C3 alkyl, 3- to 7-membered cycloalkyl, -OR 12-3 or -SR 12-4 The C1-C3 alkyl and 3-7 membered cycloalkyl groups are optionally and independently associated with one, two or three R groups. k replace.

[0196] In one of the schemes, R j OR 12-3 .

[0197] In a certain scheme, each R j independently for OR 12-3 .

[0198] In one of the schemes, R j It is a halogen or a C1-C3 alkyl group.

[0199] In a certain scheme, each R j It is independently a halogen or a C1-C3 alkyl group.

[0200] In a certain scheme, X1 and X3 are independently N; X4 and X2 are independently -CR 1 -, each R 1 When independently C1-C6 alkyl and C1-C6 alkoxy, each R j Independently halogenated, 3- to 7-membered cycloalkyl, OCH2CF 3、 or SR 12-4 .

[0201] In one of the schemes, when for At that time, each R j independently for OR 12-3 or SR 12-4 .

[0202] In a certain scheme, when X1 or X4 is -CR1 -, R 1 Independently 3- to 7-membered heterocyclic alkyl or -NR 1-1 R 1-2 At that time, each R j independently for OR 12-3 or SR 12-4 .

[0203] In one of the schemes, R 12-3 and R 12-4 It is independently a C1-C3 alkyl group.

[0204] In one of the schemes, R 12-3 and R 12-4 Independently C1-C3 alkyl; wherein the C1-C3 alkyl group is optionally independently bounded by one, two or three R groups. k-1 replace.

[0205] In one of the schemes, R 12-1 R 12-2 R 12-3 and R 12-4 It is independently a C1-C3 alkyl group.

[0206] In a certain scheme, each R k Halogens are independent of each other.

[0207] In one of the schemes, R k Halogens are independent of each other.

[0208] In a certain scheme, each R k-1 Halogens are independent of each other.

[0209] In one of the schemes, R k-1 Halogens are independent of each other.

[0210] In one embodiment, the heteroatoms in the 3-7 membered heterocyclic alkyl group, the 4-6 membered heterocyclic alkyl group, and the 5-12 membered heteroaryl group are N, O, or S, and the number of heteroatoms is 1 to 3.

[0211] In one embodiment, the heteroatoms in the 3-7 membered heterocyclic alkyl group, the 4-6 membered heterocyclic alkyl group, and the 5-12 membered heteroaryl group are N, O, or S, and the number of heteroatoms is 1 to 5.

[0212] In one embodiment, the heteroatoms in the 3-7 membered heterocyclic alkyl group, the 4-6 membered heterocyclic alkyl group, the 5-6 membered heteroaryl group, and the 5-12 membered heteroaryl group are N, O, or S, and the number of heteroatoms is 1 to 3.

[0213] In one embodiment, the heteroatoms in the 3-7 membered heterocyclic alkyl group, the 4-6 membered heterocyclic alkyl group, the 5-6 membered heteroaryl group, and the 5-12 membered heteroaryl group are selected from one, two, or three types of N, O, or S, and the number of heteroatoms is one, two, or three.

[0214] In one embodiment, the 3-7 membered heterocyclic alkyl group is a 3-6 membered heterocyclic alkyl group, and the heteroatom is, for example, one or two of N and O, and the number of heteroatoms is, for example, one or two.

[0215] In one embodiment, the 4-6 membered heterocyclic alkyl group is a 4-membered heterocyclic alkyl group, and the heteroatom is, for example, one or two of N and O, and the number of heteroatoms is, for example, one.

[0216] In one embodiment, the 5- to 6-membered heteroaryl group is a 6-membered heteroaryl group, and the heteroatom is, for example, one or two types of N and O, and the number of heteroatoms is, for example, one.

[0217] In one embodiment, the 5-12 membered heteroaryl group is a 5-10 membered heterocyclic alkyl group, and the heteroatom is, for example, one or two types of N and O, and the number of heteroatoms is, for example, one.

[0218] In a certain scheme, when A is X1, X2, and X3 are CR 1 In the compound represented by Formula I, E or F is...

[0219] In one of the schemes, R N-1 In this context, the C1-C6 alkyl group is preferably a C1-C3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, or methyl, ethyl or isopropyl.

[0220] In one of the schemes, R N-1 In this context, the C1-C6 alkoxy group is preferably a C1-C3 alkoxy group, such as methoxy, ethoxy, n-propoxy, or isopropoxy.

[0221] In one of the schemes, R N-1 In this context, the 3-7 membered cycloalkyl group is preferably a 3-6 membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane.

[0222] In one of the schemes, R N-2 In this context, the halogen is F, Cl, Br, or I, for example, F or Cl.

[0223] In one of the schemes, R 1 In this context, the halogen is F, Cl, Br, or I, for example, F or Cl, or Cl.

[0224] In one of the schemes, R 1 In this context, the C1-C6 alkyl group is preferably a C1-C3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, or methyl, ethyl or isopropyl.

[0225] In one of the schemes, R 1In this context, the C1-C6 alkoxy group is preferably a C1-C3 alkoxy group, such as methoxy, ethoxy, n-propoxy, or isopropoxy, or methoxy or ethoxy.

[0226] In one of the schemes, R 1 In this context, the C1-C6 alkylthio group is preferably a C1-C3 alkylthio group, such as methylthio, ethylthio, n-propylthio, or isopropylthio, or methylthio.

[0227] In one of the schemes, R 1 In this context, the 3-7 membered cycloalkyl group is preferably a 3-6 membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane, or cyclopropane or cyclobutane.

[0228] In one of the schemes, R 1 In this context, the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably one or two; the 3-6 membered heterocyclic alkyl group is more preferably a 4 membered heterocyclic alkyl group, for example...

[0229] In one of the schemes, R 1 In this context, the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably one or two; the 3-6 membered heterocyclic alkyl group is more preferably a 4 membered heterocyclic alkyl group, for example...

[0230] In one of the schemes, R a In this context, the halogen is preferably F, Cl, Br or I, such as F or Cl, or F.

[0231] In one of the schemes, R a In this context, the C1-C3 alkyl group is preferably methyl, ethyl, n-propyl, or isopropyl.

[0232] In one of the schemes, R a In this context, the C1-C6 alkoxy group is preferably a C1-C3 alkoxy group, such as methoxy, ethoxy, n-propoxy, or isopropoxy, or methoxy.

[0233] In one of the schemes, R a In this context, the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably one or two; the 3-6 membered heterocyclic alkyl group is more preferably a 4 membered heterocyclic alkyl group, for example...

[0234] In one of the schemes, R aIn this context, the 3-7 membered cycloalkyl group is preferably a 3-6 membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane.

[0235] In one of the schemes, R 1-1 and R 1-2 In this context, the C1-C6 alkyl group is preferably a C1-C3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, or methyl or ethyl (e.g., methyl).

[0236] In one of the schemes, R 1-1 and R 1-2 In this context, the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably 1 or 2; the 3-6 membered heterocyclic alkyl group is, for example, a 4 membered heterocyclic alkyl group, or...

[0237] In one of the schemes, R b In this context, the halogen is preferably F, Cl, Br, or I, for example, F or Cl.

[0238] In one of the schemes, R b In this context, the C1-C6 alkoxy group is preferably a C1-C3 alkoxy group, such as methoxy, ethoxy, n-propoxy, or isopropoxy.

[0239] In one of the schemes, R b In this context, the 3-7 membered cycloalkyl group is preferably a 3-6 membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane, or cyclopropane.

[0240] In one of the schemes, R b In this context, the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; and the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably one or two.

[0241] In one of the schemes, R b In this context, the C1-C3 alkyl group is preferably methyl, ethyl, n-propyl, or isopropyl, such as methyl.

[0242] In one of the schemes, R b-1 In this context, the halogen is preferably F, Cl, Br, or I, for example, F or Cl.

[0243] In one of the schemes, R b-2 In this context, the halogen is preferably F, Cl, Br, or I, for example, F.

[0244] In one of the schemes, R b-2 In this context, the C1-C6 alkyl group is preferably a C1-C3 alkyl group, such as methyl, ethyl, n-propyl, or isopropyl, or methyl (e.g., ethyl). ).

[0245] In one of the schemes, R 1-4 and R 1-5 In this context, the C1-C3 alkyl group is preferably methyl, ethyl, n-propyl, or isopropyl, such as methyl, ethyl, or n-propyl, or methyl.

[0246] In one of the schemes, R 1-4 and R 1-5 In this context, the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably one or two; the 3-6 membered heterocyclic alkyl group is more preferably a 4 membered heterocyclic alkyl group, for example...

[0247] In one of the schemes, R 1-1-1 and R 1-2-1 In this context, the C1-C3 alkyl group is preferably methyl, ethyl, n-propyl, or isopropyl.

[0248] In one of the schemes, R 1-4-1 and R 1-1-1-1 In this context, the halogen is preferably F, Cl, Br, or I, for example, F or Cl, or F.

[0249] In one of the schemes, R 2 and R 3 In this context, the halogen is preferably F, Cl, Br, or I, for example, F or Cl.

[0250] In one of the schemes, R 2 and R 3 In this context, the C1-C6 alkoxy group is preferably a C1-C3 alkoxy group, such as methoxy, ethoxy, n-propoxy, or isopropoxy.

[0251] In one of the schemes, R 2 and R 3 In this context, the 3-7 membered cycloalkyl group is preferably a 3-6 membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane.

[0252] In one of the schemes, R 2 and R 3 In this context, the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; and the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably one or two.

[0253] In one of the schemes, R 2-1 and R 2-2 In this context, the C1-C6 alkyl group is preferably a C1-C3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, or methyl or ethyl.

[0254] In one of the schemes, R 2-1 With R 2-2 In this context, the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; and the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably one or two.

[0255] In one of the schemes, R d In this context, the halogen is preferably F, Cl, Br, or I, for example, F or Cl.

[0256] In one of the schemes, R d In this context, the C1-C6 alkoxy group is preferably a C1-C3 alkoxy group, such as methoxy, ethoxy, n-propoxy, or isopropoxy.

[0257] In one of the schemes, R d In this context, the 3-7 membered cycloalkyl group is preferably a 3-6 membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane.

[0258] In one of the schemes, R d In this context, the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom of the 3-7 membered heterocyclic alkyl group is preferably N or O, and the number of heteroatoms of the 3-6 membered heterocyclic alkyl group is preferably 1 or 2.

[0259] In one of the schemes, R d In this context, the C1-C3 alkyl group is preferably methyl, ethyl, n-propyl, or isopropyl.

[0260] In one of the schemes, R 4 R 5 and R 6 In this context, the halogen is preferably F, Cl, Br, or I, for example, F or Cl.

[0261] In one of the schemes, R 4 R 5 and R 6 In this context, the C1-C6 alkoxy group is preferably a C1-C3 alkoxy group, such as methoxy, ethoxy, n-propoxy, or isopropoxy.

[0262] In one of the schemes, R 4 R 5 and R 6 In this context, the C1-C6 alkyl group is preferably a C1-C3 alkyl group, such as methyl, ethyl, n-propyl, or isopropyl.

[0263] In one of the schemes, R e In this context, the halogen is preferably F, Cl, Br, or I, for example, F or Cl.

[0264] In one of the schemes, R e In this context, the C1-C3 alkyl group is preferably methyl, ethyl, n-propyl, or isopropyl.

[0265] In one of the schemes, R e In this context, the C1-C3 alkoxy group is preferably methoxy, ethoxy, n-propoxy, or isopropoxy.

[0266] In one of the schemes, R 4-1 and R 4-2 In this context, the C1-C6 alkyl group is preferably a C1-C3 alkyl group, such as methyl, ethyl, n-propyl, or isopropyl.

[0267] In one of the schemes, R 4-1 With R 4-2 In this context, the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; and the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably one or two.

[0268] In one of the schemes, R f In this context, the halogen is preferably F, Cl, Br, or I, for example, F or Cl.

[0269] In one of the schemes, R f In this context, the 3-7 membered cycloalkyl group is preferably a 3-6 membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane.

[0270] In one of the schemes, R f In this context, the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; and the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably one or two.

[0271] In one of the schemes, R f In this context, the C1-C3 alkyl group is preferably methyl, ethyl, n-propyl, or isopropyl.

[0272] In one of the schemes, R f In this context, the C1-C3 alkoxy group is preferably methoxy, ethoxy, n-propoxy, or isopropoxy.

[0273] In one of the schemes, R 4-4 and R 4-5 In this context, the C1-C3 alkyl group is preferably methyl, ethyl, n-propyl, or isopropyl.

[0274] In a certain scheme, t is a natural number from 0 to 3, for example, 0, 1, 2 or 3, or 0, 1 or 2, for example, 0.

[0275] In one scheme, u is a natural number from 0 to 3, such as 0, 1, 2 or 3, or 0, 1 or 2, such as 1.

[0276] In one of the schemes, R 8 and R 9 In this context, the halogen is preferably F, Cl, Br, or I, for example, F or Cl.

[0277] In one of the schemes, R 8 and R 9 In this context, the C1-C6 alkyl group is preferably a C1-C3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, or methyl.

[0278] In one of the schemes, R 8 and R 9 In this context, the 3-7 membered cycloalkyl group is preferably a 3-6 membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane, or cyclopropane.

[0279] In one of the schemes, R 8 and R 9 In this context, the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably 1 or 2, and the 3-6 membered heterocyclic alkyl group is, for example, a 4 membered heterocyclic alkyl group, or oxobutane.

[0280] In one of the schemes, R g In this context, the halogen is preferably F, Cl, Br, or I, for example, F or Cl.

[0281] In one of the schemes, R g In this context, the C1-C3 alkyl group is preferably methyl, ethyl, n-propyl, or isopropyl, such as methyl.

[0282] In one of the schemes, R g In this context, the C1-C3 alkoxy group is preferably methoxy, ethoxy, n-propoxy, or isopropoxy.

[0283] In one embodiment, in B, the 3-7 membered cycloalkyl group is preferably a 3-6 membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane.

[0284] In one embodiment, in B, the 4-7 membered cycloalkyl group is preferably a 3-6 membered cycloalkyl group, such as cyclobutyl or cyclopentyl.

[0285] In one embodiment, in B, the 4- to 6-membered heterocyclic alkyl group is preferably a 4-membered, 5-membered, or 6-membered heterocyclic alkyl group; the heteroatom in the 4-, 5-, and 6-membered heterocyclic alkyl group is preferably N; the number of heteroatoms in the 4- to 6-membered heterocyclic alkyl group is preferably one or two, for example, the 4- to 6-membered heterocyclic alkyl group is a 4-membered nitrogen-containing heterocyclic alkyl group (e.g., ) or 5-membered nitrogen-containing heterocyclic alkyl groups (e.g. ).

[0286] In one embodiment, in B, the 6-10 aryl group is preferably phenyl or naphthyl, for example, phenyl.

[0287] In one of the schemes, R i In this context, the halogen is preferably F, Cl, Br, or I, for example, F or Cl, or F.

[0288] In one of the schemes, R i In this context, the C1-C3 alkyl group is preferably methyl, ethyl, n-propyl, or isopropyl, and for example, methyl.

[0289] In one of the schemes, R i In this context, the 3-7 membered cycloalkyl group is preferably a 3-6 membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane, or cyclopropane or cyclobutane, for example, cyclopropane.

[0290] In one of the schemes, R i In this context, the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; and the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably one or two.

[0291] In one of the schemes, R i-1 In this context, the halogen is preferably F, Cl, Br, or I, for example, F or Cl.

[0292] In one of the schemes, R i-1 In this context, the C1-C3 alkyl group is preferably methyl, ethyl, n-propyl, or isopropyl.

[0293] In one of the schemes, R 11-1 R 11-2 R 11-3 and R 11-4 In this context, the C1-C3 alkyl group is, for example, methyl, ethyl, n-propyl, or isopropyl.

[0294] In one of the schemes, R 11-3 and R 11-4 In this context, the 3- to 7-membered cycloalkyl group can be a 3- to 6-membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane.

[0295] In one of the schemes, R 11-3 and R 11-4 In this context, the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; and the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably one or two.

[0296] In one of the schemes, R 11-1 and R 11-2In this context, the 3-7 membered cycloalkyl group is preferably a 3-6 membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane.

[0297] In one of the schemes, R 11-1 and R 11-2 In this context, the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; and the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably one or two.

[0298] In one of the schemes, R i-2 In this context, the halogen is preferably F, Cl, Br, or I, for example, F or Cl.

[0299] In one of the schemes, R i-2 In this context, the C1-C3 alkyl group is preferably methyl, ethyl, n-propyl, or isopropyl.

[0300] In one of the schemes, R i-2 In this context, the 3-7 membered cycloalkyl group is preferably a 3-6 membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane.

[0301] In one of the schemes, R i-2 In this context, the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; and the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably one or two.

[0302] In one embodiment, in D, the halogen is preferably F, Cl, Br, or I, for example, F or Cl.

[0303] In one embodiment, in D, the C1-C6 alkyl group is preferably a C1-C3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, or methyl.

[0304] In one embodiment, in D, the 3-7 membered cycloalkyl group is preferably a 3-6 membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane, such as cyclopropane.

[0305] In one embodiment, in D, the 6- to 10 aryl groups are phenyl or naphthyl.

[0306] In one of the schemes, R j In this context, the halogen is preferably F, Cl, Br, or I, such as F or Cl, or F.

[0307] In one of the schemes, R j In this context, the C1-C3 alkyl group is preferably methyl, ethyl, n-propyl, or isopropyl, such as methyl, ethyl, or isopropyl, with methyl being the most preferred.

[0308] In one of the schemes, R jIn this context, the 3-7 membered cycloalkyl group is preferably a 3-6 membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane, or cyclopropane.

[0309] In one of the schemes, R j In this context, the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; and the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably one or two.

[0310] In one of the schemes, R 12-1 R 12-2 R 12-3 and R 12-4 In this context, the C1-C3 alkyl group is preferably methyl, ethyl, n-propyl, or isopropyl, such as methyl or ethyl, or methyl, ethyl, or isopropyl.

[0311] In one of the schemes, R 12-1 R 12-2 R 12-3 and R 12-4 In this context, the 3-7 membered cycloalkyl group is preferably a 3-6 membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane.

[0312] In one of the schemes, R 12-1 R 12-2 R 12-3 and R 12-4 In this context, the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; and the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably one or two.

[0313] In one of the schemes, R k In this context, the halogen is preferably F, Cl, Br, or I, such as F or Cl, or F.

[0314] In one of the schemes, R k In this context, the C1-C3 alkyl group is preferably methyl, ethyl, n-propyl, or isopropyl.

[0315] In one of the schemes, R k In this context, the 3-7 membered cycloalkyl group is preferably a 3-6 membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane.

[0316] In one of the schemes, R k In this context, the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; and the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably one or two.

[0317] In one of the schemes, R k-1In this context, the halogen is preferably F, Cl, Br, or I, such as F or Cl, or F.

[0318] In one of the schemes, R k-1 In this context, the C1-C3 alkyl group is preferably methyl, ethyl, n-propyl, or isopropyl, such as methyl.

[0319] In one of the schemes, R k-1 In this context, the 3-7 membered cycloalkyl group is preferably a 3-6 membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane.

[0320] In one of the schemes, R k-1 In this context, the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; and the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably one or two.

[0321] In some embodiments, the compound represented by Formula I is the compound represented by Formula I-1, Formula I-2, Formula I-3, Formula I-4, or Formula I-5;

[0322]

[0323]

[0324] Where X6 is N or CH, X1, R i ,X2,X3,X4,X5,Y,Z,m,n,E,R j R 1 B, D, W, k, F, u, R 8 and R 9 As described in any one of the present invention.

[0325] In some embodiments, the compound represented by Formula I-1 is the compound represented by Formula I-1-1, the compound represented by Formula I-1-2, the compound represented by Formula I-1-3, or the compound represented by Formula I-1-4;

[0326]

[0327] Among them, R 1 R j Z, n, X6, X2 and X4 are as described in any one of the present invention.

[0328] In some embodiments, the compound represented by Formula I-5 is the compound represented by Formula I-5-1;

[0329]

[0330] Among them, R 1 R8 R 9 and R j As described in any one of the present invention.

[0331] In some embodiments, the compound represented by Formula I-4 is the compound represented by Formula I-4-1;

[0332]

[0333] Wherein, B is as described in any one of the present invention.

[0334] In a certain scheme, X1, X2, X3, X4, and X5 are independently -CR 1 -、N、O、S、 Or chemical bonds, and the number of heteroatoms in X1, X2, X3, X4 and X5 is 0, 1, 2 or 3.

[0335] In a certain scheme, X1, X2, X3, X4, and X5 are independently -CR 1 -、N、S、 Or chemical bonds, and the number of heteroatoms in X1, X2, X3, X4 and X5 is 1 or 2.

[0336] In one scheme, X1 and X3 are independently N; X4 and X2 are independently -CR 1 -

[0337] In one scheme, X2 and X3 are independently N; X4 and X1 are independently -CR 1 -

[0338] In one scheme, X1 and X4 are independently N; X2 and X3 are independently -CR 1 -

[0339] In some of the proposals, In this context, X1, X2, X3, and X4 are independently -CR 1 - or N; the number of heteroatoms is 0, 1 or 2.

[0340] In some of the proposals, In this context, Y and Z are independently carbonyl (CO) or - (CR) groups. 2 R 3 ) r -; r is 1, R 2 and R 3 Independently H, -(CH2)-, -(NHCH2)-, -(NHCH2CH2)- or

[0341] In some of the proposals, In the equation, m is 2, n is 2, and Y and Z are independently -(CR). 2R 3 ) r -; r is 1, R 2 and R 3 H stands for H independently.

[0342] In some of the proposals, It is a phenyl-5-membered heterocyclic alkyl group, wherein the heteroatom in the 5-membered heterocyclic alkyl group is N, and the number of heteroatoms is 1, for example... e can be 1, 2, or 3 independently, for example...

[0343] In some of the proposals, It is a phenyl-5-membered heterocyclic alkyl group, wherein the heteroatom in the 5-membered heterocyclic alkyl group is N, and the number of heteroatoms is 1, for example...

[0344] In some of the proposals, It is a phenyl-7-membered heterocyclic alkyl group, wherein the heteroatom in the 7-membered heterocyclic alkyl group is N, and the number of heteroatoms is 1 or 2, for example... e can be 0, 1, 2, or 3 independently, for example...

[0345] In some of the proposals, It is a phenyl-7-membered heterocyclic alkyl group, wherein the heteroatom in the 7-membered heterocyclic alkyl group is N, and the number of heteroatoms is 1 or 2, for example...

[0346] In some of the proposals, It is a 6-membered heteroaryl and 5-membered heterocyclic alkyl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 1 or 2. Preferably, the heteroatom in the 5-membered heterocyclic alkyl group is N, and the number of heteroatoms is 1. For example...

[0347] e can be 0, 1, or 2 independently, for example...

[0348] In some of the proposals, It is a 6-membered heteroaryl and 5-membered heterocyclic alkyl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 1 or 2. Preferably, the heteroatom in the 5-membered heterocyclic alkyl group is N, and the number of heteroatoms is 1. For example...

[0349]

[0350] In some of the proposals, It is a 6-membered heteroaryl and 5-membered heterocyclic alkyl group, wherein the heteroatom in the 6-membered heteroaryl group is N and the number of heteroatoms is 2; preferably, the heteroatom in the 5-membered heterocyclic alkyl group is N and the number of heteroatoms is 1. For example... e can be 0, 1, or 2 independently.

[0351] In some of the proposals, It is a 6-membered heteroaryl-5-heterocyclic alkyl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 1, for example... e can be 0, 1, 2, or 3 independently, for example...

[0352] In some of the proposals, It is a 6-membered heteroaryl-5-heterocyclic alkyl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 1, for example...

[0353] In some of the proposals, It is a 6-membered heteroaryl-6-membered heterocyclic alkyl group, wherein the heteroatom in the 6-membered heteroaryl group is N and the number of heteroatoms is 1. Preferably, the heteroatom in the 6-membered heterocyclic alkyl group is N and the number of heteroatoms is 1. For example... e can be 0, 1, 2, or 3 independently, for example...

[0354] In some of the proposals, It is a 6-membered heteroaryl-6-membered heterocyclic alkyl group, wherein the heteroatom in the 6-membered heteroaryl group is N and the number of heteroatoms is 1. Preferably, the heteroatom in the 6-membered heterocyclic alkyl group is N and the number of heteroatoms is 1. For example...

[0355] In some of the proposals, It is a 6-membered heteroaryl and 7-membered heterocyclic alkyl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 1 or 2. Preferably, the heteroatom in the 7-membered heterocyclic alkyl group is N, and the number of heteroatoms is 1. For example... e can be 0, 1, 2, or 3 independently.

[0356] In some of the proposals, It is a 6-membered heteroaryl and 7-membered heterocyclic alkyl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 1 or 2. Preferably, the heteroatom in the 7-membered heterocyclic alkyl group is N, and the number of heteroatoms is 1. For example...

[0357]

[0358] In some of the proposals, It is a 5-membered heteroaryl alkyl group, wherein the heteroatom in the 5-membered heteroaryl group is N or S, and the number of heteroatoms is 1 or 2. Preferably, the heteroatom in the 5-membered heterocyclic alkyl group is N, and the number of heteroatoms is 1. For example...

[0359]

[0360] In some of the proposals, It is a 5-membered heteroaryl alkyl group, wherein the heteroatom in the 5-membered heteroaryl group is N and / or S, and the number of heteroatoms is 1 or 2. Preferably, the heteroatom in the 5-membered heterocyclic alkyl group is N, and the number of heteroatoms is 1. For example...

[0361] In some of the proposals, It is a 5-membered heteroaryl and 6-membered heterocyclic alkyl group, wherein the heteroatom in the 5-membered heteroaryl group is N, and the number of heteroatoms is 1 or 2. Preferably, the heteroatom in the 6-membered heterocyclic alkyl group is N, and the number of heteroatoms is 1. For example... For example

[0362] In some of the proposals, It is a 5-membered heteroaryl and 6-membered heterocyclic alkyl group, wherein the heteroatom in the 5-membered heteroaryl group is N and the number of heteroatoms is 1. Preferably, the heteroatom in the 6-membered heterocyclic alkyl group is N and the number of heteroatoms is 1. For example... For example

[0363] In some of the proposals, It is a 5-membered heteroaryl and 6-membered heterocyclic alkyl group, wherein the heteroatom in the 5-membered heteroaryl group is N and the number of heteroatoms is 1. Preferably, the heteroatom in the 6-membered heterocyclic alkyl group is N and the number of heteroatoms is 1. For example...

[0364] In some of the proposals, In this context, X1, X2, X3, X4, and X5 are independently -CR 1 -、N、S、 Or chemical bonds, and the number of heteroatoms in X1, X2, X3, X4 and X5 is 0, 1 or 2.

[0365] In some of the proposals, For C-(W) k -, where C is C is a 5-membered heteroaryl, a 6-membered heteroaryl, or a phenyl group; preferably, the heteroatom in the 5-membered heteroaryl group is N, and the number of heteroatoms is 1 or 2, or the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 1, for example, C is pyridyl, phenyl, or...

[0366] In some of the proposals, In this context, W represents -O-, -CH2-, or -NH-.

[0367] In some embodiments, in B, the 5-12-membered heteroaryl group is preferably a 5-6-membered heteroaryl group, a phenyl-5-6-membered heteroaryl group, a 5-7-membered cycloalkyl-phenyl group, a 5-7-membered cycloalkyl-5-6-membered heteroaryl group, a 5-6-membered heteroaryl-5-6-membered heteroaryl group, a 5-7-membered heterocycloalkyl-5-6-membered heteroaryl group, or a 5-7-membered heterocycloalkyl-5-6-membered aryl group; more preferably a 5-6-membered heteroaryl group, a phenyl-5-6-membered heteroaryl group, a 5-6-membered heteroaryl-5-6-membered heteroaryl group, a 5-7-membered heterocycloalkyl-5-6-membered heteroaryl group, or a 5-7-membered heterocycloalkyl-phenyl group.

[0368] In some schemes, specifically in scheme B, the heteroatom in the 4-6 membered heterocyclic alkyl group is N, and the number of heteroatoms is 1. For example... e can be 0, 1, 2, or 3 independently, for example...

[0369] In some schemes, specifically in scheme B, the heteroatom in the 4-6 membered heterocyclic alkyl group is N, and the number of heteroatoms is 1. For example...

[0370] In some schemes, B is the result of two Rs. i Substituted 4- to 6-membered heterocyclic alkyl groups, with R on two identical atoms i The atoms bonded to it form a 3- to 7-membered cycloalkyl group, preferably a 3- to 6-membered cycloalkyl group, for example, B is a 4- or 5-membered heterocycloalkyl group, and the two Rs i Forming 3- to 4-membered cycloalkyl groups, such as B.

[0371] In some schemes, B is the result of two Rs. i Substituted 4- to 6-membered heterocyclic alkyl groups, with R on two identical atoms i The atoms bonded to it form a 3- to 7-membered cycloalkyl group, preferably a 3- to 6-membered cycloalkyl group, for example, B is a 4-membered heterocycloalkyl group, and the two Rs form a 3- to 7-membered cycloalkyl group. i Forming 3- to 4-membered cycloalkyl groups, such as B.

[0372] In some schemes, B is the result of two Rs. i Substituted 4- to 6-membered heterocyclic alkyl groups, with R on two identical atoms i The atoms bonded to it form a 3- to 7-membered cycloalkyl group, preferably a 3- to 6-membered cycloalkyl group, for example, B is a 5-membered heterocycloalkyl group, and the two Rs i Forming 3- to 4-membered cycloalkyl groups, such as B.

[0373] In some schemes, B is the result of two Rs. i Ortho-substituted 4- to 6-membered heterocyclic alkyl groups, with two adjacent R groups. i The atoms bonded to it form a 3- to 7-membered cycloalkyl group (wherein, the 3- to 7-membered cycloalkyl group forms a fused ring with B), wherein the 3- to 7-membered cycloalkyl group is preferably a 3- to 6-membered cycloalkyl group, for example, B is a 5-membered heterocyclic alkyl group, and the two R groups form a fused ring. i The atoms bonded to it form a 3-membered cycloalkyl group, such as B.

[0374] In some schemes, B is a 5-membered heteroaryl group, wherein the heteroatom in the 5-membered heteroaryl group is N and / or S, and the number of heteroatoms is 1 or 2, for example...

[0375] In some schemes, B is a 5-membered heteroaryl group, wherein the heteroatom in the 5-membered heteroaryl group is N or S, and the number of heteroatoms is 1 or 2, for example...

[0376] In some schemes, B is a 6-membered heteroaryl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 1 or 2, for example...

[0377] In some schemes, B, the 6-10 aryl group is, for example, phenyl.

[0378] In some schemes, B is a phenyl-5-membered heterocyclic alkyl group, wherein the heteroatom in the 5-membered heterocyclic alkyl group is N, and the number of heteroatoms is 1, for example... e can be 0, 1, 2, or 3 independently, for example...

[0379] In some schemes, B is a phenyl-5-membered heterocyclic alkyl group, wherein the heteroatom in the 5-membered heterocyclic alkyl group is N, and the number of heteroatoms is 1, for example...

[0380] In some schemes, B is a phenyl-6-membered heteroaryl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 1 or 2, for example...

[0381] In some schemes, B is a phenyl-6-membered heterocyclic alkyl group, wherein the heteroatom in the 6-membered heterocyclic alkyl group is N and / or O, and the number of heteroatoms is 1 or 2, for example...

[0382] In some schemes, B is a phenyl-6-membered heterocyclic alkyl group, wherein the heteroatom in the 6-membered heterocyclic alkyl group is N or O, and the number of heteroatoms is 1 or 2, for example...

[0383] In some schemes, B is a 6-membered heteroaryl and a 5-membered heteroaryl, wherein the heteroatom in the 6-membered heteroaryl is N, and the number of heteroatoms is 1. Preferably, the heteroatom in the 5-membered heteroaryl is N or S, and the number of heteroatoms is 1.

[0384] In some schemes, B is a 6-membered heteroaryl-6-membered heterocyclic alkyl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 1. Preferably, the heteroatom in the 6-membered heterocyclic alkyl group is O, and the number of heteroatoms is 1. For example...

[0385] In some embodiments, in D, the 5-12-membered heteroaryl group is preferably a 5-6-membered heteroaryl group, a phenyl-5-6-membered heteroaryl group, a 5-7-membered cycloalkyl-phenyl group, a 5-7-membered cycloalkyl-5-6-membered heteroaryl group, a 5-6-membered heteroaryl-5-6-membered heteroaryl group, a 5-7-membered heterocycloalkyl-5-6-membered heteroaryl group, or a 5-7-membered heterocycloalkyl-5-6-membered aryl group; more preferably a 5-6-membered heteroaryl group, a phenyl-5-6-membered heteroaryl group, a 5-7-membered cycloalkyl-5-6-membered heteroaryl group, a 5-6-membered heteroaryl-5-6-membered heteroaryl group, a 5-7-membered heterocycloalkyl-5-6-membered heteroaryl group, or a 5-7-membered heterocycloalkyl-phenyl group.

[0386] In some schemes, in D, the 5-12 membered heteroaryl group is a 5-6 membered heteroaryl group, a phenyl-5-6 membered heteroaryl group, a 5-7 membered cycloalkyl-5-6 membered heteroaryl group, a 5-6 membered heteroaryl-5-6 membered heteroaryl group, a 5-7 membered heterocycloalkyl-5-6 membered heteroaryl group, or a 5-7 membered heterocycloalkyl-phenyl group. In the 5-6 membered heteroaryl group and the 5-7 membered heterocycloalkyl group, the heteroatom is preferably selected from one, two, or three of N, O, and S, and the number of heteroatoms is preferably one, two, or three.

[0387] In some schemes, in D, the 5- to 6-membered heteroaryl group is preferably a 5-membered heteroaryl group or a 6-membered heteroaryl group.

[0388] In some schemes, D is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, or trifluoromethyl.

[0389] In some schemes, D is a 6-membered heteroaryl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 1 or 2, for example... e can be 0, 1, 2, or 3 independently, for example...

[0390] In some schemes, D is a 6-membered heteroaryl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 1 or 2, for example...

[0391] In some schemes, D is a 5-membered heteroaryl group, wherein the heteroatom in the 5-membered heteroaryl group is one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3, for example...

[0392] In some schemes, D is a 5-membered heteroaryl group, wherein the heteroatom in the 5-membered heteroaryl group is N and / or S, and the number of heteroatoms is 1, 2, or 3, for example...

[0393] In some schemes, D is a 5-membered heteroaryl group, wherein the heteroatom in the 5-membered heteroaryl group is N or S, and the number of heteroatoms is 1, 2, or 3, for example...

[0394] In some schemes, D is a 6-membered heteroaryl and a 5-membered heterocyclic alkyl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 1. Preferably, the heteroatom in the 5-membered heterocyclic alkyl group is N or O, and the number of heteroatoms is 1. For example... e can be 0, 1, 2, or 3 independently, for example...

[0395] In some schemes, D is a 6-membered heteroaryl and a 5-membered heterocyclic alkyl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 1. Preferably, the heteroatom in the 5-membered heterocyclic alkyl group is N or O, and the number of heteroatoms is 1. For example...

[0396] In some schemes, D is a 6-membered heteroaryl and 5-membered cycloalkyl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 1, for example... e can be 0, 1, 2, or 3 independently, for example...

[0397] In some schemes, D is a 6-membered heteroaryl and 5-membered cycloalkyl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 1, for example...

[0398] In some schemes, D is a phenyl-5-membered heteroaryl group, wherein the heteroatom in the 5-membered heteroaryl group is N and / or S, and the number of heteroatoms is 2, for example... e can be 0, 1, 2, or 3 independently, for example...

[0399] In some schemes, D is a 5-6 membered heteroaryl and a 5-6 membered heteroaryl, wherein the heteroatom in the 5-6 membered heteroaryl is N and / or S, and the number of heteroatoms is 1, 2 or 3, for example e can be 0, 1, 2, or 3 independently.

[0400] In some schemes, D is a 5-6 membered heteroaryl alkyl group, wherein the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1, 2, or 3. Preferably, the heteroatom in the 5-6 membered heterocyclic alkyl group is O, and the number of heteroatoms is 1, 2, or 3. For example... e can be 0, 1, 2, or 3 independently.

[0401] In some schemes, D is a phenyl-5-6 membered heterocyclic alkyl group, wherein the heteroatom in the 5-6 membered heterocyclic alkyl group is one or more of O, N, and O, and the heteroatom is one, two, or three, for example... e can be 0, 1, 2, or 3 independently.

[0402] In some schemes, D is a phenyl-5-6-membered heteroaryl group, wherein the heteroatom in the 5-6-membered heteroaryl group is N, and the number of heteroatoms is 1, 2, or 3, for example... e can be 0, 1, 2, or 3 independently.

[0403] In one implementation plan, Preferably, it is a 6-membered heteroaryl-5-membered heterocycloalkyl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 2, for example... e can be 0, 1, or 2 independently, for example...

[0404] In one implementation plan, Preferably, it is a 6-membered heteroaryl-5-membered heterocycloalkyl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 2, for example...

[0405] In one implementation plan, Preferably, it is a 6-membered heteroaryl-7-membered heterocycloalkyl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 1 or 2, for example...

[0406] In one embodiment, in L, E is preferably a carbonyl group, F is a chemical bond, t is 0, and u is 1.

[0407] In one embodiment, B is preferably a 4-membered heterocyclic alkyl group, wherein the heteroatom in the 4-membered heterocyclic alkyl group is N, and the number of heteroatoms is 1 or 2, for example...

[0408] In one embodiment, D is preferably a 6-membered heteroaryl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 1 or 2, for example...

[0409] In a preferred embodiment, the compound represented by Formula I or a pharmaceutically acceptable salt thereof,

[0410]

[0411] in, for

[0412] m is a natural number from 0 to 3;

[0413] n is a natural number from 0 to 3; m and n are not both 0;

[0414] k is a natural number between 0 and 3;

[0415] X1, X2, X3, X4, and X5 are independently -CR 1 -、N、S、 Or chemical bonds;

[0416] R N-1 It is hydrogen, C1-C6 alkyl or 3-7 membered cycloalkyl;

[0417] Y and Z are independently carbonyl (CO) or - (CR) groups. 2 R 3 ) r -; r is a natural number from 0 to 5;

[0418] Each W is independently -O-, -(CR) 4 R 5 )-、-NR 6 -or chemical bonds;

[0419] Each R 1 Independently hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or -NR 1-1 R 1-2 The C1-C6 alkylthio group, C1-C6 alkyl group, and C1-C6 alkoxy group are optionally independently bounded by one, two, three, or four R groups. a replace;

[0420] Each R a Independently halogen, hydroxyl, C1-C6 alkoxy or -NR 1-4 R 1-5 ;

[0421] R 1-1 and R 1-2 Independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl group is optionally independently formed by one, two, three or four R atoms. b Replace; or, R 1-1 and R 1-2The atoms bonded to it form 3- to 7-membered heterocyclic alkyl groups, wherein the 3- to 7-membered heterocyclic alkyl groups are arbitrarily bound by 1, 2, 3, or 4 R atoms. b-2 replace;

[0422] Each R b It can be independently a hydroxyl group, a 3- to 7-membered cycloalkyl group, or a C1-C3 alkyl group;

[0423] Each R b-2 It is independently a halogen or a C1-C6 alkyl group;

[0424] R 1-4 and R 1-5 Independently hydrogen or C1-C3 alkyl, wherein the C1-C3 alkyl group is optionally independently formed by one, two, three or four R atoms. 1-4-1 Replace; or, R 1-4 and R 1-5 The atoms attached to it form 3- to 7-membered heterocyclic alkyl groups;

[0425] Each R 1-4-1 Halogens are independent of each other;

[0426] R 2 and R 3 Independently hydrogen or NR 2-1 R 2-2 ;

[0427] R 2-1 and R 2-2 Independently hydrogen or C1-C6 alkyl;

[0428] R 4 R 5 and R 6 Independently hydrogen or NR 4-1 R 4-2 ;

[0429] R 4-1 and R 4-2 Independently hydrogen;

[0430] L is

[0431] t is a natural number between 0 and 3;

[0432] u is a natural number from 0 to 3;

[0433] E is a carbonyl group. -NHCO- or chemical bonds;

[0434] F is a carbonyl group. -O-, -NH- or chemical bonds;

[0435] R 8 and R9 Independently hydrogen or C1-C6 alkyl, or R 8 and R 9 The atoms attached to it form 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl;

[0436] B is a 4-6 membered heterocyclic alkyl, a 6-10 membered aryl, or a 5-12 membered heteroaryl; wherein the 4-6 membered heterocyclic alkyl, the 6-10 membered aryl, and the 5-12 membered heteroaryl are optionally independently bounded by one, two, or three Rs. i replace;

[0437] Each R i Independently hydrogen, halogen, hydroxyl, or C1-C3 alkyl; or, R on two identical atoms. i It forms a 3- to 7-membered cycloalkyl group with the atoms attached to it; or, two adjacent R atoms... i The atoms attached to it form 3- to 7-membered cycloalkyl groups;

[0438] D is hydrogen, C1-C6 alkyl, or 5-12 heteroaryl; wherein the C1-C6 alkyl and 5-12 heteroaryl are optionally independently surrounded by one, two, or three R. j replace;

[0439] Each R j Independently hydrogen, halogen, C1-C3 alkyl, 3- to 7-membered cycloalkyl, -OR 12-3 or -SR 12-4 The C1-C3 alkyl and 3-7 membered cycloalkyl groups are optionally and independently associated with one, two or three R groups. k replace;

[0440] R 12-3 and R 12-4 Independently C1-C3 alkyl; wherein the C1-C3 alkyl group is optionally independently bounded by one, two or three R groups. k-1 replace;

[0441] Each R k Halogens are independent of each other;

[0442] Each R k-1 Halogens are independent of each other;

[0443] In the 3-7 membered heterocyclic alkyl, 4-6 membered heterocyclic alkyl and 5-12 membered heteroaryl groups, the heteroatom is one or more of N, O and S, and the number of heteroatoms is 1 to 3.

[0444] In a preferred embodiment, the compound represented by Formula I or a pharmaceutically acceptable salt thereof,

[0445]

[0446] in, for

[0447] m is a natural number from 0 to 3;

[0448] n is a natural number from 0 to 3; m and n are not both 0;

[0449] k is a natural number between 0 and 3;

[0450] X1, X2, X3, X4, and X5 are independently -CR 1 -、N、S、 Or chemical bonds;

[0451] R N-1 It is a C1-C6 alkyl group;

[0452] Y and Z are independently carbonyl (CO) or - (CR) groups. 2 R 3 ) r -; r is a natural number from 0 to 5;

[0453] Each W is independently -(CR) 4 R 5 )-、-NR 6 -or chemical bonds;

[0454] Each R 1 Independently hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or -NR 1-1 R 1-2 The C1-C6 alkylthio group, C1-C6 alkyl group, and C1-C6 alkoxy group are optionally independently bounded by one, two, three, or four R groups. a replace;

[0455] Each R a Independently hydroxyl, C1-C6 alkoxy or -NR 1-4 R 1-5 ;

[0456] R 1-1 and R 1-2 Independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl group is optionally independently formed by one, two, three or four R atoms. b Replace; or, R 1-1 and R 1-2 The atoms bonded to it form 3- to 7-membered heterocyclic alkyl groups, wherein the 3- to 7-membered heterocyclic alkyl groups are arbitrarily bound by 1, 2, 3, or 4 R atoms. b-2 replace;

[0457] Each Rb Independently, it is a 3- to 7-membered cycloalkyl group;

[0458] Each R b-2 It is independently a halogen or a C1-C6 alkyl group;

[0459] R 1-4 and R 1-5 Independently, it is a C1-C3 alkyl group;

[0460] R 2 and R 3 Independently hydrogen or NR 2-1 R 2-2 ;

[0461] R 2-1 and R 2-2 Independently hydrogen;

[0462] R 4 R 5 and R 6 Independently hydrogen;

[0463] L is

[0464] t is a natural number between 0 and 3;

[0465] u is a natural number from 0 to 3;

[0466] E is a carbonyl group. -NHCO- or chemical bonds;

[0467] F is a chemical bond;

[0468] R 8 and R 9 Independently hydrogen or C1-C6 alkyl, or R 8 and R 9 The atoms attached to it form 3- to 7-membered cycloalkyl groups;

[0469] B is a 4-6 membered heterocyclic alkyl, a 6-10 membered aryl, or a 5-12 membered heteroaryl; wherein the 4-6 membered heterocyclic alkyl, the 6-10 membered aryl, and the 5-12 membered heteroaryl are optionally independently bounded by one, two, or three Rs. i replace;

[0470] Each R i Independently hydrogen, halogen, hydroxyl, or C1-C3 alkyl; or, R on two identical atoms. i It forms 3- to 7-membered cycloalkyl groups with the atoms attached to it;

[0471] D is hydrogen, C1-C6 alkyl, or 5-12 heteroaryl; wherein the C1-C6 alkyl and 5-12 heteroaryl are optionally independently surrounded by one, two, or three R.j replace;

[0472] Each R j Independently hydrogen, halogen, C1-C3 alkyl, 3- to 7-membered cycloalkyl, -OR 12-3 or -SR 12-4 The C1-C3 alkyl and 3-7 membered cycloalkyl groups are optionally and independently associated with one, two or three R groups. k replace;

[0473] R 12-3 and R 12-4 Independently C1-C3 alkyl; wherein the C1-C3 alkyl group is optionally independently bounded by one, two or three R groups. k-1 replace;

[0474] Each R k Halogens are independent of each other;

[0475] Each R k-1 Halogens are independent of each other;

[0476] In the 3-7 membered heterocyclic alkyl, 4-6 membered heterocyclic alkyl and 5-12 membered heteroaryl groups, the heteroatom is one or more of N, O and S, and the number of heteroatoms is 1 to 3.

[0477] In a preferred embodiment, the compound represented by Formula I or a pharmaceutically acceptable salt thereof,

[0478]

[0479] in, for

[0480] m is a natural number from 1 to 3;

[0481] n is a natural number from 1 to 3;

[0482] k is a natural number from 1 to 3;

[0483] X1, X2, X3, X4, and X5 are independently -CR 1 -、N、O、S、 Or chemical bonds, and the number of heteroatoms in X1, X2, X3, X4 and X5 is 0, 1, 2 or 3;

[0484] R N-1 It is hydrogen or C1-C6 alkyl;

[0485] Y and Z are independently carbonyl (CO) or - (CR) groups. 2 R 3 ) r -; r is a natural number from 1 to 2;

[0486] Each W is independently -O-, -(CR) 4 R 5 )-、-NR 6 -or chemical bonds;

[0487] Each R 1 Independently hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or -NR 1-1 R 1-2 The C1-C6 alkyl and C1-C6 alkoxy groups are optionally independently bounded by one, two, three, or four R groups. a replace;

[0488] Each R a Independently hydroxyl, C1-C3 alkoxy or NR 1-4 R 1-5 ;

[0489] R 1-1 and R 1-2 Independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl group is optionally independently formed by one, two, three or four R atoms. b Replace; or, R 1-1 and R 1-2 The atoms attached to it form 3- to 7-membered heterocyclic alkyl groups;

[0490] Each R b Independently hydroxyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, C1-C3 alkyl, C1-C3 alkoxy or NR 1-1-1 R 1-2-1 In this context, the 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, and C1-C3 alkyl groups are optionally independently bound by one, two, three, or four R groups. b-1 replace;

[0491] Each R b-1 Independently, it is a hydroxyl group;

[0492] R 1-4 and R 1-5 Independently hydrogen or C1-C3 alkyl; wherein the C1-C3 alkyl group is optionally independently formed by one, two, three or four R atoms. 1-4-1 Replace; or, R 1-4 and R 1-5 The atoms attached to it form 3- to 7-membered heterocyclic alkyl groups;

[0493] Each R 1-4-1 Halogens are independent of each other;

[0494] R 1-1-1 and R 1-2-1Independently hydrogen or C1-C3 alkyl;

[0495] R 2 and R 3 Independently hydrogen or NR 2-1 R 2-2 ;

[0496] R 2-1 and R 2-2 Independently hydrogen or C1-C6 alkyl;

[0497] R 4 R 5 and R 6 Independently hydrogen;

[0498] L is

[0499] t is a natural number between 0 and 2;

[0500] u is a natural number between 0 and 2;

[0501] E is a carbonyl group, -NHCO-, or a chemical bond;

[0502] F is -O-, -NH-, or a chemical bond;

[0503] R 8 and R 9 Independently hydrogen or C1-C6 alkyl; or R 8 and R 9 The atoms attached to it form 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl;

[0504] B is a 4-6 membered heterocyclic alkyl group, a 6-10 membered aryl group, or a 5-12 membered heterocyclic alkyl group; wherein the 5-12 membered heterocyclic alkyl group, the 6-10 membered aryl group, and the 4-6 membered heterocyclic alkyl group are optionally independently bounded by one, two, or three R groups. i replace;

[0505] Each R i Independently hydrogen, hydroxyl, halogen, or C1-C3 alkyl; or, two Rs i It forms a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl with the atoms attached to it; or, two adjacent R i The atoms attached thereto form 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl (wherein, the 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl forms a fused ring with B);

[0506] D is hydrogen, a 3-7 membered cycloalkyl group, a C1-C6 alkyl group, or a 5-12 membered heteroaryl group; wherein the C1-C6 alkyl group and the 5-12 membered heteroaryl group are optionally independently surrounded by one, two, or three R groups. j replace;

[0507] Each R j Independently halogen, C1-C3 alkyl, -OR 12-3 or -SR 12-4 The C1-C3 alkyl group is optionally independently bound by one, two, or three R atoms. k Replace; each R k Halogens are independent of each other;

[0508] R 12-3 and R 12-4 Independently C1-C3 alkyl; the C1-C3 alkyl group is optionally independently surrounded by one, two or three R... k Replace; each R k Halogens are independent of each other;

[0509] In the 3-7 membered heterocyclic alkyl, 4-6 membered heterocyclic alkyl, and 5-12 membered heteroaryl groups, the heteroatom is N, O, or S, and the number of heteroatoms is 1 to 3; or, in the 3-7 membered heterocyclic alkyl, 4-6 membered heterocyclic alkyl, and 5-12 membered heteroaryl groups, the heteroatom is one or more of N, O, and S, and the number of heteroatoms is 1 to 3.

[0510] In a preferred embodiment, the compound represented by Formula I or a pharmaceutically acceptable salt thereof,

[0511]

[0512] in, for

[0513] m is a natural number from 1 to 3;

[0514] n is a natural number from 1 to 3;

[0515] X1, X2, X3, and X4 are independently -CR 1 -、N、S、 Or chemical bonds, and the number of heteroatoms in X1, X2, X3, X4 and X5 is 1 or 2;

[0516] R N-1 It is a C1-C6 alkyl group;

[0517] Y and Z are independently carbonyl (CO) or - (CR) groups. 2 R 3 ) r -; r is a natural number from 1 to 2;

[0518] Each R 1 Independently hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or -NR 1-1 R 1-2The C1-C6 alkyl and C1-C6 alkoxy groups are optionally independently bounded by one, two, three, or four R groups. a replace;

[0519] Each R a Independently hydroxyl, C1-C3 alkoxy or NR 1-4 R 1-5 ;

[0520] R 1-1 and R 1-2 Independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl group is optionally independently formed by one, two, three or four R atoms. b Replace; or, R 1-1 and R 1-2 The atoms attached to it form 3- to 7-membered heterocyclic alkyl groups;

[0521] Each R b Independently hydroxyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, C1-C3 alkyl, C1-C3 alkoxy or NR 1-1-1 R 1-2-1 In this context, the 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, and C1-C3 alkyl groups are optionally independently bound by one, two, three, or four R groups. b-1 replace;

[0522] Each R b-1 Independently, it is a hydroxyl group;

[0523] R 1-4 and R 1-5 Independently hydrogen or C1-C3 alkyl, wherein the C1-C3 alkyl group is optionally independently formed by one, two, three or four R atoms. 1-4-1 Replace; or, R 1-4 and R 1-5 The atoms attached to it form 3- to 7-membered heterocyclic alkyl groups;

[0524] R 1-1-1 and R 1-2-1 Independently hydrogen or C1-C3 alkyl;

[0525] R 1-4-1 It is a halogen;

[0526] R 2 and R 3 Independently hydrogen;

[0527] L is

[0528] t is a natural number between 0 and 2;

[0529] u is a natural number between 0 and 2;

[0530] E represents a carbonyl group or a chemical bond;

[0531] F is -O-, -NH-, or a chemical bond;

[0532] R 8 and R 9 Independently C1-C6 alkyl, or R 8 and R 9 The atoms attached to it form 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl;

[0533] B is a 4-6 membered heterocyclic alkyl group or a 5-12 membered heteroaryl group; wherein the 5-12 membered heteroaryl group and the 4-6 membered heterocyclic alkyl group are optionally independently surrounded by one, two or three R groups. i replace;

[0534] Each R i Independently hydrogen, hydroxyl, halogen, or C1-C3 alkyl; or, two Rs i It forms a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl with the atoms attached to it; or, two adjacent R i The atoms attached thereto form 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl (wherein, the 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl forms a fused ring with B);

[0535] D is hydrogen, a 3-7 membered cycloalkyl group, a C1-C6 alkyl group, or a 5-6 membered heteroaryl group; wherein the C1-C6 alkyl group and the 5-6 membered heteroaryl group are optionally independently surrounded by one, two, or three R groups. j replace;

[0536] Each R j Independently halogenated or C1-C3 alkyl; the C1-C3 alkyl group is optionally independently surrounded by one, two, or three R atoms. k Replace; each R k Halogens are independent of each other;

[0537] In the 3-7 membered heterocyclic alkyl, 4-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, and 5-12 membered heteroaryl groups, the heteroatom is N, O, or S, and the number of heteroatoms is 1 to 3; or, in the 3-7 membered heterocyclic alkyl, 4-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, and 5-12 membered heteroaryl groups, the heteroatom is one or more of N, O, and S, and the number of heteroatoms is 1 to 3.

[0538] In a preferred embodiment, the compound represented by Formula I or a pharmaceutically acceptable salt thereof,

[0539]

[0540] in, for

[0541] m is a natural number from 1 to 2;

[0542] n is a natural number between 1 and 2;

[0543] k is a natural number from 1 to 3;

[0544] X1, X2, X3, X4, and X5 are independently -CR 1 -、N、O、S、 Or chemical bonds, and the number of heteroatoms in X1, X2, X3, X4 and X5 is 0, 1, 2 or 3;

[0545] R N-1 It is a C1-C6 alkyl group;

[0546] Each W is independently -(CR) 4 R 5 )-、-O-、-NR 6 - or chemical bond; Y and Z are independently carbonyl (CO) or - (CR) groups. 2 R 3 ) r -; r is a natural number from 1 to 2;

[0547] Each R 1 Independently hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or -NR 1-1 R 1-2 The C1-C6 alkyl and C1-C6 alkoxy groups are optionally independently bounded by one, two, three, or four R groups. a replace;

[0548] Each R a Independently hydroxyl, C1-C3 alkoxy or NR 1-4 R 1-5 ;

[0549] R 1-1 and R 1-2 Independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl group is optionally independently formed by one, two, three or four R atoms. b Replace; or, R 1-1 and R 1-2 The atoms attached to it form 3- to 7-membered heterocyclic alkyl groups;

[0550] Each R b Independently hydroxyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, C1-C3 alkyl, C1-C3 alkoxy or NR 1-1-1 R 1-2-1In this context, the 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, and C1-C3 alkyl groups are optionally independently bound by one, two, three, or four R groups. b-1 replace;

[0551] Each R b-1 Independently, it is a hydroxyl group;

[0552] R 1-4 and R 1-5 Independently hydrogen or C1-C3 alkyl, wherein the C1-C3 alkyl group is optionally independently formed by one, two, three or four R atoms. 1-4-1 Replace; or, R 1-4 and R 1-5 The atoms attached to it form 3- to 7-membered heterocyclic alkyl groups;

[0553] R 1-1-1 and R 1-2-1 Independently hydrogen or C1-C3 alkyl;

[0554] Each R 1-4-1 Halogens are independent of each other;

[0555] R 2 and R 3 Independently hydrogen or NR 2-1 R 2-2 ;

[0556] R 2-1 and R 2-2 Independently hydrogen or C1-C6 alkyl;

[0557] R 4 R 5 and R 6 Independently hydrogen; L is

[0558] t is a natural number between 0 and 2;

[0559] u is a natural number between 0 and 2;

[0560] E is a carbonyl group, -NHCO-, or a chemical bond;

[0561] F is -O-, -NH-, or a chemical bond;

[0562] R 8 and R 9 Independently hydrogen or C1-C6 alkyl; or R 8 and R 9 The atoms attached to it form 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl;

[0563] B is a 4-6 membered heterocyclic alkyl group, a 6-10 membered aryl group, or a 5-12 membered heterocyclic alkyl group; wherein the 5-12 membered heterocyclic alkyl group, the 6-10 membered aryl group, and the 4-6 membered heterocyclic alkyl group are optionally independently bounded by one, two, or three R groups. i replace;

[0564] Each R i Independently hydrogen, hydroxyl, halogen, or C1-C3 alkyl; or, two Rs i It forms a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl with the atoms attached to it; or, two adjacent R i The atoms attached thereto form 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl (wherein, the 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl forms a fused ring with B);

[0565] D is hydrogen, C1-C6 alkyl, or 5-12 heteroaryl; wherein the C1-C6 alkyl and 5-12 heteroaryl are optionally independently surrounded by one, two, or three R. j replace;

[0566] Each R j Independently halogen, C1-C3 alkyl, OR 12-3 or SR 12-4 The C1-C3 alkyl group is optionally independently bound by one, two, or three R atoms. k Replace; each R k Halogens are independent of each other;

[0567] R 12-3 and R 12-4 Independently C1-C3 alkyl, wherein the C1-C3 alkyl group is optionally independently bound by one, two or three R atoms. k-1 Replace; each R k-1 The heteroatom is independently a halogen; in the 3-7 membered heterocyclic alkyl, 4-6 membered heterocyclic alkyl and 5-12 membered heteroaryl groups, the heteroatom is N, O or S, and the number of heteroatoms is 1 to 3; or, in the 3-7 membered heterocyclic alkyl, 4-6 membered heterocyclic alkyl and 5-12 membered heteroaryl groups, the heteroatom is one or more of N, O and S, and the number of heteroatoms is 1 to 3.

[0568] In a preferred embodiment, the compound represented by Formula I or a pharmaceutically acceptable salt thereof,

[0569]

[0570] in, for

[0571] m is 1;

[0572] n is 1;

[0573] X1, X2, X3, and X4 are independently -CR 1 - or N, and the number of heteroatoms in X1, X2, X3 and X4 is 2;

[0574] Y and Z are independently -(CR) 2 R 3 ) r -; r is 1;

[0575] Each R 1 Independently, it is a C1-C6 alkyl (e.g., methyl) or a C1-C6 alkoxy (e.g., methoxy);

[0576] R 2 and R 3 Independently hydrogen;

[0577] L is

[0578] t is 0;

[0579] u is 1;

[0580] E is a carbonyl group;

[0581] F is a chemical bond;

[0582] B is a 4- to 6-membered heterocyclic alkyl group; wherein the 4- to 6-membered heterocyclic alkyl group is optionally independently bound by one, two, or three R groups. i replace;

[0583] Each R i Independently hydrogen;

[0584] D is a 5- to 12-membered heteroaryl group; wherein the 5- to 12-membered heteroaryl group is optionally independently bound by one, two, or three R groups. j (e.g., 1) Replacement;

[0585] Each R j Independently for -OR 12-3 ;

[0586] R 12-3 It is a C1-C3 alkyl group (e.g., ethyl or isopropyl); the C1-C3 alkyl group is optionally independently surrounded by one, two or three R groups. k Replace; each R k Independently halogenated (e.g., F);

[0587] In the 4-6 membered heterocyclic alkyl group and the 5-12 membered heteroaryl group, the heteroatom is N, O or S, and the number of heteroatoms is 1 to 3; or, in the 4-6 membered heterocyclic alkyl group and the 5-12 membered heteroaryl group, the heteroatom is one or more of N, O and S, and the number of heteroatoms is 1 to 3.

[0588] When A is At that time, X1, X2, and X4 contain one or two heteroatoms;

[0589] When A is When L is a carbonyl group, u is a natural number from 1 to 3, and B is a 4- to 6-membered heterocyclic alkyl group, wherein the 4- to 6-membered heterocyclic alkyl group is optionally independently surrounded by one, two, or three R groups. i replace.

[0590] In a preferred embodiment, the compound represented by Formula I or a pharmaceutically acceptable salt thereof,

[0591] in, for

[0592] m is 1;

[0593] n is 1;

[0594] X2 and X3 are N;

[0595] X1 and X4 are independently -CR 1 -;

[0596] Y and Z are independently -(CR) 2 R 3 ) r -; r is 1;

[0597] Each R 1 Independently hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or -NR 1-1 R 1-2 ; wherein the C1-C6 alkyl and C1-C6 alkoxy groups are optionally independently bounded by one, two, three, or four R groups. a replace;

[0598] R 1-1 and R 1-2 Independently hydrogen or C1-C6 alkyl; or, R 1-1 and R 1-2 The atoms attached to it form 3- to 7-membered heterocyclic alkyl groups;

[0599] Each R a Independently hydroxyl, C1-C6 alkoxy or NR 1-4 R 1-5 ;

[0600] R 1-4 and R 1-5 Independently hydrogen or C1-C3 alkyl;

[0601] R 2 and R 3 Independently hydrogen;

[0602] L is

[0603] t is 0;

[0604] u is 1;

[0605] E is a carbonyl group;

[0606] F is a chemical bond;

[0607] B is a 4- to 6-membered heterocyclic alkyl group; wherein the 4- to 6-membered heterocyclic alkyl group is optionally independently bound by one, two, or three R groups. i replace;

[0608] Each R i It can be independently hydrogen, halogen, hydroxyl, or C1-C3 alkyl;

[0609] D is a 5- to 12-membered heteroaryl group; wherein the 5- to 12-membered heteroaryl group is optionally independently bound by one, two, or three R groups. j Substitution; preferably, D is a 5-6 membered heteroaryl; wherein the 5-6 membered heteroaryl is optionally independently replaced by one, two or three Rs. j Substitution; in the 5-6 membered heteroaryl group, the heteroatom is selected from 1, 2 or 3 of N, S and O, and the number of heteroatoms is 1, 2 or 3;

[0610] Each R j Independently H, halogen, C1-C3 alkyl, OR 12-3 or SR 12-4 ; wherein the C1-C3 alkyl group is optionally independently and independently surrounded by one, two or three R groups. k replace;

[0611] R 12-3 and R 12-4 Independently C1-C3 alkyl; the C1-C3 alkyl group is optionally independently surrounded by one, two or three R... k-1 replace;

[0612] Each R k It is independently a halogen or a C1-C3 alkyl group;

[0613] Each R k-1 It is independently a halogen or a C1-C3 alkyl group;

[0614] In the 3-7 membered heterocyclic alkyl, 4-6 membered heterocyclic alkyl and 5-12 membered heteroaryl groups, the heteroatom is one or more of N, O and S, and the number of heteroatoms is 1 to 3.

[0615] In a preferred embodiment, the compound represented by Formula I or a pharmaceutically acceptable salt thereof,

[0616] in, for

[0617] m is 1;

[0618] n is 1;

[0619] X1 and X3 are N;

[0620] X2 and X4 are independently -CR 1 -;

[0621] Y and Z are independently -(CR) 2 R 3 ) r -; r is 1;

[0622] Each R 1 Independently, it is hydrogen, halogen, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or -NR. 1-1 R 1-2 ; wherein the C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkylthio groups are optionally independently bounded by one, two, three, or four R groups. a replace;

[0623] R 1-1 and R 1-2 Independently hydrogen or C1-C6 alkyl; or, R 1-1 and R 1-2 The atoms attached to it form 3- to 7-membered heterocyclic alkyl groups;

[0624] Each R a Independently hydroxyl, C1-C6 alkoxy or NR 1-4 R 1-5 ;

[0625] R 1-4 and R 1-5 Independently hydrogen or C1-C3 alkyl;

[0626] R 2 and R 3 Independently hydrogen;

[0627] L is

[0628] t is 0;

[0629] u is 1;

[0630] E is a carbonyl group;

[0631] F is a chemical bond;

[0632] B is a 4- to 6-membered heterocyclic alkyl group; wherein the 4- to 6-membered heterocyclic alkyl group is optionally independently bound by one, two, or three R groups. i replace;

[0633] Each R i Independently hydrogen, halogen, hydroxyl, or C1-C3 alkyl; or, two Rs i The atoms connected to it form 3- to 7-membered cycloalkyl groups;

[0634] D is a 5- to 12-membered heteroaryl group; wherein the 5- to 12-membered heteroaryl group is optionally independently bound by one, two, or three R groups. j Substitution; preferably, D is a 5-6 membered heteroaryl; wherein the 5-6 membered heteroaryl is optionally independently replaced by one, two or three Rs. j Substitution; in the 5-6 membered heteroaryl group, the heteroatom is selected from 1, 2 or 3 of N, S and O, and the number of heteroatoms is 1, 2 or 3;

[0635] Each R j Independently hydrogen, halogen, cyano, hydroxyl, C1-C3 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, -NR 12-1 R 12-2 -OR 12-3 or -SR 12-4 ; wherein the C1-C3 alkyl, 3-7 membered cycloalkyl, and 3-7 membered heterocycloalkyl are optionally independently bound by one, two, or three R atoms. k replace;

[0636] R 12-1 R 12-2 R 12-4 and R 12-3 Independently C1-C3 alkyl; the C1-C3 alkyl group is optionally independently surrounded by one, two or three R... k-1 replace;

[0637] Each R k It is independently a halogen or a C1-C3 alkyl group;

[0638] Each R k-1 It is independently a halogen or a C1-C3 alkyl group;

[0639] In the 3-7 membered heterocyclic alkyl, 4-6 membered heterocyclic alkyl and 5-12 membered heteroaryl groups, the heteroatom is one or more of N, O and S, and the number of heteroatoms is 1 to 3.

[0640] In a certain scheme, each R 1 Independently hydrogen, methyl, Ethyl, Chlorine, methoxy Isopropyl, amino,

[0641] In a certain scheme, each R 1 Independently hydrogen, methyl, Ethyl, Chlorine, methoxy Isopropyl, amino (-NH2),

[0642]

[0643] Trifluoromethyl, Or methylthio group.

[0644] Preferably, each R 1 Independently methyl,

[0645] In one of the schemes, for

[0646]

[0647]

[0648]

[0649] Preferably, for

[0650] In one of the schemes, for

[0651]

[0652]

[0653]

[0654]

[0655] In one scheme, L is -(CH2)-, -(CH2)2-,

[0656] Preferably, L is

[0657] in It indicates that it is connected to A.

[0658] Preferably, L is

[0659] In one scheme, L is -(CH2)-, -(CH2)2-,

[0660] Preferably, L is in It indicates that it is connected to A.

[0661] In one of the proposed solutions, B is...

[0662] In one of the proposed solutions, B is...

[0663] Preferably, B is

[0664] In one of the proposed solutions, B is...

[0665] In one scheme, D represents hydrogen, methyl, Ethyl, isopropyl, cyclopropyl, trifluoromethyl or

[0666] Preferably, D is

[0667] In one scheme, D represents hydrogen, methyl, Ethyl, isopropyl, cyclopropyl, trifluoromethyl or

[0668] In one embodiment, the compound represented by Formula I is any of the following compounds:

[0669]

[0670] The present invention also provides a method for preparing the compound represented by Formula I above, which can be prepared by any of the following schemes:

[0671] Scheme (a): In an organic solvent, in the presence of a catalyst, the compound shown in Formula II undergoes a condensation reaction with the compound shown in Formula III as shown below to obtain the compound shown in Formula I;

[0672]

[0673] Scheme (b): In an organic solvent, in the presence of a catalyst, the compound shown in Formula IV undergoes a condensation reaction with the compound shown in Formula V as shown below to obtain the compound shown in Formula I;

[0674]

[0675] Scheme (C): In an organic solvent, in the presence of a catalyst, the compound shown in Formula VI undergoes a cyclization reaction with the compound shown in Formula VII as shown below to give the compound shown in Formula I;

[0676]

[0677] Wherein, Z is a halogen (e.g., chlorine or bromine), TsO-, hydroxyl, methoxy, ethoxy, n-propoxy, or isopropoxy; preferably, Z is hydroxyl, methoxy, ethoxy, n-propoxy, or isopropoxy.

[0678] A, L, B, D, X1, X2, X3, X4, Y, and m are as described in any one of the present invention.

[0679] The present invention also provides a method for preparing the compound represented by Formula I above, which can be obtained by the following scheme:

[0680] Scheme (D): In an organic solvent, in the presence of a catalyst, the compound shown in Formula VIII undergoes a cyclization reaction with the compound shown in Formula VIIII as shown below to give the compound shown in Formula I.

[0681]

[0682] Wherein, Z, A, L, B, and D are as described in any one of the present invention.

[0683] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of substance A and a pharmaceutical excipient; said substance A is a compound represented by Formula I above or a pharmaceutically acceptable salt thereof.

[0684] The present invention also provides the use of substance A in the preparation of a muscarinic receptor positive allosteric modulator, wherein substance A is a compound represented by Formula I above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0685] The present invention also provides the use of substance A in the preparation of a medicament for treating and / or preventing muscarinic receptor-mediated diseases, wherein substance A is a compound represented by Formula I above or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof; preferably, the disease is Parkinson's disease, Alzheimer's disease, Huntington's disease, schizophrenia, drug addiction, or pain.

[0686] The present invention also provides the use of substance A in the preparation of a drug for the treatment of Parkinson's disease, Alzheimer's disease, Huntington's disease, schizophrenia, drug addiction, or pain.

[0687] The positive and progressive effects of this invention are as follows: the compounds of this invention can act as positive allosteric modulators of muscarinic receptors, and the compounds of this invention can treat M receptor (muscarinic receptor) mediated (or M receptor-related) diseases.

[0688] Terminology Explanation:

[0689] The term "-" indicates that the group is attached to the rest of the molecule through that site. For example, "CH3O-" refers to an alkoxy group.

[0690] the term ( In This means that the structural segment is connected to the rest of the molecule through this site.

[0691] The term "pharmaceutical acceptable" means that something is relatively non-toxic, safe, and suitable for patient use.

[0692] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, and diethanolamine salts. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. Pharmaceutically acceptable acids include inorganic acids and organic acids (e.g., trifluoroacetic acid, hydrochloric acid, formic acid). See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition) for details, such as formate salts.

[0693] The term "pharmaceutical excipients" refers to all substances contained in pharmaceutical preparations other than the active pharmaceutical ingredient, and are generally divided into two main categories: excipients and additives. For details, please refer to the *Pharmacopoeia of the People's Republic of China (2020 Edition)* and *Handbook of Pharmaceutical Excipients* (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0694] The term "treatment" refers to eliminating the cause of an illness or relieving symptoms.

[0695] The term "prevention" refers to reducing the risk of developing a disease.

[0696] The term "patient" refers to any animal, typically a mammal such as a human, that requires treatment or prevention of disease. Mammals include, but are not limited to: cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans.

[0697] The term "therapeutic effective amount" refers to the amount of compound administered to a patient that is sufficient to effectively treat the disease. Therapeutic effective amount will vary depending on the type of compound, the type of disease, the severity of the disease, the patient's age, etc., but may be adjusted as appropriate by those skilled in the art.

[0698] The expression "a group B substituted by one or more groups A" means that one or more hydrogen atoms in group B are independently substituted by group A. When multiple groups A appear simultaneously, unless otherwise specified, their definitions are independent of each other and do not affect each other.

[0699] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0700] The term "oxo" refers to =O, where an oxygen atom replaces two hydrogen atoms on the same atom. For example, methylene (-(CH2-)) becomes carbonyl (-C(=O)-) after being oxidized.

[0701] The term "alkyl" refers to a saturated monovalent hydrocarbon group that has a specified number of carbon atoms, is straight-chain or branched. For example, C1-C6 alkyl groups (C 1-6 Alkyl) or C4-C 20 Alkyl (C) 4-20 Alkyl), preferably C1-C4 alkyl (C 1-4 Alkyl) or C9-C 15 Alkyl (C) 1-6 Alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0702] In the term "alkyl-O-", the alkyl group is defined as described above. Examples of alkyl-O- include C1-C6 alkyl-O- or C1-C4 alkyl-O-, and more specifically: CH3-O-, CH3CH2-O-, CH3CH2CH2-O-, or CH3CH(CH3)-O-, etc. Similarly, in the other expressions of the form "Rx-O-" in this application, the definition of Rx is as described in their respective definitions, for example, the definition of cycloalkyl in "cycloalkyl-O-" is as described in the "cycloalkyl" section below.

[0703] In the term "alkyl-S-", the alkyl group is defined as described above. Examples of alkyl-S- include C1-C6 alkyl-S- or C1-C4 alkyl-S-, and more specifically: CH3-S-, CH3CH2-S-, CH3CH2CH2-S-, or CH3CH(CH3)-S-, etc. Similarly, in other expressions of the form "Rx-S-" in this application, the definition of Rx is as described in their respective definitions, for example, the definition of cycloalkyl in "cycloalkyl-S-" is as described in the "cycloalkyl" section below.

[0704] The term "alkoxy" refers to an oxygen atom attached to one end of an alkyl group as a connecting bond, forming an "alkyl-O-". The definition of "alkyl-O-" is as described above.

[0705] The term "alkylthio" refers to a sulfur atom attached to one end of an alkyl group as a connecting bond, forming an "alkyl-S-". The definition of "alkyl-S-" is as described above.

[0706] The term "heteroaryl" refers to a cyclic, unsaturated monovalent group that has a specified number of ring atoms (e.g., 5-12, 5-10, or 5-6), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified heteroatom type (one or more of N, O, and S), and is aromatic.

[0707] The term "heterocyclic alkyl" refers to a saturated heterocyclic alkyl group or a partially unsaturated monocyclic or polycyclic heterocyclic group (e.g., one, two, or three heteroatoms) having a specified number of ring atoms (e.g., 4-12, 4-10, 3-7, 6-10, 4-7, 5-6), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom or heteroatom group (one or more of N, O, S, S(=O), and S(=O)2).

[0708] The term "cycloalkyl" refers to a saturated carbocyclic substituent that can be connected to the rest of the molecule via a single bond through any suitable carbon atom; C3-C7 cycloalkyl having 3 to 7 carbon atoms, preferably C3-C6 cycloalkyl having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0709] The term "aryl" refers to an aryl group having a specified number of carbon atoms (e.g., C6-C). 10 Aromatic groups are cyclic, unsaturated, monovalent hydrocarbon groups. Examples of aryl groups include, but are not limited to, phenyl or naphthyl groups.

[0710] The term "heteroaryl" refers to a cyclic or unsaturated monovalent group having a specified number of ring atoms (e.g., 5–10, 5–6), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), which can be monocyclic or polycyclic, and (at least one ring / each ring) is aromatic. Heteroaryl groups are attached to the remainder of the molecule via carbon atoms or heteroatoms; they are attached to the remainder of the molecule via rings with or without heteroatoms; they are attached to the remainder of the molecule via aromatic or non-aromatic rings.

[0711] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key To indicate the absolute configuration of a solid center, a wavy line is used to separate the atom from its substituents. When connecting, it means Or a mixture thereof.

[0712] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0713] The reagents and raw materials used in this invention are all commercially available.

[0714] Abbreviations:

[0715] PMB: 4-Methoxybenzyl.

[0716] Boc: tert-Butoxycarbonyl.

[0717] DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0718] NBS: N-bromosuccinimide.

[0719] DIEA: N,N-diisopropylethylamine.

[0720] DMF: N,N-dimethylformamide.

[0721] Et: Ethyl.

[0722] Me: Methyl group.

[0723] i-Pr: Isopropyl.

[0724] DMSO: Dimethyl sulfoxide.

[0725] HATU: 2-(7-Azobenzotriazole)-N,N,N',N'-Tetramethylurea hexafluorophosphate.

[0726] PyBOP: 1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate.

[0727] TEA (triethylamine)

[0728] LiHMDS bis(trimethylsilyl)aminolithium.

[0729] NCS: N-chlorosuccinimide. Detailed Implementation

[0730] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0731] Intermediate A

[0732] Synthesis route:

[0733]

[0734] first step

[0735] A-1 (5.0 g, 20.5 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (10 mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate of A-2. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 4.13–3.91 (m, 4H), 3.83–3.66 (m, 2H), 3.11–3.03 (m, 1H), 2.74–2.63 (m, 2H), 1.19–1.13 (m, 3H). ESI-MS theoretical calculation C₇H 14 NO2[M+H] + =144.1, measured value 144.2.

[0736] Step 2

[0737] The trifluoroacetate of A-2 (5.0 g, 19.4 mmol) and A-3 (6.0 g, 33.5 mmol) were dissolved in dimethyl sulfoxide (10 mL). Triethylamine (13.4 g, 132.2 mmol) and cesium fluoride (5.0 g, 33.0 mmol) were added sequentially, and the mixture was heated to 80 °C and stirred for 18 hours. The reaction solution was poured into a saturated ammonium chloride solution (20 mL) and extracted with dichloromethane (50 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 2, v / v) to give A-4. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.21 (d, J = 5.64Hz, 1H), 6.70 (d, J = 2.28Hz, 1H), 6.53–6.48 (m, 1H), 4.17–4.04 (m, 4H), 3.70–3.67 (m, 2H), 3.10–3.01 (m, 1H), 2.76–2.72 (m, 2H), 1.21–1.17 (m, 3H). ESI-MS theoretical calculation value C 13 H 16 F3N2O2[M+H] + =289.1, measured value 289.2.

[0738] Step 3

[0739] A-4 (1.0 g, 3.5 mmol) was dissolved in tetrahydrofuran (20 mL) and water (4 mL), and lithium hydroxide (0.22 g, 5.2 mmol) was added. The mixture was stirred at room temperature for 2 hours. The pH of the reaction solution was adjusted to 7, water (50 mL) was added, and the solution was lyophilized to obtain a crude product containing intermediate A, which was used directly in the next reaction step. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.25 (d, J = 5.64 Hz, 1H), 6.72 (d, J = 2.26 Hz, 1H), 6.55 (dd, J = 5.64, 2.26 Hz, 1H), 4.20–4.12 (m, 2H), 3.74–3.64 (m, 2H), 3.14–3.04 (m, 1H), 2.54–2.50 (m, 2H). ESI-MS theoretical calculation value C 11 H 11 F3N2O2[M+H] + =261.1, measured value 261.0.

[0740] intermediate G

[0741] Synthesis route:

[0742]

[0743] first step

[0744] G-1 (2.0 g, 11.3 mmol), NBS (4.2 g, 23.7 mmol), and azobisisobutyronitrile (370 mg, 2.26 mmol) were added sequentially to carbon tetrachloride (25 mL). The reaction system was heated to 80 °C and stirred for 16 hours under nitrogen protection. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting oily substance was diluted with ethyl acetate (20 mL), washed with saturated sodium thiosulfate solution (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 9 / 1, v / v) to obtain G-2. ESI-MS theoretical calculation: C6H5Br2Cl2N2[M+H] + =332.8, measured value 332.0.

[0745] Step 2

[0746] G-2 (4.00 g, 11.9 mmol) and potassium carbonate (4.9 g, 35.8 mmol) were added to tetrahydrofuran (4 mL), and a tetrahydrofuran solution of 4-methoxybenzylamine (1.64 g, 11.9 mmol) was added dropwise at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 9 / 1, v / v) to obtain G-3. ESI-MS theoretical calculation value C 14 H 14 Cl2N3O[M+H] + =310.0, measured value 310.0.

[0747] Step 3

[0748] G-3 (400 mg, 1.29 mmol), methylboric acid (116 mg, 1.93 mmol), potassium carbonate (535 mg, 3.87 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (189 mg, 0.26 mmol), and 1,4-dioxane (3 mL) were added to a 10 mL microwave-safe tube and heated to 90 °C under nitrogen protection with stirring for 18 hours. The reaction mixture was cooled to room temperature, filtered, diluted with water (15 mL), extracted with ethyl acetate (5 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 9 / 1, v / v) to obtain G-4. ESI-MS theoretical calculations showed that C... 15 H 17 ClN3O[M+H] +=290.1, measured value 290.0.

[0749] Step 4

[0750] G-4 (130 mg, 0.45 mmol) and cyclobutane (2 mL) were added to a 10 mL microwave tube and heated to 90 °C with stirring for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (15 mL), extracted with ethyl acetate (5 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 4 / 1, v / v) to obtain G-5. ESI-MS theoretical calculation value C 18 H 23 N4O[M+H] + =311.2, measured value 311.2.

[0751] Step 5

[0752] G-5 (120 mg, 0.39 mmol) and trifluoroacetic acid (2 mL) were added to a 5 mL microwave tube and heated to 100 °C with stirring for 8 hours. The reaction mixture was cooled to room temperature, diluted with water (15 mL), and the pH was adjusted to 8 with saturated sodium bicarbonate solution. It was extracted with ethyl acetate (5 mL × 3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate G, which was used directly in the next reaction. ESI-MS theoretical value C... 10 H 15 N4[M+H] + =191.1, measured value 191.1.

[0753] Intermediate I

[0754] Synthesis route:

[0755]

[0756] first step

[0757] G-3 (1.5 g, 4.84 mmol), 1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (710 mg, 0.97 mmol), potassium carbonate (2.0 g, 14.5 mmol), F-2 (1.21 g, 9.67 mmol), and 1,4-dioxane (10 mL) were stirred at 90 °C for 18 hours under nitrogen protection. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 4 / 1, v / v) to give I-1. ESI-MS theoretical calculation value C 16 H 20 N3O[M+H]+ =270.2, measured value 270.1.

[0758] Step 2

[0759] I-1 (120 mg, 0.45 mmol) and trifluoroacetic acid (2 mL) were added to a 5 mL microwave tube, and the mixture was heated to 90 °C and stirred for 8 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a trifluoroacetate containing intermediate I, which was directly used in the next reaction step. ESI-MS theoretical calculation value C8H 12 N3[M+H] + =150.1, measured value 150.1.

[0760] Intermediate O

[0761] Synthesis route:

[0762]

[0763] first step

[0764] O-1 (2.0 g, 15.2 mmol) was dissolved in DMF (20 mL), and O-2 (1.52 g, 15.2 mmol) and sodium hydride (60%, 1.82 g, 45.6 mmol) were added sequentially. The mixture was heated to 60 °C and stirred for 18 hours. After cooling, a saturated ammonium chloride solution (50 mL) was slowly added to the reaction solution, and the mixture was extracted with ethyl acetate (70 mL × 3). The organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 4 / 1, v / v) to obtain O-3. 1 H NMR (400MHz, DMSO-d6) δ8.21(d,J=5.50Hz,1H),7.26(dd,J=5.50,1.76Hz,1H),7.22(d,J=1.74Hz,1H),5.09-4.96(m,2H).

[0765] Step 2

[0766] O-3 (650 mg, 3.07 mmol) was dissolved in DMSO (6 mL), and intermediate A-2 (1.1 g, 3.07 mmol), TEA (1.86 g, 18.4 mmol), and cesium fluoride (700 mg, 4.02 mmol) were added sequentially. The mixture was heated to 100 °C and stirred for 18 hours. After cooling, water (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 4 / 1, v / v) to obtain O-4. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 7.76 (d, J = 5.76Hz, 1H), 6.14 (dd, J = 5.80, 1.98Hz, 1H), 5.77 (d, J = 1.96Hz, 1H), 4.93–4.84 (m, 2H), 4.10–4.01 (m, 4H), 3.61–3.56 (m, 2H), 3.05–2.97 (m, 1H), 2.74–2.68 (m, 2H), 1.20–1.16 (m, 3H). ESI-MS theoretical calculation value C 14 H 18 F3N2O3[M+H] + =319.1, measured value 319.1.

[0767] Step 3

[0768] O-4 (150 mg, 0.47 mmol) was dissolved in tetrahydrofuran (4 mL) and water (1 mL), and lithium hydroxide (29 mg, 0.71 mmol) was added. The mixture was heated to 60 °C and stirred for 1 hour. After cooling, the pH of the reaction solution was adjusted to 7 with hydrochloric acid (1 mol / L), and the solution was lyophilized with water to obtain a crude product containing intermediate O, which was directly used in the next step of the reaction. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 7.73 (d, J = 5.80Hz, 1H), 6.10 (dd, J = 5.76, 1.98Hz, 1H), 5.72 (d, J = 1.96Hz, 1H), 4.92–4.84 (m, 2H), 4.01–3.96 (m, 2H), 3.54–3.50 (m, 2H), 2.98–2.88 (m, 1H), 2.35–2.32 (m, 2H). ESI-MS theoretical calculation value C 12 H 14 F3N2O3[M+H] + =291.1, measured value 291.1.

[0769] intermediate P

[0770] Synthesis route:

[0771]

[0772] first step

[0773] P-1 (500 mg, 3.72 mmol) and A-2 (585 mg, 4.09 mmol) were dissolved in DMSO (5 mL), and TEA (1.50 g, 14.90 mmol) and cesium fluoride (152 mg, 3.72 mmol) were added. The mixture was heated to 100 °C and stirred for 18 hours. A saturated ammonium chloride solution (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain P-2. 1 ¹H NMR (400MHz, Chloroform-d) δ 4.35–4.27 (m, 2H), 4.19–4.12 (m, 2H), 3.90–3.82 (m, 2H), 3.30–3.17 (m, 1H), 2.73 (d, J = 7.84 Hz, 2H), 2.42 (s, 3H), 1.26 (t, J = 7.78 Hz, 3H). ESI-MS theoretical calculation value C 10 H 16 N3O2S[M+H] + =242.1, measured value 242.0.

[0774] Step 2

[0775] P-2 (200 mg, 0.83 mmol) was dissolved in methanol (2 mL) and water (1 mL), and lithium hydroxide monohydrate (35 mg, 0.83 mmol) was added. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 5 with dilute hydrochloric acid (1 mol / L), concentrated under reduced pressure, and then lyophilized to obtain a crude product containing intermediate P, which was directly used in the next reaction step. 1 ¹H NMR (400MHz, Chloroform-d) δ 4.39–4.29 (m, 2H), 3.97–3.86 (m, 2H), 3.35–3.22 (m, 1H), 2.78 (d, J = 8.00 Hz, 2H), 2.44 (s, 3H). ESI-MS theoretical calculation value C₈H₂ 12 N3O2S[M+H] + =214.1, measured value 214.0.

[0776] intermediate Q

[0777] Synthesis route:

[0778]

[0779] first step

[0780] Q-2 (726 mg, 3.24 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0 °C, and sodium hydride (60%, 130 mg, 3.24 mmol) was added. The mixture was stirred for 1 hour, followed by the addition of Q-1 (500 mg, 2.70 mmol) and stirring at room temperature for 18 hours. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution (5 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was then purified by silica gel column chromatography (petroleum ether / ethyl acetate, 4 / 1, v / v) to obtain Q-3. 1 H NMR(400MHz,Chloroform-d)δ5.69-5.63(m,1H),5.06-5.01(m,0.3H),4.81-4.76(m, 0.7H),4.68-4.50(m,2H),4.15-4.03(m,2H),1.40-1.36(m,12H),1.24-1.15(m,3H).

[0781] Step 2

[0782] Q-3 (500 mg, 1.96 mmol) was dissolved in methanol (10 mL), and wet palladium on carbon (10%, 450 mg) was added. The reaction system was purged with hydrogen three times and stirred at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain Q-4. 1 H NMR(400MHz,Chloroform-d)δ4.47-4.35(m,0.6H),4.13(q,J=7.14Hz,2H),4.06-3.87(m,1.4H),3.52-3.48(m,1H),3. 02-2.87(m,0.6H),2.61-2.53(m,2H),2.45-2.40(m,0.4H)1.44(s,9H),1.40(d,J=6.20Hz,1.2H),1.27-1.23(m,4.8H).

[0783] Step 3

[0784] Q-4 (250 mg, 0.97 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (3 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product containing Q-5, which was used directly in the next reaction. ESI-MS theoretical calculation value C8H16 NO2[M+H] + =158.1, measured value 158.1.

[0785] Step 4

[0786] The trifluoroacetate of Q-5 (140 mg, 0.89 mmol) and A-3 (173 mg, 0.95 mmol) were dissolved in dimethyl sulfoxide (5 mL). TEA (385 mg, 3.80 mmol) and cesium fluoride (144 mg, 0.95 mmol) were added sequentially, and the mixture was heated to 100 °C and stirred for 18 hours. The reaction mixture was poured into water (20 mL), and extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 3, v / v) to obtain Q-6. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.23–8.19 (m, 1H), 6.72 (s, 1H), 6.58 (d, J = 5.84 Hz, 1H), 4.53 (t, J = 7.24 Hz, 0.6H), 4.23–3.88 (m, 2.4H), 3.77–3.73 (m, 0.6H), 3.51–3.47 (m, 0.4H), 3.18–3.09 (m, 1H), 2.74–2.69 (m, 3H), 1.46 (d, J = 6.16 Hz, 1H), 1.31 (d, J = 6.52 Hz, 2H), 1.21–1.18 (m, 3H). ESI-MS theoretical calculation value C 14 H 18 F3N2O2[M+H] + =303.1, measured value 303.1.

[0787] Step 5

[0788] Q-6 (180 mg, 0.57 mmol) was dissolved in tetrahydrofuran (4 mL) and water (1 mL), and lithium hydroxide monohydrate (38 mg, 0.89 mmol) was added. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 5 with dilute hydrochloric acid (1 mol / L), and the solution was lyophilized with water to obtain a crude product containing intermediate Q, which was directly used in the next reaction. ESI-MS theoretical calculation value C 12 H 14 F3N2O2[M+H] + =275.1, measured value 275.0.

[0789] intermediate S

[0790] Synthesis route:

[0791]

[0792] first step

[0793] S-2 (4.54 g, 61.3 mmol) was dissolved in tetrahydrofuran (120 mL), cooled to -78 °C, and a tetrahydrofuran solution of LiHMDS (1.0 mol / L, 64.3 mL, 64.3 mmol) was slowly added dropwise, stirring for 10 minutes. Then, S-1 (10 g, 58.4 mmol) was added, and the mixture was stirred for 15 minutes. The reaction system was heated to 0 °C and stirred for 2 hours. Ice water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing S-3, which was directly used in the next reaction. ESI-MS theoretical calculation value C 11 H 20 NO5[M-56+H] + =190.1, measured value 190.1.

[0794] Step 2

[0795] S-3 (2.0 g, 8.15 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (20 mL) was added. The mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate of S-4, which was used directly in the next reaction. ESI-MS theoretical calculation of C6H... 12 NO3[M+H] + =146.1, measured value 146.2.

[0796] Step 3

[0797] The trifluoroacetate of S-4 (2.0 g, 13.8 mmol) and A-3 (2.49 g, 13.8 mmol) were dissolved in dimethyl sulfoxide (10 mL). TEA (5.58 g, 55.11 mmol) and cesium fluoride (2.1 g, 13.8 mmol) were added sequentially, and the mixture was heated to 100 °C and stirred for 18 hours. The reaction mixture was poured into water (80 mL), and extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 7, v / v) to obtain S-5. 1¹H NMR (400MHz, DMSO-d⁶) δ 8.22 (d, J = 5.68Hz, 1H), 6.76 (d, J = 2.26Hz, 1H), 6.62-6.51 (m, 1H), 6.03 (s, 1H), 4.16-4.10 (m, 2H), 3.90-3.85 (m, 2H), 3.60 (s, 3H), 2.82 (s, 2H). ESI-MS theoretical calculation value C 12 H 14 F3N2O3[M+H] + =291.1, measured value 291.1.

[0798] Step 4

[0799] S-5 (130 mg, 0.45 mmol) was dissolved in tetrahydrofuran (2 mL) and water (0.2 mL), and lithium hydroxide monohydrate (28 mg, 0.68 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 5 with dilute hydrochloric acid (1 mol / L), and the solution was lyophilized with water to obtain a crude product containing intermediate S, which was directly used in the next reaction. ESI-MS theoretical calculation value C 11 H 12 F3N2O3[M+H] + =277.1, measured value 277.0.

[0800] intermediate U

[0801] Synthesis route:

[0802]

[0803] first step

[0804] U-1 (1.0 g, 5.90 mmol) and manganese dioxide (6.66 g, 76.65 mmol) were added to dichloromethane (15 mL), and the mixture was stirred at 25 °C for 8 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain U-2, which was used directly in the next step of the reaction. 1 ¹H NMR (400MHz, Chloroform-d) δ 8.74–8.66 (m, 1H), 7.51 (d, J = 5.06 Hz, 1H), 3.24–3.17 (m, 2H), 2.88–2.80 (m, 2H). ESI-MS theoretical calculation: C₈H₇ClNO[M+H] + =168.0, measured value 168.0.

[0805] Step 2

[0806] U-2 (1.1 g, 6.56 mmol) was dissolved in dichloromethane (15 mL), and diethylaminotrifluoride (3.7 g, 22.97 mmol) was added at 0 °C. The mixture was stirred at room temperature for 18 hours. Saturated sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 1). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 7 / 3, v / v) to obtain U-3. 1 ¹H NMR (400MHz, Chloroform-d) δ 8.55 (d, J = 5.24Hz, 1H), 7.39 (d, J = 5.22Hz, 1H), 3.12–3.02 (m, 2H), 2.76–2.61 (m, 2H). ESI-MS theoretical calculation: C₈H₇ClF₂N [M+H] + =190.0, measured value 190.0.

[0807] Step 3

[0808] Compounds U-3 (300 mg, 1.58 mmol) and A-2 (249 mg, 1.74 mmol) were dissolved in DMSO (10 mL), and TEA (641 mg, 6.33 mmol) and cesium fluoride (240 mg, 1.58 mmol) were added. The mixture was heated to 70 °C and stirred for 18 hours. After the reaction solution was cooled to room temperature, saturated ammonium chloride solution (50 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 7, v / v) to obtain U-4. 1 ¹H NMR (400MHz, Chloroform-d) δ 8.24 (d, J = 5.58Hz, 1H), 6.15 (d, J = 5.60Hz, 1H), 4.36–4.30 (m, 2H), 4.16 (q, J = 7.12Hz, 2H), 3.88–3.81 (m, 2H), 3.20–3.09 (m, 1H), 3.03–2.96 (m, 2H), 2.71 (d, J = 7.78Hz, 2H), 2.62–2.48 (m, 2H), 1.27 (t, J = 7.06Hz, 3H). ESI-MS theoretical calculation value C 15 H 19 F2N2O2[M+H] + =297.1, measured value 297.1.

[0809] Step 4

[0810] U-4 (70 mg, 0.24 mmol) was dissolved in tetrahydrofuran (2 mL) and water (0.4 mL), and lithium hydroxide monohydrate (10 mg, 0.24 mmol) was added. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 5 with dilute hydrochloric acid (1 mol / L), and the solution was lyophilized with water to obtain a crude product containing intermediate U, which was directly used in the next reaction. ESI-MS theoretical calculation value C 13 H 15 F2N2O2[M+H] + =269.1, measured value 269.1.

[0811] intermediate V

[0812] Synthesis route:

[0813]

[0814] first step

[0815] Compounds V-1 (100 mg, 0.55 mmol) and A-2 (157 mg, 0.55 mmol) were dissolved in DMSO (5 mL), and TEA (221 mg, 2.19 mmol) and cesium fluoride (80 mg, 0.55 mmol) were added. The mixture was heated to 100 °C and stirred for 18 hours. After the reaction solution was cooled to room temperature, saturated ammonium chloride solution (20 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 3, v / v) to obtain V-2. 1 ¹H NMR (400MHz, Chloroform-d) δ 8.24 (d, J = 5.70Hz, 1H), 6.23 (d, J = 5.86Hz, 1H), 4.35–4.27 (m, 2H), 4.19–4.12 (m, 2H), 3.97–3.72 (m, 2H), 3.14–3.22 (m, 1H), 2.72 (d, J = 7.76Hz, 2H), 1.28–1.24 (m, 3H). ESI-MS theoretical calculation value C 12 H 15 F3N3O2[M+H] + =290.3, measured value 290.2.

[0816] Step 2

[0817] V-2 (80 mg, 0.28 mmol) was dissolved in tetrahydrofuran (2 mL) and water (0.4 mL), and lithium hydroxide monohydrate (18 mg, 0.41 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 5 with dilute hydrochloric acid (1 mol / L), and the solution was lyophilized with water to obtain a crude product containing intermediate V, which was directly used in the next reaction. ESI-MS theoretical calculation value C 10 H 11 F3N3O2[M+H] + =262.1, measured value 262.0.

[0818] Intermediate X

[0819] Synthesis route:

[0820]

[0821] first step

[0822] X-1 (900 mg, 4.68 mmol) was dissolved in 1,4-dioxane (40 mL), and X-2 (1.8 g, 5.61 mmol) was added. The mixture was then heated to 90 °C and stirred for 18 hours. After the reaction solution was cooled to room temperature, it was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. X-3 was then purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 0, v / v). 1 H NMR (400MHz, Chloroform-d) δ8.52 (d, J = 5.34Hz, 1H), 7.58 (d, J = 1.82Hz, 1H), 7.32 (dd, J = 5.30, 1.84Hz, 1H).

[0823] Step 2

[0824] X-3 (100 mg, 0.47 mmol) and A-2 (201 mg, 0.70 mmol) were dissolved in DMSO (3 mL), and TEA (142 mg, 1.40 mmol) and cesium fluoride (71 mg, 0.47 mmol) were added. The mixture was heated to 100 °C and stirred for 18 hours. After the reaction solution was cooled to room temperature, saturated ammonium chloride solution (10 mL) was added, and the mixture was extracted with dichloromethane (15 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 7 / 3, v / v) to obtain X-4. ESI-MS theoretical calculation value C 13 H 14 F3N2O2S[M+H] +=321.1, measured value 321.1.

[0825] Step 3

[0826] X-4 (150 mg, 2.50 mmol) was dissolved in tetrahydrofuran (3 mL) and water (1 mL), and lithium hydroxide monohydrate (30 mg, 0.70 mmol) was added. The mixture was heated to 40 °C and stirred for 2 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 5 with dilute hydrochloric acid (1 mol / L), and the solution was lyophilized with water to obtain a crude product containing intermediate X, which was directly used in the next reaction. ESI-MS theoretical calculation value C 11 H 12 F3N2O2S[M+H] + =293.1, measured value 293.1.

[0827] Intermediate AA

[0828] Synthesis route:

[0829]

[0830] first step

[0831] AA-1 (1.4 g, 12.2 mmol) was dissolved in DMF (30 mL), cooled to 0 °C, and sodium hydride (60%, 910 mg, 22.8 mmol) was added. The mixture was stirred for 30 minutes, followed by the addition of O-1 (2.0 g, 15.2 mmol) and stirring at room temperature for 18 hours. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution (150 mL), extracted with ethyl acetate (150 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was then purified by silica gel column chromatography (petroleum ether / ethyl acetate, 19 / 1, v / v) to obtain AA-2. 1 H NMR (400MHz, DMSO-d6) δ8.21(d,J=5.50Hz,1H),7.25(dd,J=5.54,1.78Hz,1H),7.16(d,J=1.80Hz,1H),5.95-5.86(m,1H),1.45(d,J=6.68Hz,3H).

[0832] Step 2

[0833] AA-2 (400 mg, 1.77 mmol) and A-2 (254 mg, 1.77 mmol) were dissolved in DMSO (15 mL), and TEA (1.08 g, 10.6 mmol) and cesium fluoride (404 mg, 2.66 mmol) were added. The mixture was heated to 100 °C and stirred for 10 hours. After the reaction solution was cooled to room temperature, saturated ammonium chloride solution (50 mL) was added, followed by extraction with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 17, v / v) to obtain AA-3. 1 ¹H NMR (400MHz, Chloroform-d) δ 7.75 (d, J = 5.74Hz, 1H), 6.12 (dd, J = 5.82, 1.98Hz, 1H), 5.87–5.80 (m, 1H), 5.73 (d, J = 1.96Hz, 1H), 4.10–4.01 (m, 4H), 3.62–3.54 (m, 2H), 3.07–2.97 (m, 1H), 2.70 (d, J = 7.70Hz, 2H), 1.38 (d, J = 6.54Hz, 3H), 1.18 (t, J = 7.10Hz, 3H). ESI-MS theoretical calculation value C 15 H 20 F3N2O3[M+H] + =333.1, measured value 333.1.

[0834] Step 3

[0835] AA-3 (350 mg, 1.05 mmol) was dissolved in tetrahydrofuran (2 mL) and water (0.4 mL), and lithium hydroxide monohydrate (66 mg, 1.58 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 5 with dilute hydrochloric acid (1 mol / L), filtered, and the solid was washed with water (3 mL), dried, and the intermediate AA was obtained, which was used directly in the next reaction. ESI-MS theoretical calculation value C 13 H 16 F3N2O3[M+H] + =305.1, measured value 305.1.

[0836] Intermediate AB

[0837] Synthesis route:

[0838]

[0839] first step

[0840] AB-1 (208 mg, 1.82 mmol) was dissolved in DMF (4 mL), cooled to 0 °C, and sodium hydride (60%, 137 mg, 3.43 mmol) was added. The mixture was stirred for 30 minutes, followed by the addition of O-1 (300 mg, 2.28 mmol) and stirring at room temperature for 18 hours. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was then purified by silica gel column chromatography (petroleum ether / ethyl acetate, 19 / 1, v / v) to obtain AB-2. 1 H NMR (400MHz, DMSO-d6) δ8.21(d,J=5.50Hz,1H),7.25(dd,J=5.58,1.76Hz,1H),7.16(d,J=1.74Hz,1H),5.93-5.85(m,1H),1.45(d,J=6.68Hz,3H).

[0841] Step 2

[0842] AB-2 (200 mg, 0.89 mmol) and A-2 (317 mg, 2.22 mmol) were dissolved in DMSO (5 mL), and TEA (538 mg, 5.32 mmol) and cesium fluoride (202 mg, 1.33 mmol) were added. The mixture was heated to 100 °C and stirred for 10 hours. After the reaction solution was cooled to room temperature, saturated ammonium chloride solution (20 mL) was added, followed by extraction with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 17, v / v) to obtain AB-3. ESI-MS theoretical calculation value C 15 H 20 F3N2O3[M+H] + =333.1, measured value 333.0.

[0843] Step 3

[0844] AB-3 (100 mg, 0.30 mmol) was dissolved in tetrahydrofuran (2 mL) and water (0.4 mL), and lithium hydroxide monohydrate (10 mg, 0.45 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 5 with dilute hydrochloric acid (1 mol / L), filtered, and the solid was washed with water (3 mL). After drying, intermediate AB was obtained and used directly in the next reaction. ESI-MS theoretical calculation value C 13 H 16 F3N2O3[M+H] +=305.1, measured value 305.0.

[0845] intermediate AI

[0846] Synthesis route:

[0847]

[0848] first step

[0849] Q-5 (109 mg, 0.69 mmol) and P-1 (112 mg, 0.83 mmol) were dissolved in DMSO (5 mL), and TEA (280 mg, 2.77 mmol) and cesium fluoride (105 mg, 0.69 mmol) were added. The mixture was heated to 70 °C and stirred for 18 hours. A saturated ammonium chloride solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 4 / 1, v / v) to obtain AI-1. The theoretical calculated value of C by ESI-MS is... 11 H 18 N3O2S[M+H] + =256.1, measured value 256.1.

[0850] Step 2

[0851] AI-1 (90 mg, 0.35 mmol) was dissolved in tetrahydrofuran (2 mL) and water (1 mL), and lithium hydroxide monohydrate (18 mg, 0.42 mmol) was added. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 5 with dilute hydrochloric acid (1 mol / L), concentrated under reduced pressure, and then lyophilized to obtain a crude product containing the intermediate AI, which was directly used in the next reaction. ESI-MS theoretical calculation value C9H 14 N3O2S[M+H] + =228.1, measured value 228.0.

[0852] Intermediate AK

[0853] Synthesis route:

[0854]

[0855] first step

[0856] G-4 (500 mg, 1.73 mmol), cyclopropylboronic acid (296 mg, 3.45 mmol), potassium carbonate (596 mg, 4.31 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (253 mg, 0.35 mmol) were added to 1,4-dioxane (6 mL), and the mixture was heated to 100 °C and stirred for 12 hours under nitrogen protection. The reaction solution was cooled to room temperature, filtered, diluted with water (30 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. AK-1 was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 3, v / v). 1 ¹H NMR (400MHz, DMSO-d⁶) δ 7.30 (d, J = 8.60Hz, 2H), 6.92 (d, J = 8.62Hz, 2H), 4.03–4.00 (m, 2H), 3.91–3.88 (m, 2H), 3.85 (s, 2H), 3.75 (s, 3H), 2.44 (s, 3H), 1.99–1.95 (m, 1H), 1.12–1.08 (m, 2H), 1.00–0.95 (m, 2H). ESI-MS theoretical calculation C 18 H 22 N3O[M+H] + =296.2, measured value 296.1.

[0857] Step 2

[0858] AK-1 (300 mg, 1.02 mmol) and trifluoroacetic acid (4 mL) were added to a microwave tube, and the mixture was heated to 90 °C and stirred for 10 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a trifluoroacetate containing intermediate AK, which was directly used in the next reaction step. ESI-MS theoretical calculation value C... 10 H 14 N3[M+H] + =176.1, measured value 176.0.

[0859] intermediate AO

[0860] Synthesis route:

[0861]

[0862] first step

[0863] G-4 (200 mg, 0.69 mmol), methanesulfonic acid (tricyclohexylphosphine) (2-amino-1,1-biphenyl-2-yl) palladium (45 mg, 0.07 mmol), potassium phosphate (513 mg, 2.42 mmol), and ethylboric acid (153 mg, 2.07 mmol) were added to toluene (5 mL) and water (1 mL). The mixture was heated to 100 °C and stirred for 12 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 3, v / v) to obtain AO-1. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 7.29 (d, J = 8.54Hz, 2H), 6.92 (d, J = 8.52Hz, 2H), 3.96–3.85 (m, 6H), 3.75 (s, 3H), 2.80 (q, J = 7.58Hz, 2H), 2.47 (s, 3H), 1.20 (t, J = 7.58Hz, 3H). ESI-MS theoretical calculation value C 17 H 22 N3O[M+H] + =284.2, measured value 284.1.

[0864] Step 2

[0865] AO-1 (150 mg, 0.53 mmol) and trifluoroacetic acid (4 mL) were added to a microwave tube, and the mixture was heated to 90 °C and stirred for 10 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a trifluoroacetate containing the intermediate AO, which was directly used in the next reaction. ESI-MS theoretical calculation value C9H 14 N3[M+H] + =164.1, measured value 164.0.

[0866] intermediate AP

[0867] Synthesis route:

[0868]

[0869] first step

[0870] G-3 (200 mg, 0.64 mmol), methanesulfonic acid (tricyclohexylphosphine) (2-amino-1,1-biphenyl-2-yl), palladium (42 mg, 0.06 mmol), potassium phosphate (479 mg, 2.26 mmol), and ethylboric acid (285 mg, 3.87 mmol) were added to toluene (5 mL) and water (1 mL). The mixture was heated to 100 °C and stirred for 18 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by silica gel column chromatography (dichloromethane / methanol, 9 / 1, v / v) to obtain AP-1. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 7.31 (d, J = 8.60Hz, 2H), 6.91 (d, J = 8.62Hz, 2H), 3.95 (s, 3H), 3.85 (s, 2H), 3.75 (s, 4H), 2.80 (q, J = 7.58Hz, 4H), 1.21 (t, J = 7.60Hz, 6H). ESI-MS theoretical calculation value C 18 H 24 N3O[M+H] + =298.2, measured value 298.1.

[0871] Step 2

[0872] AP-1 (150 mg, 0.50 mmol) and trifluoroacetic acid (4 mL) were added to a microwave tube, and the mixture was heated to 90 °C and stirred for 10 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a trifluoroacetate containing the intermediate AP, which was directly used in the next reaction step. ESI-MS theoretical calculation value C 10 H 16 N3[M+H] + =178.1, measured value 178.0.

[0873] intermediate AR

[0874] Synthesis route:

[0875]

[0876] first step

[0877] Intermediate I (800 mg, 5.36 mmol) and intermediate AC-1 (1.15 g, 5.36 mmol) were dissolved in DMF (10 mL), and DIEA (2.08 g, 16.1 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then HATU (3.06 g, 8.04 mmol) was added. The mixture was stirred at room temperature for another hour. After the reaction was complete, the mixture was diluted with water (100 mL), extracted with ethyl acetate (80 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was purified by silica gel column chromatography (dichloromethane / methanol, 4 / 1, v / v) to obtain AR-1. ESI-MS theoretical calculation value C 18 H 27 N4O3[M+H] + =347.3, measured value 347.2.

[0878] Step 2

[0879] AR-1 (1.00 g, 2.89 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product containing intermediate AR, which was used directly in the next reaction. ESI-MS theoretical calculation value C 13 H 19 N4O[M+H] + =247.2, measured value 247.1.

[0880] Preparation and synthesis of products

[0881] Example 12

[0882] Synthesis route:

[0883]

[0884] first step

[0885] Intermediate G (50 mg, 0.26 mmol), HATU (149.9 mg, 0.39 mmol), DIEA (0.13 mL, 0.79 mmol), and intermediate A (136.8 mg, 0.53 mmol) were added to tetrahydrofuran (2 mL) and stirred at room temperature for 3 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was then purified by preparative high-performance liquid chromatography (HPLC) (column: Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 20-50%, retention time: 9 min) to obtain compound 12. 1¹H NMR (400MHz, DMSO-d⁶) δ 8.21 (d, J = 5.66Hz, 1H), 6.74–6.70 (m, 1H), 6.56–6.51 (m, 1H), 4.88–4.84 (m, 1H), 4.81–4.77 (m, 1H), 4.66–4.61 (m, 1H), 4.58–4.55 (m, 1H), 4.19–4.14 (m, 2H), 4.13–4.08 (m, 4H), 3.73–3.65 (m, 2H), 3.17–3.06 (m, 1H), 2.89–2.80 (m, 2H), 2.40 (s, 3H), 2.38–2.29 (m, 2H). ESI-MS theoretical calculation value C 21 H 24 F3N6O[M+H] + =433.2, measured value 433.2.

[0886] Example 24

[0887] Synthesis route:

[0888]

[0889] first step

[0890] Intermediate I (100 mg, 0.67 mmol) and Intermediate A (262 mg, 1.01 mmol) were dissolved in tetrahydrofuran (4 mL). DIEA (260 mg, 2.01 mmol) and HATU (382 mg, 1.01 mmol) were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Waters-Xbridge C18 10 μm, 19*250 mm; mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution; gradient: 17-47%; retention time: 9 min) to obtain compound 24. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.21 (d, J = 5.66Hz, 1H), 6.72 (d, J = 2.24Hz, 1H), 6.54 (dd, J = 5.66, 2.24Hz, 1H), 4.95–4.90 (m, 2H), 4.76–4.69 (m, 2H), 4.22–4.15 (m, 2H), 3.75–3.68 (m, 2H), 3.17–3.10 (m, 1H), 2.90–2.82 (m, 2H), 2.57–2.52 (m, 6H). ESI-MS theoretical calculation value C 19 H 21 F3N5O[M+H] +=392.2, measured value 392.2.

[0891] Example 47

[0892] Synthesis route:

[0893]

[0894] first step

[0895] Intermediate G (30 mg, 0.16 mmol) and intermediate O (45 mg, 0.16 mmol) were dissolved in DMF (5 mL), and DIEA (122 mg, 0.95 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then HATU (72 mg, 0.19 mmol) was added. The mixture was stirred at room temperature for another hour. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (column: Waters-Xbridge-C18, 10 μm, 19*250 mm; mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution; gradient: 32-62%; retention time: 9 min) to obtain compound 47. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 7.76 (d, J = 5.78 Hz, 1H), 6.17–6.13 (m, 1H), 5.79 (t, J = 1.86 Hz, 1H), 4.94–4.77 (m, 4H), 4.64–4.56 (m, 2H), 4.14–4.06 (m, 6H), 3.65–3.56 (m, 2H), 3.13–3.02 (m, 1H), 2.85–2.82 (m, 2H), 2.40 (s, 3H), 2.41–2.33 (m, 2H). ESI-MS theoretical calculation value C 22 H 26 F3N6O2[M+H] + =463.2, measured value 463.2.

[0896] Example 50

[0897] Synthesis route:

[0898]

[0899] first step

[0900] Intermediate G (30 mg, 0.16 mmol) and intermediate P (41 mg, 0.19 mmol) were dissolved in DMF (5 mL), and DIEA (62 mg, 0.47 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then HATU (90 mg, 0.24 mmol) was added. The mixture was stirred at room temperature for another 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (column: Waters-Xbridge-C18, 10 μm, 19*250 mm; mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution; gradient: 9-39%; retention time: 9 min) to obtain compound 50. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 4.85–4.74 (m, 2H), 4.65–4.51 (m, 2H), 4.25–4.20 (m, 2H), 4.15–4.07 (m, 4H), 3.83–3.76 (m, 2H), 3.25–3.15 (m, 1H), 2.92–2.84 (m, 2H), 2.40 (s, 3H), 2.38–2.31 (m, 2H), 2.28 (s, 3H). ESI-MS theoretical calculation value C 18 H 24 N7OS[M+H] + =386.2, measured value 386.2.

[0901] Example 51

[0902] Synthesis route:

[0903]

[0904] first step

[0905] Intermediate G (30 mg, 0.16 mmol) and intermediate Q (43 mg, 0.11 mmol) were dissolved in DMF (3 mL), and DIEA (122 mg, 0.95 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then HATU (72 mg, 0.19 mmol) was added. The mixture was stirred at room temperature for another 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (HPLC) (column: Waters-Xbridge-C18, 10 μm, 19*250 mm; mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution; gradient: 22-52%; retention time: 9 min) to obtain compound 51. 1¹H NMR (400MHz, DMSO-d⁶) δ 8.20 (d, J = 5.70Hz, 1H), 6.70 (s, 1H), 6.58 (d, J = 5.64Hz, 1H), 4.92–4.84 (m, 2H), 4.66–4.51 (m, 3H), 4.15–4.02 (m, 4H), 4.01–3.96 (m, 1H), 3.76–3.71 (m, 1H), 3.24–3.20 (m, 1H), 2.89–2.77 (m, 2H), 2.42 (s, 3H), 2.39–2.34 (m, 2H), 1.37–1.34 (m, 3H). ESI-MS theoretical calculation value C 22 H 26 F3N6O[M+H] + =447.2, measured value 447.1.

[0906] Example 56

[0907] Synthesis route:

[0908]

[0909] first step

[0910] Intermediate T (20 mg, 0.11 mmol) and intermediate S (29 mg, 0.11 mmol) were dissolved in DMF (3 mL), and DIEA (55 mg, 0.42 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then HATU (48 mg, 0.13 mmol) was added. The mixture was stirred at room temperature for another hour. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (HPLC) (column: Waters-Xbridge-C18, 10 μm, 19*250 mm; mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution; gradient: 17-47%; retention time: 9 min) to obtain compound 56. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.22 (d, J = 5.68Hz, 1H), 6.76 (t, J = 2.52Hz, 1H), 6.58–6.56 (m, 1H), 5.93–5.90 (m, 1H), 4.91–4.82 (m, 2H), 4.65–4.57 (m, 2H), 4.19–4.15 (m, 2H), 4.13–4.09 (m, 4H), 3.90–3.87 (m, 2H), 2.92–2.88 (m, 2H), 2.41–2.39 (m, 3H), 2.36–2.32 (m, 2H). ESI-MS theoretical calculation value C 21 H 24 F3N6O2[M+H] +=449.2, measured value 449.1.

[0911] Example 67

[0912] Synthesis route:

[0913]

[0914] first step

[0915] Intermediate I (80 mg, 0.54 mmol) and intermediate O (156 mg, 0.54 mmol) were dissolved in DMF (5 mL), and DIEA (209 mg, 1.62 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then HATU (265 mg, 0.70 mmol) was added. The mixture was stirred at room temperature for another hour. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (column: Waters-Xbridge-C18, 10 μm, 19*250 mm; mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution; gradient: 26-56%; retention time: 9 min) to obtain compound 67. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 7.76 (d, J = 5.78Hz, 1H), 6.15 (dd, J = 5.82, 1.94Hz, 1H), 5.78 (d, J = 1.94Hz, 1H), 5.01-4.77 (m, 4H), 4.71-4.68 (m, 2H), 4.11-4.06 (m, 2H), 3.63-3.58 (m, 2H), 3.13-3.05 (m, 1H), 2.84 (d, J = 7.62Hz, 2H), 2.55-2.53 (m, 6H). ESI-MS theoretical calculation value C 20 H 23 F3N5O2[M+H] + =422.2, measured value 422.2.

[0916] Example 68

[0917] Synthesis route:

[0918]

[0919] first step

[0920] Intermediate I (54 mg, 0.36 mmol) and Intermediate X (70 mg, 0.24 mmol) were dissolved in DMF (5 mL), and DIEA (93 mg, 0.72 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then HATU (128 mg, 0.34 mmol) was added. The mixture was stirred at room temperature for another hour. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (column: Waters-Xbridge-C18, 10 μm, 19*250 mm; mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution; gradient: 25-55%; retention time: 9 min) to obtain compound 68. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.10 (d, J = 5.72Hz, 1H), 6.59 (d, J = 2.18Hz, 1H), 6.40 (dd, J = 5.76, 2.18Hz, 1H), 4.93–4.91 (m, 2H), 4.70–4.67 (m, 2H), 4.17–4.11 (m, 2H), 3.69–3.65 (m, 2H), 3.15–3.09 (m, 1H), 2.86 (d, J = 7.68Hz, 2H), 2.55–2.53 (m, 6H). ESI-MS theoretical calculation value C 19 H 21 F3N5OS[M+H] + =424.1, measured value 424.1.

[0921] Example 89

[0922] Synthesis route:

[0923]

[0924] first step

[0925] Intermediate I trifluoroacetate (49 mg, 0.33 mmol) and intermediate AB (100 mg, 0.33 mmol) were dissolved in DMF (5 mL), and DIEA (127 mg, 0.99 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then HATU (175 mg, 0.46 mmol) was added. The mixture was stirred at room temperature for another hour. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (column: Waters-Xbridge-C18, 10 μm, 19*250 mm; mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution; gradient: 35-65%; retention time: 11 min) to obtain compound 89. 1¹H NMR (400MHz, DMSO-d⁶) δ 7.75 (d, J = 5.80Hz, 1H), 6.15–6.12 (m, 1H), 5.87–5.78 (m, 1H), 5.75–5.73 (m, 1H), 4.93–4.90 (m, 2H), 4.71–4.68 (m, 2H), 4.10–4.06 (m, 2H), 3.64–3.58 (m, 2H), 3.12–3.05 (m, 1H), 2.85–2.82 (m, 2H), 2.55–2.53 (m, 6H), 1.38 (d, J = 6.50Hz, 3H). ESI-MS theoretical calculation value C 21 H 25 F3N5O2[M+H] + =436.2, measured value 436.2.

[0926] Example 98

[0927] Synthesis route:

[0928]

[0929] first step

[0930] Intermediate AK (73 mg, 0.41 mmol) and intermediate O (80 mg, 0.28 mmol) were dissolved in DMF (5 mL), and DIEA (142 mg, 1.10 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then HATU (136 mg, 0.36 mmol) was added. The mixture was stirred at room temperature for another hour. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (HPLC) (column: Waters-Xbridge-C18, 10 μm, 19*250 mm; mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution; gradient: 35-65%; retention time: 9 min) to obtain compound 98. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 7.77 (d, J = 5.76Hz, 1H), 6.16 (dd, J = 5.80, 1.96Hz, 1H), 5.79 (d, J = 1.94Hz, 1H), 5.06–5.03 (m, 1H), 4.95–4.86 (m, 3H), 4.79–4.69 (m, 2H), 4.09 (t, J = 8.04Hz, 2H), 3.65–3.58 (m, 2H), 3.14–3.05 (m, 1H), 2.88–2.83 (m, 2H), 2.53 (s, 3H), 2.11–2.01 (m, 1H), 1.18–1.13 (m, 2H), 1.09–1.04 (m, 2H). ESI-MS theoretical calculation value C22 H 25 F3N5O2[M+H] + =448.2, measured value 448.2.

[0931] Example 110

[0932] Synthesis route:

[0933]

[0934] first step

[0935] Intermediate AO (59 mg, 0.36 mmol) and intermediate O (70 mg, 0.24 mmol) were dissolved in DMF (5 mL), and DIEA (94 mg, 0.72 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then HATU (119 mg, 0.31 mmol) was added. The mixture was stirred at room temperature for another hour. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (column: Waters-Xbridge-C18, 10 μm, 19*250 mm; mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution; gradient: 31-61%; retention time: 9 min) to obtain compound 110. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 7.76 (d, J = 5.84Hz, 1H), 6.15 (dd, J = 5.80, 1.96Hz, 1H), 5.78 (d, J = 1.94Hz, 1H), 5.02–4.85 (m, 4H), 4.74–4.67 (m, 2H), 4.11–4.05 (m, 2H), 3.64–3.57 (m, 2H), 3.12–3.04 (m, 1H), 2.90–2.82 (m, 4H), 2.55 (s, 3H), 1.26 (t, J = 7.54Hz, 3H). ESI-MS theoretical calculation value C 21 H 25 F3N5O2[M+H] + =436.2, measured value 436.2.

[0936] Example 111

[0937] Synthesis route:

[0938]

[0939] first step

[0940] Intermediate AP (70 mg, 0.39 mmol) and intermediate O (115 mg, 0.39 mmol) were dissolved in DMF (5 mL), and DIEA (153 mg, 1.18 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then HATU (195 mg, 0.51 mmol) was added. The mixture was stirred at room temperature for another hour. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (column: Waters-Xbridge-C18, 10 μm, 19*250 mm; mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution; gradient: 34-64%; retention time: 9 min) to obtain compound 111. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 7.76 (d, J = 5.78Hz, 1H), 6.15 (dd, J = 5.82, 1.94Hz, 1H), 5.78 (d, J = 1.92Hz, 1H), 4.97–4.83 (m, 4H), 4.73–4.70 (m, 2H), 4.10–4.06 (m, 2H), 3.64–3.57 (m, 2H), 3.13–3.05 (m, 1H), 2.91–2.83 (m, 6H), 1.27 (t, J = 7.54Hz, 6H). ESI-MS theoretical calculation value C 22 H 27 F3N5O2[M+H] + =450.2, measured value 450.2.

[0941] Example 116

[0942] Synthesis route:

[0943]

[0944] first step

[0945] Intermediate I (66 mg, 0.44 mmol) and intermediate AA (90 mg, 0.30 mmol) were dissolved in DMF (5 mL), and DIEA (115 mg, 0.89 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then HATU (169 mg, 0.44 mmol) was added. The mixture was stirred at room temperature for another hour. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (column: Waters-Xbridge-C18, 10 μm, 19*250 mm; mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution; gradient: 32-62%; retention time: 9 min) to obtain compound 116. 1¹H NMR (400MHz, DMSO-d⁶) δ 7.76 (d, J = 5.80Hz, 1H), 6.13 (dd, J = 5.84, 2.00Hz, 1H), 5.87–5.80 (m, 1H), 5.74 (d, J = 1.96Hz, 1H), 4.93–4.90 (m, 2H), 4.71–4.68 (m, 2H), 4.12–4.03 (m, 2H), 3.64–3.55 (m, 2H), 3.14–3.03 (m, 1H), 2.86–2.82 (m, 2H), 2.58–2.52 (m, 6H), 1.38 (d, J = 6.50Hz, 3H). ESI-MS theoretical calculation value C 21 H 25 F3N5O2[M+H] + =436.2, measured value 436.2.

[0946] Example 123

[0947] Synthesis route:

[0948]

[0949] first step

[0950] Intermediate G (33 mg, 0.17 mmol), HATU (78 mg, 0.20 mmol), DIEA (66 mg, 0.51 mmol), and intermediate O (50 mg, 0.17 mmol) were added to DMF (5 mL) and stirred at room temperature for 3 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was then purified by preparative high-performance liquid chromatography (HPLC) (column: Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 30-60%, retention time: 10 min) to obtain compound 123. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 7.76 (d, J = 5.78 Hz, 1H), 6.14 (dd, J = 5.78, 1.82 Hz, 1H), 5.78 (d, J = 1.884 Hz, 1H), 4.95–4.76 (m, 4H), 4.65–4.57 (m, 2H), 4.13–4.05 (m, 6H), 3.61–3.58 (m, 2H), 3.12–3.01 (m, 1H), 2.84–2.81 (m, 2H), 2.40–2.32 (m, 5H). ESI-MS theoretical calculation value C 22 H 26 F3N6O2[M+H] + =463.2, measured value 463.0.

[0951] Example 124

[0952] Synthesis route:

[0953]

[0954] first step

[0955] Intermediate AR (67 mg, 0.27 mmol), 124-1 (50 mg, 0.27 mmol), TEA (83 mg, 0.82 mmol), and cesium fluoride (62 mg, 0.42 mmol) were added to DMSO (5 mL) and stirred at 100 °C for 10 hours. After cooling, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (column: Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 16-46%, retention time: 10 min) to obtain compound 124. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.27 (d, J = 6.02Hz, 1H), 6.59 (d, J = 6.02Hz, 1H), 4.93–4.89 (m, 2H), 4.71–4.68 (m, 2H), 4.29–4.23 (m, 2H), 3.85–3.77 (m, 2H), 3.17–3.07 (m, 1H), 2.89–2.86 (m, 2H), 2.55–2.53 (m, 6H). ESI-MS theoretical calculation value C 18 H 20 F3N6O[M+H] + =393.2, measured value 393.2.

[0956] Example 125

[0957] Synthesis route:

[0958]

[0959] first step

[0960] Intermediate AR (80 mg, 0.32 mmol), 125-1 (70 mg, 0.32 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl), palladium (28 mg, 0.03 mmol), and cesium carbonate (317 mg, 0.97 mmol) were added to 1,4-dioxane (5 mL). The mixture was heated to 100 °C and stirred for 18 hours under nitrogen protection. After cooling, the reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 18-48%, retention time: 10 min) to obtain compound 125. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 9.25 (s, 1H), 7.89 (d, J = 8.62 Hz, 1H), 7.02 (d, J = 2.18 Hz, 1H), 6.68 (dd, J = 8.62, 2.24 Hz, 1H), 4.94–4.92 (m, 2H), 4.72–4.69 (m, 2H), 4.10–4.05 (m, 2H), 3.60–3.56 (m, 2H), 3.16–3.03 (m, 1H), 2.88–2.84 (m, 2H), 2.55 (s, 3H), 2.53 (s, 3H). ESI-MS theoretical calculation value C 20 H 22 N5OS[M+H] + =380.2, measured value 380.0.

[0961] Example 126

[0962] Synthesis route:

[0963]

[0964] first step

[0965] Intermediate AR (65 mg, 0.26 mmol), 126-1 (50 mg, 0.26 mmol), cesium fluoride (60 mg, 0.40 mmol), and TEA (80 mg, 0.79 mmol) were added to DMSO (5 mL). After cooling, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (column: Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 15-45%, retention time: 10 min) to obtain compound 126. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.11 (d, J = 5.50Hz, 1H), 6.28 (d, J = 5.58Hz, 1H), 4.94–4.91 (m, 2H), 4.70–4.67 (m, 2H), 4.32–4.28 (m, 2H), 3.86–3.82 (m, 2H), 3.09–2.98 (m, 3H), 2.87–2.84 (m, 2H), 2.56–2.53 (m, 8H). ESI-MS theoretical calculation value C 21 H 24 F2N5O[M+H] + =400.2, measured value 400.2.

[0966] Example 127

[0967] Synthesis route:

[0968]

[0969] first step

[0970] Intermediate AR (106 mg, 0.43 mmol), 127-1 (100 mg, 0.43 mmol), and cesium carbonate (351 mg, 1.08 mmol) were added to DMF (3 mL). After cooling, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (column: Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 25-55%, retention time: 10 min) to obtain compound 127. 1¹H NMR (400MHz, DMSO-d⁶) δ 7.70 (s, 1H), 4.92–4.89 (m, 2H), 4.71–4.68 (m, 2H), 4.28–4.21 (m, 2H), 3.84–3.78 (m, 2H), 3.22–3.16 (m, 1H), 2.91–2.88 (m, 2H), 2.56–2.53 (m, 6H). ESI-MS theoretical calculation value C 17 H 19 F3N5OS[M+H] + =398.1, measured value 398.1.

[0971] Example 128

[0972] Synthesis route:

[0973]

[0974] first step

[0975] Intermediate I (26 mg, 0.17 mmol), HATU (78 mg, 0.20 mmol), DIEA (66 mg, 0.51 mmol), and intermediate X (50 mg, 0.17 mmol) were added to DMF (5 mL) and stirred at room temperature for 3 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was then purified by preparative high-performance liquid chromatography (HPLC) (column: Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 20-50%, retention time: 10 min) to obtain compound 128. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.10 (d, J = 5.72Hz, 1H), 6.59 (d, J = 2.20Hz, 1H), 6.40 (dd, J = 5.72, 2.22Hz, 1H), 4.93–4.90 (m, 2H), 4.70–4.67 (m, 2H), 4.16–4.12 (m, 2H), 3.68–3.64 (m, 2H), 3.17–3.03 (m, 1H), 2.88–2.85 (m, 2H), 2.55–2.52 (m, 6H). ESI-MS theoretical calculation value C 19 H 21 F3N5OS[M+H] + =424.1, measured value 424.1.

[0976] Example 129

[0977] Synthesis route:

[0978]

[0979] first step

[0980] Intermediate I (26 mg, 0.17 mmol), HATU (78 mg, 0.20 mmol), DIEA (66 mg, 0.51 mmol), and intermediate O (50 mg, 0.17 mmol) were added to DMF (5 mL) and stirred at room temperature for 3 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was then purified by preparative high-performance liquid chromatography (HPLC) (column: Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 37-47%, retention time: 10 min) to obtain compound 129. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 7.76 (d, J = 5.80Hz, 1H), 6.15 (dd, J = 5.78, 1.98Hz, 1H), 5.78 (d, J = 1.96Hz, 1H), 4.99–4.83 (m, 4H), 4.71–4.68 (m, 2H), 4.10–4.06 (m, 2H), 3.62–3.59 (m, 2H), 3.12–3.05 (m, 1H), 2.86–2.83 (m, 2H), 2.56–2.53 (m, 6H). ESI-MS theoretical calculation value C 20 H 23 F3N5O2[M+H] + =422.2, measured value 422.0.

[0981] Example 130

[0982] Synthesis route:

[0983]

[0984] first step

[0985] Intermediate AR (65 mg, 0.26 mmol), 130-1 (50 mg, 0.26 mmol), cesium fluoride (60 mg, 0.40 mmol), and TEA (80 mg, 0.79 mmol) were added to DMSO (5 mL). After cooling, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (column: Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 18-45%, retention time: 9 min) to obtain compound 130. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 4.93–4.89 (m, 2H), 4.72–4.68 (m, 2H), 4.38–4.32 (m, 2H), 3.96–3.88 (m, 2H), 3.29–3.18 (m, 1H), 2.92–2.88 (m, 2H), 2.55–2.52 (m, 6H). ESI-MS theoretical calculation value C 16 H 18 F3N6OS[M+H] + =399.1, measured value 399.1.

[0986] Example 131

[0987] Synthesis route:

[0988]

[0989] first step

[0990] Intermediate AR (67 mg, 0.27 mmol), 131-1 (50 mg, 0.27 mmol), TEA (83 mg, 0.82 mmol), and cesium fluoride (42 mg, 0.27 mmol) were added to DMSO (5 mL) and stirred at 70 °C for 18 hours. After cooling, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (column: Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 5-95%, retention time: 10 min) to obtain compound 131. 1¹H NMR (400MHz, DMSO-d⁶) δ 8.63 (d, J = 2.80Hz, 1H), 6.91 (d, J = 2.80Hz, 1H), 4.92–4.90 (m, 2H), 4.70–4.68 (m, 2H), 4.32–4.28 (m, 2H), 3.87–3.80 (m, 2H), 3.20–3.10 (m, 1H), 2.89–2.86 (m, 2H), 2.55–2.52 (m, 6H). ESI-MS theoretical calculation value C 18 H 20 F3N6O[M+H] + =393.2, measured value 392.9.

[0991] Example 132

[0992] Synthesis route:

[0993]

[0994] first step

[0995] Intermediate G-4 (500 mg, 1.60 mmol) was dissolved in methanol (20 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (127 mg, 0.17 mmol) and TEA (524 mg, 5.18 mmol) were added. The reaction mixture was purged with carbon monoxide three times and then heated to 70 °C and stirred for 18 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 4, v / v) to obtain 132-1. ESI-MS theoretical calculation value C 17 H 20 N3O3[M+H] + =314.1, measured value 314.0.

[0996] Step 2

[0997] 132-1 (200 mg, 0.64 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium borohydride (14 mg, 0.64 mmol) was slowly added at 0 °C, with stirring at room temperature for 1 hour. The reaction solution was quenched with water (30 mL), extracted with dichloromethane (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 4, v / v) to obtain 132-2. ESI-MS theoretical calculation value C 16 H 20 N3O2[M+H] + =286.2, measured value 286.2.

[0998] Step 3

[0999] 132-2 (100 mg, 0.35 mmol) and trifluoroacetic acid (2 mL) were added to a 5 mL microwave tube, and the mixture was heated to 90 °C and stirred for 8 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a crude product containing 132-3, which was directly used in the next reaction step. ESI-MS theoretical calculation value C8H 12 N3O[M+H] + =166.1, measured value 166.1.

[1000] Step 4

[1001] 132-3 (56 mg, 0.34 mmol), HATU (98 mg, 0.26 mmol), DIEA (66 mg, 0.51 mmol), and intermediate O (50 mg, 0.17 mmol) were added to DMF (5 mL) and stirred at room temperature for 3 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was then purified by preparative high-performance liquid chromatography (HPLC) (column: Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 5-95%, retention time: 10 min) to obtain compound 132. 1 ¹H NMR (400MHz, MeOD-d⁴) δ 7.74–7.71 (m, 1H), 6.14–6.12 (m, 1H), 5.82–5.75 (m, 1H), 5.12–5.10 (m, 1H), 4.97–4.89 (m, 4H), 4.82–4.78 (m, 1H), 4.74–4.68 (m, 2H), 4.19–4.14 (m, 2H), 3.73–3.64 (m, 2H), 3.26–3.08 (m, 1H), 2.95–2.91 (m, 2H), 2.65 (s, 3H). ESI-MS theoretical calculation value C 20 H 23 F3N5O3[M+H] + =438.2, measured value 437.9.

[1002] Activity Test 1: Evaluation of the PAM activity of the compound against the M4 receptor

[1003] Experimental objective:

[1004] The activity of the compound on the M4 receptor was determined using a stable cell line expressing the human M4 receptor (M4-Gα15-CHO) via the FLIPR CALCIUM 6ASSAYKIT kit.

[1005] Experimental materials:

[1006]

[1007]

[1008] Experimental instruments:

[1009]

[1010] Cell treatment:

[1011] 1. This study used a CHO cell line that stably expresses the M4-Gα15 receptor, which expresses the human CHRM4 and GNA15 genes, respectively;

[1012] 2. Cell Treatment: M4-Gα15-CHO cells were cultured in F-12 medium containing 10% fetal bovine serum, 0.4 mg / mL hygromycin B, and 0.8 mg / mL genimycin G418 at 37°C and 5% CO2. The old medium was removed and the cells were washed once with phosphate-buffered saline (PBS). Then, 1 mL of trypsin solution was added, and the cells were incubated at 37°C for approximately 2 minutes. When the cells detached from the bottom of the dish, approximately 5 mL of preheated (37°C) complete medium was added. The cell suspension was gently pipetted to separate the aggregated cells. The cell suspension was transferred to sterile centrifuge tubes and centrifuged for 5 minutes (1000 rpm).

[1013] Experimental procedure:

[1014] 1. Cell seeding: M4-Gα15-CHO cells were collected by digestion, resuspended, counted, and seeded into 384-well cell culture plates at a seeding density of 1.2 × 10⁻⁶ cells / well. 4 Cells / 25μL / well. The cell plate was then incubated at 37°C, 5% CO2 for approximately 20 hours.

[1015] 2.24 hours later, prepare the loading buffer according to the FLIPR CALCIUM 6ASSAY KIT kit instructions: freeze-thaw Component A to room temperature, dilute it with detection buffer and probenecid solution to obtain the loading buffer, and keep it at room temperature for later use;

[1016] 3. Remove the culture medium from the cell plate, quickly add 35 μL of loading buffer to each well, centrifuge, and then incubate the cell plate at 37°C in the dark for 120 minutes.

[1017] 4. Prepare the working solution of the compound to be tested, and transfer 5 μL into the corresponding cell well, and incubate at 37°C in the dark for 30 minutes;

[1018] 5. Prepare a 30 nM acetylcholine agonist working solution and transfer 20 μL / well to the 384-well plate.

[1019] 6. Place the cell plate, sample plate, and pipette tip into the corresponding positions on the FLIPR instrument. Use FLIPR to add 10 μL of the agonist diluted in step 5 into each experimental well, and collect data at a wavelength of 515 nm-575 nm.

[1020] 7. By plotting the signal values ​​against compound concentrations, curve fitting and ECG calculations were performed using the nonlinear regression method in GraphPad Prism software. 50 calculate.

[1021] Preparation of detection buffer and sample loading buffer:

[1022] 1. Prepare the detection buffer by mixing 0.5 mol / L 2-(4-(2-hydroxyethyl)piperazine)ethanesulfonic acid buffer with Hank's balanced salt solution (pH 7.4) at a volume ratio of 1:24. Add 10 mL of the detection buffer to a vial of lyophilized CALCIUM 6ASSAY KIT Component A and aliquot and store at -20°C.

[1023] 2. Dissolve probenecid powder in 1 mol / L sodium hydroxide solution to achieve a final concentration of 250 mol / L. Prepare the loading buffer by mixing the detection buffer, freeze-thawed Component A, and probenecid solution in a volume ratio of 44:5:1.

[1024] Experimental results:

[1025] compound <![CDATA[EC 50 (μM)]]> Example 12 0.35 Example 24 0.387 Example 47 0.25 Example 50 1.78 Example 51 1.37 Example 67 0.39 Example 68 0.48 Example 89 0.29 Example 98 1.13 Example 110 0.90 Example 116 0.58

[1026] Experimental conclusion:

[1027] The experimental samples (compounds) were prepared according to the corresponding examples, and the results are shown in the table above. In this experimental system, the compounds of this application showed agonistic activity against the M4 receptor.

[1028] Activity test 2: Evaluation of the pharmacokinetic properties of the compound in mice

[1029] Experimental objective:

[1030] The pharmacokinetic properties of the compounds obtained in the embodiments of the present invention in CD-1 mice were evaluated.

[1031] Experimental materials:

[1032]

[1033] Experimental procedure:

[1034] The pharmacokinetic characteristics of the compounds after intravenous and oral administration were tested in rodents using a standard protocol. In the experiment, the candidate compounds were prepared into clear solutions or suspensions using specified solvents and administered to three mice via single intravenous injection and oral administration, respectively. The solvents for both intravenous and oral administration were 5% dimethyl sulfoxide + 95% (10% polyethylene glycol (15)-hydroxystearate aqueous solution). Whole blood samples were collected within 24 hours into commercially available EDTA2K anticoagulant tubes, centrifuged to obtain the supernatant plasma sample, and proteins were precipitated by adding acetonitrile solution containing an internal standard. After centrifugation, the supernatant was collected, an equal volume of water was added, and after further centrifugation, the supernatant was injected. Blood drug concentrations were quantitatively analyzed and pharmacokinetic parameters were calculated using LCMS / MS.

[1035] Experimental methods:

[1036]

[1037] Experimental results:

[1038]

[1039] Experimental conclusion:

[1040] The test sample was prepared according to the corresponding examples, and the results showed that the compound of this application has good pharmacokinetic properties.

[1041] Activity test 3 Evaluation of the pharmacokinetic properties of the compound in rats

[1042] Experimental objective:

[1043] The pharmacokinetic properties of the compounds obtained in the embodiments of the present invention in SD rats were evaluated.

[1044] Experimental materials:

[1045]

[1046] Experimental procedure:

[1047] The pharmacokinetic characteristics of the compounds after intravenous and oral administration were tested in rodents using a standard protocol. In the experiment, candidate compounds were prepared into clear solutions or suspensions using specified solvents and administered to three rats via single intravenous injection and oral administration, respectively. The solvent for intravenous injection was 5% dimethyl sulfoxide + 95% (10% polyethylene glycol (15)-hydroxystearate aqueous solution), and the solvent for oral administration was 5% dimethyl sulfoxide + 95% (10% polyethylene glycol (15)-hydroxystearate aqueous solution) or 0.5% methylcellulose + 0.2% Tween 80 + 99.3% water. Whole blood samples were collected within 24 hours into commercially available EDTA2K anticoagulant tubes, centrifuged to obtain the supernatant plasma sample, and proteins were precipitated by adding acetonitrile solution containing internal standard. After centrifugation, the supernatant was collected, an equal volume of water was added, and after further centrifugation, the supernatant was injected. Blood drug concentrations were quantitatively analyzed and pharmacokinetic parameters were calculated using LCMS / MS.

[1048] The test sample was prepared according to the corresponding examples. The bioavailability of some compounds in this application is above 80%, the clearance rate is not higher than 16 mL / min / kg, and the half-life T0 is [not specified]. 1 / 2 Between 2 and 10 hours, the area under the curve (AUC) during drug administration... 0-last The compounds in this application exhibit favorable pharmacokinetic properties in the range of 5000-50000 hr*ng / mL.

[1049] Activity test 4 Evaluation of the pharmacokinetic properties of the compound in dogs

[1050] Experimental objective:

[1051] The pharmacokinetic properties of the compounds of the present invention in beagle dogs were evaluated.

[1052] Experimental materials:

[1053]

[1054] Experimental procedure:

[1055] The pharmacokinetic characteristics of the compound in beagle dogs after intravenous and oral administration were tested using a standard protocol. In the experiment, the candidate compound was prepared into a clear solution or suspension using a specified solvent and administered to two beagle dogs via single intravenous injection and oral administration, respectively. The solvent for intravenous injection was 5% dimethyl sulfoxide + 95% (10% polyethylene glycol (15)-hydroxystearate aqueous solution), and the solvent for oral administration was 0.5% methylcellulose + 0.2% Tween 80 + 99.3% water. Whole blood samples were collected within 24 hours into commercially available EDTA2K anticoagulant tubes, centrifuged to obtain the supernatant plasma sample, and acetonitrile solution containing an internal standard was added to precipitate proteins. After centrifugation, the supernatant was collected, an equal volume of water was added, and after further centrifugation, the supernatant was injected. Blood drug concentrations were quantitatively analyzed and pharmacokinetic parameters were calculated using LCMS / MS.

[1056] The test sample was prepared according to the corresponding examples. The bioavailability of some compounds in this application is above 80%, the clearance rate is not higher than 16 mL / min / kg, and the half-life T0 is [not specified]. 1 / 2 Between 2 and 10 hours, the area under the curve (AUC) during drug administration... 0-last The compounds in this application exhibited favorable pharmacokinetic properties in the range of 2000-20000 hr*ng / mL.

[1057] Activity Test 5: Pharmacodynamic Evaluation of Compound 5 in a Mouse Prepulse Inhibition Model

[1058] Experimental objective:

[1059] The efficacy of the present invention in the C57 mouse prepulse inhibition model was evaluated.

[1060] Experimental materials:

[1061]

[1062] Experimental procedure:

[1063] Before drug administration, animals were randomly divided into four groups of 10 animals each based on their body weight. Group 1 was the solvent control group, Group 2 was the model group, and Groups 3 and 4 were the drug administration groups. Animals in Groups 1 and 2 were administered solvent C by gavage, animals in Group 3 were administered the compound of this application by gavage at a dose of 5 mg / kg, and animals in Group 4 were administered the compound of this application by gavage at a dose of 10 mg / kg. Thirty minutes later, animals in Group 1 were injected intraperitoneally with solvent B (physiological saline), and animals in Groups 2, 3, and 4 were injected intraperitoneally with solvent B at a dose of 0.3 mg / kg. The animals were placed in the pre-pulse inhibition test chamber (MK-801) 30 minutes later to begin the experiment, and the peak response time was recorded by the instrument. First, the background noise of the pre-pulse inhibition test chamber was set to 67 dB, and the animals were gently placed in the restraint cage for 10 minutes to acclimatize. Then, the pre-experiment parameters were set: five random stimuli of 120 dB were given to the animals within 5 minutes. The formal experimental parameters were: at the beginning of the experiment, the animals were subjected to 10 shock stimuli: five at 120 dB and five at 81+120 dB, with an average stimulus interval of 7–21 seconds using the random function. The background noise was maintained at 67 dB throughout the experiment. The pre-pulse inhibition percentage of the animals was calculated as: 1 - [(peak response time at 81+120 dB stimulation) / peak response time at 120 dB stimulation] × 100%.

[1064] The test sample was prepared according to the corresponding examples, and the percentage of prepulse inhibition in mice was observed to be about 40%-80%. Some compounds of this application can effectively reverse the damage to prepulse inhibition function caused by MK-801 in mice, and show good in vivo efficacy in the C57 mouse prepulse inhibition model.

[1065] Activity Test 6: Efficacy Evaluation of Compound 6 in a Mouse Forced Swimming Model

[1066] Experimental objective:

[1067] The efficacy of the present invention in the C57 mouse forced swimming model was evaluated.

[1068] Experimental materials:

[1069] Material supplier Item number or model C57BL / 6J mice (male, 20-25g, 6-8 weeks old) Zhejiang Vitonlihua 1820230403129018 Forced swimming test frame and analysis software Vistrack XR-VT

[1070] Experimental procedure:

[1071] Before administration, animals were randomly divided into four groups of eight each, based on their body weight. Group 1 served as the solvent control group, and groups 2 through 4 were the administration groups. Animals in group 1 were administered solvent C via gavage, while animals in groups 2 through 4 were administered the compound described in this application via gavage at doses of 2, 5, and 10 mg / kg, respectively. After administration, the animals were returned to their original cages. One hour later, the animals were gently removed from their cages and calmed for 1-3 minutes until they were no longer stressed. Then, each animal was individually placed in a glass cylinder 40 cm high, 13 cm in diameter, with a water depth of 26 cm and a water temperature of 23°C. The analysis software was then used to automatically record the animals' forced swimming immobility time over a period of four minutes.

[1072] The test sample was prepared according to the corresponding examples. The immobility time of the mice was observed to be approximately 50s-150s. Some compounds of this application can significantly reduce the immobility time of mice in forced swimming and exhibit good antidepressant efficacy in the C57 mouse forced swimming model.

[1073] Activity Test 7: Pharmacodynamic Evaluation of Compound 7 in a Mouse Tail Suspension Model

[1074] Experimental objective:

[1075] The efficacy of the present invention in the C57 mouse tail suspension model was evaluated.

[1076] Experimental materials:

[1077]

[1078] Experimental procedure:

[1079] Before administration, animals were randomly divided into two groups of eight each, based on their body weight. Group 1 was the solvent control group, and Group 2 was the administration group. Animals in Group 1 were administered solvent C by gavage, while animals in Group 2 were administered the compound described in this application by gavage at a dose of 5 mg / kg. After administration, the animals were returned to their original cages. One hour later, the animals were gently removed from their cages and calmed for 1-3 minutes until they were no longer stressed. Then, medical tape was wrapped around the tip of the animal's tail, suspending it in a tail-suspending box. The analysis software automatically recorded the animal's immobility time over 4 minutes.

[1080] The test sample was prepared according to the corresponding examples, and the immobility time of the mice was observed to be within 150 seconds. Some compounds of this application showed good antidepressant efficacy in the C57 mouse tail suspension model.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, in, The compound represented by Formula I is the same as the compound represented by Formula I-3; ； X2 and X3 are N; X4 is -CR 1 -; Each R 1 Independently hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or -NR 1 -1 R 1-2 ; wherein the C1-C6 alkyl and C1-C6 alkoxy groups are optionally independently bounded by one, two, three, or four R groups. a replace; R 1-1 and R 1-2 Independently hydrogen or C1-C6 alkyl; Each R a Independently hydroxyl, C1-C6 alkoxy or NR 1-4 R 1-5 ; R 1-4 and R 1-5 Independently hydrogen or C1-C3 alkyl; Each R i It can be independently hydrogen, halogen, hydroxyl, or C1-C3 alkyl; D is , , or e can be 0, 1, 2, or 3 independently; Each R j Independently H, halogen, C1-C3 alkyl, OR 12-3 or SR 12-4 ; wherein the C1-C3 alkyl group is optionally independently and independently surrounded by one, two or three R groups. k replace; R 12-3 and R 12-4 Independently C1-C3 alkyl; the C1-C3 alkyl group is optionally independently surrounded by one, two or three R... k-1 replace; Each R k It is independently a halogen or a C1-C3 alkyl group; Each R k-1 It is independently a halogen or a C1-C3 alkyl group; In the 3- to 7-membered heterocyclic alkyl groups, the heteroatom is one or more of N, O, and S, and the number of heteroatoms is 1 to 3.

2. The compound of formula I as claimed in claim 1, characterized in that, It satisfies one or more of the following conditions; (1) R 1 In this context, the halogen is F, Cl, Br, or I; (2) R 1 In this context, the C1-C6 alkyl group is a C1-C3 alkyl group; (3) R 1 In this context, the C1-C6 alkoxy group is a C1-C3 alkoxy group; (4) R 1 In this context, the 3-7 membered cycloalkyl group is a 3-6 membered cycloalkyl group; (5) R 1 In this context, the 3-7 membered heterocyclic alkyl group is a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is N or O; and the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is 1 or 2. (6) R a In this context, the C1-C6 alkoxy group is a C1-C3 alkoxy group; (7) R 1-1 and R 1-2 In this context, the C1-C6 alkyl group is a C1-C3 alkyl group; (8) R 1-4 and R 1-5 In this context, the C1-C3 alkyl group is methyl, ethyl, n-propyl, or isopropyl; (9) R i In this context, the halogen is F, Cl, Br, or I; (10) R i In this context, the C1-C3 alkyl group is methyl; (11) R j In this context, the halogen is F, Cl, Br, or I; (12) R j In this context, the C1-C3 alkyl group is methyl, ethyl, or isopropyl; (13) R 12-3 and R 12-4 In this context, the C1-C3 alkyl group is methyl or ethyl; (14) R k In this context, the halogen is F, Cl, Br, or I; (15) R k In this context, the C1-C3 alkyl group is methyl, ethyl, n-propyl, or isopropyl; (16) R k-1 In this context, the halogen is F, Cl, Br, or I; (17) R k-1 In this context, the C1-C3 alkyl group is methyl, ethyl, n-propyl, or isopropyl.

3. The compound of formula I as claimed in claim 1, characterized in that, It satisfies one or more of the following conditions; (1) R 1 In this context, the halogen is F, Cl, Br, or I; (2) R 1 In this context, the C1-C6 alkyl group is methyl, ethyl, or isopropyl. (3) R 1 In this context, the C1-C6 alkoxy group is either methoxy or ethoxy; (4) R 1 In this context, the 3- to 7-membered cycloalkyl group is cyclopropane, cyclobutane, or cyclopentane; (5) R 1 In this context, the 3-7 membered heterocyclic alkyl group is a 4-membered heterocyclic alkyl group; (6) R a In this context, the C1-C6 alkoxy group is a methoxy, ethoxy, or isopropoxy group; (7) R 1-1 and R 1-2 In this context, the C1-C6 alkyl group is methyl or ethyl; (8) R 1-4 and R 1-5 In this context, the C1-C3 alkyl group is methyl, ethyl, or n-propyl; (9) R i In this context, the halogen is either F or Cl; (10) R j In this context, the halogen is either F or Cl; (11) R j In this context, the C1-C3 alkyl group is methyl; (12) R k In this context, the halogen is either F or Cl; (13) R k-1 In this context, the halogen is either F or Cl; (14) R k-1 In this context, the C1-C3 alkyl group is methyl.

4. The compound of formula I as claimed in claim 1, characterized in that, It satisfies one or more of the following conditions; (1) R 1 In this context, the halogen is Cl; (2) R 1 In this context, the C1-C6 alkyl group is methyl; (3) R 1 In this context, the C1-C6 alkoxy group is a methoxy group; (4) R 1 In this context, the 3-7 membered cycloalkyl group is a cyclopropane group; (5) R 1 In this context, the 3-7 membered heterocyclic alkyl group is... or ; (6) R a In this context, the C1-C6 alkoxy group is a methoxy group; (7) R 1-1 and R 1-2 In this context, the C1-C6 alkyl group is methyl; (8) R 1-4 and R 1-5 In this context, the C1-C3 alkyl group is methyl; (9) R i In this context, the halogen is F; (10) R j In this context, the halogen is F; (11) R k In this context, the halogen is F; (12) R k-1 In this context, the halogen is F.

5. The compound of Formula I as claimed in claim 1, characterized in that, It satisfies one or more of the following conditions; (1) Each R 1 It is independently a C1-C6 alkyl, a 3- to 7-membered cycloalkyl or -NR 1-1 R 1-2 ; wherein the C1-C6 alkyl group is optionally independently bound by one, two, three or four R groups. a replace; (2) Each R a Independently hydroxyl, C1-C3 alkoxy or NR 1-4 R 1-5 ; (3) Each R i It can be hydrogen, hydroxyl, or C1-C3 alkyl independently; (4) Each R j Independently H, halogen, C1-C3 alkyl, OR 12-3 or SR 12-4 ; wherein the C1-C3 alkyl group is optionally independently and independently surrounded by one, two or three R groups. k replace; (5) Each R k Halogens are independent of each other; (6) Each R k-1 Halogens are independent of each other; (7) In the 3-7 member heterocyclic alkyl group, the heteroatom is selected from 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3.

6. The compound of Formula I as claimed in claim 1, characterized in that, It satisfies one or more of the following conditions; (1) Each R 1 It can be independently hydrogen, C1-C6 alkyl, 3-7 membered cycloalkyl or -NR 1-1 R 1-2 ; (2) Each R a Independently, it is a hydroxyl group; (3) Each R i Independently hydrogen; (4) Each R j Independently H, halogen, C1-C3 alkyl, OR 12-3 or SR 12-4 ; (5) D is ; (6) In the 3-7 member heterocyclic alkyl group, the heteroatom is N, O or S, and the number of heteroatoms is 1 to 3.

7. The compound of Formula I as claimed in claim 1, characterized in that, It satisfies one or more of the following conditions; (1) Each R 1 Independently, it is a C1-C6 alkyl group; (2) Each R j Independently C1-C3 alkyl, -OR 12-3 or -SR 12-4 .

8. The compound of formula I as claimed in claim 1, characterized in that, Each R j Independently for -OR 12-3 .

9. The compound of Formula I as claimed in claim 1, characterized in that, R j It is a halogen or a C1-C3 alkyl group.

10. The compound of Formula I as claimed in claim 1, characterized in that, The compound represented by Formula I is the same as the compound shown in Formula I-1-4; ； X 6 It can be C or N; Among them, R 1 R i and R j As described in claim 1.

11. The compound of Formula I as claimed in claim 1, characterized in that, D is , or .

12. The compound of formula I as claimed in claim 1, characterized in that, D is .

13. The compound of formula I as claimed in claim 1, characterized in that, Each R 1 Independently C1-C6 alkyl, 3-7 membered cycloalkyl or ; wherein the C1-C6 alkyl group is optionally independently bound by one, two, three or four R groups. a replace; Each R a Independently, it is a hydroxyl group; Each R i It can be hydrogen, hydroxyl, or C1-C3 alkyl independently; Each R j Independently H, halogen, C1-C3 alkyl, OR 12-3 or SR 12-4 ; wherein the C1-C3 alkyl group is optionally independently and independently surrounded by one, two or three R groups. k replace; R 12-3 and R 12-4 Independently C1-C3 alkyl; the C1-C3 alkyl group is optionally independently surrounded by one, two or three R... k-1 replace; Each R k Halogens are independent of each other; Each R k-1 Halogens are independent of each other.

14. The compound of Formula I as claimed in claim 1, characterized in that, It satisfies one or more of the following conditions: (1) Each R 1 Independently methyl, , ethyl, or ; (2) for , , , , or ; (3) B is , or ; (4) D is , , , , , , or .

15. The compound of Formula I as claimed in claim 1, characterized in that, It satisfies one or more of the following conditions: (1) Each R 1 Independently methyl, or ; (2) for , or ; (3) B is or ; (4) D is , , , , , or .

16. The compound of Formula I as claimed in claim 1, characterized in that, D is or .

17. The compound of Formula I as claimed in claim 1, characterized in that, It is any of the following compounds: 。 18. A method for preparing a compound of Formula I as described in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, It is any of the following schemes: Scheme (a): In an organic solvent, in the presence of a catalyst, the compound shown in Formula II undergoes a condensation reaction with the compound shown in Formula III as shown below to obtain the compound shown in Formula I; Scheme (D): In an organic solvent, in the presence of a catalyst, the compound shown in Formula VIII undergoes a cyclization reaction with the compound shown in Formula VIIII as shown below to give the compound shown in Formula I; Wherein, Z is a halogen, TsO-, hydroxyl, methoxy, ethoxy, n-propoxy, or isopropoxy; A, L, B, and D are as described in any one of claims 1 to 17.

19. A method for preparing the compound of Formula I as described in claim 18 or a pharmaceutically acceptable salt thereof, characterized in that, Halogens are chlorine or bromine.

20. A method for preparing the compound of Formula I as described in claim 18 or a pharmaceutically acceptable salt thereof, characterized in that, Z can be hydroxyl, methoxy, ethoxy, n-propoxy, or isopropoxy.

21. A pharmaceutical composition, characterized in that, It contains a therapeutically effective amount of substance A and pharmaceutical excipients; said substance A is a compound of formula I as described in any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.

22. The use of substance A in the preparation of a muscarinic receptor positive allosteric modulator, wherein substance A is a compound of formula I as described in any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 21.

23. The use of a substance A in the preparation of a medicament for treating and / or preventing muscarinic receptor-mediated diseases, wherein the substance A is a compound of Formula I as described in any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 21.

24. The application as described in claim 23, characterized in that, The disease mentioned is Parkinson's disease, Alzheimer's disease, Huntington's disease, schizophrenia, or drug addiction.

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