Nitrogen-containing heterocyclic compounds, pharmaceutically acceptable salts thereof, and methods for preparing and using the same

Abstract

The present invention discloses nitrogen-containing heterocyclic compounds, pharmaceutically acceptable salts thereof, and methods for preparing and using the same. The present invention provides a compound represented by Formula I or a pharmaceutically acceptable salt thereof. The compounds of the present invention can be used as muscarinic receptor positive allosteric modulators, and can treat diseases mediated by (or associated with) M receptors. [Formula 1] JPEG2025534061000325.jpg13169

Description

[Technical Field]

[0001] This application claims priority from Chinese Patent Application No. 202211339268.9, filed on October 28, 2022, and cites the full text of the above Chinese patent application.

[0002] This application claims priority from Chinese Patent Application No. 202211686868.2, filed on December 26, 2022, and cites the full text of the above Chinese patent application.

[0003] This application claims priority from Chinese Patent Application No. 202310099794.0, filed on February 8, 2023, and cites the full text of the above Chinese patent application.

[0004] This application claims priority from Chinese Patent Application No. 202310186197.1, filed on March 1, 2023, and cites the full text of the above Chinese patent application.

[0005] This application claims priority from Chinese Patent Application No. 202310263463.6, filed on March 17, 2023, and cites the full text of the above Chinese patent application.

[0006] This application claims priority from Chinese Patent Application No. 202310719553.1, filed on June 16, 2023, and cites the full text of the above Chinese patent application.

[0007] This application claims priority from Chinese Patent Application No. 202311378324.4, filed on October 23, 2023, and cites the full text of the above Chinese patent application.

[0008] The present invention relates to nitrogen-containing heterocyclic compounds, pharmaceutically acceptable salts thereof, and methods for their preparation and use. [Background technology]

[0009] Muscarinic receptors (M receptors) belong to the G protein-coupled receptor family and are a type of acetylcholine receptor. There are five subtypes of M receptors, of which M1, M3, and M5 bind to Gq proteins, activate phospholipase C, and increase intracellular calcium levels. M2 and M4 bind to Gi proteins, inhibit adenylate cyclase, and decrease cAMP levels. M1 receptors are distributed throughout the central nervous system, gastrointestinal tract, and lymphatic tissues. As the major subtype of M receptor, they can regulate both cellular excitability and cholinergic transmission. M4 receptors are primarily located in the cortex, hippocampus, and striatum and play an important role in regulating dopamine release and motor activity, but do not regulate important peripheral physiological functions (Neuropharmacology 2018, 136, 362).

[0010] M receptor agonists have been widely studied by numerous scientific research institutions and pharmaceutical development companies as treatments for psychiatric disorders. For example, xanomeline, an M1 / M4 receptor agonist, was used in Phase II clinical trials for the treatment of Alzheimer's disease in the 1990s. Treatment with this drug improved cognitive function in patients, but severe peripheral and gastrointestinal toxic side effects were observed. KarXT, consisting of xanomeline and the M1 receptor antagonist trospium, is a schizophrenia treatment drug developed by Karuna. A recent Phase II clinical trial showed that the KarXT treatment group achieved a significant improvement in the Positive and Negative Symptom Scale (PANSS) scores compared with the placebo group, achieving the primary endpoint, but peripheral cholinergic side effects remained (N Engl J Med 2021, 384, 717).

[0011] M1 receptor positive allosteric modulators (PAMs) have become a hot topic of research in the field of psychiatric disorders in recent years. In a genetic mouse model of schizophrenia, the M1 receptor positive allosteric modulator TAK-071 significantly improved memory, cognitive, social, and sensorimotor gating deficits (Neurosci Lett 2021, 764, 136240). This compound is currently undergoing Phase 2 clinical trials as a treatment for Parkinson's disease. Another M1 receptor positive allosteric modulator, MK-7622, ​​is currently undergoing Phase 2 clinical trials to evaluate its efficacy in treating Alzheimer's disease (ACS Med Chem Lett 2018, 9, 652). In patients with schizophrenia participating in a clinical Ib study, Cerevel's M4 receptor positive allosteric modulator, CVL-231, significantly reduced the PANSS total score, while general adverse events were comparable to those in the placebo group and no extrapyramidal side effects were reported. Compared with conventional M receptor orthosteric agonists, positive allosteric modulators pose lower potential risks to the peripheral and central nervous systems, potentially reducing toxic side effects while maintaining efficacy. Therefore, acting on the allosteric modulatory pocket represents a new approach to targeting M receptors for the treatment of psychiatric disorders. M receptor positive allosteric modulators, with their excellent druggability, in vivo efficacy, and safety, have greater development value and market prospects. Summary of the Invention

[0012] The present invention provides nitrogen-containing heterocyclic compounds, pharmaceutically acceptable salts thereof, and methods for preparing and using the same. The compounds of the present invention can be used as muscarinic receptor positive allosteric modulators. The compounds of the present invention can treat diseases mediated by (or associated with) M receptors.

[0013] The present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0014] [ka]

[0015] however,

[0016] [ka]

[0017] teeth,

[0018] [ka]

[0019] and m is a natural number between 0 and 3, n is a natural number from 0 to 3, and m and n are not 0 at the same time; k is a natural number between 0 and 3, X1, X2, X3, X4 and X5 are independently -CR 1 -, N, O, S,

[0020] [ka]

[0021] or a chemical bond, R N-1 is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, or 3- to 7-membered cycloalkyl, wherein the C1-C6 alkyl and C1-C6 alkoxy are independently one, two, three, or four R N-2 is optionally replaced by Each R N-2 are independently halogen; Y and Z are independently carbonyl (CO), -(CR 2 R 3 ) r - or a chemical bond, and r is a natural number from 0 to 5; Each W is independently carbonyl (CO), -O-, -(CR 4 R 5 )-, -NR 6 or a chemical bond, Each R 1 are independently hydrogen, halogen, cyano, hydroxy, 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 wherein the C1-C6 alkylthio, C1-C6 alkyl, and C1-C6 alkoxy are independently one, two, three, or four R a or two R 1 form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl together with the atom to which they are linked; Each R a are independently halogen, cyano, hydroxy, C1-C3 alkyl, C1-C6 alkoxy, or -NR 1-4 R 1-5 Or, two R a form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl together with the atom to which they are linked; R 1-1 and R 1-2 are independently hydrogen or C1-C6 alkyl, wherein said C1-C6 alkyl is independently selected from one, two, three, or four R b or R 1-1 and R 1-2 together with the atom(s) connected thereto form a 3- to 7-membered heterocycloalkyl, wherein said 3- to 7-membered heterocycloalkyl is independently selected from one, two, three, or four R b-2 is optionally replaced by Each R bare independently selected from halogen, cyano, hydroxy, C1-C6 alkoxy, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, C1-C3 alkyl, and NR 1-1-1 R 1-2-1 wherein the 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, and C1-C3 alkyl are independently selected from one, two, three, or four R b-1 is optionally replaced by Each R b-1 are independently halogen, cyano or hydroxy; Each R b-2 are independently halogen, C1-C6 alkyl, or cyano; R 1-4 and R 1-5 are independently hydrogen or C1-C3 alkyl, wherein said C1-C3 alkyl is independently selected from one, two, three, or four R 1-4-1 or R 1-4 and R 1-5 form a 3- to 7-membered heterocycloalkyl with the atom to which they are attached; R 1-1-1 and R 1-2-1 are independently hydrogen or C1-C3 alkyl, wherein said C1-C3 alkyl is independently selected from one, two, three, or four R 1-1-1-1 is optionally replaced by Each R 1-4-1 and R 1-1-1-1 are independently halogen, hydroxy, or cyano; R 2 and R 3 are independently hydrogen, halogen, cyano, hydroxy, C1-C6 alkoxy, or NR 2-1 R 2-2 or R 2 and R 3 form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl with the atom to which they are linked; R 2-1 and R 2-2 are independently hydrogen or C1-C6 alkyl, wherein said C1-C6 alkyl is independently selected from one, two, three, or four R dor R 2-1 and R 2-2 form a 3- to 7-membered heterocycloalkyl with the atom to which they are attached; Each R d are independently halogen, cyano, hydroxy, C1-C6 alkoxy, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, or C1-C3 alkyl; R 4 , R 5 and R 6 are independently hydrogen, halogen, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkyl, or NR 4-1 R 4-2 wherein the C1-C6 alkyl is independently one, two, three, or four R e is optionally replaced by Each R e are independently halogen, cyano, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, or -NR 4-4 R 4-5 and R 4-1 and R 4-2 are independently hydrogen or C1-C6 alkyl, wherein said C1-C6 alkyl is independently selected from one, two, three, or four R f or R 4-1 and R 4-2 form a 3- to 7-membered heterocycloalkyl with the atom to which they are attached; Each R f are independently halogen, cyano, hydroxy, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, C1-C3 alkyl, C1-C3 alkoxy, or -NR 4-1-1 R 4-2-1 and R 4-4 and R 4-5 are independently hydrogen or C1-C3 alkyl, or R 4 and R 5 form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl together with the atom to which they are linked; R 4-1-1 and R 4-2-1are independently hydrogen or C1-C3 alkyl, L is

[0022] [ka]

[0023] and t is a natural number between 0 and 3, u is a natural number between 0 and 3, E is carbonyl,

[0024] [ka]

[0025] , -NHCO-, or a chemical bond; F is carbonyl,

[0026] [ka]

[0027] , —O—, —NH— or a chemical bond; R 8 and R 9 are independently hydrogen, halogen, cyano, hydroxy, or C1-C6 alkyl, wherein said C1-C6 alkyl is independently selected from one, two, three, or four R g or R 8 and R 9 form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl together with the atom to which they are linked; Each R g are independently halogen, cyano, hydroxy, C1-C3 alkyl, or C1-C3 alkoxy; B is a 3- to 7-membered cycloalkyl, a 4- to 6-membered heterocycloalkyl, a 6- to 10-membered aryl, or a 5- to 12-membered heteroaryl, wherein the 3- to 7-membered cycloalkyl, the 4- to 6-membered heterocycloalkyl, the 6- to 10-membered aryl, and the 5- to 12-membered heteroaryl are independently selected from one, two, or three R i is optionally replaced by Each R i are independently hydrogen, halogen, hydroxy, C1-C3 alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, cyano, -NR 11-1 R 11-2 , -OR 11-3 or -SR 11-4 wherein the C1-C3 alkyl is independently one, two, three, or four R i-1 or optionally substituted by R on two of the same atoms i form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl together with the atom connected thereto, or two adjacent R i form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl with the atom(s) linked thereto (wherein the 3- to 7-membered cycloalkyl or the 3- to 7-membered heterocycloalkyl forms a fused ring with B); Each R i-1 are independently C1-C3 alkyl, halogen, cyano, or hydroxy; R 11-1 and R 11-2 are independently hydrogen, C1-C3 alkyl, 3- to 7-membered cycloalkyl, or 3- to 7-membered heterocycloalkyl; or R 11-1 and R 11-2 form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl together with the atom to which they are linked; R 11-3 and R 11-4 are independently C1-C3 alkyl, 3- to 7-membered cycloalkyl, or 3- to 7-membered heterocycloalkyl; R 11-1 , R 11-2 , R 11-3 and R 11-4wherein the C1-C3 alkyl, 3- to 7-membered cycloalkyl, and 3- to 7-membered heterocycloalkyl are independently one, two, or three R i-2 is optionally replaced by Each R i-2 are independently C1-C3 alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, halogen, cyano, or hydroxy; D is hydrogen, halogen, cyano, hydroxy, C1-C6 alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 12-membered heteroaryl, wherein the C1-C6 alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 12-membered heteroaryl are independently selected from one, two, or three R j is optionally replaced by Each R j are independently hydrogen, halogen, cyano, hydroxy, C1-C3 alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, -NR 12-1 R 12-2 , -OR 12-3 or -SR 12-4 wherein the C1-C3 alkyl, 3- to 7-membered cycloalkyl, and 3- to 7-membered heterocycloalkyl are independently one, two, or three R k is optionally replaced by R 12-1 , R 12-2 , R 12-3 and R 12-4 are independently hydrogen, C1-C3 alkyl, 3- to 7-membered cycloalkyl, or 3- to 7-membered heterocycloalkyl, wherein the C1-C3 alkyl, 3- to 7-membered cycloalkyl, and 3- to 7-membered heterocycloalkyl are independently selected from one, two, or three R k-1 or R 12-1 and R 12-2 form a 3- to 7-membered heterocycloalkyl with the atom to which they are attached; Each R k are independently halogen, cyano, hydroxy, C1-C3 alkyl, 3- to 7-membered cycloalkyl, or 3- to 7-membered heterocycloalkyl; Each R k-1 are independently halogen, cyano, hydroxy, C1-C3 alkyl, 3- to 7-membered cycloalkyl, or 3- to 7-membered heterocycloalkyl; A is

[0028] [ka]

[0029] and X1, X2 and X3 are CR 1 In this case, the compound represented by formula I satisfies any one of the following conditions:

[0030] (1) E is -NHCO- or a chemical bond, and F is -O-, -NH- or a chemical bond; (2) E is carbonyl and F is -NH-; (3) L is -(CH2)-, -(CH2)2-,

[0031] [ka]

[0032] the condition that (4) When E or F is carbonyl, B is a 4- to 7-membered cycloalkyl, a 6- to 10-membered aryl, a 5- to 12-membered heteroaryl, or one, two, or three R i and R on the same atom is a 4- to 6-membered heterocycloalkyl substituted by i form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl together with the atom connected thereto, or two adjacent R i form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl with the atom(s) connected thereto (wherein the 3- to 7-membered cycloalkyl or the 3- to 7-membered heterocycloalkyl forms a fused ring with B), wherein the 4- to 7-membered cycloalkyl, the 6- to 10-membered aryl, and the 5- to 12-membered heteroaryl are independently selected from one, two, or three R ithe condition optionally replaced by (5)

[0033] [ka]

[0034] teeth,

[0035] [ka]

[0036] and A is

[0037] [ka]

[0038] In the case where the number of heteroatoms in X1, X2 and X4 is 1 or 2, A is

[0039] [ka]

[0040] and when L is carbonyl, u is a natural number of 1 to 3, B is a 4- to 6-membered heterocycloalkyl, and the 4- to 6-membered heterocycloalkyl is independently one, two, or three R i is optionally replaced by In the 3- to 7-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 12-membered heteroaryl, the heteroatom is one or more of N, O, and S, and the number of heteroatoms is 1 to 5.

[0041] In one embodiment, some groups in the compound represented by formula I or a pharmaceutically acceptable salt thereof have the following definitions, and the definitions of groups not mentioned are as described in any one embodiment of the present invention (hereinafter the content of this paragraph is referred to as "in one embodiment," "in some embodiments," "in one form," or "in one preferred embodiment").

[0042] In one embodiment,

[0043] [ka]

[0044] and where:

[0045] [ka]

[0046] teeth,

[0047] [ka]

[0048] and m is a natural number between 0 and 3, n is a natural number between 0 and 3, and m and n are not 0 at the same time. k is a natural number between 0 and 3, X1, X2, X3, X4 and X5 are independently -CR 1 -, N, O, S,

[0049] [ka]

[0050] or a chemical bond, R N-1 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 independently one, two, three or four R N-2 is optionally replaced by Each R N-2 are independently halogen; Y and Z are independently carbonyl (CO), -(CR 2 R 3 ) r - or a chemical bond, and r is a natural number from 0 to 5; Each W is independently carbonyl (CO), -O-, -(CR 4 R 5 )-, -NR 6 or a chemical bond, Each R 1 are independently hydrogen, halogen, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, or -NR 1-1 R 1-2 wherein the C1-C6 alkyl and C1-C6 alkoxy are independently one, two, three or four R a or two R 1 form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl with the atoms connected thereto; Each R a are independently halogen, cyano, hydroxy, C1-C3 alkyl, C1-C6 alkoxy, or -NR 1-4 R 1-5 Or, two R a form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl together with the atom to which they are linked, and R 1-1 and R 1-2 are independently hydrogen or C1-C6 alkyl, wherein said C1-C6 alkyl is independently selected from one, two, three, or four R b or R 1-1 and R 1-2form a 3- to 7-membered heterocycloalkyl with the atom to which they are attached; Each R b are independently selected from halogen, cyano, hydroxy, C1-C6 alkoxy, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, C1-C3 alkyl, and NR 1-1-1 R 1-2-1 wherein the 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, and C1-C3 alkyl are independently selected from one, two, three, or four R b-1 is optionally replaced by Each R b-1 are independently halogen, cyano or hydroxy; R 1-4 and R 1-5 are independently hydrogen or C1-C3 alkyl, wherein said C1-C3 alkyl is independently selected from one, two, three, or four R 1-4-1 or R 1-4 and R 1-5 form a 3- to 7-membered heterocycloalkyl with the atom to which they are attached; R 1-1-1 and R 1-2-1 are independently hydrogen or C1-C3 alkyl, wherein said C1-C3 alkyl is independently selected from one, two, three, or four R 1-1-1-1 is optionally replaced by Each R 1-4-1 and R 1-1-1-1 are independently halogen, hydroxy, or cyano; R 2 and R 3 are independently hydrogen, halogen, cyano, hydroxy, C1-C6 alkoxy, or NR 2-1 R 2-2 or R 2 and R 3 form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl together with the atom to which they are linked; R 2-1 and R 2-2 are independently hydrogen or C1-C6 alkyl, wherein said C1-C6 alkyl is independently selected from one, two, three, or four R dor R 2-1 and R 2-2 form a 3- to 7-membered heterocycloalkyl with the atom to which they are attached; Each R d are independently halogen, cyano, hydroxy, C1-C6 alkoxy, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, or C1-C3 alkyl; R 4 , R 5 and R 6 are independently hydrogen, halogen, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkyl, or NR 4-1 R 4-2 wherein the C1-C6 alkyl is independently one, two, three, or four R e is optionally replaced by Each R e are independently halogen, cyano, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, or -NR 4-4 R 4-5 and R 4-1 and R 4-2 are independently hydrogen or C1-C6 alkyl, wherein said C1-C6 alkyl is independently selected from one, two, three, or four R f or R 4-1 and R 4-2 form a 3- to 7-membered heterocycloalkyl with the atom to which they are attached; Each R f are independently halogen, cyano, hydroxy, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, C1-C3 alkyl, C1-C3 alkoxy, or -NR 4-1-1 R 4-2-1 and R 4-4 and R 4-5 are independently hydrogen or C1-C3 alkyl, or R 4 and R 5 form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl together with the atom to which they are linked; R 4-1-1 and R 4-2-1are independently hydrogen or C1-C3 alkyl, L is

[0051] [ka]

[0052] and t is a natural number between 0 and 3, u is a natural number between 0 and 3, E is a carbonyl, -NHCO-, or a chemical bond; F is a carbonyl, —O—, —NH—, or a chemical bond; R 8 and R 9 are independently hydrogen, halogen, cyano, hydroxy, or C1-C6 alkyl, wherein said C1-C6 alkyl is independently selected from one, two, three, or four R g or R 8 and R 9 form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl together with the atom to which they are linked; Each R g are independently halogen, cyano, hydroxy, C1-C3 alkyl, or C1-C3 alkoxy; B is a 3- to 7-membered cycloalkyl, a 4- to 6-membered heterocycloalkyl, a 6- to 10-membered aryl, or a 5- to 12-membered heteroaryl, wherein the 3- to 7-membered cycloalkyl, the 4- to 6-membered heterocycloalkyl, the 6- to 10-membered aryl, and the 5- to 12-membered heteroaryl are independently selected from one, two, or three R i is optionally replaced by Each R i are independently hydrogen, halogen, hydroxy, C1-C3 alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, cyano, -NR 11-1 R 11-2 , -OR 11-3 or -SR 11-4 wherein the C1-C3 alkyl is independently one, two, three, or four R i-1or optionally substituted by R on two of the same atoms i form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl together with the atom connected thereto, or two adjacent R i form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl with the atom(s) linked thereto (wherein the 3- to 7-membered cycloalkyl or the 3- to 7-membered heterocycloalkyl forms a fused ring with B); Each R i-1 are independently C1-C3 alkyl, halogen, cyano, or hydroxy; R 11-1 and R 11-2 are independently hydrogen, C1-C3 alkyl, 3- to 7-membered cycloalkyl, or 3- to 7-membered heterocycloalkyl; or R 11-1 and R 11-2 form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl together with the atom to which they are linked; R 11-3 and R 11-4 are independently C1-C3 alkyl, 3- to 7-membered cycloalkyl, or 3- to 7-membered heterocycloalkyl; R 11-1 , R 11-2 , R 11-3 and R 11-4 wherein the C1-C3 alkyl, 3- to 7-membered cycloalkyl, and 3- to 7-membered heterocycloalkyl are independently one, two, or three R i-2 is optionally replaced by Each R i-2 are independently C1-C3 alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, halogen, cyano, or hydroxy; D is hydrogen, halogen, cyano, hydroxy, C1-C6 alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 12-membered heteroaryl, wherein the C1-C6 alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 12-membered heteroaryl are independently selected from one, two, or three R j is optionally replaced by Each Rj are independently hydrogen, halogen, cyano, hydroxy, C1-C3 alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, -NR 12-1 R 12-2 , -OR 12-3 or -SR 12-4 wherein the C1-C3 alkyl, 3- to 7-membered cycloalkyl, and 3- to 7-membered heterocycloalkyl are independently one, two, or three R k is optionally replaced by R 12-1 , R 12-2 , R 12-3 and R 12-4 are independently hydrogen, C1-C3 alkyl, 3- to 7-membered cycloalkyl, or 3- to 7-membered heterocycloalkyl, wherein the C1-C3 alkyl, 3- to 7-membered cycloalkyl, and 3- to 7-membered heterocycloalkyl are independently selected from one, two, or three R k-1 or R 12-1 and R 12-2 form a 3- to 7-membered heterocycloalkyl with the atom to which they are attached; Each R k are independently halogen, cyano, hydroxy, C1-C3 alkyl, 3- to 7-membered cycloalkyl, or 3- to 7-membered heterocycloalkyl; Each R k-1 are independently halogen, cyano, hydroxy, C1-C3 alkyl, 3- to 7-membered cycloalkyl, or 3- to 7-membered heterocycloalkyl; A is

[0053] [ka]

[0054] and X1, X2 and X3 are CR 1 In this case, the compound of formula I satisfies any one of the following conditions:

[0055] (1) E is -NHCO- or a chemical bond, and F is -O-, -NH- or a chemical bond; (2) E is carbonyl and F is -NH-; (3) L is -(CH2)-, -(CH2)2-,

[0056] [ka]

[0057] the condition that (4) When E or F is carbonyl, B is a 4- to 7-membered cycloalkyl, a 6- to 10-membered aryl, a 5- to 12-membered heteroaryl, or one, two, or three R i and R on the same atom is a 4- to 6-membered heterocycloalkyl substituted by i form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl together with the atom connected thereto, or two adjacent R i form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl with the atom(s) connected thereto (wherein the 3- to 7-membered cycloalkyl or the 3- to 7-membered heterocycloalkyl forms a fused ring with B), wherein the 4- to 7-membered cycloalkyl, the 6- to 10-membered aryl, and the 5- to 12-membered heteroaryl are independently selected from one, two, or three R i the condition optionally replaced by (5)

[0058] [ka]

[0059] teeth,

[0060] [ka]

[0061] and A is

[0062] [ka]

[0063] In the case where the number of heteroatoms in X1, X2 and X4 is 1 or 2, A is

[0064] [ka]

[0065] and when L is carbonyl, u is a natural number from 1 to 3, B is a 4- to 6-membered heterocycloalkyl, and the 4- to 6-membered heterocycloalkyl is independently one, two, or three R i is optionally replaced by In the 3- to 7-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 12-membered heteroaryl, the heteroatom is N, O, or S, and the number of heteroatoms is 1 to 5; or in the 3- to 7-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 12-membered heteroaryl, the heteroatom is one or more of N, O, and S, and the number of heteroatoms is 1 to 5.

[0066] In one embodiment, m is preferably a natural number of 0 to 3, for example, 0, 1, 2, or 3, and also, for example, 1, 2, or 3.

[0067] In one embodiment, n is preferably a natural number of 1 to 3, for example, 1, 2, or 3, and also, for example, 1 or 2.

[0068] In one embodiment, n is 1.

[0069] In one embodiment, X1 is N, and X2, X3 and X4 are -CR 1 -, Y and Z are independently -(CH2)-, m and n are 2, and Rj is trifluoromethyl.

[0070] In one embodiment,

[0071] [ka]

[0072] teeth,

[0073] [ka]

[0074] is.

[0075] In one embodiment,

[0076] [ka]

[0077] teeth,

[0078] [ka]

[0079] is.

[0080] In one embodiment, m is 1.

[0081] In one embodiment, k is preferably a natural number of 0 to 3, for example, 0, 1, 2, or 3;

[0082] In one embodiment, r is preferably a natural number of 0 to 5, for example, 0, 1, 2, 3, 4, or 5, and also, for example, 1 or 2.

[0083] In one embodiment, r is 1.

[0084] In one embodiment, r is a natural number of 0 to 3, for example, 1 or 2.

[0085] In one embodiment, R N-1 is a C1-C6 alkyl.

[0086] In one embodiment, R N-1 is hydrogen, C1-C6 alkyl or 3- to 7-membered cycloalkyl.

[0087] In one embodiment, each W is independently -(CR 4 R 5 )-, -O-, -NR 6 -or chemical bond.

[0088] In one embodiment, each W is independently -(CR 4 R 5 )-, -NR 6 -or chemical bond.

[0089] In one embodiment, Y and Z are independently carbonyl (CO) or —(CR 2 R 3 ) r -It is.

[0090] In one embodiment, Y and Z are independently -(CR 2 R 3 ) r -It is.

[0091] In one embodiment, each R 1are independently hydrogen, halogen, 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 is.

[0092] In one embodiment, each R 1 are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio or -NR 1-1 R 1-2 is.

[0093] In one embodiment, each R 1 are independently 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 and for example, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, or -NR 1-1 R 1-2 is.

[0094] In one embodiment, each R 1 are independently hydrogen, halogen, 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 wherein the C1-C6 alkylthio, C1-C6 alkyl, and C1-C6 alkoxy are independently one, two, three, or four R a is optionally replaced by

[0095] In one embodiment, each R 1 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, or -NR 1-1 R 1-2 is.

[0096] In one embodiment, each R 1are independently C1 to C6 alkyl.

[0097] In one embodiment, each R 1 are independently C1 to C6 alkyl or C1 to C6 alkoxy.

[0098] In one embodiment, R 1-1 and R 1-2 are independently hydrogen or C1-C6 alkyl, or R 1-1 and R 1-2 form a 3- to 7-membered heterocycloalkyl with the atom to which they are attached, e.g., R 1-1 and R 1-2 form a 3- to 7-membered heterocycloalkyl with the atom to which they are attached.

[0099] In one embodiment, X1 and X3 are independently N, and X4 and X2 are independently -CR 1 - if R 1 are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, 3- to 7-membered heterocycloalkyl, or -NR 1-1 R 1-2 is.

[0100] In one embodiment, X2 is independently -CR 1 -If R 1 (in X2) is C1-C6 alkyl or C1-C6 alkoxy.

[0101] In one embodiment, when D is pyrimidinyl, each R 1 is independently halogen or 3- to 7-membered cycloalkyl.

[0102] In one embodiment, X2 and X3 are independently N, and X4 and X1 are independently -CR 1 - if R 1 is independently C1-C6 alkyl or 3- to 7-membered heterocycloalkyl.

[0103] In one embodiment, each R a are independently hydroxy, C1-C3 alkoxy or NR 1-4 R 1-5 is.

[0104] In one embodiment, each R a are independently halogen, hydroxy, C1-C6 alkoxy or -NR 1-4 R 1-5 For example, each R a are independently hydroxy, C1-C6 alkoxy or -NR 1-4 R 1-5 and also, for example, hydroxy.

[0105] In one embodiment, each R b are independently hydroxy, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, C1-C3 alkyl, C1-C3 alkoxy, or NR 1-1-1 R 1-2-1 is.

[0106] In one embodiment, each R b are independently hydroxy, 3- to 7-membered cycloalkyl, or C1-C3 alkyl, for example, each R b are independently hydroxy, 3- to 7-membered cycloalkyl.

[0107] In one embodiment, each R b is independently 3 to 7 membered cycloalkyl.

[0108] In one embodiment, R b-1 are independently hydroxy.

[0109] In one embodiment, each R b-1 are independently hydroxy.

[0110] In one embodiment, each R b-2 are independently halogen or C1-C6 alkyl.

[0111] In one embodiment, R 1-4 and R 1-5 are independently C1 to C3 alkyl.

[0112] In one embodiment, each R 1-4-1 are independently halogen.

[0113] In one embodiment, R 1-4-1 is a halogen.

[0114] In one embodiment, R 2 and R 3 are independently hydrogen or NR 2-1 R 2-2 is.

[0115] In one embodiment, R 2 and R 3 are independently hydrogen.

[0116] In one embodiment, R 2-1 and R 2-2 are independently hydrogen or C1-C6 alkyl, for example, hydrogen.

[0117] In one embodiment, R 4 , R 5 and R 6 are independently hydrogen.

[0118] In one embodiment, R 4 , R 5 and R 6 are independently hydrogen or NR 4-1 R 4-2 is.

[0119] In one embodiment, R 4-1 and R 4-2 are independently hydrogen.

[0120] In one embodiment, R e is -NR 4-4R 4-5 is.

[0121] In one embodiment, R 4-4 and R 4-5 are independently hydrogen or C1-C3 alkyl.

[0122] In one embodiment, E is carbonyl,

[0123] [ka]

[0124] , -NHCO- or a chemical bond.

[0125] In one embodiment, E is a carbonyl or a chemical bond.

[0126] In one embodiment, E is carbonyl.

[0127] In one embodiment, t is 0.

[0128] In one embodiment, F is —NH—, —O—, or a chemical bond.

[0129] In one embodiment, F is carbonyl,

[0130] [ka]

[0131] , —O—, —NH—, or a chemical bond.

[0132] In one embodiment, F is a chemical bond.

[0133] In one embodiment, R 8 and R 9are independently hydrogen or C1-C6 alkyl, or R 8 and R 9 form a 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl with the atom to which they are linked.

[0134] In one embodiment, R 8 and R 9 are independently hydrogen or C1-C6 alkyl, or R 8 and R 9 form a 3- to 7-membered cycloalkyl with the atom(s) connected thereto.

[0135] In one embodiment, R 8 and R 9 are independently C1-C6 alkyl, or R 8 and R 9 form a 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl with the atom to which they are linked.

[0136] In one embodiment, B is 4- to 6-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 12-membered heteroaryl, wherein the 5- to 12-membered heteroaryl, 6- to 10-membered aryl, and 4- to 6-membered heterocycloalkyl are independently selected from one, two, or three R i is optionally replaced by

[0137] In one embodiment, B is a 4- to 6-membered heterocycloalkyl or a 5- to 12-membered heteroaryl, wherein the 5- to 12-membered heteroaryl and the 4- to 6-membered heterocycloalkyl are independently selected from one, two, or three R i is optionally replaced by

[0138] In one embodiment, B is a 4- to 6-membered heterocycloalkyl, wherein the 4- to 6-membered heterocycloalkyl is independently selected from one, two, or three R i is optionally replaced by In one embodiment, when B is 6- to 10-membered aryl or 5- to 12-membered heteroaryl, D is hydrogen, halogen, cyano, hydroxy, C1-C6 alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, wherein the C1-C6 alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl are independently selected from one, two, or three R j Preferably, D is hydrogen, C1-C6 alkyl.

[0139] In one embodiment, X2 and X3 are independently N, and X4 and X1 are independently -CR 1 -, B is azetidinyl (e.g.

[0140] [ka]

[0141] )

[0142] In one embodiment, X1 and X3 (or X2 and X4) are -CR 1 - and R 1 is C1-C6 alkyl, each R j independently -OR 12-3 or -SR 12-4 is.

[0143] In one embodiment, R i is hydrogen, halogen, hydroxy, or C1-C3 alkyl, or two R i form a 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl with the atom to which they are linked.

[0144] In one embodiment, each R i are independently hydrogen, halogen, hydroxy, or C1-C3 alkyl, or two R i form a 3- to 7-membered cycloalkyl with the atom to which they are attached, e.g., R iis hydrogen or C1-C3 alkyl, for example, C1-C3 alkyl. i is hydrogen.

[0145] In one embodiment, D is hydrogen, C1-C6 alkyl, or 5-12 membered heteroaryl, wherein the C1-C6 alkyl and 5-12 membered heteroaryl are independently selected from one, two, or three R j is optionally replaced by

[0146] In one embodiment, D is hydrogen, 3- to 7-membered cycloalkyl, C1-C6 alkyl, or 5- to 6-membered heteroaryl, wherein the C1-C6 alkyl and 5- to 6-membered heteroaryl are independently selected from one, two, or three R j is optionally replaced by

[0147] In one embodiment, D is a 5- to 12-membered heteroaryl, wherein the 5- to 12-membered heteroaryl is independently selected from one, two, or three R j is optionally replaced by

[0148] In one embodiment, D is a 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is independently selected from one, two, or three R j is optionally replaced by

[0149] In one embodiment, X2 and X3 are independently N, and X4 and X1 are independently -CR 1 -, D is a 6-membered heteroaryl (e.g.,

[0150] [ka]

[0151] ), wherein the 6-membered heteroaryl is independently one, two, or three R j is optionally replaced by

[0152] In one embodiment, when D is a 5-membered heteroaryl, the 5-membered heteroaryl is

[0153] [ka]

[0154] and each R 1 are independently C1 to C6 alkyl or C1 to C6 alkoxy.

[0155] In one embodiment, R j is halogen, C1-C3 alkyl, OR 12-3 or SR 12-4 is.

[0156] In one embodiment, each R j are independently C1-C3 alkyl, OR 12-3 or SR 12-4 wherein the C1-C3 alkyl is independently one, two, or three R k and preferably, each R j are independently OR 12-3 or SR 12-4 is.

[0157] In one embodiment, each R j are independently halogen, C1-C3 alkyl, OR 12-3 or SR 12-4 is.

[0158] In one embodiment, each R j are independently hydrogen, halogen, C1-C3 alkyl, 3- to 7-membered cycloalkyl, -OR 12-3 or -SR 12-4 is.

[0159] In one embodiment, each R jare independently hydrogen, halogen, C1-C3 alkyl, 3- to 7-membered cycloalkyl, -OR 12-3 or -SR 12-4 wherein the C1-C3 alkyl and 3- to 7-membered cycloalkyl are independently one, two, or three R k is optionally replaced by

[0160] In one embodiment, R j is OR 12-3 is.

[0161] In one embodiment, each R j are independently OR 12-3 is.

[0162] In one embodiment, R j is halogen or C1-C3 alkyl.

[0163] In one embodiment, each R j are independently halogen or C1-C3 alkyl.

[0164] In one embodiment, X1 and X3 are independently N, and X4 and X2 are independently -CR 1 - and each R 1 are independently C1-C6 alkyl and C1-C6 alkoxy, each R j are independently halogen, 3- to 7-membered cycloalkyl, OCH2CF3,

[0165] [ka]

[0166] or SR 12-4 is.

[0167] In one embodiment,

[0168] [ka]

[0169] but

[0170] [ka]

[0171] If R j are independently OR 12-3 or SR 12-4 is.

[0172] In one embodiment, X1 or X4 is -CR 1 - and R 1 are independently 3 to 7-membered heterocycloalkyl or —NR 1-1 R 1-2 If R j are independently OR 12-3 or SR 12-4 is.

[0173] In one embodiment, R 12-3 and R 12-4 are independently C1 to C3 alkyl.

[0174] In one embodiment, R 12-3 and R 12-4 are independently C1-C3 alkyl, wherein said C1-C3 alkyl is independently one, two or three R k-1 is optionally replaced by

[0175] In one embodiment, R 12-1 , R 12-2 , R 12-3 and R 12-4 are independently C1 to C3 alkyl.

[0176] In one embodiment, each R k are independently halogen.

[0177] In one embodiment, R k are independently halogen.

[0178] In one embodiment, each R k-1 are independently halogen.

[0179] In one embodiment, R k-1 are independently halogen.

[0180] In one embodiment, the heteroatom in the 3- to 7-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 12-membered heteroaryl is N, O, or S, and the number of heteroatoms is 1 to 3.

[0181] In one embodiment, the heteroatom in the 3- to 7-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 12-membered heteroaryl is N, O, or S, and the number of heteroatoms is 1 to 5.

[0182] In one embodiment, the heteroatom in the 3- to 7-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and 5- to 12-membered heteroaryl is N, O, or S, and the number of heteroatoms is 1 to 3.

[0183] In one embodiment, the heteroatoms in the 3- to 7-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and 5- to 12-membered heteroaryl are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three.

[0184] In one embodiment, the 3- to 7-membered heterocycloalkyl is a 3- to 6-membered heterocycloalkyl, and the heteroatom is, for example, one or two of N and O, and the number of heteroatoms is, for example, 1 or 2.

[0185] In one embodiment, the 4- to 6-membered heterocycloalkyl is a 4-membered heterocycloalkyl, and the heteroatom is, for example, one or two of N and O, and the number of heteroatoms is, for example, one.

[0186] In one embodiment, the 5- to 6-membered heteroaryl is a 6-membered heteroaryl, and the heteroatom is, for example, one or two of N and O, and the number of heteroatoms is, for example, one.

[0187] In one embodiment, the 5- to 12-membered heteroaryl is a 5- to 10-membered heterocycloalkyl, and the heteroatom is, for example, one or two of N and O, and the number of heteroatoms is, for example, one.

[0188] In one embodiment, A is

[0189] [ka]

[0190] and X1, X2 and X3 are CR 1 When E or F in the compound represented by formula I is

[0191] [ka]

[0192] and In one embodiment, R N-1 The C1 to C6 alkyl in the formula (I) is preferably C1 to C3 alkyl, such as methyl, ethyl, n-propyl or isopropyl, and also, for example, methyl, ethyl or isopropyl.

[0193] In one embodiment, R N-1The C1 to C6 alkoxy in the formula (I) is preferably C1 to C3 alkoxy, for example, methoxy, ethoxy, n-propoxy or isopropoxy.

[0194] In one embodiment, R N-1 The 3- to 7-membered cycloalkyl in the above formula is preferably 3- to 6-membered cycloalkyl, for example, cyclopropyl, cyclobutyl or cyclopentyl.

[0195] In one embodiment, R N-2 The halogen in the formula (I) is F, Cl, Br or I, for example, F or Cl.

[0196] In one embodiment, R 1 The halogen in the formula (I) is F, Cl, Br or I, for example, F or Cl, and also for example, Cl.

[0197] In one embodiment, R 1 The C1 to C6 alkyl in the formula (I) is preferably C1 to C3 alkyl, such as methyl, ethyl, n-propyl or isopropyl, and also, for example, methyl, ethyl or isopropyl.

[0198] In one embodiment, R 1 The C1 to C6 alkoxy in the formula (I) is preferably C1 to C3 alkoxy, such as methoxy, ethoxy, n-propoxy or isopropoxy, and also, for example, methoxy or ethoxy.

[0199] In one embodiment, R 1 The C1 to C6 alkylthio in the above formula is preferably C1 to C3 alkylthio, for example, methylthio, ethylthio, n-propylthio or isopropylthio, and also, for example, methylthio.

[0200] In one embodiment, R 1The 3- to 7-membered cycloalkyl in the formula (I) is preferably 3- to 6-membered cycloalkyl, such as cyclopropyl, cyclobutyl, or cyclopentyl, and also, for example, cyclopropyl or cyclobutyl.

[0201] In one embodiment, R 1 The 3- to 7-membered heterocycloalkyl in the formula (I) is preferably a 3- to 6-membered heterocycloalkyl, the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O, the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2, and the 3- to 6-membered heterocycloalkyl is more preferably a 4-membered heterocycloalkyl, for example,

[0202] [ka]

[0203] is.

[0204] In one embodiment, R 1 The 3- to 7-membered heterocycloalkyl in the formula (I) is preferably a 3- to 6-membered heterocycloalkyl, the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O, the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2, and the 3- to 6-membered heterocycloalkyl is more preferably a 4-membered heterocycloalkyl, for example,

[0205] [ka]

[0206] is.

[0207] In one embodiment, R aThe halogen in is preferably F, Cl, Br or I, for example, F or Cl, and also, for example, F.

[0208] In one embodiment, R a The C1 to C3 alkyl in the formula (I) is preferably methyl, ethyl, n-propyl or isopropyl.

[0209] In one embodiment, R a The C1 to C6 alkoxy in the formula (I) is preferably C1 to C3 alkoxy, such as methoxy, ethoxy, n-propoxy or isopropoxy, and also, for example, methoxy.

[0210] In one embodiment, R a The 3- to 7-membered heterocycloalkyl in the formula (I) is preferably a 3- to 6-membered heterocycloalkyl, the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O, the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2, and the 3- to 6-membered heterocycloalkyl is more preferably a 4-membered heterocycloalkyl, for example,

[0211] [ka]

[0212] is.

[0213] In one embodiment, R a The 3- to 7-membered cycloalkyl in the above formula is preferably 3- to 6-membered cycloalkyl, for example, cyclopropyl, cyclobutyl or cyclopentyl.

[0214] In one embodiment, R 1-1 and R 1-2The C1 to C6 alkyl in the formula (I) is preferably C1 to C3 alkyl, such as methyl, ethyl, n-propyl or isopropyl, and also, for example, methyl or ethyl (eg, methyl).

[0215] In one embodiment, R 1-1 and R 1-2 The 3- to 7-membered heterocycloalkyl in the above formula is preferably a 3- to 6-membered heterocycloalkyl, and the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O. The number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2. The 3- to 6-membered heterocycloalkyl is, for example, a 4-membered heterocycloalkyl, and also, for example,

[0216] [ka]

[0217] is.

[0218] In one embodiment, R b The halogen in is preferably F, Cl, Br or I, for example, F or Cl.

[0219] In one embodiment, R b The C1 to C6 alkoxy in the formula (I) is preferably C1 to C3 alkoxy, for example, methoxy, ethoxy, n-propoxy or isopropoxy.

[0220] In one embodiment, R b The 3- to 7-membered cycloalkyl in the formula (I) is preferably 3- to 6-membered cycloalkyl, such as cyclopropyl, cyclobutyl or cyclopentyl, and also, for example, cyclopropyl.

[0221] In one embodiment, R bThe 3- to 7-membered heterocycloalkyl in the formula (I) is preferably a 3- to 6-membered heterocycloalkyl, the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O, and the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2.

[0222] In one embodiment, R b The C1 to C3 alkyl in the formula (I) is preferably methyl, ethyl, n-propyl or isopropyl, for example, methyl.

[0223] In one embodiment, R b-1 The halogen in is preferably F, Cl, Br or I, for example, F or Cl.

[0224] In one embodiment, R b-2 The halogen in is preferably F, Cl, Br or I, for example F.

[0225] In one embodiment, R b-2 The C1-C6 alkyl in the formula (I) is preferably a C1-C3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl, and also preferably methyl (e.g.,

[0226] [ka]

[0227] )

[0228] In one embodiment, R 1-4 and R 1-5 The C1 to C3 alkyl in the formula (I) is preferably methyl, ethyl, n-propyl or isopropyl, for example, methyl, ethyl or n-propyl, and also, for example, methyl.

[0229] In one embodiment, R1-4 and R 1-5 The 3- to 7-membered heterocycloalkyl in the formula (I) is preferably a 3- to 6-membered heterocycloalkyl, the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O, the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2, and the 3- to 6-membered heterocycloalkyl is more preferably a 4-membered heterocycloalkyl, for example,

[0230] [ka]

[0231] is.

[0232] In one embodiment, R 1-1-1 and R 1-2-1 The C1 to C3 alkyl in the formula (I) is preferably methyl, ethyl, n-propyl or isopropyl.

[0233] In one embodiment, R 1-4-1 and R 1-1-1-1 The halogen in is preferably F, Cl, Br or I, for example, F or Cl, and also, for example, F.

[0234] In one embodiment, R 2 and R 3 The halogen in is preferably F, Cl, Br or I, for example, F or Cl.

[0235] In one embodiment, R 2 and R 3 The C1 to C6 alkoxy in the formula (I) is preferably C1 to C3 alkoxy, for example, methoxy, ethoxy, n-propoxy or isopropoxy.

[0236] In one embodiment, R 2 and R 3The 3- to 7-membered cycloalkyl in the above formula is preferably 3- to 6-membered cycloalkyl, for example, cyclopropyl, cyclobutyl or cyclopentyl.

[0237] In one embodiment, R 2 and R 3 The 3- to 7-membered heterocycloalkyl in the formula (I) is preferably a 3- to 6-membered heterocycloalkyl, the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O, and the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2.

[0238] In one embodiment, R 2-1 and R 2-2 The C1 to C6 alkyl in the formula (I) is preferably C1 to C3 alkyl, such as methyl, ethyl, n-propyl or isopropyl, and also, for example, methyl or ethyl.

[0239] In one embodiment, R 2-1 and R 2-2 The 3- to 7-membered heterocycloalkyl in the formula (I) is preferably a 3- to 6-membered heterocycloalkyl, the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O, and the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2.

[0240] In one embodiment, R d The halogen in is preferably F, Cl, Br or I, for example, F or Cl.

[0241] In one embodiment, R d The C1 to C6 alkoxy in the formula (I) is preferably C1 to C3 alkoxy, for example, methoxy, ethoxy, n-propoxy or isopropoxy.

[0242] In one embodiment, R dThe 3- to 7-membered cycloalkyl in the above formula is preferably 3- to 6-membered cycloalkyl, for example, cyclopropyl, cyclobutyl or cyclopentyl.

[0243] In one embodiment, R d The 3- to 7-membered heterocycloalkyl in the formula (I) is preferably a 3- to 6-membered heterocycloalkyl, the heteroatom of the 3- to 7-membered heterocycloalkyl is preferably N or O, and the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2.

[0244] In one embodiment, R d The C1 to C3 alkyl in the formula (I) is preferably methyl, ethyl, n-propyl or isopropyl.

[0245] In one embodiment, R 4 , R 5 and R 6 The halogen in is preferably F, Cl, Br or I, for example, F or Cl.

[0246] In one embodiment, R 4 , R 5 and R 6 The C1 to C6 alkoxy in the formula (I) is preferably C1 to C3 alkoxy, for example, methoxy, ethoxy, n-propoxy or isopropoxy.

[0247] In one embodiment, R 4 , R 5 and R 6 The C1 to C6 alkyl in the formula (I) is preferably a C1 to C3 alkyl, such as methyl, ethyl, n-propyl or isopropyl.

[0248] In one embodiment, R e The halogen in is preferably F, Cl, Br or I, for example, F or Cl.

[0249] In one embodiment, R e The C1 to C3 alkyl in the formula (I) is preferably methyl, ethyl, n-propyl or isopropyl.

[0250] In one embodiment, R e The C1 to C3 alkoxy in the formula (I) is preferably methoxy, ethoxy, n-propoxy or isopropoxy.

[0251] In one embodiment, R 4-1 and R 4-2 The C1 to C6 alkyl in the formula (I) is preferably a C1 to C3 alkyl, such as methyl, ethyl, n-propyl or isopropyl.

[0252] In one embodiment, R 4-1 and R 4-2 The 3- to 7-membered heterocycloalkyl in the formula (I) is preferably a 3- to 6-membered heterocycloalkyl, the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O, and the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2.

[0253] In one embodiment, R f The halogen in the formula (I) is preferably F, Cl, Br or I, for example F or Cl.

[0254] In one embodiment, R f The 3- to 7-membered cycloalkyl in the above formula is preferably 3- to 6-membered cycloalkyl, for example, cyclopropyl, cyclopropyl or cyclopentyl.

[0255] In one embodiment, R fThe 3- to 7-membered heterocycloalkyl in the formula (I) is preferably a 3- to 6-membered heterocycloalkyl, the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O, and the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2.

[0256] In one embodiment, R f The C1 to C3 alkyl in the formula (I) is preferably methyl, ethyl, n-propyl or isopropyl.

[0257] In one embodiment, R f The C1 to C3 alkoxy in the formula (I) is preferably methoxy, ethoxy, n-propoxy or isopropoxy.

[0258] In one embodiment, R 4-4 and R 4-5 The C1 to C3 alkyl in the formula (I) is preferably methyl, ethyl, n-propyl or isopropyl.

[0259] In one embodiment, t is a natural number of 0 to 3, for example, 0, 1, 2, or 3, and further for example, 0, 1, or 2, for example, 0.

[0260] In one embodiment, u is a natural number of 0 to 3, for example, 0, 1, 2, or 3, and further, for example, 0, 1, or 2, for example, 1.

[0261] In one embodiment, R 8 and R 9 The halogen in is preferably F, Cl, Br or I, for example, F or Cl.

[0262] In one embodiment, R 8 and R 9The C1 to C6 alkyl in the formula (I) is preferably C1 to C3 alkyl, such as methyl, ethyl, n-propyl or isopropyl, and also, for example, methyl.

[0263] In one embodiment, R 8 and R 9 The 3- to 7-membered cycloalkyl in the formula (I) is preferably 3- to 6-membered cycloalkyl, such as cyclopropyl, cyclobutyl or cyclopentyl, and also, for example, cyclopropyl.

[0264] In one embodiment, R 8 and R 9 The 3- to 7-membered heterocycloalkyl in the above formula is preferably a 3- to 6-membered heterocycloalkyl, the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O, the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2, and the 3- to 6-membered heterocycloalkyl is, for example, a 4-membered heterocycloalkyl, or, for example, oxetane.

[0265] In one embodiment, R g The halogen in is preferably F, Cl, Br or I, for example, F or Cl.

[0266] In one embodiment, R g The C1 to C3 alkyl in the formula (I) is preferably methyl, ethyl, n-propyl or isopropyl, for example, methyl.

[0267] In one embodiment, R g The C1 to C3 alkoxy in the formula (I) is preferably methoxy, ethoxy, n-propoxy or isopropoxy.

[0268] In one embodiment, the 3- to 7-membered cycloalkyl for B is preferably 3- to 6-membered cycloalkyl, for example, cyclopropyl, cyclobutyl, or cyclopentyl.

[0269] In one embodiment, the 4- to 7-membered cycloalkyl for B is preferably 3- to 6-membered cycloalkyl, for example, cyclobutyl or cyclopentyl.

[0270] In one embodiment, the 4- to 6-membered heterocycloalkyl in B is preferably a 4-membered heterocycloalkyl, a 5-membered heterocycloalkyl, or a 6-membered heterocycloalkyl. The heteroatom in the 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, and 6-membered heterocycloalkyl is preferably N. The number of heteroatoms in the 4- to 6-membered heterocycloalkyl is preferably 1 or 2. For example, the 4- to 6-membered heterocycloalkyl is preferably a 4-membered azacycloalkyl (e.g.,

[0271] [ka]

[0272] ) or 5-membered azacycloalkyl (e.g.,

[0273] [ka]

[0274] )

[0275] In one embodiment, the 6- to 10-membered aryl in B is preferably phenyl or naphthyl, for example, phenyl.

[0276] In one embodiment, R iThe halogen in is preferably F, Cl, Br or I, for example, F or Cl, and also, for example, F.

[0277] In one embodiment, R i The C1 to C3 alkyl in the formula (I) is preferably methyl, ethyl, n-propyl or isopropyl, and is, for example, methyl.

[0278] In one embodiment, R i The 3- to 7-membered cycloalkyl in the formula (I) is preferably 3- to 6-membered cycloalkyl, such as cyclopropyl, cyclobutyl or cyclopentyl, or, for example, cyclopropyl or cyclobutyl, such as cyclopropyl.

[0279] In one embodiment, R i The 3- to 7-membered heterocycloalkyl in the formula (I) is preferably a 3- to 6-membered heterocycloalkyl, the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O, and the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2.

[0280] In one embodiment, R i-1 The halogen in is preferably F, Cl, Br or I, for example, F or Cl.

[0281] In one embodiment, R i-1 The C1 to C3 alkyl in the formula (I) is preferably methyl, ethyl, n-propyl or isopropyl.

[0282] In one embodiment, R 11-1 , R 11-2 , R 11-3 and R 11-4 The C1 to C3 alkyl in the formula (I) is, for example, methyl, ethyl, n-propyl or isopropyl.

[0283] In one embodiment, R 11-3 and R 11-4 The 3- to 7-membered cycloalkyl in the formula (I) may be a 3- to 6-membered cycloalkyl, such as cyclopropyl, cyclobutyl, or cyclopentyl.

[0284] In one embodiment, R 11-3 and R 11-4 The 3- to 7-membered heterocycloalkyl in the formula (I) is preferably a 3- to 6-membered heterocycloalkyl, the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O, and the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2.

[0285] In one embodiment, R 11-1 and R 11-2 The 3- to 7-membered cycloalkyl in the above formula is preferably 3- to 6-membered cycloalkyl, for example, cyclopropyl, cyclobutyl or cyclopentyl.

[0286] In one embodiment, R 11-1 and R 11-2 The 3- to 7-membered heterocycloalkyl in the formula (I) is preferably a 3- to 6-membered heterocycloalkyl, the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O, and the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2.

[0287] In one embodiment, R i-2 The halogen in is preferably F, Cl, Br or I, for example, F or Cl.

[0288] In one embodiment, R i-2 The C1 to C3 alkyl in the formula (I) is preferably methyl, ethyl, n-propyl or isopropyl.

[0289] In one embodiment, R i-2The 3- to 7-membered cycloalkyl in the above formula is preferably 3- to 6-membered cycloalkyl, for example, cyclopropyl, cyclobutyl or cyclopentyl.

[0290] In one embodiment, R i-2 The 3- to 7-membered heterocycloalkyl in the formula (I) is preferably a 3- to 6-membered heterocycloalkyl, the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O, and the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2.

[0291] In one embodiment, the halogen in D is preferably F, Cl, Br or I, for example, F or Cl.

[0292] In one embodiment, the C1 to C6 alkyl in D is preferably C1 to C3 alkyl, for example, methyl, ethyl, n-propyl or isopropyl, and also, for example, methyl.

[0293] In one embodiment, the 3- to 7-membered cycloalkyl in D is preferably 3- to 6-membered cycloalkyl, for example, cyclopropyl, cyclobutyl, or cyclopentyl, for example, cyclopropyl.

[0294] In one embodiment, the 6- to 10-membered aryl in D is phenyl or naphthyl.

[0295] In one embodiment, R j The halogen in is preferably F, Cl, Br or I, for example, F or Cl, and also, for example, F.

[0296] In one embodiment, R jThe C1 to C3 alkyl in the formula (I) is preferably methyl, ethyl, n-propyl or isopropyl, and is, for example, methyl, ethyl or isopropyl, and is preferably methyl.

[0297] In one embodiment, R j The 3- to 7-membered cycloalkyl in the formula (I) is preferably 3- to 6-membered cycloalkyl, such as cyclopropyl, cyclobutyl or cyclopentyl, and also, for example, cyclopropyl.

[0298] In one embodiment, R j The 3- to 7-membered heterocycloalkyl in the formula (I) is preferably a 3- to 6-membered heterocycloalkyl, the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O, and the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2.

[0299] In one embodiment, R 12-1 , R 12-2 , R 12-3 and R 12-4 The C1-C3 alkyl in the formula (I) is preferably methyl, ethyl, n-propyl or isopropyl, for example, methyl or ethyl, and also, for example, methyl, ethyl or isopropyl.

[0300] In one embodiment, R 12-1 , R 12-2 , R 12-3 and R 12-4 The 3- to 7-membered cycloalkyl in the above formula is preferably 3- to 6-membered cycloalkyl, for example, cyclopropyl, cyclobutyl or cyclopentyl.

[0301] In one embodiment, R 12-1 , R 12-2 , R 12-3 and R 12-4The 3- to 7-membered heterocycloalkyl in the formula (I) is preferably a 3- to 6-membered heterocycloalkyl, the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O, and the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2.

[0302] In one embodiment, R k The halogen in is preferably F, Cl, Br or I, for example, F or Cl, and also, for example, F.

[0303] In one embodiment, R k The C1 to C3 alkyl in the formula (I) is preferably methyl, ethyl, n-propyl or isopropyl.

[0304] In one embodiment, R k The 3- to 7-membered cycloalkyl in the above formula is preferably 3- to 6-membered cycloalkyl, for example, cyclopropyl, cyclobutyl or cyclopentyl.

[0305] In one embodiment, R k The 3- to 7-membered heterocycloalkyl in the formula (I) is preferably a 3- to 6-membered heterocycloalkyl, the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O, and the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2.

[0306] In one embodiment, R k-1 The halogen in is preferably F, Cl, Br or I, for example, F or Cl, and also, for example, F.

[0307] In one embodiment, R k-1 The C1 to C3 alkyl in the formula (I) is preferably methyl, ethyl, n-propyl or isopropyl, for example, methyl.

[0308] In one embodiment, R k-1 The 3- to 7-membered cycloalkyl in the above formula is preferably 3- to 6-membered cycloalkyl, for example, cyclopropyl, cyclobutyl or cyclopentyl.

[0309] In one embodiment, R k-1 The 3- to 7-membered heterocycloalkyl in the formula (I) is preferably a 3- to 6-membered heterocycloalkyl, the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O, and the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2.

[0310] In some embodiments, the compound of formula I is a compound of formula I-1, a compound of formula I-2, a compound of formula I-3, a compound of formula I-4, or a compound of formula I-5,

[0311] [ka]

[0312] where X6 is N or CH, and 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 is as defined in any one of the claims of the present invention.

[0313] In some embodiments, the compound represented by formula I-1 is a compound represented by formula I-1-1, a compound represented by formula I-1-2, a compound represented by formula I-1-3, or a compound represented by formula I-1-4,

[0314] [ka]

[0315] where R 1 , R j , Z, n, X6, X2 and X4 are as defined in any one of the claims of the present invention.

[0316] In some embodiments, the compound represented by formula I-5 is a compound represented by formula I-5-1:

[0317] [ka]

[0318] where R 1 , R 8 , R 9 and R j is as defined in any one of the claims of the present invention.

[0319] In some embodiments, the compound represented by formula I-4 is a compound represented by formula I-4-1:

[0320] [ka]

[0321] wherein B is as defined in any one of the claims of the present invention.

[0322] In one embodiment, X1, X2, X3, X4, and X5 are independently -CR 1 -, N, O, S,

[0323] [ka]

[0324] or a chemical bond, and the number of heteroatoms in X1, X2, X3, X4 and X5 is 0, 1, 2 or 3.

[0325] In one embodiment, X1, X2, X3, X4, and X5 are independently -CR 1 -, N, S,

[0326] [ka]

[0327] or a chemical bond, and the number of heteroatoms in X1, X2, X3, X4 and X5 is 1 or 2.

[0328] In one embodiment, X1 and X3 are independently N, and X4 and X2 are independently -CR 1 -It is.

[0329] In one embodiment, X2 and X3 are independently N, and X4 and X1 are independently -CR 1 -It is.

[0330] In one embodiment, X1 and X4 are independently N, and X2 and X3 are independently -CR 1 -It is.

[0331] In some embodiments,

[0332] [ka]

[0333] X1, X2, X3 and X4 in each group are independently -CR 1 - or N, and the number of heteroatoms is 0, 1 or 2.

[0334] In some embodiments,

[0335] [ka]

[0336] Y and Z in the formula (I) are independently carbonyl (CO) or -(CR 2 R 3 ) r -, r is 1, and R 2 and R 3 are independently H, —(CH2)—, —(NHCH2)—, —(NHCH2CH2)—, or

[0337] [ka]

[0338] is.

[0339] In some embodiments,

[0340] [ka]

[0341] In the formula, m is 2, n is 2, and Y and Z are independently -(CR 2 R 3 ) r -, r is 1, and R 2 and R 3 are independently H.

[0342] In some embodiments,

[0343] [ka]

[0344] is a benzo 5-membered heterocycloalkyl, wherein the heteroatom in the 5-membered heterocycloalkyl is N, and the number of heteroatoms is 1, for example,

[0345] [ka]

[0346] and e is independently 1, 2 or 3, and also includes, for example,

[0347] [ka]

[0348] is.

[0349] In some embodiments,

[0350] [ka]

[0351] is a benzo 5-membered heterocycloalkyl, wherein the heteroatom in the 5-membered heterocycloalkyl is N, and the number of heteroatoms is 1, for example,

[0352] [ka]

[0353] is.

[0354] In some embodiments,

[0355] [ka]

[0356] is a benzo 7-membered heterocycloalkyl, wherein the heteroatom in the 7-membered heterocycloalkyl is N, and the number of heteroatoms is 1 or 2, for example,

[0357] [ka]

[0358] and e is independently 0, 1, 2 or 3, and also includes, for example,

[0359] [ka]

[0360] is.

[0361] In some embodiments,

[0362] [ka]

[0363] is a benzo 7-membered heterocycloalkyl, wherein the heteroatom in the 7-membered heterocycloalkyl is N, and the number of heteroatoms is 1 or 2, for example,

[0364] [ka]

[0365] is.

[0366] In some embodiments,

[0367] [ka]

[0368] is a 6-membered heteroaryl-fused 5-membered heterocycloalkyl, wherein the heteroatom in the 6-membered heteroaryl is N and the number of heteroatoms is 1 or 2, preferably the heteroatom in the 5-membered heterocycloalkyl is N and the number of heteroatoms is 1, for example,

[0369] [ka]

[0370] and e is independently 0, 1 or 2, and also includes, for example,

[0371] [ka]

[0372] is.

[0373] In some embodiments,

[0374] [ka]

[0375] is a 6-membered heteroaryl-fused 5-membered heterocycloalkyl, wherein the heteroatom in the 6-membered heteroaryl is N and the number of heteroatoms is 1 or 2, preferably the heteroatom in the 5-membered heterocycloalkyl is N and the number of heteroatoms is 1, for example,

[0376] [ka]

[0377] is.

[0378] In some embodiments,

[0379] [ka]

[0380] is a 6-membered heteroaryl-fused 5-membered heterocycloalkyl, wherein the heteroatom in the 6-membered heteroaryl is N and the number of heteroatoms is 2, preferably the heteroatom in the 5-membered heterocycloalkyl is N and the number of heteroatoms is 1, for example,

[0381] [ka]

[0382] and e is independently 0, 1 or 2.

[0383] In some embodiments,

[0384] [ka]

[0385] is a 6-membered heteroaryl-fused 5-membered heterocycloalkyl, wherein the heteroatom in the 6-membered heteroaryl is N, and the number of heteroatoms is 1, for example,

[0386] [ka]

[0387] and e is independently 0, 1, 2 or 3, and also includes, for example,

[0388] [ka]

[0389] is.

[0390] In some embodiments,

[0391] [ka]

[0392] is a 6-membered heteroaryl-fused 5-membered heterocycloalkyl, wherein the heteroatom in the 6-membered heteroaryl is N, and the number of heteroatoms is 1, for example,

[0393] [ka]

[0394] is.

[0395] In some embodiments,

[0396] [ka]

[0397] is a 6-membered heteroaryl-fused 6-membered heterocycloalkyl, wherein the heteroatom in the 6-membered heteroaryl is N and the number of heteroatoms is 1, preferably the heteroatom in the 6-membered heterocycloalkyl is N and the number of heteroatoms is 1, for example,

[0398] [ka]

[0399] and e is independently 0, 1, 2 or 3, and also includes, for example,

[0400] [ka]

[0401] is.

[0402] In some embodiments,

[0403] [ka]

[0404] is a 6-membered heteroaryl-fused 6-membered heterocycloalkyl, wherein the heteroatom in the 6-membered heteroaryl is N and the number of heteroatoms is 1, preferably the heteroatom in the 6-membered heterocycloalkyl is N and the number of heteroatoms is 1, for example,

[0405] [ka]

[0406] is.

[0407] In some embodiments,

[0408] [ka]

[0409] is a 6-membered heteroaryl-fused 7-membered heterocycloalkyl, wherein the heteroatom in the 6-membered heteroaryl is N and the number of heteroatoms is 1 or 2, preferably the heteroatom in the 7-membered heterocycloalkyl is N and the number of heteroatoms is 1, for example,

[0410] [ka]

[0411] and e is independently 0, 1, 2, or 3;

[0412] [ka]

[0413] is.

[0414] In some embodiments,

[0415] [ka]

[0416] is a 6-membered heteroaryl-fused 7-membered heterocycloalkyl, wherein the heteroatom in the 6-membered heteroaryl is N and the number of heteroatoms is 1 or 2, preferably the heteroatom in the 7-membered heterocycloalkyl is N and the number of heteroatoms is 1, for example,

[0417] [ka]

[0418] is.

[0419] In some embodiments,

[0420] [ka]

[0421] is a 5-membered heteroaryl-fused 5-membered heterocycloalkyl, wherein the heteroatom in the 5-membered heteroaryl is N or S, and the number of heteroatoms is 1 or 2, preferably the heteroatom in the 5-membered heterocycloalkyl is N, and the number of heteroatoms is 1, for example,

[0422] [ka]

[0423] is.

[0424] In some embodiments,

[0425] [ka]

[0426] is a 5-membered heteroaryl-fused 5-membered heterocycloalkyl, wherein the heteroatom in the 5-membered heteroaryl is N and / or S, and the number of heteroatoms is 1 or 2, preferably the heteroatom in the 5-membered heterocycloalkyl is N, and the number of heteroatoms is 1, for example,

[0427] [ka]

[0428] is.

[0429] In some embodiments,

[0430] [ka]

[0431] is a 5-membered heteroaryl-fused 6-membered heterocycloalkyl, wherein the heteroatom in the 5-membered heteroaryl is N and the number of heteroatoms is 1 or 2, preferably the heteroatom in the 6-membered heterocycloalkyl is N and the number of heteroatoms is 1, for example,

[0432] [ka]

[0433] and, for example,

[0434] [ka]

[0435] is.

[0436] In some embodiments,

[0437] [ka]

[0438] is a 5-membered heteroaryl-fused 6-membered heterocycloalkyl, wherein the heteroatom in the 5-membered heteroaryl is N and the number of heteroatoms is 1, preferably the heteroatom in the 6-membered heterocycloalkyl is N and the number of heteroatoms is 1, for example,

[0439] [ka]

[0440] and, for example,

[0441] [ka]

[0442] is.

[0443] In some embodiments,

[0444] [ka]

[0445] is a 5-membered heteroaryl-fused 6-membered heterocycloalkyl, wherein the heteroatom in the 5-membered heteroaryl is N and the number of heteroatoms is 1, preferably the heteroatom in the 6-membered heterocycloalkyl is N and the number of heteroatoms is 1, for example,

[0446] [ka]

[0447] is.

[0448] In some embodiments,

[0449] [ka]

[0450] X1, X2, X3, X4 and X5 in each group are independently -CR 1 -, N, S,

[0451] [ka]

[0452] or a chemical bond, and the number of heteroatoms in X1, X2, X3, X4 and X5 is 0, 1 or 2.

[0453] In some embodiments,

[0454] [ka]

[0455] is C-(W) k - where C is

[0456] [ka]

[0457] wherein C is a 5-membered heteroaryl, a 6-membered heteroaryl, or a phenyl, and preferably, the heteroatom in the 5-membered heteroaryl is N and the number of heteroatoms is 1 or 2, or the heteroatom in the 6-membered heteroaryl is N and the number of heteroatoms is 1, for example, C is pyridyl, phenyl, or

[0458] [ka]

[0459] is.

[0460] In some embodiments,

[0461] [ka]

[0462] In the formula, W is —O—, —CH 2 —, or —NH—.

[0463] In some embodiments, the 5- to 12-membered heteroaryl for B is preferably a 5- to 6-membered heteroaryl, a benzo 5- to 6-membered heteroaryl, a 5- to 7-membered cycloalkyl-fused phenyl, a 5- to 7-membered cycloalkyl-fused 5- to 6-membered heteroaryl, a 5- to 6-membered heteroaryl-fused 5- to 6-membered heteroaryl, a 5- to 7-membered heterocycloalkyl-fused 5- to 6-membered heteroaryl, or a 5- to 7-membered heterocycloalkyl-fused 5- to 6-membered aryl, more preferably a 5- to 6-membered heteroaryl, a benzo 5- to 6-membered heteroaryl, a 5- to 6-membered heteroaryl-fused 5- to 6-membered heteroaryl, a 5- to 7-membered heterocycloalkyl-fused 5- to 6-membered heteroaryl, or a 5- to 7-membered heterocycloalkyl-fused phenyl.

[0464] In some embodiments, the heteroatom in the 4- to 6-membered heterocycloalkyl of B is N, and the number of heteroatoms is 1, for example,

[0465] [ka]

[0466] and e is independently 0, 1, 2 or 3, and also includes, for example,

[0467] [ka]

[0468] is.

[0469] In some embodiments, the heteroatom in the 4- to 6-membered heterocycloalkyl of B is N, and the number of heteroatoms is 1, for example,

[0470] [ka]

[0471] is.

[0472] In some embodiments, B is selected from two R i and R on the same atom. i form a 3- to 7-membered cycloalkyl with the atom connected thereto, and the 3- to 7-membered cycloalkyl is preferably a 3- to 6-membered cycloalkyl, for example, B is a 4-membered heterocycloalkyl or a 5-membered heterocycloalkyl, and two R i forms a 3-4 membered cycloalkyl, and for example, B is

[0473] [ka]

[0474] is.

[0475] In some embodiments, B is selected from two R i and R on the same atom. i form a 3- to 7-membered cycloalkyl with the atom connected thereto, and the 3- to 7-membered cycloalkyl is preferably a 3- to 6-membered cycloalkyl, for example, B is a 4-membered heterocycloalkyl, and two R i forms a 3-4 membered cycloalkyl, and for example, B is

[0476] [ka]

[0477] is.

[0478] In some embodiments, B is selected from two R i and R on the same atom. iform a 3- to 7-membered cycloalkyl with the atom connected thereto, and the 3- to 7-membered cycloalkyl is preferably a 3- to 6-membered cycloalkyl, for example, B is a 5-membered heterocycloalkyl, and two R i forms a 3-4 membered cycloalkyl, and for example, B is

[0479] [ka]

[0480] is.

[0481] In some embodiments, B is selected from two R i ortho-substituted 4- to 6-membered heterocycloalkyl, and two adjacent R i form a 3- to 7-membered cycloalkyl with the atom linked thereto (wherein the 3- to 7-membered cycloalkyl forms a fused ring with B), and the 3- to 7-membered cycloalkyl is preferably a 3- to 6-membered cycloalkyl, for example, B is a 5-membered heterocycloalkyl, and two R i form a 3-membered cycloalkyl with the atom to which it is connected, and for example, B can be

[0482] [ka]

[0483] is.

[0484] In some embodiments, B is a 5-membered heteroaryl, wherein the heteroatoms in the 5-membered heteroaryl are N and / or S, and the number of heteroatoms is 1 or 2, for example:

[0485] [ka]

[0486] is.

[0487] In some embodiments, B is a 5-membered heteroaryl, wherein the heteroatom in the 5-membered heteroaryl is N or S, and the number of heteroatoms is 1 or 2, for example:

[0488] [ka]

[0489] is.

[0490] In some embodiments, B is a 6-membered heteroaryl, wherein the heteroatom in the 6-membered heteroaryl is N, and the number of heteroatoms is 1 or 2, for example:

[0491] [ka]

[0492] is.

[0493] In some embodiments, the 6- to 10-membered aryl in B is, for example, phenyl.

[0494] In some embodiments, B is benzo 5-membered heterocycloalkyl, wherein the heteroatom in said 5-membered heterocycloalkyl is N and the number of heteroatoms is 1, for example,

[0495] [ka]

[0496] and e is independently 0, 1, 2 or 3, and also includes, for example,

[0497] [ka]

[0498] is.

[0499] In some embodiments, B is benzo 5-membered heterocycloalkyl, wherein the heteroatom in said 5-membered heterocycloalkyl is N and the number of heteroatoms is 1, for example,

[0500] [ka]

[0501] is.

[0502] In some embodiments, B is a benzo 6-membered heteroaryl, wherein the heteroatom in the 6-membered heteroaryl is N and the number of heteroatoms is 1 or 2, for example:

[0503] [ka]

[0504] is.

[0505] In some embodiments, B is a benzo 6-membered heterocycloalkyl, wherein the heteroatoms in the 6-membered heterocycloalkyl are N and / or O, and the number of heteroatoms is 1 or 2, such as, for example:

[0506] [ka]

[0507] is.

[0508] In some embodiments, B is a benzo 6-membered heterocycloalkyl, wherein the heteroatom in the 6-membered heterocycloalkyl is N or O, and the number of heteroatoms is 1 or 2, for example:

[0509] [ka]

[0510] is.

[0511] In some embodiments, B is a 6-membered heteroaryl-fused 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, for example:

[0512] [ka]

[0513] is.

[0514] In some embodiments, B is a 6-membered heteroaryl-fused 6-membered heterocycloalkyl, wherein the heteroatom in the 6-membered heteroaryl is N and the number of heteroatoms is 1, preferably the heteroatom in the 6-membered heterocycloalkyl is O and the number of heteroatoms is 1, for example,

[0515] [ka]

[0516] is.

[0517] In some embodiments, the 5- to 12-membered heteroaryl in D is preferably a 5- to 6-membered heteroaryl, a benzo 5- to 6-membered heteroaryl, a 5- to 7-membered cycloalkyl-fused phenyl, a 5- to 7-membered cycloalkyl-fused 5- to 6-membered heteroaryl, a 5- to 6-membered heteroaryl-fused 5- to 6-membered heteroaryl, a 5- to 7-membered heterocycloalkyl-fused 5- to 6-membered heteroaryl, or a 5- to 7-membered heterocycloalkyl-fused 5- to 6-membered aryl, more preferably a 5- to 6-membered heteroaryl, a benzo 5- to 6-membered heteroaryl, a 5- to 7-membered cycloalkyl-fused 5- to 6-membered heteroaryl, a 5- to 6-membered heteroaryl-fused 5- to 6-membered heteroaryl, a 5- to 7-membered heterocycloalkyl-fused 5- to 6-membered heteroaryl, or a 5- to 7-membered heterocycloalkyl-fused phenyl.

[0518] In some embodiments, the 5- to 12-membered heteroaryl in D is a 5- to 6-membered heteroaryl, a benzo 5- to 6-membered heteroaryl, a 5- to 7-membered cycloalkyl-fused 5- to 6-membered heteroaryl, a 5- to 6-membered heteroaryl-fused 5- to 6-membered heteroaryl, a 5- to 7-membered heterocycloalkyl-fused 5- to 6-membered heteroaryl, or a 5- to 7-membered heterocycloalkyl-fused phenyl, wherein the heteroatoms in the 5- to 6-membered heteroaryl and the 5- to 7-membered heterocycloalkyl are preferably one, two, or three selected from N, O, and S, and the number of heteroatoms is preferably one, two, or three.

[0519] In some embodiments, the 5- to 6-membered heteroaryl in D is preferably a 5-membered heteroaryl or a 6-membered heteroaryl.

[0520] In some embodiments, D is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, or trifluoromethyl.

[0521] In some embodiments, D is a 6-membered heteroaryl, wherein the heteroatom in the 6-membered heteroaryl is N, and the number of heteroatoms is 1 or 2, for example:

[0522] [ka]

[0523] and e is independently 0, 1, 2 or 3, and also includes, for example,

[0524] [ka]

[0525] is.

[0526] In some embodiments, D is a 6-membered heteroaryl, wherein the heteroatom in the 6-membered heteroaryl is N, and the number of heteroatoms is 1 or 2, for example:

[0527] [ka]

[0528] is.

[0529] In some embodiments, D is a 5-membered heteroaryl, wherein the heteroatoms in the 5-membered heteroaryl are one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3, such as, for example:

[0530] [ka]

[0531] is.

[0532] In some embodiments, D is a 5-membered heteroaryl, wherein the heteroatoms in the 5-membered heteroaryl are N and / or S, and the number of heteroatoms is 1, 2, or 3, e.g.,

[0533] [ka]

[0534] is.

[0535] In some embodiments, D is a 5-membered heteroaryl, wherein the heteroatom in the 5-membered heteroaryl is N or S, and the number of heteroatoms is 1, 2, or 3, for example:

[0536] [ka]

[0537] is.

[0538] In some embodiments, D is a 6-membered heteroaryl-fused 5-membered heterocycloalkyl, wherein the heteroatom in the 6-membered heteroaryl is N and the number of heteroatoms is 1, preferably the heteroatom in the 5-membered heterocycloalkyl is N or O and the number of heteroatoms is 1, for example:

[0539] [ka]

[0540] and e is independently 0, 1, 2 or 3, and also includes, for example,

[0541] [ka]

[0542] is.

[0543] In some embodiments, D is a 6-membered heteroaryl-fused 5-membered heterocycloalkyl, wherein the heteroatom in the 6-membered heteroaryl is N and the number of heteroatoms is 1, preferably the heteroatom in the 5-membered heterocycloalkyl is N or O and the number of heteroatoms is 1, for example:

[0544] [ka]

[0545] is.

[0546] In some embodiments, D is a 6-membered heteroaryl-fused 5-membered cycloalkyl, wherein the heteroatom in the 6-membered heteroaryl is N, and the number of heteroatoms is 1, for example,

[0547] [ka]

[0548] and e is independently 0, 1, 2 or 3, and also includes, for example,

[0549] [ka]

[0550] is.

[0551] In some embodiments, D is a 6-membered heteroaryl-fused 5-membered cycloalkyl, wherein the heteroatom in the 6-membered heteroaryl is N, and the number of heteroatoms is 1, for example,

[0552] [ka]

[0553] is.

[0554] In some embodiments, D is a benzo 5-membered heteroaryl, wherein the heteroatoms in the 5-membered heteroaryl are N and / or S, and the number of heteroatoms is 2, e.g.,

[0555] [ka]

[0556] and e is independently 0, 1, 2 or 3, and also includes, for example,

[0557] [ka]

[0558] is.

[0559] In some embodiments, D is a 5- to 6-membered heteroaryl-fused 5- to 6-membered heteroaryl, wherein the heteroatom in the 5- to 6-membered heteroaryl is N and / or S, and the number of heteroatoms is 1, 2, or 3, for example:

[0560] [ka]

[0561] and e is independently 0, 1, 2, or 3.

[0562] In some embodiments, D is a 5- to 6-membered heteroaryl-fused 5- to 6-membered heterocycloalkyl, wherein the heteroatom in the 5- to 6-membered heteroaryl is N and the number of heteroatoms is 1, 2, or 3, preferably the heteroatom in the 5- to 6-membered heterocycloalkyl is O and the number of heteroatoms is 1, 2, or 3, for example:

[0563] [ka]

[0564] and e is independently 0, 1, 2, or 3.

[0565] In some embodiments, D is a phenyl-fused 5-6 membered heterocycloalkyl, wherein the heteroatoms in said 5-6 membered heterocycloalkyl are selected from one or more of O, N, and O, and there are 1, 2, or 3 heteroatoms, such as, for example:

[0566] [ka]

[0567] and e is independently 0, 1, 2, or 3.

[0568] In some embodiments, D is benzo 5-6 membered heteroaryl, wherein the heteroatom in the 5-6 membered heteroaryl is N, and the number of heteroatoms is 1, 2, or 3, for example:

[0569] [ka]

[0570] and e is independently 0, 1, 2, or 3.

[0571] In one embodiment,

[0572] [ka]

[0573] is preferably a 6-membered heteroaryl-fused 5-membered heterocycloalkyl, wherein the heteroatom in the 6-membered heteroaryl is N and the number of heteroatoms is 2, for example,

[0574] [ka]

[0575] and e is independently 0, 1 or 2, and also includes, for example,

[0576] [ka]

[0577] is.

[0578] In one embodiment,

[0579] [ka]

[0580] is preferably a 6-membered heteroaryl-fused 5-membered heterocycloalkyl, wherein the heteroatom in the 6-membered heteroaryl is N and the number of heteroatoms is 2, for example,

[0581] [ka]

[0582] is.

[0583] In one embodiment,

[0584] [ka]

[0585] is preferably a 6-membered heteroaryl-fused 7-membered heterocycloalkyl, wherein the heteroatom in the 6-membered heteroaryl is N, and the number of heteroatoms is 1 or 2, for example,

[0586] [ka]

[0587] is.

[0588] In one embodiment, E in L is preferably carbonyl, F is a chemical bond, t is 0, and u is 1.

[0589] In one embodiment, B is preferably a 4-membered heterocycloalkyl, wherein the heteroatom in the 4-membered heterocycloalkyl is N, and the number of heteroatoms is 1 or 2, for example,

[0590] [ka]

[0591] is.

[0592] In one embodiment, D is preferably a 6-membered heteroaryl, wherein the heteroatom in the 6-membered heteroaryl is N, and the number of heteroatoms is 1 or 2, for example,

[0593] [ka]

[0594] is.

[0595] In one preferred embodiment, the compound is represented by formula I or a pharmaceutically acceptable salt thereof,

[0596] [ka]

[0597] where:

[0598] [ka]

[0599] teeth,

[0600] [ka]

[0601] and m is a natural number between 0 and 3, n is a natural number from 0 to 3, and m and n are not 0 at the same time; k is a natural number between 0 and 3, X1, X2, X3, X4 and X5 are independently -CR 1 -, N, S,

[0602] [ka]

[0603] or a chemical bond, R N-1 is hydrogen, C1-C6 alkyl or 3- to 7-membered cycloalkyl, Y and Z are independently carbonyl (CO) or -(CR 2 R 3 ) r -, and r is a natural number between 0 and 5, Each W independently represents -O-, -(CR 4 R 5 )-, -NR 6 or a chemical bond, Each R 1 are independently hydrogen, halogen, 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 wherein the C1-C6 alkylthio, C1-C6 alkyl, and C1-C6 alkoxy are independently one, two, three, or four R a is optionally replaced by Each R aare independently halogen, hydroxy, C1-C6 alkoxy or -NR 1-4 R 1-5 and R 1-1 and R 1-2 are independently hydrogen or C1-C6 alkyl, wherein said C1-C6 alkyl is independently selected from one, two, three, or four R b or R 1-1 and R 1-2 together with the atom to which they are connected form a 3- to 7-membered heterocycloalkyl, wherein said 3- to 7-membered heterocycloalkyl is selected from the group consisting of one, two, three, or four R b-2 is optionally replaced by Each R b are independently hydroxy, 3- to 7-membered cycloalkyl, or C1-C3 alkyl; Each R b-2 are independently halogen or C1-C6 alkyl, R 1-4 and R 1-5 are independently hydrogen or C1-C3 alkyl, wherein said C1-C3 alkyl is independently selected from one, two, three, or four R 1-4-1 or R 1-4 and R 1-5 form a 3- to 7-membered heterocycloalkyl with the atom to which they are attached; Each R 1-4-1 are independently halogen; R 2 and R 3 are independently hydrogen or NR 2-1 R 2-2 and R 2-1 and R 2-2 are independently hydrogen or C1-C6 alkyl, R 4 , R 5 and R 6 are independently hydrogen or NR 4-1 R 4-2 and R 4-1 and R 4-2 are independently hydrogen, L is

[0604] [ka]

[0605] and t is a natural number between 0 and 3, u is a natural number between 0 and 3, E is carbonyl,

[0606] [ka]

[0607] , -NHCO- or a chemical bond, F is carbonyl,

[0608] [ka]

[0609] , —O—, —NH— or a chemical bond; R 8 and R 9 are independently hydrogen or C1-C6 alkyl, or R 8 and R 9 form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl together with the atom to which they are linked; B is a 4- to 6-membered heterocycloalkyl, a 6- to 10-membered aryl, or a 5- to 12-membered heteroaryl, wherein the 4- to 6-membered heterocycloalkyl, the 4- to 6-membered aryl, and the 5- to 12-membered heteroaryl are independently selected from one, two, or three R i is optionally replaced by Each R i are independently hydrogen, halogen, hydroxy, or C1-C3 alkyl, or two R on the same atom i form a 3- to 7-membered cycloalkyl with the atom connected thereto, or two adjacent R i form a 3- to 7-membered cycloalkyl with the atom(s) connected thereto, D is hydrogen, C1-C6 alkyl, or 5-12 membered heteroaryl, wherein the C1-C6 alkyl and 5-12 membered heteroaryl are independently selected from one, two, or three R j is optionally replaced by Each R j are independently hydrogen, halogen, C1-C3 alkyl, 3- to 7-membered cycloalkyl, -OR 12-3 or -SR 12-4 wherein the C1-C3 alkyl and 3- to 7-membered cycloalkyl are independently one, two, or three R k is optionally replaced by R 12-3 and R 12-4 are independently C1-C3 alkyl, wherein said C1-C3 alkyl is independently one, two or three R k-1 is optionally replaced by Each R k are independently halogen; Each R k-1 are independently halogen; The heteroatoms in the 3- to 7-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 12-membered heteroaryl are one or more selected from N, O and S, and the number of heteroatoms is 1 to 3.

[0610] In one preferred embodiment, the compound is represented by formula I or a pharmaceutically acceptable salt thereof,

[0611] [ka]

[0612] where:

[0613] [ka]

[0614] teeth,

[0615] [ka]

[0616] and m is a natural number between 0 and 3, n is a natural number from 0 to 3, and m and n are not 0 at the same time; k is a natural number between 0 and 3, X1, X2, X3, X4 and X5 are independently -CR 1 -, N, S,

[0617] [ka]

[0618] or a chemical bond, R N-1 is a C1-C6 alkyl, Y and Z are independently carbonyl (CO) or -(CR 2 R 3 ) r -, and r is a natural number between 0 and 5, Each W is independently -(CR 4 R 5 )-, -NR 6 or a chemical bond, Each R 1 are independently hydrogen, halogen, 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 wherein the C1-C6 alkylthio, C1-C6 alkyl, and C1-C6 alkoxy are independently one, two, three, or four R a is optionally replaced by Each R a are independently hydroxy, C1-C6 alkoxy or -NR 1-4 R 1-5 and R 1-1 and R 1-2are independently hydrogen or C1-C6 alkyl, wherein said C1-C6 alkyl is independently selected from one, two, three, or four R b or R 1-1 and R 1-2 together with the atom to which they are connected form a 3- to 7-membered heterocycloalkyl, wherein said 3- to 7-membered heterocycloalkyl is selected from the group consisting of one, two, three, or four R b-2 is optionally replaced by Each R b are independently 3- to 7-membered cycloalkyl; Each R b-2 are independently halogen or C1-C6 alkyl, R 1-4 and R 1-5 are independently C1-C3 alkyl, R 2 and R 3 are independently hydrogen or NR 2-1 R 2-2 and R 2-1 and R 2-2 are independently hydrogen, R 4 , R 5 and R 6 are independently hydrogen, L is

[0619] [ka]

[0620] and t is a natural number between 0 and 3, u is a natural number between 0 and 3, E is carbonyl,

[0621] [ka]

[0622] , -NHCO- or a chemical bond, F is a chemical bond, R 8 and R 9 are independently hydrogen or C1-C6 alkyl, or R 8 and R 9 form a 3- to 7-membered cycloalkyl with the atom(s) connected thereto, B is a 4- to 6-membered heterocycloalkyl, a 6- to 10-membered aryl, or a 5- to 12-membered heteroaryl, wherein the 4- to 6-membered heterocycloalkyl, the 6- to 10-membered aryl, and the 5- to 12-membered heteroaryl are independently selected from one, two, or three R i is optionally replaced by Each R i are independently hydrogen, halogen, hydroxy, or C1-C3 alkyl, or two R on the same atom i form a 3- to 7-membered cycloalkyl with the atom(s) connected thereto, D is hydrogen, C1-C6 alkyl, or 5-12 membered heteroaryl, wherein the C1-C6 alkyl and 5-12 membered heteroaryl are independently selected from one, two, or three R j is optionally replaced by Each R j are independently hydrogen, halogen, C1-C3 alkyl, 3- to 7-membered cycloalkyl, -OR 12-3 or -SR 12-4 wherein the C1-C3 alkyl and 3- to 7-membered cycloalkyl are independently one, two, or three R k is optionally replaced by R 12-3 and R 12-4 are independently C1-C3 alkyl, wherein said C1-C3 alkyl is independently one, two or three R k-1 is optionally replaced by Each R k are independently halogen; Each R k-1 are independently halogen; The heteroatom in the 3- to 7-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 12-membered heteroaryl is one or more of N, O and S, and the number of heteroatoms is 1 to 3.

[0623] In one preferred embodiment, the compound is represented by formula I or a pharmaceutically acceptable salt thereof,

[0624] [ka]

[0625] where:

[0626] [ka]

[0627] teeth,

[0628] [ka]

[0629] and m is a natural number between 1 and 3, n is a natural number between 1 and 3, k is a natural number between 1 and 3, X1, X2, X3, X4 and X5 are independently -CR 1 -, N, O, S,

[0630] [ka]

[0631] or a chemical bond, and the number of heteroatoms in X1, X2, X3, X4, and X5 is 0, 1, 2, or 3; R N-1 is hydrogen or C1-C6 alkyl, Y and Z are independently carbonyl (CO) or -(CR 2 R 3 ) r - and r is a natural number between 1 and 2, Each W independently represents -O-, -(CR 4 R5 )-, -NR 6 or a chemical bond, Each R 1 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, or -NR 1-1 R 1-2 wherein the C1-C6 alkyl and C1-C6 alkoxy are independently one, two, three or four R a is optionally replaced by Each R a are independently hydroxy, C1-C3 alkoxy or NR 1-4 R 1-5 and R 1-1 and R 1-2 are independently hydrogen or C1-C6 alkyl, wherein said C1-C6 alkyl is independently selected from one, two, three, or four R b or R 1-1 and R 1-2 form a 3- to 7-membered heterocycloalkyl with the atom to which they are attached; Each R b are independently hydroxy, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, C1-C3 alkyl, C1-C3 alkoxy, or NR 1-1-1 R 1-2-1 wherein the 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, and C1-C3 alkyl are independently selected from one, two, three, or four R b-1 is optionally replaced by Each R b-1 are independently hydroxy; R 1-4 and R 1-5 are independently hydrogen or C1-C3 alkyl, wherein said C1-C3 alkyl is independently selected from one, two, three, or four R 1-4-1 or R 1-4 and R 1-5 form a 3- to 7-membered heterocycloalkyl with the atom to which they are attached; Each R 1-4-1are independently halogen; R 1-1-1 and R 1-2-1 are independently hydrogen or C1-C3 alkyl, R 2 and R 3 are independently hydrogen or NR 2-1 R 2-2 and R 2-1 and R 2-2 are independently hydrogen or C1-C6 alkyl, R 4 , R 5 and R 6 are independently hydrogen, L is

[0632] [ka]

[0633] and t is a natural number between 0 and 2, u is a natural number between 0 and 2, E is a carbonyl, —NHCO—, or a chemical bond; F is —O—, —NH— or a chemical bond; R 8 and R 9 are independently hydrogen or C1-C6 alkyl, or R 8 and R 9 form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl together with the atom to which they are linked; B is a 4- to 6-membered heterocycloalkyl, a 6- to 10-membered aryl, or a 5- to 12-membered heteroaryl, wherein the 5- to 12-membered heteroaryl, the 6- to 10-membered aryl, and the 4- to 6-membered heterocycloalkyl are independently selected from one, two, or three R i is optionally replaced by Each R i are independently hydrogen, hydroxy, halogen, or C1-C3 alkyl, or two R iform a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl together with the atom connected thereto, or two adjacent R i form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl with the atom(s) linked thereto (wherein the 3- to 7-membered cycloalkyl or the 3- to 7-membered heterocycloalkyl forms a fused ring with B); D is hydrogen, a 3- to 7-membered cycloalkyl, a C1-C6 alkyl, or a 5- to 12-membered heteroaryl, wherein the C1-C6 alkyl and the 5- to 12-membered heteroaryl are independently selected from one, two, or three R j is optionally replaced by Each R j are independently halogen, C1-C3 alkyl, -OR 12-3 or -SR 12-4 wherein the C1-C3 alkyl is independently one, two, or three R k and each R k are independently halogen; R 12-3 and R 12-4 are independently C1-C3 alkyl, and the C1-C3 alkyl is independently one, two or three R k and each R k are independently halogen; The heteroatom in the 3- to 7-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 12-membered heteroaryl is N, O, or S, and the number of heteroatoms is 1 to 3; alternatively, the heteroatom in the 3- to 7-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 12-membered heteroaryl is one or more of N, O, and S, and the number of heteroatoms is 1 to 3.

[0634] In one preferred embodiment, the compound is represented by formula I or a pharmaceutically acceptable salt thereof,

[0635] [ka]

[0636] where:

[0637] [ka]

[0638] teeth,

[0639] [ka]

[0640] and m is a natural number between 1 and 3, n is a natural number between 1 and 3, X1, X2, X3 and X4 are independently -CR 1 -, N, S,

[0641] [ka]

[0642] or a chemical bond, and the number of heteroatoms in X1, X2, X3, X4, and X5 is 1 or 2; R N-1 is a C1-C6 alkyl, Y and Z are independently carbonyl (CO) or -(CR 2 R 3 ) r - and r is a natural number between 1 and 2, Each R 1 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, or -NR 1-1 R 1-2 wherein the C1-C6 alkyl and C1-C6 alkoxy are independently one, two, three or four R a is optionally replaced by Each R a are independently hydroxy, C1-C3 alkoxy or NR 1-4 R1-5 and R 1-1 and R 1-2 are independently hydrogen or C1-C6 alkyl, wherein said C1-C6 alkyl is independently selected from one, two, three, or four R b or R 1-1 and R 1-2 form a 3- to 7-membered heterocycloalkyl with the atom to which they are attached; Each R b are independently hydroxy, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, C1-C3 alkyl, C1-C3 alkoxy, or NR 1-1-1 R 1-2-1 wherein the 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, and C1-C3 alkyl are independently selected from one, two, three, or four R b-1 is optionally replaced by Each R b-1 are independently hydroxy; R 1-4 and R 1-5 are independently hydrogen or C1-C3 alkyl, wherein said C1-C3 alkyl is independently selected from one, two, three, or four R 1-4-1 or R 1-4 and R 1-5 form a 3- to 7-membered heterocycloalkyl with the atom to which they are attached; R 1-1-1 and R 1-2-1 are independently hydrogen or C1-C3 alkyl, R 1-4-1 is a halogen, R 2 and R 3 are independently hydrogen, L is

[0643] [ka]

[0644] and t is a natural number between 0 and 2, u is a natural number between 0 and 2, E is a carbonyl or a chemical bond; F is —O—, —NH— or a chemical bond; R 8 and R 9 are independently C1-C6 alkyl, or R 8 and R 9 form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl together with the atom to which they are linked; B is a 4- to 6-membered heterocycloalkyl or a 5- to 12-membered heteroaryl, wherein the 5- to 12-membered heteroaryl and the 4- to 6-membered heterocycloalkyl are independently selected from one, two, or three R i is optionally replaced by Each R i are independently hydrogen, hydroxy, halogen, or C1-C3 alkyl, or two R i form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl together with the atom connected thereto, or two adjacent R i form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl with the atom(s) linked thereto (wherein the 3- to 7-membered cycloalkyl or the 3- to 7-membered heterocycloalkyl forms a fused ring with B); D is hydrogen, a 3- to 7-membered cycloalkyl, a C1-C6 alkyl, or a 5- to 6-membered heteroaryl, wherein the C1-C6 alkyl and the 5- to 6-membered heteroaryl are independently selected from one, two, or three R j is optionally replaced by Each R j are independently halogen or C1-C3 alkyl, and the C1-C3 alkyl is independently one, two or three R k and each R k are independently halogen; The heteroatom in the 3- to 7-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and 5- to 12-membered heteroaryl is N, O, or S, and the number of heteroatoms is 1 to 3; alternatively, the heteroatom in the 3- to 7-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and 5- to 12-membered heteroaryl is one or more of N, O, and S, and the number of heteroatoms is 1 to 3.

[0645] In one preferred embodiment, the compound is represented by formula I or a pharmaceutically acceptable salt thereof,

[0646] [ka]

[0647] where:

[0648] [ka]

[0649] teeth,

[0650] [ka]

[0651] and m is a natural number between 1 and 2, n is a natural number between 1 and 2, k is a natural number between 1 and 3, X1, X2, X3, X4 and X5 are independently -CR 1 -, N, O, S,

[0652] [ka]

[0653] or a chemical bond, and the number of heteroatoms in X1, X2, X3, X4, and X5 is 0, 1, 2, or 3; R N-1 is a C1-C6 alkyl, Each W is independently -(CR 4 R 5 )-, -O-, -NR 6 - or a chemical bond, and Y and Z are independently carbonyl (CO) or -(CR 2 R 3 ) r - and r is a natural number between 1 and 2, Each R 1 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, or -NR 1-1 R 1-2 wherein the C1-C6 alkyl and C1-C6 alkoxy are independently one, two, three or four R a is optionally replaced by Each R a are independently hydroxy, C1-C3 alkoxy or NR 1-4 R 1-5 and R 1-1 and R 1-2 are independently hydrogen or C1-C6 alkyl, wherein said C1-C6 alkyl is independently selected from one, two, three, or four R b or R 1-1 and R 1-2 form a 3- to 7-membered heterocycloalkyl with the atom to which they are attached; Each R b are independently hydroxy, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, C1-C3 alkyl, C1-C3 alkoxy, or NR 1-1-1 R 1-2-1 wherein the 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, and C1-C3 alkyl are independently selected from one, two, three, or four R b-1 is optionally replaced by Each R b-1 are independently hydroxy; R 1-4 and R 1-5 are independently hydrogen or C1-C3 alkyl, wherein said C1-C3 alkyl is independently selected from one, two, three, or four R 1-4-1 or R 1-4 and R 1-5 form a 3- to 7-membered heterocycloalkyl with the atom to which they are attached; R 1-1-1 and R 1-2-1 are independently hydrogen or C1-C3 alkyl, Each R 1-4-1 are independently halogen; R 2 and R 3 are independently hydrogen or NR 2-1 R 2-2 and R 2-1 and R 2-2 are independently hydrogen or C1-C6 alkyl, R 4 , R 5 and R 6 are independently hydrogen, and L is

[0654] [ka]

[0655] and t is a natural number between 0 and 2, u is a natural number between 0 and 2, E is a carbonyl, —NHCO—, or a chemical bond; F is —O—, —NH— or a chemical bond; R 8 and R 9 are independently hydrogen or C1-C6 alkyl, or R 8 and R 9 form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl together with the atom to which they are linked; B is a 4- to 6-membered heterocycloalkyl, a 6- to 10-membered aryl, or a 5- to 12-membered heteroaryl, wherein the 5- to 12-membered heteroaryl, the 6- to 10-membered aryl, and the 4- to 6-membered heterocycloalkyl are independently selected from one, two, or three R i is optionally replaced by Each R i are independently hydrogen, hydroxy, halogen, or C1-C3 alkyl, or two R i form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl together with the atom connected thereto, or two adjacent R i form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl with the atom(s) linked thereto (wherein the 3- to 7-membered cycloalkyl or the 3- to 7-membered heterocycloalkyl forms a fused ring with B); D is hydrogen, C1-C6 alkyl, or 5-12 membered heteroaryl, wherein the C1-C6 alkyl and 5-12 membered heteroaryl are independently selected from one, two, or three R j is optionally replaced by Each R j are independently halogen, C1-C3 alkyl, OR 12-3 or SR 12-4 wherein the C1-C3 alkyl is independently one, two, or three R k and each R k are independently halogen; R 12-3 and R 12-4 are independently C1-C3 alkyl, wherein said C1-C3 alkyl is independently one, two or three R k-1 and each R k-1 are independently halogen, and the heteroatom in the 3- to 7-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 12-membered heteroaryl is N, O, or S, and the number of heteroatoms is 1 to 3; or the heteroatom in the 3- to 7-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 12-membered heteroaryl is one or more of N, O, and S, and the number of heteroatoms is 1 to 3.

[0656] In one preferred embodiment, the compound is represented by formula I or a pharmaceutically acceptable salt thereof,

[0657] [ka]

[0658] where:

[0659] [ka]

[0660] teeth,

[0661] [ka]

[0662] and m is 1, n is 1, X1, X2, X3 and X4 are independently -CR 1 - or N, and the number of heteroatoms in X1, X2, X3 and X4 is 2; Y and Z are independently -(CR 2 R 3 ) r - and r is 1, Each R 1 are independently C1-C6 alkyl (e.g., methyl) or C1-C6 alkoxy (e.g., methoxy), R 2 and R 3 are independently hydrogen, L is

[0663] [ka]

[0664] and t is 0, u is 1, E is carbonyl; F is a chemical bond, B is a 4- to 6-membered heterocycloalkyl, wherein said 4- to 6-membered heterocycloalkyl is independently selected from one, two, or three R i is optionally replaced by Each R i are independently hydrogen, D is a 5- to 12-membered heteroaryl, wherein the 5- to 12-membered heteroaryl is independently selected from one, two, or three R j (e.g., one) Each R j independently -OR 12-3 and R 12-3 is a C1-C3 alkyl (e.g., ethyl or isopropyl), and the C1-C3 alkyl is independently one, two, or three R k and each R k are independently halogen (e.g., F); the heteroatom in the 4- to 6-membered heterocycloalkyl and the 5- to 12-membered heteroaryl is N, O, or S, and the number of heteroatoms is 1 to 3; or the heteroatom in the 4- to 6-membered heterocycloalkyl and the 5- to 12-membered heteroaryl is one or more of N, O, and S, and the number of heteroatoms is 1 to 3; A is

[0665] [ka]

[0666] In the case where the number of heteroatoms in X1, X2 and X4 is 1 or 2, A is

[0667] [ka]

[0668] and when L is carbonyl, u is a natural number from 1 to 3, B is a 4- to 6-membered heterocycloalkyl, and the 4- to 6-membered heterocycloalkyl is independently one, two, or three R i is optionally replaced by

[0669] In one preferred embodiment, the compound is represented by formula I or a pharmaceutically acceptable salt thereof, where:

[0670] [ka]

[0671] teeth,

[0672] [ka]

[0673] and m is 1, n is 1, X2 and X3 are N; X1 and X4 are independently -CR 1 - and Y and Z are independently -(CR 2 R 3 ) r - and r is 1, Each R 1 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, or -NR 1-1 R 1-2 wherein the C1-C6 alkyl and C1-C6 alkoxy are independently one, two, three or four R a is optionally replaced by R 1-1 and R 1-2 are independently hydrogen or C1-C6 alkyl, or R 1-1 and R1-2 form a 3- to 7-membered heterocycloalkyl with the atom to which they are attached; Each R a are independently hydroxy, C1-C6 alkoxy or NR 1-4 R 1-5 and R 1-4 and R 1-5 are independently hydrogen or C1-C3 alkyl, R 2 and R 3 are independently hydrogen, L is

[0674] [ka]

[0675] and t is 0, u is 1, E is carbonyl; F is a chemical bond, B is a 4- to 6-membered heterocycloalkyl, wherein said 4- to 6-membered heterocycloalkyl is independently selected from one, two, or three R i is optionally replaced by Each R i are independently hydrogen, halogen, hydroxy, or C1-C3 alkyl, D is a 5- to 12-membered heteroaryl, wherein the 5- to 12-membered heteroaryl is independently selected from one, two, or three R j and preferably D is a 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl is independently substituted by one, two or three R j wherein the heteroatoms in the 5- to 6-membered heteroaryl are selected from one, two, or three of N, S, and O, and the number of heteroatoms is 1, 2, or 3; Each R j are independently H, halogen, C1-C3 alkyl, OR 12-3 or SR 12-4wherein the C1-C3 alkyl is independently one, two, or three R k is optionally replaced by R 12-3 and R 12-4 are independently C1-C3 alkyl, and the C1-C3 alkyl is independently one, two or three R k-1 is optionally replaced by Each R k are independently halogen or C1-C3 alkyl, Each R k-1 are independently halogen or C1-C3 alkyl, The heteroatom in the 3- to 7-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 12-membered heteroaryl is one or more of N, O and S, and the number of heteroatoms is 1 to 3.

[0676] In one preferred embodiment, the compound is represented by formula I or a pharmaceutically acceptable salt thereof, where:

[0677] [ka]

[0678] teeth,

[0679] [ka]

[0680] and m is 1, n is 1, X1 and X3 are N; X2 and X4 are independently -CR 1 - and Y and Z are independently -(CR 2 R 3 ) r - and r is 1, Each R 1are independently hydrogen, halogen, cyano, hydroxy, 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 wherein the C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkylthio are independently one, two, three, or four R a is optionally replaced by R 1-1 and R 1-2 are independently hydrogen or C1-C6 alkyl, or R 1-1 and R 1-2 form a 3- to 7-membered heterocycloalkyl with the atom to which they are attached; Each R a are independently hydroxy, C1-C6 alkoxy or NR 1-4 R 1-5 and R 1-4 and R 1-5 are independently hydrogen or C1-C3 alkyl, R 2 and R 3 are independently hydrogen, L is

[0681] [ka]

[0682] and t is 0, u is 1, E is carbonyl; F is a chemical bond, B is a 4- to 6-membered heterocycloalkyl, wherein said 4- to 6-membered heterocycloalkyl is independently selected from one, two, or three R i is optionally replaced by Each R i are independently hydrogen, halogen, hydroxy, or C1-C3 alkyl, or two R i form a 3- to 7-membered cycloalkyl with the atom(s) connected thereto, D is a 5- to 12-membered heteroaryl, wherein the 5- to 12-membered heteroaryl is independently selected from one, two, or three R j and preferably D is a 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl is independently substituted by one, two or three R j wherein the heteroatoms in the 5- to 6-membered heteroaryl are selected from one, two, or three of N, S, and O, and the number of heteroatoms is 1, 2, or 3; Each R j are independently hydrogen, halogen, cyano, hydroxy, C1-C3 alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, -NR 12-1 R 12-2 , -OR 12-3 or -SR 12-4 wherein the C1-C3 alkyl, 3- to 7-membered cycloalkyl, and 3- to 7-membered heterocycloalkyl are independently selected from one, two, or three R k is optionally replaced by R 12-1 , R 12-2 , R 12-4 and R 12-3 are independently C1-C3 alkyl, and the C1-C3 alkyl is independently one, two or three R k-1 is optionally replaced by Each R k are independently halogen or C1-C3 alkyl, Each R k-1 are independently halogen or C1-C3 alkyl, The heteroatoms in the 3- to 7-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 12-membered heteroaryl are one or more selected from N, O and S, and the number of heteroatoms is 1 to 3.

[0683] In one embodiment, each R 1 are independently hydrogen, methyl,

[0684] [ka]

[0685] is.

[0686] In one embodiment, each R 1 are independently hydrogen, methyl,

[0687] [ka]

[0688] Or methylthio.

[0689] Preferably, each R 1 are independently methyl,

[0690] [ka]

[0691] is.

[0692] In one embodiment,

[0693] [ka]

[0694] teeth,

[0695] [ka] JPEG0007818741000197.jpg231169JPEG0007818741000198.jpg82169

[0696] and Preferably,

[0697] [ka]

[0698] teeth,

[0699] [ka]

[0700] is.

[0701] In one embodiment,

[0702] [ka]

[0703] teeth,

[0704] [ka] JPEG0007818741000203.jpg240169JPEG0007818741000204.jpg229169JPEG0007818741000205.jpg128169

[0705] is.

[0706] In one embodiment, L is

[0707] [ka]

[0708] and preferably, L is

[0709] [ka]

[0710] where "

[0711] [ka]

[0712] " indicates that it is connected to A.

[0713] Preferably, L is

[0714] [ka]

[0715] is.

[0716] In one embodiment, L is

[0717] [ka]

[0718] and preferably, L is

[0719] [ka]

[0720] where "

[0721] [ka]

[0722] " indicates that it is connected to A.

[0723] In one embodiment, B is

[0724] [ka]

[0725] is.

[0726] In one embodiment, B is

[0727] [ka]

[0728] is.

[0729] Preferably, B is

[0730] [ka]

[0731] is.

[0732] In one embodiment, B is

[0733] [ka]

[0734] is.

[0735] In one embodiment, D is hydrogen, methyl,

[0736] [ka]

[0737] is.

[0738] Preferably, D is

[0739] [ka]

[0740] is.

[0741] In one embodiment, D is hydrogen, methyl,

[0742] [ka]

[0743] is.

[0744] In one embodiment, the compound represented by formula I is any of the following compounds:

[0745] [ka]

[0746] The present invention further provides a method for preparing the compound of formula I above, which is prepared by any of the following schemes:

[0747] Scheme (a): In an organic solvent, in the presence of a catalyst, a compound represented by formula II and a compound represented by formula III are subjected to the following condensation reaction to obtain a compound represented by formula I.

[0748] [ka]

[0749] Scheme (b): A compound of formula I is obtained by carrying out the following condensation reaction between a compound of formula IV and a compound of formula V in an organic solvent in the presence of a catalyst.

[0750] [ka]

[0751] Scheme (C): In an organic solvent, in the presence of a catalyst, a compound represented by formula IV and a compound represented by formula VII are subjected to the following ring-forming reaction to obtain a compound represented by formula I.

[0752] [ka]

[0753] wherein Z is halogen (e.g., chlorine or bromine), TsO-, hydroxy, methoxy, ethoxy, n-propoxy, or isopropoxy, preferably Z is hydroxy, methoxy, ethoxy, n-propoxy, or isopropoxy; A, L, B, D, X1, X2, X3, X4, Y and m are as defined in any one of the claims of the present invention.

[0754] The present invention further provides a method for preparing the compound of formula I above, which is prepared by any of the following schemes:

[0755] Scheme (D): In an organic solvent, in the presence of a catalyst, a compound represented by formula VIII and a compound represented by formula VIIII are subjected to the following ring-forming reaction to obtain a compound represented by formula I.

[0756] [ka]

[0757] wherein Z, A, L, B, D are as defined in any one of the claims of the present invention.

[0758] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of substance A and a pharmaceutical excipient, said substance A being a compound of formula I above or a pharmaceutically acceptable salt thereof.

[0759] The present invention further provides 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 the pharmaceutical composition above.

[0760] The present invention further provides the use of substance A in the preparation of a medicament for use in the treatment and / or prevention of a disease mediated by a muscarinic receptor, said substance A being a compound represented by formula I above or a pharmaceutically acceptable salt thereof, or said pharmaceutical composition above, and preferably said disease being Parkinson's disease, Alzheimer's disease, Huntington's disease, schizophrenia, drug addiction or pain.

[0761] The invention further provides the use of substance A in the preparation of a medicament for use in the treatment of Parkinson's disease, Alzheimer's disease, Huntington's disease, schizophrenia, drug addiction or pain.

[0762] Positive and progressive effects of the present invention: The compounds of the present invention can be used as muscarinic receptor positive allosteric modulators, and the compounds of the present invention can treat diseases mediated by (or associated with) M receptors (muscarinic receptors).

[0763] Terminology: The term "-" indicates that the group is attached to the rest of the molecule through this site. For example, "CHO-" refers to alkoxy.

[0764] term

[0765] [ka]

[0766] indicates that this structural fragment is linked to the rest of the molecule through this site.

[0767] The term "pharmaceutically acceptable" refers to relatively non-toxic, safe, and suitable for use by patients.

[0768] 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 lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, 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. The pharmaceutically acceptable acid includes inorganic acids and organic acids (e.g., trifluoroacetic acid, hydrochloric acid, formic acid). Specifically, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition), for example, formate salts.

[0769] The term "pharmaceutical excipients" refers to all substances contained in pharmaceutical formulations, excluding active pharmaceutical ingredients, and are generally divided into two categories: excipients and additives. Specifically, please refer to the Pharmacopoeia of the People's Republic of China (2020 Edition), Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0770] The term "treatment" refers to eliminating the cause or alleviating the symptoms.

[0771] The term "prevention" refers to reducing the risk of developing a disease.

[0772] The term "patient" refers to any animal in need of treatment or prevention of disease, generally a mammal, such as a human, including, but not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.

[0773] The term "therapeutically effective amount" refers to the amount of a compound administered to a patient that is sufficient to effectively treat a disease. The therapeutically effective amount varies depending on the type of compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted appropriately by those skilled in the art depending on the situation.

[0774] The expression "group B substituted by one or more groups A" means that one or more hydrogen atoms of group B are independently replaced by group A. When multiple groups A appear simultaneously, their definitions are independent of each other and do not influence each other, unless otherwise specified.

[0775] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0776] The term "oxo" refers to =O, where an oxygen atom replaces two hydrogens on the same atom, for example, a methylene (-(CH2-) is oxygenated to become a carbonyl (-C(=O)-).

[0777] The term "alkyl" refers to a straight- or branched-chain saturated monovalent hydrocarbon radical having the specified number of carbon atoms. For example, C1-C6 alkyl (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 9-15 Alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0778] In the term "alkyl-O-", the definition of alkyl is the same as above. Examples of alkyl-O- include C1-C6 alkyl-O- or C1-C4 alkyl-O-, such as CH3-O-, CH3CH2-O-, CH3CH2CH2-O-, or CH3CH(CH3)-O-. Similarly, for other "Rx-O-" expressions in this application, the definition of Rx is as described in each corresponding definition, for example, the definition of cycloalkyl in "cycloalkyl-O-" is as described in "cycloalkyl" below.

[0779] In the term "alkyl-S-", the definition of alkyl is the same as above. Examples of alkyl-S- include C1-C6 alkyl-S- or C1-C4 alkyl-S-, such as CH3-S-, CH3CH2-S-, CH3CH2CH2-S-, or CH3CH(CH3)-S-. Similarly, for other "Rx-S-" expressions in this application, the definition of Rx is as described in each corresponding definition, for example, the definition of cycloalkyl in "cycloalkyl-S-" is as described in "cycloalkyl" below.

[0780] The term "alkoxy" refers to an oxygen atom attached as a connecting bond to one end of an alkyl to form "alkyl-O-," where "alkyl-O-" is defined above.

[0781] The term "alkylthio" refers to a sulfur atom attached as a connecting bond to one end of an alkyl to form "alkyl-S-", where "alkyl-S-" is defined above.

[0782] The term "heteroaryl" refers to a cyclic, unsaturated monovalent group having a specified number of ring atoms (e.g., 5 to 12 members, 5 to 10 members, or 5 to 6 members), 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), and having aromatic character.

[0783] The term "heterocycloalkyl" refers to a saturated heterocycloalkyl or a partially unsaturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or higher bridged, fused, or spirocyclic system) heterocyclyl having a specified number of ring atoms (e.g., 4 to 12 members, 4 to 10 members, 3 to 7 members, 6 to 10 members, 4 to 7 members, 5 to 6 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatom or heteroatom group (one or more of N, O, S, S(=O), and S(=O)2).

[0784] The term "cycloalkyl" refers to a saturated carbocyclic substituent which may be linked to the remainder of the molecule by a single bond through any suitable carbon atom, and is a C3-C7 cycloalkyl having 3 to 7 carbon atoms, preferably a C3-C6 cycloalkyl having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0785] The term "aryl" refers to an aryl having a specific number of carbon atoms (e.g., C6-C 10 ) Examples of aryl include, but are not limited to, phenyl or naphthyl.

[0786] The term "heteroaryl" refers to a cyclic or unsaturated monovalent group having a specified number of carbon atoms (e.g., 5-10 members, 5-6 members), 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 may be monocyclic or polycyclic and have aromatic character (at least one ring / each ring). Heteroaryls are linked to the rest of the molecule through a carbon atom or heteroatom; heteroaryls are linked to the rest of the molecule through a ring with or without a heteroatom; and heteroaryls are linked to the rest of the molecule through a ring with or without aromatic character.

[0787] Unless otherwise stated, solid wedge connections (

[0788] [ka]

[0789] ) and a dotted wedge bond represent the absolute configuration of one stereocenter, and a wavy line (

[0790] [ka]

[0791] ),

[0792] [ka]

[0793] or a mixture thereof.

[0794] Each of the above preferred conditions can be arbitrarily combined to obtain each of the preferred embodiments of the present invention, provided that it is not contrary to common knowledge in this field.

[0795] All reagents and raw materials used in the present invention are commercially available.

[0796] Abbreviation: PMB: p-methoxybenzyl.

[0797] Boc: tert-butoxycarbonyl.

[0798] DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0799] NBS: N-bromosuccinimide.

[0800] DIEA: N,N-diisopropylethylamine.

[0801] DMF: N,N-dimethylformamide.

[0802] Et: ethyl.

[0803] Me: Methyl.

[0804] i-Pr: isopropyl.

[0805] DMSO: dimethyl sulfoxide.

[0806] HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0807] PyBOP: 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate.

[0808] TEA: Triethylamine.

[0809] LiHMDS: lithium bis(trimethylsilyl)amide.

[0810] NCS: N-chlorosuccinimide. DETAILED DESCRIPTION OF THE INVENTION

[0811] The present invention will be further explained by the following examples, but the present invention is not limited to the scope of the examples. In the following examples, experimental methods for which no specific conditions are given can be selected according to conventional methods and conditions or product instructions.

[0812] Intermediate A Synthetic Route:

[0813] [ka]

[0814] Step 1 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 salt of A-2. 1 H NMR (400 MHz, 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 value: C7H 14 NO2[M+H] + = 144.1, measured value: 144.2.

[0815] Step 2 The trifluoroacetate salt 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), and triethylamine (13.4 g, 132.2 mmol) and cesium fluoride (5.0 g, 33.0 mmol) were added sequentially. The mixture was then heated to 80 °C and stirred for 18 hours. The reaction mixture was poured into 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 obtain A-4. 1 H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 5.64 Hz, 1H), 6.70 (d, J = 2.28 Hz, 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.

[0816] Step 3 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 mixture was adjusted to 7, and water (50 mL) was added. The mixture was lyophilized to give a crude product containing intermediate A, which was used directly in the next step. 1 H NMR (400 MHz, 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.

[0817] intermediate G Synthetic Route:

[0818] [ka]

[0819] Step 1 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 mixture was heated to 80 °C under nitrogen gas protection and stirred for 16 h. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure to give an oil. The oil 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 give the crude product containing the target compound. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 9 / 1, v / v) to give G-2. Theoretical calculation of ESI-MS: CHBrClN [M+H] + = 332.8, actual value: 332.0.

[0820] Step 2 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 solution of 4-methoxybenzylamine in tetrahydrofuran (1.64 g, 11.9 mmol) was added dropwise at room temperature. Stirring was continued at room temperature for 1 hour. The reaction mixture 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. The theoretically calculated value of ESI-MS was: C 14 H 14 Cl2N3O [M+H] + = 310.0, measured value: 310.0.

[0821] Step 3 G-3 (400 mg, 1.29 mmol), methylboronic acid (116 mg, 1.93 mmol), potassium carbonate (535 mg, 3.87 mmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (189 mg, 0.26 mmol), and 1,4-dioxane (3 mL) were added to a 10 mL microtube and heated to 90 °C under nitrogen gas protection. The reaction mixture was then stirred for 18 h. The reaction mixture was cooled to room temperature, filtered, diluted with water (15 mL), and extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the 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 give G-4. The theoretically calculated value of C was calculated by ESI-MS. 15 H 17 ClNO [M+H] + = 290.1, measured value: 290.0.

[0822] Step 4 G-4 (130 mg, 0.45 mmol) and azetidine (2 mL) were added to a 10 mL microtube, heated to 90 °C, and stirred for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 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 G-5. The theoretically calculated value of ESI-MS was: C 18 H 23 NO [M+H] + = 311.2, measured value: 311.2.

[0823] Step 5 G-5 (120 mg, 0.39 mmol) and trifluoroacetic acid (2 mL) were added to a 5 mL microtube, heated to 100 °C, and stirred for 8 hours. The reaction mixture was cooled to room temperature, diluted with water (15 mL), adjusted to pH 8 with saturated sodium bicarbonate solution, and extracted with ethyl acetate (5 mL x 3). The combined organic phase was 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 step. The theoretically calculated value of ESI-MS was: C 10 H 15 N4[M+H] + = 191.1, measured value: 191.1.

[0824] Intermediate I Synthetic Route:

[0825] [ka]

[0826] Step 1 G-3 (1.5 g, 4.84 mmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (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 heated to 90 °C under nitrogen gas protection and stirred for 18 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give 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. The theoretically calculated value of ESI-MS was: C 16 H 20 NO [M+H] + = 270.2, measured value: 270.1.

[0827] Step 2 I-1 (120 mg, 0.45 mmol) and trifluoroacetic acid (2 mL) were added to a 5 mL microtube, heated to 90 °C, and stirred for 8 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the trifluoroacetate salt of intermediate I, which was used directly in the next step. The theoretically calculated value of ESI-MS was: CH 12 N3[M+H] + = 150.1, Measured value: 150.1.

[0828] Intermediate O Synthetic Route:

[0829] [ka]

[0830] Step 1 O-1 (2.0 g, 15.2 mmol) was dissolved in DMF (20 mL), and then 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 h. After cooling, saturated ammonium chloride solution (50 mL) was slowly added to the reaction mixture, followed by extraction with ethyl acetate (70 mL × 3). The combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 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 O-3. 1 H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 5.50 Hz, 1H), 7.26 (dd, J = 5.50, 1.76 Hz, 1H), 7.22 (d, J = 1.74 Hz, 1H), 5.09-4.96 (m, 2H). Step 2 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 h. After cooling, water (30 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product containing the target compound. This crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate, 4 / 1, v / v) to give O-4. 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 5.76 Hz, 1H), 6.14 (dd, J = 5.80, 1.98 Hz, 1H), 5.77 (d, J = 1.96 Hz, 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: C14 H 18 F3N2O3[M+H] + = 319.1, measured value: 319.1.

[0831] Step 3 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 mixture was adjusted to 7 with hydrochloric acid (1 mol / L), water was added, and the mixture was lyophilized to obtain a crude product containing intermediate O, which was directly used in the next step. 1 H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 5.80 Hz, 1H), 6.10 (dd, J = 5.76, 1.98 Hz, 1H), 5.72 (d, J = 1.96 Hz, 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.

[0832] Intermediate P Synthetic Route:

[0833] [ka]

[0834] Step 1 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. Saturated ammonium chloride solution (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product containing the title compound. This crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to give P-2. 1 H NMR (400 MHz, 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.

[0835] Step 2 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 and 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 lyophilized to obtain a crude product containing intermediate P, which was used directly in the next step. 1 H NMR (400 MHz, 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: C8H 12 N3O2S [M+H] + = 214.1, measured value: 214.0.

[0836] Intermediate Q Synthetic Route:

[0837] [ka]

[0838] Step 1 Q-2 (726 mg, 3.24 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to 0 °C. Sodium hydride (60%, 130 mg, 3.24 mmol) was added and stirred for 1 hour. Q-1 (500 mg, 2.70 mmol) was then added and stirred at room temperature for 18 hours. After completion of the reaction, the mixture was quenched with saturated ammonium chloride solution (5 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 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 Q-3. 1 H NMR (400 MHz, Chloroform-d) δ 5.69-5.63 (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). Step 2 Q-3 (500 mg, 1.96 mmol) was dissolved in methanol (10 mL), and wet palladium carbon (10%, 450 mg) was added. The reaction mixture was purged with hydrogen gas three times, and then stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give Q-4. 1H NMR (400 MHz, Chloroform-d) δ 4.47-4.35 (m, 0.6H), 4.13 (q, J = 7.14 Hz, 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 = 6.20 Hz, 1.2H), 1.27-1.23 (m, 4.8H). Step 3 Q-4 (250 mg, 0.97 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give a crude product containing Q-5, which was used directly in the next step. The theoretically calculated value of ESI-MS was: CH 16 NO2[M+H] + = 158.1, measured value: 158.1.

[0839] Step 4 The trifluoroacetate salt of Q-5 (140 mg, 0.89 mmol) and A-3 (173 mg, 0.95 mmol) were dissolved in dimethyl sulfoxide (5 mL), and TEA (385 mg, 3.80 mmol) and cesium fluoride (144 mg, 0.95 mmol) were added sequentially. 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 combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 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 give Q-6. 1H NMR (400 MHz, 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). Theoretical calculation value of ESI-MS: C 14 H 18 F3N2O2[M+H] + = 303.1, measured value: 303.1.

[0840] Step 5 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 completed, the pH of the reaction mixture was adjusted to 5 with dilute hydrochloric acid (1 mol / L). Water was added and the mixture was lyophilized to obtain a crude product containing intermediate Q, which was used directly in the next step. The theoretically calculated value of ESI-MS was: C 12 H 14 F3N2O2[M+H] + = 275.1, measured value: 275.0.

[0841] Intermediate S Synthetic Route:

[0842] [ka]

[0843] Step 1 S-2 (4.54 g, 61.3 mmol) was dissolved in tetrahydrofuran (120 mL) and cooled to -78 °C. A solution of LiHMDS in tetrahydrofuran (1.0 mol / L, 64.3 mL, 64.3 mmol) was slowly added dropwise and stirred for 10 minutes. S-1 (10 g, 58.4 mmol) was then added and stirred for 15 minutes. The reaction mixture was warmed to 0 °C and stirred for 2 hours. Ice water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product containing S-3, which was used directly in the next step. The theoretically calculated value of ESI-MS was: C 11 H 20 NO5 [M-56+H] + = 190.1, measured value: 190.1.

[0844] Step 2 S-3 (2.0 g, 8.15 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (20 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to give the trifluoroacetate salt of S-4, which was used directly in the next step. The theoretically calculated value of ESI-MS was: CH 12 NO3[M+H] + = 146.1, measured value: 146.2.

[0845] Step 3 The trifluoroacetate salt 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), and TEA (5.58 g, 55.11 mmol) and cesium fluoride (2.1 g, 13.8 mmol) were added sequentially. The mixture was heated to 100 °C and stirred for 18 h. The reaction mixture was poured into water (80 mL) and diluted with dichloromethane (50 mL × 3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product containing the target compound. This crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 7, v / v) to give S-5. 1H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J = 5.68 Hz, 1H), 6.76 (d, J = 2.26 Hz, 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.

[0846] Step 4 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 completed, the pH of the reaction mixture was adjusted to 5 with dilute hydrochloric acid (1 mol / L). Water was added and the mixture was lyophilized to obtain a crude product containing intermediate S, which was used directly in the next step. The theoretically calculated value of ESI-MS was: C 11 H 12 F3N2O3[M+H] + = 277.1, actual value: 277.0.

[0847] Intermediate U Synthetic Route:

[0848] [ka]

[0849] Step 1 U-1 (1.0 g, 5.90 mmol) and manganese dioxide (6.66 g, 76.65 mmol) were added to dichloromethane (15 mL) and stirred for 8 hours at 25° C. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give U-2, which was used directly in the next step. 1H NMR (400 MHz, 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 value: C8H7ClNO [M+H] + = 168.0, Measured value: 168.0.

[0850] Step 2 U-2 (1.1 g, 6.56 mmol) was dissolved in dichloromethane (15 mL), and diethylaminosulfur trifluoride (3.7 g, 22.97 mmol) was added at 0°C. The mixture was warmed to room temperature and stirred for 18 hours. Saturated sodium bicarbonate solution (20 mL) was added to the reaction mixture, 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 give a crude product containing the target compound. This crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 7 / 3, v / v) to give U-3. 1 H NMR (400 MHz, Chloroform-d) δ 8.55 (d, J = 5.24 Hz, 1H), 7.39 (d, J = 5.22 Hz, 1H), 3.12-3.02 (m, 2H), 2.76-2.61 (m, 2H). ESI-MS theoretical calculation value: C8H7ClF2N [M+H] + = 190.0, measured value: 190.0.

[0851] Step 3 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 h. After cooling to room temperature, saturated ammonium chloride solution (50 mL) was added and extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product containing the target compound. This crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 7, v / v) to give U-4. 1 H NMR (400 MHz, Chloroform-d) δ 8.24 (d, J = 5.58 Hz, 1H), 6.15 (d, J = 5.60 Hz, 1H), 4.36-4.30 (m, 2H), 4.16 (q, J = 7.12 Hz, 2H), 3.88-3.81 (m, 2H), 3.20-3.09 (m, 1H), 3.03-2.96 (m, 2H), 2.71 (d, J = 7.78 Hz, 2H), 2.62-2.48 (m, 2H), 1.27 (t, J = 7.06 Hz, 3H). Theoretical calculation value of ESI-MS: C 15 H 19 F2N2O2[M+H] + = 297.1, measured value: 297.1.

[0852] Step 4 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 completed, the pH of the reaction mixture was adjusted to 5 with dilute hydrochloric acid (1 mol / L). Water was added and the mixture was lyophilized to obtain a crude product containing intermediate U, which was used directly in the next step. The theoretically calculated value of ESI-MS was: C 13 H 15 F2N2O2[M+H] + = 269.1, measured value: 269.1.

[0853] Intermediate V Synthetic Route:

[0854] [ka]

[0855] Step 1 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 h. After cooling to room temperature, saturated ammonium chloride solution (20 mL) was added and extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 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 give V-2. 1 H NMR (400 MHz, Chloroform-d) δ 8.24 (d, J = 5.70 Hz, 1H), 6.23 (d, J = 5.86 Hz, 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 = 7.76 Hz, 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.

[0856] Step 2 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 completed, the pH of the reaction mixture was adjusted to 5 with dilute hydrochloric acid (1 mol / L). Water was added and the mixture was lyophilized to obtain a crude product containing intermediate V, which was used directly in the next step. The theoretically calculated value of ESI-MS was: C 10 H 11 F3N3O2[M+H] + =262.1, actual value: 262.0.

[0857] Intermediate X Synthetic Route:

[0858] [ka]

[0859] Step 1 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. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product containing the target compound. This crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 0, v / v) to give X-3. 1 H NMR (400 MHz, Chloroform-d) δ 8.52 (d, J = 5.34 Hz, 1H), 7.58 (d, J = 1.82 Hz, 1H), 7.32 (dd, J = 5.30, 1.84 Hz, 1H). Step 2 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 cooling to room temperature, saturated ammonium chloride solution (10 mL) was added and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product containing the target compound. This crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 7 / 3, v / v) to give X-4. The theoretically calculated value of ESI-MS was: C 13 H 14 F3N2O2S [M+H] + = 321.1, measured value: 321.1.

[0860] Step 3 X-4 (150 mg, 2.50 mmol) was dissolved in tetrahydrofuran (3 mL) and water (1 mL), lithium hydroxide monohydrate (30 mg, 0.70 mmol) was added, and the mixture was heated to 40°C and stirred for 2 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 5 with dilute hydrochloric acid (1 mol / L), water was added, and the mixture was lyophilized to obtain a crude product containing intermediate X, which was used directly in the next step. The theoretically calculated value of ESI-MS was: C 11 H 12 F3N2O2S[M+H] + =293.1, Actual value: 293.1.

[0861] Intermediate AA Synthetic Route:

[0862] [ka]

[0863] Step 1 AA-1 (1.4 g, 12.2 mmol) was dissolved in DMF (30 mL) and cooled to 0 °C. Sodium hydride (60%, 910 mg, 22.8 mmol) was added and stirred for 30 min. O-1 (2.0 g, 15.2 mmol) was added and stirred at room temperature for 18 h. After completion of the reaction, the mixture was quenched with saturated ammonium chloride solution (150 mL) and extracted with ethyl acetate (150 mL × 3). The combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product containing the target compound. AA-2 was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 19 / 1, v / v) to give AA-2. 1 H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 5.50 Hz, 1H), 7.25 (dd, J = 5.54, 1.78 Hz, 1H), 7.16 (d, J = 1.80 Hz, 1H), 5.95-5.86 (m, 1H), 1.45 (d, J = 6.68 Hz, 3H). Step 2 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 h. After cooling to room temperature, saturated ammonium chloride solution (50 mL) was added and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 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 give AA-3. 1H NMR (400 MHz, Chloroform-d) δ 7.75 (d, J = 5.74 Hz, 1H), 6.12 (dd, J = 5.82, 1.98 Hz, 1H), 5.87-5.80 (m, 1H), 5.73 (d, J = 1.96 Hz, 1H), 4.10-4.01 (m, 4H), 3.62-3.54 (m, 2H), 3.07-2.97 (m, 1H), 2.70 (d, J = 7.70 Hz, 2H), 1.38 (d, J = 6.54 Hz, 3H), 1.18 (t, J = 7.10 Hz, 3H). ESI-MS theoretical calculation value: C 15 H 20 F3N2O3[M+H] + = 333.1, measured value: 333.1.

[0864] Step 3 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 completed, the pH of the reaction mixture was adjusted to 5 with dilute hydrochloric acid (1 mol / L). The mixture was filtered, and the solid was washed with water (3 mL) and dried to obtain intermediate AA, which was used directly in the next step. The theoretically calculated value of ESI-MS was: C 13 H 16 F3N2O3[M+H] + =305.1, Actual value: 305.1.

[0865] Intermediate AB Synthetic Route:

[0866] [ka]

[0867] Step 1 AB-1 (208 mg, 1.82 mmol) was dissolved in DMF (4 mL) and cooled to 0 °C. Sodium hydride (60%, 137 mg, 3.43 mmol) was added and stirred for 30 min. O-1 (300 mg, 2.28 mmol) was added and stirred at room temperature for 18 h. After completion of the reaction, the mixture was quenched with saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product containing the target compound. This crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 19 / 1, v / v) to give AB-2. 1 H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 5.50 Hz, 1H), 7.25 (dd, J = 5.58, 1.76 Hz, 1H), 7.16 (d, J = 1.74 Hz, 1H), 5.93-5.85 (m, 1H), 1.45 (d, J = 6.68 Hz, 3H). Step 2 AB-2 (200 mg, 0.89 mmol) and A-2 (317 mg, 2.22 mmol) were dissolved in DMSO (5 mL), TEA (538 mg, 5.32 mmol) and cesium fluoride (202 mg, 1.33 mmol) were added, and the mixture was heated to 100 °C and stirred for 10 h. After cooling to room temperature, saturated ammonium chloride solution (20 mL) was added and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 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 give AB-3. The theoretically calculated value of ESI-MS was: C 15 H 20 F3N2O3[M+H] + = 333.1, measured value: 333.0.

[0868] Step 3 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 completed, the pH of the reaction mixture was adjusted to 5 with dilute hydrochloric acid (1 mol / L). The mixture was filtered, and the solid was washed with water (3 mL). After drying, intermediate AB was obtained, which was used directly in the next step. The theoretically calculated value of ESI-MS was: C 13 H 16 F3N2O3[M+H] + = 305.1, measured value: 305.0.

[0869] Intermediate AI Synthetic Route:

[0870] [ka]

[0871] Step 1 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. Saturated ammonium chloride solution (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 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 AI-1. The theoretically calculated value of ESI-MS was: C 11 H 18 N3O2S [M+H] + = 256.1, measured value: 256.1.

[0872] Step 2 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 mixture was adjusted to 5 with dilute hydrochloric acid (1 mol / L), concentrated under reduced pressure, and lyophilized to obtain a crude product containing intermediate AI, which was used directly in the next step. The theoretically calculated value of ESI-MS was: CH 14 N3O2S [M+H] + = 228.1, measured value: 228.0.

[0873] Intermediate AK Synthetic Route:

[0874] [ka]

[0875] Step 1 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(diphenylphosphino)ferrocene]dichloropalladium(II) (253 mg, 0.35 mmol) were added to 1,4-dioxane (6 mL) and stirred at 100 °C under nitrogen gas protection for 12 h. The reaction mixture was cooled to room temperature, filtered, diluted with water (30 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product containing the target compound. AK-1 was obtained by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 3, v / v). 1H NMR (400 MHz, DMSO-d6) δ 7.30 (d, J = 8.60 Hz, 2H), 6.92 (d, J = 8.62 Hz, 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 value: C 18 H 22 NO [M+H] + = 296.2, actual value: 296.1.

[0876] Step 2 AK-1 (300 mg, 1.02 mmol) and trifluoroacetic acid (4 mL) were added to a microtube, heated to 90°C, and stirred for 10 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the trifluoroacetate salt of intermediate AK, which was used directly in the next step. The theoretically calculated value of ESI-MS was: C 10 H 14 N3[M+H] + = 176.1, Measured value: 176.0.

[0877] Intermediate AO Synthetic Route:

[0878] [ka]

[0879] Step 1 G-4 (200 mg, 0.69 mmol), methanesulfonato(tricyclohexylphosphine)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (45 mg, 0.07 mmol), potassium phosphate (513 mg, 2.42 mmol), and ethylboronic acid (153 mg, 2.07 mmol) were added to toluene (5 mL) and water (1 mL). The mixture was heated to 100 °C under nitrogen gas protection and stirred for 12 h. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product containing the target compound. AO-1 was obtained by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 3, v / v). 1 H NMR (400 MHz, DMSO-d6) δ 7.29 (d, J = 8.54 Hz, 2H), 6.92 (d, J = 8.52 Hz, 2H), 3.96-3.85 (m, 6H), 3.75 (s, 3H), 2.80 (q, J = 7.58 Hz, 2H), 2.47 (s, 3H), 1.20 (t, J = 7.58 Hz, 3H). ESI-MS theoretical calculation value: C 17 H 22 NO [M+H] + = 284.2, actual value: 284.1.

[0880] Step 2 AO-1 (150 mg, 0.53 mmol) and trifluoroacetic acid (4 mL) were added to a microtube, heated to 90°C, and stirred for 10 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the trifluoroacetate salt of intermediate AO, which was used directly in the next step. The theoretically calculated value of ESI-MS was: CH 14 N3[M+H] + = 164.1, measured value: 164.0.

[0881] Intermediate AP Synthetic Route:

[0882] [ka]

[0883] Step 1 G-3 (200 mg, 0.64 mmol), methanesulfonato(tricyclohexylphosphine)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (42 mg, 0.06 mmol), potassium phosphate (479 mg, 2.26 mmol), and ethylboronic acid (285 mg, 3.87 mmol) were added to toluene (5 mL) and water (1 mL) and stirred at 100 °C for 18 h under nitrogen gas protection. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product containing the target compound. AP-1 was obtained by silica gel column chromatography (dichloromethane / methanol, 9 / 1, v / v). 1 H NMR (400 MHz, DMSO-d6) δ 7.31 (d, J = 8.60 Hz, 2H), 6.91 (d, J = 8.62 Hz, 2H), 3.95 (s, 3H), 3.85 (s, 2H), 3.75 (s, 4H), 2.80 (q, J = 7.58 Hz, 4H), 1.21 (t, J = 7.60 Hz, 6H). ESI-MS theoretical calculation value: C 18 H 24 NO [M+H] + = 298.2, actual value: 298.1.

[0884] Step 2 AP-1 (150 mg, 0.50 mmol) and trifluoroacetic acid (4 mL) were added to a microtube, heated to 90°C, and stirred for 10 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the trifluoroacetate salt of intermediate AP, which was used directly in the next step. The theoretically calculated value of ESI-MS was: C 10 H 16 N3[M+H] + = 178.1, measured value: 178.0.

[0885] Intermediate AR Synthetic Route:

[0886] [ka]

[0887] Step 1 Intermediate I (800 mg, 5.36 mmol) and intermediate AC-1 (1.15 g, 5.36 mmol) were dissolved in DMF (10 mL), DIEA (2.08 g, 16.1 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. HATU (3.06 g, 8.04 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product containing the target compound. This crude product was purified by silica gel column chromatography (dichloromethane / methanol, 4 / 1, v / v) to give AR-1. The theoretically calculated value of ESI-MS was: C 18 H 27 N4O3[M+H] + = 347.3, measured value: 347.2.

[0888] Step 2 AR-1 (1.00 g, 2.89 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to give a crude product containing intermediate AR, which was used directly in the next step. The theoretically calculated value of ESI-MS was: C 13 H 19 NO [M+H] + = 247.2, actual value: 247.1.

[0889] Product preparation and synthesis Example 12 Synthetic Route:

[0890] [ka]

[0891] Step 1 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 h. The reaction mixture was filtered and concentrated under reduced pressure to give the crude product containing the target compound. This crude product was purified by preparative high-performance liquid chromatography (chromatography column: Waters-Xbridge-C18, 10 μm, 19 × 250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate, gradient: 20–50%, retention time: 9 min) to give compound 12. 1 H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 5.66 Hz, 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.

[0892] Example 24 Synthetic Route:

[0893] [ka]

[0894] Step 1 The trifluoroacetate salt of intermediate I (100 mg, 0.67 mmol) and intermediate A (262 mg, 1.01 mmol) were dissolved in tetrahydrofuran (4 mL), and DIEA (260 mg, 2.01 mmol) and HATU (382 mg, 1.01 mmol) were added. The mixture was stirred at room temperature for 3 hours. The reaction mixture 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 (chromatography column: Waters-Xbridge). Compound 24 was obtained by purification using C18, 10 μm, 19 × 250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate solution, gradient: 17-47%, retention time: 9 min). 1 H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 5.66 Hz, 1H), 6.72 (d, J = 2.24 Hz, 1H), 6.54 (dd, J = 5.66, 2.24 Hz, 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). Theoretical calculation value of ESI-MS: C 19 H 21 F3N5O [M+H] + = 392.2, measured value: 392.2.

[0895] Example 47 Synthetic Route:

[0896] [ka]

[0897] Step 1 Intermediate G (30 mg, 0.16 mmol) and intermediate O (45 mg, 0.16 mmol) were dissolved in DMF (5 mL), DIEA (122 mg, 0.95 mmol) was added, and the mixture was stirred at room temperature for 30 min. HATU (72 mg, 0.19 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude product containing the target compound. This crude product was purified by preparative high-performance liquid chromatography (chromatography column: Waters-Xbridge-C18, 10 μm, 19 × 250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate, gradient: 32–62%, retention time: 9 min) to give compound 47. 1 H NMR (400 MHz, 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). Theoretical calculation value of ESI-MS: C 22 H 26 F3N6O2[M+H] + = 463.2, Measured value: 463.2.

[0898] Example 50 Synthetic Route:

[0899] [ka]

[0900] Step 1 Intermediate G (30 mg, 0.16 mmol) and intermediate P (41 mg, 0.19 mmol) were dissolved in DMF (5 mL), DIEA (62 mg, 0.47 mmol) was added, and the mixture was stirred at room temperature for 30 min. HATU (90 mg, 0.24 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product containing the target compound. This crude product was purified by preparative high-performance liquid chromatography (chromatography column: Waters-Xbridge-C18, 10 μm, 19 × 250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate, gradient: 9–39%, retention time: 9 min) to give compound 50. 1 H NMR (400 MHz, 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 Synthetic Route:

[0902] [ka]

[0903] Step 1 Intermediate G (30 mg, 0.16 mmol) and intermediate Q (43 mg, 0.11 mmol) were dissolved in DMF (3 mL), DIEA (122 mg, 0.95 mmol) was added, and the mixture was stirred at room temperature for 30 min. HATU (72 mg, 0.19 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product containing the target compound. This crude product was purified by preparative high-performance liquid chromatography (chromatography column: Waters-Xbridge-C18, 10 μm, 19 × 250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate, gradient: 22–52%, retention time: 9 min) to give compound 51. 1 H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 5.70 Hz, 1H), 6.70 (s, 1H), 6.58 (d, J = 5.64 Hz, 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). Theoretical calculation value of ESI-MS: C 22 H 26 F3N6O [M+H] + = 447.2, actual value: 447.1.

[0904] Example 56 Synthetic Route:

[0905] [ka]

[0906] Step 1 Intermediate T (20 mg, 0.11 mmol) and intermediate S (29 mg, 0.11 mmol) were dissolved in DMF (3 mL), DIEA (55 mg, 0.42 mmol) was added, and the mixture was stirred at room temperature for 30 min. HATU (48 mg, 0.13 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude product containing the target compound. This crude product was purified by preparative high-performance liquid chromatography (chromatography column: Waters-Xbridge-C18, 10 μm, 19 × 250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate, gradient: 17–47%, retention time: 9 min) to give compound 56. 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J = 5.68 Hz, 1H), 6.76 (t, J = 2.52 Hz, 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, actual value: 449.1.

[0907] Example 67 Synthetic Route:

[0908] [ka]

[0909] Step 1 The trifluoroacetate salt of intermediate I (80 mg, 0.54 mmol) and intermediate O (156 mg, 0.54 mmol) were dissolved in DMF (5 mL), DIEA (209 mg, 1.62 mmol) was added, and the mixture was stirred at room temperature for 30 min. HATU (265 mg, 0.70 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude product containing the target compound. This crude product was purified by preparative high-performance liquid chromatography (chromatography column: Waters-Xbridge-C18, 10 μm, 19 × 250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate, gradient: 26–56%, retention time: 9 min) to give compound 67. 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 5.78 Hz, 1H), 6.15 (dd, J = 5.82, 1.94 Hz, 1H), 5.78 (d, J = 1.94 Hz, 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 = 7.62 Hz, 2H), 2.55-2.53 (m, 6H). Theoretical calculation value of ESI-MS: C 20 H 23 F3N5O2[M+H] + = 422.2, measured value: 422.2.

[0910] Example 68 Synthetic Route:

[0911] [ka]

[0912] Step 1 The trifluoroacetate salt of intermediate I (54 mg, 0.36 mmol) and intermediate X (70 mg, 0.24 mmol) were dissolved in DMF (5 mL), DIEA (93 mg, 0.72 mmol) was added, and the mixture was stirred at room temperature for 30 min. HATU (128 mg, 0.34 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude product containing the target compound. This crude product was purified by preparative high-performance liquid chromatography (chromatography column: Waters-Xbridge-C18, 10 μm, 19 × 250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate, gradient: 25–55%, retention time: 9 min) to give compound 68. 1 H NMR (400 MHz, DMSO-d6) δ 8.10 (d, J = 5.72 Hz, 1H), 6.59 (d, J = 2.18 Hz, 1H), 6.40 (dd, J = 5.76, 2.18 Hz, 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 = 7.68 Hz, 2H), 2.55-2.53 (m, 6H). Theoretical calculation value of ESI-MS: C 19 H 21 F3N5OS [M+H] + = 424.1, measured value: 424.1.

[0913] Example 89 Synthetic Route:

[0914] [ka]

[0915] Step 1 The trifluoroacetate salt of intermediate I (49 mg, 0.33 mmol) and intermediate AB (100 mg, 0.33 mmol) were dissolved in DMF (5 mL), DIEA (127 mg, 0.99 mmol) was added, and the mixture was stirred at room temperature for 30 min. HATU (175 mg, 0.46 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude product containing the target compound. This crude product was purified by preparative high-performance liquid chromatography (chromatography column: Waters-Xbridge-C18, 10 μm, 19 × 250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate, gradient: 35–65%, retention time: 11 min) to give compound 89. 1 H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J = 5.80 Hz, 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 = 6.50 Hz, 3H). ESI-MS theoretical calculation value: C 21 H 25 F3N5O2[M+H] + = 436.2, measured value: 436.2.

[0916] Example 98 Synthetic Route:

[0917] [ka]

[0918] Step 1 Intermediate AK (73 mg, 0.41 mmol) and intermediate O (80 mg, 0.28 mmol) were dissolved in DMF (5 mL), DIEA (142 mg, 1.10 mmol) was added, and the mixture was stirred at room temperature for 30 min. HATU (136 mg, 0.36 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude product containing the target compound. This crude product was purified by preparative high-performance liquid chromatography (chromatography column: Waters-Xbridge-C18, 10 μm, 19 × 250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate, gradient: 35–65%, retention time: 9 min) to give compound 98. 1 H NMR (400 MHz, DMSO-d6) δ 7.77 (d, J = 5.76 Hz, 1H), 6.16 (dd, J = 5.80, 1.96 Hz, 1H), 5.79 (d, J = 1.94 Hz, 1H), 5.06-5.03 (m, 1H), 4.95-4.86 (m, 3H), 4.79-4.69 (m, 2H), 4.09 (t, J = 8.04 Hz, 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: C 22 H 25 F3N5O2[M+H] + = 448.2, measured value: 448.2.

[0919] Example 110 Synthetic Route:

[0920] [ka]

[0921] Step 1 Intermediate AO (59 mg, 0.36 mmol) and intermediate O (70 mg, 0.24 mmol) were dissolved in DMF (5 mL), DIEA (94 mg, 0.72 mmol) was added, and the mixture was stirred at room temperature for 30 min. HATU (119 mg, 0.31 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude product containing the target compound. This crude product was purified by preparative high-performance liquid chromatography (chromatography column: Waters-Xbridge-C18, 10 μm, 19 × 250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate, gradient: 31–61%, retention time: 9 min) to give compound 110. 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 5.84 Hz, 1H), 6.15 (dd, J = 5.80, 1.96 Hz, 1H), 5.78 (d, J = 1.94 Hz, 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 = 7.54 Hz, 3H). ESI-MS theoretical calculation value: C 21 H 25 F3N5O2[M+H] + = 436.2, measured value: 436.2.

[0922] Example 111 Synthetic Route:

[0923] [ka]

[0924] Step 1 Intermediate AP (70 mg, 0.39 mmol) and intermediate O (115 mg, 0.39 mmol) were dissolved in DMF (5 mL), DIEA (153 mg, 1.18 mmol) was added, and the mixture was stirred at room temperature for 30 min. HATU (195 mg, 0.51 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude product containing the target compound. This crude product was purified by preparative high-performance liquid chromatography (chromatography column: Waters-Xbridge-C18, 10 μm, 19 × 250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate, gradient: 34–64%, retention time: 9 min) to give compound 111. 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 5.78 Hz, 1H), 6.15 (dd, J = 5.82, 1.94 Hz, 1H), 5.78 (d, J = 1.92 Hz, 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 = 7.54 Hz, 6H). Theoretical calculation value of ESI-MS: C 22 H 27 F3N5O2[M+H] + = 450.2, measured value: 450.2.

[0925] Example 116 Synthetic Route:

[0926] [ka]

[0927] Step 1 Intermediate I (66 mg, 0.44 mmol) and intermediate AA (90 mg, 0.30 mmol) were dissolved in DMF (5 mL), DIEA (115 mg, 0.89 mmol) was added, and the mixture was stirred at room temperature for 30 min. HATU (169 mg, 0.44 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude product containing the target compound. This crude product was purified by preparative high-performance liquid chromatography (chromatography column: Waters-Xbridge-C18, 10 μm, 19 × 250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate, gradient: 32–62%, retention time: 9 min) to give compound 116. 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 5.80 Hz, 1H), 6.13 (dd, J = 5.84, 2.00 Hz, 1H), 5.87-5.80 (m, 1H), 5.74 (d, J = 1.96 Hz, 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 = 6.50 Hz, 3H). Theoretical calculation of ESI-MS: C 21 H 25 F3N5O2[M+H] + = 436.2, measured value: 436.2.

[0928] Example 123 Synthetic Route:

[0929] [ka]

[0930] Step 1 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 h. The reaction mixture was filtered and concentrated under reduced pressure to give the crude product containing the target compound. This crude product was purified by preparative high-performance liquid chromatography (chromatography column: Waters-Xbridge-C18, 10 μm, 19 × 250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate, gradient: 30–60%, retention time: 10 min) to give compound 123. 1 H NMR (400 MHz, 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 values: C 22 H 26 F3N6O2[M+H] + = 463.2, actual value: 463.0.

[0931] Example 124 Synthetic Route:

[0932] [ka]

[0933] Step 1 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 h. The reaction mixture was cooled, diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product containing the target compound. This crude product was purified by preparative high-performance liquid chromatography (chromatography column: Waters-Xbridge-C18, 10 μm, 19 × 250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate, gradient: 16–46%, retention time: 10 min) to give compound 124. 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 6.02 Hz, 1H), 6.59 (d, J = 6.02 Hz, 1H), 4.93-4.89 (m, 2H), 4.71-4.68 (m, 2H), 4.29-4.23 (m, ESI-MS theoretical calculation value: C 18 H 20 F3N6O [M+H] + = 393.2, Measured value: 393.2.

[0934] Example 125 Synthetic Route:

[0935] [ka]

[0936] Step 1 Intermediate AR (80 mg, 0.32 mmol), 125-1 (70 mg, 0.32 mmol), methanesulfonato(tricyclohexylphosphine)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (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 under nitrogen gas protection and stirred for 18 h. The reaction mixture was cooled and concentrated under reduced pressure to give the crude product containing the target compound. This crude product was purified by preparative high-performance liquid chromatography (chromatography column: Waters-Xbridge-C18, 10 μm, 19 × 250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate, gradient: 18–48%, retention time: 10 min) to give compound 125. 1 H NMR (400 MHz, 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, actual value: 380.0.

[0937] Example 126 Synthetic Route:

[0938] [ka]

[0939] Step 1 Intermediate AR (65 mg, 0.26 mmol), 126-1 (50 mg, 0.26 mmol), cesium fluoride (60 mg, 0.40 mmol), and triethanolamine (80 mg, 0.79 mmol) were added to DMSO (5 mL). The reaction mixture was cooled, diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product containing the target compound. This crude product was purified by preparative high-performance liquid chromatography (chromatography column: Waters-Xbridge-C18, 10 μm, 19 × 250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate solution, gradient: 15–45%, retention time: 10 min) to give compound 126. 1 H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 5.50 Hz, 1H), 6.28 (d, J = 5.58 Hz, 1H), 4.94-4.91 (m, 2H), 4.70-4.67 (m, 2H), 4.32-4.28 (m, ESI-MS theoretical calculation: C 21 H 24 F2N5O [M+H] + = 400.2, measured value: 400.2.

[0940] Example 127 Synthetic Route:

[0941] [ka]

[0942] Step 1 Intermediate AR (106 mg, 0.43 mmol), 127-1 (100 mg, 0.43 mmol), and cesium carbonate (351 mg, 1.08 mmol) were dissolved in DMF (3 mL). The reaction mixture was cooled, diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were 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. This crude product was purified by preparative high-performance liquid chromatography (chromatography column: Waters-Xbridge-C18, 10 μm, 19 × 250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate solution, gradient: 25-55%, retention time: 10 min) to obtain compound 127. 1 H NMR (400 MHz, 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: C 17 H 19 F3N5OS [M+H] + = 398.1, Measured value: 398.1.

[0943] Example 128 Synthetic Route:

[0944] [ka]

[0945] Step 1 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 h. The reaction mixture was filtered and concentrated under reduced pressure to give the crude product containing the target compound. This crude product was purified by preparative high-performance liquid chromatography (chromatography column: Waters-Xbridge-C18, 10 μm, 19 × 250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate, gradient: 20–50%, retention time: 10 min) to give compound 128. 1 H NMR (400 MHz, DMSO-d6) δ 8.10 (d, J = 5.72 Hz, 1H), 6.59 (d, J = 2.20 Hz, 1H), 6.40 (dd, J = 5.72, 2.22 Hz, 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 values: C 19 H 21 F3N5OS [M+H] + = 424.1, measured value: 424.1.

[0946] Example 129 Synthetic Route:

[0947] [ka]

[0948] Step 1 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 h. The reaction mixture was filtered and concentrated under reduced pressure to give the crude product containing the target compound. This crude product was purified by preparative high-performance liquid chromatography (chromatography column: Waters-Xbridge-C18, 10 μm, 19 × 250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate, gradient: 37–47%, retention time: 10 min) to give compound 129. 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 5.80 Hz, 1H), 6.15 (dd, J = 5.78, 1.98 Hz, 1H), 5.78 (d, J = 1.96 Hz, 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 values: C 20 H 23 F3N5O2[M+H] + = 422.2, actual value: 422.0.

[0949] Example 130 Synthetic Route:

[0950] [ka]

[0951] Step 1 Intermediate AR (65 mg, 0.26 mmol), 130-1 (50 mg, 0.26 mmol), cesium fluoride (60 mg, 0.40 mmol), and triethanolamine (80 mg, 0.79 mmol) were added to DMSO (5 mL). The reaction mixture was cooled, diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product containing the target compound. This crude product was purified by preparative high-performance liquid chromatography (chromatography column: Waters-Xbridge-C18, 10 μm, 19 × 250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate solution, gradient: 18–45%, retention time: 9 min) to give compound 130. 1 H NMR (400 MHz, 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: C 16 H 18 F3N6OS [M+H] + = 399.1, measured value: 399.1.

[0952] Example 131 Synthetic Route:

[0953] [ka]

[0954] Step 1 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 h. The reaction mixture was cooled, diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product containing the target compound. This crude product was purified by preparative high-performance liquid chromatography (chromatography column: Waters-Xbridge-C18, 10 μm, 19 × 250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate, gradient: 5-95%, retention time: 10 min) to give compound 131. 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J = 2.80 Hz, 1H), 6.91 (d, J = 2.80 Hz, 1H), 4.92-4.90 (m, 2H), 4.70-4.68 (m, 2H), 4.32-4.28 (m, ESI-MS theoretical calculation value: C 18 H 20 F3N6O [M+H] + = 393.2, actual value: 392.9.

[0955] Example 132 Synthetic Route:

[0956] [ka]

[0957] Step 1 Intermediate G-4 (500 mg, 1.60 mmol) was dissolved in methanol (20 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane 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, then heated to 70 °C and stirred for 18 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 4, v / v) to give 132-1. The theoretically calculated value of ESI-MS was: C 17 H 20 N3O3[M+H] + =314.1, actual value: 314.0.

[0958] Step 2 132-1 (200 mg, 0.64 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium borohydride (14 mg, 0.64 mmol) was added slowly at 0°C. The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (30 mL) and extracted with dichloromethane (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (petroleum ether / ethyl acetate, 1 / 4, v / v) to give 132-2. The theoretically calculated value of ESI-MS was: C 16 H 20 N3O2[M+H] + = 286.2, measured value: 286.2.

[0959] Step 3 132-2 (100 mg, 0.35 mmol) and trifluoroacetic acid (2 mL) were added to a 5 mL microtube, heated to 90 °C, and stirred for 8 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a crude product containing 132-3, which was used directly in the next step. The theoretically calculated value of ESI-MS was: CH 12 NO [M+H] + = 166.1, measured value: 166.1.

[0960] Step 4 132-3 (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 h. The reaction mixture was filtered and concentrated under reduced pressure to give the crude product containing the target compound. This crude product was purified by preparative high-performance liquid chromatography (chromatography column: Waters-Xbridge-C18, 10 μm, 19 × 250 mm, mobile phase: acetonitrile-10 mmol / L aqueous ammonium bicarbonate, gradient: 5–95%, retention time: 10 min) to give compound 132. 1 H NMR (400 MHz, 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, actual value: 437.9.

[0961] Activity Test 1: Evaluation of PAM activity of compounds against M4 receptors Objective of the experiment: Using stably transformed cells (M4-Gα15-CHO) expressing human M4 receptor, the activity of the compound against the M4 receptor is measured with the FLIPR CALCIUM 6 ASSAY KIT.

[0962] Test materials:

[0963] [Table 1]

[0964] Experimental equipment:

[0965] [Table 2]

[0966] Cell treatment: 1. In this study, we used a CHO cell line stably expressing the M4-Gα15 receptor to express the human CHRM4 gene and GNA15 gene, respectively.

[0967] 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 geneticin G418 at 37°C with 5% carbon dioxide. After removing the old medium and washing once with phosphate buffer, 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 complete medium preheated to 37°C was added. The cell suspension was gently pipetted to separate any clumped cells. The cell suspension was transferred to a sterile centrifuge tube and centrifuged (1000 rpm) for 5 minutes.

[0968] Experimental Procedure: 1. Cell plating: M4-Gα15-CHO cells were digested, collected, resuspended, counted, and then seeded into 384-well cell plates at a seeding density of 1.2 × 10 4 The cell plate was then cultured in a 37°C, 5% CO2 incubator for approximately 20 hours.

[0969] After 24 hours, the loading buffer was prepared according to the FLIPR Calcium 6 Assay Kit instructions. Component A was thawed to room temperature and diluted with detection buffer and probenecid solution to make the loading buffer. The solution was then stored at room temperature for later use.

[0970] 3. The medium in the cell plate was removed, and 35 μL of loading buffer was quickly added to each well. After centrifugation, the cell plate was cultured in the dark at 37° C. for 120 minutes.

[0971] 4. A working solution of the test compound was prepared, and 5 μL was transferred to the corresponding cell wells and incubated in the dark at 37° C. for 30 minutes.

[0972] A 5.30 nM acetylcholine agonist working solution was prepared and transferred to a 384-well loading plate at 20 μL / well.

[0973] 6. Place the cell plate, loading plate, and pipette tips in the corresponding positions on the FLIPR instrument. Add 10 μL of the agonist diluted in step 5 to each experimental well using the FLIPR, and collect data at wavelengths between 515 nm and 575 nm.

[0974] 7. Plot the signal values ​​versus compound concentrations and perform curve fitting using the nonlinear regression method in GraphPad Prism software to obtain the EC 50 The calculation was performed.

[0975] Preparation of detection buffer and loading buffer: A detection buffer was prepared by mixing 1.0.5 mol / L 2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid buffer with Hank's balanced salt solution (pH 7.4) in a volume ratio of 1:24. 10 mL of the detection buffer was added to a bottle of Calcium 6 Assay Kit Component A in lyophilized powder form, and the mixture was stored frozen at -20°C.

[0976] Probenecid powder was dissolved in 2.1 mol / L sodium hydroxide solution to a final concentration of 250 mol / L. The detection buffer, thawed Component A, and probenecid solution were mixed in a volume ratio of 44:5:1 to prepare a loading buffer.

[0977] Test Results:

[0978] [Table 3]

[0979] Testing Conclusion: The experimental samples (compounds) were prepared according to the corresponding examples, and the results were as shown in the above table, and the compounds of the present application exhibited agonistic activity against M4 receptors in this test system.

[0980] Activity Test 2: Evaluation of the pharmacokinetic properties of compounds in mice Objective of the experiment: The pharmacokinetic properties of the compounds obtained in the examples of the present invention are evaluated in CD-1 mice.

[0981] Test materials:

[0982] [Table 4]

[0983] Experimental Procedure: Standard protocols were used to test the pharmacokinetic properties of compounds in rodents after intravenous injection and oral administration. Candidate compounds were prepared as clear solutions or suspensions in the designated solvents and administered intravenously or orally to three mice, respectively. The solvent for both intravenous and oral administration was 5% dimethyl sulfoxide + 95% (10% aqueous polyethylene glycol (15)-hydroxystearic acid). Whole blood samples collected within 24 hours were collected in commercially available EDTA2K anticoagulation tubes and centrifuged to obtain the upper plasma sample. An acetonitrile solution containing an internal standard was added to precipitate proteins, and the supernatant was collected by centrifugation. An equal volume of water was added, followed by further centrifugation. The supernatant was then collected and the sample injected. Blood drug concentrations were quantitatively analyzed using LCMS / MS analysis, and pharmacokinetic parameters were calculated.

[0984] Experimental Method:

[0985] [Table 5]

[0986] Test Results:

[0987] [Table 6]

[0988] Testing Conclusion: The test articles were prepared according to the corresponding examples, and the results showed that the compounds of the present application had good pharmacokinetic properties.

[0989] Activity Test 3: Evaluation of the pharmacokinetic properties of compounds in rats Objective of the experiment: The pharmacokinetic properties of the compounds obtained in the examples of the present invention are evaluated in SD rats.

[0990] Test materials:

[0991] [Table 7]

[0992] Experimental Procedure: The pharmacokinetic properties of compounds were tested in rodents after intravenous injection and oral administration using standard protocols. In the experiments, candidate compounds were prepared as clear solutions or suspensions in the designated solvents and administered intravenously and orally in a single dose to three rats. The intravenous solvent was 5% dimethyl sulfoxide + 95% (10% aqueous polyethylene glycol (15)-hydroxystearic acid solution). The oral solvent was 5% dimethyl sulfoxide + 95% (10% aqueous polyethylene glycol (15)-hydroxystearic acid solution) or 0.5% methylcellulose + 0.2% Tween 80 + 99.3% water. Whole blood samples within 24 hours were collected in commercially available EDTA2K anticoagulation tubes and centrifuged to obtain the upper plasma sample. An acetonitrile solution containing an internal standard was added to precipitate proteins, and the supernatant was collected by centrifugation. The same volume of water was added, and the sample was centrifuged again to collect the supernatant. The sample was then injected, and the blood drug concentration was quantitatively analyzed using LCMS / MS analysis, and the pharmacokinetic parameters were calculated.

[0993] The test products were prepared according to the corresponding examples, and some compounds of the present application had bioavailability of 80% or more, clearance of 16 mL / min / kg or less, and half-life T 1 / 2 is between 2 and 10 hours, and the area under the drug-time curve, AUC 0-last was between 5000 and 50000 hr×ng / mL, and the compounds of the present application had good pharmacokinetic properties.

[0994] Activity Test 4: Evaluation of the pharmacokinetic properties of compounds in dogs Objective of the experiment: The pharmacokinetic properties of the compounds obtained in the examples of the present invention are evaluated in vivo.

[0995] Test materials:

[0996] [Table 8]

[0997] Experimental Procedure: Standard protocols were used to test the pharmacokinetic properties of compounds in vigulls after intravenous injection and oral administration. In the experiment, candidate compounds were prepared as clear solutions or suspensions in the designated solvents and administered intravenously and orally in a single dose to two vigulls, respectively. The intravenous solvent was 5% dimethyl sulfoxide + 95% (10% aqueous polyethylene glycol (15)-hydroxystearic acid), and the oral solvent was 0.5% methylcellulose + 0.2% Tween 80 + 99.3% water. Whole blood samples collected within 24 hours were collected in commercially available EDTA2K anticoagulation tubes and centrifuged to obtain the upper plasma sample. An acetonitrile solution containing an internal standard was added to precipitate proteins, and the supernatant was centrifuged and removed. An equal volume of water was added and centrifuged again to obtain the supernatant. The sample was then injected, and blood drug concentrations were quantitatively analyzed using LCMS / MS analysis, and pharmacokinetic parameters were calculated.

[0998] The test products were prepared according to the corresponding examples, and some compounds of the present application had bioavailability of 80% or more, clearance of 16 mL / min / kg or less, and half-life T 1 / 2 is between 2 and 10 hours, and the area under the drug-time curve, AUC 0-last was between 2000 and 20000 hr×ng / mL, and the compounds of the present application had good pharmacokinetic properties.

[0999] Activity Test 5: Evaluation of compound efficacy in the mouse prepulse inhibition model Objective of the experiment: The efficacy of examples of the present invention is evaluated in the C57 mouse prepulse inhibition model.

[1000] Test materials:

[1001] [Table 9]

[1002] Experimental Procedure: Before administration, animals were randomly divided into four groups (10 animals per group) based on their body weight. Group 1 was the vehicle control group, Group 2 was the model group, and Groups 3 and 4 were drug-treated groups. Animals in Groups 1 and 2 were intragastrically administered with Solvent C, animals in Group 3 were intragastrically administered with the compound of the present application at a dose of 5 mg / kg, and animals in Group 4 were intragastrically administered with the compound of the present application at a dose of 10 mg / kg. After 30 minutes, animals in Group 1 were intraperitoneally injected with Solvent B (saline), and animals in Groups 2, 3, and 4 were intraperitoneally injected with dizocilpine (MK-801) at a dose of 0.3 mg / kg. After 30 minutes, the animals were placed in the prepulse inhibition test box and the experiment began. The peak response period of the animals was recorded by the instrument. First, the background noise of the prepulse inhibition test box parameters was set to 67 decibels, and the animals were gently placed in the restraining cage and allowed to adapt for 10 minutes. Next, the pre-experimental parameters were set as follows: Within a 5-minute period, animals were given five random 120-dB stimuli. Formal experimental parameters were as follows: at the start of the experiment, animals received five 120-dB shocks and five 81+120-dB shocks, for a total of 10 shocks. The average inter-stimulus time was randomly selected between 7 and 21 seconds. A background noise level of 67 decibels was maintained throughout the experiment. The animal's prepulse inhibition rate was calculated as 1 - [(peak response duration of 81+120-dB stimuli) / peak response duration of 120-dB stimuli] × 100%.

[1003] Test samples were prepared from the corresponding examples, and it was observed that the rate of prepulse inhibition in mice was about 40%-80%. Some of the compounds of the present application can effectively restore the damage caused by MK-801 to the prepulse inhibition function of mice, and showed good in vivo efficacy in the prepulse inhibition model of C57 mice.

[1004] Activity Test 6: Evaluation of compound efficacy in the mouse forced swimming model Objective of the experiment: The efficacy of examples of the present invention is evaluated in a C57 mouse forced swim model.

[1005] Test materials:

[1006] [Table 10]

[1007] Experimental Procedure: Before administration, animals were randomly divided into four groups (8 animals per group) based on body weight. Group 1 was the vehicle control group, and Groups 2-4 were the treatment groups. Animals in Group 1 were intragastrically administered with Vehicle C, while animals in Groups 2-4 were intragastrically administered with the compounds of the present application at doses of 2, 5, and 10 mg / kg, respectively. After administration, the animals were returned to their original cages. After 1 hour, the animals were gently removed from their cages and allowed to settle for 1-3 minutes. Once the animals were no longer nervous, they were individually placed in glass cylinders (40 cm high, 13 cm diameter, 26 cm deep, and 23°C). The analysis software was turned on, and the animals' forced swimming resting time was automatically recorded within 4 minutes.

[1008] The test articles were prepared according to the corresponding examples, and the immobility time of the mice was observed to be about 50 to 150 seconds. Some compounds of the present application could significantly shorten the immobility time of the forced swimming mice, and showed good antidepressant effects in the C57 mouse forced swimming model.

[1009] Activity Test 7: Evaluation of compound efficacy in the mouse tail suspension model Objective of the experiment: The efficacy of examples of the present invention is evaluated in the C57 mouse tail suspension model.

[1010] Test materials:

[1011] [Table 11]

[1012] Experimental Procedure: Before administration, animals were randomly divided into two groups (8 animals per group) based on their body weight. Group 1 was the vehicle control group, and Group 2 was the treatment group. Animals in Group 1 were intragastrically administered with Vehicle C, and animals in Group 2 were intragastrically administered with a compound of the present application at a dose of 5 mg / kg. After administration, the animals were returned to their original cages. After 1 hour, the animals were gently removed from their cages and allowed to settle for 1-3 minutes. When the animals were no longer tense, the tip of the animal's tail was wrapped with medical tape and the animal was suspended in a tail suspension measurement chamber. The analysis software was turned on and the animal's immobility time was automatically recorded for 4 minutes. Test articles were prepared according to the corresponding examples. The immobility time of the mice was observed to be within 150 seconds. Some compounds of the present application showed good antidepressant effects in the C57 mouse tail suspension model.

Claims

1. A compound represented by formula I-3 or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 X ２ and X ３ is N, X ４ is -CR １ - and Each R １ are independently hydrogen, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, or —NR １－１ R １－２ wherein said C １ ~C ６ Alkyl and C １ ~C ６ Alkoxy is independently one, two, three or four R ａ is optionally replaced by R １－１ and R １－２ are independently hydrogen or C １ ~C ６ alkyl, or R １－１ and R １－２ form a 3- to 7-membered heterocycloalkyl with the atom to which they are attached; Each R ａ are independently hydroxy, C １ ~C ６ Alkoxy or NR １－４ R １－５ and R １－４ and R １－５ are independently hydrogen or C １ ~C ３ It is an alkyl R ｉ is hydrogen, halogen, hydroxy or C １ ~C ３ is alkyl, D is a 5- to 12-membered heteroaryl, wherein said 5- to 12-membered heteroaryl is independently selected from one, two, or three R ｊ is optionally replaced by Each R ｊ are independently H, halogen, C １ ~C ３ Alkyl, OR １２－３ or SR １２－４ wherein said C １ ~C ３ Alkyl is independently one, two or three R ｋ is optionally replaced by R １２－３ and R １２－４ is independently C １ ~C ３ alkyl, １ ~C ３ Alkyl is independently one, two or three R ｋ－１ is optionally replaced by Each R ｋ are independently halogen or C １ ~C ３ is alkyl, Each R ｋ－１ are independently halogen or C １ ~C ３ is alkyl, In the 3- to 7-membered heterocycloalkyl and 5- to 12-membered heteroaryl, the heteroatom is one or more of N, O, and S, and the number of heteroatoms is 1 to 3.

2. (1) R １ wherein the halogen is F, Cl, Br or I; (2) R １ In the above, １ ~C ６ alkyl is methyl, ethyl, n-propyl or isopropyl; (3) R １ In the above, １ ~C ６ alkoxy is methoxy, ethoxy, n-propoxy or isopropoxy; (4) R １ wherein said 3- to 7-membered cycloalkyl is cyclopropyl, cyclobutyl, or cyclopentyl; (5) R １ wherein the 3- to 7-membered heterocycloalkyl is a 3- to 6-membered heterocycloalkyl, the heteroatom in the 3- to 6-membered heterocycloalkyl is N or O, and the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is 1 or 2; (6) R ａ In the above, １ ~C ６ alkoxy is methoxy, ethoxy, n-propoxy or isopropoxy; (7) R １－１ and R １－２ In the above, １ ~C ６ alkyl is methyl, ethyl, n-propyl or isopropyl; (8) R １－１ and R １－２ wherein the 3- to 7-membered heterocycloalkyl is a 3- to 6-membered heterocycloalkyl, the heteroatom in the 3- to 6-membered heterocycloalkyl is N or O, and the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is 1 or 2; (9) R １－４ and R １－５ In the above, １ ~C ３ alkyl is methyl, ethyl, n-propyl or isopropyl; (10) R ｉ wherein the halogen is F, Cl, Br or I; (11) R ｉ In the above, １ ~C ３ alkyl is methyl, ethyl, n-propyl or isopropyl; (12) R ｊ wherein the halogen is F, Cl, Br or I; (13) R ｊ In the above, １ ~C ３ alkyl is methyl, ethyl, n-propyl or isopropyl; (14) R １２－３ and R １２－４ In the above, １ ~C ３ alkyl is methyl, ethyl, n-propyl or isopropyl; (15) R ｋ wherein the halogen is F, Cl, Br or I; (16) R ｋ In the above, １ ~C ３ alkyl is methyl, ethyl, n-propyl or isopropyl; (17) R ｋ－１ wherein the halogen is F, Cl, Br or I; (18) R ｋ－１ In the above, １ ~C ３ alkyl is methyl, ethyl, n-propyl or isopropyl; 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that it satisfies one or more of the following conditions:

3. (1) In R 1 , the halogen is Cl; (2) In R 1 , the C 1 -C 6 alkyl is methyl, ethyl, or isopropyl; (3) In R 1 , the C 1 -C 6 alkoxy is methoxy or ethoxy; (4) In R 1 , the 3- to 7-membered cycloalkyl is cyclopropyl; (5) In R 1 , the 3- to 7-membered heterocycloalkyl is 【Chemistry 2】 the condition that (6) In R a , the C 1 -C 6 alkoxy is methoxy; (7) In R 1-1 and R 1-2 , the C 1 to C 6 alkyl is methyl; (8) In R 1-1 and R 1-2 , the 3- to 7-membered heterocycloalkyl is 【Transformation 3】 the condition that (9) In R 1-4 and R 1-5 , the C 1 -C 3 alkyl is methyl; (10) The condition that, in R i , the halogen is F; (11) The provision that, in R i , the C 1 -C 3 alkyl is methyl; (12) The condition that, in R j , the halogen is F; (13) The condition that, in R j , the C 1 -C 3 alkyl is methyl; (14) In R 12-3 and R 12-4 , the C 1 to C 3 alkyl is methyl or ethyl; (15) The condition that, in R k , the halogen is F; (16) The condition that in R k-1 , the halogen is F; (17) In R k-1 , the C 1 to C 3 alkyl is methyl; 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that it satisfies one or more of the following conditions:

4. (1) Each R １ is independently C １ ~C ６ Alkyl, 3- to 7-membered cycloalkyl or —NR １－１ R １－２ wherein said C １ ~C ６ Alkyl is independently one, two, three, or four R ａ the condition optionally replaced by (2) Each R ａ are independently hydroxy, C １ ~C ３ Alkoxy or NR １－４ R １－５ the condition that (3) R １－１ and R １－２ forms a 3- to 7-membered heterocycloalkyl with the atom to which it is attached; (4) Each R ｉ are independently hydrogen, hydroxy or C １ ~C ３ The condition that it is alkyl, (5) Each R ｊ is independently C １ ~C ３ Alkyl, -OR １２－３ or -SR １２－４ the condition that (6) Each R ｋ are independently halogens, (7) Each R ｋ－１ are independently halogens, (8) D is a 5- to 6-membered heteroaryl, wherein said 5- to 6-membered heteroaryl is independently selected from one, two, or three R ｊ the condition optionally replaced by (9) In the 3- to 7-membered heterocycloalkyl and 5- to 12-membered heteroaryl, the heteroatom is N, O, or S, and the number of heteroatoms is 1 to 3.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that it satisfies one or more of the following conditions:

5. (1) The proviso that each R 1 is independently C 1 -C 6 alkyl; (2) R a is hydroxy; (3) R i is hydrogen; (4) each R j is independently —OR 12-3 ; (5) each R k is independently a halogen; (6) each R k-1 is independently halogen; (7) D is a 5- to 6-membered heteroaryl, and the 5- to 6-membered heteroaryl is 【Chemistry 4】 wherein said 5-6 membered heteroaryl is optionally substituted independently by 1, 2 or 3 R j ; 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that it satisfies one or more of the following conditions:

6. The compound is represented by formula I-1-4, 【Transformation 5】 X ６ is C or N, Here, R １ , R ｉ and R ｊ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: (a) D is a 6-membered heteroaryl, wherein the heteroatom in the 6-membered heteroaryl is N, and the number of heteroatoms is 1 or 2; (b) D is a 5-membered heteroaryl, wherein the heteroatoms in said 5-membered heteroaryl are one or more of N, S, and O, and the number of heteroatoms is 1, 2, or 3; (c) D is a 6-membered heteroaryl-fused 5-membered cycloalkyl, wherein the heteroatom in the 6-membered heteroaryl is N and the number of heteroatoms is 1; (d) D is a 5-membered benzo heteroaryl, wherein the heteroatoms in the 5-membered heteroaryl are N and / or S, and the number of heteroatoms is two; 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which satisfies any one of the following conditions:

8. (a) D is 【Transformation 6】 and e is independently 0, 1, 2, or 3; (b) D is 【Transformation 7】 the condition that (c) D is 【Transformation 8】 and e is independently 0, 1, 2, or 3; (d) D is 【Chemistry 9】 and e is independently 0, 1, 2, or 3; 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which satisfies any one of the following conditions:

9. (a) D is 【Chemistry 10】 the condition that (b) D is 【Chemistry 11】 the condition that (c) 【Chemistry 12】 the condition that (d) D is 【Chemistry 13】 the condition that 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which satisfies any one of the following conditions:

10. X ２ and X ３ is N, X ４ is -CR １ - and Each R １ is independently C １ ~C ６ Alkyl, 3- to 7-membered cycloalkyl or —NR １－１ R １－２ wherein said C １ ~C ６ Alkyl is independently one, two, three, or four R ａ and R １－１ and R １－２ form a 3- to 7-membered heterocycloalkyl with the atom to which they are attached; Each R ａ are independently hydroxy; R ｉ is hydrogen, hydroxy or C １ ~C ３ is alkyl, D is a 5- to 12-membered heteroaryl, wherein said 5- to 12-membered heteroaryl is independently selected from one, two, or three R ｊ is optionally replaced by Each R ｊ are independently H, halogen, C １ ~C ３ Alkyl, OR １２－３ or SR １２－４ wherein said C １ ~C ３ Alkyl is independently one, two or three R ｋ is optionally replaced by R １２－３ and R １２－４ is independently C １ ~C ３ alkyl, １ ~C ３ Alkyl is independently one, two or three R ｋ－１ is optionally replaced by Each R ｋ are independently halogen; Each R ｋ－１ are independently halogen; In the 3- to 7-membered heterocycloalkyl and 5- to 12-membered heteroaryl, the heteroatom is one or more of N, O, and S, and the number of heteroatoms is 1 to 3; Or, X ２ and X ３ is N, X ４ is -CR １ - and Each R １ is independently C １ ~C ６ Alkyl, 3- to 7-membered cycloalkyl or —NR １－１ R １－２ wherein said C １ ~C ６ Alkyl is independently one, two, three, or four R ａ and R １－１ and R １－２ form a 3- to 7-membered heterocycloalkyl with the atoms connected thereto, wherein the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three; Each R ａ are independently hydroxy; R ｉ is hydrogen, hydroxy or C １ ~C ３ is alkyl, D is a 5- to 6-membered heteroaryl, wherein said 5- to 6-membered heteroaryl is independently selected from one, two, or three R ｊ wherein the 5- to 6-membered heteroaryl is selected from one, two, or three heteroatoms selected from N, O, and S, and the number of heteroatoms is one, two, or three; Each R ｊ are independently H, halogen, C １ ~C ３ Alkyl, OR １２－３ or SR １２－４ wherein said C １ ~C ３ Alkyl is independently one, two or three R ｋ is optionally replaced by R １２－３ and R １２－４ is independently C １ ~C ３ alkyl, １ ~C ３ Alkyl is independently one, two or three R ｋ－１ is optionally replaced by Each R ｋ are independently halogen; Each R ｋ－１ are independently halogen; 2. A compound according to claim 1, characterized in that it is represented by any one of the schemes below, or a pharmaceutically acceptable salt thereof.

11. (1) Each R １ are independently methyl, 【Chemistry 14】 the condition that （２） 【Chemistry 15】 teeth, 【Chemistry 16】 the condition that （３） 【Chemistry 17】 teeth, [Chemistry 18] the condition that (5) D is 【Chemistry 19】 the condition that 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that it satisfies one or more of the following conditions:

12. 2. The compound according to claim 1, which is any one of the following compounds or a pharmaceutically acceptable salt thereof: 【Chemistry 20】

13. 10. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient.

14. 10. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a muscarinic receptor positive allosteric modulator.

15. 10. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing a disease mediated by a muscarinic receptor.

16. The use described in claim 15, characterized in that the disease is Parkinson's disease, Alzheimer's disease, Huntington's disease, schizophrenia or drug addiction.

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