HK40106830A - Nitrogen-containing heterocyclic compound, pharmaceutically acceptable salt thereof, preparation method thereof and the use thereof - Google Patents

Description

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

Technical Field

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

Background Technology

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

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

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

Summary of the Invention

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

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

Among them,

m is a natural number from 0 to 3;

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

k is a natural number between 0 and 3;

_X1 , _X2 , _X3 , _X4 and _X5 are independently ^-CR1- , N, O, S, or chemical bonds;

RN ^-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 optionally independently substituted by 1, 2, 3 or 4 RN ^-2 ;

Each RN ^-2 is independently a halogen;

^Y and Z are independently carbonyl (CO), -( ^CR₂R₃ ) _r- , or chemical bonds; r is a natural number from 0 to 5;

^Each W can be independently a carbonyl (CO), -O-, -( ^CR4R5 )-, ^-NR6- , or a chemical bond;

Each ^R1 is independently hydrogen, halogen, cyano, hydroxyl, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 alkylthio, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or ^-NR1-1R1-2 , ^wherein the _C1 - _C6 alkylthio, _C1 - _C6 alkyl, and _C1 - _C6 alkoxy are optionally independently substituted by one, two, three, or four ^Ra ; or two ^R1s and the atoms attached thereto form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl.

Each ^Ra is independently a halogen, cyano, hydroxyl, _C1 - _C3 alkyl, _C1 - _C6 alkoxy, or ^-NR1-4R1-5 ; or, two ^Ra and the atoms attached thereto form a 3- to 7-membered cycloalkyl or ^a 3- to 7-membered heterocycloalkyl.

^R1-1 and ^R1-2 are independently hydrogen or _C1 - _C6 alkyl, wherein the _C1 - _C6 alkyl is optionally independently substituted by 1, 2, 3 or 4 ^Rb ; or, ^R1-1 and ^R1-2 form a 3- to 7-membered heterocyclic alkyl with the atoms attached thereto, wherein the 3- to 7-membered heterocyclic alkyl is optionally substituted by 1, 2, 3 or 4 Rb ^-2 ;

Each ^Rb is independently a halogen, cyano, hydroxyl, _C1 - _C6 alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, _C1 - _C3 alkyl and NR ^1-1-1 R ^1-2-1 , wherein the 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl and _C1 - _C3 alkyl are optionally independently substituted by 1, 2, 3 or 4 Rb ^-1 ;

Each Rb ^-1 is independently halogenated, hydroxyl, or cyano;

Each Rb ^-2 is independently halogenated, _C1 - _C6 alkyl, or cyano;

^R1-4 and ^R1-5 are independently hydrogen or _C1 - _C3 alkyl, wherein the _C1 - _C3 alkyl is optionally independently substituted by one, two, three or four ^R1-4-1 ; or, ^R1-4 and ^R1-5 form a 3- to 7-membered heterocyclic alkyl with the atom to which they are attached.

^R1-1-1 and ^R1-2-1 are independently hydrogen or _C1 - _C3 alkyl, wherein the _C1 - _C3 alkyl is optionally independently substituted by one, two, three or four ^R1-1-1-1 ;

Each R ^1-4-1 and R ^1-1-1-1 is independently a halogen, hydroxyl, or cyano group;

^R2 and ^R3 are independently hydrogen, halogen, cyano, hydroxyl, _C1 - _C6 alkoxy, or ^NR2-1R2-2 ; or ^{R2 and R3} form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl with the atoms attached to them.

^R2-1 and ^R2-2 are independently hydrogen or _C1 - _C6 alkyl, wherein the _C1 - _C6 alkyl is optionally independently substituted by one, two, three or four ^Rd ; or, ^R2-1 and ^R2-2 form a 3- to 7-membered heterocyclic alkyl with the atom attached to them.

Each R ^d is independently a halogen, cyano, hydroxyl, _C1 - _C6 alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or _C1 - _C3 alkyl;

^R4 , ^R5 and ^R6 are independently hydrogen, halogen, cyano, hydroxyl, _C1 - _C6 alkoxy, _C1 - _C6 alkyl or ^{NR4-1 R4-2} , wherein the _C1 - _C6 alkyl is optionally independently substituted by one, two, three or four ^Re .

Each ^Re is independently a halogen, cyano, hydroxyl, _C1 - _C3 alkyl, _C1 - _C3 alkoxy, or -NR ^4-4 R ^4-5 ;

^R4-1 and ^R4-2 are independently hydrogen or _C1 - _C6 alkyl, wherein the _C1 - _C6 alkyl is optionally independently substituted by one, two, three or four ^Rf ; or, ^R4-1 and ^R4-2 form a 3- to 7-membered heterocyclic alkyl with the atom to which they are attached.

Each ^Rf is independently a halogen, cyano, hydroxyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, _C1 - _C3 alkyl, _C1 - _C3 alkoxy, or -NR ^4-1-1 R ^4-2-1 ;

^R4-4 and ^R4-5 are independently hydrogen or _C1 - _C3 alkyl; or ^R4 and ^R5 form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl with the atoms attached to them;

R ^4-1-1 and R ^4-2- are independently hydrogen or _C1 - _C3 alkyl;

L is

t is a natural number between 0 and 3;

u is a natural number from 0 to 3;

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

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

^R8 and ^R9 are independently hydrogen, halogen, cyano, hydroxyl or _C1 - _C6 alkyl, wherein the _C1 - _C6 alkyl is optionally independently substituted by one, two, three or four ^Rg ; or ^R8 and ^R9 form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl with the atoms attached to them.

Each R ^g is independently a halogen, cyano, hydroxyl, _C1 - _C3 alkyl, or _C1 - _C3 alkoxy group;

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 optionally and independently substituted by one, two, or three ^Ri ;

Each ^Ri is independently hydrogen, halogen, hydroxyl, _C1 - _C3 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, cyano, -NR ^11-1 R ^11-2 , -OR ^11-3 or -SR ^11-4 ; wherein the _C1 - _C3 alkyl is optionally independently substituted by 1, 2, 3 or 4 Ri ^-1 , or, two ^Ri on the same atom and the atom attached thereto form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl; or, two adjacent ^Ri and the atom attached thereto form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl (wherein, the 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl forms a fused ring with B);

Each Ri ^-1 is independently _C1 - _C3 alkyl, halogen, cyano, or hydroxyl;

R ^11-1 and R ^11-2 are independently hydrogen, _C1 - _C3 alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl; or, R ^11-1 and R ^11-2 form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl with the atoms connected to them.

R ^11-3 and R ^11-4 are independently _C1 - _C3 alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl;

In R ^11-1 , R ^11-2 , R ^11-3 and R ^11-4 , the C ₁ -C ₃ alkyl, 3-7 membered cycloalkyl and 3-7 membered heterocycloalkyl are optionally independently replaced by one, two or three Ri ^-2 ;

Each Ri ^-2 is independently a _C1 - _C3 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, halogen, cyano or hydroxyl;

D is hydrogen, halogen, cyano, hydroxyl, _C1 - _C6 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, or 5-12 membered heteroaryl; wherein the _C1 - _C6 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-12 membered heteroaryl are optionally and independently substituted by one, two, or three ^Rj ;

Each ^Rj is independently hydrogen, halogen, cyano, hydroxyl, _C1 - _C3 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, -NR ^12-1 R ^12-2 , -OR ^12-3 or -SR ^12-4 ; the _C1 - _C3 alkyl, 3-7 membered cycloalkyl and 3-7 membered heterocycloalkyl are optionally independently substituted by one, two or three ^Rk ;

^R12-1 , ^R12-2 , ^R12-3 , and ^R12-4 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 optionally independently substituted by one, two, or three Rk ^-1 ; or, ^R12-1 forms a 3- to 7-membered heterocycloalkyl with ^R12-2 and the atom attached thereto.

Each ^Rk is independently a halogen, cyano, hydroxyl, _C1 - _C3 alkyl, 3-7 membered cycloalkyl, or 3-7 membered heterocycloalkyl;

Each Rk ^-1 is independently a halogen, cyano, hydroxyl, _C1 - _C3 alkyl, 3-7 membered cycloalkyl, or 3-7 membered heterocycloalkyl;

When A is _X1 , _X2 , and _X3 are ^CR1 , the compound shown in Formula I satisfies any of the following conditions:

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

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

(3) L is -( _CH₂ )-, -( _CH₂ ) _₂- ,

(4) When E or F is a carbonyl group, B is a 4-7 membered cycloalkyl, a 6-10 membered aryl, a 5-12 membered heteroaryl, or a 4-6 membered heterocycloalkyl substituted with 1, 2, or 3 ^Ri , wherein two ^Ri on the same atom and the atom attached thereto form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl; or, two adjacent ^Ri and the atom attached thereto form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl (wherein, the 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl forms a fused ring with B); wherein the 4-7 membered cycloalkyl, 6-10 membered aryl, and 5-12 membered heteroaryl are optionally independently substituted with 1, 2, or 3 ^Ri .

(5)

When A is , the number of heteroatoms in _X1 , _X2 and _X4 is 1 or 2;

When A is a carbonyl group and L is a carbonyl group, u is a natural number from 1 to 3, B is a 4- to 6-membered heterocyclic alkyl group, and the 4- to 6-membered heterocyclic alkyl group may be independently substituted by 1, 2 or 3 Ri ^groups ;

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

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

In one of the schemes,

Among them,

m is a natural number from 0 to 3;

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

k is a natural number between 0 and 3;

_X1 , _X2 , _X3 , _X4 and _X5 are independently ^-CR1- , N, O, S, or chemical bonds;

RN ^-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 optionally independently substituted by 1, 2, 3 or 4 RN ^-2 ;

Each RN ^-2 is independently a halogen;

^Y and Z are independently carbonyl (CO), -( ^CR₂R₃ ) _r- , or chemical bonds; r is a natural number from 0 to 5;

^Each W can be independently a carbonyl (CO), -O-, -( ^CR4R5 )-, ^-NR6- , or a chemical bond;

Each ^R1 is independently hydrogen, halogen, cyano, hydroxyl, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or ^-NR1-1R1-2 , wherein the _C1 - _C6 alkyl and _C1 - _C6 alkoxy are optionally independently substituted by one, two, three ^, or four ^Ra ; or two ^R1s and the atoms attached thereto form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl.

Each ^Ra is independently halogenated, cyano, hydroxyl, _C1 - _C3 alkyl, _C1 - _C6 alkoxy, or ^-NR1-4R1-5 ; or, two ^Ra and the atoms attached thereto form a 3- to 7-membered cycloalkyl or a 3- ^to 7-membered heterocycloalkyl; ^R1-1 and ^R1-2 are independently hydrogen or _C1 - _C6 alkyl, wherein the _C1 - _C6 alkyl is optionally independently substituted by one, two, three, or four ^Rb ; or, ^R1-1 and ^R1-2 and the atoms attached thereto form a 3- to 7-membered heterocycloalkyl.

Each ^Rb is independently a halogen, cyano, hydroxyl, _C1 - _C6 alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, _C1 - _C3 alkyl and NR ^1-1-1 R ^1-2-1 , wherein the 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl and _C1 - _C3 alkyl are optionally independently substituted by 1, 2, 3 or 4 Rb ^-1 ;

Each Rb ^-1 is independently halogenated, hydroxyl, or cyano;

^R1-4 and ^R1-5 are independently hydrogen or _C1 - _C3 alkyl, wherein the _C1 - _C3 alkyl is optionally independently substituted by one, two, three or four ^R1-4-1 ; or, ^R1-4 and ^R1-5 form a 3- to 7-membered heterocyclic alkyl with the atom to which they are attached.

^R1-1-1 and ^R1-2-1 are independently hydrogen or _C1 - _C3 alkyl, wherein the _C1 - _C3 alkyl is optionally independently substituted by one, two, three or four ^R1-1-1-1 ;

Each R ^1-4-1 and R ^1-1-1-1 is independently a halogen, hydroxyl, or cyano group;

^R2 and ^R3 are independently hydrogen, halogen, cyano, hydroxyl, _C1 - _C6 alkoxy, or ^NR2-1R2-2 ; or ^{R2 and R3} form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl with the atoms attached to them.

^R2-1 and ^R2-2 are independently hydrogen or _C1 - _C6 alkyl, wherein the _C1 - _C6 alkyl is optionally independently substituted by one, two, three or four ^Rd ; or, ^R2-1 and ^R2-2 form a 3- to 7-membered heterocyclic alkyl with the atom to which they are attached.

Each R ^d is independently a halogen, cyano, hydroxyl, _C1 - _C6 alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or _C1 - _C3 alkyl;

^R4 , ^R5 and ^R6 are independently hydrogen, halogen, cyano, hydroxyl, _C1 - _C6 alkoxy, _C1 - _C6 alkyl or ^{NR4-1 R4-2} , wherein the _C1 - _C6 alkyl is optionally independently substituted by one, two, three or four ^Re .

Each ^Re is independently a halogen, cyano, hydroxyl, _C1 - _C3 alkyl, _C1 - _C3 alkoxy, or -NR ^4-4 R ^4-5 ;

^R4-1 and ^R4-2 are independently hydrogen or _C1 - _C6 alkyl, wherein the _C1 - _C6 alkyl is optionally independently substituted by one, two, three or four ^Rf ; or, ^R4-1 and ^R4-2 form a 3- to 7-membered heterocyclic alkyl with the atom to which they are attached.

Each ^Rf is independently a halogen, cyano, hydroxyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, _C1 - _C3 alkyl, _C1 - _C3 alkoxy, or -NR ^4-1-1 R ^4-2-1 ;

^R4-4 and ^R4-5 are independently hydrogen or _C1 - _C3 alkyl; or ^R4 and ^R5 form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl with the atoms attached to them;

R ^4-1-1 and R ^4-2- are independently hydrogen or _C1 - _C3 alkyl;

L is

t is a natural number between 0 and 3;

u is a natural number from 0 to 3;

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

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

^R8 and ^R9 are independently hydrogen, halogen, cyano, hydroxyl or _C1 - _C6 alkyl, wherein the _C1 - _C6 alkyl is optionally independently substituted by one, two, three or four ^Rg ; or ^R8 and ^R9 form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl with the atoms attached to them.

Each R ^g is independently a halogen, cyano, hydroxyl, _C1 - _C3 alkyl, or _C1 - _C3 alkoxy group;

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 optionally and independently substituted by one, two, or three ^Ri ;

Each ^Ri is independently hydrogen, halogen, hydroxyl, _C1 - _C3 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, cyano, -NR ^11-1 R ^11-2 , -OR ^11-3 or -SR ^11-4 ; wherein the _C1 - _C3 alkyl is optionally independently substituted by 1, 2, 3 or 4 Ri ^-1 , or, two ^Ri on the same atom and the atom attached thereto form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl; or, two adjacent ^Ri and the atom attached thereto form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl (wherein, the 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl forms a fused ring with B);

Each Ri ^-1 is independently _C1 - _C3 alkyl, halogen, cyano, or hydroxyl;

R ^11-1 and R ^11-2 are independently hydrogen, _C1 - _C3 alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl; or, R ^11-1 and R ^11-2 form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl with the atoms connected to them.

R ^11-3 and R ^11-4 are independently _C1 - _C3 alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl;

In R ^11-1 , R ^11-2 , R ^11-3 and R ^11-4 , the C ₁ -C ₃ alkyl, 3-7 membered cycloalkyl and 3-7 membered heterocycloalkyl are optionally independently replaced by one, two or three Ri ^-2 ;

Each Ri ^-2 is independently a _C1 - _C3 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, halogen, cyano or hydroxyl;

D is hydrogen, halogen, cyano, hydroxyl, _C1 - _C6 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, or 5-12 membered heteroaryl; wherein the _C1 - _C6 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-12 membered heteroaryl are optionally and independently substituted by one, two, or three ^Rj ;

Each ^Rj is independently hydrogen, halogen, cyano, hydroxyl, _C1 - _C3 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, -NR ^12-1 R ^12-2 , -OR ^12-3 or -SR ^12-4 ; the _C1 - _C3 alkyl, 3-7 membered cycloalkyl and 3-7 membered heterocycloalkyl are optionally independently substituted by one, two or three ^Rk ;

^R12-1 , ^R12-2 , ^R12-3 , and ^R12-4 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 optionally independently substituted by one, two, or three Rk ^-1 ; or, ^R12-1 forms a 3- to 7-membered heterocycloalkyl with ^R12-2 and the atom attached thereto.

Each ^Rk is independently a halogen, cyano, hydroxyl, _C1 - _C3 alkyl, 3-7 membered cycloalkyl, or 3-7 membered heterocycloalkyl;

Each Rk ^-1 is independently a halogen, cyano, hydroxyl, _C1 - _C3 alkyl, 3-7 membered cycloalkyl, or 3-7 membered heterocycloalkyl;

When A is _X1 , _X2 , and _X3 are ^CR1 , the compound shown in Formula I satisfies any of the following conditions:

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

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

(3) L is -( _CH₂ )-, -( _CH₂ ) _₂- ,

(4) When E or F is a carbonyl group, B is a 4-7 membered cycloalkyl, a 6-10 membered aryl, a 5-12 membered heteroaryl, or a 4-6 membered heterocycloalkyl substituted with 1, 2, or 3 ^Ri , wherein two ^Ri on the same atom and the atom attached thereto form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl; or, two adjacent ^Ri and the atom attached thereto form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl (wherein, the 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl forms a fused ring with B); wherein the 4-7 membered cycloalkyl, 6-10 membered aryl, and 5-12 membered heteroaryl are optionally independently substituted with 1, 2, or 3 ^Ri .

(5)

When A is , the number of heteroatoms in _X1 , _X2 and _X4 is 1 or 2;

When A is a carbonyl group and L is a carbonyl group, u is a natural number from 1 to 3, B is a 4- to 6-membered heterocyclic alkyl group, and the 4- to 6-membered heterocyclic alkyl group may be independently substituted by 1, 2 or 3 Ri ^groups ;

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

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

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

In one particular scheme, n is 1.

In one scheme, when _X1 is N, _X2 , _X3 and _X4 are ^-CR1- , Y and Z are independently -( _CH2 )-, m and n are 2, and ^Rj is trifluoromethyl.

In one of the schemes, for

In one of the schemes, for

In one particular scheme, m is 1.

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

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

In one particular scheme, r is 1.

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

In one scheme, ^RN-1 is a _C1 - _C6 alkyl group.

In one scheme, ^RN-1 is hydrogen, _C1 - _C6 alkyl, or 3- to 7-membered cycloalkyl.

In one ^scheme , each W is independently -( ^CR4R5 )-, -O-, ^-NR6- , or a chemical bond.

In one scheme, each W is independently ^a -( ^CR4R5 )-, ^-NR6- , or a chemical bond.

In one scheme, Y and Z are independently carbonyl (CO) or - ^{( CR₂R₃} ) _r- .

In a certain scheme, Y and Z are independently -(CR ² R ³ ) _r -.

In one scheme, each ^R1 is independently hydrogen, halogen, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 alkylthio, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, ^{or -NR1-1R1-2} .

In one scheme, each ^R1 is independently _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 alkylthio ^, or ^-NR1-1R1-2 .

In one scheme, each ^R1 is independently hydrogen, _C1 - _C6 alkyl, C1- _C6 alkoxy, _C1 - _C6 alkylthio, _3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or ^-NR1-1R1-2 , for example, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, ^C1 _{- C6} alkylthio, ^{or -NR1-1R1-2} .

In one embodiment, each ^R1 is independently hydrogen, halogen, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 alkylthio, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, ^{or -NR1-1R1-2} , wherein the _C1 - _C6 alkylthio, _C1 - _C6 alkyl, and _C1 - _C6 alkoxy are optionally independently substituted by one, two, three, or four ^Ra .

In one scheme, each ^R1 is independently hydrogen, halogen, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl ^, or ^-NR1-1R1-2 .

In one scheme, each ^R1 is independently a _C1 - _C6 alkyl group.

In one scheme, each ^R1 is independently a _C1 - _C6 alkyl or _C1 - _C6 alkoxy.

In one embodiment, ^R1-1 and ^R1-2 are independently hydrogen or _C1 - _C6 alkyl; or, ^R1-1 and ^R1-2 form 3- to 7-membered heterocyclic alkyl groups with the atoms attached to them; for example, ^R1-1 and ^R1-2 form 3- to 7-membered heterocyclic alkyl groups with the atoms attached to them.

In one scheme, when _X1 and _X3 are independently N; and _X4 and _X2 are independently ^-CR1- , each ^R1 is independently _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 alkylthio, ^3- to 7-membered heterocyclic alkyl, or ^-NR1-1R1-2 .

In one scheme, when _X2 is independently ^-CR1- , ^R1 (at _X2 ) is a _C1 - _C6 alkyl or _C1 - _C6 alkoxy.

In one scheme, when D is pyrimidinyl, each ^R1 is independently a halogen or a 3- to 7-membered cycloalkyl group.

In one scheme, when _X2 and _X3 are independently N; and _X4 and _X1 are independently ^-CR1- , each ^R1 is independently _C1 - _C6 alkyl or 3- to 7-membered heterocyclic alkyl.

In one scheme, each ^Ra is independently a hydroxyl, _C1 - _C3 alkoxy ^, or ^NR1-4R1-5 .

In one scheme, each ^Ra is independently halogenated, hydroxyl, _C1 - _C6 alkoxy, or ^-NR1-4R1-5 , for ^example , each ^Ra is independently hydroxyl, _C1 - _C6 alkoxy, or ^-NR1-4R1-5 , or ^hydroxyl .

In one scheme, each ^Rb is independently a hydroxyl group, a 3-7 membered cycloalkyl group, a 3-7 membered heterocycloalkyl group, a _C1 - _C3 alkyl group, a _C1 - _C3 alkoxy group, or an NR ^1-1-1 R ^1-2-1 .

In one scheme, each ^Rb is independently a hydroxyl group, a 3- to 7-membered cycloalkyl group, or a _C1 - _C3 alkyl group, for example, each ^Rb is independently a hydroxyl group, a 3- to 7-membered cycloalkyl group.

In one scheme, each ^Rb is independently a 3- to 7-membered cycloalkyl group.

In one scheme, Rb ^-1 is independently a hydroxyl group.

In one scheme, each Rb ^-1 is independently a hydroxyl group.

In one scheme, each Rb ^-2 is independently halogenated or _C1 - _C6 alkyl.

In one scheme, ^R1-4 and ^R1-5 are independently _C1 - _C3 alkyl groups.

In one scheme, each ^R1-4-1 is independently a halogen.

In one scheme, ^R1-4-1 is a halogen.

In one scheme, ^R2 and ^R3 are independently hydrogen or ^{NR2-1 R2-2} .

In one scheme, ^R2 and ^R3 are hydrogen independently.

In one embodiment, ^R2-1 and ^R2-2 are independently hydrogen or _C1 - _C6 alkyl, for example, hydrogen.

In one scheme, ^R4 , ^R5 , and ^R6 are hydrogen independently.

In one scheme, ^R4 , ^R5 , and ^R6 are independently hydrogen or ^{NR4-1 R4-2} .

In one scheme, R ^4-1 and R ^4-2 are hydrogen independently.

In one scheme, ^Re is -NR ^4-4 R ^4-5 .

In one embodiment, ^R4-4 and ^R4-5 are independently hydrogen or _C1 - _C3 alkyl.

In one scheme, E is a carbonyl group, -NHCO-, or a chemical bond.

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

In one particular scheme, E represents a carbonyl group.

In one particular scheme, t is 0.

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

In one scheme, F is a carbonyl group, -O-, -NH-, or a chemical bond.

In one particular scheme, F represents a chemical bond.

In one embodiment, ^R8 and ^R9 are independently hydrogen or _C1 - _C6 alkyl; or ^R8 and ^R9 form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl with the atoms attached to them.

In one scheme, ^R8 and ^R9 are independently hydrogen or _C1 - _C6 alkyl, or ^R8 and ^R9 form a 3- to 7-membered cycloalkyl group with the atoms they are attached to.

In one embodiment, ^R8 and ^R9 are independently _C1 - _C6 alkyl groups; or ^R8 and ^R9 form 3-7 membered cycloalkyl groups or 3-7 membered heterocycloalkyl groups with the atoms attached to them.

In one embodiment, B is a 4-6 membered heterocyclic alkyl, a 6-10 membered aryl, or a 5-12 membered heteroaryl, wherein the 5-12 membered heteroaryl, 6-10 membered aryl, and 4-6 membered heterocyclic alkyl are optionally and independently substituted by one, two, or three ^Ri .

In one embodiment, B is a 4- to 6-membered heterocyclic alkyl group or a 5- to 12-membered heteroaryl group, wherein the 5- to 12-membered heteroaryl group and the 4- to 6-membered heterocyclic alkyl group are optionally and independently substituted by one, two, or three ^Ri .

In one embodiment, B is a 4- to 6-membered heterocyclic alkyl group, wherein the 4- to 6-membered heterocyclic alkyl group is optionally and independently substituted by one, two, or three ^Ri ;

In one embodiment, when B is a 6-10 aryl or a 5-12 heteroaryl, D is hydrogen, halogen, cyano, hydroxyl, _C1 - _C6 alkyl, 3-7 cycloalkyl, or 3-7 heterocycloalkyl, wherein the _C1 - _C6 alkyl, 3-7 cycloalkyl, or 3-7 heterocycloalkyl may be optionally and independently substituted by one, two, or three ^Rj ; preferably, D is hydrogen or a _C1 - _C6 alkyl.

In one embodiment, when _X2 and _X3 are independently N and _X4 and _X1 are independently ^-CR1- , B is an azahexacyclic butyl group (e.g.).

In one scheme, when _X1 ^and _X3 (or _X2 and _X4 ) are ^-CR1- and ^R1 is a _C1 - _C6 alkyl group, each ^Rj is independently ^-OR12-3 or ^-SR12-4 .

In one embodiment, ^Ri is hydrogen, halogen, hydroxyl, or _C1 - _C3 alkyl; or, two ^Ri and the atoms attached thereto form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl.

In one embodiment, each ^Ri is independently hydrogen, halogen, hydroxyl, or _C1 - _C3 alkyl; or, two ^Ri and the atoms attached to them form a 3- to 7-membered cycloalkyl ring, for example, ^Ri is hydrogen or _C1 - _C3 alkyl, such as _C1 - _C3 alkyl. In another embodiment, ^Ri is hydrogen.

In one embodiment, D is hydrogen, _C1 - _C6 alkyl, or 5-12 heteroaryl; wherein the _C1 - _C6 alkyl and 5-12 heteroaryl are optionally and independently substituted by one, two, or three ^Rj .

In one embodiment, D is hydrogen, a 3- to 7-membered cycloalkyl group, a _C1 - _C6 alkyl group, or a 5- to 6-membered heteroaryl group, wherein the _C1 - _C6 alkyl group and the 5- to 6-membered heteroaryl group are optionally and independently substituted by one, two, or three ^Rj .

In one embodiment, D is a 5- to 12-membered heteroaryl group; wherein the 5- to 12-membered heteroaryl group is optionally and independently replaced by one, two, or three ^Rj .

In one embodiment, D is a 5- to 6-membered heteroaryl group; wherein the 5- to 6-membered heteroaryl group is optionally and independently replaced by one, two, or three ^Rj .

In one embodiment, when _X2 and _X3 are independently N; and _X4 and _X1 are independently ^-CR1- , D is a 6-membered heteroaryl (for example); wherein the 6-membered heteroaryl is optionally and independently replaced by 1, 2 or 3 ^Rj .

In one embodiment, when D is a five-membered heteroaryl group, ^each of the five-membered heteroaryl groups is independently a _C1 - _C6 alkyl or _C1 - _C6 alkoxy group.

In one scheme, ^Rj is a halogen, _C1 - _C3 alkyl, OR ^12-3 , or SR ^12-4 .

In one embodiment, each ^Rj is independently a _C1 - _C3 alkyl, OR ^12-3 , or SR ^12-4 , wherein the _C1 - _C3 alkyl is optionally independently substituted by one, two, or three ^Rk , and preferably, each ^Rj is independently OR ^12-3 or SR ^12-4 .

In one scheme, each ^Rj is independently a halogen, _C1 - _C3 alkyl, OR ^12-3 , or SR ^12-4 .

In one scheme, each ^Rj is independently hydrogen, halogen, _C1 - _C3 alkyl, 3-7 membered cycloalkyl, -OR ^12-3 or -SR ^12-4 .

In one embodiment, each ^Rj is independently hydrogen, halogen, _C1 - _C3 alkyl, 3- to 7-membered cycloalkyl, -OR ^12-3 or -SR ^12-4 ; the _C1 - _C3 alkyl and 3- to 7-membered cycloalkyl are optionally independently substituted by one, two or three ^Rk .

In one particular scheme, R_^j is OR ^12-3 .

In one scheme, each ^Rj is independently OR ^12-3 .

In one scheme, ^Rj is a halogen or a _C1 - _C3 alkyl group.

In one scheme, each ^Rj is independently a halogen or a _C1 - _C3 alkyl group.

In one scheme, when _X1 and _X3 are independently N; _X4 and _X2 are independently ^-CR1- ; each ^R1 is independently _C1 - _C6 alkyl and _C1 - _C6 alkoxy; and each ^Rj is independently halogen, 3- to 7-membered cycloalkyl, _{OCH2CF3 ,} or ^SR12-4 .

In a certain scheme, when , each ^Rj is independently OR ^12-3 or SR ^12-4 .

In one scheme, when _X1 or _X4 is ^-CR1- , ^R1 is independently ^a 3- to 7-membered heterocyclic alkyl group or ^-NR1-1R1-2 , each ^Rj is independently ^OR12-3 or ^SR12-4 .

In one embodiment, ^R12-3 and ^R12-4 are independently _C1 - _C3 alkyl groups.

In one embodiment, ^R12-3 and ^R12-4 are independently _C1 - _C3 alkyl groups; wherein the _C1 - _C3 alkyl groups are optionally independently substituted by one, two or three Rk ^-1 groups.

In one embodiment, ^R12-1 , ^R12-2 , ^R12-3 and ^R12-4 are independently _C1 - _C3 alkyl groups.

In one scheme, each ^Rk is an independent halogen.

In one scheme, ^Rk is independently a halogen.

In one scheme, each Rk ^-1 is independently a halogen.

In one scheme, Rk ^-1 is independently a halogen.

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

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

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

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

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

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

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

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

In one embodiment, when A is _X1 , _X2 , and _X3 are ^CR1 , in the compound represented by Formula I, E or F is...

In one embodiment, in RN ^-1 , the _C1 - _C6 alkyl group is preferably a _C1 - _C3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, or methyl, ethyl or isopropyl.

In one embodiment, in RN ^-1 , the _C1 - _C6 alkoxy group is preferably a _C1 - _C3 alkoxy group, such as methoxy, ethoxy, n-propoxy, or isopropoxy.

In one embodiment, in RN ^-1 , the 3- to 7-membered cycloalkyl group is preferably a 3- to 6-membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane.

In one embodiment, the halogen in ^RN-2 is F, Cl, Br, or I, for example, F or Cl.

In one embodiment, in ^R1 , the halogen is F, Cl, Br, or I, for example, F or Cl, or Cl.

In one embodiment, in ^R1 , the _C1 - _C6 alkyl group is preferably a _C1 - _C3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, or methyl, ethyl or isopropyl.

In one embodiment, in ^R1 , the _C1 - _C6 alkoxy group is preferably a _C1 - _C3 alkoxy group, such as methoxy, ethoxy, n-propoxy, or isopropoxy, or methoxy or ethoxy.

In one embodiment, in ^R1 , the _C1 - _C6 alkylthio group is preferably a _C1 - _C3 alkylthio group, such as methylthio, ethylthio, n-propylthio, or isopropylthio, or methylthio.

In one embodiment, in ^R1 , the 3-7 membered cycloalkyl group is preferably a 3-6 membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane, or cyclopropane or cyclobutane.

In one embodiment, in ^R1 , the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably one or two; the 3-6 membered heterocyclic alkyl group is more preferably a 4 membered heterocyclic alkyl group, for example...

In one embodiment, in ^R1 , the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably one or two; the 3-6 membered heterocyclic alkyl group is more preferably a 4 membered heterocyclic alkyl group, for example...

In one embodiment, the halogen in ^Ra is preferably F, Cl, Br, or I, such as F or Cl, or F.

In one embodiment, in ^Ra , the _C1 - _C3 alkyl group is preferably methyl, ethyl, n-propyl, or isopropyl.

In one embodiment, in ^Ra , the _C1 - _C6 alkoxy group is preferably a _C1 - _C3 alkoxy group, such as methoxy, ethoxy, n-propoxy, or isopropoxy, or methoxy.

In one embodiment, in ^Ra , the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably one or two; the 3-6 membered heterocyclic alkyl group is more preferably a 4 membered heterocyclic alkyl group, for example...

In one embodiment, in ^Ra , the 3- to 7-membered cycloalkyl group is preferably a 3- to 6-membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane.

In one embodiment, in ^R1-1 and ^R1-2 , the _C1 - _C6 alkyl group is preferably a _C1 - _C3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, or methyl or ethyl (e.g., methyl).

In one embodiment, in ^R1-1 and ^R1-2 , the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably 1 or 2; the 3-6 membered heterocyclic alkyl group is, for example, a 4 membered heterocyclic alkyl group, or...

In one embodiment, the halogen in ^Rb is preferably F, Cl, Br, or I, for example, F or Cl.

In one embodiment, the _C1 - _C6 alkoxy group in ^Rb is preferably a _C1 - _C3 alkoxy group, such as methoxy, ethoxy, n-propoxy, or isopropoxy.

In one embodiment, the 3-7 membered cycloalkyl group in ^Rb is preferably a 3-6 membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane, or cyclopropane.

In one embodiment, in ^Rb , the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; and the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably one or two.

In one embodiment, in ^Rb , the _C1 - _C3 alkyl group is preferably methyl, ethyl, n-propyl, or isopropyl, for example, methyl.

In one embodiment, the halogen in Rb ^-1 is preferably F, Cl, Br, or I, for example, F or Cl.

In one embodiment, the halogen in Rb ^-2 is preferably F, Cl, Br, or I, for example, F.

In one embodiment, in Rb ^-2 , the _C1 - _C6 alkyl group is preferably a _C1 - _C3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, or methyl (for example).

In one embodiment, in ^R1-4 and ^R1-5 , the _C1 - _C3 alkyl group is preferably methyl, ethyl, n-propyl or isopropyl, such as methyl, ethyl or n-propyl, or methyl.

In one embodiment, in ^R1-4 and ^R1-5 , the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably one or two; the 3-6 membered heterocyclic alkyl group is more preferably a 4 membered heterocyclic alkyl group, for example...

In one embodiment, in ^R1-1-1 and ^R1-2-1 , the _C1 - _C3 alkyl group is preferably methyl, ethyl, n-propyl or isopropyl.

In one scheme, in R ^1-4-1 and R ^1-1-1-1 , the halogen is preferably F, Cl, Br or I, for example F or Cl, or F.

In one embodiment, the halogen in ^R2 and ^R3 is preferably F, Cl, Br or I, for example F or Cl.

In one embodiment, the _C1 - _C6 alkoxy group in ^R2 and ^R3 is preferably a _C1 - _C3 alkoxy group, such as methoxy, ethoxy, n-propoxy, or isopropoxy.

In one embodiment, the 3-7 membered cycloalkyl group in ^R2 and ^R3 is preferably a 3-6 membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane.

In one embodiment, in ^R2 and ^R3 , the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; and the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably 1 or 2.

In one embodiment, in R ^2-1 and R ^2-2 , the C ₁ -C ₆ alkyl group is preferably a C ₁ -C ₃ alkyl group, such as methyl, ethyl, n-propyl or isopropyl, or methyl or ethyl.

In one embodiment, in R ^2-1 and R ^2-2 , the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; and the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably 1 or 2.

In one embodiment, the halogen in ^Rd is preferably F, Cl, Br, or I, for example, F or Cl.

In one embodiment, the _C1 - _C6 alkoxy group in ^Rd is preferably a _C1 - _C3 alkoxy group, such as methoxy, ethoxy, n-propoxy, or isopropoxy.

In one embodiment, the 3-7 membered cycloalkyl group in ^Rd is preferably a 3-6 membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane.

In one embodiment, in R ^d , the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom of the 3-7 membered heterocyclic alkyl group is preferably N or O, and the number of heteroatoms of the 3-6 membered heterocyclic alkyl group is preferably 1 or 2.

In one embodiment, the _C1 - _C3 alkyl group in ^Rd is preferably methyl, ethyl, n-propyl, or isopropyl.

In one embodiment, the halogen in ^R4 , ^R5 and ^R6 is preferably F, Cl, Br or I, for example F or Cl.

In one embodiment, among ^R4 , ^R5 and ^R6 , the _C1 - _C6 alkoxy group is preferably a _C1 - _C3 alkoxy group, such as methoxy, ethoxy, n-propoxy or isopropoxy.

In one embodiment, among ^R4 , ^R5 and ^R6 , the _C1 - _C6 alkyl group is preferably a _C1 - _C3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl.

In one embodiment, the halogen in ^Re is preferably F, Cl, Br, or I, for example, F or Cl.

In one embodiment, in ^Re , the _C1 - _C3 alkyl group is preferably methyl, ethyl, n-propyl, or isopropyl.

In one embodiment, in ^Re , the _C1 - _C3 alkoxy group is preferably methoxy, ethoxy, n-propoxy, or isopropoxy.

In one embodiment, in R ^4-1 and R ^4-2 , the _C1 - _C6 alkyl group is preferably a _C1 - _C3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl.

In one embodiment, in R ^4-1 and R ^4-2 , the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; and the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably 1 or 2.

In one embodiment, the halogen in ^Rf is preferably F, Cl, Br, or I, for example, F or Cl.

In one embodiment, in ^Rf , the 3- to 7-membered cycloalkyl group is preferably a 3- to 6-membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane.

In one embodiment, in ^Rf , the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; and the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably 1 or 2.

In one embodiment, in ^Rf , the _C1 - _C3 alkyl group is preferably methyl, ethyl, n-propyl, or isopropyl.

In one embodiment, the _C1 - _C3 alkoxy group in ^Rf is preferably methoxy, ethoxy, n-propoxy, or isopropoxy.

In one embodiment, in R ^4-4 and R ^4-5 , the C ₁ -C ₃ alkyl group is preferably methyl, ethyl, n-propyl, or isopropyl.

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

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

In one embodiment, the halogen in ^R8 and ^R9 is preferably F, Cl, Br or I, for example F or Cl.

In one embodiment, in ^R8 and ^R9 , the _C1 - _C6 alkyl group is preferably a _C1 - _C3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, or methyl.

In one embodiment, the 3-7 membered cycloalkyl group in ^R8 and ^R9 is preferably a 3-6 membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane, or cyclopropane.

In one embodiment, in ^R8 and ^R9 , the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably 1 or 2, and the 3-6 membered heterocyclic alkyl group is, for example, a 4 membered heterocyclic alkyl group, or oxobutane.

In one embodiment, the halogen in ^Rg is preferably F, Cl, Br, or I, for example, F or Cl.

In one embodiment, in ^Rg , the _C1 - _C3 alkyl group is preferably methyl, ethyl, n-propyl, or isopropyl, for example, methyl.

In one embodiment, the _C1 - _C3 alkoxy group in ^Rg is preferably methoxy, ethoxy, n-propoxy, or isopropoxy.

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

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

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

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

In one embodiment, the halogen in ^Ri is preferably F, Cl, Br, or I, for example, F or Cl, or F.

In one embodiment, in ^Ri , the _C1 - _C3 alkyl group is preferably methyl, ethyl, n-propyl, or isopropyl, or methyl.

In one embodiment, in ^Ri , the 3-7 membered cycloalkyl group is preferably a 3-6 membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane, or cyclopropane or cyclobutane, for example, cyclopropane.

In one embodiment, in ^Ri , the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; and the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably one or two.

In one embodiment, in Ri ^-1 , the halogen is preferably F, Cl, Br, or I, for example, F or Cl.

In one embodiment, in Ri ^-1 , the _C1 - _C3 alkyl group is preferably methyl, ethyl, n-propyl, or isopropyl.

In one embodiment, in R ^11-1 , R ^11-2 , R ^11-3 and R ^11-4 , the C ₁ -C ₃ alkyl group is, for example, methyl, ethyl, n-propyl or isopropyl.

In one embodiment, in R ^11-3 and R ^11-4 , the 3- to 7-membered cycloalkyl group can be a 3- to 6-membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane.

In one embodiment, in R ^11-3 and R ^11-4 , the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; and the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably one or two.

In one embodiment, in R ^11-1 and R ^11-2 , the 3- to 7-membered cycloalkyl group is preferably a 3- to 6-membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane.

In one embodiment, in R ^11-1 and R ^11-2 , the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; and the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably 1 or 2.

In one embodiment, the halogen in Ri ^-2 is preferably F, Cl, Br, or I, for example, F or Cl.

In one embodiment, in Ri ^-2 , the _C1 - _C3 alkyl group is preferably methyl, ethyl, n-propyl, or isopropyl.

In one embodiment, in Ri ^-2 , the 3- to 7-membered cycloalkyl group is preferably a 3- to 6-membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane.

In one embodiment, in Ri ^-2 , the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; and the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably one or two.

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

In one embodiment, in D, the _C1 - _C6 alkyl group is preferably a _C1 - _C3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, or methyl.

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

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

In one embodiment, the halogen in ^Rj is preferably F, Cl, Br or I, for example F or Cl, or F.

In one embodiment, in ^Rj , the _C1 - _C3 alkyl group is preferably methyl, ethyl, n-propyl, or isopropyl, such as methyl, ethyl, or isopropyl, with methyl being the most preferred.

In one embodiment, in ^Rj , the 3-7 membered cycloalkyl group is preferably a 3-6 membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane, or cyclopropane.

In one embodiment, in ^Rj , the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; and the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably 1 or 2.

In one embodiment, in R ^12-1 , R ^12-2 , R ^12-3 and R ^12-4 , the C ₁ -C ₃ alkyl group is preferably methyl, ethyl, n-propyl or isopropyl, for example methyl or ethyl, or methyl, ethyl or isopropyl.

In one embodiment, among R ^12-1 , R ^12-2 , R ^12-3 and R ^12-4 , the 3- to 7-membered cycloalkyl group is preferably a 3- to 6-membered cycloalkyl group, such as cyclopropane, cyclobutane or cyclopentane.

In one embodiment, among R ^12-1 , R ^12-2 , R ^12-3 and R ^12-4 , the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; and the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably one or two.

In one embodiment, the halogen in ^Rk is preferably F, Cl, Br, or I, such as F or Cl, or F.

In one embodiment, in ^Rk , the _C1 - _C3 alkyl group is preferably methyl, ethyl, n-propyl, or isopropyl.

In one embodiment, the 3- to 7-membered cycloalkyl group in ^Rk is preferably a 3- to 6-membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane.

In one embodiment, in ^Rk , the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; and the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably 1 or 2.

In one embodiment, in Rk ^-1 , the halogen is preferably F, Cl, Br or I, for example F or Cl, or F.

In one embodiment, in Rk ^-1 , the _C1 - _C3 alkyl group is preferably methyl, ethyl, n-propyl, or isopropyl, for example, methyl.

In one embodiment, in R ^k-1 , the 3- to 7-membered cycloalkyl group is preferably a 3- to 6-membered cycloalkyl group, such as cyclopropane, cyclobutane, or cyclopentane.

In one embodiment, in R ^k-1 , the 3-7 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group; the heteroatom in the 3-6 membered heterocyclic alkyl group is preferably N or O; and the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably 1 or 2.

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

Wherein, _X6 is N or CH, and _X1 , ^Ri , _X2 , _X3 , X4, _X5 , Y _, Z, m, n, E, ^Rj , ^R1 , B, D, W, k, F, u, ^R8 and ^R9 are as described in any one of the present invention.

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

Wherein, ^R1 , ^Rj , Z, n, _X6 , _X2 and _X4 are as described in any one of the present invention.

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

Wherein, ^R1 , ^R8 , ^R9 and ^Rj are as described in any one of the present invention.

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

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

In one scheme, _X1 , _X2 , _X3 , _X4 and _X5 are independently ^-CR1- , N, O, S, or chemical bonds, and the number of heteroatoms in _X1 , _X2 , _X3 , _X4 and _X5 is 0, 1, 2 or 3.

In one scheme, _X1 , _X2 , _X3 , _X4 and _X5 are independently ^-CR1- , N, S, or chemical bonds, and the number of heteroatoms in _X1 , _X2 , _X3 , _X4 and _X5 is 1 or 2.

In a certain scheme, _X1 and _X3 are independently N; _X4 and _X2 are independently ^-CR1- .

In a certain scheme, _X2 and _X3 are independently N; _X4 and _X1 are independently ^-CR1- .

In a certain scheme, _X1 and _X4 are independently N; _X2 and _X3 are independently ^-CR1- .

In some schemes, _X1 , _X2 , _X3 , and _X4 are independently ^-CR1- or N; the number of heteroatoms is 0, 1, or 2.

In some schemes, Y and Z are independently carbonyl (CO) or - ^{( CR₂R₃} ) _r- ; _when r is 1, ^R₂ and ^R₃ are independently H, -( _CH₂ )-, -( _NHCH₂ )-, -( _NHCH₂CH₂ )-, or

In some schemes, m is 2, n is 2, Y and Z are independently -(CR ² R ³ ) _r -; r is 1, R ² and R ³ are independently H.

In some schemes, it is a phenyl-5-membered heterocyclic alkyl group, wherein the heteroatom in the 5-membered heterocyclic alkyl group is N, and the number of heteroatoms is 1, for example, e is independently 1, 2 or 3, or as...

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

In some schemes, the heteroatom is a phenyl-7-membered heterocyclic alkyl group, wherein the heteroatom in the 7-membered heterocyclic alkyl group is N, and the number of heteroatoms is 1 or 2, for example, e independently is 0, 1, 2 or 3, or for example...

In some schemes, it is a phenyl-7-membered heterocyclic alkyl group, wherein the heteroatom in the 7-membered heterocyclic alkyl group is N, and the number of heteroatoms is 1 or 2, for example

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

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

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

In some schemes, it is a 6-membered heteroaryl and a 5-membered heterocyclic alkyl group, wherein the heteroatom in the 6-membered heteroaryl group is N and the number of heteroatoms is 2. Preferably, the heteroatom in the 5-membered heterocyclic alkyl group is N and the number of heteroatoms is 1. For example, e is independently 0, 1 or 2.

In some schemes, it is a 6-membered heteroaryl-5-heterocyclic alkyl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 1, for example, e is independently 0, 1, 2 or 3, or for example...

In some schemes, it is a 6-membered heteroaryl-5-heterocyclic alkyl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 1, for example...

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

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

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

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

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

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

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

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

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

In some schemes, _X1 , _X2 , _X3 , _X4 , and _X5 are independently ^-CR1- , N, S, or chemical bonds, and the number of heteroatoms in _X1 , _X2 , _X3 , _X4 , and _X5 is 0, 1, or 2.

In some schemes, it is C-(W) _k- , where C is a 5-membered heteroaryl, a 6-membered heteroaryl, or a phenyl group; 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...

In some schemes, W is -O-, _-CH2- , or -NH-.

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

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

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

In some schemes, B is a 4- to 6-membered heterocyclic alkyl group substituted with two Ri ^atoms , and the two Ri ^atoms on the same atom and the atoms attached to them form a 3- to 7-membered cycloalkyl group. The 3- to 7-membered cycloalkyl group is preferably a 3- to 6-membered cycloalkyl group. For example, B is a 4- or 5-membered heterocyclic alkyl group, and the two Ri ^atoms form a 3- to 4-membered cycloalkyl group. Another example is B...

In some schemes, B is a 4- to 6-membered heterocyclic alkyl group substituted with two Ri ^atoms , and the two Ri ^atoms on the same atom and the atoms attached to them form a 3- to 7-membered cycloalkyl group. The 3- to 7-membered cycloalkyl group is preferably a 3- to 6-membered cycloalkyl group. For example, B is a 4-membered heterocyclic alkyl group, and the two Ri ^atoms form a 3- to 4-membered cycloalkyl group. Another example is B...

In some schemes, B is a 4- to 6-membered heterocyclic alkyl group substituted with two Ri ^atoms . The two Ri ^atoms on the same atom and the atoms attached to them form a 3- to 7-membered cycloalkyl group. The 3- to 7-membered cycloalkyl group is preferably a 3- to 6-membered cycloalkyl group. For example, B is a 5-membered heterocyclic alkyl group, and the two Ri ^atoms form a 3- to 4-membered cycloalkyl group. Another example is B...

In some schemes, B is a 4- to 6-membered heterocyclic alkyl group substituted at the ortho positions of two Ri ^groups . The two adjacent Ri ^groups and their attached atoms form a 3- to 7-membered cycloalkyl group (wherein, the 3- to 7-membered cycloalkyl group forms a fused ring with B). The 3- to 7-membered cycloalkyl group is preferably a 3- to 6-membered cycloalkyl group. For example, B is a 5-membered heterocyclic alkyl group, and the two Ri ^groups and their attached atoms form a 3-membered cycloalkyl group. Another example is B as...

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In one embodiment, the preferred form is a 6-membered heteroaryl-5-membered heterocycloalkyl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 2, for example, e is independently 0, 1, or 2, or for example...

In one embodiment, the preferred form is a 6-membered heteroaryl-5-membered heterocycloalkyl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 2, for example...

In one embodiment, the preferred form is a 6-membered heteroaryl-7-membered heterocycloalkyl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is one or two, for example...

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

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

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

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

Among them,

m is a natural number from 0 to 3;

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

k is a natural number between 0 and 3;

_X1 , _X2 , _X3 , _X4 and _X5 are independently ^-CR1- , N, S, or chemical bonds;

^RN-1 is hydrogen, _C1 - _C6 alkyl, or 3- to 7-membered cycloalkyl;

^Y and Z are independently carbonyl (CO) or -( ^CR₂R₃ ) _r- ; r is a natural number from 0 to 5;

Each W can be independently -O-, -( ^CR4R5 )-, ^{-NR6- ,} or a chemical bond;

Each ^R1 is independently hydrogen, halogen, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 alkylthio, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or ^-NR1-1R1-2 , wherein the _C1 - _C6 alkylthio, _C1 - _C6 alkyl, and _C1 - ^C6 alkoxy are optionally independently substituted by one, two, three, or _four ^Ra ;

Each ^Ra is independently halogenated, hydroxyl, _C1 - _C6 alkoxy, or ^{-NR1-4R1-5 ;}

^R1-1 and ^R1-2 are independently hydrogen or _C1 - _C6 alkyl, wherein the _C1 - _C6 alkyl is optionally independently substituted by 1, 2, 3 or 4 ^Rb ; or, ^R1-1 and ^R1-2 form a 3- to 7-membered heterocyclic alkyl with the atoms attached thereto, wherein the 3- to 7-membered heterocyclic alkyl is optionally substituted by 1, 2, 3 or 4 Rb ^-2 ;

Each ^Rb is independently a hydroxyl group, a 3- to 7-membered cycloalkyl group, or a _C1 - _C3 alkyl group;

Each Rb ^-2 is independently halogenated or _C1 - _C6 alkyl;

^R1-4 and ^R1-5 are independently hydrogen or _C1 - _C3 alkyl, wherein the _C1 - _C3 alkyl is optionally independently substituted by one, two, three or four ^R1-4-1 ; or, ^R1-4 and ^R1-5 form a 3- to 7-membered heterocyclic alkyl with the atom to which they are attached.

Each R ^1-4-1 is independently a halogen;

^R2 and ^R3 are independently hydrogen or ^{NR2-1 R2-2} ;

^R2-1 and ^R2-2 are independently hydrogen or _C1 - _C6 alkyl;

^R4 , ^R5 and ^R6 are independently hydrogen or ^{NR4-1 R4-2} ;

R ^4-1 and R ^4-2 are hydrogen independently;

L is

t is a natural number between 0 and 3;

u is a natural number from 0 to 3;

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

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

^R8 and ^R9 are independently hydrogen or _C1 - _C6 alkyl, or ^R8 and ^R9 form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl with the atoms attached to them;

B is a 4-6 membered heterocyclic alkyl, a 6-10 membered aryl, or a 5-12 membered heteroaryl; wherein the 4-6 membered heterocyclic alkyl, the 6-10 membered aryl, and the 5-12 membered heteroaryl are optionally and independently substituted by one, two, or three ^Ri ;

Each ^Ri is independently hydrogen, halogen, hydroxyl, or _C1 - _C3 alkyl; or, two ^Ri on the same atom and the atom attached thereto form a 3- to 7-membered cycloalkyl group; or, two adjacent ^Ri and the atom attached thereto form a 3- to 7-membered cycloalkyl group.

D is hydrogen, _C1 - _C6 alkyl or 5-12 heteroaryl; wherein the _C1 - _C6 alkyl and 5-12 heteroaryl are optionally independently substituted by one, two or three ^Rj ;

Each ^Rj is independently hydrogen, halogen, _C1 - _C3 alkyl, 3- to 7-membered cycloalkyl, -OR ^12-3 or -SR ^12-4 ; the _C1 - _C3 alkyl and 3- to 7-membered cycloalkyl are optionally independently substituted by one, two or three ^Rk ;

^R12-3 and ^R12-4 are independently _C1 - _C3 alkyl groups; wherein the _C1 - _C3 alkyl group is optionally independently substituted by one, two or three Rk ^-1 groups;

Each ^Rk is an independent halogen;

Each Rk ^-1 is independently a halogen;

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

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

Among them,

m is a natural number from 0 to 3;

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

k is a natural number between 0 and 3;

_X1 , _X2 , _X3 , _X4 and _X5 are independently ^-CR1- , N, S, or chemical bonds;

^RN-1 is a _C1 - _C6 alkyl group;

^Y and Z are independently carbonyl (CO) or -( ^CR₂R₃ ) _r- ; r is a natural number from 0 to 5;

Each W is independently ^a -( ^CR4R5 )-, ^-NR6- , or a chemical bond;

Each ^R1 is independently hydrogen, halogen, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 alkylthio, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or ^-NR1-1R1-2 , wherein the _C1 - _C6 alkylthio, _C1 - _C6 alkyl, and _C1 - ^C6 alkoxy are optionally independently substituted by one, two, three, or _four ^Ra ;

Each ^Ra is independently a hydroxyl, _C1 - _C6 alkoxy, or ^{-NR1-4R1-5 ;}

^R1-1 and ^R1-2 are independently hydrogen or _C1 - _C6 alkyl, wherein the _C1 - _C6 alkyl is optionally independently substituted by 1, 2, 3 or 4 ^Rb ; or, ^R1-1 and ^R1-2 form a 3- to 7-membered heterocyclic alkyl with the atoms attached thereto, wherein the 3- to 7-membered heterocyclic alkyl is optionally substituted by 1, 2, 3 or 4 Rb ^-2 ;

Each ^Rb is independently a 3- to 7-membered cycloalkyl group;

Each Rb ^-2 is independently halogenated or _C1 - _C6 alkyl;

^R1-4 and ^R1-5 are independently _C1 - _C3 alkyl groups;

^R2 and ^R3 are independently hydrogen or ^{NR2-1 R2-2} ;

^R2-1 and ^R2-2 are independently hydrogen;

^R4 , ^R5 and ^R6 are hydrogen independently;

L is

t is a natural number between 0 and 3;

u is a natural number from 0 to 3;

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

F is a chemical bond;

^R8 and ^R9 are independently hydrogen or _C1 - _C6 alkyl, or ^R8 and ^R9 form a 3- to 7-membered cycloalkyl group with the atoms attached to them;

B is a 4-6 membered heterocyclic alkyl, a 6-10 membered aryl, or a 5-12 membered heteroaryl; wherein the 4-6 membered heterocyclic alkyl, the 6-10 membered aryl, and the 5-12 membered heteroaryl are optionally and independently substituted by one, two, or three ^Ri ;

Each ^Ri is independently hydrogen, halogen, hydroxyl, or _C1 - _C3 alkyl; or, two ^Ri on the same atom and the atom attached to them form a 3- to 7-membered cycloalkyl group.

D is hydrogen, _C1 - _C6 alkyl or 5-12 heteroaryl; wherein the _C1 - _C6 alkyl and 5-12 heteroaryl are optionally independently substituted by one, two or three ^Rj ;

Each ^Rj is independently hydrogen, halogen, _C1 - _C3 alkyl, 3- to 7-membered cycloalkyl, -OR ^12-3 or -SR ^12-4 ; the _C1 - _C3 alkyl and 3- to 7-membered cycloalkyl are optionally independently substituted by one, two or three ^Rk ;

^R12-3 and ^R12-4 are independently _C1 - _C3 alkyl groups; wherein the _C1 - _C3 alkyl group is optionally independently substituted by one, two or three Rk ^-1 groups;

Each ^Rk is an independent halogen;

Each Rk ^-1 is independently a halogen;

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

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

Among them,

m is a natural number from 1 to 3;

n is a natural number from 1 to 3;

k is a natural number from 1 to 3;

_X1 , _X2 , _X3 , _X4 and _X5 are independently ^-CR1- , N, O, S, or chemical bonds, and the number of heteroatoms in _X1 , _X2 , _X3 , _X4 and _X5 is 0, 1, 2 or 3;

RN ^-1 is hydrogen or _C1 - _C6 alkyl;

^Y and Z are independently carbonyl (CO) or -( ^CR₂R₃ ) _r- ; r is a natural number from 1 to 2;

Each W can be independently -O-, -( ^CR4R5 )-, ^{-NR6- ,} or a chemical bond;

Each ^R1 is independently hydrogen, halogen, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, 3-7 membered cycloalkyl, ^3-7 membered heterocycloalkyl or ^-NR1-1R1-2 , wherein _{the C1-C6 alkyl and C1-C6 alkoxy are optionally} independently substituted by 1, 2, 3 or 4 ^Ra ;

Each ^Ra is independently hydroxyl, _C1 - _C3 alkoxy, or ^{NR1-4R1-5 ;}

^R1-1 and ^R1-2 are independently hydrogen or _C1 - _C6 alkyl, wherein the _C1 - _C6 alkyl is optionally independently substituted by one, two, three or four ^Rb ; or, ^R1-1 and ^R1-2 form a 3- to 7-membered heterocyclic alkyl with the atom to which they are attached.

Each ^Rb is independently a hydroxyl group, a 3-7 membered cycloalkyl group, a 3-7 membered heterocycloalkyl group, a _C1 - _C3 alkyl group, a _C1 - _C3 alkoxy group, or an NR ^1-1-1 R ^1-2-1 , wherein the 3-7 membered cycloalkyl group, the 3-7 membered heterocycloalkyl group, and the _C1 - _C3 alkyl group are optionally independently substituted by one, two, three, or four Rb ^-1 groups;

Each Rb ^-1 is independently a hydroxyl group;

^R1-4 and ^R1-5 are independently hydrogen or _C1 - _C3 alkyl; wherein the _C1 - _C3 alkyl is optionally independently substituted by one, two, three or four ^R1-4-1 ; or, ^R1-4 and ^R1-5 form a 3- to 7-membered heterocyclic alkyl with the atom to which they are attached.

Each R ^1-4-1 is independently a halogen;

^R1-1-1 and ^R1-2-1 are independently hydrogen or _C1 - _C3 alkyl;

^R2 and ^R3 are independently hydrogen or ^{NR2-1 R2-2} ;

^R2-1 and ^R2-2 are independently hydrogen or _C1 - _C6 alkyl;

^R4 , ^R5 and ^R6 are hydrogen independently;

L is

t is a natural number between 0 and 2;

u is a natural number between 0 and 2;

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

F is -O-, -NH-, or a chemical bond;

^R8 and ^R9 are independently hydrogen or _C1 - _C6 alkyl; or ^R8 and ^R9 form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl with the atoms attached to them;

B is a 4-6 membered heterocyclic alkyl, a 6-10 membered aryl, or a 5-12 membered heteroaryl; wherein the 5-12 membered heteroaryl, 6-10 membered aryl, and 4-6 membered heterocyclic alkyl are optionally and independently substituted by one, two, or three ^Ri ;

Each ^Ri is independently hydrogen, hydroxyl, halogen, or _C1 - _C3 alkyl; or, two ^Ri and the atoms attached thereto form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl; or, two adjacent ^Ri and the atoms attached thereto form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl (wherein, the 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl forms a fused ring with B);

D is hydrogen, a 3-7 membered cycloalkyl, a _C1 - _C6 alkyl, or a 5-12 membered heteroaryl; wherein the _C1 - _C6 alkyl and the 5-12 membered heteroaryl are optionally and independently substituted by one, two, or three ^Rj ;

Each ^Rj is independently a halogen, a _C1 - _C3 alkyl group, -OR ^12-3 , or -SR ^12-4 ; the _C1 - _C3 alkyl group is optionally independently substituted by one, two, or three ^Rk ; each ^Rk is independently a halogen;

^R12-3 and ^R12-4 are independently _C1 - _C3 alkyl groups; the _C1 - _C3 alkyl groups are optionally and independently substituted by one, two or three ^Rk groups; each Rk ^group is independently a halogen.

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

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

Among them,

m is a natural number from 1 to 3;

n is a natural number from 1 to 3;

_X1 , _X2 , _X3 and _X4 are independently ^-CR1- , N, S, or chemical bonds, and the number of heteroatoms in _X1 , _X2 , _X3 , _X4 and _X5 is 1 or 2;

^RN-1 is a _C1 - _C6 alkyl group;

^Y and Z are independently carbonyl (CO) or -( ^CR₂R₃ ) _r- ; r is a natural number from 1 to 2;

Each ^R1 is independently hydrogen, halogen, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, 3-7 membered cycloalkyl, ^3-7 membered heterocycloalkyl or ^-NR1-1R1-2 , wherein _{the C1-C6 alkyl and C1-C6 alkoxy are optionally} independently substituted by 1, 2, 3 or 4 ^Ra ;

Each ^Ra is independently hydroxyl, _C1 - _C3 alkoxy, or ^{NR1-4R1-5 ;}

^R1-1 and ^R1-2 are independently hydrogen or _C1 - _C6 alkyl, wherein the _C1 - _C6 alkyl is optionally independently substituted by one, two, three or four ^Rb ; or, ^R1-1 and ^R1-2 form a 3- to 7-membered heterocyclic alkyl with the atom to which they are attached.

Each ^Rb is independently a hydroxyl group, a 3-7 membered cycloalkyl group, a 3-7 membered heterocycloalkyl group, a _C1 - _C3 alkyl group, a _C1 - _C3 alkoxy group, or an NR ^1-1-1 R ^1-2-1 , wherein the 3-7 membered cycloalkyl group, the 3-7 membered heterocycloalkyl group, and the _C1 - _C3 alkyl group are optionally independently substituted by one, two, three, or four Rb ^-1 groups;

Each Rb ^-1 is independently a hydroxyl group;

^R1-4 and ^R1-5 are independently hydrogen or _C1 - _C3 alkyl, wherein the _C1 - _C3 alkyl is optionally independently substituted by one, two, three or four ^R1-4-1 ; or, ^R1-4 and ^R1-5 form a 3- to 7-membered heterocyclic alkyl with the atom to which they are attached.

^R1-1-1 and ^R1-2-1 are independently hydrogen or _C1 - _C3 alkyl;

^R1-4-1 is a halogen;

^R2 and ^R3 are hydrogen independently;

L is

t is a natural number between 0 and 2;

u is a natural number between 0 and 2;

E represents a carbonyl group or a chemical bond;

F is -O-, -NH-, or a chemical bond;

^R8 and ^R9 are independently _C1 - _C6 alkyl groups, or ^R8 and ^R9 form 3-7 membered cycloalkyl groups or 3-7 membered heterocycloalkyl groups with the atoms attached to them;

B is a 4- to 6-membered heterocyclic alkyl group or a 5- to 12-membered heteroaryl group; wherein the 5- to 12-membered heteroaryl group and the 4- to 6-membered heterocyclic alkyl group are optionally and independently substituted by one, two or three Ri ^groups ;

Each ^Ri is independently hydrogen, hydroxyl, halogen, or _C1 - _C3 alkyl; or, two ^Ri and the atoms attached thereto form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl; or, two adjacent ^Ri and the atoms attached thereto form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl (wherein, the 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl forms a fused ring with B);

D is hydrogen, a 3- to 7-membered cycloalkyl group, a _C1 - _C6 alkyl group, or a 5- to 6-membered heteroaryl group; wherein the _C1 - _C6 alkyl group and the 5- to 6-membered heteroaryl group are optionally and independently substituted by one, two, or three Rj ^groups ;

Each ^Rj is independently a halogen or a _C1 - _C3 alkyl group; the _C1 - _C3 alkyl group is optionally independently substituted by one, two, or three ^Rk ; each ^Rk is independently a halogen.

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

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

Among them,

m is a natural number from 1 to 2;

n is a natural number between 1 and 2;

k is a natural number from 1 to 3;

_X1 , _X2 , _X3 , _X4 and _X5 are independently ^-CR1- , N, O, S, or chemical bonds, and the number of heteroatoms in _X1 , _X2 , _X3 , _X4 and _X5 is 0, 1, 2 or 3;

^RN-1 is a _C1 - _C6 alkyl group;

Each W is independently -( ^CR4R5 )-, -O-, ^-NR6- or a chemical bond; Y and Z are independently carbonyl (CO) or -( ^{CR2R3 )} _r- ; r is ^a natural number from 1 to 2;

Each ^R1 is independently hydrogen, halogen, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, 3-7 membered cycloalkyl, ^3-7 membered heterocycloalkyl or ^-NR1-1R1-2 , wherein _{the C1-C6 alkyl and C1-C6 alkoxy are optionally} independently substituted by 1, 2, 3 or 4 ^Ra ;

Each ^Ra is independently hydroxyl, _C1 - _C3 alkoxy, or ^{NR1-4R1-5 ;}

^R1-1 and ^R1-2 are independently hydrogen or _C1 - _C6 alkyl, wherein the _C1 - _C6 alkyl is optionally independently substituted by one, two, three or four ^Rb ; or, ^R1-1 and ^R1-2 form a 3- to 7-membered heterocyclic alkyl with the atom to which they are attached.

Each ^Rb is independently a hydroxyl group, a 3-7 membered cycloalkyl group, a 3-7 membered heterocycloalkyl group, a _C1 - _C3 alkyl group, a _C1 - _C3 alkoxy group, or an NR ^1-1-1 R ^1-2-1 , wherein the 3-7 membered cycloalkyl group, the 3-7 membered heterocycloalkyl group, and the _C1 - _C3 alkyl group are optionally independently substituted by one, two, three, or four Rb ^-1 groups;

Each Rb ^-1 is independently a hydroxyl group;

^R1-4 and ^R1-5 are independently hydrogen or _C1 - _C3 alkyl, wherein the _C1 - _C3 alkyl is optionally independently substituted by one, two, three or four ^R1-4-1 ; or, ^R1-4 and ^R1-5 form a 3- to 7-membered heterocyclic alkyl with the atom to which they are attached.

^R1-1-1 and ^R1-2-1 are independently hydrogen or _C1 - _C3 alkyl;

Each R ^1-4-1 is independently a halogen;

^R2 and ^R3 are independently hydrogen or ^{NR2-1 R2-2} ;

^R2-1 and ^R2-2 are independently hydrogen or _C1 - _C6 alkyl;

^R4 , ^R5 , and ^R6 are independently hydrogen; L is...

t is a natural number between 0 and 2;

u is a natural number between 0 and 2;

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

F is -O-, -NH-, or a chemical bond;

^R8 and ^R9 are independently hydrogen or _C1 - _C6 alkyl; or ^R8 and ^R9 form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl with the atoms attached to them;

B is a 4-6 membered heterocyclic alkyl, a 6-10 membered aryl, or a 5-12 membered heteroaryl; wherein the 5-12 membered heteroaryl, 6-10 membered aryl, and 4-6 membered heterocyclic alkyl are optionally and independently substituted by one, two, or three ^Ri ;

Each ^Ri is independently hydrogen, hydroxyl, halogen, or _C1 - _C3 alkyl; or, two ^Ri and the atoms attached thereto form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl; or, two adjacent ^Ri and the atoms attached thereto form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl (wherein, the 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl forms a fused ring with B);

D is hydrogen, _C1 - _C6 alkyl or 5-12 heteroaryl; wherein the _C1 - _C6 alkyl and 5-12 heteroaryl are optionally independently substituted by one, two or three ^Rj ;

Each ^Rj is independently a halogen, a _C1 - _C3 alkyl group, an OR ^{12-3 group} , or an SR ^12-4 group; the _C1 - _C3 alkyl group is optionally independently substituted by one, two, or three ^Rk groups; each Rk ^group is independently a halogen.

^R12-3 and ^R12-4 are independently _C1 - _C3 alkyl groups, wherein the _C1 - _C3 alkyl group is optionally and independently substituted by one, two or three Rk ^-1 groups; each Rk ^-1 group is independently a halogen; in the 3-7-membered heterocyclic alkyl group, the 4-6-membered heterocyclic alkyl group and the 5-12-membered heteroaryl group, the heteroatom is N, O or S, and the number of heteroatoms is 1 to 3; or, in the 3-7-membered heterocyclic alkyl group, the 4-6-membered heterocyclic alkyl group and the 5-12-membered heteroaryl group, the heteroatom is one or more of N, O and S, and the number of heteroatoms is 1 to 3.

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

Among them,

m is 1;

n is 1;

_X1 , _X2 , _X3 and _X4 are independently ^-CR1- 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 -; r is 1;

Each ^R1 is independently a _C1 - _C6 alkyl (e.g., methyl) or a _C1 - _C6 alkoxy (e.g., methoxy);

^R2 and ^R3 are hydrogen independently;

L is

t is 0;

u is 1;

E is a carbonyl group;

F is a chemical bond;

B is a 4- to 6-membered heterocyclic alkyl group; wherein the 4- to 6-membered heterocyclic alkyl group is optionally and independently substituted by one, two or three ^Ri ;

Each ^Ri is independently hydrogen;

D is a 5- to 12-membered heteroaryl group; wherein the 5- to 12-membered heteroaryl group is optionally and independently replaced by one, two or three ^Rj (e.g., one);

Each ^Rj is independently -OR ^12-3 ;

^R12-3 is a _C1 - _C3 alkyl group (e.g., ethyl or isopropyl); the _C1 - _C3 alkyl group is optionally and independently substituted by one, two or three Rk ^groups ; each Rk ^group is independently a halogen (e.g., F);

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

When A is , the number of heteroatoms in _X1 , _X2 and _X4 is 1 or 2;

When A is a carbonyl group and L is a carbonyl group, u is a natural number from 1 to 3, B is a 4- to 6-membered heterocyclic alkyl group, and the 4- to 6-membered heterocyclic alkyl group may be independently substituted by 1, 2 or 3 ^Ri .

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

Among them,

m is 1;

n is 1;

_X2 and _X3 are N;

_X1 and _X4 are independently ^-CR1- ;

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

Each ^R1 is independently hydrogen, halogen, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or ^-NR1-1R1-2 ; wherein the _C1 - _C6 alkyl and _C1 - _C6 alkoxy are optionally independently substituted by one, two, ^three , or four ^Ra ;

^R1-1 and ^R1-2 are independently hydrogen or _C1 - _C6 alkyl; or, ^R1-1 and ^R1-2 form 3- to 7-membered heterocyclic alkyl groups with the atoms attached to them.

Each ^Ra is independently hydroxyl, _C1 - _C6 alkoxy, or ^{NR1-4R1-5 ;}

^R1-4 and ^R1-5 are independently hydrogen or _C1 - _C3 alkyl;

^R2 and ^R3 are hydrogen independently;

L is

t is 0;

u is 1;

E is a carbonyl group;

F is a chemical bond;

B is a 4- to 6-membered heterocyclic alkyl group; wherein the 4- to 6-membered heterocyclic alkyl group is optionally and independently substituted by one, two or three ^Ri ;

Each ^Ri is independently hydrogen, halogen, hydroxyl, or _C1 - _C3 alkyl;

D is a 5- to 12-membered heteroaryl group; wherein the 5- to 12-membered heteroaryl group is optionally and independently substituted by 1, 2, or 3 ^Rj ; preferably, D is a 5- to 6-membered heteroaryl group; wherein the 5- to 6-membered heteroaryl group is optionally and independently substituted by 1, 2, or 3 ^Rj ; in the 5- to 6-membered heteroaryl group, the heteroatom is selected from 1, 2, or 3 of N, S, and O, and the number of heteroatoms is 1, 2, or 3;

Each ^Rj is independently H, halogen, _C1 - _C3 alkyl, OR ^12-3 or SR ^12-4 ; wherein the _C1 - _C3 alkyl is optionally independently substituted by one, two or three ^Rk ;

^R12-3 and ^R12-4 are independently _C1 - _C3 alkyl groups; the _C1 - _C3 alkyl groups are optionally independently substituted by one, two or three Rk ^-1 groups;

Each ^Rk is independently a halogen or a _C1 - _C3 alkyl group;

Each Rk ^-1 is independently halogenated or _C1 - _C3 alkyl;

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

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

Among them,

m is 1;

n is 1;

_X1 and _X3 are N;

_X2 and _X4 are independently ^-CR1 -;

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

Each ^R1 is independently hydrogen, halogen, cyano, hydroxyl, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 alkylthio, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, or ^-NR1-1R1-2 ; wherein the _C1 - _C6 alkyl, _C1 - _C6 alkoxy, and _C1 - _C6 alkylthio are optionally independently substituted by one, two, three, ^or four ^Ra ;

^R1-1 and ^R1-2 are independently hydrogen or _C1 - _C6 alkyl; or, ^R1-1 and ^R1-2 form 3- to 7-membered heterocyclic alkyl groups with the atoms attached to them.

Each ^Ra is independently hydroxyl, _C1 - _C6 alkoxy, or ^{NR1-4R1-5 ;}

^R1-4 and ^R1-5 are independently hydrogen or _C1 - _C3 alkyl;

^R2 and ^R3 are hydrogen independently;

L is

t is 0;

u is 1;

E is a carbonyl group;

F is a chemical bond;

B is a 4- to 6-membered heterocyclic alkyl group; wherein the 4- to 6-membered heterocyclic alkyl group is optionally and independently substituted by one, two or three ^Ri ;

Each ^Ri is independently hydrogen, halogen, hydroxyl, or _C1 - _C3 alkyl; or, two ^Ri and the atoms attached to them form a 3- to 7-membered cycloalkyl group.

D is a 5- to 12-membered heteroaryl group; wherein the 5- to 12-membered heteroaryl group is optionally and independently substituted by 1, 2, or 3 ^Rj ; preferably, D is a 5- to 6-membered heteroaryl group; wherein the 5- to 6-membered heteroaryl group is optionally and independently substituted by 1, 2, or 3 ^Rj ; in the 5- to 6-membered heteroaryl group, the heteroatom is selected from 1, 2, or 3 of N, S, and O, and the number of heteroatoms is 1, 2, or 3;

Each ^Rj is independently hydrogen, halogen, cyano, hydroxyl, _C1 - _C3 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, -NR ^12-1 R ^12-2 , -OR ^12-3 or -SR ^12-4 ; wherein the _{C1- C3} alkyl, 3-7 membered cycloalkyl and 3-7 membered heterocycloalkyl are optionally independently substituted by one, two or three ^Rk ;

^R12-1 , ^R12-2 , ^R12-4 and ^R12-3 are independently _C1 - _C3 alkyl groups; the _C1 - _C3 alkyl groups are optionally independently substituted by one, two or three Rk ^-1 groups;

Each ^Rk is independently a halogen or a _C1 - _C3 alkyl group;

Each Rk ^-1 is independently halogenated or _C1 - _C3 alkyl;

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

In one scheme, each ^R1 is independently hydrogen, methyl, ethyl, chlorine, methoxy, isopropyl, amino,

In one scheme, each ^R1 is independently hydrogen, methyl, ethyl, chlorine, methoxy, isopropyl, amino ( _-NH2 ),

Trifluoromethyl or methylthio.

Preferably, each ^R1 is independently methyl,

In one of the schemes, for

Preferably, for

In one of the schemes, for

In one scheme, L is -( _CH₂ )-, -( _CH₂ ) _₂- ,

Preferably, L is

This indicates that it is connected to A.

Preferably, L is

In one scheme, L is -( _CH₂ )-, -( _CH₂ ) _₂- ,

Preferably, L represents a connection to A.

In one of the proposed solutions, B is...

In one of the proposed solutions, B is...

Preferably, B is

In one of the proposed solutions, B is...

In one scheme, D is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, or...

Preferably, D is

In one scheme, D is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, or...

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

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

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

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

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

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

A, L, B, D, _X1 , _X2 , _X3 , _X4 , Y, and m are as described in any one of the present invention.

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

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

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

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

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

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

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

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

Terminology Explanation:

The term "-" indicates that the group is attached to the rest of the molecule through that site. For example, "CH ₃ O-" refers to an alkoxy group.

The term (in the context) refers to the connection between the structural segment and the rest of the molecule through that site.

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

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

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

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

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

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

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

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

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

The term "oxo" refers to =O, where an oxygen atom replaces two hydrogen atoms on the same atom. For example, methylene (-(CH ₂ -)) becomes carbonyl (-C(=O)-) after being oxosubstituted.

The term "alkyl" refers to a saturated monovalent hydrocarbon group that is straight-chain or branched and has a specified number of carbon atoms. Examples include _C1 - _C6 alkyl ( _C1-6 alkyl) or _C4 - _C20 alkyl ( _C4-20 alkyl), preferably _C1 - _C4 alkyl ( _C1-4 alkyl) or _C9 - _C15 alkyl ( _C1-6 alkyl). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

In the term "alkyl-O-", the alkyl group is defined as described above. Examples of alkyl-O- include _C1 - _C6 alkyl-O- or _C1 - _C4 alkyl-O-, and more specifically: _CH3 -O-, _{CH3CH2 - O- , CH3CH2CH2} -O-, or _CH3CH ( _CH3 )-O-, etc. Similarly, in other expressions of the form "Rx-O-" in this application, the definition of Rx is as described in their respective definitions, for example, the definition of cycloalkyl in "cycloalkyl-O-" is as described in the "cycloalkyl" section below.

In the term "alkyl-S-", the alkyl group is defined as described above. Examples of alkyl-S- include _C1 - _C6 alkyl-S- or _C1 - _C4 alkyl-S-, and more specifically: _CH3 -S-, _{CH3CH2 - S- , CH3CH2CH2} -S-, or _CH3CH ( _CH3 )-S-, etc. Similarly, in other expressions of the form "Rx-S-" in this application, the definition of Rx is as described in its respective definition; for example, the definition of cycloalkyl in "cycloalkyl-S-" is as described in the "cycloalkyl" section below.

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

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

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

The term "heterocyclic alkyl" refers to a saturated heterocyclic alkyl group or a partially unsaturated monocyclic or polycyclic heterocyclic group (e.g., one or more of bicyclic, tricyclic or more cyclic bridged rings, fused rings or spirocyclic systems) having a specified number of ring atoms (e.g., 4-12, 4-10, 3-7, 6-10, 4-7, 5-6), a specified number of heteroatoms (e.g., 1, 2 or 3), a specified type of heteroatom or heteroatom group (N, O, S, S(=O) and S(=O) ₂ ).

The term "cycloalkyl" refers to a saturated carbocyclic substituent that can be linked to the rest of the molecule via a single bond through any suitable carbon atom; _C3 - _C7 cycloalkyl having 3 to 7 carbon atoms, preferably _C3 -C6 cycloalkyl having 3 to ₆ carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

The term "aryl" refers to a cyclic, unsaturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., _C6 - _C10 ). Examples of aryl groups include, but are not limited to, phenyl or naphthyl groups.

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

Unless otherwise stated, the absolute configuration of a solid center is indicated by wedge solid lines and wedge dashed lines, and when an atom is connected to its substituent by a wavy line, it indicates a mixture thereof.

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

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

Abbreviations:

PMB: 4-Methoxybenzyl.

Boc: tert-Butoxycarbonyl.

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

NBS: N-bromosuccinimide.

DIEA: N,N-diisopropylethylamine.

DMF: N,N-dimethylformamide.

Et: Ethyl.

Me: Methyl group.

i-Pr: Isopropyl.

DMSO: Dimethyl sulfoxide.

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

PyBOP: 1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate.

TEA (triethylamine)

LiHMDS bis(trimethylsilyl)aminolithium.

NCS: N-chlorosuccinimide.

Detailed Implementation

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

Intermediate A

Synthesis route:

first step

A-1 (5.0 g, 20.5 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (10 mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate of A-2. ^¹H 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 value C₇H₁₄NO₂ [} M+H] ^⁺ = _144.1 , measured value 144.2.

Step 2

The trifluoroacetate of A-2 (5.0 g, 19.4 mmol) and A-3 (6.0 g, 33.5 mmol) were dissolved in dimethyl sulfoxide (10 mL). Triethylamine (13.4 g, 132.2 mmol) and cesium fluoride (5.0 g, 33.0 mmol) were added sequentially, and the mixture was heated to 80 °C and stirred for 18 hours. The reaction solution was poured into a saturated ammonium chloride solution (20 mL) and extracted with dichloromethane (50 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 3/2, v/v) to give A-4. ^1H NMR (400MHz, DMSO- _d₆ ) δ 8.21 (d, J = 5.64Hz, 1H), 6.70 (d, J = 2.28Hz, 1H), 6.53-6.48 (m, 1H), 4.17-4.04 (m, 4H), 3.70-3.67 (m, 2H), 3.10-3.01 (m, 1H), 2.76-2.72 (m, 2H), 1.21-1.17 (m, _3H ). _{ESI-MS theoretical calculation value C₁₃H₁₆F₃N₂O₂ [ M} +H] ^⁺ = _289.1 , measured value 289.2.

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 solution was adjusted to 7, water (50 mL) was added, and the solution was lyophilized to obtain a crude product containing intermediate A, which was used directly in the next reaction step. ^1H NMR (400MHz, DMSO- _d₆ ) δ 8.25 (d, J = 5.64Hz, 1H), 6.72 (d, J = 2.26Hz, 1H), 6.55 (dd, J = 5.64, 2.26Hz, 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 C₁₁H₁₁F₃N₂O₂ [ M +} H] ^⁺ = _261.1 , measured value 261.0.

intermediate G

Synthesis route:

first step

G-1 (2.0 g, 11.3 mmol), NBS (4.2 g, 23.7 mmol), and azobisisobutyronitrile (370 mg, 2.26 mmol) were added sequentially to carbon tetrachloride (25 mL). The reaction system was heated to 80 °C and stirred for 16 hours under nitrogen protection. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting oily substance was diluted with ethyl acetate (20 mL), washed with saturated sodium thiosulfate solution (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was purified by silica gel column chromatography (petroleum ether/ _ethyl acetate, 9/1, v/v) to obtain G-2 _. The theoretical ESI-MS value of _C6H5Br2Cl2N2 [M+H] ⁺ was _332.8 , _and the measured value was 332.0.

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 tetrahydrofuran solution of 4-methoxybenzylamine (1.64 g, 11.9 mmol) was added dropwise at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 9/1, v/v) to obtain G-3. The theoretical ESI-MS value of _C14H14Cl2N3O [M+H] ⁺ was _310.0 , and the measured value _{was also} 310.0.

Step 3

G-3 (400 mg, 1.29 mmol), methylboric acid (116 mg, 1.93 mmol), potassium carbonate (535 mg, 3.87 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (189 mg, 0.26 mmol), and 1,4-dioxane (3 mL) were added to a 10 mL microwave-safe tube. The mixture was heated to 90 °C and stirred for 18 hours under nitrogen protection. The reaction solution was cooled to room temperature, filtered, diluted with water (15 mL), extracted with ethyl acetate (5 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 9/1, v/v) to obtain G-4. The theoretical ESI-MS value of _C15H17ClN3O [M+H] ⁺ was _290.1 , _and the measured value was 290.0.

Step 4

G-4 (130 mg, 0.45 mmol) and cyclobutane (2 mL) were added to a 10 mL microwave tube and heated to 90 °C with stirring for 16 hours. The reaction solution was cooled to room temperature, diluted with water (15 mL), extracted with ethyl acetate (5 mL × 3), the organic phases were combined, washed with saturated brine ( ₂₀ mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. G-5 was purified by silica gel column chromatography (petroleum ether/ _ethyl acetate, 4/1, v/v). The theoretical ESI-MS value of _C18H23N4O [M+H] ⁺ was 311.2, and the measured value was also 311.2.

Step 5

G-5 (120 mg, 0.39 mmol) and trifluoroacetic acid (2 mL) were added to a 5 mL microwave tube and heated to 100 °C with stirring for 8 hours. The reaction solution was cooled to room temperature, diluted with water (15 mL), and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The solution was extracted with ethyl acetate (5 mL × 3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate G, which was used directly in the next reaction. The theoretical ESI-MS value of C ₁₀ H ₁₅ N ₄ [M+H] ⁺ ＝191.1, and the measured value was 191.1.

Intermediate I

Synthesis route:

first step

G-3 (1.5 g, 4.84 mmol), 1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (710 mg, 0.97 mmol), potassium carbonate (2.0 g, 14.5 mmol), F-2 (1.21 g, 9.67 mmol), and 1,4-dioxane (10 mL) were stirred at 90 °C for 18 hours under nitrogen protection. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was purified by silica gel column chromatography (petroleum ether/ _ethyl acetate, 4/1, v/v) to obtain I-1. The theoretical ESI-MS value of _C16H20N3O [M+H] ⁺ was 270.2, _and the measured value was 270.1.

Step 2

I-1 (120 mg, 0.45 mmol) and trifluoroacetic acid (2 mL) were added to a 5 mL microwave tube, and the mixture was heated to 90 °C and stirred for 8 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a trifluoroacetate containing intermediate I, _which was directly used in the next reaction. The theoretical _{ESI-MS value of C8H12N3 [} M+H] ⁺ was 150.1, and the measured value was 150.1.

Intermediate O

Synthesis route:

first step

O-1 (2.0 g, 15.2 mmol) was dissolved in DMF (20 mL), and O-2 (1.52 g, 15.2 mmol) and sodium hydride (60%, 1.82 g, 45.6 mmol) were added sequentially. The mixture was heated to 60 °C and stirred for 18 hours. After cooling, a saturated ammonium chloride solution (50 mL) was slowly added to the reaction solution, and the mixture was extracted with ethyl acetate (70 mL × 3). The organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 4/1, v/v) to obtain O-3. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.21 (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 hours. After cooling, water (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 4/1, v/v) to obtain O-4. ^1H NMR (400MHz, DMSO- _d₆ ) δ 7.76 (d, J = 5.76Hz, 1H), 6.14 (dd, J = 5.80, 1.98Hz, 1H), 5.77 (d, J = 1.96Hz, 1H), 4.93-4.84 (m, 2H), 4.10-4.01 (m, 4H), 3.61-3.56 (m, 2H), 3.05-2.97 (m, 1H), 2.74-2.68 (m, 2H), _{1.20-1.16 (m, 3H). ESI-MS theoretical calculation value C₁₄H₁₈F₃N₂O₃ [ M + H} ] ^⁺ = 319.1, measured value 319.1.

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 solution was adjusted to 7 with hydrochloric acid (1 mol/L), and the solution was lyophilized with water to obtain a crude product containing intermediate O, which was directly used in the next reaction step. ^1H NMR (400MHz, DMSO- _d₆ ) δ 7.73 (d, J = 5.80Hz, 1H), 6.10 (dd, J = 5.76, 1.98Hz, 1H), 5.72 (d, J = 1.96Hz, 1H), 4.92-4.84 (m, 2H), 4.01-3.96 (m, 2H), 3.54-3.50 (m, 2H), 2.98-2.88 (m, 1H), _2.35-2.32 (m, 2H) _. ESI-MS theoretical calculation value _{C₁₂H₁₄F₃N₂O₃ [} M+H] ^⁺ = _291.1 , measured value 291.1.

intermediate P

Synthesis route:

first step

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

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. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 5 with dilute hydrochloric acid (1 mol/L), concentrated under reduced pressure, and then lyophilized to obtain a crude product containing intermediate P, which was directly used in the next reaction. ^¹H 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 value _{C₈H₁₂N₃O₂S} [M+H] ^⁺ = 214.1, measured value 214.0.

intermediate Q

Synthesis route:

first step

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

Step 2

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

Step 3

Q-4 (250 mg, 0.97 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (3 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product containing Q-5, _which was used directly in the next reaction. The theoretical ESI-MS value of _C8H16NO2 [M+H] ⁺ was 158.1, _and the measured value was 158.1.

Step 4

The trifluoroacetate of Q-5 (140 mg, 0.89 mmol) and A-3 (173 mg, 0.95 mmol) were dissolved in dimethyl sulfoxide (5 mL). TEA (385 mg, 3.80 mmol) and cesium fluoride (144 mg, 0.95 mmol) were added sequentially, and the mixture was heated to 100 °C and stirred for 18 hours. The reaction mixture was poured into water (20 mL), and extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 2/3, v/v) to obtain Q-6. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 8.23–8.19 (m, 1H), 6.72 (s, 1H), 6.58 (d, J = 5.84 Hz, 1H), 4.53 (t, J = 7.24 Hz, 0.6H), 4.23–3.88 (m, 2.4H), 3.77–3.73 (m, 0.6H), 3.51–3.47 (m, 0.4H), 3.18–3.09 (m, 1H), 2.74–2.69 (m, 3H), 1.46 (d, J = 6.16 Hz, 1H), 1.31 (d, J = 6.52 Hz, 2H), _1.21–1.18 (m, 3H) _. ESI-MS theoretical calculation ^: _{C¹⁴H¹⁸F³N₂O₂} [ _M +H] _⁺ =303.1, measured value 303.1.

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 complete, the pH of the reaction solution was adjusted to 5 with dilute hydrochloric acid (1 mol/L ₎ , and the solution was lyophilized with water to obtain a _crude product containing _intermediate Q, which was directly used in the next reaction. The theoretical ESI-MS value of _C12H14F3N2O2 [M+H] ⁺ was _275.1 , and the measured value was 275.0.

intermediate S

Synthesis route:

first step

S-2 (4.54 g, 61.3 mmol) was dissolved in tetrahydrofuran (120 mL), cooled to -78 °C, and a tetrahydrofuran solution of LiHMDS (1.0 mol/L, 64.3 mL, 64.3 mmol) was slowly added dropwise, and the mixture was stirred for 10 minutes. Then, S-1 (10 g, 58.4 mmol) was added, and the mixture was stirred for 15 minutes. The reaction system was heated to 0 °C and stirred for 2 hours. Ice water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing S-3, which was directly used in the next reaction. The theoretical ESI-MS value _{of C11H20NO5} [M-56+H] ⁺ was 190.1, _and the measured value was 190.1.

Step 2

S-3 (2.0 g, 8.15 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (20 mL) was added. The mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate of S- ₄ , which was used directly in the next reaction. The theoretical ESI-MS value of _C6H12NO3 [M+H] ⁺ was 146.1, _and the measured value was 146.2.

Step 3

The trifluoroacetate of S-4 (2.0 g, 13.8 mmol) and A-3 (2.49 g, 13.8 mmol) were dissolved in dimethyl sulfoxide (10 mL). TEA (5.58 g, 55.11 mmol) and cesium fluoride (2.1 g, 13.8 mmol) were added sequentially, and the mixture was heated to 100 °C and stirred for 18 hours. The reaction mixture was poured into water (80 mL), and extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 3/7, v/v) to obtain S-5. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 8.22 (d, J = 5.68Hz, 1H), 6.76 (d, J = 2.26Hz, 1H), 6.62 -6.51 (m, 1H), 6.03 (s, 1H), 4.16-4.10 (m, 2H), 3.90-3.85 (m, 2H), 3.60 (s, 3H), 2.82 ₍ s, _2H ) _{. ESI-MS theoretical calculation C₁₂H₁₄F₃N₂O₃ [} M+H] ^⁺ = _291.1 , measured value 291.1.

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 complete, the pH of the reaction solution was adjusted to 5 with dilute hydrochloric acid (1 mol/L ₎ , and the solution was lyophilized with water to obtain a _crude product containing _intermediate S, which was directly used in the next reaction. The theoretical ESI-MS value of _C11H12F3N2O3 [M+H] ⁺ was 277.1, _and the measured value was 277.0.

intermediate U

Synthesis route:

first step

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 at 25 °C for 8 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain U-2, which was directly used in the next reaction. ^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 value C₈H₇ClNO [} M+H] ^⁺ = 168.0, measured value 168.0.

Step 2

U-2 (1.1 g, 6.56 mmol) was dissolved in dichloromethane (15 mL), and diethylaminotrifluoride (3.7 g, 22.97 mmol) was added at 0 °C. The mixture was stirred at room temperature for 18 hours. Saturated sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 1). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 7/3, v/v) to obtain U-3. ^1H NMR (400MHz, Chloroform-d) δ 8.55 (d, J = 5.24Hz, 1H), 7.39 (d, J = 5.22Hz, 1H), 3.12-3.02 (m, 2H), 2.76-2.61 (m, 2H). ESI _{-MS theoretical calculation value C8H7ClF2N [} M+H] ⁺ = _190.0 , measured value 190.0.

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

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 complete, the pH of the reaction solution was adjusted to 5 with dilute hydrochloric acid (1 mol/L ₎ , and the solution was lyophilized with water to obtain a _crude product containing _intermediate U, which was directly used in the next reaction. The theoretical ESI-MS value of _C13H15F2N2O2 [M+H] ⁺ was 269.1, _and the measured value was 269.1.

intermediate V

Synthesis route:

first step

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

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 complete, the pH of the reaction solution was adjusted to 5 with dilute hydrochloric acid (1 mol/L), and the solution was lyophilized with water to obtain a crude product containing intermediate V, which was directly used in the next reaction. The ESI-MS theoretical calculation value C ₁₀ H ₁₁ F ₃ N ₃ O ₂ [M+H] ⁺ ＝262.1, and the measured value was 262.0.

Intermediate X

Synthesis route:

first step

X-1 (900 mg, 4.68 mmol) was dissolved in 1,4-dioxane (40 mL), and X-2 (1.8 g, 5.61 mmol) was added. The mixture was then heated to 90 °C and stirred for 18 hours. After the reaction solution was cooled to room temperature, it was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. X-3 was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1/0, v/v). ^1H 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 the reaction solution was cooled to room temperature, saturated ammonium chloride solution (10 mL) was added, and the mixture was extracted with dichloromethane (15 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. X-4 was purified by silica gel column chromatography (petroleum ether/ _ethyl acetate, _7/3 , _v /v). The theoretical ESI-MS value of _{C13H14F3N2O2S} [M+H] ⁺ was 321.1, and the measured value was _also 321.1.

Step 3

X-4 (150 mg, 2.50 mmol) was dissolved in tetrahydrofuran (3 mL) and water (1 mL), and lithium hydroxide monohydrate (30 mg, 0.70 mmol) was added. The mixture was heated to 40 °C and stirred for ₂ hours. After the reaction was complete, the pH of the reaction solution was adjusted to 5 with dilute hydrochloric acid (1 mol/L), and the solution was lyophilized with water to obtain a _crude product containing _intermediate X, which was directly used in the next reaction. The theoretical ESI-MS value of _{C11H12F3N2O2S} [M+H] ⁺ was _293.1 , and the measured value was 293.1.

Intermediate AA

Synthesis route:

first step

AA-1 (1.4 g, 12.2 mmol) was dissolved in DMF (30 mL), cooled to 0 °C, and sodium hydride (60%, 910 mg, 22.8 mmol) was added. The mixture was stirred for 30 minutes, followed by the addition of O-1 (2.0 g, 15.2 mmol) and stirring at room temperature for 18 hours. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution (150 mL), extracted with ethyl acetate (150 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was then purified by silica gel column chromatography (petroleum ether/ethyl acetate, 19/1, v/v) to obtain AA-2. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.21 (d, J = 5.50Hz, 1H), 7.25 (dd, J = 5.54, 1.78Hz, 1H), 7.16 (d, J = 1.80Hz, 1H), 5.95-5.86 (m, 1H), 1.45 (d, J = 6.68Hz, 3H).

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

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 complete, the pH of the reaction solution was adjusted to 5 with dilute hydrochloric acid (1 mol/L _{), filtered, and the solid was washed with water (3 mL) and dried to obtain intermediate AA, which was directly used in the next reaction. The ESI-MS theoretical calculation value C13H16F3N2O3 [ M +} H] ⁺ ＝ _305.1 , and the measured value was 305.1.

Intermediate AB

Synthesis route:

first step

AB-1 (208 mg, 1.82 mmol) was dissolved in DMF (4 mL), cooled to 0 °C, and sodium hydride (60%, 137 mg, 3.43 mmol) was added. The mixture was stirred for 30 minutes, followed by the addition of O-1 (300 mg, 2.28 mmol) and stirring at room temperature for 18 hours. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was then purified by silica gel column chromatography (petroleum ether/ethyl acetate, 19/1, v/v) to obtain AB-2. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.21 (d, J = 5.50Hz, 1H), 7.25 (dd, J = 5.58, 1.76Hz, 1H), 7.16 (d, J = 1.74Hz, 1H), 5.93-5.85 (m, 1H), 1.45 (d, J = 6.68Hz, 3H).

Step 2

AB-2 (200 mg, 0.89 mmol) and A-2 (317 mg, 2.22 mmol) were dissolved in DMSO (5 mL), and TEA (538 mg, 5.32 mmol) and cesium fluoride (202 mg, 1.33 mmol) were added. The mixture was heated to 100 °C and stirred for 10 hours. After the reaction solution was cooled to room temperature, saturated ammonium chloride solution (20 mL) was added, followed by extraction with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. AB-3 was then purified by silica gel column chromatography (petroleum ether/ _{ethyl acetate} , _3/17 , v/v). The theoretical ESI-MS value of _C15H20F3N2O3 [M+H] ⁺ was _333.1 , and the measured value was 333.0.

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 complete, the pH of the reaction solution was adjusted to 5 with dilute hydrochloric acid (1 mol/L _{), filtered, and the solid was washed with water (3 mL) and dried to obtain intermediate AB, which was directly used in the next reaction. The theoretical ESI-MS value of C13H16F3N2O3 [ M} +H] ⁺ was _305.1 , _and the measured value was 305.0.

intermediate AI

Synthesis route:

first step

Q-5 (109 mg, 0.69 mmol) and P-1 (112 mg, 0.83 mmol) were dissolved in DMSO (5 mL), and TEA (280 mg, 2.77 mmol) and cesium fluoride (105 mg, 0.69 mmol) were added. The mixture was heated to 70 °C and stirred for 18 hours. A saturated ammonium chloride solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, _4/1 , v/v) to obtain AI-1. The theoretical ESI-MS value of _C11H18N3O2S [M+H] ⁺ was _256.1 , and the measured value was _also 256.1.

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 solution was adjusted to 5 with dilute hydrochloric acid (1 mol/L), concentrated under reduced pressure _{, and then lyophilized to obtain a crude product containing the intermediate AI, which was directly used in the next reaction. The theoretical ESI-MS value of C9H14N3O2S [ M} +H] ⁺ was 228.1, _and the measured value was 228.0.

Intermediate AK

Synthesis route:

first step

G-4 (500 mg, 1.73 mmol), cyclopropylboronic acid (296 mg, 3.45 mmol), potassium carbonate (596 mg, 4.31 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (253 mg, 0.35 mmol) were added to 1,4-dioxane (6 mL), and the mixture was heated to 100 °C and stirred for 12 hours under nitrogen protection. The reaction solution was cooled to room temperature, filtered, diluted with water (30 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. AK-1 was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 2/3, v/v). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 7.30 (d, J = 8.60Hz, 2H), 6.92 (d, J = 8.62Hz, 2H), 4.03-4.00 (m, 2H), 3.91-3.88 (m, 2H), 3.85 (s, 2H), 3.75 (s, 3H), 2.44 (s, 3H), 1.99-1.95 (m, 1H), 1.12-1.08 (m, 2H), 1.00-0.95 (m, 2H). ESI-MS theoretical calculation _{C₁₈H₂₂N₃O [ M} +H] ^⁺ = 296.2, measured value 296.1.

Step 2

AK-1 (300 mg, 1.02 mmol) and trifluoroacetic acid (4 mL) were added to a microwave tube, and the mixture was heated to 90 °C and stirred for 10 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain trifluoroacetate containing intermediate AK, _which was directly used in the next reaction. The theoretical ESI-MS value of _C10H14N3 [M+H] ⁺ was 176.1, _and the measured value was 176.0.

intermediate AO

Synthesis route:

first step

G-4 (200 mg, 0.69 mmol), methanesulfonic acid (tricyclohexylphosphine) (2-amino-1,1-biphenyl-2-yl) palladium (45 mg, 0.07 mmol), potassium phosphate (513 mg, 2.42 mmol), and ethylboric acid (153 mg, 2.07 mmol) were added to toluene (5 mL) and water (1 mL). The mixture was heated to 100 °C and stirred for 12 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 2/3, v/v) to obtain AO-1. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 7.29 (d, J = 8.54Hz, 2H), 6.92 (d, J = 8.52Hz, 2H), 3.96-3.85 (m, 6H), 3.75 (s, 3H), 2.80 (q, J = 7.58Hz, 2H), 2.47 (s, 3H), 1.20 (t, J = _7.58Hz , _3H ). ESI-MS theoretical calculation _{C₁₇H₂₂N₃O} [M+H] ^⁺ = 284.2, measured value 284.1.

Step 2

AO-1 (150 mg, 0.53 mmol) and trifluoroacetic acid (4 mL) were added to a microwave tube, and the mixture was heated to 90 °C and stirred for 10 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain trifluoroacetate containing intermediate AO, _which was directly used in the next reaction. The theoretical ESI-MS value of _C9H14N3 [M+H] ⁺ was 164.1, _and the measured value was 164.0.

intermediate AP

Synthesis route:

first step

G-3 (200 mg, 0.64 mmol), methanesulfonic acid (tricyclohexylphosphine) (2-amino-1,1-biphenyl-2-yl), palladium (42 mg, 0.06 mmol), potassium phosphate (479 mg, 2.26 mmol), and ethylboric acid (285 mg, 3.87 mmol) were added to toluene (5 mL) and water (1 mL). The mixture was heated to 100 °C and stirred for 18 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by silica gel column chromatography (dichloromethane/methanol, 9/1, v/v) to obtain AP-1. ^1H NMR (400MHz, DMSO- _d₆ ) δ 7.31 (d, J = 8.60Hz, 2H), 6.91 (d, J = 8.62Hz, 2H), 3.95 (s, 3H), 3.85 (s, 2H), 3.75 (s, 4H), 2.80 (q, J = 7.58Hz, 4H), 1.21 (t, J = _7.60Hz , _{6H). ESI-MS theoretical calculation C₁₈H₂₄N₃O [} M+H] ^⁺ = 298.2, measured value 298.1.

Step 2

AP-1 (150 mg, 0.50 mmol) and trifluoroacetic acid (4 mL) were added to a microwave tube, and the mixture was heated to 90 °C and stirred for 10 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain trifluoroacetate containing intermediate AP, _{which was directly used in the next reaction. The theoretical ESI-MS value of C10H16N3 [} M+H] ⁺ was 178.1, _and the measured value was 178.0.

intermediate AR

Synthesis route:

first step

Intermediate I (800 mg, 5.36 mmol) and intermediate AC-1 (1.15 g, 5.36 mmol) were dissolved in DMF (10 mL), and DIEA (2.08 g, 16.1 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then HATU (3.06 g, 8.04 mmol) was added. The mixture was stirred at room temperature for another hour. After the reaction was complete, the mixture was diluted with water (100 mL), extracted with ethyl acetate (80 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (150 mL), dried over _anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by silica gel column chromatography (dichloromethane/methanol, 4/1, v/v) to obtain AR-1. The theoretical _ESI -MS value of _C18H27N4O3 [M+H] ⁺ was _347.3 , and the measured value was 347.2.

Step 2

AR-1 (1.00 g, 2.89 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product containing _intermediate AR, which was used directly in the next reaction. The theoretical ESI-MS value of _C13H19N4O [M+H] ⁺ was 247.2, _and the measured value was 247.1.

Preparation and synthesis of products

Example 12

Synthesis route:

first step

Intermediate G (50 mg, 0.26 mmol), HATU (149.9 mg, 0.39 mmol), DIEA (0.13 mL, 0.79 mmol), and intermediate A (136.8 mg, 0.53 mmol) were added to tetrahydrofuran (2 mL) and stirred at room temperature for 3 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was then purified by preparative high-performance liquid chromatography (HPLC) (column: Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 20-50%, retention time: 9 min) to obtain compound 12. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 8.21 (d, J = 5.66Hz, 1H), 6.74–6.70 (m, 1H), 6.56–6.51 (m, 1H), 4.88–4.84 (m, 1H), 4.81–4.77 (m, 1H), 4.66–4.61 (m, 1H), 4.58–4.55 (m, 1H), 4.19–4.14 (m, 2H), 4.13–4.08 (m, 4H), 3.73–3.65 (m, 2H), 3.17–3.06 (m, 1H), 2.89–2.80 (m, 2H), 2.40 (s, 3H), 2.38–2.29 (m, 2H) _. ESI-MS theoretical calculation values _{: C₂¹H₂⁴F₃} N ₆ O[M+H] ⁺ ＝433.2, measured value 433.2.

Example 24

Synthesis route:

first step

Intermediate I (100 mg, 0.67 mmol) and Intermediate A (262 mg, 1.01 mmol) were dissolved in tetrahydrofuran (4 mL). DIEA (260 mg, 2.01 mmol) and HATU (382 mg, 1.01 mmol) were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Waters-Xbridge C18 10 μm, 19*250 mm; mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution; gradient: 17-47%; retention time: 9 min) to obtain compound 24. ^1H NMR (400MHz, DMSO-d ₆ )δ8.21(d,J＝5.66Hz,1H),6.72(d,J＝2.24Hz,1H),6.54(dd,J＝5.66,2.24Hz,1H),4.95-4.90(m,2H),4.76-4.69(m,2H),4.22-4.15(m,2H),3.75-3.68(m,2H),3.17-3.10(m,1H),2.90-2.82(m,2H),2.57-2.52(m,6H). ESI-MS theoretical calculation value C ₁₉ H ₂₁ F ₃ N ₅ O[M+H] ⁺ ＝392.2, measured value 392.2.

Example 47

Synthesis route:

first step

Intermediate G (30 mg, 0.16 mmol) and intermediate O (45 mg, 0.16 mmol) were dissolved in DMF (5 mL), and DIEA (122 mg, 0.95 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then HATU (72 mg, 0.19 mmol) was added. The mixture was stirred at room temperature for another hour. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (column: Waters-Xbridge-C18, 10 μm, 19*250 mm; mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution; gradient: 32-62%; retention time: 9 min) to obtain compound 47. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 7.76 (d, J = 5.78Hz, 1H), 6.17-6.13 (m, 1H), 5.79 (t, J = 1.86Hz, 1H), 4.94-4.77 (m, 4H), 4.64-4.56 (m, 2H), 4.14-4.06 (m, 6H), 3.65-3.56 (m, 2H), 3.13-3.02 (m, 1H), 2.85-2.82 (m, 2H), 2.40 (s, 3H), 2.41-2.33 (m, _2H ). _{ESI-MS theoretical calculation value C₂₂H₂₆F₃N₆O₂ [ M} +H] ^⁺ = _463.2 , measured value 463.2.

Example 50

Synthesis route:

first step

Intermediate G (30 mg, 0.16 mmol) and intermediate P (41 mg, 0.19 mmol) were dissolved in DMF (5 mL), and DIEA (62 mg, 0.47 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then HATU (90 mg, 0.24 mmol) was added. The mixture was stirred at room temperature for another 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (column: Waters-Xbridge-C18, 10 μm, 19*250 mm; mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution; gradient: 9-39%; retention time: 9 min) to obtain compound 50. ^1H NMR (400MHz, DMSO- _d₆ ) δ 4.85-4.74 (m, 2H), 4.65-4.51 (m, 2H), 4.25-4.20 (m, 2H), 4.15-4.07 (m, 4H), 3.83-3.76 (m, 2H), 3.25-3.15 (m, 1H), 2.92-2.84 (m, 2H), 2.40 (s, 3H), 2.38-2.31 (m, 2H), 2.28 (s, 3H) _{. ESI-MS theoretical calculation value C₁₈H₂₄N₇OS [} M+H] ^⁺ ＝ _386.2 , measured value 386.2.

Example 51

Synthesis route:

first step

Intermediate G (30 mg, 0.16 mmol) and intermediate Q (43 mg, 0.11 mmol) were dissolved in DMF (3 mL), and DIEA (122 mg, 0.95 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then HATU (72 mg, 0.19 mmol) was added. The mixture was stirred at room temperature for another 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (HPLC) (column: Waters-Xbridge-C18, 10 μm, 19*250 mm; mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution; gradient: 22-52%; retention time: 9 min) to obtain compound 51. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 8.20 (d, J = 5.70Hz, 1H), 6.70 (s, 1H), 6.58 (d, J = 5.64Hz, 1H), 4.92–4.84 (m, 2H), 4.66–4.51 (m, 3H), 4.15–4.02 (m, 4H), 4.01–3.96 (m, 1H), 3.76–3.71 (m, 1H), 3.24–3.20 (m, 1H), 2.89–2.77 (m, 2H), 2.42 (s, 3H), 2.39–2.34 (m, 2H), _1.37–1.34 (m, _3H ). ESI-MS theoretical calculation _{: C₂²⁻²⁶⁻²} ^... =447.2, measured value 447.1.

Example 56

Synthesis route:

first step

Intermediate T (20 mg, 0.11 mmol) and intermediate S (29 mg, 0.11 mmol) were dissolved in DMF (3 mL), and DIEA (55 mg, 0.42 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then HATU (48 mg, 0.13 mmol) was added. The mixture was stirred at room temperature for another hour. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (HPLC) (column: Waters-Xbridge-C18, 10 μm, 19*250 mm; mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution; gradient: 17-47%; retention time: 9 min) to obtain compound 56. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 8.22 (d, J = 5.68Hz, 1H), 6.76 (t, J = 2.52Hz, 1H), 6.58–6.56 (m, 1H), 5.93–5.90 (m, 1H), 4.91–4.82 (m, 2H), 4.65–4.57 (m, 2H), 4.19–4.15 (m, 2H), 4.13–4.09 (m, 4H), 3.90–3.87 (m, 2H), 2.92–2.88 (m, 2H), 2.41–2.39 (m, 3H), _2.36–2.32 (m, _{2H ) . ESI-MS theoretical calculation: C₂¹H₂₄F₃N₆O₂ [} M+H] ^⁺ =449.2, measured value 449.1.

Example 67

Synthesis route:

first step

Intermediate I (80 mg, 0.54 mmol) and intermediate O (156 mg, 0.54 mmol) were dissolved in DMF (5 mL), and DIEA (209 mg, 1.62 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then HATU (265 mg, 0.70 mmol) was added. The mixture was stirred at room temperature for another hour. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (column: Waters-Xbridge-C18, 10 μm, 19*250 mm; mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution; gradient: 26-56%; retention time: 9 min) to obtain compound 67. ^1H NMR (400MHz, DMSO-d ₆ )δ7.76(d,J＝5.78Hz,1H),6.15(dd,J＝5.82,1.94Hz,1H),5.78(d,J＝1.94Hz,1H),5.01-4.77(m,4H),4.71-4.68(m,2H),4.11-4.06(m,2H),3.63-3.58(m,2H),3.13-3.05(m,1H),2.84(d,J＝7.62Hz,2H),2.55-2.53(m,6H). ESI-MS theoretical calculation value C ₂₀ H ₂₃ F ₃ N ₅ O ₂ [M+H] ⁺ ＝422.2, measured value 422.2.

Example 68

Synthesis route:

first step

Intermediate I (54 mg, 0.36 mmol) and Intermediate X (70 mg, 0.24 mmol) were dissolved in DMF (5 mL), and DIEA (93 mg, 0.72 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then HATU (128 mg, 0.34 mmol) was added. The mixture was stirred at room temperature for another hour. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (column: Waters-Xbridge-C18, 10 μm, 19*250 mm; mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution; gradient: 25-55%; retention time: 9 min) to obtain compound 68. ^1H NMR (400MHz, DMSO-d ₆ )δ8.10(d,J＝5.72Hz,1H),6.59(d,J＝2.18Hz,1H),6.40(dd,J＝5.76,2.18Hz,1H),4.93-4.91(m,2H),4.70-4.67(m,2H),4.17-4.11(m,2H),3.69-3.65(m,2H),3.15-3.09(m,1H),2.86(d,J＝7.68Hz,2H),2.55-2.53(m,6H). ESI-MS theoretical calculation value C ₁₉ H ₂₁ F ₃ N ₅ OS[M+H] ⁺ ＝424.1, measured value 424.1.

Example 89

Synthesis route:

first step

Intermediate I trifluoroacetate (49 mg, 0.33 mmol) and intermediate AB (100 mg, 0.33 mmol) were dissolved in DMF (5 mL), and DIEA (127 mg, 0.99 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then HATU (175 mg, 0.46 mmol) was added. The mixture was stirred at room temperature for another hour. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (HPLC) (column: Waters-Xbridge-C18, 10 μm, 19*250 mm; mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution; gradient: 35-65%; retention time: 11 min) to obtain compound 89. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 7.75 (d, J = 5.80Hz, 1H), 6.15–6.12 (m, 1H), 5.87–5.78 (m, 1H), 5.75–5.73 (m, 1H), 4.93–4.90 (m, 2H), 4.71–4.68 (m, 2H), 4.10–4.06 (m, 2H), 3.64–3.58 (m, 2H), 3.12–3.05 (m, 1H), 2.85–2.82 ( _m , 2H), 2.55–2.53 (m, 6H), 1.38 (d, _{J = 6.50Hz, 3H). ESI-MS theoretical calculation: C₂¹H₂₅F₃N₅O₂ [ M +} H] ^⁺ =436.2, measured value 436.2.

Example 98

Synthesis route:

first step

Intermediate AK (73 mg, 0.41 mmol) and intermediate O (80 mg, 0.28 mmol) were dissolved in DMF (5 mL), and DIEA (142 mg, 1.10 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then HATU (136 mg, 0.36 mmol) was added. The mixture was stirred at room temperature for another hour. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. Purification by preparative high-performance liquid chromatography (HPLC) (column: Waters-Xbridge-C18, 10 μm, 19*250 mm; mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution; gradient: 35-65%; retention time: 9 min) yielded compound 98. ^¹H NMR (400 MHz, DMSO-d6 ₎ was used to obtain compound 98. 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 values: C ₂₂ H ₂₅ F ₃ N ₅ O ₂ [M+H] ⁺ ＝448.2, measured value 448.2.

Example 110

Synthesis route:

first step

Intermediate AO (59 mg, 0.36 mmol) and intermediate O (70 mg, 0.24 mmol) were dissolved in DMF (5 mL), and DIEA (94 mg, 0.72 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then HATU (119 mg, 0.31 mmol) was added. The mixture was stirred at room temperature for another hour. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (column: Waters-Xbridge-C18, 10 μm, 19*250 mm; mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution; gradient: 31-61%; retention time: 9 min) to obtain compound 110. ^1H NMR (400MHz, DMSO- _d₆ ) δ 7.76 (d, J = 5.84Hz, 1H), 6.15 (dd, J = 5.80, 1.96Hz, 1H), 5.78 (d, J = 1.94Hz, 1H), 5.02-4.85 (m, 4H), 4.74-4.67 (m, 2H), 4.11-4.05 (m, 2H), 3.64-3.57 (m, 2H), 3.12-3.04 (m, 1H), 2.90-2.82 ( _m , 4H), 2.55 (s, 3H), 1.26 (t, J = _7.54Hz , 3H) _. ESI-MS theoretical calculation value _{C₂₁H₂₅F₃N₅O₂} [M+H] ^⁺ = _436.2 , measured value 436.2.

Example 111

Synthesis route:

first step

Intermediate AP (70 mg, 0.39 mmol) and intermediate O (115 mg, 0.39 mmol) were dissolved in DMF (5 mL), and DIEA (153 mg, 1.18 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then HATU (195 mg, 0.51 mmol) was added. The mixture was stirred at room temperature for another hour. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (column: Waters-Xbridge-C18, 10 μm, 19*250 mm; mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution; gradient: 34-64%; retention time: 9 min) to obtain compound 111. ^1H NMR (400MHz, DMSO- _d₆ ) δ 7.76 (d, J = 5.78Hz, 1H), 6.15 (dd, J = 5.82, 1.94Hz, 1H), 5.78 (d, J = 1.92Hz, 1H), 4.97-4.83 (m, 4H), 4.73-4.70 (m, 2H), 4.10-4.06 (m, 2H), 3.64-3.57 (m, 2H), 3.13-3.05 (m, 1H), 2.91-2.83 (m, 6H), 1.27 (t, J = _7.54Hz , _{6H). ESI-MS theoretical calculation value C₂₂H₂₇F₃N₅O₂ [ M} +H] ^⁺ = _450.2 , measured value 450.2.

Example 116

Synthesis route:

first step

Intermediate I (66 mg, 0.44 mmol) and intermediate AA (90 mg, 0.30 mmol) were dissolved in DMF (5 mL), and DIEA (115 mg, 0.89 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then HATU (169 mg, 0.44 mmol) was added. The mixture was stirred at room temperature for another hour. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (column: Waters-Xbridge-C18, 10 μm, 19*250 mm; mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution; gradient: 32-62%; retention time: 9 min) to obtain compound 116. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 7.76 (d, J = 5.80Hz, 1H), 6.13 (dd, J = 5.84, 2.00Hz, 1H), 5.87-5.80 (m, 1H), 5.74 (d, J = 1.96Hz, 1H), 4.93-4.90 (m, 2H), 4.71-4.68 (m, 2H), 4.12-4.03 (m, 2H), 3.64-3.55 (m, 2H), 3.14-3.03 (m, 1H), 2.86-2.82 (m, 2H), 2.58-2.52 (m, 6H), 1.38 (d, J = 6.50Hz, _{3H). ESI-MS theoretical calculation value: C₂¹H₂₅F₃N₅O₂ [ M + H} ] ⁺ = 436.2, measured value 436.2.

Example 123

Synthesis route:

first step

Intermediate G (33 mg, 0.17 mmol), HATU (78 mg, 0.20 mmol), DIEA (66 mg, 0.51 mmol), and intermediate O (50 mg, 0.17 mmol) were added to DMF (5 mL) and stirred at room temperature for 3 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was then purified by preparative high-performance liquid chromatography (HPLC) (column: Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 30-60%, retention time: 10 min) to obtain compound 123. ^1H NMR (400MHz, DMSO- _d₆ ) δ 7.76 (d, J = 5.78Hz, 1H), 6.14 (dd, J = 5.78, 1.82Hz, 1H), 5.78 (d, J = 1.884Hz, 1H), 4.95-4.76 (m, 4H), 4.65-4.57 (m, 2H), 4.13-4.05 (m, 6H), 3.61-3.58 (m, 2H), 3.12-3.01 (m, 1H), 2.84-2.81 (m, 2H), 2.40-2.32 (m, 5H). _{ESI - MS} theoretical calculation value _{C₂₂H₂₆F₃N₆O₂} [M+H] ^⁺ = _463.2 , measured value 463.0.

Example 124

Synthesis route:

first step

Intermediate AR (67 mg, 0.27 mmol), 124-1 (50 mg, 0.27 mmol), TEA (83 mg, 0.82 mmol), and cesium fluoride (62 mg, 0.42 mmol) were added to DMSO (5 mL) and stirred at 100 °C for 10 hours. After cooling, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (column: Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 16-46%, retention time: 10 min) to obtain compound 124. ^¹H NMR (400MHz, DMSO- _d₆ ) δ 8.27 (d, J = 6.02Hz, 1H), 6.59 (d, J = 6.02Hz, 1H), 4.93-4.89 (m, 2H), 4.71-4.68 (m, 2H), 4.29-4.23 (m, 2H), 3.85-3.77 (m, 2H), 3.17-3.07 (m, 1H), 2.89-2.86 (m, 2H), 2.55-2.53 (m, 6H) _. ESI-MS theoretical calculation _{C₁₈H₂₀F₃N₆O} [M+H] ^⁺ = _393.2 , measured value 393.2 _.

Example 125

Synthesis route:

first step

Intermediate AR (80 mg, 0.32 mmol), 125-1 (70 mg, 0.32 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl), palladium (28 mg, 0.03 mmol), and cesium carbonate (317 mg, 0.97 mmol) were added to 1,4-dioxane (5 mL). The mixture was heated to 100 °C and stirred for 18 hours under nitrogen protection. After cooling, the reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 18-48%, retention time: 10 min) to obtain compound 125. ^1H NMR (400MHz, DMSO- _d₆ ) δ 9.25(s, 1H), 7.89(d, J = 8.62Hz, 1H), 7.02(d, J = 2.18Hz, 1H), 6.68(dd, J = 8.62, 2.24Hz, 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 _{C₂₀H₂₂N₅OS} [M+H] ^⁺ = _380.2 , measured value 380.0.

Example 126

Synthesis route:

first step

Intermediate AR (65 mg, 0.26 mmol), 126-1 (50 mg, 0.26 mmol), cesium fluoride (60 mg, 0.40 mmol), and TEA (80 mg, 0.79 mmol) were added to DMSO (5 mL). After cooling, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (column: Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 15-45%, retention time: 10 min) to obtain compound 126. ^1H NMR (400MHz, DMSO- _d₆ ) δ 8.11 (d, J = 5.50Hz, 1H), 6.28 (d, J = 5.58Hz, 1H), 4.94-4.91 (m, 2H), 4.70-4.67 (m, 2H), 4.32-4.28 (m, 2H), 3.86-3.82 (m, 2H), 3.09-2.98 (m, 3H), 2.87-2.84 (m, 2H), 2.56-2.53 (m, 8H) _. ESI-MS theoretical calculation value _{C₂₁H₂₄F₂N₅O} [M+H] _⁺ ⁼ 400.2, measured value 400.2 _.

Example 127

Synthesis route:

first step

Intermediate AR (106 mg, 0.43 mmol), 127-1 (100 mg, 0.43 mmol), and cesium carbonate (351 mg, 1.08 mmol) were added to DMF (3 mL). After cooling, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (column: Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 25-55%, retention time: 10 min) to obtain compound 127. ^1H NMR (400MHz, DMSO- _d₆ ) δ 7.70 (s, 1H), 4.92-4.89 (m, 2H), 4.71-4.68 (m, 2H), 4.28-4.21 (m, 2H), 3.84-3.78 (m, 2H), 3.22-3.16 (m, 1H), 2.91-2.88 (m, 2H), 2.56-2.53 (m, 6H). _{ESI - MS} theoretical calculation _{C₁₇H₁₉F₃N₅OS} [M+H] ^⁺ ＝398.1, measured value 398.1.

Example 128

Synthesis route:

first step

Intermediate I (26 mg, 0.17 mmol), HATU (78 mg, 0.20 mmol), DIEA (66 mg, 0.51 mmol), and intermediate X (50 mg, 0.17 mmol) were added to DMF (5 mL) and stirred at room temperature for 3 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was then purified by preparative high-performance liquid chromatography (HPLC) (column: Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 20-50%, retention time: 10 min) to obtain compound 128. ^1H NMR (400MHz, DMSO-d ₆ )δ8.10(d,J＝5.72Hz,1H),6.59(d,J＝2.20Hz,1H),6.40(dd,J＝5.72,2.22Hz,1H),4.93-4.90(m,2H),4.70-4.67(m,2H),4.16-4.12(m,2H),3.68-3.64(m,2H),3.17-3.03(m,1H),2.88-2.85(m,2H),2.55-2.52(m,6H). ESI-MS theoretical calculation value C ₁₉ H ₂₁ F ₃ N ₅ OS[M+H] ⁺ ＝424.1, measured value 424.1.

Example 129

Synthesis route:

first step

Intermediate I (26 mg, 0.17 mmol), HATU (78 mg, 0.20 mmol), DIEA (66 mg, 0.51 mmol), and intermediate O (50 mg, 0.17 mmol) were added to DMF (5 mL) and stirred at room temperature for 3 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was then purified by preparative high-performance liquid chromatography (HPLC) (column: Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 37-47%, retention time: 10 min) to obtain compound 129. ^1H NMR (400MHz, DMSO-d ₆ )δ7.76(d,J＝5.80Hz,1H),6.15(dd,J＝5.78,1.98Hz,1H),5.78(d,J＝1.96Hz,1H),4.99-4.83(m,4H),4.71-4.68(m,2H),4.10-4.06(m,2H),3.62-3.59(m,2H),3.12-3.05(m,1H),2.86-2.83(m,2H),2.56-2.53(m,6H). ESI-MS theoretical calculation value C ₂₀ H ₂₃ F ₃ N ₅ O ₂ [M+H] ⁺ ＝422.2, measured value 422.0.

Example 130

Synthesis route:

first step

Intermediate AR (65 mg, 0.26 mmol), 130-1 (50 mg, 0.26 mmol), cesium fluoride (60 mg, 0.40 mmol), and TEA (80 mg, 0.79 mmol) were added to DMSO (5 mL). After cooling, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (column: Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 18-45%, retention time: 9 min) to obtain compound 130. ^1H NMR (400MHz, DMSO- _d₆ ) δ 4.93-4.89 (m, 2H), 4.72-4.68 (m, 2H), 4.38-4.32 (m, 2H), 3.96-3.88 (m, 2H), 3.29-3.18 (m, 1H), 2.92-2.88 (m, 2H), 2.55-2.52 (m, 6H). _{ESI-MS theoretical calculation value C₁₆H₁₈F₃N₆OS [ M} + _H ] ⁺ ＝399.1, measured value 399.1.

Example 131

Synthesis route:

first step

Intermediate AR (67 mg, 0.27 mmol), 131-1 (50 mg, 0.27 mmol), TEA (83 mg, 0.82 mmol), and cesium fluoride (42 mg, 0.27 mmol) were added to DMSO (5 mL) and stirred at 70 °C for 18 hours. After cooling, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by preparative high performance liquid chromatography (column: Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 5-95%, retention time: 10 min) to obtain compound 131. ^1H NMR (400MHz, DMSO- _d₆ ) δ 8.63 (d, J = 2.80Hz, 1H), 6.91 (d, J = 2.80Hz, 1H), 4.92-4.90 (m, 2H), 4.70-4.68 (m, 2H), 4.32-4.28 (m, 2H), 3.87-3.80 (m, 2H), 3.20-3.10 (m, 1H), 2.89-2.86 (m, 2H), 2.55-2.52 (m, 6H) _. ESI-MS theoretical calculation _{C₁₈H₂₀F₃N₆O} [M+H] ^⁺ = _393.2 , measured value 392.9 _.

Example 132

Synthesis route:

first step

Intermediate G-4 (500 mg, 1.60 mmol) was dissolved in methanol (20 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (127 mg, 0.17 mmol) and TEA (524 mg, 5.18 mmol) were added. The reaction system was purged with carbon monoxide three times and then heated to 70 °C and stirred for 18 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1/4, v/v) to obtain 132-1. The theoretical ESI-MS value of _C17H20N3O3 [M+H] ⁺ was _314.1 , _and the measured value _was 314.0.

Step 2

132-1 (200 mg, 0.64 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium borohydride (14 mg, 0.64 mmol) was slowly added at 0 °C, with stirring at room temperature for 1 hour. The reaction solution was quenched with water (30 mL), extracted with dichloromethane (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1/4, v/v) to obtain 132-2. The theoretical ESI-MS value _{of C16H20N3O2} [M+H] ⁺ was _286.2 , _and the measured value was 286.2.

Step 3

132-2 (100 mg, 0.35 mmol) and trifluoroacetic acid (2 mL) were added to a 5 mL microwave tube, and the mixture was heated to 90 °C and stirred for 8 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a crude product containing 132-3, which was directly used in the next reaction. The theoretical ESI-MS value of _C8H12N3O [M+H] ⁺ was _166.1 , _and the measured value was 166.1.

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 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was then purified by preparative high-performance liquid chromatography (HPLC) (column: Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 5-95%, retention time: 10 min) to obtain compound 132. ^¹H NMR (400MHz, MeOD- _d⁴ ) δ 7.74-7.71 (m, 1H), 6.14-6.12 (m, 1H), 5.82-5.75 (m, 1H), 5.12-5.10 (m, 1H), 4.97-4.89 (m, 4H), 4.82-4.78 (m, 1H), 4.74-4.68 (m, 2H), 4.19-4.14 (m, 2H), 3.73-3.64 (m, 2H), 3.26-3.08 (m, 1H), 2.95-2.91 (m, 2H), 2.65 (s, _{3H ). ESI-MS theoretical value C₂₀H₂₃F₃N₅O₃ [ M} +H] ^⁺ ＝ _438.2 , measured value 437.9.

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

Experimental objective:

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

Experimental materials:

Experimental instruments:

Cell treatment:

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

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

Experimental procedure:

1. Cell plating: M4-Gα15-CHO cells were digested and collected, resuspended, counted, and seeded into 384-well cell plates at a density of 1.2 × ^10⁴ cells/25 μL/well. The cell plates were then incubated at 37°C in a 5% _CO₂ incubator for approximately 20 hours.

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

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

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

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

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

7. Plot the signal values against the compound concentrations, and use the nonlinear regression method in GraphPad Prism software to perform curve fitting and calculate _EC50 .

Preparation of detection buffer and sample loading buffer:

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

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

Experimental results:

compound <![CDATA[EC₅₀(μM)]]> Example 12 0.35 Example 24 0.387 Example 47 0.25 Example 50 1.78 Example 51 1.37 Example 67 0.39 Example 68 0.48 Example 89 0.29 Example 98 1.13 Example 110 0.90 Example 116 0.58

Experimental conclusion:

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

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

Experimental objective:

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

Experimental materials:

Experimental procedure:

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

Experimental methods:

Experimental results:

Experimental conclusion:

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

Activity test 3 Evaluation of the pharmacokinetic properties of the compound in rats

Experimental objective:

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

Experimental materials:

Experimental procedure:

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

The test sample was prepared according to the corresponding examples. The bioavailability of some compounds in this application is above 80%, the clearance rate is not higher than 16 mL/min/kg, the half-life T _1/2 is between 2hr and 10hr, and the area under the curve (AUC _0-last) is between 5000 and 50000hr*ng/mL. The compounds in this application have good pharmacokinetic properties.

Activity test 4 Evaluation of the pharmacokinetic properties of the compound in dogs

Experimental objective:

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

Experimental materials:

Experimental procedure:

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

The test samples were prepared according to the corresponding examples. The bioavailability of some compounds in this application is above 80%, the clearance rate is not higher than 16 mL/min/kg, the half-life T _1/2 is between 2hr and 10hr, and the area under the curve (AUC _0-last) is between 2000 and 20000hr*ng/mL. The compounds in this application exhibit good pharmacokinetic properties.

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

Experimental objective:

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

Experimental materials:

Experimental procedure:

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

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

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

Experimental objective:

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

Experimental materials:

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

Experimental procedure:

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

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

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

Experimental objective:

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

Experimental materials:

Experimental procedure:

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

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