Heterocyclic GLP-1 receptor agonist and use thereof

Abstract

The present application relates to a GLP-1 receptor agonist, which is a compound of formula (II) or a pharmaceutically acceptable salt thereof, and a method for treating or preventing a GLP-1 receptor-mediated disease or disorder or regulating a GLP-1 receptor.

Description

A heterocyclic GLP-1 receptor agonist and its application Technical Field

[0001] This invention relates to a heterocyclic GLP-1 receptor agonist compound or a pharmaceutically acceptable salt thereof, and methods for treating or preventing GLP-1 receptor-mediated diseases or disorders or modulating GLP-1 receptors. Background Technology

[0002] Diabetes is a chronic disease characterized by high blood sugar due to defects in insulin secretion, insulin action, or both. Type 2 diabetes, also known as non-insulin-dependent diabetes mellitus, is the most common acquired disease, accounting for more than 90% of diabetes cases. It typically occurs in obese or sedentary adults and begins with insulin resistance, later associated with elevated blood sugar levels due to the combined effects of impaired insulin secretion and insulin resistance. While lifestyle modifications can help manage the disease, people with type 2 diabetes may need to take antidiabetic medications, including dipeptidyl peptidase-4 inhibitors, SGLT2 inhibitors, and sulfonylureas.

[0003] Insulin-metabolizing hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), are important in the regulation of glucose homeostasis. Drugs targeting this family of intestinal peptides (e.g., GLP-1 agonists) have been shown to inhibit glucagon production, reduce gastric motility, and increase satiety.

[0004] Semaglutide, a GLP-1 receptor agonist, can improve the pathophysiological mechanisms of type 2 diabetes, such as impaired incretin function, increased hepatic glucose production, abnormal nerve conduction, decreased insulin secretion, increased glucagon secretion, and decreased glucose uptake. It also has cardiovascular protective effects, acting on multiple organs and tissues to comprehensively improve cardiovascular metabolic risk factors and slow the progression of atherosclerotic cardiovascular disease. However, most GLP-1 receptor agonists, including semaglutide, currently require invasive subcutaneous administration. Although certain formulations of semaglutide under development can be administered orally, they still suffer from inconvenient dosing regimens and poor bioavailability.

[0005] LY3502970 is a novel, highly effective, orally administered non-peptide GLP-1R agonist. Preclinical studies have shown that LY3502970 has a hypoglycemic effect comparable to exenatide. Pharmacokinetic studies in cynomolgus monkeys showed that LY3502970 has a half-life of 3.4–4.6 h and a bioavailability of 21–28%.

[0006] Currently, small molecule GLP-1 receptor agonists have become a hot topic in drug development in recent years due to their potential for high oral bioavailability. Summary of the Invention

[0007] This invention provides compounds of formula (II) or pharmaceutically acceptable salts thereof.

[0008] in,

[0009] Selected from

[0010] R5 is selected from (CR) C R C ) 0-2 -cyclic hydrocarbon group, (CR C R C ) 0-2 -Aryl, (CR C R C ) 0-2 - Heterocyclic group or (CR) C R C ) 0-2 - Heteroaryl, wherein the cyclic hydrocarbon group is a spirocyclic hydrocarbon group, a bridged cyclic hydrocarbon group, or a monocyclic hydrocarbon group, and the aryl, heterocyclic, or heteroaryl group is a spirocyclic, bridged ring, fused ring, or monocyclic ring; the cyclic hydrocarbon group, aryl, heterocyclic, or heteroaryl group is optionally substituted by one or more substituents independently selected from: C1-C6 alkyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, oxo, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, -NO2, phenyl or heteroaryl; or when the carbon atom on the cycloalkyl, phenyl, aryl, heteroaryl or heterocyclic ring is replaced by two C1-C6 alkyl groups, the two C1-C6 alkyl groups together with the carbon atoms to which they are attached form a C3-C... 10 Cyclic hydrocarbon groups; each R C Independently selected from H, C1-C3 alkyl, or C1-C3 haloalkyl; or two R C Together with the carbon atoms to which they are attached, they form C3-C 10 Cyclic hydrocarbon group; the C3-C 10 The cyclic hydrocarbon group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

[0011] A is selected from cycloalkyl, aryl, heterocyclic, or heteroaryl groups, wherein the cycloalkyl group is a spirocyclic, bridged, or monocyclic group, and the heterocyclic or heteroaryl group is a spirocyclic, bridged, fused, or monocyclic group; the cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxy-substituted alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, oxo, or thio.

[0012] Or A is selected from Wherein, U and V are independently selected from empty, N-Rd, N-Re or C-RfRg, C-RhRi, where E is selected from O or S; Rd, Re, Rf, Rg, Rh, Ri, R 10 Or R 11 Independently selected from H, halogens, C1-C6 alkyl groups, C3-C 10 Cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, phenyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 12-membered heterocyclic, 5- to 12-membered aryl or 5- to 12-membered heteroaryl; the C1-C6 alkyl, C3-C 10 The cycloalkyl group, C1-C6 alkoxy group, C1-C6 alkylamino group, phenyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, 3- to 12-membered heterocyclic group, 5- to 12-membered aryl group, or 5- to 12-membered heteroaryl group is optionally substituted by one or more substituents independently selected from the following: D, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C3-C 12 Cycloalkyl, OH, halogen, NH2, oxo, methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, 3 to 12-membered heterocyclic, 5 to 12-membered heteroaryl or 5 to 12-membered aryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 The cycloalkyl group, NH2, 3- to 12-membered heterocyclic group, 5- to 12-membered heteroaryl group, or 5- to 12-membered aryl group is optionally substituted by one or more substituents independently selected from the following: D, halogen, cyano, amino, methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, where n is an integer from 0 to 10; m is 0 or 1; or Rf and Rg, Rh and Ri, R when n is not 0. 10 and R 11 Independently, together with the carbon atoms to which they are attached, they form C3-C. 10 Cyclic hydrocarbon group, the C3-C 10The cycloalkyl group is optionally substituted by one or more substituents independently selected from: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen; or when m is 0, Rd and Re independently form a C3-C group together with the nitrogen atom to which they are attached. 10 Heterocyclic groups, the C3-C 10 The heterocyclic group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

[0013] B is selected from C3-C 10 The aryl group, aryl group (preferably phenyl), heterocyclic group comprising one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S, or heteroaryl group comprising one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S, wherein the aryl group, heterocyclic group, or heteroaryl group is a spirocyclic, bridged ring, fused ring, or monocyclic ring; wherein the aryl group, aryl (phenyl), heterocyclic group, or heteroaryl group is optionally substituted by one or more substituents independently selected from: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C 12 Cycloalkyl groups, C1-C6 alkyl groups, C3-C6 alkyl groups 12 Cyclic hydrocarbon groups, OH, halogens, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, NH-S(=O)2Ra, CN, -NO2, P(=O)RaRb, S(=O)2Ra, oxo, thio Wherein, the cyclic hydrocarbon group is a spirocyclic hydrocarbon group, a bridged cyclic hydrocarbon group, or a monocyclic hydrocarbon group, and Ra and Rb are each independently selected from H, halogens, C1-C6 alkyl groups, and C3-C6 alkyl groups. 10 Cyclic hydrocarbon group, phenyl group.

[0014] When A is empty, B is or

[0015] Z is selected from CH or N.

[0016] C is selected from CH2 or C=O.

[0017] Selected from

[0018] R4, R 12 Independently selected from H, halogens, C1-C6 alkyl groups, C3-C 10Cycloalkyl, C1-C6 alkoxy, phenyl, vinyl, ethynyl, cyano, 3- to 12-membered heterocyclic, or 5- to 12-membered heteroaryl, wherein the alkyl, cycloalkyl, alkoxy, phenyl, vinyl, ethynyl, heterocyclic, or heteroaryl is optionally substituted by one or more substituents independently selected from: halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, NH2, carboxyl, oxo, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, -NO2, or -C1-C6 alkyl C1-C6 alkyl; or when the heterocyclic or heteroaryl group is replaced by a C1-C6 alkyl group, the two C1-C6 alkyl groups together with the carbon atoms to which they are attached can form a C3-C... 10 Cyclic hydrocarbon group.

[0019] L is selected from C3-C 10 A cycloalkyl group, carbonyl group, phenylene group, or heteroaryl group comprising one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S, wherein the cycloalkyl group, phenylene group, or heteroaryl group is optionally substituted by one or more substituents independently selected from: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or halogen, or wherein when the phenylene group is substituted by two substituents attached to adjacent carbon atoms in the phenylene ring, the two substituents together with the carbon atoms to which they are attached are capable of forming a 5- or 6-membered ring, the 5- or 6-membered ring optionally comprising 1-3 heteroatoms selected from N, O, and S.

[0020] R6 and R7 are each independently selected from H, D, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen, or R6 and R7 together with the carbon atom to which they are attached form a C3-C... 10 Cyclic hydrocarbon group, the C3-C 10 The cyclic hydrocarbon group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

[0021] T is selected from H, C(O)OH, (CH2)NHS(O)2-(C1-C6 alkyl), or a heteroaryl group comprising a 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the heteroaryl group is optionally substituted with a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, OH, a halogen, or an oxo group.

[0022] R1, R2, R3, R 13 R14 and R 15 Each is independently selected from H, D, halogen, C1-C6 alkyl, C3-C 10 Cyclic hydrocarbon groups, phenyl groups; wherein, C1-C6 alkyl groups, C3-C6 alkyl groups, and C3-C6 alkyl groups are present. 10 The cycloalkyl group or phenyl group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN or -NO2; or R1, R2, R3, R 13 R 14 and R 15 Independently, together with the carbon atoms to which they are attached, they form C3-C. 10 Cyclic hydrocarbon group or C3-C 10 Heterocyclic groups, the C3-C 10 Cyclic hydrocarbon group or C3-C 10 The heterocyclic group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

[0023] In some embodiments of the present invention, the above-mentioned compound is selected from the structure shown in formula (I).

[0024] R1, R2, and R3 are each independently selected from H, D, halogens, C1-C6 alkyl groups, and C3-C4 alkyl groups. 10 Cycloalkyl, phenyl, wherein C1-C6 alkyl, C3-C 10 The cyclic hydrocarbon group and phenyl group are optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN or -NO2.

[0025] In some embodiments of the present invention, R1 and R... 13 Not H.

[0026] In some embodiments of the present invention, R2 and R... 14 Not H.

[0027] In some embodiments of the present invention, R3 and R... 15 Not H.

[0028] In some embodiments of the present invention, the above-mentioned Selected from

[0029] In some embodiments of the present invention, R5 is selected from (CR) C R C ) 0-2 -C3-C6 cyclic hydrocarbon group, (CR C R C ) 0-2 -Phenyl, containing two 5- or 6-membered rings (CR C R C ) 0-2 -aryl, comprising one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S (CR C R C ) 0-2 - Heteroaryl groups or groups containing one or two 3- to 6-membered rings and 1-3 heteroatoms selected from N, O, and S (CR C R C ) 0-2 - Heterocyclic group, wherein the cyclic hydrocarbon group, phenyl group, aryl group, heteroaryl group, or heterocyclic group is optionally substituted by one or more substituents independently selected from: C1-C6 alkyl group, C1-C6 haloalkyl group, C3-C6 alkyl group, C4-C6 alkyl group, C5-C6 alkyl group, C6 ... 10 Cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, -NO2, C3-C6 cycloalkyl, phenyl or heteroaryl; or when the carbon atom on the cycloalkyl, phenyl, aryl, heteroaryl or heterocyclic ring is replaced by two C1-C6 alkyl groups, the two C1-C6 alkyl groups together with the carbon atoms to which they are attached form a C3-C... 10 Cyclic hydrocarbon groups; each R C Independently selected from H, C1-C3 alkyl, or C1-C3 haloalkyl; or two R C Together with the carbon atoms to which they are attached, they form C3-C 10 Cyclic hydrocarbon group, the C3-C 10 The cyclic hydrocarbon group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

[0030] In some embodiments of the present invention, R5 is selected from (CR) C R C ) 0-2 -C3-C6 cyclic hydrocarbon group, (CR C R C ) 0-2 -Phenyl, containing two 5- or 6-membered rings (CR C R C ) 0-2 -Aryl or containing one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S (CRC R C ) 0-2 - Heteroaryl, wherein the cycloalkyl, phenyl, aryl, or heteroaryl group is optionally substituted by one or more substituents independently selected from: C1-C6 alkyl, C1-C6 haloalkyl, C3-C 10 Cyclic hydrocarbon group, C1-C6 alkoxy group, C1-C6 haloalkoxy group, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, -NO2 or C3-C6 cyclic hydrocarbon group, each R C Independently selected from H, C1-C3 alkyl, or C1-C3 haloalkyl; or when the carbon atom on the cycloalkyl, phenyl, aryl, or heteroaryl ring is replaced by two C1-C6 alkyl groups, the two C1-C6 alkyl groups together with the carbon atoms to which they are attached form a C3-C... 10 Cyclic hydrocarbon group; or two R groups C Together with the carbon atoms to which they are attached, they form C3-C 10 Cyclic hydrocarbon group, the C3-C 10 The cyclic hydrocarbon group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

[0031] In some embodiments of the present invention, the B mentioned above is selected from a heterocyclic group comprising one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S, or a heteroaryl group comprising one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclic group or the heteroaryl group is optionally substituted by one or more substituents independently selected from: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C 12 Cyclic hydrocarbon group, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN or -NO2.

[0032] In some embodiments of the present invention, A is selected from heterocyclic groups, heteroaryl groups, or is empty, wherein the heteroaryl or heterocyclic group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxy-substituted alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, oxo, thio.

[0033] In some embodiments of the present invention, A is selected from... Or it may be empty, wherein R8 and R9 are each independently selected from H, D, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxy-substituted alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, oxo, thio, or R8 and R9 together with the carbon atom to which they are attached form a C3-C 10 Cyclic hydrocarbon group or C3-C 10 Heterocyclic hydrocarbon groups, the C3-C 10 Cyclic hydrocarbon group or C3-C 10 The heterocyclic hydrocarbon group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxy-substituted alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

[0034] In some embodiments of the present invention, A is selected from... R8 and R9 are each independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxy-substituted alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen, or R8 and R9 together with the carbon atom to which they are attached form a C3-C6 cyclic hydrocarbon group or a C3-C6 heterocyclic hydrocarbon group, wherein the C3-C6 cyclic hydrocarbon group or the C3-C6 heterocyclic hydrocarbon group is optionally substituted by one or more substituents independently selected from: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxy-substituted alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen.

[0035] In some embodiments of the present invention, A is selected from...

[0036] In some embodiments of the present invention, A is selected from...

[0037] In some embodiments of the present invention, A is selected from... U and V are independently selected from N-Rd, N-Re, or C-RfRg, C-RhRi, where E is selected from O or S; Rd, Re, Rf, Rg, Rh, or Ri are independently selected from H, halogens, C1-C6 alkyl groups, C3-C 10 Cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, phenyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 12-membered heterocyclic, 5- to 12-membered aryl or 5- to 12-membered heteroaryl; the C1-C6 alkyl, C3-C 10The cycloalkyl group, C1-C6 alkoxy group, C1-C6 alkylamino group, phenyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, 3- to 12-membered heterocyclic group, 5- to 12-membered aryl group, or 5- to 12-membered heteroaryl group is optionally substituted by one or more substituents independently selected from the following: D, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C3-C 12 Cycloalkyl, OH, halogen, NH2, oxo, methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, 3 to 12-membered heterocyclic, 5 to 12-membered heteroaryl or 5 to 12-membered aryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 The cycloalkyl group, NH2, 3 to 12-membered heterocyclic group, 5 to 12-membered heteroaryl group, or 5 to 12-membered aryl group is optionally substituted by one or more substituents independently selected from: D, halogen, cyano, amino, methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, where n is an integer from 0 to 10; m is 0 or 1; or Rf and Rg, Rh and Ri together with the carbon atom to which they are attached form a C3-C 10 Cyclic hydrocarbon group, the C3-C 10 The cyclic hydrocarbon group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

[0038] In some embodiments of the present invention, A is selected from... Where E is selected from O or S; Rd and Re are independently selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, phenyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 12-membered heterocyclic, 5- to 12-membered aryl or 5- to 12-membered heteroaryl; the C1-C6 alkyl, C3-C 10 The cycloalkyl group, C1-C6 alkoxy group, C1-C6 alkylamino group, phenyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, 3- to 12-membered heterocyclic group, 5- to 12-membered aryl group, or 5- to 12-membered heteroaryl group is optionally substituted by one or more substituents independently selected from the following: D, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C3-C 12 Cycloalkyl, OH, halogen, NH2, oxo, methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, 3 to 12-membered heterocyclic, 5 to 12-membered heteroaryl or 5 to 12-membered aryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C3-C 12The cycloalkyl group, NH2, 3- to 12-membered heterocyclic group, 5- to 12-membered heteroaryl group, or 5- to 12-membered aryl group is optionally substituted by one or more substituents independently selected from the following: D, halogen, cyano, amino, methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, where n is an integer from 0 to 10; or Rd and Re independently form a C3-C group together with the nitrogen atom to which they are attached. 10 Heterocyclic group, the C3-C 10 The heterocyclic group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

[0039] In some embodiments of the present invention, A is selected from... Where E is selected from O; Rd and Re are independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cyclic hydrocarbon group or C1-C6 alkoxy group; the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 The cyclic hydrocarbon group or C1-C6 alkoxy group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C 10 Cyclic hydrocarbon group, OH, halogen, NH2, Oxylated, methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, 3 to 12-membered heterocyclic, C1-C6 alkyl or C1-C6 haloalkyl-substituted 3 to 12-membered heterocyclic, phenyl or halophenyl; n is 0 or 1.

[0040] In some embodiments of the present invention, A is selected from... Where E is selected from O or S; Rd, Re, Rf, Rg, Rh or Ri are independently selected from H, halogens, C1-C6 alkyl groups, C3-C 10 Cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, phenyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 12-membered heterocyclic, 5- to 12-membered aryl or 5- to 12-membered heteroaryl; the C1-C6 alkyl, C3-C 10The cycloalkyl group, C1-C6 alkoxy group, C1-C6 alkylamino group, phenyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, 3- to 12-membered heterocyclic group, 5- to 12-membered aryl group, or 5- to 12-membered heteroaryl group is optionally substituted by one or more substituents independently selected from the following: D, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C3-C 12 Cycloalkyl, OH, halogen, NH2, oxo, methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, 3 to 12-membered heterocyclic, 5 to 12-membered heteroaryl or 5 to 12-membered aryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 The cycloalkyl group, NH2, 3 to 12-membered heterocyclic group, 5 to 12-membered heteroaryl group, or 5 to 12-membered aryl group is optionally substituted by one or more substituents independently selected from the following: D, halogen, cyano, amino, methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, where n is an integer from 0 to 10; or Rf and Rg, Rh and Ri independently form a C3-C group together with the carbon atom to which they are attached. 10 Cyclic hydrocarbon group, the C3-C 10 The cyclic hydrocarbon group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

[0041] In some embodiments of the present invention, A is selected from... Rd and Re are independently selected from H, C1-C6 alkyl groups, and C3-C4 alkyl groups. 10 Cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, phenyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 12-membered heterocyclic, 5- to 12-membered aryl or 5- to 12-membered heteroaryl; the C1-C6 alkyl, C3-C 10 The cycloalkyl group, C1-C6 alkoxy group, C1-C6 alkylamino group, phenyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, 3- to 12-membered heterocyclic group, 5- to 12-membered aryl group, or 5- to 12-membered heteroaryl group is optionally substituted by one or more substituents independently selected from the following: D, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C3-C 12 Cycloalkyl, OH, halogen, NH2, oxo, methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, 3 to 12-membered heterocyclic, 5 to 12-membered heteroaryl or 5 to 12-membered aryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12The cycloalkyl group, NH2, 3 to 12-membered heterocyclic group, 5 to 12-membered heteroaryl group, or 5 to 12-membered aryl group is optionally substituted by one or more substituents independently selected from the following: D, halogen, cyano, amino, methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, where n is an integer from 0 to 10.

[0042] In some embodiments of the present invention, A is selected from... Wherein, E is selected from O or S; V is selected from N-Re or C-RhRi; Re, Rh, Ri, R 10 Or R 11 Independently selected from H, halogens, C1-C6 alkyl groups, C3-C 10 Cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, phenyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 12-membered heterocyclic, 5- to 12-membered aryl or 5- to 12-membered heteroaryl; the C1-C6 alkyl, C3-C 10 The cycloalkyl group, C1-C6 alkoxy group, C1-C6 alkylamino group, phenyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, 3- to 12-membered heterocyclic group, 5- to 12-membered aryl group, or 5- to 12-membered heteroaryl group is optionally substituted by one or more substituents independently selected from the following: D, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C3-C 12 Cycloalkyl, OH, halogen, NH2, oxo, methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, 3 to 12-membered heterocyclic, 5 to 12-membered heteroaryl or 5 to 12-membered aryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 The cycloalkyl group, NH2, 3 to 12-membered heterocyclic group, 5 to 12-membered heteroaryl group, or 5 to 12-membered aryl group is optionally substituted by one or more substituents independently selected from the following: D, halogen, cyano, amino, methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, where n is an integer from 0 to 10; or Rh and Ri, R when n is not 0. 10 and R 11 Independently, together with the carbon atoms to which they are attached, they form C3-C. 10 Cyclic hydrocarbon group, the C3-C 10 The cyclic hydrocarbon group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

[0043] In some embodiments of the present invention, A is selected from... Where R 10 Or R 11 Independently selected from H, halogens, C1-C6 alkyl groups, C3-C 10 Cyclic hydrocarbon group or C1-C6 alkoxy group; the C1-C6 alkyl group, C3-C 10 The cyclic hydrocarbon group or C1-C6 alkoxy group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C 10 Cyclic hydrocarbon group, OH, halogen, NH2, Oxylated, methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, 3- to 12-membered heterocyclic groups, C1-C6 alkyl or C1-C6 haloalkyl-substituted 3- to 12-membered heterocyclic groups, phenyl or halophenyl; n is 0 or 1; or when n is not 0, R 10 and R 11 Together with the carbon atoms to which they are attached, they form C3-C 10 Cyclic hydrocarbon group, the C3-C 10 The cyclic hydrocarbon group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

[0044] In some embodiments of the present invention, Rd and Re are independently selected from H,

[0045] In some embodiments of the present invention, A is selected from... in Selected from

[0046] In some embodiments of the present invention, A is selected from...

[0047] In some embodiments of the present invention, A is selected from...

[0048] In some embodiments of the present invention, A is selected from...

[0049] In some embodiments of the present invention, n is 0.

[0050] In some embodiments of the present invention, n is 1.

[0051] In some embodiments of the present invention, m is 0.

[0052] In some embodiments of the present invention, m is 1.

[0053] In some embodiments of the present invention, B is selected from...

[0054] In some embodiments of the present invention, Z is selected from N.

[0055] In some embodiments of the present invention, C is selected from C=O.

[0056] In some embodiments of the present invention, the above-mentioned Selected from

[0057] In some embodiments of the present invention, R4 is independently selected from halogens, C1-C6 alkyl groups, and C3-C4 alkyl groups. 10 Cycloalkyl, C1-C6 alkoxy, phenyl, vinyl, ethynyl, cyano, heterocyclic group comprising one or two 3- to 6-membered rings and 1-3 heteroatoms selected from N, O, and S, or heteroaryl group comprising one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl, alkoxy, phenyl, vinyl, ethynyl, heterocyclic, or heteroaryl group is optionally substituted by one or more substituents independently selected from: halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, NH2, oxo, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, -NO2, or -C1-C6 alkyl C1-C6 alkyl groups.

[0058] In some embodiments of the present invention, R4 is selected from C3-C 10 Cyclic hydrocarbon group, the C3-C 10 The cyclic hydrocarbon group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN or -NO2, wherein the cyclic hydrocarbon group is selected from spirocyclic hydrocarbon groups, bridged cyclic hydrocarbon groups or monocyclic hydrocarbon groups.

[0059] In some embodiments of the present invention, R4 is selected from vinyl or ethynyl groups, wherein the vinyl or ethynyl groups are optionally substituted by one or more substituents independently selected from the following:

[0060] In some embodiments of the present invention, R4 is selected from tetrahydropyranyl, which is optionally substituted by one or more substituents independently selected from: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN and -NO2.

[0061] In some embodiments of the present invention, L is selected from... R6 and R7 are each independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen, or R6 and R7 together with the carbon atom to which they are attached form a C3-C group. 10 Cyclic hydrocarbon group, the C3-C 10 The cyclic hydrocarbon group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

[0062] In some embodiments of the present invention, the T mentioned above is selected from a heteroaryl group comprising a 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the heteroaryl group is optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, or oxo.

[0063] In some embodiments of the present invention, R1, R2, R3, R 13 R 14 and R 15 Each is independently selected from H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0064] In some embodiments of the present invention, R1, R2 and R3 are independently selected from H, halogens, C1-C6 alkyl groups, or C1-C6 haloalkyl groups.

[0065] In some embodiments of the present invention, R1, R2, R3, R... 13 R 14 and R 15 Independently, together with the carbon atoms to which they are attached, they form C3-C. 10 Cyclic hydrocarbon group or C3-C 10 Heterocyclic groups, the C3-C 10 Cyclic hydrocarbon group or C3-C 10 The heterocyclic group may optionally be substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, OH, or halogen.

[0066] In some embodiments of the present invention, R5 is selected from...

[0067] In some embodiments of the present invention, R4 is selected from...

[0068] In some embodiments of the present invention, the above-mentioned R 12 Selected from H, halogens, C1-C6 alkyl groups, C3-C 10 Cycloalkyl, C1-C6 alkoxy, phenyl, vinyl, ethynyl, or cyano.

[0069] In some embodiments of the present invention, the above-mentioned R 12 Selected from H, F, Cl, methyl, ethyl, or cyclopropyl.

[0070] In some embodiments of the present invention, L is selected from...

[0071] In some embodiments of the present invention, the T mentioned above is selected from oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiazolyl, oxadiazolone, thiazolyl, wherein each is optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen or oxo.

[0072] In some embodiments of the present invention, T is...

[0073] In some embodiments of the present invention, T is C(O)OH.

[0074] In some embodiments of the present invention, the above-mentioned for

[0075] In some embodiments of the present invention, the above-mentioned compounds have formula (II-1), formula (II-2), formula (II-3), or formula (II-4):

[0076] Among them, A, B, L, T, R1, R2, R3, R 13 R 14 R 15 R4, R5 and R 12 As defined in this invention.

[0077] In some embodiments of the present invention, the above-mentioned compounds have formula (I-1), formula (I-2), formula (I-3), formula (I-4), or formula (I-5):

[0078] Among them, A, B, L, T, R1, R4, R5, R 12 and R 13As defined in this invention.

[0079] Some solutions in this invention are derived from arbitrary combinations of the above variables.

[0080] [Revised according to Rule 91, 16.01.2025] This invention also provides the following compounds or pharmaceutically acceptable salts thereof, selected from:

[0081] This invention also provides the following compounds or pharmaceutically acceptable salts thereof, selected from:

[0082] Another aspect of the present invention provides a pharmaceutical composition comprising the above-described compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0083] Another aspect of the present invention provides a method for treating or preventing GLP-1 receptor-mediated diseases or disorders or for modulating GLP-1 receptors, comprising administering a therapeutically effective amount of the above-described compound or a pharmaceutically acceptable salt thereof or the above-described pharmaceutical composition to a subject in need.

[0084] Another aspect of the present invention provides a method for treating non-insulin-dependent diabetes mellitus (type 2 diabetes), hyperglycemia, impaired glucose tolerance, insulin-dependent diabetes mellitus (type 1 diabetes), diabetic complications, obesity, hypertension, hyperlipidemia, arteriosclerosis, coronary heart disease, cerebral infarction, non-alcoholic steatohepatitis, Parkinson's disease, or dementia, the method comprising administering to a subject requiring the treatment a therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition.

[0085] The present invention provides a method for treating non-insulin-dependent diabetes mellitus (type 2 diabetes) or obesity, the method comprising administering to a subject requiring the treatment a therapeutically effective amount of the above-described compound or a pharmaceutically acceptable salt thereof or the above-described pharmaceutical composition.

[0086] Technical effect

[0087] The compounds of this invention have a good agonistic effect on GLP-1 receptors.

[0088] Definitions and Explanations

[0089] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0090] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0091] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound having specific substituents discovered in this invention with a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of acid in a pure solution or a suitable inert solvent.

[0092] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0093] "Pharmaceutical composition" means containing one or more of the compounds described in this application, their isomers or pharmaceutically acceptable salts thereof, and other components such as physiologically / pharmaceuticalally acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0094] The term "therapeutic effective amount" refers to an amount of a compound, when administered, sufficient to stop or slow the progression of one or more symptoms or conditions of a disease to a certain extent. The term "therapeutic effective amount" also refers to an amount of a compound sufficient to detect a biological or pharmaceutical response (e.g., a protein, enzyme, RNA, or DNA) in a biomolecule, cell, tissue, system, animal, or human. This response is desirable to researchers, veterinarians, physicians, or clinicians.

[0095] Unless otherwise stated, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereo isomers, enantiomers, optical isomers, diastereomers and tautomers.

[0096] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups, and all such isomers and mixtures thereof are included within the scope of this invention.

[0097] Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

[0098] Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" arise because the single bonds of double bonds or cyclic carbon atoms cannot rotate freely.

[0099] Unless otherwise stated, the term "diastereomer" refers to a stereoisomer of a molecule having two or more chiral centers and being in a non-mirror relationship with each other.

[0100] Unless otherwise stated, "(+)" indicates right-handed rotation, "(-)" indicates left-handed rotation, and "(±)" indicates racemic rotation.

[0101] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid is indicated by a wavy line. Indicates wedge-shaped solid line key or wedge-shaped dashed key Or use wavy lines Indicates a straight solid line key Or straight dashed key

[0102] Unless otherwise stated, the terms "rich in one isomer," "isomer enrichment," "rich in one enantiomer," or "enantiomer enrichment" mean that the content of one isomer or enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0103] Unless otherwise stated, the terms "isomer excess" or "enantiomer excess" refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomer excess (ee value) is 80%.

[0104] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated, and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0105] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14 C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0106] The terms “optional” or “optionally” refer to events or conditions that may occur but are not required to occur as described below, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0107] The terms "substituted" or "substituted" refer to the substitution of one or more hydrogen atoms on a particular atom by a substituent, which can include deuterium and hydrogen variants, provided the valence state of the particular atom is normal and the resulting compound is stable. When the substituent is oxygen (i.e., =O) or sulfur (i.e., =S), it means that two hydrogen atoms are substituted. Oxygen substitution or sulfur substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents can be arbitrary on a chemically feasible basis.

[0108] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0109] When the number of a linking group is 0, such as -(CRR)0-, it indicates that the linking group is a single bond.

[0110] When the number of a substituent is 0, it means that the substituent does not exist. For example, -A-(R)0 means that the structure is actually -A.

[0111] When a substituent is vacant, it means that the substituent does not exist. For example, if X is vacant in AX, it means that the structure is actually A.

[0112] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0113] When a substituent can be cross-bonded to two or more atoms on a ring, this substituent can bond with any atom on that ring, for example, structural units. This indicates that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene. When the listed substituents do not specify which atom they are attached to the substituted group, such substituents can be bonded to any of their atoms. For example, a pyridyl group as a substituent can be attached to the substituted group through any carbon atom on the pyridine ring.

[0114] When the listed linking groups do not specify their linking direction, the linking direction is arbitrary, for example, The linker group L is -MW-. In this case, -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form a ring. Alternatively, rings A and B can be connected in the opposite direction to the left-to-right reading order to form a ring. The combination of linking groups, substituents, and / or their variants is permitted only if such a combination produces a stable compound.

[0115] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of that group can be connected to other groups by chemical bonds. When the chemical bond connection is non-directional and the connectable site contains H atoms, the number of H atoms at that site will decrease accordingly with the number of chemical bonds connected, resulting in a group with a corresponding valence. The chemical bonds connecting the site to other groups can be straight solid line bonds. Straight dashed key or wavy line For example, a straight solid line bond in -OCH3 indicates that the oxygen atom in that group is connected to other groups; The straight dashed bond in the diagram indicates that the group is connected to other groups through both ends of the nitrogen atom in the group; The wavy lines in the diagram indicate that the phenyl group is connected to other groups through the carbon atoms at positions 1 and 2.

[0116] Unless otherwise specified, the number of atoms in a ring is usually defined as the elemental number of the ring. For example, a “5-7 elemental ring” refers to a “ring” with 5-7 atoms arranged around it.

[0117] Unless otherwise specified, C n-n+m Or C n -C n+m This includes any specific case with n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 C 11 and C 12 It also includes any range from n to n+m, such as C 1-12 Including C 1-3 C 1-6 C 1-9 C 3-6 C 3-9 C 3-12 C 6-9 C 6-12 and C 9-12 Similarly, n-membered to n+m-membered rings represent the number of atoms in the ring from n to n+m. For example, 3-12-membered rings include 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, and also any range from n to n+m. For example, 3-12-membered rings include 3-6-membered, 3-9-membered, 5-6-membered, 5-7-membered, 6-7-membered, 6-8-membered, and 6-10-membered rings, etc.

[0118] Unless otherwise specified, the term "C1-C6 alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C1-C6 alkyl group includes C...1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6, C5, C4, and C3 alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). 1-8 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, heptyl, octyl, etc.

[0119] Unless otherwise specified, the term "C" 1-4 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C 1-4 Alkyl groups include C 1-2 C 1-3 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-4 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), etc.

[0120] Unless otherwise specified, the term "C" 1-3 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0121] Unless otherwise specified, "C3-C 10 "Cyclic hydrocarbon group" refers to a saturated or unsaturated cyclic hydrocarbon group consisting of 3 to 10 carbon atoms, including monocyclic, bicyclic, and tricyclic systems, wherein bicyclic and tricyclic systems include spirocyclic, fused, and bridged rings. The C3-C 10 Cyclic hydrocarbon groups include C 3-8 C 3-6 C 3-5 C 4-10 C 4-8 C 4-6 C 4-5 C 5-8 Or C5-6 etc.; it can be monovalent, divalent, or polyvalent. C 3-10 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornelalkyl, [2.2.2]bicyclooctane, [4.4.0]bicyclodecane, spiro[2.4]cyclohexane, cyclopentenyl, cyclohexenyl, etc.

[0122] Unless otherwise specified, "C3-C6 cyclic hydrocarbon group" refers to a saturated or unsaturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, including monocyclic, bicyclic, and tricyclic systems, wherein bicyclic and tricyclic systems include spirocyclic, fused, and bridged rings. The C3-C6 cyclic hydrocarbon group includes C 3-6 C 3-5 C 4-6 C 4-5 or C 5-6 etc.; it can be monovalent, divalent, or polyvalent. C 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl.

[0123] Unless otherwise specified, the term "3-10 membered heterocyclic alkyl" on its own or in combination with other terms refers to a saturated cyclic group consisting of 3 to 10 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, N, P, and Se, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen, sulfur, and phosphorus heteroatoms may optionally be oxidized (i.e., NO, S(O)). p and P(O) p (where p is 1 or 2). It includes monocyclic, bicyclic, and tricyclic systems, with bicyclic and tricyclic systems including spirocyclic, fused, and bridged rings. Furthermore, regarding the "3-10 membered heterocyclic alkyl," the heteroatom can occupy the connection position between the heterocyclic alkyl group and the rest of the molecule. The 3-10 membered heterocyclic alkyl groups include 3-9, 3-8, 3-6, 5-9, 5, 6, 7, 8, and 9 membered heterocyclic alkyl groups, etc. Examples of 3-10 membered heterocyclic alkyl groups include, but are not limited to, azirrobutyl, oxacyclobutyl, thiocyclobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiopheneyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxane, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, homopiperidinyl, homopiperidinyl, or dioxaneheptyl, etc.

[0124] Unless otherwise specified, the term "5-membered heterocyclic alkyl" on its own or in combination with other terms refers to a saturated cyclic group consisting of 5 ring atoms, wherein 1, 2, or 3 of the ring atoms are heteroatoms independently selected from O, S, N, P, and Se, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen, sulfur, and phosphorus heteroatoms may optionally be oxidized (i.e., NO, S(O)). p and P(O) p (where p is 1 or 2). Examples of 5-membered heterocyclic alkyl groups include, but are not limited to, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, etc.

[0125] Unless otherwise specified, the term "aryl" refers to a fused or non-fused group or ring system having at least one aromatic ring, either monocyclic or polycyclic (e.g., bicyclic, tricyclic or more rings, wherein at least one is aromatic and the additional rings may be cyclic hydrocarbon groups or aromatic rings). Aryl groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, indanyl, azulel, benzocyclopropyl, benzocyclobutyl, benzocyclopentyl, benzocyclohexyl, benzocyclohexenyl, benzocyclopentenyl, and similar groups.

[0126] Unless otherwise specified, the term "heteroaryl" refers to a fused or non-fused group or ring system having at least one aromatic ring, having five to twelve ring atoms (one of which is selected from S, O, and N; zero, one, or two of which are other heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon) of either monocyclic or polycyclic (e.g., bicyclic, tricyclic, or more rings). Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrroleyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophene, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxolinyl, oxadiazolone, and similar groups.

[0127] Unless otherwise specified, the term “heterocyclic group” or “heterocyclic hydrocarbon group” refers to a saturated or unsaturated non-aromatic 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic ring system, a 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring system (fused ring, bridged ring, or spirocyclic ring), or an 11-, 12-, 13-, or 14-membered tricyclic ring system (fused ring, bridged ring, or spirocyclic ring), wherein (i) each ring contains one to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, (ii) each 5-membered ring has 0 to 1 double bonds, and each 6-membered ring has 0 to 2 double bonds, (iii) the nitrogen heteroatom and sulfur heteroatom may optionally be oxidized, and (iv) the nitrogen heteroatom may optionally be quaternized. Representative heterocyclic hydrocarbon groups include, but are not limited to, [1,3]dioxacyclopentyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, imidazolinyl, imidazolinyl, imidazoketyl, piperidinyl, piperazinyl, 2-pyridinone, oxazolyl, isoxazolyl, morpholinyl, tetrahydropyranyl, thiazolinyl, isothiazolyl, tetrahydrofuranyl, dioxacyclohexyl, oxetanyl, azetidinyl, thietanyl, oxiranyl, aziridinyl, thiiranyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2,6-diazabicyclo[2.2.1]heptyl, and 2,6-diazabicyclo[2.2.1]heptyl. Zazzi[3.3]heptyl, 1,4-dioxa-8-azaspiro[4.5]decyl, 2-azaspiro[3.3]hept-5-amine, 1-azaspiro[3.3]hept-5-amine, 1-oxa-6-azaspiro[3.3]hept-3-amine, 2-azaspiro[3.3]hept-6-amine, 1-azaspiro[3.3]hept-6-amine, 6-azaspiro[3.4]oct-2-amine, 5-azaspiro[3.4]octyl -2-amine, 6-azaspiro[3.4]oct-1-amine, 5-azaspiro[3.4]oct-1-amine, 5-oxa-2-azaspiro[3.4]oct-7-amine, 7-amino-5-thia-2-azaspiro[3.4]octane 5,5-dioxide, 5-oxa-2-azaspiro[3.4]oct-8-amine, 8-amino-5-thia-2-azaspiro[3.4]octane 5,5-dioxide and similar groups.

[0128] According to this application, any one of the aryl, substituted aryl, heteroaryl, and substituted heteroaryl groups described herein can be any aromatic group. The aromatic group can be substituted or unsubstituted.

[0129] According to this application, the aryl, heteroaryl, heterocyclic, and heterocyclic groups described herein can be spirocyclic, bridged rings, fused rings, or monocyclic. The ring formed by two rings can be a spirocyclic, bridged ring, fused ring, or monocyclic. The two 5-membered or 6-membered rings can be two 5-membered rings, two 6-membered rings, or a ring composed of one 5-membered ring and one 6-membered ring. This includes, but is not limited to, spiro[2.2]pentane, spiro[5.4]decane, bicyclo[4.3.0]nonane, bicyclo[2.2.1]heptane, bicyclo[3.2.1]octane, and similar groups.

[0130] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0131] The structures of the compounds of this invention can be confirmed by conventional methods well known to those skilled in the art. If this invention relates to the absolute configuration of a compound, that absolute configuration can be confirmed by conventional techniques in the art. For example, single-crystal X-ray diffraction (SXRD) is used, where the cultured single crystal is used to collect diffraction intensity data using a Bruker D8 venture diffractometer with CuKα radiation as the light source. The scanning method is as follows: After scanning and collecting relevant data, the crystal structure can be further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0132] The solvent used in this invention is commercially available.

[0133] This invention uses the following abbreviations:

[0134] MeCN or ACN represents acetonitrile; Boc represents tert-butyloxycarbonyl; Bn represents benzyl; DCM represents dichloromethane; DMSO represents dimethyl sulfoxide; ℃ represents degrees Celsius; hr represents hours; LiBH4 represents sodium borohydride; THF represents tetrahydrofuran; Ts represents p-toluenesulfonyl; Ac represents acetyl; Me represents methyl; Et represents ethyl; N2 represents nitrogen; PE represents petroleum ether; EA represents ethyl acetate; DIPEA represents N,N-diisopropylethylamine; K2CO3 represents potassium carbonate; CuI represents cuprous iodide; TBAF represents tetrabutylammonium fluoride; CuBr represents bromine. Cuprous chloride; DMF represents N,N-dimethylformamide; HCl represents hydrochloric acid; MeOH represents methanol; TEA or Et3N represents triethylamine; DMAP represents 4-dimethylaminopyridine; EDCI represents 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; MeI represents iodomethane; Pd2(dba)3 represents tris[dibenzylideneacetone]palladium; Pd(dppf)Cl2 represents [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride; Xantphos represents 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene; HATU represents 2-( 7-Azobenzotriazole)-N,N,N',N'-Tetramethylurea hexafluorophosphate; Pd(PPh3)2Cl2 represents bis(triphenylphosphine)palladium(II) dichloride; TBAF represents tetrabutylammonium fluoride; NaH represents sodium hydride; LiOH represents lithium hydroxide; DMPU represents N,N-dimethylpropenylurea; KHMDS represents bis(trimethylsilyl)aminopotassium; DBU represents 1,8-diazahexacyclic[5,4,0]undecene-7; CDI represents N,N'-carbonyldiimidazole; t-BuOK represents potassium tert-butoxide; DCE represents dichloroethane; Triphos gene represents triphosgene; NaBH3CN represents sodium cyanoborohydride; HCl represents hydrochloric acid; Toluene or Tol represents toluene; Dioxane represents dioxane; AcOH represents acetic acid; TFA represents trifluoroacetic acid; NaBH4 represents sodium borohydride; Cu(OTf)2 represents copper trifluoromethanesulfonate; n-BuLi represents n-butyllithium; MsCl represents methanesulfonyl chloride; NaI represents sodium iodide; DMA represents N,N-dimethylacetamide; py represents pyridine; DMEDA represents N,N'-dimethylethylenediamine; LAH represents lithium aluminum hydride; rt represents room temperature.

[0135] Compounds are named according to conventional naming principles in the field or using Software naming conventions are used; commercially available compounds use supplier catalog names. Detailed Implementation

[0136] The present invention will be described in detail below with reference to embodiments, but this does not imply any adverse limitation on the invention. The present invention has been described in detail, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope thereof.

[0137] Example 1

[0138] Synthesis steps:

[0139] Step 1: Synthesis of compounds 1-3

[0140] Compound 1-1 (5.0 g, 24.62 mmol) was added to a clean three-necked flask and dissolved in anhydrous THF (40 mL). The flask was then evacuated under N2 protection and slowly added n-butyllithium (1.6 mol / L, 13.85 mL, 22.16 mmol) dropwise at -78 °C, stirring for 1-2 h after each addition. Then, compound 1-2 (5.5 g, 23.89 mmol) dissolved in anhydrous THF (40 mL) was added dropwise, and the mixture was slowly brought to room temperature and stirred for 2-3 h. Post-treatment: The solution was quenched at 0 °C with 20% ammonium chloride solution (40 mL), followed by extraction with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA(V / V) = 10 / 1) to obtain a colorless oily compound 1-3, 3.73 g, yield: 42.7%. MS:(ESI,pos.ion)m / z:377.1841[M+Na] + .

[0141] Step 2: Synthesis of compounds 1-4

[0142] Compounds 1-3 (3.73 g, 10.52 mmol) were added to a clean single-necked flask and dissolved in isopropanol (40 mL). Then, dioxane hydrochloride solution (4 mol / L, 15.78 mL, 63.14 mmol) was added. The mixture was stirred at room temperature for 3 h under N2 protection. Post-treatment: The solution was concentrated to dryness, yielding 2.01 g of brown solid compound 1-4. MS: (ESI, pos.ion) m / z: 155.0975 [M+H] + .

[0143] Step 3: Synthesis of compounds 1-6

[0144] Compounds 1-4 (2.01 g, 10.54 mmol) and 1-5 (1.76 g, 7.38 mmol) were added to a clean single-necked flask and dissolved in ethanol (30 mL). Then, DIPEA (1.57 g, 12.12 mmol) was added, and the mixture was refluxed at 80 °C for 4 h. Post-treatment: The mixture was cooled to room temperature and purified by column chromatography (PE / EA (V / V) = 3 / 1) to give a yellow solid, compound 1-6, 2.0 g, in 72.3% yield. MS: (ESI, pos.ion) m / z: 375.2280 [M+H] + .

[0145] Step 4: Synthesis of compounds 1-7

[0146] In a 25 mL double-necked flask, compounds 1-6 (100 mg, 267.05 μmol), CuSO4·5H2O (26.67 mg, 106.82 μmol), and K2CO3 (332.17 mg, 2.4 mmol) were added sequentially to 3 mL of methanol. The mixture was purged with nitrogen five times. Under nitrogen protection, 1H-imidazolium-1-sulfonyl azide hydrochloride (84 mg, 400.58 μmol) dissolved in 1 mL of methanol was slowly added. The reaction was allowed to proceed overnight at room temperature. Post-treatment: The organic phase was filtered, concentrated under reduced pressure, and purified by column chromatography (PE / EA(V / V) = 8 / 1). The product was collected to give a brown oily compound 1-7, 17 mg, yield 16%. MS: (ESI, pos.ion) m / z: 401.2182 [M+H] + .

[0147] Step 5: Synthesis of compounds 1-9

[0148] Compounds 1-8 (500 mg, 2.18 mmol), bis(triphenylphosphine) palladium dichloride (76.61 mg, 109.15 μmol), CuI (41.57 mg, 218.29 μmol), and triphenylphosphine (57.7 mg, 0.22 mmol) were added sequentially to triethylamine (2.5 mL) and toluene (2.5 mL) in a 25 mL double-necked flask. The mixture was purged with nitrogen five times. Under nitrogen protection, trimethylethynylsilane (1.07 g, 10.91 mmol) was slowly added dropwise. After the addition was complete, the mixture was heated to 80 °C and reacted overnight. Post-treatment: The mixture was diluted with EA (20 mL), filtered through diatomaceous earth, and the organic phase was collected. The organic phase was washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, and purified by column chromatography (PE / EA (V / V) = 10 / 1). The product was collected and concentrated under reduced pressure to give a yellow oily compound 1-9, 400 mg, yield 74.5%. MS:(ESI,pos.ion)m / z:247.1113[M+H] + .

[0149] Step 6: Synthesis of compounds 1-10

[0150] In a 25 mL double-necked flask, compound 1-9 (400 mg, 1.62 mmol) was added to THF (5 mL), followed by slow dropwise addition of a 1 mol / L TBAF THF solution (3.5 mL). The reaction was allowed to proceed at room temperature for 4 h after the addition was complete. Post-treatment: The reaction solution was concentrated under reduced pressure to remove most of the solvent, diluted with EA (10 mL), and the organic phase was washed sequentially with water (5 mL × 3), washed once with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, and purified by column chromatography (PE / EA (V / V) = 9 / 1). The product was collected to give a white solid compound 1-10, 215 mg, yield 76.2%. MS: (ESI, pos.ion) m / z: 175.0672 [M+H] + .

[0151] Step 7: Synthesis of compounds 1-11

[0152] Compounds 1-7 (17 mg, 42.45 μmol) and 1-10 (7.4 mg, 42.45 μmol), along with CuBr (2 mg, 14.0 μmol), were added sequentially to DMF (1 mL) and H₂O (1 mL). The mixture was reacted at room temperature for 2 h, then transferred to a 40 °C oil bath for another 2 h. Post-treatment: The mixture was diluted with EA (5 mL), washed with saturated ammonium chloride solution (1 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (PE / EA (V / V) = 5 / 1) to obtain compound 1-11, 20 mg, in 82% yield. MS: (ESI, pos.ion) m / z: 575.2714 [M+H] + .

[0153] Step 8: Synthesis of compounds 1-12

[0154] Compound 1-11 (20 mg, 34.8 μmol) was added to DCM (2 mL), followed by dropwise addition of HCl / dioxane solution (1 mL, 4.0 M). The mixture was reacted overnight at room temperature. Post-treatment: The solution was concentrated under reduced pressure to constant weight to obtain compound 1-12, 18 mg, which was directly added to the next step.

[0155] Step 9: Synthesis of Compound 1

[0156] Compounds 1-13 were synthesized by the method reported in Example 67 of Patent WO2018056453.

[0157] Compounds 1-13 (14.5 mg, 35.23 μmol), DMF (2 mL), and HATU (20 mg, 52.85 μmol) were added sequentially to a 25 mL single-necked flask. After stirring for 0.5 h, compound 1-12 (18 mg, 35.23 μmol) was added, and DIPEA (22.76 mg, 176.15 μmol) was added dropwise at 0 °C. After the addition was complete, the mixture was transferred to 25 °C and reacted for 1 h. Post-treatment: The reaction solution was poured into water (10 mL) and extracted with EA (10 mL × 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (10 mL × 4), dried over anhydrous sodium sulfate, and purified by column chromatography (DCM / MeOH (V / V) = 15 / 1). The product was collected to give compound 1, 13.45 mg, yield 44.0%. MS: (ESI, pos.ion) m / z: 868.3870 [M+H] + .

[0158] Example 2

[0159] Synthesis steps:

[0160] Note: Intermediate compounds 1-6 are synthesized according to the method described in Example 1.

[0161] Step 1: Synthesis of Compound 2-1

[0162] In a 25 mL single-necked flask, 1-6 (0.2 g, 0.534 mmol), CuBr (0.263 g, 1.84 mmol), and amyl nitrite (0.22 g, 1.89 mmol) were added and dissolved in acetonitrile (2 mL). The mixture was stirred at room temperature for 4 h. Post-treatment: Ethyl acetate (20 mL) and water (20 mL) were added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA(V / V) = 3 / 1) to give a colorless oily compound 2-1, 0.181 g, yield 77.5%. MS-ESI: (ESI, pos.ion) m / z: 438.1259 [M+H] + .

[0163] Step 2: Synthesis of Compound 2-2

[0164] Compound 2-1 (0.18 g, 0.41 mmol), 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazole (0.233 g, 0.82 mmol), Pd(dppf)Cl2 (29 mg, 0.041 mmol), and sodium carbonate (130 mg, 1.23 mmol) were added to a 25 mL single-necked flask and dissolved in Dioxane (4 mL) and H2O (1 mL). The mixture was purged with nitrogen three times and stirred at 95 °C for 6 h. Post-treatment: The solvent was concentrated, and the mixture was purified by column chromatography (PE / EA(V / V) = 3 / 1) to give a yellow solid compound 2-2, 0.105 g, yield 49.5%. MS-ESI: (ESI, pos.ion) m / z: 516.2882 [M+H] + .

[0165] Step 3: Synthesis of compounds 2-3

[0166] Compound 2-2 (0.105 g, 0.2 mmol) dissolved in 9 mL of ethanol was added to a 25 mL single-necked flask. Palladium on carbon (0.1 g) was added, and the mixture was purged with hydrogen. The reaction was carried out at 80 °C for 12 h. Post-treatment: The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give a yellow solid compound 2-3, 0.086 g, in 100% yield. MS-ESI: (ESI, pos.ion) m / z: 426.2406 [M+H] + .

[0167] Step 4: Synthesis of compounds 2-4

[0168] Compound 2-3 (130 mg, 0.3 mmol), 5-bromo-4-fluoro-1-methyl-1H-indole (91.2 mg, 0.4 mmol), CuI (29 mg, 0.15 mmol), (1R,2R)-N,N-dimethyl-1,2-cyclohexanediamine (43 mg, 0.3 mmol), and potassium carbonate (127 mg, 0.9 mmol) were added to a 25 mL single-necked flask and dissolved in toluene (5 mL). The mixture was purged with nitrogen and reacted at 110 °C for 12 h. Post-treatment: The mixture was filtered through diatomaceous earth, concentrated under reduced pressure, and purified by column chromatography (PE / EA(V / V) = 3 / 1) to give a yellow solid compound 2-4, 0.12 g, yield 57%. MS-ESI: (ESI, pos.ion) m / z: 574.2816 [M+H] + .

[0169] Step 5: Synthesis of compounds 2-5

[0170] Compound 2-4 (0.12 g, 0.21 mmol) was added to a 25 mL single-necked flask and dissolved in dioxane hydrochloride (4.0 M, 4 mL). The mixture was stirred at room temperature for 2 h. Post-treatment: The solution was concentrated under reduced pressure to give a yellow solid, compound 2-5, 0.12 g, in 100% yield.

[0171] Step 6: Synthesis of Compound 2

[0172] Compounds 1-13 were synthesized by the method reported in Example 67 of Patent WO2018056453.

[0173] Compounds 1-13 (116 mg, 0.28 mmol), DMF (5 mL), and HATU (161 mg, 0.42 mmol) were added sequentially to a 25 mL single-necked flask. After stirring for 0.5 h, compound 2-5 (120 mg, 0.23 mmol) was added, and DIPEA (145 mg, 1.12 mmol) was added dropwise at 0 °C. After the addition was complete, the mixture was transferred to 25 °C and reacted for 2 h. Post-treatment: The reaction solution was poured into water (20 mL) and extracted with EA (20 mL × 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (20 mL × 4), dried over anhydrous sodium sulfate, and purified by column chromatography (DCM / MeOH (V / V) = 15 / 1). The product was collected to give compound 2,102 mg, yield 50.0%. MS: (ESI, pos.ion) m / z: 867.9723 [M+H] + .

[0174] Example 3

[0175] Synthesis steps:

[0176] Step 1: Synthesis of compound 3-3

[0177] Compound 3-1 (4.0 g, 23.25 mmol) and DMAP (3.69 g, 30.23 mmol) were added to a 100 mL single-necked flask and dissolved in dichloromethane (30 mL). Then, compound 3-2 (4.68 g, 23.25 mmol) and EDCI (5.79 g, 30.23 mmol) were added, and the mixture was stirred at room temperature for 2 h. Post-treatment: The system was concentrated under reduced pressure and purified by column chromatography (PE / EA(V / V) = 3 / 1) to give a white solid, compound 3-3, 6.23 g, yield 75.42%. MS: (ESI, pos.ion) m / z: 299.0038 [M-55] + .

[0178] Step 2: Synthesis of compounds 3-4

[0179] Compound 3-3 (1.00 g, 2.82 mmol) was added to a two-necked flask and dissolved in anhydrous tetrahydrofuran (10 mL). NaH (270.22 mg, 11.26 mmol) was slowly added at 0 °C. After stirring for 2-3 min, the mixture was purged with nitrogen three times. MeI (2.40 g, 16.89 mmol) was then slowly added dropwise at 0 °C. After the addition was complete, the mixture was transferred to room temperature and reacted for 3 h. Post-treatment: The system was concentrated under reduced pressure, and then quenched by slow addition of sodium thiosulfate. The system was extracted twice with ethyl acetate (30 mL) and H₂O (30 mL). The organic phase was washed twice with brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE / EA(V / V) = 3 / 1) to give a white solid compound 3-4, 930.00 mg, yield 89.47%. MS:(ESI,pos.ion)m / z:315.0168[M-55] + .

[0180] Step 3: Synthesis of compounds 3-5

[0181] Compound 3-4 (930.00 mg, 2.52 mmol), (1,3-bis(2,3-diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-yl)dichloro(3-chloropyridin-2-yl)palladium (II) (170.87 mg, 251.86 μmol), and sodium tert-butoxide (363.07 mg, 3.78 mmol) were added to a 25 mL two-necked flask, dissolved in toluene (5 mL). The mixture was purged with nitrogen three times and reacted at 110 °C for 3 h. Post-treatment: The mixture was filtered through diatomaceous earth, concentrated under reduced pressure, and purified by column chromatography (PE / EA(V / V) = 3 / 1) to give a white solid, compound 3-5, 599.00 mg, yield 82.48%. MS: (ESI, pos.ion) m / z: 235.1077 [M-55] + .

[0182] Step 4: Synthesis of compounds 3-6

[0183] Compound 3-5 (599.00 mg, 2.08 mmol) was added to a 25 mL single-necked flask, followed by 6 mL of 4.0 M dioxane hydrochloride solution. The reaction was carried out at room temperature for 2 h. Post-treatment: Concentration under reduced pressure yielded a yellow solid, compound 3-6, 391.02 mg, in 100% yield. MS: (ESI, pos.ion) m / z: 189.1028 [M+H] + .

[0184] Step 5: Synthesis of compounds 3-7

[0185] Compounds 1-6 (3.40 g, 9.08 mmol) and CuI (5.95 g, 31.23 mmol) were added to a 25 mL single-necked flask and dissolved in acetonitrile (34 mL). Amyl nitrite (3.75 g, 32.05 mmol) was added dropwise at 0 °C. After addition, the mixture was brought to room temperature and stirred overnight. Post-treatment: The solution was quenched with saturated ammonium chloride solution, extracted with EA, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (PE / EA (V / V) = 2 / 1) to give a yellow oily compound 3-7, 2.19 g, yield 49.7%. MS: (ESI, pos.ion) m / z: 486.12 [M+H] + .

[0186] Step 6: Synthesis of compounds 3-8

[0187] Compounds 3-6 (50.00 mg, 265.63 μmol), 3-7 (154.71 mg, 318.76 μmol), Pd2(dba)3 (24.32 mg, 26.56 μmol), Pd(dppf)Cl2 (19.44 mg, 26.56 μmol), Xantphos (61.48 mg, 106.25 μmol), and cesium carbonate (173.10 mg, 531.26 μmol) were added to a 25 mL two-necked flask and dissolved in DMF (2 mL). After purging with nitrogen three times, the mixture was stirred at 80 °C for 8 h. Post-treatment: The system was extracted twice with ethyl acetate (10 mL) and H₂O (10 mL), the organic phase was washed twice with brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by thin-layer chromatography (PE / EA (V / V) = 1:1) to give a yellow solid compound 3-8, 50.00 mg, yield 34.50%. MS: (ESI, pos.ion) m / z: 546.3000 [M+H] + .

[0188] Step 7: Synthesis of compounds 3-9

[0189] Compound 3-8 (32.00 mg, 58.64 μmol) was added to a 25 mL single-necked flask, followed by 2 mL of 4.0 M dioxane hydrochloride solution. The reaction was carried out at room temperature for 2 h. Post-treatment: Concentration under reduced pressure yielded a yellow solid, compound 3-9, 28.27 mg, in 100% yield. MS: (ESI, pos.ion) m / z: 446.2300 [M+H] + .

[0190] Step 8: Synthesis of Compound 3

[0191] Compound 1-13 (28.68 mg, 69.71 μmol) was added to a 25 mL two-necked flask and dissolved in DMF (2 mL). Then, HATU (33.13 mg, 87.14 μmol) and DIPEA (37.542 mg, 290.46 μmol) were added at 0 °C. After activation for half an hour, compound 3-9 (28.00 mg, 62.92 μmol) was added, and the mixture was transferred to room temperature and stirred for 2 h. Post-treatment: The system was extracted twice with ethyl acetate (10 mL) and H₂O (10 mL), and the organic phase was washed twice with brine (20 mL). After drying with anhydrous sodium sulfate, the mixture was concentrated under reduced pressure and separated by thin-layer chromatography (PE / EA (V / V) = 1 / 1) to give a yellow solid compound 3, 13.00 mg, yield 24.66%. MS: (ESI, negative ion) m / z: 837.8000 [MH] - .

[0192] Example 4

[0193] Synthesis steps:

[0194] Step 1: Synthesis of compound 4-2

[0195] Compound 3-7 (500 mg, 1.03 mmol), Pd(PPh3)2Cl2 (108.47 mg, 154.53 μmol), CuI (29.43 mg, 154.53 μmol), triphenylphosphine (27.02 mg, 103.02 μmol), triethylamine (3 mL), and toluene (3 mL) were added to a 25 mL two-necked flask. The mixture was evacuated to nitrogen three times, and then trimethylsilylacetylene (505.93 mg, 5.15 mmol) was added dropwise. After the addition was complete, the temperature was raised to 80 °C and the reaction was allowed to proceed for 17 h. Post-treatment: EA (10 mL) and water (3 mL) were added, the layers separated, and the organic phase was washed with water (3 mL × 2). The mixture was purified by column chromatography (PE / EA (V / V) = 9 / 1) to give a yellow oily compound 4-2, 186.00 mg, yield 39.6%. MS:(ESI,pos.ion)m / z:456.2618[M+H] + .

[0196] Step 2: Synthesis of Compound 4-3

[0197] Compound 4-2 (186 mg, 408.21 μmol) was added sequentially to a 25 mL single-necked flask, followed by tetrahydrofuran (5 mL), and then TBAF (213.47 mg, 816.42 μmol). The reaction mixture was reacted for 12 h. Post-treatment: The reaction solution was concentrated and purified by column chromatography (PE / EA(V / V) = 4 / 1) to give a yellow, fluffy solid compound 4-3, 107.00 mg, yield 68.3%. MS: (ESI, pos.ion) m / z: 384.2225 [M+H] + .

[0198] Step 3: Synthesis of compound 4-4

[0199] Compound 4-1 (100 mg, 605.43 μmol) and acetonitrile (5 mL) were added to a 25 mL two-necked flask. The mixture was purged with nitrogen five times, cooled to 0 °C, and then tert-butyl nitrite (187.30 mg, 1.82 mmol) and trimethylethynylsilane (167.41 mg, 1.70 mmol) were added. After the addition was complete, the mixture was allowed to stand at room temperature for 30 min. The reaction solution was then concentrated and purified by column chromatography (PE / EA(V / V) = 7 / 1) to give a yellow solid, compound 4-4, 78.00 mg, yield 67.5%. MS: (ESI, pos.ion) m / z: 192.0683 [M+H] + .

[0200] Step 4: Synthesis of compounds 4-5

[0201] Compound 4-3 (105 mg, 273.82 μmol), compound 4-4 (52.35 mg, 273.82 μmol), and DMF (3 mL) were added to a 25 mL single-necked flask. After stirring and clarifying, cuprous bromide (3.93 mg, 27.38 μmol) was added, followed by dropwise addition of water (0.5 mL). The reaction was allowed to proceed for 20 h. The mixture was washed with 15 mL of saturated ammonium chloride solution (5 mL × 3), dried over anhydrous sodium sulfate, and purified by column chromatography (PE / EA (V / V) = 7 / 3) to give a yellow oily compound 4-5, 42 mg, in 26.6% yield. MS: (ESI, pos.ion) m / z: 575.2739 [M+H] + .

[0202] Step 5: Synthesis of compounds 4-6

[0203] Compound 4-5 (42 mg, 73.09 μmol) was added to a 25 mL single-necked flask, and dioxane hydrochloride solution (4.0 M, 3 mL) was slowly added dropwise. The reaction was allowed to proceed for 2 h. Post-treatment: The mixture was directly concentrated to give a white solid, compound 4-6, 37.35 mg.

[0204] Step 6: Synthesis of Compound 4

[0205] Compounds 1-13 were synthesized by the method reported in Example 67 of Patent WO2018056453.

[0206] Compound 1-13 (36.09 mg, 87.71 μmol), DMF (2 mL), and HATU (41.69 mg, 109.64 μmol) were added to a 25 mL single-necked flask and stirred at room temperature until dissolved. Then, DIPEA (47.24 mg, 365.5 μmol) was added dropwise at 0 °C. After stirring at room temperature for 0.5 h, compound 4-6 (37.35 mg, 73.10 μmol) dissolved in DMF (1 mL) was added dropwise at 0 °C. After the addition was complete, the reaction was allowed to proceed at room temperature for 15 h. Post-treatment: The mixture was extracted with water (30 mL) and ethyl acetate (20 mL). The organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (DCM / MeOH (V / V) = 40 / 1) to obtain the title compound 4, an off-white solid, 28.00 mg, in 44.1% yield. MS:(ESI,pos.ion)m / z:868.3848[M+H] + .

[0207] Example 5

[0208] Synthesis steps:

[0209] Step 1: Synthesis of Compound 5-1

[0210] (4-fluorophenyl)hydrazine hydrochloride (3 g, 18.45 mmol) and (2S)-3-cyano-2-methyl-4-oxopiperidin-1-carboxylic acid tert-butyl ester (3.08 g, 12.92 mmol) were added to a 100 mL single-necked flask, dissolved in 60 mL of ethanol, and refluxed at 80 °C with stirring for 2 h. Post-treatment: purification by silica gel column chromatography (PE / EA(V / V) = 2 / 1) yielded a pale yellow solid compound 5-1, 1.7 g, yield 26.6%. MS: (ESI, pos.ion) m / z: 347.209 [M+H] + .

[0211] Step 2: Synthesis of Compound 5-2

[0212] Compound 5-1 (1.7 g, 4.91 mmol) and CuI (3.22 g, 16.88 mmol) were weighed into a 50 mL single-necked flask and dissolved in acetonitrile (17 mL). Amyl nitrite (2.03 g, 17.32 mmol) was added dropwise at 0 °C. After addition, the mixture was brought to room temperature and stirred overnight. Post-treatment: The solution was quenched with saturated ammonium chloride solution, extracted with EA, dried over anhydrous sodium sulfate on the organic phase, filtered, and purified by column chromatography (PE / EA(V / V) = 2 / 1) to give 1.58 g of a yellow oily compound 5-2, yield 70.41%.

[0213] Step 3: Synthesis of compound 5-3

[0214] 5-Bromo-4-fluoro-1-methyl-1H-indazole (1 g, 4.37 mmol) was added to a 100 mL three-necked flask and dissolved in anhydrous THF (10 mL). Under nitrogen protection at -78 °C, n-butyllithium (2.73 mL, 4.37 mmol, 1.6 mol / L THF solution) was added dropwise. After the addition was complete, the mixture was stirred at this temperature for 0.5 h, followed by the addition of tert-butyl 3-oxoazacyclobutane-1-carboxylate (373.7 mg, 2.18 mmol) dissolved in anhydrous THF (5 mL). The reaction mixture was then allowed to stand at room temperature for 6 h. Post-treatment: The reaction was quenched by adding saturated ammonium chloride solution at 0 °C, extracted with EA (30 mL × 3), separated, dried over anhydrous sodium sulfate, and filtered. Column chromatography purification (PE / EA (V / V) = 1 / 1) yielded a yellow solid compound 5-3, 1.34 g, yield 95.51%.

[0215] Step 4: Synthesis of Compound 5-4

[0216] Compound 5-3 (1.34 g, 4.17 mmol) was added to a 25 mL three-necked flask and dissolved in anhydrous THF (50 mL). NaH (400.27 mg, 16.68 mmol) was added at 0 °C. After stirring for 5 min, MeI (3.55 g, 25.02 mmol) was added dropwise under nitrogen protection. The reaction mixture was then allowed to stand at room temperature for 2 h. Post-treatment: The reaction was quenched dropwise with water at 0 °C, extracted with EA, and the organic phase was dried over anhydrous sodium sulfate and filtered. The solution was concentrated and dried to obtain a pale yellow oily compound 5-4, 1.4 g, in 100% yield.

[0217] Step 5: Synthesis of compound 5-5

[0218] Compound 5-4 (1.4 g, 4.17 mmol) and dioxane hydrochloride solution (14 mL, 4 mol / L) were added to a 50 mL single-necked flask, and the mixture was stirred at room temperature for 2 h. Post-treatment: The mixture was concentrated and dried to give 1.13 g of white solid compound 5-5, yield 100%.

[0219] Step 6: Synthesis of compounds 5-6

[0220] Compound 5-2 (100.00 mg, 218.68 μmol), compound 5-5 (59.26 mg, 218.68 μmol), cesium carbonate (142.50 mg, 437.36 μmol), Pd₂(dba)₃ (20.03 mg, 21.87 μmol), Pd(dppf)Cl₂ (16.00 mg, 21.87 μmol), and XantPhos (50.62 mg, 87.48 μmol) were added to a 25 mL single-necked flask and dissolved in DMF (3 mL). The mixture was stirred at 80 °C for 12 h. Post-treatment: The mixture was separated by adding water and ethyl acetate. The organic phase was washed three times with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (PE / EA(V / V) = 2 / 1) to give a yellow solid compound 5-6, 25 mg, yield 20.25%. MS: (ESI, pos.ion)m / z: 565.45[M+H] + .

[0221] Step 7: Synthesis of compounds 5-7

[0222] Compound 5-6 (25.00 mg, 44.31 μmol) was weighed into a 25 mL single-necked flask and reacted with 2 mL of dioxane hydrochloride solution (4 mol / L) at room temperature for 2 h. Post-treatment: The solution was concentrated and dried to give a yellow solid compound 5-7, 22.18 mg, with a yield of 100%.

[0223] Step 8: Synthesis of Compound 5

[0224] Compounds 1-13 were synthesized by the method reported in Example 67 of Patent WO2018056453.

[0225] Compounds 1-13 (19.71 mg, 47.91 μmol) and HATU (22.77 mg, 59.88 μmol) were added to a 25 mL single-necked flask and dissolved in anhydrous DMF (3 mL). DIPEA (25.80 mg, 199.61 μmol) was slowly added dropwise at 0 °C. After addition, the mixture was kept warm and stirred for 0.5 h. Then, compound 5-7 (20.00 mg, 39.92 μmol) dissolved in anhydrous DMF (2 mL) was added dropwise. After addition, the mixture was kept warm and stirred for 0.5 h, and then the reaction was carried out at room temperature for 2 h. Post-treatment: The mixture was separated by adding water and ethyl acetate, and the organic phase was washed three times with saturated sodium chloride solution. The solution was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (PE / EA (V / V) = 2 / 1) to give a yellow solid compound 5, 11 mg, in a yield of 32.19%. MS: (ESI, neg.ion) m / z: 858.0 [MH] - .

[0226] Example 6

[0227] Synthesis steps:

[0228] Note: Compounds 1-6 are synthesized according to the method described in Example 1.

[0229] Step 1: Synthesis of Compound 6-4

[0230] Compound 1-6 (500 mg, 1.34 mmol) and DMF (20 mL) were added to a 100 mL single-necked flask. Sodium hydride (35.25 mg, 1.47 mmol) was added under ice bath conditions. After stirring at room temperature for 30 min, 3-bromopropene (190.61 mg, 1.60 mmol) was added dropwise under ice bath conditions. After the addition was complete, the mixture was stirred at room temperature for 4 h. Post-treatment: The remaining sodium hydride was quenched by slowly adding water under ice bath conditions. Ethyl acetate (50 mL) and water (200 mL) were added and separated. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (200 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA (V / V) = 5 / 1) to give a light brown oily compound 6-4, 160 mg, yield 29.05%. MS:(ESI,pos.ion)m / z:413.2420[M+H] + .

[0231] Step 2: Synthesis of Compound 6-1

[0232] 5-Bromo-4-fluoro-1-methyl-1H-indazole (4 g, 17.46 mmol), dioxane (40 mL), diphenylmethyleneimine (4.75 g, 26.19 mmol), cesium carbonate (5.69 g, 17.46 mmol), Pd(dba)3 (1.599 g, 1.75 mmol), and XantPhos (2.02 g, 3.49 mmol) were added to a 100 mL single-necked flask. The mixture was purged with nitrogen three times and heated to 110 °C under nitrogen protection with stirring for 12 h. Post-treatment: The reaction solution was filtered to remove insoluble solids. The filtrate was directly mixed with alkaline silica gel and placed into a sample column packed with alkaline silica gel. Column chromatography purification was performed (PE / EA(V / V) = 20 / 1) to obtain a white solid compound 6-1, 5.3 g, yield 92.27%. MS:(ESI,pos.ion)m / z:330.1452[M+H] + .

[0233] Step 3: Synthesis of Compound 6-2

[0234] Compound 6-1 (5.29 g, 16.08 mmol), MeOH (53 mL), hydroxylamine hydrochloride (111.60 mg, 1.61 mmol), and sodium acetate (131.75 mg, 1.61 mmol) were added to a 100 mL single-necked flask and stirred at room temperature for 2 h. Post-treatment: The reaction solution was filtered to remove insoluble solids. The pH was adjusted to neutral with sodium bicarbonate solution. Ethyl acetate (50 mL) and water (300 mL) were added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (300 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA(V / V) = 5 / 1) to give a colorless oily liquid compound 6-2, 2.35 g, yield 88.59%. MS: (ESI, pos.ion) m / z: 166.0778 [M+H] + .

[0235] Step 4: Synthesis of Compound 6-3

[0236] Add triphosgene (359.30 mg, 1.21 mmol) and ethyl acetate (2 mL) to a 100 mL single-necked flask. Add a mixture of ethyl acetate (2 mL), compound 6-2 (100 mg, 0.61 mmol) and triethylamine dropwise under ice bath. After the addition is complete, react under ice bath for 30 min, then raise the temperature to 60 °C and stir for 3 hours. Then, evaporate the solution directly to dryness for the next step.

[0237] Step 5: Synthesis of Compounds 6-5

[0238] Compound 6-4 (160 mg, 0.39 mmol), toluene (4 mL), and compound 6-3 (88.98 mg, 0.47 mmol) were added to a 100 mL single-necked flask. The mixture was purged with nitrogen for protection, heated to 110 °C, and stirred for 1 h. Silver trifluoromethanesulfonate (9.97 mg, 0.039 mmol) was then added, purged with nitrogen for protection, and the mixture was stirred at 110 °C for another 3 h. Post-treatment: The reaction mixture was filtered to remove insoluble solids. Ethyl acetate (20 mL) and water (120 mL) were added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (120 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA(V / V) = 2 / 1) to give a colorless oily liquid compound 6-5, 70 mg, yield 29.90%. MS:(ESI,pos.ion)m / z:604.2898[M+H] + .

[0239] Step 6: Synthesis of compound 6-6

[0240] Compound 6-5 (70 mg, 0.12 mmol) and dioxane hydrochloride (4.0 M, 2 mL) were added to a 50 mL single-necked flask, and the mixture was stirred at room temperature for 4 h. Post-treatment: The product was directly evaporated to dryness for the next step, yielding a light brown solid, compound 6-6, 62 mg, in 99% yield. MS: (ESI, pos.ion) m / z: 504.2338 [M+H] + .

[0241] Step 7: Synthesis of Compound 6

[0242] Compound 1-13 (56.42 mg, 0.14 mmol), DMF (2 mL), and HATU (65.48 mg, 0.17 mmol) were added to a 50 mL two-necked flask. DIPEA (74.20 mg, 0.57 mmol) was added dropwise under ice bath conditions. After the addition was complete, the mixture was stirred at room temperature for 30 min. Compound 6-6 (62 mg, 0.11 mmol), dissolved in DMF (2 mL), was added dropwise under ice bath conditions. The mixture was stirred at room temperature for 2 h. Post-treatment: Ethyl acetate (20 mL) and water (200 mL) were added and the mixture was separated. The aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (200 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by Pre-TLC (PE / EA (V / V) = 2 / 1) to give a light brown solid compound 6, 30 mg, in a yield of 29.1%. MS:(ESI,pos.ion)m / z:897.4077[M+H] + .

[0243] Example 7

[0244] Synthesis steps:

[0245] Step 1: Synthesis of Compound 7-2

[0246] Ethyl 5-bromo-1H-indole-2-carboxylic acid (2.00 g, 7.46 mmol) and anhydrous DMF (20 mL) were added to a 100 mL three-necked flask. 60% NaH (0.45 g, 11.19 mmol) was added at 0 °C. The mixture was stirred at room temperature for 0.5 h under nitrogen protection, followed by dropwise addition of 1 mL of bromoacetonitrile dissolved in anhydrous DMF (1.79 g, 14.92 mmol). After the addition was complete, the mixture was moved to room temperature and stirred overnight under nitrogen protection. Post-treatment: 80 mL of water was added at 0 °C and stirred for 1 h. The mixture was filtered, and the filter cake was washed with water (20 mL × 3). The cake was dried in a forced-air dryer at 50 °C to obtain a yellow solid compound 7-2, 2.17 g, with a yield of 94.63%.

[0247] Step 2: Synthesis of Compound 7-3

[0248] Compound 7-2 (1 g, 3.26 mmol), 3-methyl-3-(methanesulfonyl)but-1-yne (0.95 g, 6.51 mmol), toluene (5 mL), bis(triphenylphosphine)palladium dichloride (0.228 g, 0.33 mmol), CuI (93.01 mg, 0.49 mmol), triphenylphosphine (85.40 mg, 0.33 mmol), and triethylamine (5 mL) were added to a 50 mL reaction flask. The mixture was evacuated to a vacuum, purged with nitrogen, and reacted overnight at 90 °C. Post-treatment: The mixture was filtered, extracted with water and ethyl acetate, and the organic phase was separated. The solution was dried over anhydrous sodium sulfate, filtered, and subjected to column chromatography (PE / EA(V / V) = 2 / 1) to give compound 7-3, 0.63 g, in 52.5% yield. MS: (ESI, pos.ion) m / z: 372.1237 [M+H] + .

[0249] Step 3: Synthesis of Compound 7-4

[0250] Compound 7-3 (0.62 g, 1.66 mmol), THF (7 mL), and LiOH dissolved in water (4 mL) (79.73 mg, 3.33 mmol) were added to a 50 mL reaction flask and stirred at room temperature for 2 h. Post-treatment: The pH was adjusted to 4-5 with 20 mL of 10% citric acid aqueous solution, and the mixture was stirred overnight. The mixture was filtered and dried under blast heat at 50 °C to give a yellow solid, compound 7-4, 0.42 g, with a yield of 72.95%. MS: (ESI, pos.ion) m / z: 362.1174 [M+H2O] + .

[0251] Step 4: Synthesis of Compounds 7-5

[0252] Compound 7-4 (2.26 g, 6.56 mmol), DMF (23 mL), and HATU (3.74 g, 9.84 mmol) were added to a 100 mL reaction flask. After stirring at room temperature for 0.5 h, N-methylaniline (1.05 g, 9.84 mmol) was added at 0 °C, followed by dropwise addition of DIPEA (2.54 g, 19.68 mmol). The reaction was stirred at room temperature for 4 h after the addition was complete. Post-treatment: Water (100 mL) and EA (50 mL) were added for extraction and separation. The organic phase was washed with saturated brine (50 mL × 4), dried over anhydrous sodium sulfate, filtered, and subjected to column chromatography (PE / EA (V / V) = 1 / 1). The solution was concentrated to constant weight to give a yellow solid compound 7-5, 1.30 g, yield 45.77%. MS: (ESI, pos.ion) m / z: 434.1560 [M+H] + .

[0253] Step 5: Synthesis of compounds 7-6

[0254] Compound 7-5 (0.1 g, 230.67 μmol), (R)-4-methyl-1,3,2-dioxane-2,2-dioxide (79.66 mg, 576.67 μmol), and DMPU (1.5 mL) were added to a 50 mL double-necked flask. Under nitrogen protection, 1 mol / L KHMDS (0.92 mL, 922.68 μmol) was added dropwise at 0 °C. After the addition was complete, the reaction was continued at 0 °C for 4 h. Post-treatment: Water (20 mL) and EA (20 mL) were added for extraction and separation. The organic phase was separated, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and subjected to column chromatography (DCM / MeOH (V / V) = 50 / 1). The solution was concentrated to constant weight to give a white oily compound 7-6, 23 mg, yield 21.05%. MS:(ESI,pos.ion)m / z:474.1889[M+H] + .

[0255] Step 6: Synthesis of Compound 7-7

[0256] Compound 7-6 (0.1 g, 211.15 μmol), DMSO (1 mL), and 50% hydroxylamine aqueous solution (0.28 g, 4.22 mmol) were added to a 50 mL reaction flask and stirred overnight at room temperature. Post-treatment: Water (20 mL) and EA (10 mL) were added for extraction and separation. The organic phase was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to constant weight to give a white oily compound 7-7, 32 mg, yield 29.91%. MS: (ESI, pos.ion) m / z: 507.2087 [M+H] + .

[0257] Step 7: Synthesis of compounds 7-8

[0258] Add 7-7 (225 mg, 444.12 μmol), DMSO (2.25 mL), CDI (144.03 mg, 888.24 μmol), and DBU (169.03 mg, 1.11 mmol) to a 50 mL reaction flask, and heat to 60 °C for 4 h. Post-treatment: Extract with 20 mL of 10% citric acid aqueous solution and 20 mL of EA, separate the organic phase, dry to anhydrous sodium sulfate, filter, and perform column chromatography (PE / EA (V / V) = 1 / 1). Concentrate to constant weight to give compound 7-8, 210 mg, yield 88.8%. MS: (ESI, pos.ion) m / z: 533.1894 [M+H] + .

[0259] Step 8: Synthesis of compounds 7-9

[0260] Compound 7-8 (0.12 g, 225.30 μmol), t-BuOK (505.64 mg, 4.51 mmol), and ethylene glycol dimethyl ether (6 mL) were added to a 50 mL reaction flask and reacted at 130 °C for 48 h. Post-treatment: Water (20 mL) and EA (20 mL) were added for extraction and separation. The aqueous phase was further extracted with EA (10 mL). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and subjected to column chromatography (DCM / MeOH (V / V) = 10:1). The solution was concentrated to constant weight to give a red oily compound 7-9, 69 mg, yield 69.13%. MS: (ESI, pos.ion) m / z: 444.33 [M+H] + .

[0261] Step 9: Synthesis of Compound 7

[0262] Compound 7-9 (41 mg, 92.45 μmol), DMF (1 mL), and HATU (70.31 mg, 184.91 μmol) were added to a 50 mL reaction flask. After stirring at room temperature for 0.5 h, compound 7-10 (63.22 mg, 120.19 μmol) was added at 0 °C, followed by dropwise addition of DIPEA (119.49 mg, 924.49 μmol). The mixture was stirred at room temperature overnight. Post-treatment: Water (10 mL) and EA (10 mL) were added for extraction and separation. The organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and subjected to column chromatography (DCM / MeOH (V / V) = 40 / 1). The solution was concentrated to constant weight to give a yellow solid, compound 7, 37 mg, in 43.74% yield. MS: (ESI, pos.ion) m / z: 915.3145 [M+H] + .

[0263] 1H NMR (600MHz, CDCl3, 120℃) δ11.26(d,J=25.0Hz,1H),8.10(d,J=58.5Hz,1H),7.84(d,J=16.7Hz,1H),7.59(dd,J=28.2,8.5Hz,1H),7.46( ddd,J=23.9,15.3,8.5Hz,2H),7.31(d,J=8.9Hz,1H),7.18(d,J=5.7Hz,1H),7.11–7.05(m,1H),6.73(s,1H),6.56(d,J=94.0Hz,1H),6.33 (d,J=2.6Hz,1H),5.82(d,J=6.6Hz,1H),4.13(d,J=17.4Hz,3H),3.70–3.59(m,1H),3.20–3.09(m,3H),3.05(d,J=12.4Hz,1H),2.82(d,J= 12.7Hz,2H),2.30(d,J=21.9Hz,6H),1.80(d,J=7.6Hz,6H),1.28(s,3H),1.23(d,J=6.1Hz,2H),1.06(d,J=5.8Hz,1H),1.00–0.86(m,3H).

[0264] Example 8

[0265] Synthesis steps:

[0266] Using 1-benzyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole and 2-1 as starting materials, the target compound 8 was obtained according to steps 2 to 6 of Example 2. MS: (ESI, pos.ion) m / z: 867.4013 [M+H] + .

[0267] Example 9

[0268] Synthesis steps:

[0269] Step 1: Synthesis of Compound 9-1

[0270] Triphosgene (131.28 mg, 442.41 μmol) and DCM (4 mL) were added to a 25 mL two-necked flask. The mixture was cooled to -30 °C, and triethylamine (223.85 mg, 2.21 mmol) was added. Then, a DCM solution of compound 6-4 (365 mg, 884.83 μmol) in 1 mL was added. After the addition was complete, the mixture was stirred at the incubation temperature for 15 min, and then allowed to react at room temperature for 2 h. Post-treatment: The mixture was directly evaporated to dryness and purified by column chromatography (PE / EA(V / V) = 3 / 1) to give a white solid compound 9-1, 256 mg, with a yield of 60.91%.

[0271] Step 2: Synthesis of Compound 9-2

[0272] Compounds 9-1 (200 mg, 421.09 μmol), 6-2 (69.55 mg, 421.09 μmol), sodium bicarbonate (176.87 mg, 2.11 mmol), and DCM (8 mL) were added sequentially to a 50 mL single-necked flask, and the mixture was refluxed for 25 h. Post-treatment: The mixture was cooled to room temperature, evaporated directly to dryness, and purified by column chromatography (PE / EA(V / V) = 3 / 2) to give a yellow oily compound 9-2, 113 mg, yield 44.45%. MS: (ESI, pos.ion) m / z: 604.2958 [M+H] + .

[0273] Step 3: Synthesis of Compound 9

[0274] Using compound 9-2 as a starting material, and following the synthetic method described in steps 8 and 9 of Example 1, a white solid compound 9 was obtained. MS: (ESI, pos.ion) m / z: 897.4095 [M+H] + . 1 H NMR (500MHz, DMSO, 120℃) δ11.48(s,2H),7.98(s,3H),7.54(s,1H),7.41(d,J=8.0Hz,1H),7 .31(d,J=5.8Hz,2H),7.27(d,J=8.4Hz,1H),6.86(s,1H),5.73(s,1H),4.53(s,1H),4.09(s, 1H),4.01(s,3H),3.74(d,J=7.6Hz,2H),3.51(s,1H),3.04(d,J=12.6Hz,2H),2.72(s,4H), 2.29(s,6H),1.62(ddd,J=38.9,36.3,16.8Hz,10H),1.29(s,3H),1.20(s,3H),1.17(s,2H).

[0275] Example 10

[0276] Synthesis steps:

[0277] Note: Intermediate compounds 1-6 are synthesized according to the method described in Example 1.

[0278] Step 1: Synthesis of Compound 10-1

[0279] In a clean single-necked flask, 1-6 (100 mg, 0.267 mmol), cyclopropylformaldehyde (22.46 mg, 0.320 mmol), and acetic acid (16.04 mg, 0.267 mmol) dissolved in DCE (2 ml) were added. The mixture was refluxed at 100 °C for 4 h, then cooled to 0 °C, and sodium cyanoborohydride (50 mg, 0.796 mmol) was added. The mixture was then brought to room temperature and stirred for another 5 h. Post-treatment: The mixture was concentrated under reduced pressure and purified by column chromatography (PE / EA(V / V) = 5 / 1) to give a yellow oily compound 10-1, 114 mg, in 99.60% yield.

[0280] Step 2: Synthesis of Compound 10

[0281] Using compound 10-1 as a starting material, and following the synthetic method described in steps 8 and 9 of Example 1, a white solid compound 10 was obtained. MS: (ESI, pos.ion) m / z: 913.4384 [M+H] + .

[0282] 1 H NMR (600MHz, DMSO, 120℃) δ11.50(s,2H),7.97(s,3H),7.56(s,1H),7.44(d,J=8.5Hz,1H),7.33( d,J=6.3Hz,2H),7.29(d,J=8.4Hz,1H),6.88(s,1H),5.70(d,J=65.3Hz,2H),4.52(s,1H),3.78–3 .72(m,3H),3.54(s,1H),3.11–2.96(m,3H),2.74(s,4H),2.31(d,J=1.5Hz,6H),1.80–1.61(m,1 0H),1.58(dd,J=22.0,9.2Hz,3H),1.31(s,3H),1.30(d,J=4.1Hz,1H),1.22(s,3H),1.14(s,3H).

[0283] Example 11

[0284] Synthesis steps:

[0285] Note: Intermediate compounds 1-6 were synthesized according to the method described in Example 1.

[0286] Step 1: Synthesis of Compound 11

[0287] Using compound 11-1 as a starting material, and following the synthetic method described in Example 10, compound 11, a white solid, was obtained. MS: (ESI, pos.ion) m / z: 927.4521 [M+H] + .

[0288] 1 H NMR (600MHz, DMSO, 120℃) δ11.48(s,1H),8.00(d,J=20.9Hz,3H),7.56(s,1H),7.44(d,J=8 .5Hz,1H),7.31(dd,J=29.5,7.3Hz,4H),6.88(s,1H),5.55(s,2H),4.54(s,2H),4.04(s,3 H),3.77–3.74(m,2H),3.57–3.48(m,2H),3.11–3.03(m,2H),2.92(s,4H),2.77(s,3H),2. 31(s,6H),1.70(ddd,J=25.1,18.1,10.3Hz,10H),1.31(s,3H),1.22(s,3H),1.20(s,3H).

[0289] Example 12

[0290] Synthesis steps:

[0291] Note: Intermediate compounds 1-6 were synthesized according to the method in Example 1, and compounds 6-2 were synthesized according to the method in Example 6.

[0292] Step 1: Synthesis of Compound 12-1

[0293] Add triphosgene (359.30 mg, 1.21 mmol) and ethyl acetate (2 ml) to a clean 100 ml single-necked flask. Under ice bath conditions, add a mixed solvent of ethyl acetate (2 ml), compound 6-2 (100 mg, 0.605 mmol) and triethylamine dropwise. After the addition is complete, react under ice bath conditions for 30 min, then move to 60 °C and stir for 3 hours. Filter, concentrate under vacuum, and set aside for the next step.

[0294] Step 2: Synthesis of Compound 12-2

[0295] Compound 1-6 (100.00 mg, 267.05 μmol) was added to a clean flask, along with 1-bromo-3-methoxypropane (32.69 mg, 213.63 μmol) dissolved in 3 mL of DMF. The mixture was substituted three times with N2. Under N2 protection, a KHMDS THF solution (1 M, 256.37 μL, 256.37 μmol) was slowly added dropwise at 0 °C. After stirring at 0 °C for 15 min, the mixture was transferred to room temperature and reacted overnight. Post-treatment: The system was extracted with saturated brine (10 mL x 2) and EA (10 mL x 2). The organic phase was washed twice with 10 mL of saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE / EA (V / V) = 4 / 1) to give a yellow oily compound 12-2, 95 mg, yield 99.64%. MS-ESI:(ESI,pos.ion)m / z:447.2858[M+H] + .

[0296] Step 3: Synthesis of Compound 12-3

[0297] Compound 12-2 (100.00 mg, 223.93 μmol) and compound 12-1 (85.62 mg, 447.86 μmol) were added to a clean flask and dissolved in 4 mL of toluene. The mixture was substituted with N2 three times and reacted at 110 °C for 10 h under N2 protection. Post-treatment: The system was extracted with water (10 mL x 3) and EA (10 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE / EA (V / V) = 1 / 1) to give a yellow oily compound 12-3, 40 mg, yield 28.01%. MS-ESI: (ESI, pos.ion) m / z: 638.5337 [M+H] + .

[0298] Step 4: Synthesis of Compound 12

[0299] Using compound 12-3 as a starting material, and following the synthetic method described in Example 10, a yellow solid compound 12 was obtained. MS: (ESI, pos.ion) m / z: 931.4489 [M+H] + .

[0300] 1H NMR (600MHz, DMSO, 120℃) δ11.40(s,1H),8.01(d,J=32.3Hz,3H),7.54(s,1H),7.42(d,J=8.5Hz ,1H),7.29(dd,J=25.9,7.4Hz,4H),6.86(s,1H),5.56(dd,J=12.9,11.2Hz,2H),4.52(s,2H),4. 02(s,3H),3.78–3.74(m,2H),3.52(d,J=10.7Hz,3H),3.24(s,2H),3.06(t,J=12.3Hz,6H),2.30 (d,J=1.6Hz,6H),1.80–1.61(m,10H),1.31(s,3H),1.22(d,J=1.8Hz,3H),1.20(d,J=7.1Hz,3H)

[0301] Example 13

[0302] Synthesis steps:

[0303] Note: Intermediate compounds 1-6 are synthesized according to the method described in Example 1.

[0304] Step 1: Synthesis of Compound 13

[0305] Using compound 13-1 as a starting material, and following the synthetic method described in Example 10, compound 13 was obtained as a white solid. MS: (ESI, pos.ion) m / z: 1003.4048 [M+H] + .

[0306] 1 H NMR (600MHz, DMSO, 120℃) δ11.44(s,1H),8.14(d,J=117.4Hz,4H),7.56(s,1H),7.44(d,J=8.4Hz ,1H),7.30(d,J=8.0Hz,1H),7.20–7.04(m,4H),6.86(s,1H),5.34(dd,J=26.3,21.8Hz,1H),4.5 2(s,3H),4.05(d,J=13.5Hz,3H),3.82–3.73(m,2H),3.51(d,J=13.0Hz,1H),3.11–3.05(m,1H), 2.97(s,1H),2.25(s,6H),1.82–1.54(m,10H),1.32(s,3H),1.23(s,3H),1.21(d,J=7.1Hz,3H).

[0307] Example 14

[0308] Synthesis steps:

[0309] Note: Intermediate compounds 1-6 are synthesized according to the method described in Example 1.

[0310] Step 1: Synthesis of Compound 14-1

[0311] In a 50 mL double-necked flask, compound 1-6 (1.30 g, 3.47 mmol) and DMF (10 mL) were added. The mixture was cooled to 0 °C, and 60% sodium hydride (208.28 mg, 5.21 mmol) was added. The mixture was stirred for 30 min, and then 1-bromo-2-butyne (692.53 mg, 5.21 mmol) was added. After the addition was complete, the mixture was allowed to rise to room temperature and reacted for 17 h. Post-treatment: EA (50 mL) and water (100 mL) were added, and the mixture was separated. The organic phase was washed with saturated sodium chloride solution (100 mL * 2), dried over anhydrous sodium sulfate, and purified by column chromatography (PE / EA (V / V) = 17 / 3) to give a yellow, fluffy solid compound 14-1, 384 mg, yield 25.95%. MS: (ESI, pos.ion) m / z: 427.2558 [M+H] + .

[0312] Step 2: Synthesis of Compound 14

[0313] Using compound 14-1 as a starting material, and following the synthetic method described in Example 10, compound 14 was obtained as a white solid. MS: (ESI, pos.ion) m / z: 911.4222 [M+H] + .

[0314] 1 H NMR (600MHz, DMSO, 120℃) δ11.50(s,2H),7.99(s,3H),7.55(s,1H),7.43(d,J=8.4Hz,1H),7.3 3(d,J=6.3Hz,2H),7.28(d,J=8.4Hz,1H),6.88(s,1H),5.78(d,J=22.1Hz,2H),4.53(s,2H),4 .03(s,3H),3.78–3.74(m,2H),3.53(d,J=11.4Hz,1H),3.11–2.95(m,3H),2.31(d,J=1.8Hz,6 H),1.79–1.61(m,10H),1.57(t,J=12.9Hz,3H),1.32(s,3H),1.22(s,3H),1.22–1.17(m,3H).

[0315] Example 15

[0316] Synthesis steps:

[0317] Note: Intermediate compounds 1-6 are synthesized according to the method described in Example 1.

[0318] Step 1: Synthesis of Compound 15

[0319] Using compound 15-1 as a starting material, and following the synthetic method described in Example 10, compound 15 was obtained as a white solid. MS: (ESI, pos.ion) m / z: 967.4252 [M+H] + .

[0320] 1 H NMR (600MHz, DMSO, 120℃) δ11.47(s,1H),8.02(s,2H),7.56(s,1H),7.36(dd,J=80.7,8.4Hz ,3H),7.17–6.99(m,5H),6.84(s,3H),4.70(d,J=14.6Hz,1H),4.47(s,2H),4.04(s,3H),3. 81–3.73(m,2H),3.49(t,J=11.5Hz,1H),3.08(ddd,J=12.4,9.1,3.5Hz,1H),2.94(s,1H),2 .83(s,2H),2.25(s,6H),1.83–1.49(m,10H),1.32(s,3H),1.23(s,3H),1.22–1.15(m,3H).

[0321] Example 16

[0322] Synthesis steps:

[0323] Note: Intermediate compounds 1-6 are synthesized according to the method described in Example 1.

[0324] Step 1: Synthesis of Compound 16

[0325] Using compound 16-2 as a starting material, and following the synthetic method described in Example 10, compound 16 was obtained as a white solid. MS: (ESI, pos.ion) m / z: 929.4294 [M+H] + .

[0326] Example 17

[0327] Synthesis steps:

[0328] Note: Intermediate compounds 1-6 are synthesized according to the method described in Example 1.

[0329] Step 1: Synthesis of Compound 17

[0330] Using compound 17-2 as a starting material, and following the synthetic method described in Example 10, a pale yellow solid, compound 17, was obtained. MS: (ESI, pos.ion) m / z: 941.3924 [M+H] + .

[0331] 1 H NMR (600MHz, DMSO, 120℃) δ11.43(s,2H),8.44–7.88(m,3H),7.55(s,1H),7.44(d,J=8.5Hz,1H),7.34 (d,J=6.3Hz,2H),7.28(d,J=8.0Hz,1H),7.14(dd,J=13.0,4.5Hz,1H),5.67(s,1H),4.48(s,2H),4.04 (s,3H),3.78–3.73(m,2H),3.54(t,J=11.1Hz,1H),3.07(ddd,J=12.5,8.0,3.5Hz,2H),2.96(d,J=20. 3Hz,2H),2.32(d,J=1.7Hz,6H),1.80–1.55(m,10H),1.31(s,3H),1.22(s,3H),1.21(d,J=7.1Hz,3H).

[0332] Example 18

[0333] Synthesis steps:

[0334] Note: Intermediate compounds 1-6 are synthesized according to the method described in Example 1.

[0335] Step 1: Synthesis of Compound 18

[0336] Using compound 16-4 as a starting material, and following the synthetic method described in Example 10, compound 18 was obtained as a white solid. MS: (ESI, pos.ion) m / z: 965.4060 [M+H] + .

[0337] Example 19

[0338] Synthesis steps:

[0339] Note: Intermediate compounds 1-6 are synthesized according to the method described in Example 1.

[0340] Step 1: Synthesis of Compound 19-3

[0341] In a 50 mL double-necked flask, compound 19-1 (1.00 g, 6.62 mmol), compound 19-2 (3.71 mg, 13.23 mmol), and EA (10 mL) were added. After the addition was complete, the temperature was raised to 80 °C and the reaction was carried out for 4 h. Post-treatment: diatomaceous earth filtration, concentrated silica gel mixing, and column chromatography purification (PE / EA (V / V) = 5 / 1) were performed to obtain a white, fluffy solid, compound 19-3, 840 mg, with a yield of 85%.

[0342] Step 2: Synthesis of Compound 19

[0343] Using compounds 19-3 and 1-6 as starting materials, and following the synthetic method described in Example 10, a pale yellow solid compound 19 was obtained. MS: (ESI, pos.ion) m / z: 992.4194 [M+H] + .

[0344] 1 H NMR (600MHz, DMSO, 120℃) δ11.45(s,1H),8.29(s,1H),8.04(d,J=12.6Hz,1H),7.57(s,1H),7.44(d,J= 8.5Hz,1H),7.41–7.28(m,4H),7.11(d,J=5.8Hz,2H),6.87(s,1H),5.59–5.33(m,1H),4.69(d,J=181.6 Hz,4H),4.04(s,3H),3.77(dd,J=9.4,2.0Hz,2H),3.56–3.48(m,1H),3.09(tt,J=12.4,3.3Hz,1H),2.9 8(d,J=32.5Hz,1H),2.24(s,6H),1.82–1.55(m,10H),1.32(s,3H),1.23(s,3H),1.21(d,J=7.1Hz,3H).

[0345] Example 20

[0346] Synthesis steps:

[0347] Note: Intermediate compounds 1-6 are synthesized according to the method described in Example 1.

[0348] Step 1: Synthesis of Compound 20

[0349] Using compound 20-2 as a starting material, and following the synthetic method described in Example 10, a pale yellow solid, compound 20, was obtained. MS: (ESI, pos.ion) m / z: 992.4194 [M+H]+ .

[0350] 1 H NMR (600MHz, DMSO, 120℃) δ11.47(s,2H),8.41(d,J=21.7Hz,1H),8.01(d,J=32.1Hz,2H),7.63–7.51(m ,2H),7.44(d,J=8.5Hz,1H),7.35–7.26(m,2H),7.15(d,J=5.1Hz,2H),7.07(s,1H),6.84(s,1H),4.53( s,2H),4.04(s,3H),3.79–3.74(m,2H),3.51(s,1H),3.08(ddd,J=12.3,7.9,3.4Hz,1H),2.92(s,2H), 2.77(s,2H),2.24(s,6H),1.83–1.50(m,10H),1.32(s,3H),1.23(s,3H),1.18(dd,J=28.1,6.5Hz,3H).

[0351] Example 21

[0352] Synthesis steps:

[0353] Note: Intermediate compounds 1-6 are synthesized according to the method described in Example 1, and intermediate compounds 21-2 are synthesized according to the method described in Example 19.

[0354] Step 1: Synthesis of Compound 21

[0355] Using compounds 21-3 as starting material, and following the synthetic method described in Example 12, compound 21 was obtained as a white solid. MS: (ESI, pos.ion) m / z: 954.4401 [M+H] + .

[0356] Example 22

[0357] Synthesis steps:

[0358] Note: Intermediate compounds 1-6 are synthesized according to the method described in Example 1.

[0359] Step 1: Synthesis of Compound 22

[0360] Using compounds 22-2 and 6-2 as starting materials, and following the synthetic method described in Example 10, a yellow solid compound 22 was obtained. MS-ESI: (ESI, pos.ion) m / z: 953.4453 [M+H] + .

[0361] 1 H NMR (600MHz, DMSO, 120℃) δ11.50(s,1H),8.10–7.90(m,3H),7.56(s,1H),7.43(d,J=8.0Hz,2H),7.29(d, J=8.5Hz,1H),7.21(d,J=6.3Hz,3H),7.01(s,1H),6.84(s,1H),4.52(s,2H),4.37–4.24(m,2H),4.03(s,3 H),3.78–3.75(m,2H),3.67–3.56(m,3H),3.50(d,J=10.9Hz,2H),3.08(ddd,J=12.4,9.1,3.7Hz,2H),2.2 7(d,J=1.4Hz,6H),1.67(dddd,J=43.1,33.7,19.0,11.1Hz,10H),1.32(s,3H),1.23(s,3H),1.21(s,3H).

[0362] Example 23

[0363] Synthesis steps:

[0364] Note: Intermediate compounds 1-6 are synthesized according to the method described in Example 1.

[0365] Step 1: Synthesis of compound 23-2

[0366] Compounds 1-6 (0.20 g, 0.534 mmol), 23-1 (0.137 g, 1.6 mmol), pyridine (0.127 g, 1.6 mmol), sodium carbonate (0.113 g, 1.068 mmol), and Cu(OTf)₂ (0.386 g, 1.068 mmol) dissolved in toluene (2 mL) were added to a clean flask. The mixture was refluxed open at 110 °C for 10 h. Post-treatment: The solvent was concentrated, and the mixture was purified by column chromatography (PE / EA(V / V) = 3 / 1) to give 39 mg of reddish-brown oily compound 23-2, yield 18%. MS: (ESI, pos.ion) m / z: 415.2548 [M+H] + .

[0367] Step 2: Synthesis of Compound 23

[0368] Using compounds 23-2 and 12-1 as starting materials, and following the synthetic method described in Example 12, compound 23 was obtained as a white solid. MS: (ESI, pos.ion) m / z: 899.4222 [M+H] + .

[0369] Example 24

[0370] Synthesis steps:

[0371] Note: Intermediate compounds 1-6 are synthesized according to the method described in Example 1.

[0372] Step 1: Synthesis of Compound 24-2

[0373] In a clean three-necked flask, compound 24-1 (1.0 g, 15.13 mmol) dissolved in THF (10 mL) was added, and the mixture was purged three times with nitrogen. The reaction mixture was placed at -40 °C, and n-butyllithium (1.6 M, 10.4 mL, 16.64 mmol) was added. After the addition was complete, the mixture was stirred for 1 h. Then, DMF (2.21 g, 30.26 mmol) was added, and the mixture was brought to room temperature and stirred for 1 h. Post-treatment: A sodium dihydrogen phosphate solution was prepared under ice bath conditions. The reaction mixture was slowly added dropwise to the sodium dihydrogen phosphate solution to quench the reaction. The system was extracted with EA (30 mL * 3), and the organic phase was collected. After drying with anhydrous sodium sulfate, the solution was concentrated under reduced pressure to give a yellow oily compound 24-2, 1.88 g, yield 132%.

[0374] Step 2: Synthesis of Compound 24

[0375] Using compounds 24-3 and 12-1 as starting materials, and following the synthetic method described in Example 12, compound 24 was obtained as a white solid. MS: (ESI, pos.ion) m / z: 937.4339 [M+H] + .

[0376] Example 25

[0377] Synthesis steps:

[0378] Note: Intermediate compounds 1-6 are synthesized according to the method in Example 1, intermediate compound 25-1 is synthesized according to step 1 in Example 10, and intermediate compound 25-2 is synthesized according to step 1 in Example 12.

[0379] Step 1: Synthesis of Compound 25

[0380] Using compound 25-1 as a starting material, and following the synthetic method described in Example 12, compound 25 was obtained as a white solid. MS: (ESI, pos.ion) m / z: 897.4006 [M+H] + .

[0381] Example 26

[0382] Synthesis steps:

[0383] Note: Intermediate compound 12-2 is synthesized according to the method in Example 12, and intermediate compound 26-2 is synthesized according to step 1 in Example 6.

[0384] Step 1: Synthesis of Compound 26

[0385] Using compound 26-1 as a starting material, and following the synthetic method described in Example 10, compound 26 was obtained as a white solid. MS: (ESI, pos.ion) m / z: 957.4631 [M+H] + .

[0386] Example 27

[0387] Synthesis steps:

[0388] Note: The intermediate compound 12-2 is synthesized according to the method described in Example 12.

[0389] Step 1: Synthesis of Compound 27-1

[0390] Compound 12-2 (350 mg, 0.784 mmol), DMAP (19.15 mg, 0.157 mmol), and DIEA (119 mg, 0.92 mmol) dissolved in THF (6 mL) were added to a clean single-necked flask. Oxaloyl chloride monoethyl ester (139.11 mg, 1.02 mmol) was slowly added dropwise, and the mixture was stirred at 70 °C for 18 h. Post-treatment: The solvent was concentrated under reduced pressure and purified by column chromatography (PE / EA (V / V) = 3 / 1) to give a yellow oily compound 27-1, 428 mg, in 100% yield. MS: (ESI, pos.ion) m / z: 547.3089 [M+H] + .

[0391] Step 2: Synthesis of compound 27-2

[0392] Compound 27-1 (122 mg, 0.223 mmol) and LiOH (53.45 mg, 2.23 mmol) dissolved in methanol (3 mL) and water (1 mL) were added to a clean single-necked flask and reacted with stirring at 50 °C for 2 h. Post-treatment: The solvent was concentrated under reduced pressure, the pH was adjusted to neutral with 10% citric acid, and DCM (10 mL * 2) was added for extraction and separation. The mixture was dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated to give a yellow oily compound 27-2, 115 mg, in 100% yield. MS: (ESI, pos.ion) m / z: 519.2702 [M+H] + .

[0393] Step 3: Synthesis of compound 27-3

[0394] In a clean single-necked flask, 27-2 (115 mg, 0.221 mmol), compound 6-2 (43.95 mg, 0.266 mmol), and HATU (126 mg, 0.332 mmol) dissolved in DMF (2 mL) were added. DIEA (143 mg, 1.06 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 14 h. Post-treatment: Ethyl acetate (20 mL) and water (20 mL) were added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA (V / V) = 2 / 1) to give a yellow oily compound 27-3, 61 mg, yield 41.5%. MS: (ESI, pos.ion) m / z: 666.3228 [M+H] + .

[0395] Step 4: Synthesis of Compound 27

[0396] Using compound 27-3 as a starting material, and following the synthetic method described in Example 10, compound 27 was obtained as a white solid. MS: (ESI, pos.ion) m / z: 959.4381 [M+H] + .

[0397] Example 28

[0398] Synthesis steps:

[0399] Synthesis steps:

[0400] Step 1: Synthesis of compound 28-2

[0401] Compound 28-1 (5.0 g, 34.7 mmol) was dissolved in DCM (50 mL) under ice bath conditions. Triethylamine (7.11 g, 69.4 mmol) and MsCl (4.37 g, 38.1 mmol) were added. After the addition was complete, the mixture was allowed to react at room temperature for 2 h. The mixture was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated to give a yellow liquid compound 28-2, 7.7 g, in 100% yield.

[0402] Step 2: Synthesis of compound 28-4

[0403] In a clean single-necked flask, compound 28-3 (3.2 g, 26.54 mmol) dissolved in acetonitrile (32 mL) was added, followed by compound 28-2 (8.85 g, 39.81 mmol), potassium carbonate (11.0 g, 79.62 mmol), and sodium iodide (0.398 g, 2.654 mmol). The mixture was reacted at 70 °C for 8 h. After filtration, the solvent was concentrated, and the mixture was purified by column chromatography (PE / EA(V / V) = 1 / 1) to give a yellow oily compound 28-4, 4.16 g, in 74.6% yield. MS: (ESI, pos.ion) m / z: 211.1458 [M+H] + .

[0404] Step 3: Synthesis of compound 28-5

[0405] Compound 28-4 (0.4 g, 1.90 mmol) was dissolved in DCM (4 mL) under ice bath conditions. Triethylamine (0.384 g, 3.80 mmol) and (Boc)₂O (0.498 g, 2.28 mmol) were added. After the addition was complete, the mixture was allowed to react at room temperature for 12 h. The mixture was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (PE / EA(V / V) = 4 / 1) to give 0.35 g of colorless oily compound 28-5, yield 59.3%.

[0406] Step 4: Synthesis of compound 28-6

[0407] In a clean single-necked flask, compound 28-5 (0.35 g, 1.13 mmol) dissolved in toluene (4 mL) was added, followed by the addition of potassium tert-butoxide (0.152 g, 1.35 mmol). The mixture was reacted at 80 °C for 2 h. The solvent was concentrated, and the mixture was purified by column chromatography (PE / EA(V / V) = 3 / 1) to give 0.12 g of a yellow oily compound 28-6, yield 40.3%. MS: (ESI, pos.ion) m / z: 165.1023 [M+H-100] + .

[0408] Step 5: Synthesis of compound 28-8

[0409] Compound 28-7 (0.130 g, 0.681 mmol) was dissolved in ethanol (2 mL) and compound 28-6 (0.12 g, 0.454 mmol) in an ice bath. After the addition was complete, the mixture was reacted at 80 °C for 2 h. The solvent was concentrated and purified by column chromatography (PE / EA (V / V) = 3 / 1) to give 0.05 g of a yellow oily compound 28-8, yield 27.5%. MS: (ESI, pos.ion) m / z: 401.2440 [M+H] + .

[0410] Step 6: Synthesis of Compound 28-10

[0411] Note: Intermediates 28-9 were synthesized according to the method reported in Example 11 of CN109790161A.

[0412] In a clean single-necked flask, compound 28-8 (0.05 g, 0.125 mmol) dissolved in DMA (1 mL) was added, followed by compound 28-9 (0.029 g, 0.150 mmol). The mixture was reacted at 60 °C for 2 h. The system was extracted with saturated brine (10 mL x 2) and EA (10 mL x 2). The organic phase was washed twice with 10 mL of saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE / EA (V / V) = 2 / 1) to give a yellow solid, compound 28-10, 0.035 g, yield 52.7%. MS: (ESI, pos.ion) m / z: 532.3008 [M+H] + .

[0413] Step 7: Synthesis of compound 28-11

[0414] In a clean single-necked flask, compound 28-10 (0.035 g, 0.066 mmol) dissolved in THF (1 mL) was added, followed by the addition of methanesulfonic acid (5 mg, 0.053 mmol). The mixture was reacted at 60 °C for 2 h, concentrated under reduced pressure, and purified by column chromatography (PE / EA(V / V) = 1 / 1) to give a yellow solid, compound 28-11, 0.030 g, yield 97.5%. MS: (ESI, pos.ion) m / z: 468.2425 [M+H] + .

[0415] Step 8: Synthesis of Compounds 28-14

[0416] In a clean double-necked flask, compounds 28-11 (0.079 g, 0.169 mmol), 28-12 (0.046 g, 0.203 mmol), 28-13 (0.024 g, 0.169 mmol), cuprous iodide (0.016 g, 0.084 mmol), and potassium carbonate (0.070 g, 0.507 mmol) dissolved in toluene (1 mL) were added. The mixture was purged three times with nitrogen and reacted at 110 °C for 9 h. The mixture was then concentrated under reduced pressure and purified by column chromatography (PE / EA(V / V) = 2 / 1) to give a yellow solid, compound 28-14, 0.066 g, yield 63.5%. MS: (ESI, pos.ion) m / z: 616.2868 [M+H] + .

[0417] Step 9: Synthesis of compounds 1-15

[0418] Compound 28-14 (0.066 g, 0.107 mmol) dissolved in HCl / THF (4 mL) was added to a clean single-necked flask and reacted overnight at room temperature. The solution was then concentrated under reduced pressure to give 0.059 g of a yellow solid hydrochloride compound 28-15, in 100% yield. MS: (ESI, pos.ion) m / z: 516.2361 [M+H] + .

[0419] Step 10: Synthesis of Compound 1

[0420] In a clean single-necked flask, compounds 28-15 (0.059 g, 0.114 mmol), 1-13 (0.052 g, 0.126 mmol), HATU (0.087 g, 0.229 mmol), and DIEA (0.074 g, 0.572 mmol) dissolved in DMF (2 mL) were added. The mixture was reacted at room temperature for 4 h. The system was then extracted with saturated brine (10 mL x 2) and EA (10 mL x 2). The organic phase was washed twice with 10 mL of saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE / EA (V / V) = 1 / 1) to give a pale yellow solid, compound 28, 0.060 g, yield 57.7%. MS: (ESI, pos.ion) m / z: 909.4011 [M+H] + .

[0421] Example 29

[0422] Synthesis steps:

[0423] Synthesis steps:

[0424] Step 1: Synthesis of Compound 29-1

[0425] Compound 28-8 (200.00 mg, 499.38 μmol) was added to a clean flask. 1-Bromo-2-butyne (199.23 mg, 1.50 mmol) dissolved in 3 mL of acetone was added, followed by the addition of DIPEA (322.72 mg, 2.50 mmol). The mixture was stirred at 60 °C for 24 h. Post-treatment: The mixture was concentrated under reduced pressure and purified by column chromatography (PE / EA (V / V) = 3 / 1) to give a yellow oily compound 29-1, 100 mg, in 44.25% yield.

[0426] Step 3: Synthesis of Compound 29-2

[0427] Compound 12-1 (110.88 mg, 580.02 μmol) and compound 29-1 (105.00 mg, 232.01 μmol) were added to a clean flask and dissolved in 4 mL of toluene. The mixture was substituted with N2 three times and reacted at 110 °C for 10 h under N2 protection. Post-treatment: The system was extracted with water (10 mL * 3) and EA (10 mL * 3), and the organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE / EA (V / V) = 1 / 2) to give a yellow oily compound 29-2, 19 mg, yield 12.72%.

[0428] Step 4: Synthesis of Compound 29

[0429] Using compound 29-2 as a starting material, and following steps 8 and 9 of Example 1, a yellow solid compound 29 was obtained. MS: (ESI, pos.ion) m / z: 937.4318 [M+H] + .

[0430] Example 30

[0431] Synthesis steps:

[0432] Step 1: Synthesis of Compound 30

[0433] Following the synthetic method of Example 28, a yellow solid compound 30 was obtained. MS: (ESI, pos.ion) m / z: 911.4182 [M+H] + .

[0434] Example 31

[0435] Synthesis steps:

[0436] Step 1: Synthesis of Compound 31

[0437] Following the synthetic method of Example 29, a yellow solid compound 31 was obtained. MS: (ESI, pos.ion) m / z: 939.4469 [M+H] + .

[0438] Example 32

[0439] Synthesis steps:

[0440] Note: Intermediate 32-1 was obtained by the synthesis method reported in Example 80 of CN109790161A.

[0441] Synthesis steps:

[0442] Step 1: Synthesis of Compound 32

[0443] Using compound 32-1 as a starting material, and following the synthetic method described in Example 29, a yellow solid compound 32 was obtained. MS: (ESI, pos.ion) m / z: 925.4318 [M+H] + .

[0444] Similarly, referring to the examples above, the compounds given in Table 1 were prepared.

[0445] Table 1

[0446] Example 60

[0447] Synthesis steps:

[0448] Note: Intermediate compounds 1-6 are synthesized according to the method described in Example 1.

[0449] Step 1: Synthesis of Compound 60-2

[0450] Compound 60-1 (2.00 g, 10.57 mmol) and HCl / Dioxane (4.0 M, 12 mL) were added to a 50 mL single-necked flask, and the reaction was allowed to proceed for 0.5 h. Post-treatment: The solvent was concentrated to give 1.33 g of white solid hydrochloride compound 60-2, yield 100%.

[0451] Step 2: Synthesis of Compound 60-3

[0452] Compound 60-2 (1.33 g, 10.59 mmol), sodium bicarbonate (1.3 g, 15.47 mmol), H₂O (13 mL), DCM (13 mL), and phosgene (1.22 g, 10.59 mmol) were added at 0 °C, and the reaction was carried out for 1 h. Post-treatment: The system was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to give 1.18 g of a yellow oily compound 60-3, yield 84.8%.

[0453] Step 3: Synthesis of Compound 60-4

[0454] In a 25 mL single-necked flask, compounds 1-6 (200 mg, 0.534 mmol), 60-3 (105.07 mg, 0.801 mmol), and pyridine (2 mL) were added, and the reaction was allowed to proceed for 15 h. Post-treatment: Column chromatography purification (PE / EA (V / V) = 2 / 1) yielded a yellow solid, compound 60-4, 0.213 g, in 78.9% yield. MS: (ESI, pos.ion) m / z: 506.2313 [M+H] + .

[0455] Step 4: Synthesis of Compound 60-5

[0456] In a 25 mL single-necked flask, compound 60-4 (230 mg, 0.455 mmol), LiOH (108.93 mg, 4.55 mmol), and THF (3 mL), along with 3 mL of water, were added, and the reaction was allowed to proceed for 2 h. Post-treatment: The pH was adjusted to 4 with 10% citric acid. The system was extracted using DCM (10 mL x 2), and the organic phase was washed once with 10 mL of saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH (V / V) = 10 / 1) to give a yellow solid compound 60-5, 0.090 g, yield 40%. MS: (ESI, pos.ion) m / z: 492.2166 [M+H] + .

[0457] Step 5: Synthesis of compound 60-6

[0458] In a 25 mL single-necked flask, compound 60-5 (90 mg, 0.183 mmol), dimethylhydroxylamine hydrochloride (21.43 mg, 0.220 mmol), EDCI.HCl (52.62 mg, 0.274 mmol), and DCM (3 mL) were added, and the reaction was allowed to proceed for 0.5 h. Post-treatment: The mixture was concentrated under reduced pressure and purified by column chromatography (PE / EA(V / V) = 1 / 1) to give a yellow solid, compound 60-6, 0.042 g, yield 42.9%. MS: (ESI, pos.ion) m / z: 535.2578 [M+H] + .

[0459] Step 6: Synthesis of Compound 60-7

[0460] Compound 60-6 (42 mg, 0.0786 mmol) and LAH (0.4 mL, 0.4 mmol) were added at 0 °C and reacted for 20 min. Post-treatment: The system was quenched with EA (10 mL), followed by the addition of 1.0 g of Glauber's salt, diatomaceous earth filtration solution, and solvent concentration to obtain a yellow oily compound 60-7, 35 mg, in 93.7% yield. MS: (ESI, pos.ion) m / z: 476.2188 [M+H] + .

[0461] Step 7: Synthesis of Compound 60

[0462] Using compounds 60-7 as starting materials, and following the synthetic method described in Example 28, a pale yellow solid, compound 60, was obtained. MS: (ESI, pos.ion) m / z: 899.3666 [M+H] + .

[0463] Similarly, referring to the examples above, the compounds given in Table 2 were prepared.

[0464] Table 2

[0465] Example 63:

[0466] Synthesis steps:

[0467] Note: Intermediate compounds 1-6 are synthesized according to the method described in Example 1.

[0468] Step 1: Synthesis of Compound 63-1

[0469] In a 100 mL single-necked flask, 2-chloroethylamine hydrochloride (2.0 g, 17.24 mmol), sulfonyl chloride (13.96 g, 103.46 mmol), and acetonitrile (20 mL) were added, and the mixture was reacted at 80 °C for 10 h. Post-treatment: The solvent was concentrated to give a yellow oily compound 63-1, 3.0 g, in 98.3% yield.

[0470] Step 2: Synthesis of Compound 63-2

[0471] Compound 63-1 (3.0 g, 16.96 mmol) and compound 1-6 (2.5 g, 6.68 mmol) were added to DCM (25 mL) at 0 °C, followed by triethylamine (1.35 g, 13.35 mmol). The reaction mixture was stirred overnight. Post-treatment: The solvent was concentrated, and the mixture was purified by column chromatography to give a yellow solid, compound 63-2, 0.700 g, yield: 20.3%. MS: (ESI, pos.ion) m / z: 516.1898 [M+H] + .

[0472] Step 3: Synthesis of Compound 63-3

[0473] In a 25 mL single-necked flask, compound 63-2 (200 mg, 0.386 mmol), potassium carbonate (107.13 mg, 0.775 mmol), and DMSO (2 mL) were added, and the reaction was allowed to proceed for 1 h. Post-treatment: 10 mL of water and 10 mL of ethyl acetate were added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (10 mL * 2), washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (PE / EA (V / V) = 2 / 1) to give a yellow solid, compound 63-3, 0.162 g, yield 87.16%. MS: (ESI, pos.ion) m / z: 480.2157 [M+H] + .

[0474] Step 4: Synthesis of compound 63-4

[0475] In a 25 mL double-necked flask, compounds 63-3 (50 mg, 0.104 mmol), 60-9 (35.82 mg, 0.156 mmol), CuI (10 mg, 0.052 mmol), DMEDA (9 mg, 0.104 mmol), potassium carbonate (43 mg, 0.0313 mmol), and Dioxane (3 mL) were added. The mixture was purged with nitrogen three times and reacted at 110 °C for 2 h. Post-treatment: The mixture was concentrated under reduced pressure and purified by column chromatography (PE / EA(V / V) = 1 / 1) to give a yellow solid compound 63-4, 0.037 g, yield 56.5%. MS: (ESI, pos.ion) m / z: 628.2566 [M+H] + .

[0476] Step 5: Synthesis of compound 63-5

[0477] Compound 63-4 (111 mg, 0.177 mmol) and HCl / Dioxane (2 mL, 4.0 M) were added to a 25 mL single-necked flask, and the reaction was allowed to proceed for 0.5 h. Post-treatment: Concentration under reduced pressure yielded a yellow solid, compound 63-5, 0.099 g, with a yield of 99.3%.

[0478] Step 6: Synthesis of Compound 63

[0479] Compound 63-5 (99 mg, 0.175 mmol), HATU (0.133 g, 0.350 mmol), and compound 1-13 (86.66 mg, 0.211 mmol) were added at 0 °C, followed by DIEA (113 mg, 0.8776 mmol). The reaction was carried out overnight at room temperature. Post-treatment: 10 mL of water and 10 mL of ethyl acetate were added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (10 mL * 2), washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (PE / EA (V / V) = 1 / 1) to give a yellow solid, compound 63, 0.092 g, yield 56.9%. MS: (ESI, pos.ion) m / z: 921.3688 [M+H] + .

[0480] Similarly, referring to the examples above, the compounds given in Table 3 were prepared.

[0481] Table 3

[0482] Example 76

[0483] Synthesis steps:

[0484] Note: Intermediate compounds 1-6 were synthesized according to the method in Example 1, compound 26-2 was synthesized according to the method in Example 6 for intermediate 6-2, and compound 14-2 was prepared according to the method in Example 14.

[0485] Step 1: Synthesis of Compound 76

[0486] Using compound 14-2 as a starting material, and following the synthetic method described in Example 10, a white solid compound 76 was obtained. MS: (ESI, pos.ion) m / z: 937.4362 [M+H] + . 1H NMR (600MHz, DMSO, 120℃) δ11.50(s,2H),7.97(s,3H),7.56(s,1H),7.44(d,J=8.5Hz,1H),7.33( d,J=6.3Hz,2H),7.29(d,J=8.4Hz,1H),6.88(s,1H),5.70(d,J=65.3Hz,2H),4.52(s,1H),3.78–3 .72(m,3H),3.54(s,1H),3.11–2.96(m,3H),2.74(s,4H),2.31(d,J=1.5Hz,6H),1.80–1.61(m,1 0H),1.58(dd,J=22.0,9.2Hz,3H),1.31(s,3H),1.30(d,J=4.1Hz,1H),1.22(s,3H),1.14(s,3H).

[0487] Similarly, referring to the examples above, the compounds given in Table 4 were prepared.

[0488] Table 4

[0489] Example 88 h-GLP-1 Activity Assay

[0490] The h-GLP-1 activity was determined as follows:

[0491] 1) Prepare the Assay buffer (1XHBSS+20mM HEPES+0.1%BSA+500μM IBMX) in advance according to the table below, dispense it, and store it at -20℃ for later use.

[0492] Table 5 Preparation of Stock Solution Reagents

[0493] 2) CHO-K1GLP-1R cells were cultured in a CO2 incubator at 37°C using complete culture medium until the cell density reached 70-80% confluence, at which point the cell suspension was collected. Experimental wells and blank control wells were also provided.

[0494] 3) Compound preparation: First, prepare a 400X working solution concentration using DMSO. Dilute the natural peptide 3-fold and the test compound 5-fold. Apply 10 spots, either in replicates or single wells. Then, dilute the compound 100-fold using Assy buffer to prepare a 4X working solution concentration (the working concentration should be 4 times the final concentration). The final DMSO concentration is 0.25%.

[0495] 4) CHO-K1GLP-1R cells were seeded at a density of approximately 2000 cells / well in 7.5 μL of serum-containing complete medium into 384-well microplates with an opaque white bottom. An equal volume of complete medium was added to each well of the blank control.

[0496] 5) Add 2.5 μL / well of the serially diluted test compound or quality control STD (cAMP) from step 2 to a 384 microplate, centrifuge at 200g for 30s, and incubate at 37℃ for 30min. Add an equal volume of Assay buffer to each blank control well.

[0497] 6) Remove the 384-well plate after incubation. Add 5 μL of Uligh-anti-cAMP (1 / 5 times) to each well, then add 5 μL of Eu-Camp tracer (1 / 5 times) to each well. Cover the plate, centrifuge at 200g for 30s, and incubate at 25℃ for 60min.

[0498] 7) Data were read using an Enhance 2014 multi-functional microplate reader. Detection conditions were: excitation light: 340 nM, emission light: 665 nM and 620 nM. Data reading: Ratio = 665 nM / 620 nM * 1000.

[0499] 8) Data Analysis: Fit the data using the "log(agonist) vs. response -- variable slope" model in GraphPad Prism 8.0 to calculate EC. 50 %Activity = (VC - detection data) / (VC - PC) * 100%; PC: average value of well data corresponding to 10nM GLP-1 (7-37); VC: average value of well data corresponding to 0.25% DMSO.

[0500] 9) Use GraphPad Prism 8.0 to process experimental data.

[0501] As shown in Table 6 below, the compounds exhibit effective h-GLP-1 agonist activity (“A” means >0 nM and ≤1 nM; “B” means >1 nM and ≤10 nM; “C” means >10 nM).

[0502] Table 6. h-GLP-1 activity of the compounds in this application.

[0503] Conclusion: In vivo / in vitro GLP-1 receptor activity tests show that the compounds of the present invention have a good agonistic effect on GLP-1 receptors.

[0504] Example 89 Pharmacokinetic Evaluation of C57 Mice

[0505] Test Methods: The pharmacokinetic characteristics of the compounds in C57 mice after a single intravenous injection or a single oral administration were tested using a standard protocol. In the experiment, all candidate compounds were prepared into a clear solution using a solvent system of 5% DMSO + 10% Solutol + 85% Saline. A single intravenous injection (iv, n=3) of 1 mg / kg and a single oral administration (po, n=3) of 5 mg / kg were administered. Whole blood was collected from the animals at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. Plasma was separated, and pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.2.0 based on the blood drug concentration data at different time points. The parameters, including AUC0-t, AUC0-∞, MRT0-∞, Cmax, Tmax, T1 / 2, and F, along with their mean and standard deviation, were provided.

[0506] Table 7 Pharmacokinetic Parameters

[0507] Conclusion: The compounds of this invention significantly increased plasma exposure compared to orforglipron, and the compound of Example 76 exhibited slower elimination rate, longer half-life, and better pharmacokinetic properties.

[0508] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. The compound represented by formula (II) or a pharmaceutically acceptable salt thereof, in, Selected from R5 is selected from (CR) C R C ) 0-2 -cyclic hydrocarbon group, (CR C R C ) 0-2 -Aryl, (CR C R C ) 0-2 - Heterocyclic group or (CR) C R C ) 0-2 - Heteroaryl, wherein the cyclic hydrocarbon group is a spirocyclic hydrocarbon group, a bridged cyclic hydrocarbon group, or a monocyclic hydrocarbon group, and the aryl, heterocyclic, or heteroaryl group is a spirocyclic, bridged ring, fused ring, or monocyclic ring; the cyclic hydrocarbon group, aryl, heterocyclic, or heteroaryl group is optionally substituted by one or more substituents independently selected from: C1-C6 alkyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, oxo, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, -NO2, phenyl or heteroaryl; or when the carbon atom on the cycloalkyl, phenyl, aryl, heteroaryl or heterocyclic ring is replaced by two C1-C6 alkyl groups, the two C1-C6 alkyl groups together with the carbon atoms to which they are attached form a C3-C... 10 Cyclic hydrocarbon groups; each R C It is independently H, C1-C3 alkyl, or C1-C3 haloalkyl; or two R C Together with the carbon atoms to which they are attached, they form C3-C 10 Cyclic hydrocarbon group; the C3-C 10 The cyclic hydrocarbon group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen; A is selected from cycloalkyl, aryl, heterocyclic, or heteroaryl groups; wherein the cycloalkyl group is a spirocyclic, bridged, or monocyclic group, and the heterocyclic or heteroaryl group is a spirocyclic, bridged, fused, or monocyclic group; the cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxy-substituted alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, oxo, or thio. Or, A is selected from Wherein, U and V are independently selected from empty, N-Rd, N-Re or C-RfRg, C-RhRi; where, E is selected from O or S; Rd, Re, Rf, Rg, Rh, Ri, R 10 Or R 11 Independently selected from H, halogens, C1-C6 alkyl groups, C3-C 10 Cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, phenyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 12-membered heterocyclic, 5- to 12-membered aryl or 5- to 12-membered heteroaryl; the C1-C6 alkyl, C3-C 10 The cycloalkyl group, C1-C6 alkoxy group, C1-C6 alkylamino group, phenyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, 3- to 12-membered heterocyclic group, 5- to 12-membered aryl group, or 5- to 12-membered heteroaryl group is optionally substituted by one or more substituents independently selected from the following: D, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C3-C 12 Cyclic hydrocarbon group, OH, halogen, NH2, oxo, methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, 3 to 12-membered heterocyclic group, 5 to 12-membered heteroaryl or 5 to 12-membered aryl; wherein, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 The cycloalkyl group, NH2, 3 to 12-membered heterocyclic group, 5 to 12-membered heteroaryl group, or 5 to 12-membered aryl group is optionally substituted by one or more substituents independently selected from the following: D, halogen, cyano, amino, methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl; n is an integer from 0 to 10; m is 0 or 1; or Rf and Rg, Rh and Ri, R when n is not 0. 10 and R 11 Independently, together with the carbon atoms to which they are attached, they form C3-C. 10 Cyclic hydrocarbon group; the C3-C 10 The cycloalkyl group is optionally substituted by one or more substituents independently selected from: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen; or when m is 0, Rd and Re independently form a C3-C group together with the nitrogen atom to which they are attached. 10 Heterocyclic groups, the C3-C 10 The heterocyclic group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen; B is selected from C3-C 10 Cycloalkyl, aryl (preferably phenyl), heterocyclic group comprising one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S, or heteroaryl group comprising one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S; wherein the aryl, heterocyclic, or heteroaryl group is a spirocyclic, bridged ring, fused ring, or monocyclic ring; wherein the cycloalkyl, aryl (phenyl), heterocyclic, or heteroaryl group is optionally substituted by one or more substituents independently selected from: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C 12 Cycloalkyl groups, C1-C6 alkyl groups, C3-C6 alkyl groups 12 Cyclic hydrocarbon groups, OH, halogens, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, NH-S(=O)2Ra, CN, -NO2, P(=O)RaRb, S(=O)2Ra, oxo, thio Wherein, the cyclic hydrocarbon group is a spirocyclic hydrocarbon group, a bridged cyclic hydrocarbon group, or a monocyclic hydrocarbon group, and Ra and Rb are each independently selected from H, halogens, C1-C6 alkyl groups, and C3-C6 alkyl groups. 10 Cyclic hydrocarbon group, phenyl group; When A is empty, B is or Z is selected from CH or N; C is selected from CH2 or C=O; Selected from R4, R 12 Independently selected from H, halogens, C1-C6 alkyl groups, C3-C 10 Cycloalkyl, C1-C6 alkoxy, phenyl, vinyl, ethynyl, cyano, 3- to 12-membered heterocyclic, or 5- to 12-membered heteroaryl; wherein the alkyl, cycloalkyl, alkoxy, phenyl, vinyl, ethynyl, heterocyclic, or heteroaryl group is optionally substituted by one or more substituents independently selected from: halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, NH2, carboxyl, oxo, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, -NO2, or -C1-C6 alkyl C1-C6 alkyl; or when the heterocyclic or heteroaryl group is replaced by a C1-C6 alkyl group, the two C1-C6 alkyl groups together with the carbon atoms to which they are attached form a C3-C... 10 Cyclic hydrocarbon group; L is selected from C3-C 10 A cycloalkyl group, carbonyl group, phenylene group, or heteroaryl group comprising one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S, wherein the cycloalkyl group, phenylene group, or heteroaryl group is optionally substituted by one or more substituents independently selected from: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or halogen; or wherein when the phenylene group is substituted by two substituents attached to adjacent carbon atoms in the phenylene ring, the two substituents together with the carbon atoms to which they are attached are capable of forming a 5- or 6-membered ring, wherein the 5- or 6-membered ring optionally comprises 1-3 heteroatoms selected from N, O, and S; R6 and R7 are each independently selected from H, D, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen, or R6 and R7 together with the carbon atom to which they are attached form a C3-C... 10 Cyclic hydrocarbon group, the C3-C 10 The cyclic hydrocarbon group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen; T is selected from H, C(O)OH, (CH2)NS(O)2-(C1-C6 alkyl), or a heteroaryl group comprising a 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the heteroaryl group is optionally substituted with a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, OH, a halogen, or an oxo group; R1, R2, R3, R 13 R 14 and R 15 Each is independently selected from H, D, halogen, C1-C6 alkyl, C3-C 10 Cyclic hydrocarbon groups, phenyl groups; wherein, C1-C6 alkyl groups, C3-C6 alkyl groups, and C3-C6 alkyl groups are present. 10 The cycloalkyl group or phenyl group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN or -NO2; or R1, R2, R3, R 13 R 14 and R 15 Independently, together with the carbon atoms to which they are attached, they form C3-C. 10 Cyclic hydrocarbon group or C3-C 10 Heterocyclic group; the C3-C 10 Cyclic hydrocarbon group or C3-C 10 The heterocyclic group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

2. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is selected from the structure shown in formula (I). R1, R2, and R3 are each independently selected from H, D, halogens, C1-C6 alkyl groups, and C3-C4 alkyl groups. 10 Cyclic hydrocarbon groups, phenyl groups; wherein, C1-C6 alkyl groups, C3-C6 alkyl groups, and C3-C6 alkyl groups are present. 10 The cyclic hydrocarbon group and phenyl group are optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN or -NO2.

3. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R1 and R 13 Not H.

4. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R2 and R 14 Not H.

5. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R3 and R 15 Not H.

6. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, Selected from 7. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The R5 is selected from (CR) C R C ) 0-2 -C3-C6 cyclic hydrocarbon group, (CR C R C ) 0-2 -Phenyl, containing two 5- or 6-membered rings (CR C R C ) 0-2 -aryl, comprising one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S (CR C R C ) 0-2 - Heteroaryl groups or groups containing one or two 3- to 6-membered rings and 1-3 heteroatoms selected from N, O, and S (CR C R C ) 0-2 - Heterocyclic group; wherein the cyclic hydrocarbon group, phenyl group, aryl group, heteroaryl group or heterocyclic group is optionally substituted by one or more substituents independently selected from: C1-C6 alkyl group, C1-C6 haloalkyl group, C3-C6 alkyl group, C4-C6 alkyl group, C5-C6 alkyl group, C6 ... 10 Cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, -NO2, C3-C6 cycloalkyl, phenyl or heteroaryl; or when the carbon atom on the cycloalkyl, phenyl, aryl, heteroaryl or heterocyclic ring is replaced by two C1-C6 alkyl groups, the two C1-C6 alkyl groups together with the carbon atoms to which they are attached form a C3-C... 10 Cyclic hydrocarbon groups; each R C Independently selected from H, C1-C3 alkyl, or C1-C3 haloalkyl; or two R C Together with the carbon atoms to which they are attached, they form C3-C 10 Cyclic hydrocarbon group; the C3-C 10 The cyclic hydrocarbon group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

8. The compound of formula (II) according to claim 1 or 6, or a pharmaceutically acceptable salt thereof, characterized in that, The R5 is selected from (CR) C R C ) 0-2 -C3-C6 cyclic hydrocarbon group, (CR C R C ) 0-2 -Phenyl, containing two 5- or 6-membered rings (CR C R C ) 0-2 -Aryl or containing one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S (CR C R C ) 0-2 - Heteroaryl; the cycloalkyl, phenyl, aryl, or heteroaryl group is optionally substituted by one or more substituents independently selected from: C1-C6 alkyl, C1-C6 haloalkyl, C3-C 10 Cyclic hydrocarbon group, C1-C6 alkoxy group, C1-C6 haloalkoxy group, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, -NO2 or C3-C6 cyclic hydrocarbon group, each R C Independently selected from H, C1-C3 alkyl, or C1-C3 haloalkyl; or when the carbon atom on the cycloalkyl, phenyl, aryl, or heteroaryl ring is replaced by two C1-C6 alkyl groups, the two C1-C6 alkyl groups together with the carbon atoms to which they are attached form a C3-C... 10 Cyclic hydrocarbon group; or two R groups C Together with the carbon atoms to which they are attached, they form C3-C 10 Cyclic hydrocarbon group; the C3-C 10 The cyclic hydrocarbon group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

9. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The A is selected from U and V are independently selected from N-Rd, N-Re, or C-RfRg, C-RhRi; E is selected from O or S; Rd, Re, Rf, Rg, Rh, or Ri are independently selected from H, halogens, C1-C6 alkyl groups, C3-C 10 Cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, phenyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 12-membered heterocyclic, 5- to 12-membered aryl or 5- to 12-membered heteroaryl; the C1-C6 alkyl, C3-C 10 The cycloalkyl group, C1-C6 alkoxy group, C1-C6 alkylamino group, phenyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, 3- to 12-membered heterocyclic group, 5- to 12-membered aryl group, or 5- to 12-membered heteroaryl group is optionally substituted by one or more substituents independently selected from the following: D, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C3-C 12 Cyclic hydrocarbon group, OH, halogen, NH2, oxo, methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, 3 to 12-membered heterocyclic group, 5 to 12-membered heteroaryl or 5 to 12-membered aryl; wherein, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 The cycloalkyl group, NH2, 3 to 12-membered heterocyclic group, 5 to 12-membered heteroaryl group, or 5 to 12-membered aryl group is optionally substituted by one or more substituents independently selected from: D, halogen, cyano, amino, methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, where n is an integer from 0 to 10; m is 0 or 1; or Rf and Rg, Rh and Ri together with the carbon atom to which they are attached form a C3-C 10 Cyclic hydrocarbon group, the C3-C 10 The cyclic hydrocarbon group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

10. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The A is selected from Where E is selected from O or S; Rd and Re are independently selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, phenyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 12-membered heterocyclic, 5- to 12-membered aryl or 5- to 12-membered heteroaryl; the C1-C6 alkyl, C3-C 10 The cycloalkyl group, C1-C6 alkoxy group, C1-C6 alkylamino group, phenyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, 3- to 12-membered heterocyclic group, 5- to 12-membered aryl group, or 5- to 12-membered heteroaryl group is optionally substituted by one or more substituents independently selected from the following: D, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C3-C 12 Cycloalkyl, OH, halogen, NH2, oxo, methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, 3 to 12-membered heterocyclic, 5 to 12-membered heteroaryl or 5 to 12-membered aryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 The cycloalkyl group, NH2, 3- to 12-membered heterocyclic group, 5- to 12-membered heteroaryl group, or 5- to 12-membered aryl group is optionally substituted by one or more substituents independently selected from the following: D, halogen, cyano, amino, methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, where n is an integer from 0 to 10; or Rd and Re independently form a C3-C group together with the nitrogen atom to which they are attached. 10 Heterocyclic groups, the C3-C 10 The heterocyclic group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

11. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The A is selected from Where E is selected from O or S; Rd, Re, Rf, Rg, Rh or Ri are independently selected from H, halogens, C1-C6 alkyl groups, C3-C 10 Cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, phenyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 12-membered heterocyclic, 5- to 12-membered aryl or 5- to 12-membered heteroaryl; the C1-C6 alkyl, C3-C 10 The cycloalkyl group, C1-C6 alkoxy group, C1-C6 alkylamino group, phenyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, 3- to 12-membered heterocyclic group, 5- to 12-membered aryl group, or 5- to 12-membered heteroaryl group is optionally substituted by one or more substituents independently selected from the following: D, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C3-C 12 Cycloalkyl, OH, halogen, NH2, oxo, methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, 3 to 12-membered heterocyclic, 5 to 12-membered heteroaryl or 5 to 12-membered aryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 The cycloalkyl group, NH2, 3 to 12-membered heterocyclic group, 5 to 12-membered heteroaryl group, or 5 to 12-membered aryl group is optionally substituted by one or more substituents independently selected from the following: D, halogen, cyano, amino, methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, where n is an integer from 0 to 10; or Rf and Rg, Rh and Ri independently form a C3-C group together with the carbon atom to which they are attached. 10 Cyclic hydrocarbon group, the C3-C 10 The cyclic hydrocarbon group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

12. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The A is selected from Rd and Re are independently selected from H, C1-C6 alkyl groups, and C3-C4 alkyl groups. 10 Cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, phenyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 12-membered heterocyclic, 5- to 12-membered aryl or 5- to 12-membered heteroaryl; the C1-C6 alkyl, C3-C 10 The cycloalkyl group, C1-C6 alkoxy group, C1-C6 alkylamino group, phenyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, 3- to 12-membered heterocyclic group, 5- to 12-membered aryl group, or 5- to 12-membered heteroaryl group is optionally substituted by one or more substituents independently selected from the following: D, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C3-C 12 Cyclic hydrocarbon group, OH, halogen, NH2, oxo, methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, 3 to 12-membered heterocyclic group, 5 to 12-membered heteroaryl or 5 to 12-membered aryl; wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 The cycloalkyl group, NH2, 3 to 12-membered heterocyclic group, 5 to 12-membered heteroaryl group, or 5 to 12-membered aryl group is optionally substituted by one or more substituents independently selected from the following: D, halogen, cyano, amino, methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, where n is an integer from 0 to 10.

13. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The A is selected from Wherein, E is selected from O or S; V is selected from N-Re or C-RhRi; Re, Rh, Ri, R 10 Or R 11 Independently selected from H, halogens, C1-C6 alkyl groups, C3-C 10 Cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, phenyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 12-membered heterocyclic, 5- to 12-membered aryl or 5- to 12-membered heteroaryl; the C1-C6 alkyl, C3-C 10 The cycloalkyl group, C1-C6 alkoxy group, C1-C6 alkylamino group, phenyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, 3- to 12-membered heterocyclic group, 5- to 12-membered aryl group, or 5- to 12-membered heteroaryl group is optionally substituted by one or more substituents independently selected from the following: D, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C3-C 12 Cyclic hydrocarbon group, OH, halogen, NH2, oxo, methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, 3 to 12-membered heterocyclic group, 5 to 12-membered heteroaryl or 5 to 12-membered aryl; wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 The cycloalkyl group, NH2, 3 to 12-membered heterocyclic group, 5 to 12-membered heteroaryl group, or 5 to 12-membered aryl group is optionally substituted by one or more substituents independently selected from the following: D, halogen, cyano, amino, methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, where n is an integer from 0 to 10; or Rh and Ri, R when n is not 0. 10 and R 11 Independently, together with the carbon atoms to which they are attached, they form C3-C. 10 Cyclic hydrocarbon group; the C3-C 10 The cyclic hydrocarbon group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

14. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The B is selected from a heterocyclic group comprising one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S, or a heteroaryl group comprising one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S; wherein the heterocyclic group or the heteroaryl group is optionally substituted by one or more substituents independently selected from: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C 12 Cyclic hydrocarbon group, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN or -NO2.

15. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, A is selected from heterocyclic groups, heteroaryl groups, or empty; the heteroaryl or heterocyclic group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxy-substituted alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, oxo, thio.

16. The compound of formula (II) according to claim 15, or a pharmaceutically acceptable salt thereof, characterized in that, The A is selected from Or empty; wherein R8 and R9 are each independently selected from H, D, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxy-substituted alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, oxo, thio, or R8 and R9 together with the carbon atom to which they are attached form a C3-C 10 Cyclic hydrocarbon group or C3-C 10 Heterocyclic hydrocarbon group; the C3-C 10 Cyclic hydrocarbon group or C3-C 10 The heterocyclic hydrocarbon group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxy-substituted alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

17. The compound of formula (II) according to claim 16, or a pharmaceutically acceptable salt thereof, characterized in that, The A is selected from R8 and R9 are each independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxy-substituted alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen, or R8 and R9 together with the carbon atom to which they are attached form a C3-C6 cyclic hydrocarbon group or a C3-C6 heterocyclic hydrocarbon group; the C3-C6 cyclic hydrocarbon group or C3-C6 heterocyclic hydrocarbon group is optionally substituted by one or more substituents independently selected from: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxy-substituted alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen.

18. The compound of formula (II) according to claim 17, or a pharmaceutically acceptable salt thereof, characterized in that, The A is selected from 19. The compound of formula (II) according to claim 16, or a pharmaceutically acceptable salt thereof, characterized in that, The A is selected from 20. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The A is selected from Wherein, E is selected from O; Rd and Re are independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cyclic hydrocarbon group or C1-C6 alkoxy group; the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 The cyclic hydrocarbon group or C1-C6 alkoxy group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C 10 Cyclic hydrocarbon group, OH, halogen, NH2, Oxylated, methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, 3 to 12-membered heterocyclic, C1-C6 alkyl or C1-C6 haloalkyl-substituted 3 to 12-membered heterocyclic, phenyl or halophenyl; n is 0 or 1.

21. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The A is selected from Where R 10 Or R 11 Independently selected from H, halogens, C1-C6 alkyl groups, C3-C 10 Cycloalkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl, C3-C 10 The cyclic hydrocarbon group or C1-C6 alkoxy group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C 10 Cyclic hydrocarbon group, OH, halogen, NH2, Oxylated, methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, 3- to 12-membered heterocyclic groups, C1-C6 alkyl or C1-C6 haloalkyl-substituted 3- to 12-membered heterocyclic groups, phenyl or halophenyl; n is 0 or 1; or when n is not 0, R 10 and R 11 Together with the carbon atoms to which they are attached, they form C3-C 10 Cyclic hydrocarbon group, the C3-C 10 The cyclic hydrocarbon group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

22. The compound of formula (II) according to claim 20, or a pharmaceutically acceptable salt thereof, characterized in that, Rd and Re are independently selected from H, 23. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The A is selected from in Selected from 24. The compound of formula (II) according to claim 1 or 11, or a pharmaceutically acceptable salt thereof, characterized in that, The A is selected from 25. The compound of formula (II) according to claim 1 or 12, or a pharmaceutically acceptable salt thereof, characterized in that, The A is selected from 26. The compound of formula (II) according to claim 1 or 13, or a pharmaceutically acceptable salt thereof, characterized in that, The A is selected from 27. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, n is 0.

28. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, n is 1.

29. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, m is 0.

30. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, m is 1.

31. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The B is selected from 32. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, Z is selected from N.

33. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The C is selected from C=O.

34. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The Selected from 35. The compound of formula (II) according to claim 1 or 34, or a pharmaceutically acceptable salt thereof, characterized in that, The R4 is independently selected from halogens, C1-C6 alkyl groups, and C3-C4 alkyl groups. 10 Cycloalkyl, C1-C6 alkoxy, phenyl, vinyl, ethynyl, cyano, heterocyclic group comprising one or two 3- to 6-membered rings and 1-3 heteroatoms selected from N, O, and S, or heteroaryl group comprising one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S; wherein the alkyl, cycloalkyl, alkoxy, phenyl, vinyl, ethynyl, heterocyclic, or heteroaryl group is optionally substituted by one or more substituents independently selected from: halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, NH2, oxo, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, -NO2, or -C1-C6 alkyl C1-C6 alkyl groups.

36. The compound of formula (II) according to claim 1 or 34, or a pharmaceutically acceptable salt thereof, characterized in that, R4 is selected from C3-C 10 Cyclic hydrocarbon group, the C3-C 10 The cyclic hydrocarbon group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN or -NO2; wherein the cyclic hydrocarbon group is selected from spirocyclic hydrocarbon groups, bridged cyclic hydrocarbon groups or monocyclic hydrocarbon groups.

37. The compound of formula (II) according to claim 1 or 34, or a pharmaceutically acceptable salt thereof, characterized in that, The R4 is selected from vinyl or ethynyl groups, which are optionally substituted by one or more substituents independently selected from the following:

38. The compound of formula (II) according to claim 1 or 34, or a pharmaceutically acceptable salt thereof, characterized in that, The R4 is selected from tetrahydropyranyl, which is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN and -NO2.

39. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The L is selected from R6 and R7 are each independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen; or R6 and R7 together with the carbon atoms to which they are attached form a C3-C... 10 Cyclic hydrocarbon group, the C3-C 10 The cyclic hydrocarbon group is optionally substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

40. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The T is selected from heteroaryl groups comprising a 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the heteroaryl group is optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, or oxo.

41. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The R1, R2, R3, R 13 R 14 and R 15 Each is independently selected from H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

42. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, characterized in that, R1, R2 and R3 are independently selected from H, halogens, C1-C6 alkyl groups, or C1-C6 haloalkyl groups.

43. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The R1, R2, R3, R 13 R 14 and R 15 Independently, together with the carbon atoms to which they are attached, they form C3-C. 10 Cyclic hydrocarbon group or C3-C 10 Heterocyclic groups, the C3-C 10 Cyclic hydrocarbon group or C3-C 10 The heterocyclic group may optionally be substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, OH, or halogen.

44. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R5 is selected from 45. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R4 is selected from 46. ​​The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The R 12 Selected from H, halogens, C1-C6 alkyl groups, C3-C 10 Cycloalkyl, C1-C6 alkoxy, phenyl, vinyl, ethynyl, or cyano.

47. The compound of formula (II) according to claim 1 or 46, or a pharmaceutically acceptable salt thereof, characterized in that, The R 12 Selected from H, F, Cl, methyl, ethyl, or cyclopropyl.

48. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The L is selected from 49. The compound of formula (II) according to claim 1 or 40, or a pharmaceutically acceptable salt thereof, characterized in that, The T is selected from oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiazolyl, oxadiazolone, thiazolyl, wherein each is optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen or oxo.

50. The compound of formula (II) according to claim 49, or a pharmaceutically acceptable salt thereof, characterized in that, The T is 51. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The T is C(O)OH.

52. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that... The for 53. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound has formula (II-1), formula (II-2), formula (II-3), or formula (II-4): Among them, A, B, L, T, R1, R2, R3, R 13 R 14 R 15 R4, R5 and R 12 As defined in claim 1.

54. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, characterized in that, The compound has formula (I-1), formula (I-2), formula (I-3), formula (I-4), or formula (I-5): Among them, A, B, L, T, R1, R4, R5, R 12 and R 13 As defined in claim 2.

55. [Amended 16.01.2025 according to Rule 91] A compound of the following formula or a pharmaceutically acceptable salt thereof, 56. The compound of claim 55 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

57. A pharmaceutical composition comprising, as an active ingredient, a compound according to any one of claims 1-56 or a pharmaceutically acceptable salt thereof.

58. A method for treating or preventing GLP-1 receptor-mediated diseases or disorders or modulating GLP-1 receptors, comprising administering to a subject in need a therapeutically effective amount of the compound of any one of claims 1-56 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 57.

59. A method for treating non-insulin-dependent diabetes mellitus (type 2 diabetes), hyperglycemia, impaired glucose tolerance, insulin-dependent diabetes mellitus (type 1 diabetes), diabetic complications, obesity, hypertension, hyperlipidemia, arteriosclerosis, coronary heart disease, cerebral infarction, non-alcoholic steatohepatitis, Parkinson's disease, or dementia, the method comprising administering to a subject requiring the treatment a therapeutically effective amount of any one of the compounds of claims 1-56 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 57.

60. A method for treating non-insulin-dependent type 2 diabetes or obesity, the method comprising administering to a subject requiring the treatment a therapeutically effective amount of any one of claims 1-56 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 57.

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