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] The present invention relates to a heterocyclic GLP-1 receptor agonist compound or a pharmaceutically acceptable salt thereof, and a method for treating or preventing GLP-1 receptor-mediated diseases or disorders or regulating GLP-1 receptors. Background Art

[0002] Diabetes is a chronic disease characterized by high blood sugar levels 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 over 90% of diabetes cases. The disease typically develops in obese or sedentary adults and begins with insulin resistance, which is then associated with elevated blood sugar levels due to the combined effects of impaired insulin secretion and insulin resistance. Although lifestyle changes 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-promoting hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are important in the regulation of glucose homeostasis. Drugs targeting this family of gut peptides, such as 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 delay the progression of atherosclerotic cardiovascular disease. However, most current GLP-1 receptor agonists, including semaglutide, require invasive subcutaneous administration. Although the specific formulation semaglutide under development can be administered orally, it still has disadvantages such as inconvenient dosing regimens and poor bioavailability.

[0005] LY3502970 is a novel, highly potent, oral, non-peptide GLP-1R agonist. Preclinical studies have shown that LY3502970's glucose-lowering efficacy is comparable to that of exenatide. Pharmacokinetic studies in cynomolgus monkeys revealed a half-life of 3.4 to 4.6 hours and a bioavailability of 21 to 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] The present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt 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 cycloalkyl is a spirocyclic hydrocarbon group, a bridged cycloalkyl group or a monocyclic hydrocarbon group, and the aryl, heterocyclyl or heteroaryl is a spirocyclic ring, a bridged ring, a fused ring or a monocyclic ring; the cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted by one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 alkyl, C1-C6 alkyl haloalkyl, C3 ... 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 a carbon atom on a cycloalkyl, phenyl, aryl, heteroaryl or heterocyclyl ring is substituted with two C1-C6 alkyl groups, the two C1-C6 alkyl groups together with the carbon atoms to which they are attached form a C3-C6 alkyl group. 10 Cycloalkyl; each R C are independently selected from H, C1-C3 alkyl or C1-C3 haloalkyl; or two R C Together with the carbon atom to which they are attached, they form C3-C 10 Cyclic hydrocarbon group; the C3-C 10 The cycloalkyl group is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen.

[0011] A is selected from cycloalkyl, aryl, heterocyclic radical or heteroaryl, wherein the cycloalkyl is a spirocyclic hydrocarbon radical, a bridged cycloalkyl radical or a monocyclic hydrocarbon radical, and the heterocyclic radical or heteroaryl is a spirocyclic ring, a bridged ring, a condensed ring or a monocyclic ring; the cycloalkyl, aryl, heteroaryl or heterocyclic radical 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, thioxo.

[0012] Or A is selected from wherein U and V are independently selected from space, N-Rd, N-Re or C-RfRg, C-RhRi, wherein E is selected from O or S; Rd, Re, Rf, Rg, Rh, Ri, R 10 or R 11 Independently selected from H, halogen, 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 group, 5- to 12-membered aryl or 5- to 12-membered heteroaryl; the C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, phenyl, C2-C6 alkenyl, C2-C6 alkynyl, 3 to 12 membered heterocyclyl, 5 to 12 membered aryl or 5 to 12 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, OH, halogen, NH2, oxo, methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopropylsulfonyl, 3 to 12 membered heterocyclyl, 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 Cycloalkyl, NH2, 3 to 12 membered heterocyclyl, 5 to 12 membered heteroaryl or 5 to 12 membered aryl are optionally substituted with one or more substituents independently selected from the group consisting of D, halogen, cyano, amino, methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopropylsulfonyl, 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 atom to which they are attached to form C3-C 10 Cycloalkyl, the C3-C 10The cycloalkyl group is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen; or when m is 0, Rd and Re are independently taken together with the nitrogen atom to which they are attached to form a C3-C6 alkyl group. 10 Heterocyclic group, the C3-C 10 The heterocyclyl group is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

[0013] B is selected from C3-C 10 Cycloalkyl, aryl (preferably phenyl), heterocyclyl comprising one or two 5-membered or 6-membered rings and 1-3 heteroatoms selected from N, O and S, or heteroaryl comprising one or two 5-membered or 6-membered rings and 1-3 heteroatoms selected from N, O and S, wherein the aryl, heterocyclyl or heteroaryl is a spirocycle, a bridged ring, a fused ring or a monocycle; wherein the cycloalkyl, aryl (phenyl), heterocyclyl or heteroaryl 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, C3-C6 alkyl ... 12 Cycloalkyl, C1-C6 alkyl-C3-C 12 Cyclic hydrocarbon group, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, NH-S(=O)2Ra, CN, -NO2, P(=O)RaRb, S(=O)2Ra, oxo, thioxo, wherein the cyclic hydrocarbon group is a spirocyclic hydrocarbon group, a bridged cyclic hydrocarbon group or a monocyclic hydrocarbon group, and the Ra and Rb are each independently selected from H, halogen, C1-C6 alkyl, C3-C 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, halogen, C1-C6 alkyl, C3-C 10Cycloalkyl, C1-C6 alkoxy, phenyl, vinyl, ethynyl, cyano, 3 to 12 membered heterocyclyl or 5 to 12 membered heteroaryl, wherein the alkyl, cycloalkyl, alkoxy, phenyl, vinyl, ethynyl, heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of 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 group or heteroaryl is substituted by a C1-C6 alkyl, two C1-C6 alkyl groups together with the carbon atom to which they are attached can form a C3-C 10 Cyclic hydrocarbon group.

[0019] L is selected from C3-C 10 a cycloalkyl, carbonyl, phenylene, 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, phenylene, or heteroaryl group is optionally substituted with 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 with 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-C6 alkyl radical. 10 Cycloalkyl, the C3-C 10 The cycloalkyl group is optionally substituted with one or more substituents independently selected from the group consisting of 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-membered 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.

[0022] R1, R2, R3, R 13 、R14 and R 15 Each independently selected from H, D, halogen, C1-C6 alkyl, C3-C 10 Cyclic hydrocarbon group, phenyl group; wherein, C1-C6 alkyl group, C3-C 10 Cycloalkyl, phenyl are optionally substituted by one or more substituents independently selected from the group consisting of 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 atom to which they are attached to form C3-C 10 Cyclic hydrocarbon or C3-C 10 Heterocyclic group, the C3-C 10 Cyclic hydrocarbon or C3-C 10 The heterocyclyl group is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

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

[0024] wherein R1, R2 and R3 are each independently selected from H, D, halogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, phenyl, C1-C6 alkyl, C3-C 10 The cycloalkyl group and the phenyl group are optionally substituted by one or more substituents independently selected from the group consisting of 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, the above R1 and R 13 Not for H.

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

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

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

[0029] In some embodiments of the present invention, the above R5 is selected from (CR C R C ) 0-2 -C3-C6 cycloalkyl, (CR C R C ) 0-2 -phenyl, containing two 5-membered or 6-membered rings (CR C R C ) 0-2 -aryl, (CR C R C ) 0-2 -heteroaryl or (CR) containing one or two 3- to 6-membered rings and 1-3 heteroatoms selected from N, O and S C R C ) 0-2 -heterocyclyl, wherein the cycloalkyl, phenyl, aryl, heteroaryl or heterocyclyl is optionally substituted by one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 alkyl, C1-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 a carbon atom on the cycloalkyl, phenyl, aryl, heteroaryl or heterocyclyl ring is substituted with two C1-C6 alkyl groups, the two C1-C6 alkyl groups together with the carbon atoms to which they are attached form a C3-C6 alkyl group. 10 Cycloalkyl; each R C are independently selected from H, C1-C3 alkyl or C1-C3 haloalkyl; or two R C Together with the carbon atom to which they are attached, they form C3-C 10 Cycloalkyl, the C3-C 10 The cycloalkyl group is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen.

[0030] In some embodiments of the present invention, the above R5 is selected from (CR C R C ) 0-2 -C3-C6 cycloalkyl, (CR C R C ) 0-2 -phenyl, containing two 5-membered or 6-membered rings (CR C R C ) 0-2 -aryl or (CR) containing one or two 5-membered or 6-membered rings and 1-3 heteroatoms selected from N, O and SC R C ) 0-2 -heteroaryl, said cycloalkyl, phenyl, aryl or heteroaryl being optionally substituted by one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, -NO2 or C3-C6 cycloalkyl, each R C independently selected from H, C1-C3 alkyl or C1-C3 haloalkyl; or when a carbon atom on a cycloalkyl, phenyl, aryl or heteroaryl ring is substituted with 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 C Together with the carbon atom to which they are attached, they form C3-C 10 Cycloalkyl, the C3-C 10 The cycloalkyl group is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen.

[0031] In some embodiments of the present invention, the above-mentioned B is selected from a heterocyclic group containing one or two 5-membered or 6-membered rings and 1-3 heteroatoms selected from N, O and S, or a heteroaryl group containing one or two 5-membered 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 the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 alkyl, C1-C6 alkyloxy, C1-C6 alkyloxy, C3-C6 alkyloxy, C1 ... 12 Cycloalkyl, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN or -NO2.

[0032] In some embodiments of the present invention, the above-mentioned A is selected from a heterocyclic group, a heteroaryl group or is empty, and the heteroaryl group 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, and thioxo.

[0033] In some embodiments of the present invention, the above-mentioned A is selected from or is 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, thioxo, or R8 and R9 together with the carbon atom to which they are attached form a C3-C 10 Cyclic hydrocarbon or C3-C 10 Heterocyclic hydrocarbon group, the C3-C 10 Cyclic hydrocarbon or C3-C 10 The heterocycloalkyl group is optionally substituted with one or more substituents independently selected from the group consisting of 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, the above-mentioned A is selected from wherein 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 atoms to which they are attached form a C3-C6 cycloalkyl or C3-C6 heterocycloalkyl, which is optionally substituted with 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.

[0035] In some embodiments of the present invention, the above-mentioned A is selected from

[0036] In some embodiments of the present invention, the above-mentioned A is selected from

[0037] In some embodiments of the present invention, the above-mentioned A is selected from wherein U and V are independently selected from N-Rd, N-Re or C-RfRg, C-RhRi, wherein E is selected from O or S; Rd, Re, Rf, Rg, Rh or Ri are independently selected from H, halogen, 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 group, 5- to 12-membered aryl or 5- to 12-membered heteroaryl; the C1-C6 alkyl, C3-C 10Cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, phenyl, C2-C6 alkenyl, C2-C6 alkynyl, 3 to 12 membered heterocyclyl, 5 to 12 membered aryl or 5 to 12 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, OH, halogen, NH2, oxo, methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopropylsulfonyl, 3 to 12 membered heterocyclyl, 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 Cycloalkyl, NH2, 3 to 12 membered heterocyclyl, 5 to 12 membered heteroaryl or 5 to 12 membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of D, halogen, cyano, amino, methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopropylsulfonyl, 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 together with the carbon atom to which they are attached form a C3-C6 alkyl radical. 10 Cycloalkyl, the C3-C 10 The cycloalkyl group is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen.

[0038] In some embodiments of the present invention, the above-mentioned A is selected from Wherein 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 group, 5- to 12-membered aryl or 5- to 12-membered heteroaryl; the C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, phenyl, C2-C6 alkenyl, C2-C6 alkynyl, 3 to 12 membered heterocyclyl, 5 to 12 membered aryl or 5 to 12 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, OH, halogen, NH2, oxo, methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopropylsulfonyl, 3 to 12 membered heterocyclyl, 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 12Cycloalkyl, NH2, 3 to 12 membered heterocyclyl, 5 to 12 membered heteroaryl or 5 to 12 membered aryl are optionally substituted with one or more substituents independently selected from the group consisting of D, halogen, cyano, amino, methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopropylsulfonyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, n is an integer from 0 to 10; or Rd and Re are independently taken together with the nitrogen atom to which they are attached to form a C3-C6 alkyl radical. 10 Heterocyclic group, the C3-C 10 The heterocyclyl group is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

[0039] In some embodiments of the present invention, the above-mentioned 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 Cycloalkyl or C1-C6 alkoxy; the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 The cycloalkyl or C1-C6 alkoxy group is optionally substituted by one or more substituents independently selected from the group consisting of 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-C6 alkyl ... 10 Cyclic hydrocarbon, OH, halogen, NH2, oxo, methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopropylsulfonyl, a 3- to 12-membered heterocyclic group, a 3- to 12-membered heterocyclic group substituted with a C1-C6 alkyl group or a C1-C6 haloalkyl group, a phenyl group or a halophenyl group; n is 0 or 1.

[0040] In some embodiments of the present invention, the above-mentioned A is selected from wherein E is selected from O or S; Rd, Re, Rf, Rg, Rh or Ri are independently selected from H, halogen, 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 group, 5- to 12-membered aryl or 5- to 12-membered heteroaryl; the C1-C6 alkyl, C3-C 10Cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, phenyl, C2-C6 alkenyl, C2-C6 alkynyl, 3 to 12 membered heterocyclyl, 5 to 12 membered aryl or 5 to 12 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, OH, halogen, NH2, oxo, methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopropylsulfonyl, 3 to 12 membered heterocyclyl, 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 Cycloalkyl, NH2, 3 to 12 membered heterocyclyl, 5 to 12 membered heteroaryl or 5 to 12 membered aryl are optionally substituted with one or more substituents independently selected from the group consisting of D, halogen, cyano, amino, methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopropylsulfonyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, n is an integer from 0 to 10; or Rf and Rg, Rh and Ri are independently taken together with the carbon atom to which they are attached to form a C3-C6 alkyl group. 10 Cycloalkyl, the C3-C 10 The cycloalkyl group is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen.

[0041] In some embodiments of the present invention, the above-mentioned A is selected from wherein 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 group, 5- to 12-membered aryl or 5- to 12-membered heteroaryl; the C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, phenyl, C2-C6 alkenyl, C2-C6 alkynyl, 3 to 12 membered heterocyclyl, 5 to 12 membered aryl or 5 to 12 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, OH, halogen, NH2, oxo, methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopropylsulfonyl, 3 to 12 membered heterocyclyl, 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 12Cycloalkyl, NH2, 3 to 12 membered heterocyclyl, 5 to 12 membered heteroaryl or 5 to 12 membered aryl are optionally substituted with one or more substituents independently selected from the group consisting of D, halogen, cyano, amino, methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopropylsulfonyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and n is an integer from 0 to 10.

[0042] In some embodiments of the present invention, the above-mentioned 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, halogen, 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 group, 5- to 12-membered aryl or 5- to 12-membered heteroaryl; the C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, phenyl, C2-C6 alkenyl, C2-C6 alkynyl, 3 to 12 membered heterocyclyl, 5 to 12 membered aryl or 5 to 12 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, OH, halogen, NH2, oxo, methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopropylsulfonyl, 3 to 12 membered heterocyclyl, 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 Cycloalkyl, NH2, 3 to 12 membered heterocyclyl, 5 to 12 membered heteroaryl or 5 to 12 membered aryl are optionally substituted with one or more substituents independently selected from the group consisting of D, halogen, cyano, amino, methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopropylsulfonyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 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 atom to which they are attached to form C3-C 10 Cycloalkyl, the C3-C 10 The cycloalkyl group is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen.

[0043] In some embodiments of the present invention, the above-mentioned A is selected from where R 10 or R 11 Independently selected from H, halogen, C1-C6 alkyl, C3-C 10 Cycloalkyl or C1-C6 alkoxy; the C1-C6 alkyl, C3-C 10 The cycloalkyl or C1-C6 alkoxy group is optionally substituted by one or more substituents independently selected from the group consisting of 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-C6 alkyl ... 10 Cyclic hydrocarbon, OH, halogen, NH2, oxo, methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopropylsulfonyl, 3- to 12-membered heterocyclic group, 3- to 12-membered heterocyclic group substituted with C1-C6 alkyl or C1-C6 haloalkyl, phenyl or halophenyl; n is 0 or 1; or when n is not 0, R 10 and R 11 Together with the carbon atom to which they are attached, they form C3-C 10 Cycloalkyl, the C3-C 10 The cycloalkyl group is optionally substituted with one or more substituents independently selected from the group consisting of 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, the above-mentioned A is selected from in Selected from

[0046] In some embodiments of the present invention, the above-mentioned A is selected from

[0047] In some embodiments of the present invention, the above-mentioned A is selected from

[0048] In some embodiments of the present invention, the above-mentioned A is selected from

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

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

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

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

[0053] In some embodiments of the present invention, the above-mentioned B is selected from

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

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

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

[0057] In some embodiments of the present invention, the above R4 is independently selected from halogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkoxy, phenyl, vinyl, ethynyl, cyano, heterocyclyl containing one or two 3- to 6-membered rings and 1-3 heteroatoms selected from N, O and S, or heteroaryl containing 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, heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from the following: 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.

[0058] In some embodiments of the present invention, the above R4 is selected from C3-C 10 Cycloalkyl, the C3-C 10 The cycloalkyl group is optionally substituted by one or more substituents independently selected from the group consisting of 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 cycloalkyl group is selected from a spirocyclic hydrocarbon group, a bridged cycloalkyl group or a monocyclic hydrocarbon group.

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

[0060] In some embodiments of the present invention, the above-mentioned R4 is selected from tetrahydropyranyl, and the tetrahydropyranyl 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.

[0061] In some embodiments of the present invention, the above 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-C6 alkyl group. 10 Cycloalkyl, the C3-C 10 The cycloalkyl group is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen.

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

[0065] In some embodiments of the present invention, the above R1, R2, R3, R 13 、R 14 and R 15 independently together with the carbon atom to which they are attached to form C3-C 10 Cyclic hydrocarbon or C3-C 10 Heterocyclic group, the C3-C 10 Cyclic hydrocarbon or C3-C 10 The heterocyclyl group is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, OH or halogen.

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

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

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

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

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

[0071] In some embodiments of the present invention, the above-mentioned T is selected from oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, oxadiazolone, thiadiazolyl, each of which 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, the above-mentioned T is

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

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

[0075] In some embodiments of the present invention, the above compound has 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 the present invention.

[0077] In some embodiments of the present invention, the above compound has 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 the present invention.

[0079] Some other solutions of the present invention are obtained by any combination of the above variables.

[0080] [Corrected 16.01.2025 according to Rule 91] The present invention also provides the following compounds or pharmaceutically acceptable salts thereof, which are selected from:

[0081] The present invention also provides the following compounds or pharmaceutically acceptable salts thereof, which are selected from:

[0082] Another aspect of the present invention provides a pharmaceutical composition comprising the above-mentioned 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 a GLP-1 receptor-mediated disease or disorder or regulating the GLP-1 receptor, comprising administering a therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition to a subject in need thereof.

[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 fatty liver disease, Parkinson's disease or dementia, which comprises administering a therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition to a subject in need of such treatment.

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

[0086] Technical Effects

[0087] The compound of the present invention has a good agonistic effect on the GLP-1 receptor.

[0088] Definition and Description

[0089] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0090] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0091] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in neat solution or in 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 the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.

[0092] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. 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 of the two.

[0093] A "pharmaceutical composition" refers to a composition containing one or more compounds described herein, their isomers, or pharmaceutically acceptable salts thereof, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0094] The term "therapeutically effective amount" is intended to encompass an amount of a compound that, when administered, is sufficient to prevent or alleviate to some extent one or more symptoms of a disease or condition being treated. The term "therapeutically effective amount" also refers to an amount of a compound that is sufficient to detect a biological or pharmaceutical response in a biomolecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human. Such a response is desired by the researcher, veterinarian, medical doctor, or clinician.

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

[0096] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present 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 and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present 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 the present invention.

[0097] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0098] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability to rotate freely about double bonds or single bonds forming ring carbon atoms.

[0099] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0100] Unless otherwise indicated, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemic.

[0101] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond or straight dashed key

[0102] Unless otherwise indicated, the terms "enriched in one isomer", "isomerically enriched", "enriched in one enantiomer" or "enantiomerically enriched" mean that the content of one isomer or enantiomer is less than 100%, and the content of that 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 indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric 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 or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, 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 pure desired enantiomer. 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 diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are resolved by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0105] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute 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, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this invention.

[0106] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

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

[0108] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0109] When the number of a linking group is 0, such as -(CRR)0-, it means 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, when X in AX is vacant, it means that the structure is actually A.

[0112] When one of the variables is selected from a single bond, it means that the two groups it connects 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's bond can cross-link to two or more atoms in a ring, the substituent can be bonded to any atom in the ring, e.g. The substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene. When the listed substituent does not specify the atom through which it is bonded to the substituted group, the substituent can be bonded through any atom. For example, a pyridyl substituent can be bonded to the substituted group through any carbon atom on the pyridine ring.

[0114] When the linking group is listed without specifying its linking direction, its linking direction is arbitrary, for example, The connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

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

[0116] Unless otherwise specified, the number of atoms in a ring is generally defined as the number of members of the ring, for example, a "5-7 membered ring" refers to a "ring" having 5-7 atoms arranged around it.

[0117] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including 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 , 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 means that the number of atoms in the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range from n to n+m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-7-membered ring, a 6-8-membered ring, and a 6-10-membered ring, etc.

[0118] Unless otherwise specified, the term "C1-C6 alkyl" is used to represent a straight or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms.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, etc.; which can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as 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 and the like.

[0119] Unless otherwise specified, the term “C 1-4 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms. 1-4 Alkyl groups include C 1-2 、C 1-3 and C 2-3 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 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), and the like.

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

[0121] Unless otherwise specified, "C3-C 10 "Cycloalkyl" means a saturated or unsaturated cyclic hydrocarbon group consisting of 3 to 10 carbon atoms, including monocyclic, bicyclic and tricyclic ring systems, wherein the bicyclic and tricyclic ring systems include spirocyclic, fused and bridged rings. 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 multivalent. 3-10 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclodecane, spiro[2.4]cyclohexane, cyclopentenyl, cyclohexenyl, and the like.

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

[0123] Unless otherwise specified, the term "3-10 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 10 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S, N, P and Se, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized and the nitrogen, sulfur and phosphorus heteroatoms are optionally oxidized (i.e., NO, S(O) p and P(O) p , p is 1 or 2). It includes monocyclic, bicyclic and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include spirocyclic, fused and bridged rings. In addition, with respect to the "3-10 membered heterocycloalkyl", a heteroatom may occupy the position at which the heterocycloalkyl is connected to the rest of the molecule. The 3-10 membered heterocycloalkyl includes 3-9 membered, 3-8 membered, 3-6 membered, 5-9 membered, 5 membered, 6 membered, 7 membered, 8 membered and 9 membered heterocycloalkyls, etc. Examples of 3-10 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or dioxepanyl, etc.

[0124] Unless otherwise specified, the term "5-membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 5 ring atoms, 1, 2 or 3 of which are heteroatoms independently selected from O, S, N, P and Se, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen, sulfur and phosphorus heteroatoms are optionally oxidized (i.e., NO, S(O) p and P(O) p , p is 1 or 2). Examples of 5-membered heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-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, monocyclic or polycyclic (e.g., bicyclic, tricyclic or more rings, at least one of which is aromatic, and the other rings may be cycloalkyl or aromatic rings). Aryl groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, indanyl, azulenyl, benzocyclopropyl, benzocyclobutyl, benzocyclopentyl, benzocyclohexyl, benzocyclohexenyl, benzocyclopentenyl, and the like.

[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 from five to twelve ring atoms (one of which is selected from S, O, and N; zero, one, or two of which are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon). Heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl, oxadiazolonyl, and the like.

[0127] Unless otherwise specified, the term "heterocyclyl" or "heterocycloalkyl" 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, bridged, or spiro), or an 11-, 12-, 13-, or 14-membered tricyclic ring system (fused, bridged, or spiro), wherein (i) each ring contains between one and 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 can be optionally oxidized, and (iv) the nitrogen heteroatom can be optionally quaternized. Representative heterocycloalkyl groups include, but are not limited to, [1,3]dioxolanyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolinyl, imidazolidinyl, imidazolonyl, piperidinyl, piperazinyl, 2-pyridone, oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, dioxanyl, oxetanyl, azetidinyl, thietanyl, oxiranyl, aziridinyl, thiiranyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazabicyclo[2.2.1]heptanyl, Heptanyl, 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]octan-2-amine, 5-azaspiro[3.4]octan- [3.4]octane-5,5-dioxide, 5-oxa-2-azaspiro[3.4]octane-8-amine, 8-amino-5-thia-2-azaspiro[3.4]octane-5,5-dioxide and similar groups.

[0128] According to the present application, any 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 the application, the aryl, heteroaryl, heterocyclic radical, and heterocyclic radical described herein can be a spirocycle, a bridged ring, a condensed ring, or a monocycle. The ring formed by two rings can be a spirocycle, a bridged ring, a condensed ring, or a monocycle. The two 5-membered or 6-membered rings can be a ring composed of two 5-membered rings, two 6-membered rings, or 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 well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

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

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

[0133] The present 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]dipalladium; Pd(dppf)Cl2 represents [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium; Xantphos represents 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; HATU represents 2-( 7-azobenzotriazole)-N,N,N',N'-tetramethyluronium 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-dimethylpropyleneurea; KHMDS represents potassium bis(trimethylsilyl)amide; DBU represents 1,8-diazacyclo[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; and rt represents room temperature.

[0135] Compounds are named according to the conventional nomenclature in the art or using Software naming, commercially available compounds use supplier catalog names. DETAILED DESCRIPTION

[0136] The present invention is described in detail below by way of examples, but is not intended to limit the present invention in any way. While the present invention has been described in detail herein, 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 of the present invention.

[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 mixture was evacuated under N2 protection. n-Butyllithium (1.6 mol / L, 13.85 ml, 22.16 mmol) was slowly added dropwise at -78°C and stirred for 1-2 hours. Compound 1-2 (5.5 g, 23.89 mmol) dissolved in anhydrous THF (40 mL) was then added dropwise. The mixture was slowly warmed to room temperature and stirred for 2-3 hours. Workup: 20% ammonium chloride solution (40 mL) was added to quench the mixture at 0°C. The extracts were then extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (PE / EA (V / V) = 10 / 1) afforded 3.73 g of compound 1-3 as a colorless oil in a 42.7% yield. MS:(ESI,pos.ion)m / z:377.1841[M+Na] + .

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

[0142] Compound 1-3 (3.73 g, 10.52 mmol) was added to a clean, single-necked flask and dissolved in isopropanol (40 mL). Hydrochloric acid in dioxane (4 mol / L, 15.78 mL, 63.14 mmol) was then added. Under nitrogen, the mixture was stirred at room temperature for 3 h. Post-treatment: Concentrate to dryness to obtain a brown solid, compound 1-4, 2.01 g. MS: (ESI, pos. ion) m / z: 155.0975 [M+H] + .

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

[0144] Compound 1-4 (2.01 g, 10.54 mmol) and compound 1-5 (1.76 g, 7.38 mmol) were added to a clean, single-necked flask and dissolved in ethanol (30 mL). DIPEA (1.57 g, 12.12 mmol) was then 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 afford compound 1-6 as a yellow solid (2.0 g, yield 72.3%). MS: (ESI, pos. ion) m / z: 375.2280 [M+H] + .

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

[0146] In a 25 mL two-necked flask, compound 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 methanol (3 mL). The atmosphere was purged with nitrogen five times. 1H-imidazole-1-sulfonyl azide hydrochloride (84 mg, 400.58 μmol) dissolved in methanol (1 mL) was slowly added under nitrogen. The mixture was allowed to react overnight at room temperature. Workup: Filtration and concentration of the organic phase under reduced pressure were performed, followed by column chromatography (PE / EA (v / v) = 8 / 1). The product was collected as a brown oil, compound 1-7, 17 mg, in a 16% yield. MS: (ESI, pos. ion) m / z: 401.2182 [M+H] + .

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

[0148] To a 25 mL two-necked flask, compound 1-8 (500 mg, 2.18 mmol), bistriphenylphosphine 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). The atmosphere was purged with nitrogen five times. Trimethylethynylsilane (1.07 g, 10.91 mmol) was slowly added dropwise under nitrogen. After addition, the temperature was raised to 80°C and the reaction was allowed to react overnight. Post-treatment: EA (20 mL) was added for dilution, the mixture was filtered through celite, and the organic phase was collected and 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 obtain 400 mg of compound 1-9 as a yellow oil in a yield of 74.5%. MS:(ESI,pos.ion)m / z:247.1113[M+H] + .

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

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

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

[0152] Compound 1-7 (17 mg, 42.45 μmol) and compound 1-10 (7.4 mg, 42.45 μmol) were sequentially added to DMF (1 mL) and H2O (1 mL). The mixture was reacted at room temperature for 2 h and then moved to a 40°C oil bath for 2 h. Workup: Dilute with EA (5 mL), wash with saturated ammonium chloride solution (1 mL x 3), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by column chromatography (PE / EA (V / V) = 5 / 1) to afford compound 1-11, 20 mg, in an 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), and HCl / dioxane solution (1 mL, 4.0 M) was added dropwise. The mixture was reacted at room temperature overnight. Post-treatment: the mixture was concentrated under reduced pressure to constant weight to obtain compound 1-12 (18 mg), which was used directly in the next step.

[0155] Step 9: Synthesis of Compound 1

[0156] Compound 1-13 was synthesized by the method reported in Example 67 of patent WO2018056453.

[0157] Compound 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 vial. After stirring for 0.5 h, compound 1-12 (18 mg, 35.23 μmol) was added. DIPEA (22.76 mg, 176.15 μmol) was added dropwise at 0°C. The mixture was then transferred to 25°C and allowed to react for 1 h. Post-treatment: The reaction mixture was poured into water (10 mL) and extracted with EA (10 mL x 2). The combined organic phases were washed with saturated sodium chloride (10 mL x 4), dried over anhydrous sodium sulfate, and purified by column chromatography (DCM / MeOH (v / v) = 15 / 1). The product was collected to yield compound 1, 13.45 mg, in a 44.0% yield. MS: (ESI, pos. ion) m / z: 868.3870 [M+H] + .

[0158] Example 2

[0159] Synthesis steps:

[0160] Note: Intermediate compounds 1-6 refer to the synthesis method in Example 1

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

[0162] To a 25 mL single-necked flask, 1-6 (0.2 g, 0.534 mmol), CuBr (0.263 g, 1.84 mmol), and isoamyl 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 for separation. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (PE / EA (V / V) = 3 / 1) afforded compound 2-1 as a colorless oil, 0.181 g, in a yield of 77.5%. MS-ESI: (ESI, pos. ion) m / z: 438.1259 [M+H] + .

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

[0164] To a 25 mL single-necked flask, compound 2-1 (0.18 g, 0.41 mmol), 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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. The mixture was dissolved in dioxane (4 mL) and H2O (1 mL). The atmosphere was purged with nitrogen three times and the mixture was stirred at 95°C for 6 h. Post-processing: The solvent was concentrated and the mixture was purified by column chromatography (PE / EA (V / V) = 3 / 1) to afford compound 2-2 as a yellow solid, 0.105 g, in a yield of 49.5%. MS-ESI: (ESI, pos. ion) m / z: 516.2882 [M+H] + .

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

[0166] Compound 2-2 (0.105 g, 0.2 mmol) was dissolved in ethanol (9 mL) in a 25 mL single-necked flask. Palladium on carbon (0.1 g) was added, the atmosphere was replaced with hydrogen, and the reaction was continued at 80°C for 12 h. Post-treatment: filtration through celite and concentration of the filtrate under reduced pressure afforded compound 2-3 as a yellow solid, 0.086 g, in a 100% yield. MS-ESI: (ESI, pos. ion) m / z: 426.2406 [M+H] + .

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

[0168] To a 25 mL single-necked flask, 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. The mixture was dissolved in toluene (5 mL), the atmosphere was purged with nitrogen, and the reaction was incubated at 110°C for 12 h. Post-treatment: filtration through Celite, concentration of the filtrate under reduced pressure, and purification by column chromatography (PE / EA (V / V) = 3 / 1) afforded compound 2-4 as a yellow solid, 0.12 g, in a 57% yield. MS-ESI: (ESI, pos. ion) m / z: 574.2816 [M+H] + .

[0169] Step 5: Synthesis of Compound 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: Concentration under reduced pressure afforded compound 2-5 as a yellow solid, 0.12 g, in a 100% yield.

[0171] Step 6: Synthesis of Compound 2

[0172] Compound 1-13 was synthesized by the method reported in Example 67 of patent WO2018056453.

[0173] To a 25 mL single-necked flask, compound 1-13 (116 mg, 0.28 mmol), DMF (5 mL), and HATU (161 mg, 0.42 mmol) were added sequentially. After stirring for 0.5 h, compound 2-5 (120 mg, 0.23 mmol) was added. DIPEA (145 mg, 1.12 mmol) was added dropwise at 0°C. The mixture was then transferred to 25°C and allowed to react for 2 h. Post-treatment: The reaction mixture was poured into water (20 mL) and extracted with EA (20 mL x 2). The combined organic phases were washed with saturated sodium chloride aqueous solution (20 mL x 4), dried over anhydrous sodium sulfate, and purified by column chromatography (DCM / MeOH (v / v) = 15 / 1). The product was collected to yield 102 mg of compound 2 in a 50.0% yield. 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). Compound 3-2 (4.68 g, 23.25 mmol) and EDCI (5.79 g, 30.23 mmol) were then added and 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 afford compound 3-3 as a white solid, 6.23 g, in a yield of 75.42%. MS: (ESI, pos. ion) m / z: 299.0038 [M-55] + .

[0178] Step 2: Synthesis of compound 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 atmosphere was replaced with nitrogen three times. MeI (2.40 g, 16.89 mmol) was slowly added dropwise at 0°C. After addition, the mixture was allowed to react at room temperature for 3 h. Post-treatment: The system was concentrated under reduced pressure and quenched with 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 obtain compound 3-4 as a white solid, 930.00 mg, in a yield of 89.47%. MS:(ESI,pos.ion)m / z:315.0168[M-55] + .

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

[0181] To a 25 mL two-necked flask were added compound 3-4 (930.00 mg, 2.52 mmol), (1,3-bis(2,3-diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene)dichloro(3-chloropyridin-2-yl)palladium salt (II) (170.87 mg, 251.86 μmol), and sodium tert-butoxide (363.07 mg, 3.78 mmol). The mixture was dissolved in toluene (5 mL), the atmosphere was purged with nitrogen three times, and the reaction was incubated at 110°C for 3 h. Post-treatment: filtration through celite, concentration of the filtrate under reduced pressure, and purification by column chromatography (PE / EA (V / V) = 3 / 1) afforded compound 3-5 as a white solid (599.00 mg, 82.48% yield). 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, along with a 4.0 M dioxane hydrochloride solution (6 mL). The mixture was allowed to react at room temperature for 2 h. Post-treatment: Concentration under reduced pressure afforded compound 3-6 as a yellow solid, 391.02 mg, in a 100% yield. MS: (ESI, pos. ion) m / z: 189.1028 [M+H] + .

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

[0185] Compound 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). Isoamyl nitrite (3.75 g, 32.05 mmol) was added dropwise at 0°C. After completion, the mixture was brought to room temperature and stirred overnight. Post-treatment: quenching was performed by adding saturated ammonium chloride solution, extracting with EA, and drying the organic phase over anhydrous sodium sulfate. Filtering and column chromatography (PE / EA (V / V) = 2 / 1) afforded compound 3-7 as a yellow oil, 2.19 g, 49.7% yield. MS: (ESI, pos. ion) m / z: 486.12 [M+H] + .

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

[0187] Compound 3-6 (50.00 mg, 265.63 μmol), compound 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 nitrogen replacement three times, the reaction 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 obtain a yellow solid compound 3-8, 50.00 mg, in a yield of 34.50%. MS: (ESI, pos. ion) m / z: 546.3000 [M+H] + .

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

[0189] Compound 3-8 (32.00 mg, 58.64 μmol) was added to a 25 mL single-necked flask, along with a 4.0 M dioxane hydrochloride solution (2 mL). The mixture was allowed to react at room temperature for 2 h. Post-treatment: Concentration under reduced pressure afforded compound 3-9 as a yellow solid, 28.27 mg, in a 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). HATU (33.13 mg, 87.14 μmol) and DIPEA (37.542 mg, 290.46 μmol) were then 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 stirred at room temperature for 2 hours. Workup: The mixture 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 afford compound 3 as a yellow solid (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] To a 25 mL two-necked flask were added 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). The mixture was evacuated and replaced with nitrogen three times. Trimethylsilylacetylene (505.93 mg, 5.15 mmol) was then added dropwise. The temperature was raised to 80°C and the reaction was allowed to react for 17 h. Post-treatment: EA (10 mL) and water (3 mL) were added, the layers were separated, and the organic phase was washed with water (3 mL x 2). Purification by column chromatography (PE / EA (V / V) = 9 / 1) afforded compound 4-2 as a yellow oil, 186.00 mg, in a yield of 39.6%. MS:(ESI,pos.ion)m / z:456.2618[M+H] + .

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

[0197] To a 25 mL single-necked flask, compound 4-2 (186 mg, 408.21 μmol) and tetrahydrofuran (5 mL) were added, followed by TBAF (213.47 mg, 816.42 μmol) and allowed to react for 12 h. Post-treatment: The reaction mixture was concentrated and purified by column chromatography (PE / EA (V / V) = 4 / 1) to afford compound 4-3 as a yellow, fluffy solid (107.00 mg, 68.3% yield). 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 atmosphere was purged with nitrogen five times, and the temperature was lowered to 0°C. Tert-butyl nitrite (187.30 mg, 1.82 mmol) and trimethylethynylsilane (167.41 mg, 1.70 mmol) were added dropwise. The mixture was allowed to react at room temperature for 30 minutes. After post-processing, the reaction solution was concentrated and purified by column chromatography (PE / EA (V / V) = 7 / 1) to afford compound 4-4 as a yellow solid, 78.00 mg, in a 67.5% yield. MS: (ESI, pos. ion) m / z: 192.0683 [M+H] + .

[0200] Step 4: Synthesis of compound 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 vial. After stirring until the solution became clear, 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. EA (15 mL) and saturated ammonium chloride solution (5 mL x 3) were added for washing, followed by drying over anhydrous sodium sulfate and purification by column chromatography (PE / EA (V / V) = 7 / 3) to afford compound 4-5 as a yellow oil (42 mg, 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 vial, and a 4.0 M dioxane hydrochloride solution (3 mL) was slowly added dropwise. The reaction was allowed to react for 2 h. Post-treatment: The mixture was concentrated directly to afford 37.35 mg of an off-white solid compound 4-6.

[0204] Step 6: Synthesis of compound 4

[0205] Compound 1-13 was synthesized by the method reported in Example 67 of patent WO2018056453.

[0206] To a 25 mL single-necked flask, compound 1-13 (36.09 mg, 87.71 μmol), DMF (2 mL), and HATU (41.69 mg, 109.64 μmol) were added. After stirring at room temperature to dissolve, 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. The mixture was allowed to react for 15 h at room temperature. Post-treatment: Water (30 mL) and ethyl acetate (20 mL) were added for extraction. 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 as an off-white solid, compound 4, 28.00 mg, in a yield of 44.1%. 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] To a 100 mL single-necked flask, (4-fluorophenyl)hydrazine hydrochloride (3 g, 18.45 mmol) and tert-butyl (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylate (3.08 g, 12.92 mmol) were added, dissolved in ethanol (60 mL), and stirred under reflux at 80°C for 2 h. Post-treatment: Purification by silica gel column chromatography (PE / EA (V / V) = 2 / 1) afforded compound 5-1 as a pale yellow solid (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). Isoamyl nitrite (2.03 g, 17.32 mmol) was added dropwise at 0°C. The mixture was brought to room temperature and stirred overnight. Post-treatment: quenching with saturated ammonium chloride solution, extraction with EA, drying the organic phase over anhydrous sodium sulfate, and filtration. Purification by column chromatography (PE / EA (V / V) = 2 / 1) afforded compound 5-2 as a yellow oil, 1.58 g, in a yield of 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). n-Butyl lithium (2.73 mL, 4.37 mmol, 1.6 mol / L THF solution) was added dropwise under nitrogen at -78°C. After stirring for 0.5 h, tert-butyl 3-oxoazetidine-1-carboxylate (373.7 mg, 2.18 mmol) dissolved in anhydrous THF (5 mL) was added dropwise. The mixture was allowed to react at room temperature for 6 h. Post-treatment: quenching was performed by dropwise addition of saturated ammonium chloride solution at 0°C. The mixture was extracted with EA (30 mL x 3), separated, dried over anhydrous sodium sulfate, and filtered. Purification by column chromatography (PE / EA (V / V) = 1 / 1) afforded compound 5-3 as a yellow solid, 1.34 g, in a yield of 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 and stirred for 5 minutes. MeI (3.55 g, 25.02 mmol) was then added dropwise under nitrogen. The mixture was allowed to react at room temperature for 2 hours. Post-treatment: Water was added dropwise at 0°C to quench the mixture. The mixture was extracted with EA, and the organic phase was dried over anhydrous sodium sulfate and filtered. Concentration and extraction to dryness afforded compound 5-4 as a pale yellow oil (1.4 g, 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 bottle and stirred at room temperature for 2 h. Post-treatment: Concentrate and dry to obtain compound 5-5 as a white solid, 1.13 g, in a 100% yield.

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

[0220] To a 25 mL single-necked vial were added 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). The mixture was dissolved in DMF (3 mL) and stirred at 80°C for 12 h. Post-treatment: The mixture was separated by addition of 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 afford compound 5-6 as a yellow solid (25 mg, yield 20.25%). MS: (ESI, pos.ion)m / z: 565.45[M+H] + .

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

[0222] Compound 5-6 (25.00 mg, 44.31 μmol) and dioxane hydrochloride solution (2 mL, 4 mol / L) were weighed into a 25 mL single-necked bottle and reacted at room temperature for 2 h. Post-treatment: Concentrate and drain to obtain a yellow solid compound 5-7 (22.18 mg, 100% yield).

[0223] Step 8: Synthesis of compound 5

[0224] Compound 1-13 was synthesized by the method reported in Example 67 of patent WO2018056453.

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

[0226] Example 6

[0227] Synthesis steps:

[0228] Note: Compounds 1-6 were synthesized according to 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-cooling. After stirring at room temperature for 30 min, 3-bromopropylene (190.61 mg, 1.60 mmol) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 4 h. Post-treatment: Water was slowly added dropwise under ice-cooling to quench the remaining sodium hydride. Ethyl acetate (50 mL) and water (200 mL) were added for separation. 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. Purification by column chromatography (PE / EA (V / V) = 5 / 1) gave compound 6-4 as a light brown oil, 160 mg, in a yield of 29.05%. MS:(ESI,pos.ion)m / z:413.2420[M+H] + .

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

[0232] To a 100 mL single-necked flask were added 5-bromo-4-fluoro-1-methyl-1H-indazole (4 g, 17.46 mmol), dioxane (40 mL), diphenylmethaneimine (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). The atmosphere was purged with nitrogen three times and the mixture was heated to 110°C under nitrogen and stirred for 12 h. Post-treatment: The reaction mixture was filtered to remove insoluble solids. The filtrate was directly mixed with basic silica gel, and the sample column was packed with basic silica gel. Purification by column chromatography (PE / EA (V / V) = 20 / 1) afforded 5.3 g of compound 6-1 as a white solid in a 92.27% yield. 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 mixture was filtered to remove insoluble solids, and the pH was adjusted to neutral with sodium bicarbonate solution. Ethyl acetate (50 mL) and water (300 mL) were added for separation. The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (PE / EA (V / V) = 5 / 1) afforded compound 6-2 as a colorless oily liquid, 2.35 g, in a yield of 88.59%. MS: (ESI, pos. ion) m / z: 166.0778 [M+H] + .

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

[0236] Triphosgene (359.30 mg, 1.21 mmol) and ethyl acetate (2 mL) were added to a 100 mL single-necked flask. A mixed solvent of ethyl acetate (2 mL), compound 6-2 (100 mg, 0.61 mmol) and triethylamine was added dropwise under ice bath. After completion of the addition, the mixture was reacted under ice bath for 30 min, then the temperature was raised to 60 ° C and stirred for 3 hours. The mixture was directly spin-dried and used in the next step.

[0237] Step 5: Synthesis of compound 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 atmosphere was purged with nitrogen and protected. The temperature was raised to 110°C and stirred for 1 h. Silver trifluoromethanesulfonate (9.97 mg, 0.039 mmol) was added, the atmosphere was purged with nitrogen and protected, and the reaction was continued at 110°C with stirring for 3 h. Post-treatment: The reaction solution was filtered to remove insoluble solids. Ethyl acetate (20 mL) and water (120 mL) were added for separation. The aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (120 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (PE / EA (V / V) = 2 / 1) gave compound 6-5 as a colorless oily liquid, 70 mg, in a yield of 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 stirred at room temperature for 4 h. Post-treatment: The product was directly spin-dried and used in the next step to obtain a light brown solid compound 6-6 (62 mg, 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-cooling. 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-cooling. The mixture was stirred at room temperature for 2 h. Post-treatment: Ethyl acetate (20 mL) and water (200 mL) were added for separation. 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. Pre-TLC purification (PE / EA (V / V) = 2 / 1) gave compound 6 as a light brown solid, 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] To a 100 mL three-necked flask, ethyl 5-bromo-1H-indole-2-carboxylate (2.00 g, 7.46 mmol) and anhydrous DMF (20 mL) were added. 60% NaH (0.45 g, 11.19 mmol) was added at 0°C. The mixture was stirred at room temperature under nitrogen for 0.5 h. Bromoacetonitrile (1.79 g, 14.92 mmol) dissolved in 1 mL of anhydrous DMF was then added dropwise. The mixture was brought to room temperature under nitrogen and stirred overnight. Post-treatment: 80 mL of water was added at 0°C, stirred for 1 h, filtered, and the filter cake was washed with water (20 mL x 3) and dried at 50°C to afford 2.17 g of compound 7-2 as a yellow solid in a yield of 94.63%.

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

[0248] To a 50 mL reaction flask were added compound 7-2 (1 g, 3.26 mmol), 3-methyl-3-(methylsulfonyl)but-1-yne (0.95 g, 6.51 mmol), toluene (5 mL), bistriphenylphosphine 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). The mixture was evacuated, replaced with nitrogen, and reacted at 90°C overnight. Workup: Filtration, extraction with water and ethyl acetate, separation of the organic phase, drying over anhydrous sodium sulfate, filtration, and column chromatography (PE / EA (V / V) = 2 / 1) afforded compound 7-3, 0.63 g, in a 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 (79.73 mg, 3.33 mmol) dissolved in water (4 mL) were added to a 50 mL reaction flask and stirred at room temperature for 2 h. Post-treatment: 10% aqueous citric acid solution (20 mL) was added to adjust the pH to 4-5, stirred overnight, filtered, and air-dried at 50°C to obtain a yellow solid, compound 7-4, 0.42 g, in a yield of 72.95%. MS: (ESI, pos. ion) m / z: 362.1174 [M+H2O] + .

[0251] Step 4: Synthesis of compound 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. Post-treatment: Water (100 mL) and EA (50 mL) were added for extraction. The organic phase was separated and washed with saturated brine (50 mL x 4), dried over anhydrous sodium sulfate, filtered, and concentrated to constant weight by column chromatography (PE / EA (V / V) = 1 / 1). Compound 7-5 was obtained as a yellow solid (1.30 g, yield 45.77%). MS: (ESI, pos. ion) m / z: 434.1560 [M+H] + .

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

[0254] Compound 7-5 (0.1 g, 230.67 μmol), (R)-4-methyl-1,3,2-dioxolane 2,2-dioxide (79.66 mg, 576.67 μmol), and DMPU (1.5 mL) were added to a 50 mL two-necked flask. 1 mol / L KHMDS (0.92 mL, 922.68 μmol) was added dropwise at 0°C under nitrogen. The reaction was continued at 0°C for 4 h. Post-treatment: Water (20 mL) and EA (20 mL) were added for extraction, and the organic phase was separated. The organic phase was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to constant weight by column chromatography (DCM / MeOH (v / v) = 50 / 1). The mixture was obtained as a white oil, 23 mg, with a yield of 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% aqueous hydroxylamine solution (0.28 g, 4.22 mmol) were added to a 50 mL reaction flask and stirred at room temperature overnight. Post-treatment: Water (20 mL) and EA (10 mL) were added for extraction. The organic phase was separated and washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to constant weight to obtain compound 7-7 as a white oil (32 mg, yield 29.91%). MS: (ESI, pos. ion) m / z: 507.2087 [M+H] + .

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

[0258] To a 50 mL reaction vial were added 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). The reaction was heated to 60°C and allowed to react for 4 h. Workup: 10% aqueous citric acid (20 mL) and EA (20 mL) were added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (PE / EA (V / V) = 1 / 1). The product was concentrated to constant weight to afford compound 7-8, 210 mg, in an 88.8% yield. 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 vial and reacted at 130°C for 48 h. Workup: Water (20 mL) and EA (20 mL) were added to separate the liquids. 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 purified by column chromatography (DCM / MeOH (v / v) = 10:1). The mixture was concentrated to constant weight to afford compound 7-9 as a red oil (69 mg, 69.13% yield). 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 vial. 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 reaction was stirred overnight at room temperature. Workup: Water (10 mL) and EA (10 mL) were added for extraction. The organic phase was separated and washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to constant weight by column chromatography (DCM / MeOH (v / v) = 40 / 1). Compound 7 was obtained as a yellow solid (37 mg, 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-dioxaborolan-2-yl)-1H-pyrazole and 2-1 as raw materials, the target compound 8 was obtained by referring to the preparation method of 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] To a 25 mL two-necked flask, triphosgene (131.28 mg, 442.41 μmol) and DCM (4 mL) were added. The temperature was lowered to -30°C, and triethylamine (223.85 mg, 2.21 mmol) was added. Compound 6-4 (365 mg, 884.83 μmol) in DCM (1 mL) was then added. The mixture was added dropwise and stirred for 15 minutes. The mixture was then allowed to warm to room temperature and allowed to react for 2 hours. The residue was then spin-dried and purified by column chromatography (PE / EA (V / V) = 3 / 1) to afford 256 mg of an off-white solid, compound 9-1, in a 60.91% yield.

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

[0272] Compound 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 refluxed for 25 h. Workup: Cool to room temperature, spin dry, and purify by column chromatography (PE / EA (V / V) = 3 / 2) to afford 9-2 as a yellow oil (113 mg, 44.45% yield). MS: (ESI, pos. ion) m / z: 604.2958 [M+H] + .

[0273] Step 3: Synthesis of compound 9

[0274] Compound 9-2 was used as the starting material, and the synthetic method of step 8 and step 9 of Example 1 was referred to obtain white solid compound 9. 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 refer to the synthesis method in Example 1

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

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

[0280] Step 2: Synthesis of compound 10

[0281] Compound 10-1 was used as the starting material, and the synthetic method of steps 8 and 9 of Example 1 was referred to obtain white solid compound 10. 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 in Example 1

[0286] Step 1: Synthesis of compound 11

[0287] Compound 11-1 was used as the starting material and the synthesis method of Example 10 was referred to obtain white solid compound 11. 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 compound 1-6 was synthesized by referring to the method in Example 1, and compound 6-2 was synthesized by referring to the method in Example 6.

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

[0293] Triphosgene (359.30 mg, 1.21 mmol) and ethyl acetate (2 ml) were added to a clean 100 ml single-necked flask. A mixed solvent of ethyl acetate (2 ml), compound 6-2 (100 mg, 0.605 mmol) and triethylamine was added dropwise under ice bath. After completion of the addition, the mixture was reacted under ice bath for 30 min and then moved to 60 °C for reaction. After stirring for 3 hours, the mixture was filtered and concentrated under vacuum for use in the next step.

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

[0295] To a clean flask, compound 1-6 (100.00 mg, 267.05 μmol) and 1-bromo-3-methoxypropane (32.69 mg, 213.63 μmol) were dissolved in 3 mL of DMF. The atmosphere was replaced with N2 three times. Under N2 protection, a 1 M solution of KHMDS in THF (256.37 μmol, 256.37 μmol) was slowly added dropwise at 0°C. The mixture was stirred at 0°C for 15 min and then transferred to room temperature for overnight reaction. Workup: The mixture 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, and concentrated under reduced pressure. The organic phase was purified by column chromatography (PE / EA (v / v) = 4 / 1) to afford compound 12-2 as a yellow oil (95 mg, 99.64% yield). 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 atmosphere was replaced with N2 three times and the reaction was carried out at 110°C under N2 protection for 10 h. Post-treatment: Water (10 mL x 3) and EA (10 mL x 3) were added to extract the mixture. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (PE / EA (V / V) = 1 / 1) afforded compound 12-3 as a yellow oil, 40 mg, in a yield of 28.01%. MS-ESI: (ESI, pos. ion) m / z: 638.5337 [M+H] + .

[0298] Step 4: Synthesis of compound 12

[0299] Compound 12-3 was used as the starting material and the synthetic method of Example 10 was referred to obtain yellow solid compound 12. 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 refer to the synthesis method in Example 1

[0304] Step 1: Synthesis of compound 13

[0305] Compound 13-1 was used as the starting material and the synthesis method of Example 10 was used to obtain a white solid compound 13. 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 refer to the synthesis method in Example 1

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

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

[0312] Step 2: Synthesis of compound 14

[0313] Compound 14-1 was used as the starting material and the synthesis method of Example 10 was referred to obtain an off-white solid compound 14. 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 refer to the synthesis method in Example 1

[0318] Step 1: Synthesis of compound 15

[0319] Compound 15-1 was used as the starting material and the synthesis method of Example 10 was referred to obtain white solid compound 15. 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 refer to the synthesis method in Example 1

[0324] Step 1: Synthesis of compound 16

[0325] Compound 16-2 was used as the starting material and the synthesis method of Example 10 was referred to obtain an off-white solid compound 16. MS: (ESI, pos.ion) m / z: 929.4294 [M+H] + .

[0326] Example 17

[0327] Synthesis steps:

[0328] Note: Intermediate compounds 1-6 refer to the synthesis method in Example 1

[0329] Step 1: Synthesis of compound 17

[0330] Compound 17-2 was used as the starting material and the synthesis method of Example 10 was used to obtain a light yellow solid compound 17. 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 refer to the synthesis method in Example 1

[0335] Step 1: Synthesis of compound 18

[0336] Compound 16-4 was used as the starting material and the synthesis method of Example 10 was referred to obtain an off-white solid compound 18. MS: (ESI, pos.ion) m / z: 965.4060 [M+H] + .

[0337] Example 19

[0338] Synthesis steps:

[0339] Note: Intermediate compounds 1-6 refer to the synthesis method in Example 1

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

[0341] To a 50 mL two-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. The temperature was raised to 80°C and the reaction was allowed to proceed for 4 h. Post-processing: filtration through celite, concentration of the sample on silica gel, and purification by column chromatography (PE / EA (V / V) = 5 / 1) afforded 840 mg of compound 19-3, a white, fluffy solid, in an 85% yield.

[0342] Step 2: Synthesis of compound 19

[0343] Compounds 19-3 and 1-6 were used as raw materials and the synthesis method of Example 10 was referred to obtain a light yellow solid compound 19. 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 refer to the synthesis method in Example 1

[0348] Step 1: Synthesis of compound 20

[0349] Compound 20-2 was used as the starting material and the synthesis method of Example 10 was referred to obtain a light yellow solid compound 20. 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 compound 1-6 was synthesized according to the method in Example 1, and intermediate compound 21-2 was synthesized according to the method in Example 19.

[0354] Step 1: Synthesis of compound 21

[0355] Compound 21-3 was used as the starting material and the synthesis method of Example 12 was referred to obtain white solid compound 21. MS: (ESI, pos.ion) m / z: 954.4401 [M+H] + .

[0356] Example 22

[0357] Synthesis steps:

[0358] Note: Intermediate compounds 1-6 refer to the synthesis method in Example 1

[0359] Step 1: Synthesis of compound 22

[0360] Compounds 22-2 and 6-2 were used as raw materials and the synthesis method of Example 10 was used to obtain yellow solid compound 22. 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 refer to the synthesis method in Example 1

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

[0366] To a clean flask, compound 1-6 (0.20 g, 0.534 mmol), compound 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 2 ml of toluene were added. The mixture was refluxed at 110°C for 10 h. Workup: The solvent was concentrated and the mixture was purified by column chromatography (PE / EA (V / V) = 3 / 1) to afford 39 mg of compound 23-2 as a reddish-brown oil, in an 18% yield. MS: (ESI, pos. ion) m / z: 415.2548 [M+H] + .

[0367] Step 2: Synthesis of compound 23

[0368] Compounds 23-2 and 12-1 were used as raw materials and the synthesis method of Example 12 was referred to obtain white solid compound 23. MS: (ESI, pos.ion) m / z: 899.4222 [M+H] + .

[0369] Example 24

[0370] Synthesis steps:

[0371] Note: Intermediate compounds 1-6 refer to the synthesis method in Example 1

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

[0373] To a clean three-necked flask, compound 24-1 (1.0 g, 15.13 mmol) was dissolved in THF (10 ml) and the atmosphere was replaced with nitrogen three times. The reaction system was placed at -40°C, and n-butyl lithium (1.6 M, 10.4 mL, 16.64 mmol) was added. Stirring continued for 1 hour after addition. DMF (2.21 g, 30.26 mmol) was added, and the mixture was warmed to room temperature and stirred for 1 hour. Post-treatment: Sodium dihydrogen phosphate solution was prepared under an ice bath and slowly added dropwise to the reaction mixture to quench the reaction. The system was extracted with EA (30 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 24-2 as a yellow oil, 1.88 g, in a yield of 132%.

[0374] Step 2: Synthesis of compound 24

[0375] Compounds 24-3 and 12-1 were used as raw materials and the synthesis method of Example 12 was referred to obtain white solid compound 24. MS: (ESI, pos.ion) m / z: 937.4339 [M+H] + .

[0376] Example 25

[0377] Synthesis steps:

[0378] Note: For intermediate compound 1-6, refer to the synthesis method in Example 1; for intermediate compound 25-1, refer to the synthesis method in Step 1 in Example 10; for intermediate compound 25-2, refer to the synthesis method in Step 1 in Example 12.

[0379] Step 1: Synthesis of compound 25

[0380] Compound 25-1 was used as the starting material and the synthesis method of Example 12 was used to obtain a white solid compound 25. MS: (ESI, pos.ion) m / z: 897.4006 [M+H] + .

[0381] Example 26

[0382] Synthesis steps:

[0383] Note: The intermediate compound 12-2 was synthesized according to the method in Example 12, and the intermediate compound 26-2 was synthesized according to the method in Step 1 in Example 6.

[0384] Step 1: Synthesis of compound 26

[0385] Compound 26-1 was used as the starting material and the synthesis method of Example 10 was used to obtain a white solid compound 26. MS: (ESI, pos.ion) m / z: 957.4631 [M+H] + .

[0386] Example 27

[0387] Synthesis steps:

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

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

[0390] To a clean, single-necked flask, 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. Ethyl oxalyl chloride (139.11 mg, 1.02 mmol) was slowly added dropwise. 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 afford compound 27-1 as a yellow oil (428 mg, 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) were dissolved in methanol (3 mL) and water (1 mL) in a clean, single-necked flask and stirred at 50°C for 2 h. Post-treatment: The solvent was concentrated under reduced pressure, the pH was adjusted to neutral by adding 10% citric acid, and the extract was added with DCM (10 mL x 2). The extract was dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated to afford 115 mg of compound 27-2 as a yellow oil in a 100% yield. MS: (ESI, pos. ion) m / z: 519.2702 [M+H] + .

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

[0394] To 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) were dissolved in DMF (2 mL). 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 for separation. 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. Purification by column chromatography (PE / EA (V / V) = 2 / 1) afforded compound 27-3 as a yellow oil, 61 mg, in a yield of 41.5%. MS: (ESI, pos. ion) m / z: 666.3228 [M+H] + .

[0395] Step 4: Synthesis of compound 27

[0396] Compound 27-3 was used as the starting material and the synthesis method of Example 10 was used to obtain a white solid compound 27. 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-cooling. Triethylamine (7.11 g, 69.4 mmol) and MsCl (4.37 g, 38.1 mmol) were added. After addition, 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 afford 7.7 g of compound 28-2, a yellow liquid, in a 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. 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) were then added. The mixture was reacted at 70°C for 8 h. The mixture was filtered, the solvent was concentrated, and the mixture was purified by column chromatography (PE / EA (V / V) = 1 / 1) to afford compound 28-4 as a yellow oil (4.16 g, yield 74.6%). 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. Triethylamine (0.384 g, 3.80 mmol) and (Boc)2O (0.498 g, 2.28 mmol) were added. After addition, the mixture was warmed to room temperature and reacted for 12 h. The mixture was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated and purified by column chromatography (PE / EA (V / V) = 4 / 1) to afford compound 28-5 as a colorless oil, 0.35 g, in a yield of 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 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 afford compound 28-6 as a yellow oil, 0.12 g, in a yield of 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) under ice. After addition, the mixture was allowed to react at 80°C for 2 h. The concentrated solvent was purified by column chromatography (PE / EA (V / V) = 3 / 1) to afford compound 28-8 as a yellow oil, 0.05 g, in a yield of 27.5%. MS: (ESI, pos. ion) m / z: 401.2440 [M+H] + .

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

[0411] Note: Intermediate 28-9 was obtained by referring to the synthesis 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), and the mixture was reacted at 60°C for 2 h. Saturated brine (10 mL x 2) and EA (10 mL x 2) were then added for extraction. The organic phase was washed twice with 10 mL of saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (PE / EA (V / V) = 2 / 1) afforded compound 28-10 as a yellow solid, 0.035 g, in a yield of 52.7%. MS: (ESI, pos. ion) m / z: 532.3008 [M+H] + .

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

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

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

[0416] To a clean two-necked flask, compound 28-11 (0.079 g, 0.169 mmol), compound 28-12 (0.046 g, 0.203 mmol), compound 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) were added and dissolved in toluene (1 mL). The atmosphere was purged with nitrogen three times and the mixture was 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 afford compound 28-14 as a yellow solid, 0.066 g, in a yield of 63.5%. MS: (ESI, pos. ion) m / z: 616.2868 [M+H] + .

[0417] Step 9: Synthesis of Compound 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. The mixture was allowed to react overnight at room temperature and concentrated under reduced pressure to afford the yellow solid hydrochloride of compound 28-15 (0.059 g, 100% yield). MS: (ESI, pos. ion) m / z: 516.2361 [M+H] + .

[0419] Step 10: Synthesis of Compound 1

[0420] To a clean single-necked flask, compound 28-15 (0.059 g, 0.114 mmol), compound 1-13 (0.052 g, 0.126 mmol), HATU (0.087 g, 0.229 mmol), and DIEA (0.074 g, 0.572 mmol) were dissolved in DMF (2 mL). The mixture was reacted at room temperature for 4 h. Saturated brine (10 mL x 2) and EA (10 mL x 2) were then added for extraction. The organic phase was washed twice with 10 mL of saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The organic phase was purified by column chromatography (PE / EA (V / V) = 1 / 1) to afford compound 28 as a pale yellow solid, 0.060 g, in a yield of 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] To a clean flask, compound 28-8 (200.00 mg, 499.38 μmol) and 1-bromo-2-butyne (199.23 mg, 1.50 mmol) were dissolved in 3 mL of acetone. DIPEA (322.72 mg, 2.50 mmol) was added and stirred at 60°C for 24 h. Workup: Concentrate under reduced pressure and purify by column chromatography (PE / EA (v / v) = 3 / 1) to afford compound 29-1 as a yellow oil (100 mg, 44.25% yield).

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

[0427] To a clean flask, compound 12-1 (110.88 mg, 580.02 μmol) and compound 29-1 (105.00 mg, 232.01 μmol) were added and dissolved in 4 mL of toluene. The atmosphere was replaced with N2 three times and the reaction was carried out at 110°C under N2 protection for 10 h. Post-treatment: Water (10 mL*3) and EA (10 mL*3) were added to extract the system. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (PE / EA (V / V) = 1 / 2) afforded compound 29-2 as a yellow oil (19 mg, yield 12.72%).

[0428] Step 4: Synthesis of compound 29

[0429] Compound 29-2 was used as the starting material, and the synthetic method of steps 8 and 9 of Example 1 was referred to obtain yellow solid compound 29. MS: (ESI, pos.ion) m / z: 937.4318 [M+H] + .

[0430] Example 30

[0431] Synthesis steps:

[0432] Step 1: Synthesis of compound 30

[0433] Refer to the synthesis method of Example 28 to obtain yellow solid compound 30. MS: (ESI, pos.ion) m / z: 911.4182 [M+H] + .

[0434] Example 31

[0435] Synthesis steps:

[0436] Step 1: Synthesis of compound 31

[0437] Refer to the synthesis method of Example 29 to obtain yellow solid compound 31. MS: (ESI, pos.ion) m / z: 939.4469 [M+H] + .

[0438] Example 32

[0439] Synthesis steps:

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

[0441] Synthesis steps:

[0442] Step 1: Synthesis of compound 32

[0443] Compound 32-1 was used as the starting material and the synthesis method of Example 29 was referred to obtain yellow solid compound 32. MS: (ESI, pos.ion) m / z: 925.4318 [M+H] + .

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

[0445] Table 1

[0446] Example 60

[0447] Synthesis steps:

[0448] Note: Intermediate compounds 1-6 refer to the synthesis method in Example 1

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

[0450] In a 50 mL single-necked bottle, compound 60-1 (2.00 g, 10.57 mmol) and HCl / Dioxane (4.0 M, 12 mL) were added and reacted for 0.5 h. Post-treatment: The solvent was concentrated to obtain the hydrochloride salt of compound 60-2 as a white solid, 1.33 g, in a 100% yield.

[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 thiophosgene (1.22 g, 10.59 mmol) were added at 0°C and reacted for 1 h. Post-treatment: The mixture was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain compound 60-3 as a yellow oil, 1.18 g, in a yield of 84.8%.

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

[0454] To a 25 mL single-necked vial, compound 1-6 (200 mg, 0.534 mmol), compound 60-3 (105.07 mg, 0.801 mmol), and pyridine (2 mL) were added and allowed to react for 15 h. Post-treatment: Purification by column chromatography (PE / EA (V / V) = 2 / 1) afforded compound 60-4 as a yellow solid, 0.213 g, in a yield of 78.9%. MS: (ESI, pos. ion) m / z: 506.2313 [M+H] + .

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

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

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

[0458] To a 25 mL single-necked vial, 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 allowed to react for 0.5 h. Workup: Concentration under reduced pressure and purification by column chromatography (PE / EA (V / V) = 1 / 1) afforded compound 60-6 as a yellow solid, 0.042 g, in a yield of 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: EA (10 mL) was added to quench the reaction, followed by 1.0 g of Glauber's salt. The solution was filtered through celite and the solvent was concentrated to afford 35 mg of compound 60-7 as a yellow oil in a 93.7% yield. MS: (ESI, pos. ion) m / z: 476.2188 [M+H] + .

[0461] Step 7: Synthesis of compound 60

[0462] Compound 60-7 was used as the starting material and the synthesis method of Example 28 was referred to obtain a light yellow solid compound 60. MS: (ESI, pos.ion) m / z: 899.3666 [M+H] + .

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

[0464] Table 2

[0465] Example 63:

[0466] Synthesis steps:

[0467] Note: Intermediate compounds 1-6 refer to the synthesis method in Example 1

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

[0469] In a 100 mL single-necked flask, add 2-chloroethylamine hydrochloride (2.0 g, 17.24 mmol), sulfonyl chloride (13.96 g, 103.46 mmol), and acetonitrile (20 mL). React at 80°C for 10 h. Post-treatment: Concentrate the solvent to obtain compound 63-1 as a yellow oil (3.0 g, 98.3% yield).

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

[0471] At 0°C, 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) and triethylamine (1.35 g, 13.35 mmol). The reaction was stirred overnight. Post-treatment: The solvent was concentrated and purified by column chromatography to obtain compound 63-2 as a yellow solid, 0.700 g, in a yield of 20.3%. MS: (ESI, pos. ion) m / z: 516.1898 [M+H] + .

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

[0473] Compound 63-2 (200 mg, 0.386 mmol), potassium carbonate (107.13 mg, 0.775 mmol), and DMSO (2 mL) were added to a 25 mL single-necked flask and allowed to react for 1 h. Post-treatment: 10 mL of water and 10 mL of ethyl acetate were added for separation. The aqueous phase was extracted with ethyl acetate (10 mL x 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 afford compound 63-3 as a yellow solid, 0.162 g, in a yield of 87.16%. MS: (ESI, pos. ion) m / z: 480.2157 [M+H] + .

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

[0475] To a 25 mL two-necked flask were added compound 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). The atmosphere was purged with nitrogen three times and the mixture was allowed to react at 110°C for 2 h. Workup: Concentration under reduced pressure and purification by column chromatography (PE / EA (V / V) = 1 / 1) afforded compound 63-4 as a yellow solid, 0.037 g, in a yield of 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 bottle and reacted for 0.5 h. Post-treatment: Concentration under reduced pressure afforded compound 63-5 as a yellow solid, 0.099 g, in a 99.3% yield.

[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, along with DIEA (113 mg, 0.8776 mmol). The mixture was allowed to react overnight at room temperature. Post-treatment: 10 ml of water and 10 ml of ethyl acetate were added, and the aqueous phase was extracted with ethyl acetate (10 ml x 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 afford compound 63 as a yellow solid, 0.092 g, in a yield of 56.9%. MS: (ESI, pos. ion) m / z: 921.3688 [M+H] + .

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

[0481] Table 3

[0482] Example 76

[0483] Synthesis steps:

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

[0485] Step 1: Synthesis of compound 76

[0486] Compound 14-2 was used as the starting material and the synthesis method of Example 10 was referred to obtain an off-white solid compound 76. 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 above examples, the compounds given in Table 4 were prepared

[0488] Table 4

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

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

[0491] 1) Prepare assay buffer (1X HBSS + 20 mM HEPES + 0.1% BSA + 500 μM IBMX) in advance according to the following table, aliquot, and store at -20°C until use.

[0492] Table 5 Preparation of stock solution reagents

[0493] 2) CHO-K1GLP-1R cells were cultured in complete medium in a CO2 incubator at 37°C until the logarithmic growth phase and the cell density reached 70-80% confluence. The cell suspension was then harvested. Experimental wells and blank control wells were also set up.

[0494] 3) Compound Preparation: Prepare the native peptide or test compound in DMSO to a 400X working concentration. Dilute the native peptide 3-fold, or the test compound 5-fold, in 10 wells, in duplicate or in a single well. Then, dilute the compound 100-fold in Assy buffer to a 4X working concentration (the working concentration should be 4 times the final concentration). The final DMSO concentration is 0.25%.

[0495] 4) CHO-K1 GLP-1R cells were seeded into a 384-well white opaque-bottom microplate at a density of approximately 2000 cells / well in 7.5 μL of serum-containing complete medium. For blank control wells, an equal volume of complete medium was added to each well.

[0496] 5) Add 2.5 μL / well of the serially diluted test compound or control (cAMP) from step 2 to a 384-well microplate. Centrifuge at 200 g for 30 seconds and incubate at 37°C for 30 minutes. Add an equal volume of assay buffer to each blank control well.

[0497] 6) Remove the incubated 384-well plate and add 5 μL of Uligh-anti-cAMP (1 / 5) to each experimental well. Then add 5 μL of Eu-Camp tracer (1 / 5) to each experimental well. Cover the plate, centrifuge at 200 g for 30 seconds, and incubate in a 25°C incubator for 60 minutes.

[0498] 7) Data were read using a multifunctional microplate reader (Envision 2014) under the following detection conditions: excitation light: 340 nM, emission light: 665 nM and 620 nM. Read data: Ratio = 665 nM / 620 nM*1000.

[0499] 8) Data analysis: The “log(agonist) vs. response—Variable slope” model in GraphPad Prism 8.0 was used to fit the data and calculate the EC 50 % Activity = (VC - detection data) / (VC - PC) * 100%; PC: average data of wells corresponding to 10 nM GLP-1 (7-37); VC: average data of wells corresponding to 0.25% DMSO.

[0500] 9) GraphPad Prism 8.0 was used to process the experimental data.

[0501] As shown in Table 6 below, the compounds exhibited potent 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 of the present application

[0503] Conclusion: The in vivo / in vitro GLP-1 receptor activity tests showed that the above compounds of the present invention have a good agonist effect on the GLP-1 receptor.

[0504] Example 89 Pharmacokinetic Evaluation in C57 Mice

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

[0506] Table 7 Pharmacokinetic parameters

[0507] Conclusion: The exposure of the compound of the present invention in plasma is significantly higher than that of orforglipron. The compound of Example 76 has a slower elimination rate and a longer half-life, and has better pharmacokinetic properties.

[0508] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A 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 cycloalkyl is a spirocyclic alkyl, a bridged cycloalkyl or a monocyclic alkyl, and the aryl, heterocyclic or heteroaryl is a spirocyclic, a bridged ring, a condensed ring or a monocyclic ring; the cycloalkyl, aryl, heterocyclic or heteroaryl is optionally substituted by one or more substituents independently selected from the following: 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 a carbon atom on a cycloalkyl, phenyl, aryl, heteroaryl or heterocyclyl ring is substituted with two C1-C6 alkyl groups, the two C1-C6 alkyl groups together with the carbon atoms to which they are attached form a C3-C6 alkyl group. 10 Cycloalkyl; each R C are independently H, C1-C3 alkyl or C1-C3 haloalkyl; or two R C Together with the carbon atom to which they are attached, they form C3-C 10 Cyclic hydrocarbon group; the C3-C 10 The cycloalkyl group is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen; A is selected from cycloalkyl, aryl, heterocyclic group or heteroaryl; wherein the cycloalkyl is a spirocyclic hydrocarbon group, a bridged cycloalkyl group or a monocyclic hydrocarbon group, and the heterocyclic group or heteroaryl group is a spirocyclic ring, a bridged ring, a condensed ring or a monocyclic ring; 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, thio; Or, A is selected from Wherein, U and V are independently selected from space, N-Rd, N-Re or C-RfRg, C-RhRi; Wherein, E is selected from O or S; Rd, Re, Rf, Rg, Rh, Ri, R 10 or R 11 independently selected from H, halogen, C1-C6 alkyl, C3-C 10 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, phenyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 12-membered heterocyclyl, 5- to 12-membered aryl or 5- to 12-membered heteroaryl; the C1-C6 alkyl, C3-C 10 The cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, phenyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 12-membered heterocyclyl, 5- to 12-membered aryl, or 5- to 12-membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, OH, halogen, NH2, oxo, methanesulfonyl, ethylsulfonyl, propanesulfonyl, cyclopropanesulfonyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl or 5-12 membered aryl; wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, NH2, 3 to 12 membered heterocyclyl, 5 to 12 membered heteroaryl or 5 to 12 membered aryl are optionally substituted with one or more substituents independently selected from the group consisting of D, halogen, cyano, amino, methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopropylsulfonyl, 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 Together with the carbon atom to which they are attached, they form C3-C 10 Cyclic hydrocarbon group; the C3-C 10 The cycloalkyl group is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen; or when m is 0, Rd and Re are independently taken together with the nitrogen atom to which they are attached to form a C3-C6 alkyl group. 10 Heterocyclic group, the C3-C 10 The heterocyclyl group is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen; B is selected from C3-C 10 The cycloalkyl, aryl (preferably phenyl), heterocyclyl containing one or two 5-membered or 6-membered rings and 1-3 heteroatoms selected from N, O and S, or heteroaryl containing one or two 5-membered or 6-membered rings and 1-3 heteroatoms selected from N, O and S; the aryl, heterocyclyl and heteroaryl are spirocyclic, bridged, condensed or monocyclic; wherein the cycloalkyl, aryl (phenyl), heterocyclyl or heteroaryl 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, C3-C6 ... 12 Cycloalkyl, C1-C6 alkyl-C3-C 12 Cyclic hydrocarbon group, OH, halogen, 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 cycloalkyl is a spirocyclic hydrocarbon group, a bridged cycloalkyl group or a monocyclic hydrocarbon group, and Ra and Rb are each independently selected from H, halogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, phenyl; 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, halogen, C1-C6 alkyl, C3-C 10 wherein the alkyl, cycloalkyl, alkoxy, phenyl, vinyl, ethynyl, heterocyclyl or heteroaryl is optionally substituted by one or more substituents independently selected from the following: 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 group or heteroaryl is substituted by a C1-C6 alkyl, two C1-C6 alkyl groups together with the carbon atoms to which they are attached form a C3-C 10 Cycloalkyl; L is selected from C3-C 10 Cycloalkyl, carbonyl, phenylene or heteroaryl comprising one or two 5-membered or 6-membered rings and 1-3 heteroatoms selected from N, O and S, wherein the cycloalkyl, phenylene or heteroaryl is optionally substituted with one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or halogen; or wherein when the phenylene is substituted with 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-membered or 6-membered ring, the 5-membered or 6-membered ring optionally comprising 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-C6 alkyl radical. 10 Cycloalkyl, the C3-C 10 The cycloalkyl group is optionally substituted with one or more substituents independently selected from the group consisting of 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 heteroaryl comprising a 5-membered or 6-membered ring and 1-3 heteroatoms selected from N, O and S, wherein the heteroaryl is optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen or oxo; R1, R2, R3, R 13 , R 14 and R 15 Each independently selected from H, D, halogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, phenyl; wherein C1-C6 alkyl, C3-C 10 The cycloalkyl group and the phenyl group are optionally substituted by one or more substituents independently selected from the group consisting of 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 Together with the carbon atom to which they are attached, they form C3-C 10 Cyclic hydrocarbon or C3-C 10 Heterocyclic group; the C3-C 10 Cyclic hydrocarbon or C3-C 10 The heterocyclyl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

2. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound is selected from the structure shown in formula (I), Wherein, R1, R2 and R3 are each independently selected from H, D, halogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, phenyl; wherein C1-C6 alkyl, C3-C 10 The cycloalkyl group and the 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) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R1 and R 13 Not for H.

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

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

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

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

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

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

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

12. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The A is selected from Wherein 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 heterocyclyl, 5- to 12-membered aryl or 5- to 12-membered heteroaryl; the C1-C6 alkyl, C3-C 10 The cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, phenyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 12-membered heterocyclyl, 5- to 12-membered aryl, or 5- to 12-membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, OH, halogen, NH2, oxo, methanesulfonyl, ethylsulfonyl, propanesulfonyl, cyclopropanesulfonyl, 3- to 12-membered heterocyclyl, 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 Cycloalkyl, NH2, 3 to 12 membered heterocyclyl, 5 to 12 membered heteroaryl or 5 to 12 membered aryl are optionally substituted by one or more substituents independently selected from the group consisting of D, halogen, cyano, amino, methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopropylsulfonyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and n is an integer from 0 to 10.

13. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to claim 1, 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, halogen, C1-C6 alkyl, C3-C 10 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, phenyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 12-membered heterocyclyl, 5- to 12-membered aryl or 5- to 12-membered heteroaryl; the C1-C6 alkyl, C3-C 10 The cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, phenyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 12-membered heterocyclyl, 5- to 12-membered aryl, or 5- to 12-membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, OH, halogen, NH2, oxo, methanesulfonyl, ethylsulfonyl, propanesulfonyl, cyclopropanesulfonyl, 3- to 12-membered heterocyclyl, 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 Cycloalkyl, NH2, 3 to 12 membered heterocyclyl, 5 to 12 membered heteroaryl or 5 to 12 membered aryl are optionally substituted with one or more substituents independently selected from the group consisting of D, halogen, cyano, amino, methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopropylsulfonyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, n is an integer from 0 to 10; or Rh and Ri, R when n is not 0 10 and R 11 Together with the carbon atom to which they are attached, they form C3-C 10 Cyclic hydrocarbon group; the C3-C 10 The cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

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

15. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The A is selected from a heterocyclic group, a heteroaryl group or is empty; the heteroaryl group or the 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, thioxo.

16. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to claim 15, characterized in that: The A is selected from or is 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 or C3-C 10 Heterocyclic hydrocarbon group; the C3-C 10 Cyclic hydrocarbon or C3-C 10 The heterocycloalkyl is optionally substituted with 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.

17. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to claim 16, characterized in that: The A is selected from wherein 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 atoms to which they are attached form a C3-C6 cycloalkyl or C3-C6 heterocycloalkyl; the C3-C6 cycloalkyl or C3-C6 heterocycloalkyl 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) or a pharmaceutically acceptable salt thereof according to claim 17, characterized in that: The A is selected from 19. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to claim 16, characterized in that: The A is selected from 20. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to claim 1, 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 Cycloalkyl or C1-C6 alkoxy; the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 The cycloalkyl or C1-C6 alkoxyl group is optionally substituted by one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, C3-C6 alkyl ... 10 Cyclic hydrocarbon, OH, halogen, NH2, Oxo, methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopropylsulfonyl, a 3- to 12-membered heterocyclyl, a 3- to 12-membered heterocyclyl substituted with a C1-C6 alkyl group or a C1-C6 haloalkyl group, a phenyl group or a halophenyl group; n is 0 or 1.

21. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The A is selected from Where R 10 or R 11 independently selected from H, halogen, C1-C6 alkyl, C3-C 10 Cycloalkyl or C1-C6 alkoxy, the C1-C6 alkyl, C3-C 10 The cycloalkyl or C1-C6 alkoxyl group is optionally substituted by one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, C3-C6 alkyl ... 10 Cyclic hydrocarbon, OH, halogen, NH2, oxo, methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopropylsulfonyl, 3- to 12-membered heterocyclic group, 3- to 12-membered heterocyclic group substituted with C1-C6 alkyl or C1-C6 haloalkyl, phenyl or halophenyl; n is 0 or 1; or when n is not 0, R 10 and R 11 Together with the carbon atom to which they are attached, they form C3-C 10 Cycloalkyl, the C3-C 10 The cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

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

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

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

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

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

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

34. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: Said Selected from 35. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to claim 1 or 34, characterized in that: The R4 is independently selected from halogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkoxy, phenyl, vinyl, ethynyl, cyano, heterocyclyl containing one or two 3- to 6-membered rings and 1-3 heteroatoms selected from N, O and S, or heteroaryl containing 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, heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from the following: 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.

36. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to claim 1 or 34, characterized in that: The R4 is selected from C3-C 10 Cycloalkyl, the C3-C 10 The cycloalkyl 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 cycloalkyl group is selected from a spirocyclic hydrocarbon group, a bridged cycloalkyl group or a monocyclic hydrocarbon group.

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

38. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to claim 1 or 34, 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) or a pharmaceutically acceptable salt thereof according to claim 1, 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 atom to which they are attached form a C3-C 10 Cycloalkyl, the C3-C 10 The cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH or halogen.

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

41. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: 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) or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that: The R1, R2 and R3 are independently selected from H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

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

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

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

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

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

52. The compound of formula (II) according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that , said for 53. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to claim 1, 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) or a pharmaceutically acceptable salt thereof according to claim 2, 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. [Corrected 16.01.2025 as per Rule 91] A compound of the formula or a pharmaceutically acceptable salt thereof, 56. The compound according to claim 55 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

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

58. A method for treating or preventing a GLP-1 receptor mediated disease or disorder or modulating a GLP-1 receptor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 56 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to 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 fatty liver disease, Parkinson's disease or dementia, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of any one of claims 1 to 56 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition described in claim 57.

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

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