Compounds containing a polycyclic ring structure

Abstract

The present disclosure belongs to the field of medicinal chemistry, and relates to a compound containing a polycyclic structure, in particular to a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, a preparation method thereof, or a pharmaceutical composition thereof, and a use thereof in the preparation of a drug for treating a disease related to diabetes or obesity.

Description

[0001] This application is a divisional application of Chinese patent application No. 202480004478.3, filed on June 28, 2024, entitled "Compounds Containing Polyfused Ring Structures".

[0002] Cross-references to related applications

[0003] This application claims priority and benefit to Chinese patent application No. 202310802212.0 filed with the China National Intellectual Property Administration (CNIPA) on June 30, 2023; Chinese patent application No. 202311497217.3 filed with the CNIPA on November 3, 2023; and Chinese patent application No. 202410808056.3 filed with the CNIPA on June 20, 2024, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0004] This disclosure pertains to the field of medicinal chemistry and relates to compounds containing polycyclic aromatic hydrocarbons, their stereoisomers or pharmaceutically acceptable salts thereof, methods of their preparation, or pharmaceutical compositions thereof, and their use in the preparation of medicaments for the treatment of diabetes or obesity-related diseases. Background Technology

[0005] Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by elevated blood glucose levels, with high morbidity and mortality. Obesity is considered a significant risk factor for T2DM, with approximately 85% of T2DM patients being overweight or obese. Glucagon-like peptide-1 (GLP-1) is an intestinal hypoglycemic agent secreted by L cells in the small intestine as nutrients pass through the digestive tract. GLP-1 is known to exhibit various physiological effects through its receptor, such as promoting glucose-dependent insulin secretion, inhibiting glucagon secretion, delaying gastric emptying, and suppressing appetite. Although GLP-1 analogs have been commercialized as diabetes treatments and are considered among the most effective due to their efficacy in lowering HbA1c and reducing weight, they must be administered subcutaneously, leading to poor patient compliance. Therefore, the development of non-peptide GLP-1 receptor small molecule agonists to improve patient compliance is of great importance and has become a hot research topic in the field of diabetes. Summary of the Invention

[0006] This application provides a compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0007]

[0008] in,

[0009] X1 X 2 Each is independently selected from C or N;

[0010] Y 1 Y 2 Y 3 Or Y 4 Each is independently selected from CH, C, or N;

[0011] R 1 Selected from C 11-15 cycloalkyl, C 11-15 Aryl, 11-15 membered heteroaryl, 11-15 membered heterocyclic, said C 11-15 cycloalkyl, C 11-15 The aryl, 11-15 membered heteroaryl, and 11-15 membered heterocyclic group are tricyclic rings, and the C 11-15 cycloalkyl, C 11-15 Aryl, 11-15 membered heteroaryl, and 11-15 membered heterocyclic groups can be optionally and independently bonded by one or more R groups. a replace;

[0012] Or, R 1 Selected from C 3-7 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-7 membered heterocyclic, wherein R 1 By a C 2-4 Alkyne substitution, R 1 Further, it can be optionally and independently controlled by one or more R a Instead, the C 2-4 The alkynyl group may optionally be replaced by one or more R groups. b replace;

[0013] Each R a Each is independently selected from deuterium, halogen, =O, and deuterated C. 1-6 Alkyl, -OH, -CN, NH2, -COOH, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclic group, wherein the deuterated C 1-6 Alkyl, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy or C1-6 Alkoxy C 1-3 Alkylenes are optionally and independently controlled by one or more R c1 Replace; the C 3-6 Cycloalkyl, phenyl, 5-6-membered heteroaryl, or 3-6-membered heterocyclic groups may be independently bound by one or more R groups. d1 replace;

[0014] Each R 2 Each is independently selected from halogens, -OH, -CN, NH2, -COOH, and C. 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclic group, wherein C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-3 Alkylenes are optionally and independently controlled by one or more R c2 Replace; the C 3-6 Cycloalkyl, phenyl, 5-6-membered heteroaryl, or 3-6-membered heterocyclic groups may be independently bound by one or more R groups. d2 replace;

[0015] Or, R on two adjacent carbon atoms 2 Together with the carbon atom it is attached to, they form C 4-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-6 membered heterocyclic group, wherein C 4-6 Cycloalkyl, phenyl, 5-6-membered heteroaryl, or 4-6-membered heterocyclic groups are optionally and independently bound by one or more R groups. d3 replace;

[0016] Each R 3 Each is independently selected from deuterium, halogens, -OH, -CN, NH2, -COOH, and C. 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclic group, wherein C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-3 Alkylenes are optionally and independently controlled by one or more R c3 Replace; the C 3-6 Cycloalkyl, phenyl, 5-6-membered heteroaryl, or 3-6-membered heterocyclic groups may be independently bound by one or more R groups. d4 replace;

[0017] R 4 Selected from H, deuterium, halogens, -CN, NH2, -COOH, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-3 Alkylene, the C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-3 Alkylenes are optionally and independently controlled by one or more R c4 replace;

[0018] Each R 5 Each is independently selected from halogens, -CN, -OH, -SH, -NH2, and C. 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 1-6 Alkylthio, -CONH2, -CONHC 1-3 Alkyl, -NHCOC 1-3Alkyl group, -SO2NH2, -SO2NHC 1-3 Alkyl or -NHSO2C 1-3 Alkyl, the C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 1-6 Alkylthio, -CONH2, -CONHC 1-3 Alkyl, -NHCOC 1-3 Alkyl group, -SO2NH2, -SO2NHC 1-3 Alkyl or -NHSO2C 1-3 Alkyl groups are optionally and independently influenced by one or more R groups. c5 replace;

[0019] R' and R" are independently selected from H, halogens, -CN, -OH, -SH, -NH2, and C, respectively. 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 1-6 Alkylthio, -CONH2, -CONHC 1-3 Alkyl, -NHCOC 1-3 Alkyl group, -SO2NH2, -SO2NHC 1-3 Alkyl or -NHSO2C 1-3 Alkyl, the C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 1-6 Alkylthio, -CONH2, -CONHC 1-3 Alkyl, -NHCOC 1-3 Alkyl group, -SO2NH2, -SO2NHC 1-3 Alkyl or -NHSO2C 1-3 Alkyl groups are optionally and independently influenced by one or more R groups. c6 replace;

[0020] Alternatively, R' and R" together with their attached carbon atoms form C. 3-6Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl groups are optionally and independently constituting one or more R groups. d5 replace;

[0021] Each Each is independently selected from either a single bond or a double bond;

[0022] Each R b Selected independently from deuterium, halogens, -CN, -OH, -NH2, and C respectively. 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy group may be independently substituted by one or more substituents selected from deuterium, halogen, OH, CN or NH2;

[0023] Each R c1 R c2 R c3 R c4 R c5 and R c6 Each is independently selected from deuterium, halogens, -CN, -OH, or -NH2;

[0024] Each R d1 R d2 R d3 R d4 and R d5 Each element is independently selected from deuterium, halogens, -CN, -OH, =O, -NH2, and C. 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy group may be independently substituted by one or more substituents selected from deuterium, halogen, OH, CN or NH2;

[0025] q is selected from 0, 1, 2, 3, or 4;

[0026] n is selected from 0, 1, 2, 3 or 4;

[0027] m is selected from 0, 1, 2, 3 or 4.

[0028] In some implementations, "replaced by one or more" is each independently selected from being replaced by 1, 2, 3, 4, 5 or 6.

[0029] In some implementations, "replaced by one or more" is each independently selected from being replaced by 1, 2, 3, 4 or 5.

[0030] In some implementations, “replaced by one or more” is independently selected from being replaced by 1, 2, 3 or 4.

[0031] In some implementations, “replaced by one or more” is independently selected from being replaced by 1, 2 or 3.

[0032] In some embodiments, the “hetero” in the heteroaryl or heterocyclic group is independently selected from heteroatoms of oxygen, sulfur and nitrogen, wherein the nitrogen atom is optionally quaternized or oxidized to N(O), the sulfur atom is optionally oxidized to S(O) or S(O)2, and other variables are as defined in this application.

[0033] In some implementations, the three rings are selected from single-ring fused two-ring, single-ring fused two-ring, or single-ring fused two-ring.

[0034] In some implementations, the three rings are selected from single-ring fused bi-rings or single-ring fused helical bi-rings.

[0035] In some implementations, the three rings are selected from single-ring fused two-ring, single-ring fused two-ring, or single-ring fused two-ring, wherein the single ring and the structural unit Connected.

[0036] In some implementations, the aromatic ring in the three rings is related to the structural unit. Connected.

[0037] In other embodiments, the three rings are selected from a single-ring fused bicyclic ring, a single-ring spiral bicyclic ring, or a single-ring bridged bicyclic ring, wherein the single ring is an aromatic ring, and the single ring is connected to the structural unit. Connected.

[0038] In other embodiments, the tricyclic ring is selected from a monocyclic fused bicyclic ring, a monocyclic spirocyclic bicyclic ring, or a monocyclic bridged bicyclic ring, wherein the monocyclic ring is a benzene ring or a 5-6 membered heteroaromatic ring, and the monocyclic ring is connected to the structural unit. Connected.

[0039] In other embodiments, the tricyclic ring is selected from monocyclic fused bicyclic rings, monocyclic fused spirocyclic rings, or monocyclic fused bridged bicyclic rings, wherein the monocyclic ring is a benzene ring or a 5-6 member heteroaromatic ring containing 1-2 nitrogen atoms, and the monocyclic ring is related to the structural unit. Connected.

[0040] In other embodiments, the tricyclic ring is selected from monocyclic fused bicyclic rings, monocyclic fused spirocyclic rings, or monocyclic bridged bicyclic rings, wherein the monocyclic ring is a benzene ring or a 6-membered heteroaromatic ring containing 1-2 nitrogen atoms, and the monocyclic ring is related to the structural unit. Connected.

[0041] In other embodiments, the tricyclic ring is selected from a monocyclic fused bicyclic ring, a monocyclic spirocyclic bicyclic ring, or a monocyclic bridged bicyclic ring, wherein the monocyclic ring is a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, or a pyridazine ring, and the monocyclic ring is connected to the structural unit. Connected.

[0042] In other embodiments, the tricyclic ring is selected from a monocyclic fused bicyclic ring, a monocyclic fused spirocyclic ring, or a monocyclic bridged bicyclic ring, wherein the monocyclic ring is a benzene ring or a pyridine ring, and the monocyclic ring is connected to the structural unit. Connected.

[0043] In this application, R 1 Middle and structural units When the connected rings are aromatic rings, R 1 It is defined as aryl or heteroaryl.

[0044] In some implementation schemes, R 1 Selected from C 11-15 Aryl or 11-15 quinone heteroaryl, wherein C 11-15 The aryl or 11-15 membered heteroaryl group is a tricyclic ring, wherein the C 11-15 The aryl or 11-15 quinone heteroaryl group may optionally be independently bounded by one or more R groups. a replace.

[0045] In some implementation schemes, R 1 Selected from benzo[C] 7-11 Fused bicycloalkyl, benzo7-11 fused diheterocyclic, benzo7-11 fused diheteroaryl, pyridoC 7-11 Fused bicycloalkyl, pyrido7-11 fused diheterocyclic, pyrido7-11 fused diheteroaryl, pyrimidoC 7-11 Fused bicycloalkyl, pyrimido-7-11 fused diheterocyclic, pyrimido-7-11 fused diheteroaryl, pyridazinc 7-11 Fused bicycloalkyl, pyridazino 7-11 fused biheteroalkyl, pyridazino 7-11 fused biheteroaryl, pyrazino C 7-11 Fused bicycloalkyl, pyrazino 7-11 fused bicycloalkyl, pyrazino 7-11 fused biaryl, benzo[C] 7-11 Spirobicycloalkyl, benzo[C] 7-11 Spirodiheterocyclic, pyrido-C 7-11 Spirobicycloalkyl, pyridoC 7-11 Spirodiheterocyclic group, pyrimidine C 7-11 Spirobicycloalkyl, pyrimidine C 7-11 Spirodihexyl, pyridazine C 7-11 Spirobicycloalkyl, pyridazine C 7-11 Spirodihexyl, pyrazine C 7-11 Spirobicycloalkyl or pyrazine C 7-11 spirodicyclic heterocyclic group, the R 1 Can be optionally and independently controlled by one or more R a replace.

[0046] In some implementation schemes, R 1 Selected from benzo[C] 7-9Fused bicycloalkyl, benzo7-9 fused diheterocyclic, benzo7-9 fused diheteroaryl, pyridoC 7-9 Fused bicycloalkyl, pyrido7-9 fused diheterocyclic, pyrido7-9 fused diheteroaryl, pyrimidoC 7-9 Fused bicycloalkyl, pyrimido-7-9 fused diheterocyclic, pyrimido-7-9 fused diheteroaryl, pyridazinc 7-9 Fused bicycloalkyl, pyridazino 7-9 fused biheteroalkyl, pyridazino 7-9 fused biheteroaryl, pyrazino C 7-9 Fused bicycloalkyl, pyrazino 7-9 fused bicycloalkyl, pyrazino 7-9 fused biaryl, benzo[C] 7-9 Spirobicycloalkyl, benzo[C] 7-9 Spirodiheterocyclic, pyrido-C 7-9 Spirobicycloalkyl, pyridoC 7-9 Spirodiheterocyclic group, pyrimidine C 7-9 Spirobicycloalkyl, pyrimidine C 7-9 Spirodihexyl, pyridazine C 7-9 Spirobicycloalkyl, pyridazine C 7-9 Spirodihexyl, pyrazine C 7-9 Spirobicycloalkyl or pyrazine C 7-9 spirodicyclic heterocyclic group, the R 1 Can be optionally and independently controlled by one or more R a replace.

[0047] In some implementation schemes, R 1 Selected from benzo7-9 fused diheterocyclic, benzo7-9 fused diheteroaryl, benzoC 7-9 Spirobicycloalkyl, benzo[C] 7-9 Spirodihexyl or pyrido-C 7-9 Spirobicycloalkyl, wherein R 1 Can be optionally and independently controlled by one or more R a replace.

[0048] In some implementation schemes, R 1 Selected from benzo7-9 fused diheterocyclic, benzo7-9 fused diheteroaryl, benzoC 7-9 Spirobicycloalkyl, benzo[C] 7-9 Spirodihexyl or pyrido-C 7-9 Spirobicycloalkyl, wherein R 1 Middle and structural units The connected rings are benzene rings or pyridine rings; the R 1 Can be optionally and independently controlled by one or more R a replace.

[0049] In some implementation schemes, R 1 Selected from benzo7-9 fused diheterocyclic groups, benzoC 7-9Spirobicycloalkyl or benzo[C] 7-9 spirodicyclic heterocyclic group, the R 1 Can be optionally and independently controlled by one or more R a replace.

[0050] In some implementation schemes, R 1 Selected from benzo7-9 fused diheterocyclic groups, benzoC 7-9 Spirobicycloalkyl or benzo[C] 7-9 spirodicyclic heterocyclic group, the R 1 Middle and structural units The connected rings are benzene rings; the R 1 Can be optionally and independently controlled by one or more R a replace.

[0051] In some implementation schemes, R 1Selected from benzo5-membered cycloalkyl fused with 3-membered cycloalkyl, benzo5-membered cycloalkyl fused with 4-membered cycloalkyl, benzo5-membered cycloalkyl fused with 5-membered cycloalkyl, benzo6-membered cycloalkyl fused with 4-membered cycloalkyl, benzo6-membered cycloalkyl fused with 5-membered cycloalkyl, benzo5-membered cycloalkyl fused with 3-membered heterocyclic group, benzo5-membered cycloalkyl fused with 4-membered heterocyclic group, benzo5-membered cycloalkyl fused with 5-membered heterocyclic group, benzo6-membered cycloalkyl fused with 4-membered heterocyclic group, benzo6-membered cycloalkyl fused with 5-membered heterocyclic group, benzo5-membered heterocyclic group fused with 3-membered cycloalkyl, benzo5-membered heterocyclic group fused with 4-membered cycloalkyl, benzo6-membered heterocyclic group fused with 5-membered cycloalkyl, benzo5-membered heterocyclic group fused with 5-membered cycloalkyl, benzo5-membered heterocyclic group fused with 3-membered heterocyclic group, benzo5-membered heterocyclic group fused with 4-membered heterocyclic group, benzo5-membered heterocyclic group fused with 5-membered heterocyclic group Benzene 6-membered heterocyclic group, benzo6-membered heterocyclic group fused with 4-membered heterocyclic group, benzo6-membered heterocyclic group fused with 5-membered heterocyclic group, benzo5-membered heteroaryl group fused with 3-membered cycloalkyl group, benzo5-membered heteroaryl group fused with 4-membered cycloalkyl group, benzo5-membered heteroaryl group fused with 5-membered cycloalkyl group, benzo5-membered heteroaryl group fused with 6-membered cycloalkyl group, benzo6-membered heteroaryl group fused with 5-membered cycloalkyl group, benzo5-membered heteroaryl group fused with 3-membered heterocyclic group, benzo5-membered heteroaryl group fused with 4-membered heterocyclic group, benzo5-membered heteroaryl group fused with 5-membered heterocyclic group, benzo5-membered heteroaryl group fused with 6-membered heterocyclic group, benzo6-membered heteroaryl group fused with 4-membered heterocyclic group, benzo6-membered heteroaryl group fused with 5-membered heterocyclic group, benzo5-membered cycloalkyl group fused with 5-membered heteroaryl group, benzo5-membered cycloalkyl group fused with 6-membered heteroaryl group, benzo5-membered heterocyclic group Blended 5-membered heteroaryl, benzo6-membered heterocyclic blister blister 5-membered heteroaryl, benzo5-membered heterocyclic blister 6-membered heteroaryl, pyridinium 5-membered cycloalkyl blister 3-membered cycloalkyl, pyridinium 5-membered cycloalkyl blister 4-membered cycloalkyl, pyridinium 5-membered cycloalkyl blister 5-membered cycloalkyl, pyridinium 6-membered cycloalkyl blister 4-membered cycloalkyl, pyridinium 6-membered cycloalkyl blister 5-membered cycloalkyl, pyridinium 5-membered cycloalkyl blister 3-membered heterocyclic, pyridinium 5-membered cycloalkyl blister 4-membered heterocyclic, pyridinium 5-membered cycloalkyl blister 5-membered heterocyclic, pyridinium 5-membered cycloalkyl blister 5-membered heterocyclic, pyridinium 5-membered cycloalkyl blister 4-membered cycloalkyl, pyridinium 5-membered heterocyclic blister 5-membered cycloalkyl, pyridinium 6-membered heterocyclic blister 4-membered cycloalkyl, pyridinium 6-membered cycloalkyl Heterocyclic groups fused with 5-membered cycloalkyl groups, pyrido5-membered heterocyclic groups fused with 3-membered heterocyclic groups, pyrido5-membered heterocyclic groups fused with 4-membered heterocyclic groups, pyrido5-membered heterocyclic groups fused with 5-membered heterocyclic groups, pyrido6-membered heterocyclic groups fused with 4-membered heterocyclic groups, pyrido6-membered heterocyclic groups fused with 5-membered heterocyclic groups, pyrido5-membered heteroaryl groups fused with 3-membered cycloalkyl groups, pyrido5-membered heteroaryl groups fused with 4-membered cycloalkyl groups, pyrido5-membered heteroaryl groups fused with 5-membered cycloalkyl groups, pyrido5-membered heteroaryl groups fused with 5-membered cycloalkyl groups, pyrido5-membered heteroaryl groups fused with 6-membered cycloalkyl groups, pyrido6-membered heteroaryl groups fused with 4-membered heterocyclic groups, pyrido5-membered heteroaryl groups fused with 5-membered heterocyclic groups, pyrido5-membered heteroaryl groups fused with 6-membered heterocyclic groups, pyrido6-membered heteroaryl groups fused with 4-membered heterocyclic groups.Pyridinium 6-membered heteroaryl fused 5-membered heterocyclic group, pyridinium 5-membered cycloalkyl fused 5-membered heteroaryl group, pyridinium 6-membered cycloalkyl fused 5-membered heteroaryl group, pyridinium 5-membered cycloalkyl fused 6-membered heteroaryl group, pyridinium 5-membered heterocyclic group fused 5-membered heteroaryl group, pyridinium 5-membered heterocyclic group fused 6-membered heteroaryl group, benzo[5-membered cycloalkyl]spiro[3-membered cycloalkyl], benzo[5-membered cycloalkyl]spiro[4-membered cycloalkyl], benzo[5-membered cycloalkyl]spiro[5-membered cycloalkyl], benzo[6-membered cycloalkyl]spiro[4-membered cycloalkyl], benzo[6-membered cycloalkyl]spiro[5-membered cycloalkyl], benzo[5-membered cycloalkyl]spiro[5-membered cycloalkyl] Cycloalkyl spiro-3 heterocyclic, benzo5-membered cycloalkyl spiro-4 heterocyclic, benzo5-membered cycloalkyl spiro-5 heterocyclic, benzo6-membered cycloalkyl spiro-4 heterocyclic, benzo6-membered cycloalkyl spiro-5 heterocyclic, benzo5-membered heterocyclic spiro-3 heterocyclic, benzo5-membered heterocyclic spiro-4 heterocyclic, benzo5-membered heterocyclic spiro-5 heterocyclic, benzo6-membered heterocyclic spiro-4 heterocyclic, benzo6-membered heterocyclic spiro-5 heterocyclic, benzo5-membered heterocyclic spiro-3 heterocyclic, benzo5-membered heterocyclic spiro-4 heterocyclic, benzo5-membered heterocyclic spiro-5 heterocyclic, benzo5-membered heterocyclic 6-membered heterocyclic spiro-4-membered heterocyclic, benzo6-membered heterocyclic spiro-5-membered heterocyclic, benzo5-membered heteroaryl spiro-3-membered cycloalkyl, pyridino5-membered cycloalkyl spiro-3-membered cycloalkyl, pyridino5-membered cycloalkyl spiro-4-membered cycloalkyl, pyridino5-membered cycloalkyl spiro-5-membered cycloalkyl, pyridino6-membered cycloalkyl spiro-4-membered cycloalkyl, pyridino6-membered cycloalkyl spiro-5-membered cycloalkyl, pyridino5-membered cycloalkyl spiro-3-membered heterocyclic, pyridino5-membered cycloalkyl spiro-4-membered heterocyclic, pyridino5-membered cycloalkyl spiro-5-membered heterocyclic, pyridino6-membered cycloalkyl spiro-4-membered heterocyclic, pyridino6 Cycloalkyl spiro-5-membered heterocyclic group, pyrido-5-membered heterocyclic spiro-3-membered heterocyclic group, pyrido-5-membered heterocyclic spiro-4-membered heterocyclic group, pyrido-5-membered heterocyclic spiro-5-membered heterocyclic group, pyrido-6-membered heterocyclic spiro-4-membered heterocyclic group, pyrido-6-membered heterocyclic spiro-5-membered heterocyclic group, pyrido-5-membered heterocyclic spiro-3-membered heterocyclic group, pyrido-5-membered heterocyclic spiro-4-membered heterocyclic group, pyrido-5-membered heterocyclic spiro-5-membered heterocyclic group, pyrido-6-membered heterocyclic spiro-4-membered heterocyclic group, pyrido-6-membered heterocyclic spiro-5-membered heterocyclic group, or pyrido-5-membered heteroaryl spiro-3-membered heterocyclic group, wherein R, 1 Can be optionally and independently controlled by one or more R a replace.

[0052] In other implementations, R 1 Selected from benzo5-membered heteroaryl fused 5-membered heterocyclic group, benzo5-membered heteroaryl fused 6-membered heterocyclic group, benzo5-membered heterocyclic fused 5-membered heteroaryl group, benzo5-membered cycloalkyl spiro3-membered cycloalkyl group, benzo5-membered heterocyclic spiro3-membered cycloalkyl group, benzo5-membered heterocyclic spiro4-membered cycloalkyl group, benzo5-membered cycloalkyl spiro4-membered heterocyclic group, pyridinium 5-membered heteroaryl fused 5-membered cycloalkyl group, or pyridinium 5-membered cycloalkyl spiro3-membered cycloalkyl group, wherein R 1 Can be optionally and independently controlled by one or more R a replace.

[0053] In other implementations, R 1 Selected from benzo5-membered heteroaryl fused 5-membered heterocyclic group, benzo5-membered heteroaryl fused 6-membered heterocyclic group, benzo5-membered heterocyclic fused 5-membered heteroaryl group, benzo5-membered cycloalkyl spiro3-membered cycloalkyl group, benzo5-membered heterocyclic spiro3-membered cycloalkyl group, benzo5-membered heterocyclic spiro4-membered cycloalkyl group, benzo5-membered cycloalkyl spiro4-membered heterocyclic group, pyridinium 5-membered heteroaryl fused 5-membered cycloalkyl group, or pyridinium 5-membered cycloalkyl spiro3-membered cycloalkyl group, wherein R 1 Middle and structural units The connected rings are benzene rings or pyridine rings; the R 1 Can be optionally and independently controlled by one or more R a replace.

[0054] In some implementation schemes, R 1 The R is selected from benzo5-membered heteroaryl fused 5-membered cycloalkyl, benzo5-membered heteroaryl fused 5-membered heterocyclic, benzo5-membered heteroaryl fused 6-membered heterocyclic, benzo5-membered heterocyclic fused 5-membered heteroaryl, benzo5-membered cycloalkyl spiro3-membered cycloalkyl, benzo5-membered heterocyclic spiro3-membered cycloalkyl, benzo5-membered heterocyclic spiro4-membered cycloalkyl, benzo5-membered cycloalkyl spiro4-membered heterocyclic, or pyridinium-membered cycloalkyl spiro3-membered cycloalkyl. 1 Can be optionally and independently controlled by one or more R a replace.

[0055] In some implementation schemes, R 1 The R is selected from benzo5-membered heteroaryl fused 5-membered cycloalkyl, benzo5-membered heteroaryl fused 5-membered heterocyclic, benzo5-membered heteroaryl fused 6-membered heterocyclic, benzo5-membered heterocyclic fused 5-membered heteroaryl, benzo5-membered cycloalkyl spiro3-membered cycloalkyl, benzo5-membered heterocyclic spiro3-membered cycloalkyl, benzo5-membered heterocyclic spiro4-membered cycloalkyl, benzo5-membered cycloalkyl spiro4-membered heterocyclic, or pyridinium-membered cycloalkyl spiro3-membered cycloalkyl. 1 Middle and structural units The connected rings are benzene rings or pyridine rings; the R 1 Can be optionally and independently controlled by one or more R a replace.

[0056] In some implementation schemes, R 1 The R is selected from benzo5-membered cycloalkyl spiro3-membered cycloalkyl or benzo5-membered heterocyclic spiro3-membered cycloalkyl. 1 Can be optionally and independently controlled by one or more R a replace.

[0057] In some implementation schemes, R 1 The R is selected from benzo5-membered cycloalkyl spiro3-membered cycloalkyl or benzo5-membered heterocyclic spiro3-membered cycloalkyl. 1 Middle and structural units The connected rings are benzene rings; the R1 Can be optionally and independently controlled by one or more R a replace.

[0058] In some implementation schemes, R 1 Selected from

[0059]

[0060] The R 1 Can be optionally and independently controlled by one or more R a replace.

[0061] In some implementation schemes, R 1 Selected from

[0062] The R 1 Can be optionally and independently controlled by one or more R a Replacement. In other implementations, R 1 Selected from The R 1 Can be optionally and independently controlled by one or more R a replace.

[0063] In some implementation schemes, R 1 Selected from The R 1 Can be optionally and independently controlled by one or more R a replace.

[0064] In other implementations, R 1 Selected from The R 1 Can be optionally and independently controlled by one or more R a replace.

[0065] In other implementations, R 1 Selected from The R 1 Can be optionally and independently controlled by one or more R a replace.

[0066] In some implementation schemes, R 1 Selected from phenyl or 5-6-membered heteroaryl, said R 1 By a C 2-4 Alkyne substitution, R 1 Further, it can be optionally and independently controlled by one or more R a Instead, the C 2-4The alkynyl group may optionally be replaced by one or more R groups. b replace.

[0067] In some implementation schemes, R 1 The R group is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl. 1 By a C 2-4 Alkyne substitution, R 1 Further, it can be optionally and independently controlled by one or more R a Instead, the C 2-4 The alkynyl group may optionally be replaced by one or more R groups. b replace.

[0068] In some implementation schemes, R 1 Selected from phenyl or pyridinyl, wherein R 1 By a C 2-4 Alkyne substitution, R 1 Further, it can be optionally and independently controlled by one or more R a Instead, the C 2-4 The alkynyl group may optionally be replaced by one or more R groups. b replace.

[0069] In some implementation schemes, R 1 Selected from phenyl or pyridinyl, wherein R 1 Replaced by an acetylenic or propynic group, R 1 Further, it can be optionally and independently controlled by one or more R a The acetylene or propyne group may optionally be replaced by one or more R groups. b replace.

[0070] In some implementation schemes, R 1 Selected from phenyl or pyridinyl, wherein R 1 Replaced by an acetylenic or 1-propynic group, R 1 Further, it can be optionally and independently controlled by one or more R a The acetylene or propyne group may optionally be replaced by one or more R groups. b replace.

[0071] In some implementations, each R a Each is independently selected from halogens, =O, and deuterated C. 1-5 Alkyl, -OH, -CN, NH2, C 1-5 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-5 Alkoxy, C 1-5 Alkoxy C 1-3 Alkylene, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclic group, wherein the deuterated C1-5 Alkyl, C 1-5 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-5 Alkoxy or C 1-5 Alkoxy C 1-3 Alkylenes are optionally and independently controlled by one or more R c1 Replace; the C 3-6 Cycloalkyl, phenyl, 5-6-membered heteroaryl, or 3-6-membered heterocyclic groups may be independently bound by one or more R groups. d1 replace.

[0072] In some implementations, each R a Each is independently selected from halogens, =O, and deuterated C. 1-3 Alkyl, -OH, -CN, NH2, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkoxymethylene, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, 5-6 membered heteroaryl or 3-5 membered heterocyclic group, wherein the deuterated C 1-3 Alkyl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy or C 1-3 Alkoxymethylene is optionally and independently controlled by one or more R c1 Substitution; the cyclopropyl, cyclobutyl, cyclopentyl, phenyl, 5-6 membered heteroaryl or 3-5 membered heterocyclic group is optionally independently replaced by one or more R d1 replace.

[0073] In some implementations, each R a Each is independently selected from halogens, =O, and deuterated C. 1-3 Alkyl, C 1-3 Alkyl or C 3-6 cycloalkyl, the deuterated C 1-3 Alkyl or C 1-3 Alkyl groups are optionally and independently influenced by one or more R groups. c1 Replace; the C 3-6 The cycloalkyl group is optionally and independently controlled by one or more R d1 replace.

[0074] In some implementations, each R aEach of the following is independently selected from F, Cl, Br, I, =O, -CD3, -C2D5, -OH, -CN, methyl, ethyl, propyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, methoxymethylene, ethoxymethylene, cyclopropyl, cyclobutyl, cyclopentyl, or phenyl, wherein the methyl, ethyl, propyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, methoxymethylene, or ethoxymethylene is optionally independently separated by one or more R c1 Substitution; the cyclopropyl, cyclobutyl, cyclopentyl, or phenyl group may optionally be independently replaced by one or more R groups. d1 replace.

[0075] In some implementations, each R a The methyl, ethyl, propyl, methoxymethylene, ethoxymethylene, cyclopropyl, cyclobutyl, or cyclopentyl groups are each independently selected from F, Cl, Br, I, =O, -CD3, -C2D5, -OH, -CN, methyl, ethyl, propyl, methoxymethylene, or ethoxymethylene groups, wherein the methyl, ethyl, propyl, methoxymethylene, or ethoxymethylene groups are optionally and independently converted by one or more R groups. c1 Substitution; the cyclopropyl, cyclobutyl, or cyclopentyl group may optionally be independently replaced by one or more R groups. d1 replace.

[0076] In some implementations, each R a The groups are independently selected from F, Cl, Br, =O, -CD3, -C2D5, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, or cyclopentyl, wherein the methyl, ethyl, or propyl groups are optionally independently converted by one or more R groups. c1 Substitution; the cyclopropyl, cyclobutyl, or cyclopentyl group may optionally be independently replaced by one or more R groups. d1 replace.

[0077] In some implementations, each R a Each is independently selected from F, methyl, =O, -CD3 or cyclopropyl.

[0078] In some implementations, each R a Each is independently selected from methyl or =O.

[0079] In some implementations, each R a Each is independently selected from F or methyl.

[0080] In some implementation schemes, R 1 Selected from

[0081] The R 1It may optionally be independently substituted by one, two, or three substituents selected from F, methyl, =O, -CD3, or cyclopropyl. In other embodiments, R 1 Selected from The R 1 It can be optionally and independently substituted by one, two or three substituents selected from F, methyl, =O, -CD3 or cyclopropyl.

[0082] In other implementations, R 1 Selected from The R 1 It can be optionally and independently substituted by one, two or three substituents selected from F, methyl, =O, -CD3 or cyclopropyl.

[0083] In other implementations, R 1 Selected from The R 1 It can be optionally and independently substituted by one, two or three substituents selected from F, methyl, =O, -CD3 or cyclopropyl.

[0084] In some implementation schemes, R 1 Selected from

[0085] In other implementations, R 1 Selected from

[0086] In some implementation schemes, R 1 Selected from

[0087] In other implementations, R 1 Selected from

[0088] In other implementations, R 1 Selected from

[0089] In some implementations, each R b Each of the following is independently selected from halogen, -CN, -OH, -NH2, methyl, ethyl, methoxy, or ethoxy, wherein the methyl, ethyl, methoxy, or ethoxy group is optionally independently substituted by one or more substituents selected from deuterium, halogen, OH, CN, or NH2.

[0090] In some implementations, each R b Selected independently from C 1-3 Alkoxy, the C 1-3 The alkoxy group may be independently substituted by one or more substituents selected from deuterium, halogen, OH, CN or NH2.

[0091] In some implementations, each R b Each is independently selected from F, Cl, Br, I, or methoxy.

[0092] In some implementations, each R b Each is independently selected from methoxy groups.

[0093] In some implementation schemes, R 1 Selected from phenyl or pyridinyl, wherein R 1 Replaced by an acetylenic or propynic group, R 1 It may further be optionally substituted independently by 1, 2 or 3 substituents selected from F or methyl, wherein the ethynyl or propynyl group may be optionally substituted by 1, 2 or 3 methoxy groups.

[0094] In some implementation schemes, R 1 Selected from phenyl or pyridinyl, wherein R 1 Replaced by a 1-propynyl group, R 1 It may be optionally substituted independently with 1, 2 or 3 F, and the 1-propynyl group may be optionally substituted with 1 methoxy group.

[0095] In some implementation schemes, R 1 Selected from

[0096] In some implementation schemes, R 1 Selected from

[0097] In some implementations, each R 2 Each is independently selected from halogens, -OH, -CN, and C. 1-5 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-5 Alkoxy, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclic group, wherein C 1-5 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-5 The alkoxy group is optionally and independently controlled by one or more R groups. c2 Replace; the C 3-6 Cycloalkyl, phenyl, 5-6-membered heteroaryl, or 3-6-membered heterocyclic groups may be independently bound by one or more R groups. d2 replace.

[0098] In some implementations, each R 2 Each is independently selected from halogens, -OH, -CN, and C. 1-3 Alkyl, C2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 3-5 Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-5 membered heterocyclic group, wherein C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-3 The alkoxy group is optionally and independently controlled by one or more R groups. c2 Replace; the C 3-6 Cycloalkyl, phenyl, 5-6-membered heteroaryl, or 3-6-membered heterocyclic groups may be independently bound by one or more R groups. d2 replace.

[0099] In some implementations, each R 2 Selected independently from halogens and C 1-3 Alkyl, or C 3-5 cycloalkyl, the C 1-3 Alkyl groups are optionally and independently influenced by one or more R groups. c2 Replace; the C 3-6 The cycloalkyl group is optionally and independently controlled by one or more R d2 replace.

[0100] In some implementations, each R 2 The groups are independently selected from F, Cl, Br, I, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, or cyclopentyl, wherein the methyl, ethyl, or propyl groups are optionally independently converted by one or more R groups. c2 Substitution; the cyclopropyl, cyclobutyl, or cyclopentyl group may optionally be independently replaced by one or more R groups. d2 replace.

[0101] In some implementations, each R 2 The radical is independently selected from F, methyl, or cyclopropyl, wherein the methyl group is optionally independently converted by one or more R radicals. c2 Substitution; the cyclopropyl group is optionally and independently replaced by one or more R d2 replace.

[0102] In some implementations, each R 2 Each is independently selected from F, methyl, or cyclopropyl.

[0103] In some implementations, R on two adjacent carbon atoms 2 Together with the carbon atom it is attached to, they form C 5-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclic group, wherein C 5-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclic group may be independently construed by one or more R groups. d3 replace.

[0104] In some implementations, R on two adjacent carbon atoms 2 Together with the carbon atom it is attached to, they form C 5-6 cycloalkyl or 5-6 membered heterocyclic group, wherein the C 5-6 Cycloalkyl or 5-6 membered heterocyclic groups are optionally and independently construed by one or more R groups. d3 replace.

[0105] In some implementations, R on two adjacent carbon atoms 2 Together with the carbon atom it is attached to, they form C 5-6 cycloalkyl, the C 5-6 The cycloalkyl group is optionally and independently controlled by one or more R d3 replace.

[0106] In some implementations, R on two adjacent carbon atoms 2 Together with the carbon atom to which it is attached, it forms a cyclopentyl, pyrrole, tetrahydrofuranyl, or tetrahydrothiophene group, wherein the cyclopentyl, pyrrole, tetrahydrofuranyl, or tetrahydrothiophene group is optionally independently atomized by one or more R groups. d3 Replacement. In some implementations, the R atoms on two adjacent carbon atoms... 2 Together with the carbon atom to which it is attached, it forms a cyclopentyl group, which is optionally independently reacted with one or more R atoms. d3 replace.

[0107] In some implementations, R on two adjacent carbon atoms 2 Together with the carbon atom it is attached to, it forms a cyclopentyl group.

[0108] In this application, the R on two adjacent carbon atoms 2 The cyclopentyl group formed together with the attached carbon atom should be understood as the structural unit formed as... R on two adjacent carbon atoms 2 The pyrrole group formed together with the attached carbon atom should be understood as the structural unit formed as...

[0109] In some implementations, R on two adjacent carbon atoms 2 Together with the carbon atom it is attached to, it forms a cyclopentyl group, and the resulting structural unit is...

[0110] In some implementations, q is selected from 0, 1, 2, or 3.

[0111] In some implementations, q is selected from 1, 2, or 3.

[0112] In some implementations, q is selected from 2.

[0113] In some implementations, q is selected from 3.

[0114] In some implementation schemes, structural units Selected from In some implementation schemes, structural units Selected from In some implementation schemes, structural units Selected from In some implementation schemes, structural units Selected from In some implementation schemes, structural units Selected from In some implementation schemes, structural units Selected from In some implementation schemes, X 1 X 2 One of them is selected from C, and the other is selected from N.

[0115] In some implementation schemes, structural units Selected from In some implementation schemes, structural units Selected from In some implementation schemes, Y 1 Y 2 Y 3 Each is independently selected from C or N, Y 4 Selected from CH.

[0116] In some implementation schemes, Y 1 Y 2 Y 3 At least one is selected from N, Y 4 Selected from CH.

[0117] In some implementation schemes, Y 1 Selected from C and Y 2 Selected from N, Y 3 Selected from C, Y 4 Selected from CH.

[0118] In some implementation schemes, Y 1 Selected from C and Y 2 Selected from C and Y 3 Selected from N, Y 4 Selected from CH.

[0119] In some implementation schemes, Y 1 Selected from N, Y 2 Selected from C and Y 3 Selected from C, Y 4 Selected from CH.

[0120] In some implementation schemes, structural units Selected from

[0121] In some implementation schemes, structural units Selected from

[0122] In some implementations, each R 3 Selected independently from deuterium, halogens, and C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclic group, wherein C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 The alkynyl group is optionally and independently controlled by one or more R groups. c3 Replace; the C 3-6 Cycloalkyl, phenyl, 5-6-membered heteroaryl, or 3-6-membered heterocyclic groups may be independently bound by one or more R groups. d4 replace.

[0123] In some implementations, each R 3 Each is independently selected from deuterium, halogen, or C. 1-3 Alkyl, the C 1-3 Alkyl groups are optionally and independently influenced by one or more R groups. c3 replace.

[0124] In some implementations, each R 3 Selected independently from C 1-3 Alkyl, the C 1-3 Alkyl groups are optionally and independently influenced by one or more R groups. c3 replace.

[0125] In some implementations, each R 3 The radicals are independently selected from deuterium, F, Cl, Br, I, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, or cyclopentyl, wherein the methyl, ethyl, or propyl radicals are optionally independently converted by one or more R radicals. c3 Substitution; the cyclopropyl, cyclobutyl, or cyclopentyl group may optionally be independently replaced by one or more R groups. d4 replace.

[0126] In some implementations, each R 3 Each is independently selected from methyl, ethyl, or propyl, wherein the methyl, ethyl, or propyl group is optionally converted by one or more R... c3 replace.

[0127] In some implementations, the R 3 Selected from methyl.

[0128] In some implementations, n is selected from 0, 1, 2, or 3.

[0129] In some implementations, n is selected from 1, 2, or 3.

[0130] In some implementations, n is selected from 1.

[0131] In some implementation schemes, R 4 Selected from H, deuterium, halogens, -CN, C 1-3 Alkyl, deuterated C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl, deuterated C 1-3 Alkyl or C 1-3 The alkoxy group is optionally and independently controlled by one or more R groups. c4 replace.

[0132] In some implementation schemes, R 4 Selected from H or C 1-3 Alkyl, the C 1-3 Alkyl groups are optionally and independently influenced by one or more R groups. c4 replace.

[0133] In some implementation schemes, R 4 Selected from H or methyl, said methyl group optionally being separated by one or more R c4 replace.

[0134] In some implementation schemes, R 4 Selected from H or methyl.

[0135] In some implementation schemes, R 4 Selected from H.

[0136] In some implementation schemes, R 4 Selected from methyl.

[0137] In some implementation schemes, R 5 Selected from halogens, -CN, C 1-3 Alkyl, deuterated C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl, deuterated C 1-3 Alkyl or C 1-3 The alkoxy group is optionally and independently controlled by one or more R groups. c5 replace.

[0138] In some implementation schemes, R 5 Selected from C 1-3 Alkyl, the C 1-3 Alkyl groups are optionally and independently influenced by one or more R groups. c5 replace.

[0139] In some implementation schemes, R5 Selected from methyl.

[0140] In some implementations, m is selected from 0, 1, 2, or 3.

[0141] In some implementations, m is selected from 0, 1, or 2.

[0142] In some implementations, m is selected from 0.

[0143] In some implementations, m is selected from 1.

[0144] In some implementations, R' and R" are independently selected from H, deuterium, halogen, -CN, and C, respectively. 1-3 Alkyl, deuterated C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl, deuterated C 1-3 Alkyl or C 1-3 The alkoxy group is optionally and independently controlled by one or more R groups. c6 replace.

[0145] In some implementations, R' and R" are independently selected from H or C. 1-3 Alkyl, the C 1-3 Alkyl groups are optionally and independently influenced by one or more R groups. c6 replace.

[0146] In some embodiments, R' and R" are each independently selected from H or methyl, wherein the methyl group is optionally separated by one or more R c6 replace.

[0147] In some implementations, both R' and R" are selected from methyl groups.

[0148] In some implementations, R' and R" together with the carbon atom they are attached to form C 3-4 Cycloalkyl or 3-4 membered heterocycloalkyl, wherein C 3-4 Cycloalkyl or 3-4 membered heterocyclic alkyl groups are optionally and independently constituting one or more R groups. d5 replace.

[0149] In some embodiments, R' and R" and their associated carbon atoms together form a cyclopropyl group, which is optionally independently atomized by one or more R's. d5 replace.

[0150] In some implementations, R' and R" together with the carbon atom they are attached to form a cyclopropyl group.

[0151] In some implementations, each R c1 R c2 R c3 R c4 Rc5 and R c6 Each can be independently selected from halogens, -CN, -OH, or -NH2.

[0152] In some implementations, each R c1 R c2 R c3 R c4 R c5 and R c6 Each can be independently selected from F, -CN, -OH, or -NH2.

[0153] In some implementations, each R c1 R c2 R c3 R c4 R c5 and R c6 Each is independently selected from F or OH.

[0154] In some implementations, each R c1 R c2 R c3 R c4 R c5 and R c6 Each is selected independently from F.

[0155] In some implementations, each R d1 R d2 R d3 R d4 and R d5 Selected independently from halogens, -CN, -OH, -NH2, and C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy group may be independently substituted by one or more substituents selected from halogens, OH, CN or NH2.

[0156] In some implementations, each R d1 R d2 R d3 R d4 and R d5 The substituents are independently selected from F, -CN, -OH, -NH2, methyl or methoxy, wherein the methyl or methoxy group is optionally independently substituted by one or more substituents selected from F, OH, CN or NH2.

[0157] In some implementations, each R d1 R d2 R d3 R d4 and R d5Each of the following is independently selected from F, -CN, -OH, -NH2, methyl, or methoxy.

[0158] In some implementations, each R d1 R d2 R d3 R d4 and R d5 Each is independently selected from F or methyl.

[0159] In some implementations, each R d1 R d2 R d3 R d4 and R d5 Each is selected independently from F.

[0160] The compounds of formula (I), their stereoisomers, or pharmaceutically acceptable salts thereof in this application are selected from compounds of formula (IA), (IB), (IC), or (ID), their stereoisomers, or pharmaceutically acceptable salts thereof.

[0161]

[0162] Among them, R 1 R 2 R 3 R 4 R 5 The definitions of R′, R”, q, n or m are as described in compound (I).

[0163] The compounds of formula (I) of this application, their stereoisomers or pharmaceutically acceptable salts thereof, are selected from compounds of formula (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), (II-J), (II-K) or (II-L), their stereoisomers or pharmaceutically acceptable salts thereof.

[0164]

[0165]

[0166] in, R 1 R 2 R 3 R 4 R 5 、R′、R”、R a The definitions of , q, n, or m are as described in the compound of formula (I);

[0167] r is selected from 0, 1, 2, 3 or 4;

[0168] X is selected from C or N;

[0169] X 3 X 4 X 5 or X 6 Each is independently selected from C or N;

[0170] X 7 X 8 X 9 X 10 or X 11 Each is independently selected from C, CH, or N.

[0171] In some implementations, X is selected from C. In some implementations, X is selected from N.

[0172] In some implementation schemes, X 3 Selected from N, X 4 X 5 or X 6 Each is independently selected from C or N.

[0173] In some implementation schemes, X 3 X 6 Selected from N, X 4 X 5 Selected from C.

[0174] In some implementation schemes, X 3 X 4 Selected from N, X 5 X 6 Selected from C.

[0175] In some implementation schemes, X 7 and X 11 One of them is selected from N, and the other is selected from C.

[0176] In some implementation schemes, X 7 and X 9 Selected from N, X 11 Selected from C, X 8 and X 10 Selected from CH.

[0177] In some implementations, r is selected from 0, 1, or 2.

[0178] In some implementations, r is selected from 0 or 2.

[0179] This application also provides a compound of formula (I'), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0180]

[0181] Among them, X1 X 2 Y 1 Y 2 Y 3 Y 4 , R 1 R 2 R 3 R 4 R 5 The definitions of R′, R”, q, n or m are as described in compound (I).

[0182] The compounds of formula (I), their stereoisomers, or pharmaceutically acceptable salts thereof in this application are selected from compounds of formula (I-A'), (I-B'), (I-C'), or (I-D'), their stereoisomers, or pharmaceutically acceptable salts thereof.

[0183]

[0184] Among them, R 1 R 2 R 3 R 4 R 5 The definitions of R′, R”, q, n or m are as described in compound (I).

[0185] The compounds of formula (I) of this application, their stereoisomers or pharmaceutically acceptable salts thereof, are selected from compounds of formula (II-A'), (II-B'), (II-C'), (II-D'), (II-E'), (II-F'), (II-G'), (II-H'), (II-I'), (II-J'), (II-K') or (II-L'), their stereoisomers or pharmaceutically acceptable salts thereof.

[0186]

[0187]

[0188] in, R 1 R 2 R 3 R 4 R 5 、R′、R”、R a The definitions of , q, n, or m are as described in the compound of formula (I);

[0189] r is selected from 0, 1, 2, 3 or 4;

[0190] X is selected from C or N;

[0191] X 3 X4 X 5 or X 6 Each is independently selected from C or N;

[0192] X 7 X 8 X 9 X 10 or X 11 Each is independently selected from C, CH, or N.

[0193] In some implementation schemes, X, X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 or X 11 The definition is as described in compounds (II-D), (II-F), and (II-J) above.

[0194] The compounds of formula (I), their stereoisomers, or pharmaceutically acceptable salts thereof in this application are selected from compounds of formula (III-A), their stereoisomers, or pharmaceutically acceptable salts thereof.

[0195]

[0196] Among them, X 1 X 2 Y 1 Y 2 Y 3 Y 4 , R 1 R 2 R 3 R 4 R 5 The definitions of R′, R″ and q are as described in compound (I).

[0197] The compounds of formula (I), their stereoisomers, or pharmaceutically acceptable salts thereof in this application are selected from compounds of formula (III-A'), formula (III-B'), or formula (III-C'), their stereoisomers, or pharmaceutically acceptable salts thereof.

[0198]

[0199]

[0200] Among them, X 1 X 2 Y 1 Y 2 Y3 Y 4 , R 1 R 2 R 3 R 4 R 5 The definitions of R′, R″ and q are as described in compound (I).

[0201] The compounds of formula (I), their stereoisomers, or pharmaceutically acceptable salts thereof in this application are selected from compounds of formula (IV-A), their stereoisomers, or pharmaceutically acceptable salts thereof.

[0202]

[0203] Among them, X 1 X 2 Y 1 Y 2 Y 3 Y 4 , R 1 R 2 R 3 R 4 The definitions of R′, R″ and q are as described in compound (I).

[0204] The compounds of formula (I), their stereoisomers, or pharmaceutically acceptable salts thereof in this application are selected from compounds of formula (IV-A'), formula (IV-B'), or formula (IV-C'), their stereoisomers, or pharmaceutically acceptable salts thereof.

[0205]

[0206] Among them, X 1 X 2 Y 1 Y 2 Y 3 Y 4 , R 1 R 2 R 3 R 4 The definitions of R′, R″ and q are as described in compound (I).

[0207] In some implementations, this disclosure includes the variables defined above and their implementations, as well as any combination thereof.

[0208] On the other hand, this disclosure provides the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof:

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215] On the other hand, this disclosure also provides pharmaceutical compositions comprising the compounds described above, their stereoisomers, or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions of this disclosure further include pharmaceutically acceptable excipients.

[0216] On the other hand, this disclosure also provides a method for treating various GLP-1-related diseases, comprising administering to a mammal, preferably a human, a therapeutically effective amount of the above-described compound of this disclosure, its stereoisomer, its pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0217] On the other hand, this disclosure also provides the use of the above-described compounds, their stereoisomers, their pharmaceutically acceptable salts, or pharmaceutical compositions thereof in the preparation of medicaments for treating various GLP-1-related diseases.

[0218] On the other hand, this disclosure also provides the use of the above-described compounds, their stereoisomers, their pharmaceutically acceptable salts, or pharmaceutical compositions thereof in the treatment of various GLP-1-related diseases.

[0219] On the other hand, this disclosure also provides the above-described compounds, stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the treatment of various GLP-1-related diseases.

[0220] In some implementations, the various GLP-1-related diseases are selected from diabetes or obesity.

[0221] The compounds disclosed herein possess good in vivo and in vitro agonistic activity (e.g., GLP-1 in vitro enzyme agonistic activity) and metabolic stability (e.g., liver microsomal metabolic stability) related to GLP-1.

[0222] definition

[0223] Unless otherwise stated, the following terms as used in this disclosure have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0224] When the covalent bonds in certain structural units or groups in this disclosure are not connected to specific atoms, it means that the covalent bonds can be connected to any atom in the structural unit or group, as long as the rules of valence bond connection are not violated.

[0225] The term "substitution" refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted; oxo substitution does not occur on aromatic groups.

[0226] The terms “optional” or “optionally” mean that the event or condition subsequently described may or may not occur, including both the occurrence and non-occurrence of said event or condition. For example, the ethyl group “optionally” being halogenated means that the ethyl group can be unsubstituted (CH2CH3), monosubstituted (e.g., CH2CH2F), polysubstituted (e.g., CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized is introduced.

[0227] C in this article m-n This means that the part has an integer number of carbon atoms within a given range. For example, "C 1-6 "" means that the group can have 1, 2, 3, 4, 5, or 6 carbon atoms. For example, C 1-3 This means that the group can have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0228] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by two Rs, each R has an independent option.

[0229] When the number of a linking group is 0, such as -(CH2)0-, it indicates that the linking group is a covalent bond.

[0230] When one of the variables is selected as a covalent bond, it means that the two groups connected to it are directly linked. For example, when L' represents a covalent bond in A-L'-Z, it means that the structure is actually AZ.

[0231] When a substituent is cross-bonded to two atoms on a ring, this substituent can bond to any atom on that ring. For example, in the above example of ring A, the bonds on either side can be connected to any two different atoms on ring A.

[0232] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0233] The term "alkyl" refers to a compound with the general formula C10. n H 2n+1 The alkyl group typically has 1 to 12, 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. The alkyl group can be straight-chain or branched, for example, it can be "C 1-12 Alkyl or C 1-6 Alkyl groups, etc. For example, the term "C 1-12 "Alkyl" refers to alkyl groups containing 1 to 12 carbon atoms, including C1, C2, C3, C4, C5, C6, C7, C8, C9, C1 ...1, C1, C1, C1, C1, C1, C1, C1, C1, C1, C1, C1, C1, C1, C 10 C 11 and C 12 Alkyl groups and any combination thereof. For example, the term "C 1-6 "Alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups has the same definition. For example, the term "C"... 1-3 "Alkyl" refers to an alkyl group containing 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl, and isopropyl).

[0234] The term "deuterated C" 1-n "Alkyl" refers to an alkyl group substituted with 1 to 2n+1 deuterium atoms. The definition of alkyl is as described above. The maximum number of deuterium atoms that can be substituted depends on the maximum number of hydrogen atoms that can be present in the alkyl group itself. The substitution positions can be arbitrary. For example, the term "deuterated C..." 1-3 "Alkyl" refers to an alkyl group containing 1 to 3 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl) that is substituted with 1 to 7 deuterium atoms, wherein methyl can be substituted with 1, 2, or 3 deuterium atoms; ethyl can be substituted with 1, 2, 3, 4, or 5 deuterium atoms; and n-propyl and isopropyl can be substituted with 1, 2, 3, 4, 5, 6, or 7 deuterium atoms.

[0235] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one double bond. It typically has 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms, for example, it can be "C 2-12 "Alkenyl" or "C" 2-6 "Alkenyl", etc. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc.

[0236] The term "alkynyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one triple bond. It typically has 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. For example, it could be "C 2-12 "Alkyne" or "C" 2-6 "Alynyl", etc. Non-limiting examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), propynyl (e.g., 1-propynyl (-C≡C-CH3), 2-propynyl (-CH2-C≡CH)), butynyl (e.g., 1,3-butyrynyl (-C≡CC≡CH)), etc.

[0237] The term "alkoxy" refers to -O-alkyl.

[0238] The term "alkylthio" refers to -S-alkyl.

[0239] The term "cycloalkyl" refers to a fully or partially saturated cyclic hydrocarbon that can exist as a monocyclic, bridged, fused, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 10-membered, 4- to 8-membered, 5- to 8-membered, or 5- to 6-membered ring. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, bicyclo[1.1.1]pent-1-yl, etc. For example, C 3-4 Cycloalkyl groups include cyclopropyl and cyclobutyl groups.

[0240] The term "heterocyclic group" refers to a fully saturated or partially saturated non-aromatic or partially non-aromatic ring that can exist as a monocyclic, bridged, fused, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3- to 13-membered ring (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered ring), a 10- to 13-membered ring, or an 11- to 13-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and / or boron (preferably 1 or 2 heteroatoms). Non-limiting examples of heterocyclic groups include, but are not limited to, spiro[cyclopropane-1,3'-dihydroindole]yl, 1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazinyl, 2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazolyl, 1',3'-dihydrospiro[cyclopropane-1,2'-indene]yl, phenyl, pyridyl, 1,3-dihydrospiro[indene-2]yl [3'-oxacyclobutane]yl, spiro[cyclobutane-1,3'-dihydroindole]yl, spiro[cyclopropane-1,1'-isoindole]yl, spiro[cyclopenta[c]pyridin-5,1'-cyclopropane]yl, spiro[cyclopropane-1,3'-indole]yl, 5H-imidazo[5,1-a]isoindole or 2,3-dihydro-1H-cyclopenta[3,4]pyrazolo[1,5-a]pyridinyl, etc.

[0241] The term "aryl" refers to an aromatic carbocyclic group, which may contain a non-aromatic portion in addition to the aromatic portion. The ring may be monocyclic or bicyclic or tricyclic formed by a benzene ring and an aromatic or non-aromatic portion. For example, an aryl group may have 6-20 carbon atoms, 6-15 carbon atoms, 6-14 carbon atoms, 6-12 carbon atoms, or 6-11 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, 1,2,3,4-tetrahydronaphthalene, isochoryl, 2,4-dihydro-1H-isoquinoline-3-one, or spirocyclic [cyclopropane-1,2'-indene]-1'(3'H)-one.

[0242] The term "heteroaryl" refers to a monocyclic or polycyclic system containing at least one ring atom selected from N, O, and S, with the remaining ring atoms being C, and having at least one aromatic ring. In addition to the aromatic moiety, it may contain a non-aromatic moiety. The ring can be monocyclic or it can be a benzene ring or a bicyclic or tricyclic ring formed by a monocyclic heteroaryl ring and an aromatic or non-aromatic moiety. Preferred heteroaryls have a single 5- to 8-membered ring (e.g., 5-, 6-, 7-, or 8-membered), or multiple fused rings containing 6 to 15, especially 6 to 12, ring atoms (e.g., 6, 7, 8, 9, 10, 11, or 12 ring atoms). Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrole, furanyl, thiophene, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyridinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothiophene, indolyl, isoindolyl, pyridopyrroleyl, or spirocyclic [cyclopropane-1,3'-indoline]-2'-keto.

[0243] The term "alkylene" refers to a divalent group formed by removing a hydrogen atom from any position of an alkyl group, for example, the term "C 1-3 "Alkylene" refers to an alkylene containing 1 to 3 carbon atoms, including but not limited to methylene (-CH2-), ethylene (-CH2CH2-), and propylene (-CH2CH2CH2- or -CH2CH(CH3)-).

[0244] The compounds disclosed herein may exist in specific geometric or stereoisomeric forms. This disclosure envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this disclosure.

[0245] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid is indicated by a wavy line. Indicates wedge-shaped solid line key or wedge-shaped dashed key Or use wavy lines Indicates a straight solid line key and straight dashed key

[0246] Unless otherwise stated, when a compound contains a double bond structure, such as a carbon-carbon double bond, a carbon-nitrogen double bond, or a nitrogen-nitrogen double bond, and each atom in the double bond is attached to two different substituents (in a double bond containing a nitrogen atom, the lone pair of electrons on the nitrogen atom is considered as one of the substituents it is attached to), if the atoms in the double bond and their substituents in the compound are separated by a wavy line... The connection indicates that the compound is a (Z) type isomer, an (E) type isomer, or a mixture of the two isomers.

[0247] The term "treatment" means administering the compounds or preparations described in this disclosure to improve or eliminate a disease or one or more symptoms related to said disease, and includes:

[0248] (i) Suppress the disease or disease state, that is, curb its development;

[0249] (ii) Relieve the disease or disease state, even if the disease or disease state subsides.

[0250] The term "therapeutic or preventive effective amount" means (i) the amount of the disclosed compound used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the disclosed compound constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the content of this disclosure.

[0251] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0252] As pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, and salts formed with basic or acidic amino acids may be mentioned.

[0253] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or salts thereof with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the disclosed compounds to an organism.

[0254] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0255] The word “comprise” or “include” and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, meaning “including but not limited to”.

[0256] The compounds and intermediates disclosed herein may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is the imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions via the recombination of some bonding electrons.

[0257] This disclosure also includes compounds of this disclosure that are identical to those described herein, but in which one or more atoms are labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F,123 I, 125 I and 36 Cl, etc.

[0258] Certain isotopically labeled compounds of this disclosure (e.g., those labeled with 3H and 14C) can be used in the analysis of compound and / or substrate tissue distribution. Tritiumization (i.e. 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes, such as... 15 O、 13 N、 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. The isotopically labeled compounds of this disclosure can typically be prepared by replacing the unlabeled reagent with an isotopically labeled reagent using a procedure similar to those disclosed in the schemes and / or examples below.

[0259] In addition, heavier isotopes (such as deuterium) are used. 2 H)) substitution can provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and may therefore be preferred in certain situations, wherein deuterium substitution can be partial or complete, and partial deuterium substitution means that at least one hydrogen is substituted by at least one deuterium, and all such compounds are included within the scope of this disclosure.

[0260] The compounds disclosed herein may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds containing asymmetric carbon atoms of this disclosure can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0261] The pharmaceutical compositions disclosed herein can be prepared by combining the compounds disclosed herein with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0262] Typical routes of administration of the disclosed compounds or their pharmaceutically acceptable salts or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0263] The pharmaceutical compositions disclosed herein can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.

[0264] In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of this disclosure to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, liquids, gels, pastes, suspensions, etc., for oral administration to patients.

[0265] Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated formulation. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0266] The pharmaceutical composition may also be suitable for parenteral administration, such as in suitable unit dosage forms of sterile solutions, suspensions or lyophilized products.

[0267] The therapeutic dose of the disclosed compound may be determined based on factors such as the specific therapeutic use, the method of administration, the patient's health and condition, and the prescribing physician's judgment. The proportion or concentration of the disclosed compound in the pharmaceutical composition may not be fixed and may depend on various factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the disclosed compound may be provided, for example, by means of a physiologically buffered aqueous solution containing about 0.1 to 10% w / v of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg / kg to about 1 g / kg body weight / day. In some embodiments, the dosage range is from about 0.01 mg / kg to about 100 mg / kg body weight / day. The dosage is likely to depend on variables such as the type and severity of the disease or condition, the general health status of the specific patient, the relative biological potency of the selected compound, the excipient formulation, and the route of administration. The effective dose can be obtained by extrapolation from dose-response curves derived from in vitro or animal model testing systems.

[0268] The compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments disclosed herein.

[0269] The chemical reactions in the specific embodiments of this disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes of this disclosure and the reagents and materials required therefor. In order to obtain the compounds of this disclosure, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction flow based on existing embodiments.

[0270] An important consideration in synthetic route planning in this field is the selection of appropriate protecting groups for reactive functional groups (such as amino groups in this disclosure), for example, see Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0271] In some embodiments, the compounds disclosed herein can be prepared by those skilled in the art of organic synthesis by referring to the following routes:

[0272]

[0273] The following abbreviations are used in this disclosure:

[0274] Among them, R 1 R 2 R 3 R 4 R 5 , q, X 1 X 2 Y 1 Y 2 Y 3 Y 4 The definitions of R' or R" are as described above, and Z is a leaving group, including but not limited to F, Cl, Br, I, etc.

[0275] The following abbreviations are used in this disclosure:

[0276] NaHMDS represents sodium bis(trimethylsilyl)amino; DCM represents dichloromethane; MeOH represents methanol.

[0277] For clarity, this disclosure is further illustrated by examples, but these examples are not intended to limit the scope of this disclosure. All reagents used in this disclosure are commercially available and can be used without further purification.

[0278] Example 1

[0279]

[0280] Step 1: Synthesis of intermediates 1-2

[0281] 5'-Bromo-1',2'-dihydrospiro[cyclopropane-1,3'-dihydroindole]-2'-one (500 mg) and N,N-dimethylformamide (7 mL) were mixed, and sodium hydride (126 mg, 60% dispersed in mineral oil) was added under ice bath conditions. The reaction mixture was stirred for 30 minutes. Iodomethane (0.055 mL) was added dropwise to the reaction mixture, and the reaction mixture was transferred to room temperature and stirred for 1.5 hours. The reaction mixture was poured into a mixture of ethyl acetate (30 mL) and water (50 mL). The aqueous phase was extracted with ethyl acetate (2 × 30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 450 mg of intermediate 1-2.

[0282] MS(ESI, [M+H]) + )m / z:252.05.

[0283] 1 H-NMR (500MHz, DMSO-d6): δ7.43 (dd, J=8.3, 2.0Hz, 1H), 7.28 (d, J=2.0Hz, 1H), 7 .03(d,J=8.2Hz,1H),3.20(s,3H),1.69(q,J=3.8Hz,2H),1.52(q,J=3.8Hz,2H).

[0284] Step 2: Synthesis of intermediates 1-3

[0285] Intermediate A-1 (250 mg), intermediate 1-2 (186 mg), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (40.3 mg), potassium carbonate (235 mg), cuprous iodide (21.57 mg), and N-methylpyrrolidone (4 mL) were mixed and reacted overnight in an oil bath at 120 °C under nitrogen protection. The reaction solution was cooled to room temperature and poured into water (50 mL). The resulting solution was extracted with ethyl acetate (30 mL). The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 3:2) to obtain 0.3 g of intermediate 1-3.

[0286] MS(ESI, [M+H]) + )m / z:613.37.

[0287] 1H-NMR (500MHz, DMSO-d6): δ7.49 (dd, J=8.4, 2.2Hz, 1H), 7.24 (d, J=1.9Hz, 1H), 7 .15(t,J=5.9Hz,2H),7.10(d,J=6.3Hz,2H),6.91(s,1H),5.18-5.03(m,1H),4.3 7-4.13(m,1H),3.23(s,3H),3.19-3.06(m,1H),2.77-2.61(m,2H),2.19(d,J=1. 7Hz,6H),1.68-1.63(m,2H),1.58-1.53(m,2H),1.43(s,9H),1.22-1.18(m,3H).

[0288] Step 3: Synthesis of intermediates 1-4

[0289] Intermediate 1-3 (0.28 g), dichloromethane (2 mL), and 4N dioxane hydrochloride solution (2 mL) were mixed and stirred at room temperature for 1 hour. Stirring was then stopped, and the mixture was concentrated under reduced pressure to obtain 0.24 g of intermediate 1-4.

[0290] MS(ESI, [M+H]) + )m / z:513.1.

[0291] Step Six: Synthesis of Compound 1 and Compound 1-A

[0292] Intermediate B-1 (0.1 g), N,N-dimethylformamide (5 mL), triethylamine (0.576 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.236 g) were stirred for 5 minutes. Then, intermediate 1-4 (0.125 g) was added, and the mixture was stirred at 30 °C. The reaction solution was poured into water (50 mL), and the resulting solution was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:MeOH = 95:5) to obtain compound 1. Compound 1 was prepared and separated by chiral HPLC (column: REFLECT I-Cellulose B, 30 × 250 mm, 10 μm; mobile phase: ethanol-dichloromethane (1:3):n-hexane = 25:75; flow rate: 40 mL / min) to obtain compound 1-A (43 mg).

[0293] Compound 1-A: R t = 1.34 min (UPCC conditions: column: CHIRALPAK IB-3, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: ethanol: isopropanol = 40:30:30; flow rate: 2.0 mL / min; column temperature: 40℃)

[0294] HRMS:(ESI, [M+H]) + )m / z:906.4130.

[0295] 1 H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),7.58-7.31(m,3H),7.30-7.03(m,6H),7.01 -6.68(m,2H),5.61-5.49(m,1H),4.46-4.29(m,1H),3.77-3.66(m,2H),3.66-3.58(m, 1H),3.28-3.15(m,4H),3.08-2.98(m,1H),2.94-2.83(m,1H),2.29-2.13(m,6H),1.8 4-1.62(m,6H),1.58-1.50(m,4H),1.42-1.37(m,2H),1.27(s,3H),1.25-1.13(m,8H).

[0296] Example 2

[0297]

[0298] Step 1: Synthesis of Intermediate 2-1

[0299] 5'-Bromo-1',2'-dihydrospiro[cyclopropane-1,3'-dihydroindole]-2'-one (500 mg) and N,N-dimethylformamide (8 mL) were mixed, and sodium hydroxide (126 mg, 60% dispersed in mineral oil) was added under ice bath conditions. The mixture was stirred for 10 minutes, followed by the addition of deuterated iodomethane (457 mg), and the reaction was allowed to proceed to room temperature for 2 hours. After the reaction was complete, the reaction solution was poured into a saturated ammonium chloride solution (20 mL), and extracted with ethyl acetate (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give 400 mg of intermediate 2-1.

[0300] MS(ESI, [M+H]) + )m / z:255.08.

[0301] 1 H-NMR (500MHz, DMSO-d6): δ7.42(dd,J=8.3,2.0Hz,1H),7.28(d,J=2.0Hz,1H),7.02(d,J=8.2Hz,1H),1.72-1.67(m,2H),1.54-1.49(m,2H).

[0302] Step 2: Synthesis of intermediate 2-2

[0303] Intermediate A-1 (250 mg), intermediate 2-1 (188 mg), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (40.3 mg), potassium carbonate (235 mg), cuprous iodide (21.57 mg), and N-methylpyrrolidone (6 mL) were mixed and reacted at 120 °C for 12 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was poured into water, and ethyl acetate (50 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 70:30) to give 260 mg of intermediate 2-2.

[0304] MS(ESI, [M+H]) + )m / z:616.39.

[0305] 1 H NMR (500MHz, DMSO-d6): δ7.49(dd,J=8.4,2.2Hz,1H),7.24(d,J=2.1Hz,1H),7.19-7.14(m,2H),7.10(d,J=6.2Hz,2H),6.96-6.87(m,1 H),2.79-2.61(m,2H),2.19(d,J=2.0Hz,6H),1.69-1.62(m,2H),1.58-1.53(m,2H),1.44(s,9H),1.38-1.22(m,3H),1.21-1.14(m,3H).

[0306] Step 3: Synthesis of intermediates 2-3

[0307] Intermediate 2-2 (260 mg) was mixed with 5 mL of 4N dioxane hydrochloride solution and reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain 230 mg of intermediate 2-3.

[0308] Step 4: Synthesis of intermediates 2-4 and compound 2

[0309] Intermediate B-1 (0.1 g), N,N-dimethylformamide (5 mL), triethylamine (0.678 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.277 g) were mixed and stirred at room temperature for 5 minutes. Intermediate 2-3 (0.148 g) was then added, and the mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction solution was poured into water, and ethyl acetate (50 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give 70 mg of intermediate 2-4. Intermediates 2-4 were prepared and separated by chiral HPLC (column: CHIRAL ART Cellulose-SB, 30×250mm, 5μm, mobile phase: ethanol-dichloromethane (1:1): n-hexane = 30:70, flow rate: 38mL / min) to obtain compound 2 (35mg).

[0310] Compound 2: Rt = 2.80 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6 × 100 mm, 3 μm); mobile phase: carbon dioxide: methanol (containing 0.1% ammonia) = 50:50; flow rate: 2.0 mL / min; column temperature: 40℃)

[0311] HRMS:(ESI, [M+H]) + )m / z:909.4328.

[0312] 1 H NMR(500MHz,DMSO)δ11.73(s,1H),7.56-7.48(m,2H),7.45-7.32(m,2H),7.29-7.23(m,2H),7.2 0(s,1H),7.16-7.13(m,2H),6.94(s,2H),5.63-5.50(m,1H),4.44-4.33(m,1H),3.73-3.68(m,2H ),3.67-3.56(m,1H),3.18(s,1H),3.06-3.00(m,1H),2.93-2.85(m,1H),2.22(s,6H),1.76-1.6 5(m,6H),1.64-1.59(m,2H),1.57-1.47(m,6H),1.39(d,J=6.3Hz,2H),1.24(s,4H),1.18(s,3H).

[0313] Example 3

[0314]

[0315] Step 1: Synthesis of Intermediate 3-1

[0316] 5'-Bromo-1',2'-dihydrospiro[cyclopropane-1,3'-dihydroindole]-2'-one (500 mg) and toluene (50 mL) were mixed, and cyclopropylboronic acid (360 mg), 4-dimethylaminopiperidine (800 mg), copper acetate (440 mg), and a 2M tetrahydrofuran solution of sodium bis(trimethylsilyl)aminoacetate (1.1 mL) were added sequentially. The mixture was heated to 95 °C and stirred for 16 hours. The reaction solution was diluted with ethyl acetate, filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 3:2) to obtain 0.5 g of intermediate 3-1.

[0317] MS(ESI, [M+H]) + )m / z:278.09.

[0318] 1 H-NMR (500MHz, DMSO-d6): δ7.43(dd,J=8.3,2.0Hz,1H),7.25(d,J=2.0Hz,1H),7.10(d,J=8.3Hz,1H),2.73 (tt,J=7.0,3.8Hz,1H),1.65(q,J=3.7Hz,2H),1.49(q,J=3.7Hz,2H),1.06-0.95(m,2H),0.85-0.73(m,2H).

[0319] Step 2: Synthesis of intermediate 3-2

[0320] Intermediate A-1 (250 mg), intermediate 3-1 (250 mg), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (50 mg), potassium carbonate (250 mg), cuprous iodide (25 mg), and N-methylpyrrolidone (5 mL) were mixed and reacted overnight in an oil bath at 120 °C under nitrogen protection. The reaction solution was cooled to room temperature and poured into water (50 mL). The resulting solution was extracted with ethyl acetate (30 mL). The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 3:2) to obtain 0.3 g of intermediate 3-2.

[0321] MS(ESI, [M+H]) + )m / z:639.33.

[0322] 1H-NMR (500MHz, DMSO-d6): δ7.49 (dd, J=8.4, 2.3Hz, 1H), 7.24 (d, J=8.4Hz, 1H), 7.20 (d ,J=2.1Hz,1H),7.15(d,J=3.2Hz,1H),7.10(d,J=6.3Hz,2H),6.91(s,1H),5.12(s,1H), 4.21(s,1H),3.15(s,1H),2.80-2.61(m,3H),2.19(s,6H),1.67-1.57(m,2H),1.51(q,J =3.4Hz,2H),1.43(s,9H),1.19(d,J=5.8Hz,3H),1.07-0.99(m,2H),0.86-0.78(m,2H).

[0323] Step 3: Synthesis of intermediate 3-3

[0324] Intermediate 3-2 (0.3 g) and 4N dioxane hydrochloride solution (3 mL) were mixed and stirred at room temperature for 1 hour. Stirring was stopped, and the mixture was concentrated under reduced pressure to obtain 0.26 g of intermediate 3-3.

[0325] MS(ESI, [M+H]) + )m / z:539.32.

[0326] Step 4: Synthesis of intermediates 3-4 and compound 3

[0327] Intermediate B-1 (0.12 g), N,N-dimethylformamide (4 mL), triethylamine (0.068 g), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.14 g) were stirred for 5 minutes. Then, intermediate 3-3 (0.16 g) was added, and the mixture was stirred at 30 °C. The reaction mixture was poured into water (50 mL), and the resulting solution was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:MeOH = 95:5) to obtain intermediate 3-4. Intermediate 3-4 was prepared and separated by chiral HPLC (column: Pre-packed REGIS IB, 30 × 250 mm, 10 μm; mobile phase: ethanol-dichloromethane (1:3):n-hexane = 30:70; flow rate: 40 mL / min) to obtain 85 mg of compound 3.

[0328] Compound 3: Rt = 2.02 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6 × 100 mm, 3 μm); mobile phase: carbon dioxide: methanol (containing 0.1% ammonia) = 30:70; flow rate: 2.0 mL / min; column temperature: 40℃)

[0329] HRMS:(ESI, [M+H]) + )m / z:932.4280.

[0330] 1 H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),7.55-7.49(m,2H),7.42-7.36(m,1H),7.28-7.13(m,6H),6.95(s,2H) ,5.55(d,J=6.0Hz,1H),4.38(d,J=9.5Hz,1H),3.72(d,J=10.4Hz,2H),3.63(t,J=11.2Hz,1H),3.53-3.39(m,1H ),3.24-3.11(m,1H),3.03(t,J=11.9Hz,1H),2.88(d,J=15.6Hz,1H),2.81-2.69(m,2H),2.22(s,6H),1.73-1.6 2(m,6H),1.56-1.51(m,4H),1.39(d,J=6.9Hz,2H),1.19-1.12(m,6H),1.03(t,J=7.3Hz,3H),0.89-0.78(m,4H).

[0331] Example 4

[0332] Synthesis of compound 4:

[0333]

[0334] Intermediate 1-4 (133 mg), N,N-dimethylformamide (5 mL), triethylamine (492 mg), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (277 mg) were mixed and stirred for 5 minutes. Then, intermediate B-2 (100 mg) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water (50 mL), and the resulting solution was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (DCM:MeOH = 95:5) to obtain intermediate 4-1. Intermediate 4-1 was prepared and separated by chiral HPLC (column: REGIS IB, 30 × 250 mm, 10 μm; mobile phase: n-hexane:dichloromethane:ethanol = 70:15:15; flow rate: 40 mL / min) to obtain 40 mg of compound 4.

[0335] Compound 4: Rt = 3.89 min (UPCC conditions: column: CHIRALPAK IB-3, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: methanol (containing 0.1% ammonia) = 60:40; flow rate: 2.0 mL / min; column temperature: 40℃)

[0336] HRMS: (ESI, [M+H]+)m / z:892.3949.

[0337] 1H NMR(500MHz,DMSO-d6)δ12.08(s,1H),7.57–7.38(m,3H),7.34–7.05(m,6H),7.00 -6.90(m,1H),6.85-6.71(m,1H),5.50(s,1H),4.47-4.30(m,1H),3.72(d,J=8.9Hz ,2H),3.55(d,J=36.8Hz,1H),3.23(s,3H),3.09-2.98(m,1H),2.89-2.75(m,1H), 2.20(d,J=10.8Hz,6H),1.76-1.51(m,9H),1.36-1.22(m,10H),1.21-1.16(m,3H).

[0338] Example 5

[0339]

[0340] Step 1: Synthesis of Intermediate 5-2

[0341] 0.5 g of 6'-bromospiro[cyclopropane-1,3'-dihydroindole]-2'-one was dissolved in 10 mL of N,N-dimethylformamide, followed by the addition of 1.38 g of cesium carbonate and 0.17 mL of iodomethane. The mixture was heated to 80 °C and stirred for 1 h. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give 0.51 g of intermediate 5-2.

[0342] MS(ESI, [M+H+2]) + )m / z:254.02.

[0343] 1H-NMR (500MHz, CDCl3): δ7.15 (dd, J=7.9, 1.7Hz, 1H), 7.04 (d, J=1.8Hz, 1H), 6. 69(d,J=7.9Hz,1H),3.27(s,3H),1.75(q,J=4.1Hz,2H),1.51(q,J=4.2Hz,2H).

[0344] Step 2: Synthesis of intermediate 5-3

[0345] Intermediate 5-2 (0.14 g), intermediate A-1 (0.2 g), cuprous iodide (17.25 mg), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (25.8 mg), potassium carbonate (125 mg), and N-methylpyrrolidone (5 mL) were mixed. Under nitrogen protection, the mixture was heated to 130 °C and stirred for 6 h. The mixture was diluted with water and ethyl acetate, extracted with ethyl acetate, and the organic layer was washed successively with water, saturated NaCl aqueous solution, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 0.18 g of intermediate 5-3.

[0346] MS(ESI, [M+H]) + )m / z:613.38.

[0347] 1 H-NMR (500MHz, CDCl3): δ7.26 (s, 1H), 7.09 (d, J = 6.2Hz, 2H), 7.05 (d, J = 7.4Hz, 1H), 6.87(d,J=7.9Hz,1H),6.68(d,J=3.2Hz,1H),6.29(s,1H),5.43-5.16(m,1H),4.59- 4.21(m,1H),3.31(s,3H),3.23-3.06(m,1H),2.82-2.75(m,2H),2.22(d,J=2.2Hz,6 H),1.77(q,J=4.2Hz,2H),1.54(q,J=4.1Hz,2H),1.50(s,9H),1.32(d,J=6.7Hz,3H).

[0348] Step 3: Synthesis of intermediate 5-4

[0349] Intermediate 5-3 (0.17 g) was mixed with 1 mL of 6N dioxane hydrochloride solution and stirred at room temperature for 1 h. After concentrating and removing the solvent, a saturated sodium bicarbonate aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to obtain 0.11 g of intermediate 5-4.

[0350] MS(ESI, [M+H]) + )m / z:513.36.

[0351] Step 4: Synthesis of intermediate 5-5

[0352] Intermediate B-1 (0.08 g) and N,N-dimethylformamide (2 mL) were mixed, followed by the addition of triethylamine (44 mg) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (110 mg). After stirring for 10 min, intermediate 5-4 (0.082 g) was added, and the mixture was stirred at 40 °C for 2 h. The mixture was diluted with water and ethyl acetate, extracted with ethyl acetate, and the organic layer was washed successively with water, saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The filtrate was concentrated and purified by column chromatography (dichloromethane:methanol = 98:2) to obtain 60 mg of intermediate 5-5. The above intermediate 5-5 was prepared and separated by chiral HPLC (column: CHIRALARTCellulose-SB, 30×250mm, 10μm; mobile phase: n-hexane:dichloromethane:ethanol = 72:21:7; flow rate: 40mL / min), yielding 17mg of compound 5.

[0353] Compound 5: Rt = 2.08 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6 × 100 mm, 3 μm); mobile phase: carbon dioxide: methanol (containing 0.1% ammonia) = 30:70; flow rate: 2.0 mL / min; column temperature: 40℃)

[0354] HRMS:(ESI, [M+H]) + )m / z:906.4103.

[0355] 1H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),7.53(s,1H),7.41-7.32(m,3H),7.31-7.24(m,2H),7.17-7.11( m,3H),7.00-6.95(m,2H),5.57(d,J=6.8Hz,1H),4.38(d,J=13.9Hz,1H),3.71(d,J=8.9Hz,2H),3.24(s,3 H),3.09-3.03(m,1H),2.89(d,J=16.7Hz,1H),2.22-2.18(m,7H),1.64-1.62(m,2H),1.55-1.53(m,2H),1 .40(d,J=6.4Hz,2H),1.36-1.33(m,4H),1.30(s,2H),1.27(s,3H),1.24(s,4H),1.18(s,3H),1.15(s,2H).

[0356] Example 6

[0357]

[0358] Step 1: Synthesis of Intermediate 6-1

[0359] Intermediate A-2 (700 mg), intermediate 1-2 (506 mg), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (132 mg), potassium carbonate (640 mg), cuprous iodide (88 mg), and N-methylpyrrolidone (10 mL) were mixed and reacted at 120 °C for 12 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was poured into water, and ethyl acetate (50 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give 0.75 g of intermediate 6-1.

[0360] MS(ESI, [M+H]) + m / z:625.42

[0361] Step 2: Synthesis of intermediate 6-2

[0362] Intermediate 6-1 (0.75 g) and 4N dioxane hydrochloride solution (10 mL) were mixed and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain 0.65 g of intermediate 6-2.

[0363] Step 3: Synthesis of intermediate 6-3 and compound 6

[0364] Intermediate B-1 (0.1 g), N,N-dimethylformamide (5 mL), triethylamine (0.678 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.277 g) were mixed and stirred at room temperature for 5 minutes. Intermediate 6-2 (0.15 g) was then added, and the mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction solution was poured into water, and ethyl acetate (50 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give 90 mg of intermediate 6-3. The above intermediate 6-3 was prepared and separated by chiral HPLC (column: CHIRALART Cellulose-SB, 30×250mm, 5μm; mobile phase: ethanol-dichloromethane (1:1):n-hexane = 30:70; flow rate: 40mL / min), and compound 6 (40mg) was obtained.

[0365] Compound 6: Rt = 5.58 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6 × 100 mm, 3 μm); mobile phase: carbon dioxide: methanol (containing 0.1% ammonia) = 60:40; flow rate: 2.0 mL / min; column temperature: 40℃)

[0366] HRMS:(ESI, [M+H]) + )m / z:918.4083.

[0367] 1 H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),7.57-7.50(m,2H),7.42-7.36(m,2H),7.32-7.26(m,4H),7.26-7.22(m ,2H),6.93-6.87(m,2H),5.58-5.51(m,1H),4.41-4.34(m,1H),3.73-3.70(m,2H),3.66-3.58(m,1H),3.26-3.23 (m,3H),3.21(s,1H),3.05-3.00(m,1H),2.92-2.87(m,1H),2.11-2.00(m,2H),1.72-1.64(m,6H),1.63-1.59(m, 2H),1.58-1.51(m,6H),1.41-1.38(m,2H),1.34-1.33(m,3H),1.30(s,3H),0.99-0.96(m,2H),0.60-0.55(m,2H).

[0368] Example 7

[0369]

[0370] Step 1: Synthesis of Intermediate 7-2

[0371] 3-O-piperazine-1-carboxylic acid tert-butyl ester (3.52 g) and N,N-dimethylformamide (80 mL) were mixed, and sodium hydride (0.960 g, 60% dispersed in mineral oil) was added under ice bath conditions. The mixture was stirred at room temperature for 10 minutes, and then 2-fluoro-4-bromonitrobenzene (3.52 g) was added. After the addition was complete, the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was poured into a saturated ammonium chloride solution (100 mL), and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give 2.29 g of intermediate 7-2.

[0372] 1 H-NMR (500MHz, CDCl3) δ7.93 (d, J=8.5Hz, 1H), 7.64 (dd, J=8.5, 2.0Hz, 1H), 7.52 (d, J=2.0Hz,1H),4.32-4.14(m,2H),4.00-3.86(m,2H),3.85-3.67(m,2H),1.51(s,9H).

[0373] Step 2: Synthesis of intermediate 7-3

[0374] Intermediate 7-2 (1.7 g), acetic acid (34 mL), and iron powder (1.2 g) were mixed and heated to 120 °C for 1 hour under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, filtered with diatomaceous earth, and the filtrate was directly concentrated. The residue was dissolved in ethyl acetate (100 mL), washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 1.26 g of intermediate 7-3.

[0375] MS(ESI, [M+H]) + )m / z:352.14.

[0376] Step 3: Synthesis of intermediate 7-4

[0377] Intermediate 7-3 (1.26 g) was mixed with 4N hydrochloric acid aqueous solution (12 mL), and the mixture was heated to 100 °C for 1 hour under nitrogen protection. After the reaction was completed, the reaction solution was poured into a saturated sodium bicarbonate solution to adjust the pH to 8-9, and dichloromethane (100 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give 0.64 g of intermediate 7-4.

[0378] MS(ESI, [M+H]) + )m / z:252.13.

[0379] 1 H-NMR (500MHz, DMSO-d6): δ7.74(d,J=1.5Hz,1H),7.49(d,J=8.5Hz,1H),7.30( dd,J=8.5,2Hz,1H),4.03(t,J=5.5Hz,4H),3.18(t,J=5.5Hz,2H),2.87(s,1H).

[0380] Step 4: Synthesis of intermediate 7-5

[0381] Intermediate 7-4 (0.22 g), methanol (7 mL), 37% formaldehyde aqueous solution (0.354 g), and acetic acid (0.150 mL) were mixed and stirred at room temperature for 10 minutes. Sodium triacetoxyborohydride (0.925 g) was added, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction solution was poured into a saturated sodium bicarbonate solution, and extracted with dichloromethane (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain 0.2 g of intermediate 7-5.

[0382] MS(ESI, [M+H]) + )m / z:266.13.

[0383] 1 H-NMR (500MHz, DMSO-d6): δ7.76(d,J=2Hz,1H),7.51(d,J=8.5Hz,1H),7.32(dd,J=8 .5,2Hz,1H),4.13(t,J=5.5Hz,2H),3.74(s,2H),2.92(t,J=5.5Hz,2H),2.44(s,3H).

[0384] Step 5: Synthesis of intermediates 7-6

[0385] Intermediate A-1 (200 mg), intermediate 7-5 (181 mg), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (32.2 mg), potassium carbonate (188 mg), cuprous iodide (17.25 mg), and N-methylpyrrolidone (5 mL) were mixed and reacted at 120 °C for 12 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was poured into water, and ethyl acetate (50 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give 0.245 g of intermediate 7-6.

[0386] MS(ESI, [M+H]) + )m / z:627.48.

[0387] 1 H-NMR (500MHz, DMSO-d6): δ7.74(s,1H),7.63(d,J=8.5Hz,1H),7.40(dd,J=8.5,2.5Hz,1H), 7.26(d,J=3Hz,1H),7.12(d,J=6Hz,2H),6.95(s,1H),5.22-5.05(m,1H),4.36-4.18(m,1H), 4.14(t,J=5.5Hz,2H),3.77(s,2H),3.20-3.05(m,1H),2.94(t,J=5.5Hz,2H),2.77-2.71(m, 1H),2.70-2.62(m,1H),2.45(s,3H),2.20(d,J=1.5Hz,6H),1.44(s,9H),1.22-1.18(m,3H).

[0388] Step Six: Synthesis of Intermediate 7-7

[0389] Intermediate 7-6 (0.24 g), dichloromethane (2 mL), and 4N dioxane hydrochloride solution (2 mL) were mixed and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain 0.2 g of intermediate 7-7.

[0390] MS(ESI, [M+H]) + )m / z:527.34.

[0391] Step 7: Synthesis of intermediates 7-8 and compound 7

[0392] Intermediate B-1 (0.1 g), N,N-dimethylformamide (5 mL), triethylamine (0.678 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.277 g) were mixed and stirred at room temperature for 5 minutes. Intermediate 7-7 (0.151 g) was then added, and the mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction solution was poured into water, and ethyl acetate (50 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give 0.12 g of intermediate 7-8. Intermediates 7-8 were separated by supercritical fluid chromatography (column: CHIRALART Cellulose-SB, 20×100mm, 5μm; mobile phase: carbon dioxide: ethanol (0.1% ammonia) = 68:32; flow rate: 60mL / min) to obtain 54mg of compound 7.

[0393] Compound 7: Rt = 2.97 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6 × 100 mm, 3 μm); mobile phase: carbon dioxide: methanol (containing 0.1% ammonia) = 50:50; flow rate: 2.0 mL / min; column temperature: 40℃)

[0394] HRMS:(ESI, [M+H]) + )m / z:920.4379.

[0395] 1H NMR(500MHz,DMSO-d6)δ11.74(s,1H),7.78(s,1H),7.65(d,J=8.5Hz,1H),7.53(s,1H),7.44-7.38(m,2H),7.29-7.24(m,2H),7 .20-7.14(m,2H),6.97-6.91(m,2H),5.62-5.55(m,1H),4.42-4.34(m,1H),4.19-4.12(m,2H),4.08-3.92(m,1H),3.79-3.76(m, 2H),3.73-3.70(m,2H),3.66-3.56(m,1H),3.24-3.15(m,1H),3.06-3.00(m,1H),2.96-2.92(m,2H),2.45(s,3H),2.23(s,6H), 1.80-1.75(m,1H),1.73-1.64(m,4H),1.62-1.57(m,2H),1.55-1.49(m,2H),1.41-1.39(m,1H),1.28-1.22(m,6H),1.18(s,3H).

[0396] Example 8

[0397]

[0398] Step 1: Synthesis of Intermediate 8-2

[0399] 0.426 g of 2-pyrrolidone and 15 mL of N,N-dimethylformamide were mixed, and 0.273 g of sodium hydride (60% dispersed in mineral oil) was added under ice bath conditions. The mixture was stirred at room temperature for 10 minutes, and then 1 g of 2-fluoro-4-bromonitrobenzene was added. After the addition was complete, the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into 100 mL of saturated ammonium chloride solution and extracted with 100 mL of ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give 0.83 g of intermediate 8-2.

[0400] MS(ESI, [M+H]) + )m / z:285.02.

[0401] 1H-NMR (500MHz, DMSO-d6): δ7.91(d,J=8.5Hz,1H),7.89(d,J=2Hz,1H),7.70(dd ,J=8.5,2Hz,1H),3.93(t,J=7Hz,2H),2.41(t,J=8.0Hz,2H),2.17-2.11(m,2H).

[0402] Step 2: Synthesis of intermediate 8-3

[0403] Intermediate 8-2 (0.7 g), acetic acid (20 mL), and iron powder (0.7 g) were mixed and heated to 120 °C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, filtered with diatomaceous earth, and the filtrate was directly concentrated. The residue was dissolved in ethyl acetate (100 mL), washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 0.5 g of intermediate 8-3.

[0404] MS(ESI, [M+H]) + )m / z:237.12.

[0405] 1 H-NMR (500MHz, DMSO-d6): δ7.71(d,J=2Hz,1H),7.48(d,J=8.5Hz,1H),7.26(dd ,J=8.5,2Hz,1H),4.10(t,J=7Hz,2H),2.94(t,J=7.5Hz,2H),2.65-2.59(m,2H).

[0406] Step 3: Synthesis of intermediate 8-4

[0407] Intermediate A-1 (200 mg), intermediate 8-3 (0.129 g), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (32.2 mg), potassium carbonate (188 mg), cuprous iodide (17.25 mg), and N-methylpyrrolidone (5 mL) were mixed and reacted at 120 °C for 12 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was poured into water, and ethyl acetate (50 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give 0.25 g of intermediate 8-4.

[0408] MS(ESI, [M+H]) + )m / z:598.39.

[0409] 1H-NMR (500MHz, DMSO-d6): δ7.76-7.70(m,1H),7.66-7.57(m,1H),7.34(d,J=7Hz,1 H),7.25(d,J=3Hz,1H),7.12(d,J=6Hz,2H),6.97(s,1H),5.22-5.06(m,1H),4.36- 4.18(m,1H),4.12(t,J=7Hz,2H),3.21-3.08(m,1H),2.99-2.90(m,2H),2.77-2.71 (m,1H),2.69-2.59(m,3H),2.20(d,J=1.5Hz,6H),1.44(s,9H),1.23-1.19(m,3H).

[0410] Step 4: Synthesis of intermediate 8-5

[0411] Intermediate 8-4 (0.25 g), dichloromethane (2 mL), and 4N dioxane hydrochloride solution (2 mL) were mixed and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain 0.2 g of intermediate 8-5.

[0412] MS(ESI, [M+H]) + )m / z:498.40.

[0413] Step 5: Synthesis of intermediates 8-6 and compound 8

[0414] Intermediate B-1 (0.1 g), N,N-dimethylformamide (5 mL), triethylamine (0.678 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.277 g) were mixed and stirred at room temperature for 5 minutes. Intermediate 8-5 (0.130 g) was then added, and the mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction solution was poured into water, and ethyl acetate (50 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give 0.12 g of intermediate 8-6. The above intermediate 8-6 was chirally separated by supercritical fluid chromatography (column: CHIRALART Cellulose-SB, 20×100mm, 5μm; mobile phase: carbon dioxide: ethanol (0.1% ammonia) = 53:47; flow rate: 60mL / min) to obtain 30mg of compound 8.

[0415] Compound 8: Rt = 3.57 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6 × 100 mm, 3 μm); mobile phase: carbon dioxide: methanol (containing 0.1% ammonia) = 50:50; flow rate: 2.0 mL / min; column temperature: 40℃)

[0416] HRMS:(ESI, [M+H]) + )m / z:891.4119.

[0417] 1 H NMR(500MHz,DMSO-d6)δ11.74(s,1H),7.75(s,1H),7.64-7.59(m,1H),7.53(s,1H),7.41-7.34(m,2H),7.29-7.24(m,2 H),7.19-7.14(m,2H),7.00-6.91(m,2H),5.62-5.55(m,1H),4.42-4.35(m,1H),4.17-4.11(m,2H),3.76-3.67(m,2H), 3.22-3.16(m,1H),3.08-3.00(m,1H),2.99-2.93(m,2H),2.92-2.85(m,1H),2.68-2.59(m,3H),2.22(s,6H),1.82-1.7 5(m,1H),1.71-1.64(m,4H),1.62-1.57(m,2H),1.55-1.52(m,2H),1.41-1.39(m,1H),1.28-1.22(m,6H),1.18(s,3H).

[0418] Example 9

[0419]

[0420] Step 1: Synthesis of intermediate 9-2

[0421] Sodium hydride (0.995 g, 60% dispersed in mineral oil) and N,N-dimethylformamide (10 mL) were mixed and stirred in an ice-water bath for 10 minutes under nitrogen protection. A solution of 6-bromoindanone (1 g) and 1,2-dibromoethane (3.12 g) in N,N-dimethylformamide (10 mL) was added dropwise. After the addition was complete, the temperature was maintained and the reaction was stirred. The reaction was stopped, and the reaction solution was poured into water (150 mL). The resulting solution was extracted with ethyl acetate (50 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 95:5) to give 0.69 g of intermediate 9-2.

[0422] 1H-NMR (500MHz, DMSO-d6): δ7.90(s,1H),7.65(d,J=7.9Hz,1H),7.59(d,J=8.0Hz,1H),3.25(s,2H),1.24(d,J=10.1Hz,4H).

[0423] Step 2: Synthesis of intermediate 9-3

[0424] Intermediate A-1 (250 mg), intermediate 9-2 (175 mg), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (40.3 mg), potassium carbonate (235 mg), cuprous iodide (21.57 mg), and N-methylpyrrolidone (4 mL) were mixed and reacted overnight in an oil bath at 120 °C under nitrogen protection. The reaction was stopped, the reaction solution was cooled to room temperature, and poured into water (50 mL). The resulting solution was extracted with ethyl acetate (30 mL). The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 85:15) to obtain 0.27 g of intermediate 9-3.

[0425] MS(ESI, [M+H]) + )m / z:598.34.

[0426] 1 H-NMR (500MHz, DMSO-d6): δ7.99(s,1H),7.84(d,J=8.5Hz,1H),7.75(d,J=8.4Hz,1H),7.48(d,J=3.3Hz,1H),7.11(d,J=6.3Hz,2H),7.07(s,1H), 5.21-5.01(m,1H),4.39-4.11(m,1H),3.27(s,2H),3.22-3.04(m,1H),2 .77-2.62(m,2H),2.18(d,J=1.3Hz,6H),1.44(s,9H),1.27-1.18(m,7H).

[0427] Step 3: Synthesis of intermediate 9-4

[0428] Intermediate 9-3 (0.25 g), dichloromethane (2 mL), and 4N dioxane hydrochloride solution (2 mL) were mixed and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain 0.21 g of intermediate 9-4.

[0429] MS(ESI, [M+H]) + )m / z:498.0.

[0430] Step 4: Synthesis of intermediate 9-5, compound 9-A, and compound 9-B

[0431] Intermediate B-1 (0.14 g), N,N-dimethylformamide (5 mL), triethylamine (0.806 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.330 g) were mixed and stirred for 5 minutes. Then, intermediate 9-4 (0.170 g) was added, and the mixture was stirred at room temperature. The reaction mixture was poured into water (50 mL), and the resulting solution was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:MeOH = 95:5) to obtain 130 mg of intermediate 9-5. The above intermediate 9-5 was prepared and separated by chiral HPLC (column: REFLECT I-Cellulose B, 30×250mm, 10μm; mobile phase: ethanol-dichloromethane (1:4):n-hexane = 25:75; flow rate: 40mL / min) to obtain compound 9-A (26mg) and compound 9-B (30mg).

[0432] Compound 9-A:R t = 2.59 min (UPCC conditions: column: CHIRALPAK IB-3, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: ethanol: isopropanol = 40:30:30; flow rate: 2.0 mL / min; column temperature: 40℃)

[0433] HRMS:(ESI, [M+H]) + )m / z:891.4030.

[0434] 1 H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),8.06-7.74(m,3H),7.57-7.37(m ,3H),7.28-6.94(m,5H),5.65-5.53(m,1H),4.46-4.31(m,1H),3.79-3.59( m,3H),3.29(s,3H),3.10-2.98(m,1H),2.94-2.85(m,1H),2.23-2.15(m,6 H),1.83-1.47(m,8H),1.44-1.37(m,2H),1.28(s,3H),1.25-1.15(m,10H).

[0435] Compound 9-B: R t= 2.03 min (UPCC conditions: column: CHIRALPAK IB-3, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: ethanol: isopropanol = 40:30:30; flow rate: 2.0 mL / min; column temperature: 40℃)

[0436] HRMS:(ESI, [M+H]) + )m / z:891.4026.

[0437] 1 H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),8.07-7.68(m,3H),7.56-7.37(m, 3H),7.29-6.85(m,5H),5.64-5.54(m,1H),4.48-4.32(m,1H),3.77-3.59(m, 3H),3.30-3.13(m,3H),3.09-2.99(m,1H),2.96-2.86(m,1H),2.24-2.13(m, 6H),1.83-1.46(m,8H),1.43-1.36(m,2H),1.27(s,3H),1.25-1.14(m,10H).

[0438] Example 10

[0439]

[0440] Step 1: Synthesis of intermediate 10-2

[0441] 1-Bromo-2-fluoro-4-iodobenzene (2 g), cuprous iodide (0.076 g), bis(triphenylphosphine)palladium dichloride (0.140 g), diisopropylamine (20 mL), and tert-butyldimethyl(propyl-2-yn-1-yloxy)silane (1.359 g) were mixed and stirred overnight at room temperature. The reaction solution was added to a mixture of ethyl acetate (30 mL) and water (40 mL). The two phases were separated, and the aqueous phase was extracted with ethyl acetate (2 × 30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 98:2) to obtain 1.8 g of intermediate 10⁻².

[0442] 1 H-NMR (500MHz, DMSO-d6): δ7.60(t,J=7.8Hz,1H),7.32(dd,J=9.5,2.0Hz,1H),7.09(dd,J=8.3,1.9Hz,1H),4.42(s,2H),0.76(s,9H),-0.00(s,6H).

[0443] Step 2: Synthesis of intermediate 10-3

[0444] Intermediate 10-2 (1.8 g), tetrabutylammonium fluoride (1 M, 10.49 mL), and tetrahydrofuran (10 mL) were mixed and stirred at room temperature for 1 hour. The reaction system was directly evaporated to dryness and purified by column chromatography (dichloromethane:methanol = 100:0) to obtain 1.67 g of intermediate 10-3.

[0445] MS(ESI, [M+H]) + )m / z:228.23.

[0446] 1 H-NMR (500MHz, DMSO-d6): δ7.79-7.72(m,1H),7.49(dd,J=9.5,1.9Hz,1H),7.26(dd,J=8.3,1.9Hz,1H),5.42(s,1H),4.39-4.30(m,2H).

[0447] Step 3: Synthesis of intermediate 10-4

[0448] Intermediate 10⁻³ (500 mg), tetrahydrofuran (10 mL), and sodium hydride (175 mg, 60% dispersed in mineral oil) were mixed. The reaction system was placed in an ice-water bath. Iodomethane (372 mg) was added dropwise to the reaction solution. The reaction mixture was transferred to room temperature and stirred for 2 hours. After quenching the reaction solution with water, a mixture of ethyl acetate (30 mL) and water (40 mL) was added. The two phases were separated. The aqueous phase was extracted with ethyl acetate (2 × 30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 320 mg of intermediate 10⁻⁴.

[0449] 1 H-NMR (500MHz, DMSO-d6): δ7.77-7.71(m,1H),7.52(dd,J=9.5,1.9Hz,1H),7.26(dd,J=8.2,2.1Hz,1H),4.33(s,2H),3.33(s,3H)

[0450] Step 4: Synthesis of intermediate 10-5

[0451] Cuprous iodide (21.57 mg), potassium carbonate (235 mg), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (40.3 mg), intermediate A-1 (250 mg), intermediate 10⁻⁴ (210 mg), and N-methylpyrrolidone (4 mL) were added to the reaction mixture under nitrogen protection. The reaction mixture was then placed in an oil bath at 130 °C for 3 hours. The reaction solution was then added to a mixture of ethyl acetate (30 mL) and water (40 mL). The two phases were separated, and the aqueous phase was extracted with ethyl acetate (2 × 30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 220 mg of intermediate 10⁻⁵.

[0452] MS(ESI, [M+H]) + )m / z:604.33.

[0453] Step 5: Synthesis of intermediate 10-6

[0454] Intermediate 10-5 (210 mg, 0.348 mmol), dichloromethane (2 mL), and 4 M dioxane hydrochloride (1.5 mL) were mixed and stirred at room temperature for 2 hours. The reaction system was then concentrated under reduced pressure to obtain 190 mg of intermediate 10-6.

[0455] MS(ESI, [M+H]) + )m / z:504.26.

[0456] Step Six: Synthesis of Intermediate 10-7 and Compounds 10-A and 10-B

[0457] Intermediate B-1 (100 mg), N,N-dimethylformamide (5 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (236 mg), and triethylamine (418 mg) were stirred for 5 minutes, then intermediate 10-6 (123 mg) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into water (50 mL), and the resulting solution was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by preparative chromatography under high pressure to obtain 80 mg of compound 10-7. Compound 10-7 was then preparatively separated by chiral HPLC (column: REGIS IB, 30 × 250 mm, 10 μm; mobile phase: ethanol-dichloromethane (1:1):n-hexane = 27:73; flow rate: 42 mL / min) to obtain compound 10-A (26 mg) and compound 10-B (30 mg).

[0458] Compound 10-A: Rt = 2.790 min (UPCC conditions: column: CHIRALPAK IB-3, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: ethanol: isopropanol = 50:25:25; flow rate: 2.0 mL / min; column temperature: 40 °C)

[0459] HRMS:(ESI, [M+H]) + )m / z:897.3933.

[0460] 1 H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),7.59(t,J=8.6Hz,2H),7.53(s,1H),7.45(d,J=8.3Hz,1H),7.40(d,J=8.6Hz ,1H),7.26(d,J=8.4Hz,1H),7.17-7.06(m,3H),6.95(d,J=10.8Hz,2H),5.57(d,J=7.1Hz,1H),4.36(s,2H),3.72(d,J= 9.5Hz,3H),3.65-3.60(m,1H),3.2-3.15(m,1H),3.02(d,J=12.3Hz,1H),2.22(d,J=15.4Hz,6H),1.99(s,1H),1.75-1. 63(m,4H),1.57-1.47(m,2H),1.41(d,J=6.7Hz,3H),1.29(d,J=12.2Hz,5H),1.24(d,J=6.7Hz,3H),1.21-1.12(m,5H).

[0461] Compound 10-B: Rt = 2.169 min (UPCC conditions: column: CHIRALPAK IB-3, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: ethanol: isopropanol = 50:25:25; flow rate: 2.0 mL / min; column temperature: 40 °C)

[0462] HRMS:(ESI, [M+H]) + )m / z:897.3928.

[0463] 1H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),7.60(d,J=9.6Hz,2H),7.53(s,1H),7.44(d,J=8.3Hz,1H),7.40(d,J=8.5Hz,1H) ,7.26(d,J=8.6Hz,1H),7.15(d,J=6.3Hz,2H),7.09(s,1H),6.95(d,J=13.0Hz,2H),5.63-5.52(m,1H),4.36(s,2H),3.72( d,J=9.6Hz,2H),3.65-3.59(m,1H),3.35(s,3H),3.20-3.15(s,2H),3.02(d,J=12.6Hz,1H),2.90(t,J=15.9Hz,1H),2.22( d,J=15.4Hz,6H),1.69-1.65(m,J=8.9Hz,3H),1.53-1.48(m,2H),1.29-1.27(m,6H),1.24-1.23(m,3H),1.18-1.16(m,5H).

[0464] Example 11

[0465]

[0466] Step 1: Synthesis of Intermediate 11-2

[0467] 2-Bromo-5-iodopyridine (2 g), cuprous iodide (0.040 g), palladium dichloride bis(triphenylphosphine) (0.198 g), tetrahydrofuran (30 mL), triethylamine (10.86 g), and propyne (0.367 g) were mixed and stirred at room temperature for 2.5 hours. The reaction mixture was then poured into a mixture of ethyl acetate (30 mL) and water (40 mL), and the two phases were separated. The aqueous phase was extracted with ethyl acetate (2 × 30 mL), and the organic phases were combined. The mixture was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 97:3) to give 1.2 g of intermediate 11-2.

[0468] MS(ESI, [M+H]) + )m / z:196.05.

[0469] 1 H-NMR (500MHz, DMSO-d6): δ8.41(d,J=2.4Hz,1H),7.75(dd,J=8.3,2.5Hz,1H),7.64(d,J=9.0Hz,1H),2.08(s,3H).

[0470] Step 2: Synthesis of Intermediate 11-3

[0471] Intermediate A-1 (370 mg), intermediate 11-2 (246 mg), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (69 mg), cuprous iodide (32 mg), potassium carbonate (232 mg), and N-methylpyrrolidone (4 mL) were mixed, purged with nitrogen, and heated and stirred in an oil bath at 130 °C for 3 hours. The reaction mixture was added to a mixture of ethyl acetate (30 mL) and water (40 mL), and the two phases were separated. The aqueous phase was extracted with ethyl acetate (2 × 30 mL), and the organic phases were combined. The mixture was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 420 mg of intermediate 11-3.

[0472] Step 3: Synthesis of intermediate 11-4

[0473] Intermediate 11-3 (450 mg), dichloromethane (2 mL), and 4N dioxane hydrochloride solution (2 mL) were mixed and stirred at room temperature for 1 hour. After stirring was stopped, the mixture was concentrated under reduced pressure to obtain 347 mg of intermediate 11-4.

[0474] MS(ESI, [M+H]) + )m / z:457.30.

[0475] Step 4: Synthesis of intermediate 11-5 and compounds 11-A and 11-B

[0476] Intermediate 11-4 (132 mg), intermediate B-1 (100 mg), triethylamine (492 mg), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (277 mg), and N,N-dimethylformamide (5 mL) were mixed and stirred at room temperature for 3 hours. The reaction mixture was poured into water (50 mL), and the resulting solution was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane:methanol = 95:5) to obtain 70 mg of 11-5. Intermediate 11-5 was prepared and separated by chiral HPLC (column: REFLECTI-Cellulose B, 30×250mm, 10μm; mobile phase: ethanol-dichloromethane (1:3):n-hexane = 20:80; flow rate: 40mL / min) to obtain compound 11-A (15mg) and compound 11-B (12mg).

[0477] Compound 11-A:R t=1.58 min (UPCC conditions: column: CHIRALPAK IB-3, 4.6×100 mm, 3 μm; mobile phase: carbon dioxide: ethanol: isopropanol = 40:30:30; flow rate: 2.0 mL / min; column temperature: 40℃).

[0478] HRMS:(ESI, [M+H]) + m / z:850.3866

[0479] 1 H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),8.53-7.88(m,2H),7.63-6.67(m,9H),5.76-5.54(m,1H),4.51-4.35(m,1H),3.76-3.51(m,3H) ),3.24-3.14(m,1H),3.08-2.99(m,1H),2.96-2.85(m,1H),2.24-2.14(m,6H),2.11-2.04(m,3H),1.80-1.44(m,8H),1.34(s,3H),1.24 -1.17(m,8H).

[0480] Compound 11-B: R t =1.31 min (UPCC conditions: column: CHIRALPAK IB-3, 4.6×100 mm, 3 μm; mobile phase: carbon dioxide: ethanol: isopropanol = 40:30:30; flow rate: 2.0 mL / min; column temperature: 40℃).

[0481] HRMS:(ESI, [M+H]) + m / z:850.3867

[0482] 1 H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),8.56-7.91(m,2H),7.66-6.64(m,9H),5.76-5.52(m,1H),4.50-4.33(m,1H),3.83-3.54(m,3H),3.26-3 .15(m,1H),3.09-2.96(m,1H),2.96-2.84(m,1H),2.28-2.14(m,6H),2.1 3-2.03(m,3H),1.81-1.45(m,8H),1.37-1.32(m,3H),1.25-1.17(m,8H).

[0483] Example 12

[0484]

[0485] Step 1: Synthesis of Intermediate 12-2

[0486] Sodium hydride (1.167 g, 60% dispersed in mineral oil) was added to a mixed solvent of tetrahydrofuran (60 mL) and ethanol (20 mL) at 0 °C and stirred for 10 minutes. Intermediate 12-1 (5 g) and diethyl malonate (2.336 g) were then added to the reaction mixture, and the reaction was carried out at room temperature for 4 hours. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried and concentrated the organic phase, and purified by column chromatography (petroleum ether:ethyl acetate = 90:10) to obtain 4.3 g of intermediate 12-2.

[0487] 1 H-NMR (500MHz, DMSO-d6): δ7.45(d,J=1.8Hz,1H),7.34(dd,J=8.0,1.9Hz,1H),7.19(d ,J=8.1Hz,1H),4.15(q,J=7.1Hz,4H),3.49(s,2H),3.43(s,2H),1.17(t,J=7.1Hz,6H).

[0488] Step 2: Synthesis of Intermediate 12-3

[0489] Intermediate 12-2 (0.5 g), THF (6 mL), and lithium borohydride (0.064 g) were mixed and reacted overnight at room temperature. The reaction solution was poured into a saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL × 3), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography (dichloromethane:methanol = 95:5) to give 0.24 g of intermediate 12-3.

[0490] 1 H-NMR (500MHz, DMSO-d6): δ7.34(s,1H),7.25(d,J=8.0Hz,1H),7.10(d,J=8.0H z,1H),4.62(t,J=5.3Hz,2H),3.34(d,J=5.3Hz,4H),2.71(s,2H),2.65(s,2H).

[0491] Step 3: Synthesis of intermediate 12-4

[0492] Intermediate 12-3 (1 g) and tetrahydrofuran (15 mL) were mixed, and sodium hydride (0.187 g, 60% dispersed in mineral oil) was added at 0 °C and reacted for half an hour. Then, p-toluenesulfonyl chloride (0.741 g) was added and the reaction was continued for 1.5 hours. The reaction solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried and concentrated the organic phase, and purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain 1.2 g of intermediate 12-4.

[0493] 1 H-NMR (500MHz, DMSO-d6): δ7.76(d,J=8.3Hz,2H),7.46(d,J=8.0Hz,2H),7.34 -7.25(m,2H),7.08(d,J=8.0Hz,1H),4.94(s,1H),3.97(d,J=4.3Hz,2H),3.28(s,2H),2.77-2.58(m,4H),2.42(s,3H).

[0494] Step 4: Synthesis of Intermediate 12-5

[0495] Intermediate 12-4 (500 mg) and tetrahydrofuran (10 mL) were mixed, and sodium hydride (97 mg, 60% dispersed in mineral oil) was added at 0 °C. The mixture was reacted overnight in an oil bath at 70 °C. The reaction solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried and concentrated the organic phase, and purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to give 0.19 g of intermediate 12-5.

[0496] 1 H-NMR (500MHz, DMSO-d6): δ7.43-7.38(m,1H),7.33-7.27(m,1H),7.17(d,J=8.0Hz,1H),4.52(s,4H),3.21(s,2H),3.15(s,2H).

[0497] Step 5: Synthesis of intermediate 12-6

[0498] Intermediate A-1 (0.1 g), dichloromethane (1 mL), and 4N dioxane hydrochloride solution (1 mL) were mixed and reacted at room temperature for 1 hour. Stirring was stopped, and the mixture was concentrated under reduced pressure to obtain 0.1 g of intermediate 12-6.

[0499] MS(ESI, [M+H]) + )m / z:342.19.

[0500] Step Six: Synthesis of Intermediate 12-7

[0501] Intermediate 12-6 (0.25 g), N,N-dimethylformamide (4 mL), intermediate B-1 (0.251 g), N,N-diisopropylethylamine (0.358 g), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.253 g) were mixed and reacted overnight at room temperature. The reaction mixture was poured into water (50 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography (dichloromethane:methanol = 95:5) to give 0.2 g of intermediate 12-7.

[0502] MS(ESI, [M+H]) + )m / z:735.44.

[0503] Step 7: Synthesis of intermediate 12-8 and compounds 12-A and 12-B

[0504] Intermediate 12-7 (0.2 g), N-methylpyrrolidone (4 mL), 12-5 (0.130 g), potassium carbonate (0.113 g), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (0.015 g), and cuprous iodide (10.37 mg) were heated to 130 °C and reacted for 3 hours under nitrogen protection. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mL × 3), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was prepared into sand. The crude product was purified by column chromatography (dichloromethane:methanol = 95:5) to obtain 80 mg of intermediate 12-8. Intermediate 12-8 was prepared and separated by chiral HPLC (column: REGIS IB, size: 30×250mm, 10μm; mobile phase: n-hexane: dichloromethane: ethanol = 70:15:15; flow rate: 40mL / min) to obtain compound 12-A (29mg) and compound 12-B (25mg).

[0505] Compound 12-A:R t = 2.22 min (UPCC conditions: column: CHIRALPAK IB-3, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: ethanol: isopropanol = 40:30:30; flow rate: 2.0 mL / min; column temperature: 40℃)

[0506] HRMS:(ESI, [M+H]) + )m / z:893.4172.

[0507] 1H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),7.55-7.28(m,5H),7.27-7.06(m,4H),7 .02-6.77(m,2H),5.63-5.49(m,1H),4.61-4.50(m,4H),4.43-4.34(m,1H),3.77-3 .57(m,3H),3.27-3.11(m,5H),3.08-3.00(m,1H),2.95-2.84(m,1H),2.26-2.14(m ,6H),1.87-1.44(m,8H),1.40-1.35(m,2H),1.29-1.27(m,3H),1.25-1.17(m,6H).

[0508] Compound 12-B: R t = 1.76 min (UPCC conditions: column: CHIRALPAK IB-3, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: ethanol: isopropanol = 40:30:30; flow rate: 2.0 mL / min; column temperature: 40℃)

[0509] HRMS:(ESI, [M+H]) + )m / z:893.4167.

[0510] 1 H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),7.58-7.28(m,5H),7.27-7.07(m,4H),6.9 9-6.75(m,2H),5.62-5.52(m,1H),4.61-4.50(m,4H),4.45-4.33(m,1H),3.79-3.56 (m, 3H), 3.27-3.12(m, 5H), 3.07-2.97(m, 1H), 2.92-2.83(m, 1H), 2.26-2.16(m, 6H), 1.81-1.46(m, 8H), 1.40-1.35(m, 2H), 1.29-1.26(m, 3H), 1.24-1.15(m, 6H). Example 13

[0511]

[0512] Step 1: Synthesis of Intermediate 13-1

[0513] 0.5 g of 6'-bromo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2'-one and 5 mL of N,N-dimethylformamide were mixed and cooled in an ice-water bath. Sodium hydroxide (0.13 g, 60% dispersed in mineral oil) was added in portions. After the addition was complete, the ice bath was removed, and the mixture was allowed to rise naturally to room temperature and stirred for 10 minutes. Then, the mixture was cooled in an ice-water bath, and 0.46 g of deuterated iodomethane was added. After the addition was complete, the ice bath was removed, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into a saturated ammonium chloride solution (50 mL), extracted with ethyl acetate, and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give 0.53 g of intermediate 13-1.

[0514] 1 H-NMR (500MHz, DMSO-d6): δ7.31(d,J=1.8Hz,1H),7.18(dd,J=7.9,1.8Hz,1H),6.98(d,J=7.9Hz,1H),1.65-1.61(m,2H),1.55-1.50(m,2H).

[0515] Step 2: Synthesis of Intermediate 13-2

[0516] Intermediate A-1 (0.2 g), N-methylpyrrolidone (4 mL), intermediate 13-2 (0.19 g), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (0.032 g), potassium carbonate (0.19 g), and cuprous iodide (0.017 g) were mixed and heated to 130 °C for 2 hours under nitrogen protection. The reaction mixture was poured into water (50 mL), extracted with ethyl acetate, and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol = 95:5) to obtain 0.13 g of intermediate 13-2.

[0517] MS(ESI, [M+H]) + )m / z:616.42.

[0518] 1H-NMR (500MHz, DMSO-d6): δ7.35(s,1H),7.30(d,J=3.4Hz,1H),7.27(dd,J=8.1,2.0Hz,1H),7.14-7.07(m,3H),6.97(s,1H),5.14(s, 1H),4.21(s,1H),3.14(s,1H),2.80-2.70(m,2H),2.19(s,6H),1.66-1.60(m,2H),1.56-1.51(m,2H),1.44(s,9H),1.22-1.16(m,3H).

[0519] Step 3: Synthesis of intermediate 13-3

[0520] Intermediate 13-2 (0.13 g), dichloromethane (2 mL), and 4N dioxane hydrochloride solution (2 mL) were mixed and stirred at room temperature for 1.5 hours. The mixture was then concentrated under reduced pressure to obtain 0.11 g of intermediate 13-3.

[0521] MS(ESI, [M+H]) + )m / z:516.36.

[0522] Step 4: Synthesis of intermediate 13-4 and compound 13

[0523] Intermediate B-1 (0.08 g), N,N-dimethylformamide (2 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.22 g), and triethylamine (0.39 g) were mixed and stirred at room temperature for 5 minutes. Then, a solution of N,N-dimethylformamide (1 mL) containing intermediate 1-3 (0.12 g) was added. After the addition was complete, the mixture was stirred overnight at room temperature. The reaction solution was poured into water (50 mL), extracted with ethyl acetate, and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 95:5) to obtain 80 mg of intermediate 13-4. Intermediate 13-4 was prepared and separated by chiral HPLC (column: REGIS IB, 30×250mm, 10μm; mobile phase: n-hexane-ethanol (80:20): dichloromethane = 1:1; flow rate: 40mL / min) to give compound 13 (38mg).

[0524] Compound 13: Rt = 2.077 min (UPCC conditions: column: CHIRALPAK IB-3, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: methanol = 30:70; flow rate: 2.0 mL / min; column temperature: 40 °C)

[0525] HRMS:(ESI, [M+H])+ )m / z:909.4308.

[0526] 1 H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),7.57-7.46(m,1H),7.43-7.23(m,5H),7.20-7 .06(m,3H),7.04-6.77(m,2H),5.77-5.53(m,1H),4.46-4.32(m,1H),3.80-3.54(m,3H) ,3.24-3.12(m,1H),3.08-2.96(m,1H),2.95-2.85(m,1H),2.26-2.15(m,6H),1.82-1.4 5(m,12H),1.43-1.36(m,2H),1.35-1.30(m,2H),1.29-1.25(m,4H),1.19-1.15(m,3H).

[0527] Example 14

[0528]

[0529] Step 1: Synthesis of Intermediate 14-1

[0530] 8.4 g of 6-bromo-7-fluorodihydroindole-2,3-dione, 150 mL of ethanol, and 1.5 mL of 85% hydrazine hydrate solution were mixed and heated to 85 °C for 1 hour under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filter cake, 150 mL of ethanol, and 12 g of potassium tert-butoxide were mixed and heated to 85 °C for 2 hours under nitrogen protection. After the reaction was complete, the reaction solution was poured into water, and 50 mL of 2N hydrochloric acid aqueous solution was added to adjust the pH to 2-3. The mixture was filtered, and the filter cake was dried to give 4.2 g of intermediate 14-1.

[0531] MS(ESI, [MH]) - )m / z:227.95.

[0532] 1 H-NMR (500MHz, DMSO-d6): δ11.03 (s, 1H), 7.24-7.19 (m, 1H), 7.01 (d, J = 7.5Hz, 1H), 3.55 (s, 2H).

[0533] Step 2: Synthesis of Intermediate 14-2

[0534] At -40°C, a tetrahydrofuran solution (8.69 ml) of 2N diisopropylaminolithium was added to a mixture of intermediate 14-1 (1 g) and tetrahydrofuran (20 ml), and stirred for 30 minutes. Then, 1,2-dibromoethane (2.45 g) was added to the reaction mixture, and the reaction was carried out at room temperature for 12 hours. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried and concentrated the organic phase, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 90:10) to give 0.27 g of intermediate 14-2.

[0535] 1 H-NMR (500MHz, DMSO-d6): δ11.24(s,1H),7.24-7.19(m,1H),6.81(d,J=8.0Hz,1H),1.66-1.64(m,2H),1.56-1.52(m,2H).

[0536] Step 3: Synthesis of Intermediate 14-3

[0537] Intermediate 14-2 (0.27 g), N,N-dimethylformamide (5 mL), iodomethane (0.19 g), and cesium carbonate (0.68 g) were mixed and heated to 80 °C for 1 hour under nitrogen protection. After the reaction was completed, the reaction solution was poured into water, and ethyl acetate (50 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 90:10) to give 0.13 g of intermediate 14-3.

[0538] 1 H-NMR (500MHz, DMSO-d6): δ7.29-7.26(m,1H),6.85(d,J=8.0Hz,1H),3.38(d,J=3.0Hz,3H),1.70-1.68(m,2H),1.59-1.57(m,2H).

[0539] Step 4: Synthesis of Intermediate 14-4

[0540] Intermediate A-1 (200 mg), intermediate 14-3 (0.13 g), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (32 mg), potassium carbonate (188 mg), cuprous iodide (17.25 mg), and N-methylpyrrolidone (5 mL) were mixed and reacted at 100 °C for 12 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was poured into water, and ethyl acetate (50 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give 0.14 g of intermediate 14-4.

[0541] MS(ESI, [M+H]) + )m / z:631.39.

[0542] 1 H-NMR (500MHz, DMSO-d6): δ7.12 (d, J=6.5Hz, 2H), 7.08-7.04 (m, 1H), 6.99-6 .97(m,2H),6.92(s,1H),5.19-5.04(m,1H),4.39-4.14(m,1H),3.40(d,J=2. 5Hz,3H),3.23-3.06(m,1H),2.75-2.69(m,1H),2.67-2.62(m,1H),2.23(s,6 H),1.72-1.70(m,2H),1.62-1.59(m,2H),1.44(s,9H),1.21(d,J=7.0Hz,3H).

[0543] Step 5: Synthesis of intermediate 14-5

[0544] Intermediate 14-4 (0.14 g), dichloromethane (2 mL), and 4N dioxane hydrochloride solution (2 mL) were mixed and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain 0.11 g of intermediate 14-5.

[0545] MS(ESI, [M+H]) + )m / z:531.31.

[0546] Step Six: Synthesis of Compound 14

[0547] Intermediate B-3 (0.07 g), N,N-dimethylformamide (4 mL), triethylamine (0.47 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.19 g) were mixed and stirred at room temperature for 5 minutes. Intermediate 14-5 (0.1 g) was then added, and the mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction solution was poured into water, and ethyl acetate (50 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give 0.048 g of compound 14.

[0548] HRMS:(ESI, [M+H]) + )m / z:924.4014.

[0549] 1H-NMR(500MHz,DMSO-d6)δ11.73(s,1H),7.53(s,1H),7.42-7.39(m,1H),7.37-7.36(m,1H),7.29-7.24(m,1H),7.19-7.1 5(m,2H),7.12-7.09(m,1H),7.01(s,1H),6.94(s,2H),5.59-5.52(m,1H),4.42-4.34(m,1H),3.72-3.70(m,2H),3.41(s, 3H),3.25-3.14(m,1H),3.07-2.99(m,1H),2.93-2.85(m,1H),2.75-2.70(m,1H),2.25(s,6H),1.75-1.71(m,2H),1.69-1 .64(m,2H),1.64-1.60(m,2H),1.52-1.49(m,2H),1.43-1.38(m,3H),1.34(s,3H),1.30(s,3H),1.24(s,3H),1.18(s,3H).

[0550] Example 15

[0551]

[0552] Step 1: Synthesis of Intermediate 15-1

[0553] At -60°C, a tetrahydrofuran solution (15.7 mL) of 2N diisopropylaminolithium was added to a mixture of 6-bromo-5-fluorodihydroindol-2-one (1.8 g) and tetrahydrofuran (6 mL), and stirred for 30 minutes. Then, 1,2-dibromoethane (4.41 g) was added to the reaction mixture, and the reaction was carried out at room temperature for 12 hours. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried and concentrated the organic phase, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:2) to give 0.72 g of intermediate 15-1.

[0554] MS(ESI, [MH]) - )m / z:253.96.

[0555] 1 H-NMR (500MHz, DMSO-d6): δ10.64(s,1H),7.16-7.12(m,1H),7.10-7.07(m,1H),1.67-1.62(m,2H),1.54-1.49(m,2H).

[0556] Step 2: Synthesis of Intermediate 15-2

[0557] Intermediate 15-1 (0.7 g) and N,N-dimethylformamide (15 mL) were mixed, and sodium hydride (0.33 g, 60% dispersed in mineral oil) was added under ice bath conditions. The reaction mixture was stirred for 30 minutes. Iodimethane (1.94 g) was added dropwise to the reaction mixture, and the reaction mixture was transferred to room temperature and stirred for 2 hours. After the reaction was completed, the reaction mixture was poured into a saturated ammonium chloride aqueous solution (100 mL), and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:4) to give 0.40 g of intermediate 15-2.

[0558] MS(ESI, [M+H]) + )m / z:269.87.

[0559] 1 H-NMR (500MHz, DMSO-d6): δ7.41(d,J=6.0Hz,1H),7.20(d,J=8.5Hz,1H),3.20(s,3H),1.73-1.66(m,2H),1.59-1.53(m,2H).

[0560] Step 3: Synthesis of Intermediate 15-3

[0561] Intermediate A-1 (400 mg), intermediate 15-2 (367 mg), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (90 mg), potassium carbonate (376 mg), cuprous iodide (50 mg), and N-methylpyrrolidone (10 mL) were mixed and reacted at 100 °C for 12 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was poured into water, and ethyl acetate (50 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:2) to give 0.52 g of intermediate 15-3.

[0562] MS(ESI, [M+H]) + )m / z:631.43.

[0563] 1H-NMR (500MHz, DMSO-d6): δ7.24(d,J=9.5Hz,1H),7.22-7.19(m,1H),7.12(d,J= 6.5Hz,2H),6.98(d,J=3.0Hz,1H),6.91(s,1H),5.19-5.03(m,1H),4.37-4.14(m, 1H),3.22(s,3H),3.17-3.07(m,1H),2.76-2.70(m,1H),2.69-2.62(m,1H),2.22( s,6H),1.74-1.70(m,2H),1.60-1.55(m,2H),1.44(s,9H),1.22(d,J=6.0Hz,3H).

[0564] Step 4: Synthesis of Intermediate 15-4

[0565] Intermediate 15-3 (0.25 g), dichloromethane (5 mL), and 4N dioxane hydrochloride solution (5 mL) were mixed and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain 0.22 g of intermediate 15-4.

[0566] MS(ESI, [M+H]) + )m / z:531.32.

[0567] Step 5: Synthesis of Compound 15

[0568] Intermediate B-3 (0.07 g), N,N-dimethylformamide (3 mL), triethylamine (0.47 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.2 g) were mixed and stirred at room temperature for 5 minutes. Intermediate 15-4 (0.1 g) was then added, and the mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction solution was poured into water, and ethyl acetate (50 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give 0.06 g of compound 15.

[0569] HRMS:(ESI, [M+H]) + )m / z:924.4020.

[0570] 1H-NMR (500MHz, DMSO-d6): δ11.77(s,1H),7.52(s,1H),7.41-7.40(m,1H),7.28-7.26(m,2H),7.2 4-7.20(m,3H),7.03-6.99(m,1H),6.93-6.89(m,2H),5.61-5.51(m,1H),4.45-4.34(m,1H),3.76 -3.71(m,2H),3.23(s,3H),3.19-3.13(m,2H),3.04-3.00(m,1H),2.91-2.84(m,1H),2.24(s,6H) ,1.76-1.70(m,4H),1.60-1.56(m,4H),1.46-1.40(m,3H),1.30-1.26(m,6H),1.20-1.16(m,6H).

[0571] Example 16

[0572]

[0573] Step 1: Synthesis of Intermediate 16-1

[0574] At -78°C, a tetrahydrofuran solution (9 mL) of 2N diisopropylaminolithium was added to a mixed solution of 6-bromo-4-fluorodihydro-2-one (1 g) and tetrahydrofuran (5 mL). The mixture was stirred at this temperature for 30 minutes. A tetrahydrofuran solution (5 mL) of 2.44 g of 1,2-dibromoethane was then added dropwise. After the addition was complete, the mixture was slowly brought to room temperature and stirred overnight. The reaction was stopped, and the reaction solution was poured into a saturated ammonium chloride solution (100 mL). The resulting solution was extracted with ethyl acetate (50 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give 0.54 g of intermediate 16-1.

[0575] MS(ESI, [MH]) - )m / z:253.91.

[0576] 1 H-NMR (500MHz, DMSO-d6): δ10.91(s,1H),7.07(dd,J=9.3,1.5Hz,1H),6.93(d,J=1.5Hz,1H),1.78(q,J=4.0Hz,2H),1.48(q,J=3.9Hz,2H).

[0577] Step 2: Synthesis of Intermediate 16-2

[0578] Intermediate 16-1 (540 mg) and N,N-dimethylformamide (11 mL) were mixed, and sodium hydride (132 mg, 60% dispersed in mineral oil) was added under ice bath conditions. The reaction mixture was stirred for 30 minutes. Iodimethane (935 mg) was added dropwise to the reaction mixture, and the reaction mixture was transferred to room temperature and stirred for 2 hours. The reaction mixture was poured into a mixture of ethyl acetate (50 mL) and water (50 mL). The aqueous phase was extracted with ethyl acetate (2 × 50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 500 mg of intermediate 16-2.

[0579] MS(ESI, [M+H]) + )m / z:269.98.

[0580] 1 H-NMR (500MHz, DMSO-d6): δ7.25(d,J=1.7Hz,1H),7.15(dd,J=9.3,1.5Hz,1H),3.21(s,3H),1.82(q,J=4.0Hz,2H),1.53(q,J=4.0Hz,2H).

[0581] Step 3: Synthesis of intermediate 16-3

[0582] Intermediate A-1 (500 mg), intermediate 16-2 (500 mg), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (100 mg), potassium carbonate (300 mg), cuprous iodide (70 mg), and N-methylpyrrolidone (10 mL) were mixed and reacted under nitrogen protection at 150 °C with microwave stirring for 1 hour. The reaction solution was cooled to room temperature and poured into water (50 mL). The resulting solution was extracted with ethyl acetate (50 mL). The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 0.4 g of intermediate 16-3.

[0583] MS(ESI, [M+H]) + )m / z:631.44.

[0584] 1H-NMR (500MHz, DMSO-d6): δ7.42(d,J=3.4Hz,1H),7.36-7.28(m,2H),7.11(d,J=6.3Hz,2H),7.03(s,1H),5.14(s,1H),4.22(s,1H) ,3.23(s,3H),3.19-3.02(m,1H),2.67(m,1H),2.19(s,6H),1.82(m,2H),1.53(q,J=3.9Hz,2H),1.44(s,9H),1.18(t,J=7.2Hz,4H).

[0585] Step 4: Synthesis of intermediate 16-4

[0586] Intermediate 16-3 (0.4 g), dichloromethane (2 mL), and 4N dioxane hydrochloride solution (4 mL) were mixed and stirred at room temperature for 1 hour. Stirring was then stopped, and the mixture was concentrated under reduced pressure to obtain 0.2 g of intermediate 16-4.

[0587] MS(ESI, [M+H]) + )m / z:531.32

[0588] Step 5: Synthesis of Compound 16

[0589] Intermediate B-3 (0.15 g), N,N-dimethylformamide (4 mL), triethylamine (0.72 g), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.4 g) were mixed and stirred for 5 minutes. Then, intermediate 16-4 (0.2 g) was added, and the mixture was stirred overnight at 30°C. The reaction mixture was poured into water (50 mL), and the resulting solution was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane:methanol = 95:5) to give 80 mg of compound 16.

[0590] HRMS:(ESI, [M+H]) + )m / z:924.4023.

[0591] 1H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),7.50(d,J=35.6Hz,2H),7.43-7.23(m,5H),7.16( d,J=6.1Hz,2H),6.95(s,1H),5.58(s,1H),4.39(d,J=10.2Hz,1H),3.71(d,J=8.2Hz,2H),3. 24(s,4H),3.04(d,J=10.2Hz,2H),2.89(d,J=14.8Hz,1H),2.25(s,6H),1.82(d,J=7.6Hz,2H ),1.69(d,J=12.5Hz,5H),1.58(d,J=31.6Hz,7H),1.39(d,J=6.4Hz,3H),1.21-1.10(m,6H).

[0592] Example 17

[0593]

[0594] Step 1: Synthesis of Intermediate 17-1

[0595] 0.72 g of 6'-bromo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2'-one, 0.80 g of copper acetate, 1.54 g of 4-dimethylaminepyridine, and 20 mL of toluene were mixed. Then, 2.21 mL of 2N bis(trimethylsilyl)aminosodium tetrahydrofuran solution was added dropwise to the reaction mixture. The reaction mixture was stirred at 95 °C for 16 hours and then allowed to cool naturally to room temperature. The reaction mixture was poured into 30 mL of ethyl acetate and 70 mL of water. The two phases were separated, and the aqueous phase was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 90:10) to give 350 mg of intermediate 17-1.

[0596] 1 H-NMR (500MHz, DMSO-d6): δ7.28(d,J=1.8Hz,1H),7.18(dd,J=7.9,1.8Hz,1H),6.95(d,J=7.9Hz,1H),2.72 (tt,J=7.2,3.8Hz,1H),1.58(q,J=4.0Hz,2H),1.48(q,J=4.0Hz,2H),1.03-0.98(m,2H),0.82-0.77(m,2H).

[0597] Step 2: Synthesis of Intermediate 17-2

[0598] Cuprous iodide (43.1 mg), potassium carbonate (391 mg), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (40.3 mg), intermediate A-1 (250 mg), intermediate 17-1 (205 mg), and N-methylpyrrolidone (5 mL) were mixed. The reaction mixture was stirred at 125 °C for 16 hours under nitrogen protection, and then naturally cooled to room temperature. The reaction mixture was poured into ethyl acetate (20 mL) and water (30 mL), and the two phases were separated. The aqueous phase was extracted with (20 mL × 2) syringes, and the organic phases were combined. The mixture was then washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain 210 mg of intermediate 17-2.

[0599] MS(ESI, [M+H]) + )m / z:639.48.

[0600] Step 3: Synthesis of intermediate 17-3

[0601] Intermediate 17-2 (200 mg), dichloromethane (2 mL), and 4N dioxane hydrochloride solution (4 mL) were mixed and stirred at room temperature for 1.5 hours. The mixture was then concentrated under reduced pressure to obtain 180 mg of intermediate 17-3.

[0602] MS(ESI, [M+H]) + )m / z:539.35.

[0603] Step 4: Synthesis of intermediate 17-4 and compound 17

[0604] Intermediate B-1 (114 mg), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (317 mg), triethylamine (563 mg), and N,N-dimethylformamide (3 mL) were mixed and stirred at room temperature for 10 minutes. Then, intermediate 17-3 (160 mg) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was poured into water (50 mL), and the resulting solution was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (dichloromethane:methanol = 95:5) to obtain 60 mg of intermediate 17-4. Intermediate 17-4 was prepared and separated by chiral HPLC (column: CHIRALART Cellulose-SB, 30×250mm, 5μm; mobile phase: ethanol / 0.1% ammonia: n-hexane = 30:70, isocratic elution) to give compound 17 (18mg).

[0605] Compound 17: Rt = 2.01 min (UPCC conditions: column: CHIRALPAK IB, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: methanol / 0.1% ammonia = 30:70; flow rate: 0.5 mL / min; column temperature: 40 °C)

[0606] HRMS:(ESI, [M+H]) + )m / z:932.4291.

[0607] 1 H NMR (500MHz, DMSO-d6): δ11.76(s,1H),7.51(d,J=17.9Hz,1H),7.40(dd,J=8.6,4.0Hz,1H),7.35(d,J=17.7Hz,2H),7.28-7.20(m,2H),7.1 7(d,J=6.7Hz,2H),7.09(s,1H),6.98(d,J=28.8Hz,2H),5.58(d,J=6.3Hz,1H),4.38(d,J=11.9Hz,1H),3.71(d,J=7.9Hz,2H),3.51(s,1H), 3.18(s,1H),3.03(t,J=12.1Hz,1H),2.89(d,J=16.5Hz,1H),2.75(s,1H),2.21(d,J=16.5Hz,5H),1.68(s,2H),1.59(d,J=3.5Hz,2H),1.50 (t,J=3.7Hz,2H),1.41(d,J=3.5Hz,2H),1.34(d,J=7.8Hz,3H),1.30(s,3H),1.28(s,2H),1.26(s,4H),1.23(s,4H),1.19(d,J=2.6Hz,4H).

[0608] Example 18

[0609]

[0610] Step 1: Synthesis of Intermediate 18-1

[0611] Intermediate A-2 (400 mg), intermediate 5-2 (320 mg), and (1S,2S)-N were added. 1 N 2Dimethylcyclohexane-1,2-diamine (64 mg), potassium carbonate (400 mg), cuprous iodide (38 mg), and N-methylpyrrolidone (8 mL) were mixed and reacted in a microwave oven at 140 °C for 1 hour under nitrogen protection. The reaction solution was cooled to room temperature and poured into water (50 mL). The resulting solution was extracted with ethyl acetate (50 mL). The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give 0.45 g of intermediate 18-1.

[0612] MS(ESI, [M+H]) + )m / z:625.43.

[0613] 1 H-NMR (500MHz, DMSO-d6): δ7.37(s,1H),7.34(d,J=3.2Hz,1H),7.31-7.28(m,1H),7.27-7.23 (m,2H),7.11(d,J=7.9Hz,1H),6.98(s,1H),6.87(dd,J=6.8,2.5Hz,1H),5.13(s,1H),4.21(s ,1H),3.25(s,3H),3.19-3.00(m,1H),2.83-2.61(m,2H),2.10-2.01(m,1H),1.64(q,J=3.9Hz ,2H),1.53(q,J=3.7Hz,2H),1.43(s,9H),1.21-1.17(m,3H),0.95(m,2H),0.63-0.49(m,2H).

[0614] Step 2: Synthesis of intermediate 18-2

[0615] Intermediate 18-1 (0.45 g), dichloromethane (2 mL), and 4N dioxane hydrochloride solution (10 mL) were mixed and stirred at room temperature for 1 hour. Stirring was then stopped, and the mixture was concentrated under reduced pressure to obtain 0.33 g of intermediate 18-2.

[0616] MS(ESI, [M+H]) + )m / z:525.23.

[0617] 1H-NMR (500MHz, DMSO-d6): δ7.36(d,J=2.0Hz,1H),7.33(d,J=3.4Hz,1H),7.29(dd,J=8.0,2.1Hz,1H),7.27-7.22(m,2H),7.10(d, J=8.1Hz,1H),6.95-6.89(m,1H),6.89-6.84(m,1H),4.10(s,1H),4.00(q,J=6.6Hz,1H),3.27(q,J=3.9Hz,1H),3.17(s,3H),2.98 -2.85(m,1H),2.77-2.60(m,2H),2.11-1.97(m,1H),1.63(q,J=4.0Hz,2H),1.53(q, J=3.8Hz,2H),1.13(d,J=6.6Hz,3H),0.95(dd,J=8.4,2.1Hz,2H),0.67-0.49(m,2H).

[0618] Step 3: Synthesis of intermediate 18-3 and compound 18

[0619] Intermediate B-1 (0.155 g), N,N-dimethylformamide (4 mL), triethylamine (0.075 g), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.18 g) were mixed and stirred for 5 minutes. Then, intermediate 18-2 (0.16 g) was added, and the mixture was stirred at 30 °C. The reaction mixture was poured into water (50 mL), and the resulting solution was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane:methanol = 95:5) to obtain intermediate 18-3. The above intermediate 18-3 was prepared and separated by chiral HPLC (mobile phase A: ethanol-dichloromethane (1:1), B: n-hexane, mobile phase A:B = 30%:70%, flow rate: 40 mL / min; column temperature: 25℃; column: CHIRALART Cellulose-SB) to obtain 80 mg of compound 18.

[0620] Compound 18: Rt = 2.08 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6 x 100 mm, 3 μm), mobile phase: carbon dioxide: methanol (0.1% ammonia) = 30:70; flow rate: 2 ml / min, column temperature: 40 °C)

[0621] HRMS:(ESI, [M+H]) + )m / z:918.4135.

[0622] 1H-NMR (500MHz, DMSO-d6): δ11.74(s,1H),7.53(s,1H),7.42-7.35(m,3H),7.29(dq,J =19.5,9.0Hz,5H),7.12(d,J=8.0Hz,1H),7.03-6.89(m,3H),5.65-5.49(m,1H),4.47 -4.31(m,1H),3.71(d,J=8.2Hz,3H),3.66-3.54(m,1H),3.24(s,3H),3.22-3.13(m,1H),3 .03(t,J=12.2Hz,1H),2.90(d,J=15.2Hz,1H),2.83-2.66(m,1H),2.13-1.95(m,2H),1.70 -1.61(m,6H),1.56-1.53(m,3H),1.40(d,J=5.9Hz,2H),1.20-1.13(m,6H),0.99(s,3H),0.60(dd,J=8.8,4.1Hz,3H).

[0623] Example 19

[0624]

[0625] Step 1: Synthesis of intermediate 19-1 and compound 19

[0626] Intermediate B-2 (0.07 g) and N,N-dimethylformamide (2 mL) were mixed, and triethylamine (178 mg) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (134 mg) were added sequentially. After stirring for 10 min, intermediate 5-4 (0.09 g) was added, and the mixture was stirred overnight at room temperature. The mixture was diluted with water and ethyl acetate, extracted with ethyl acetate, and the organic layer was washed sequentially with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The filtrate was concentrated and purified by column chromatography (dichloromethane:methanol = 98:2) to obtain 60 mg of intermediate 19-1. Intermediate 19-1 was prepared and isolated by chiral HPLC (mobile phase: n-hexane:ethanol = 80:20; flow rate: 40 mL / min; column temperature: 25℃; column: YMC CHIRALART Cellulose-SB 30×250) to obtain 20 mg of compound 19.

[0627] Compound 19: Rt = 3.55 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6 x 100 mm, 3 μm), mobile phase: carbon dioxide: methanol (0.1% ammonia) = 60:40; flow rate: 2 ml / min, column temperature: 40 °C)

[0628] HRMS:(ESI, [M+H]) + )m / z:892.3960.

[0629] 1 H-NMR (500MHz, DMSO-d6): δ12.08(s,1H),7.48(d,J=10.0Hz,1H),7.40(d,J=8.7Hz,1H),7.38-7.35(m,1H),7.34-7.32(m,1H),7.29(d,J=7.9Hz,1 H),7.26(dd,J=8.6,2.5Hz,1H),7.22(d,J=8.5Hz,1H),7.17-7.10(m,2H) ,6.91-6.89(m,1H),6.70(s,1H),3.72(d,J=8.9Hz,2H),3.24(s,3H),3.08 -3.02(m,1H),2.86-2.79(m,1H),2.72(t,J=8.0Hz,1H),2.55-2.52(m,1H ),2.19(d,J=15.4Hz,6H),1.65-1.62(m,2H),1.53-1.51(m,2H),1.36-1.3 5(m,3H),1.34-1.33(m,2H),1.31-1.29(m,3H),1.28-1.27(m,3H),1.26- 1.25(m,2H),1.24-1.23(m,2H),1.23-1.22(m,2H),1.18(d,J=4.4Hz,2H).

[0630] Example 20

[0631]

[0632] Step 1: Synthesis of intermediate 20-1 and compound 20

[0633] Intermediate B-2 (0.083 g), N,N-dimethylformamide (2 mL), triethylamine (0.265 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.109 g) were mixed and stirred at room temperature for 5 minutes. Intermediate 6-3 (0.10 g) was then added, and the mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction solution was poured into water, and ethyl acetate (50 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give 0.12 g of intermediate 20-1. The above intermediate 20-1 was prepared and separated by chiral HPLC (column: Pre-packed REGIS IB, 30×250mm, 10μm; mobile phase: ethanol-dichloromethane (1:1):n-hexane = 30:70; flow rate: 40mL / min) to obtain 33mg of compound 20.

[0634] Compound 20: Rt = 7.47 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6 x 100 mm, 3 μm); mobile phase: carbon dioxide: methanol (containing 0.1% ammonia) = 30:70; flow rate: 2.0 ml / min; column temperature: 40 °C)

[0635] HRMS:(ESI, [M+H]) + )m / z:904.3973.

[0636] 1 H-NMR (500MHz, DMSO-d6): δ12.09(s,1H),7.52-7.43(m,2H),7.42-7.35(m,2H),7.34-7.18(m,4H),7.15-7.0 9(m,1H),7.03-6.97(m,1H),6.93-6.87(m,1H),6.85-6.65(m,1H),3.78-3.64(m,2H),3.24(s,1H),3.04(s,1H ),2.91-2.77(m,1H),2.10-1.96(m,1H),1.82(s,2H),1.75-1.58(m,6H),1.57-1.45(m,4H),1.37-1.34(m,3H) ,1.31-1.27(m,5H),1.26(s,3H),1.20-1.17(m,2H),1.02-0.91(m,2H),0.90-0.79(m,2H),0.66-0.50(m,2H).

[0637] Example 21

[0638]

[0639] Step 1: Synthesis of Intermediate 21-1

[0640] At -5°C, a tetrahydrofuran solution (46.7 mL) of 2N diisopropylaminolithium was added to a mixture of 5-bromo-2-hydroxyindole (5 g) and tetrahydrofuran (50 mL), and stirred for 30 minutes. Then, 1,3-dibromopropane (14.28 g) was added to the reaction mixture, and the reaction was carried out at room temperature for 12 hours. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried and concentrated the organic phase, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give 1.9 g of intermediate 21-1.

[0641] MS(ESI, [M+H]) + )m / z:251.98.

[0642] 1 H NMR (500MHz, DMSO-d6): δ10.34(s,1H),7.75(d,J=2.1Hz,1H),7.33(dd,J=8.2,2.1Hz ,1H),6.74(d,J=8.1Hz,1H),2.44-2.37(m,2H),2.36-2.29(m,2H),2.22-2.14(m,2H).

[0643] Step 2: Synthesis of intermediate 21-2

[0644] Intermediate 21-1 (0.7 g) and N,N-dimethylformamide (10 mL) were mixed, and sodium hydride (0.14 g, 60% dispersed in mineral oil) was added under ice bath conditions. The mixture was stirred for 10 minutes, and iodomethane (0.51 g) was added dropwise to the reaction mixture. The reaction mixture was then transferred to room temperature and stirred for 2 hours. After the reaction was completed, the reaction mixture was poured into a saturated ammonium chloride aqueous solution (100 mL), and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 88:12) to give 0.58 g of intermediate 21-2.

[0645] MS(ESI, [M+H]) + )m / z:266.06.

[0646] 1H NMR (500MHz, DMSO-d6): δ7.82(d,J=2.0Hz,1H),7.45(dd,J=8.3,2.0Hz,1H),6.92(d, J=8.2Hz,1H),3.09(s,3H),2.46-2.39(m,2H),2.38-2.31(m,2H),2.25-2.17(m,2H).

[0647] Step 3: Synthesis of intermediate 21-3

[0648] Intermediate A-1 (220 mg), intermediate 21-2 (172 mg), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (42.5 mg), potassium carbonate (207 mg), cuprous iodide (28.5 mg), and N-methylpyrrolidone (6 mL) were mixed and reacted at 130 °C for 12 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was poured into water, and ethyl acetate (50 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 55:45) to give 0.26 g of intermediate 21-3.

[0649] MS(ESI, [M+H]) + )m / z:627.45.

[0650] 1 H NMR (500MHz, DMSO-d6): δ7.81(d,J=2.2Hz,1H),7.50(dd,J=8.4,2.2Hz,1H),7.27(d,J=3.2 Hz,1H),7.12(d,J=6.2Hz,2H),7.04(d,J=8.4Hz,1H),6.94(s,1H),5.14(s,1H),4.23(s,1H ),3.13(s,3H),2.77-2.72(m,1H),2.70(s,2H),2.48-2.41(m,2H),2.40-2.32(m,2H),2.20 (d,J=2.0Hz,6H),2.17(d,J=8.2Hz,2H),1.92-1.88(m,1H),1.44(s,9H),1.23-1.20(m,2H).

[0651] Step 4: Synthesis of intermediate 21-4

[0652] Intermediate 21-3 (0.25 g), dichloromethane (5 mL), and 4N dioxane hydrochloride solution (5 mL) were mixed and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain 0.21 g of intermediate 21-4.

[0653] MS(ESI, [M+H]) + )m / z:527.35.

[0654] Step 5: Synthesis of intermediate 21-5 and compound 21

[0655] Intermediate B-1 (100 mg), N,N-dimethylformamide (5 mL), triethylamine (0.678 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (277 mg) were mixed and stirred at room temperature for 5 minutes. Intermediate 21-5 (151 mg) was then added, and the mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction solution was poured into water, and ethyl acetate (50 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 97:3) to give 0.18 g of intermediate 21-5. The above intermediate 21-5 was prepared and separated by chiral HPLC (column: CHIRAL ART Cellulose-SB, 30×250mm, 5μm; mobile phase: ethanol-dichloromethane (3:2):n-hexane = 27:73; flow rate: 40mL / min) to obtain 60mg of compound 21.

[0656] Compound 21: Rt = 2.78 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6 × 100 mm, 3 μm); mobile phase: carbon dioxide: methanol (containing 0.1% ammonia) = 50:50; flow rate: 2.0 ml / min; column temperature: 40℃)

[0657] HRMS:(ESI, [M+H]) + )m / z:920.4281.

[0658] 1H-NMR (500MHz, DMSO-d6): δ11.74(s,1H),7.83(s,1H),7.57-7.50(m,2H),7.42-7.38(m,1H),7.31(d,J=3.2Hz,1H),7.26(d,J=8 .4Hz,1H),7.19-7.15(m,2H),7.05(d,J=8.4Hz,1H),7.00-6.90(m,2H),5.64-5.52(m,1H),4.43-4.34(m,1H),3.74-3.69(m,2H) ,3.13(s,3H),3.11-3.06(m,1H),3.05-2.99(m,1H),2.92-2.86(m,1H),2.69(s,1H),2.47-2.41(m,2H),2.40-2.35(m,2H),2.23 (s,6H),2.21-2.18(m,2H),1.74-1.65(m,4H),1.62-1.48(m,5H),1.42(d,J=6.6Hz,2H),1.34(s,2H),1.30(s,2H),1.18(s,4H).

[0659] Example 22

[0660]

[0661] Step 1: Synthesis of Intermediate 22-1

[0662] 4-Bromopyridine-2-carboxaldehyde (25 g), ethyl acrylate (26.9 g), and triethylenediamine (9.8 g) were mixed and stirred overnight at room temperature. The mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 80:20) to give 34.2 g of intermediate 22-1.

[0663] MS(ESI, [M+H]) + )m / z:286.04.

[0664] 1 H-NMR (500MHz, DMSO-d6): δ8.35(d,J=5.3Hz,1H),7.68(d,J=2.0Hz,1H),7.54(dd,J=5.2,2.0Hz,1H),6.22(s,1H ),6.06(d,J=5.7Hz,1H),5.90(t,J=1.5Hz,1H),5.48(d,J=5.7Hz,1H),4.16–3.99(m,2H),1.10(t,J=7.1Hz,3H).

[0665] Step 2: Synthesis of intermediate 22-2

[0666] Intermediate 22-1 (33.2 g) and dichloromethane (300 mL) were mixed, cooled in an ice-water bath, and pyridine (9.18 g) was added. Then, acetyl chloride (9.11 g) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water (200 mL), the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 35 g of intermediate 22-2.

[0667] MS(ESI, [M+H+2]) + )m / z:330.04.

[0668] 1 H-NMR (500MHz, DMSO-d6): δ8.42(d,J=5.3Hz,1H),7.73(d,J=1.8Hz,1H),7.65(dd,J=5.3,1.9Hz,1 H),6.53(s,1H),6.37(s,1H),5.87(s,1H),4.12-4.08(m,2H),2.15(s,3H),1.14(t,J=7.1Hz,3H).

[0669] Step 3: Synthesis of intermediate 22-3

[0670] Intermediate 22-2 (39 g) and toluene (250 mL) were mixed and heated to 120 °C overnight. Heating was stopped, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 80:20) to give 6.4 g of intermediate 22-3.

[0671] MS(ESI, [M+H+2]) + )m / z:270.05.

[0672] 1 H-NMR (500MHz, DMSO-d6): δ8.26(d,J=7.4Hz,1H),8.13(d,J=1.6Hz,1H),7.78(d,J=2.1Hz, 1H), 6.78 (dd, J=7.4, 2.1Hz, 1H), 6.74 (s, 1H), 4.27 (q, J=7.1Hz, 2H), 1.30 (t, J=7.1Hz, 3H).

[0673] Step 4: Synthesis of intermediate 22-4

[0674] Intermediate 22-3 (3.6 g), 1,4-dioxane (50 mL), pinacol diborate (4.43 g), potassium acetate (2.64 g), and 1,1-bis(diphenylphosphine)diberberine palladium dichloride (0.49 g) were mixed and heated to 90 °C overnight under nitrogen protection. Heating was stopped, and the mixture was cooled to room temperature. The reaction solution was poured into water (100 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to give 4.1 g of intermediate 22-4.

[0675] MS(ESI, [M+H]) + )m / z:316.19.

[0676] 1 H-NMR (500MHz, DMSO-d6): δ8.24(d,J=7.0Hz,1H),8.16(d,J=1.7Hz,1H),7.88(s,1H) ,6.94(s,1H),6.74(dd,J=7.0,1.2Hz,1H),4.28(q,J=7.1Hz,2H),1.32-1.28(m,15H).

[0677] Step 5: Synthesis of intermediate 22-5

[0678] Intermediate 22-4 (4.1 g), 1,4-dioxane (2 mL), water (0.2 mL), a mixture of 6,6-dimethyl-3,6-dihydro-2H-pyran-4-yltrifluoromethanesulfonate and 2,2-dimethyl-3,6-dihydro-2H-pyran-4-yltrifluoromethanesulfonate (5.08 g), potassium carbonate (3.60 g), and 1,1-bis(diphenylphosphine)diferropalladium dichloride (0.48 g) were heated to 90 °C and reacted for 3 hours under nitrogen protection. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to give 3.6 g of intermediate 22-5.

[0679] MS(ESI, [M+H]) + )m / z:300.19.

[0680] Step Six: Synthesis of Intermediate 22-6

[0681] Intermediate 22-5 (4.1 g) and methanol (80 mL) were mixed, and 10% Pd / C (1.46 g) was added. The mixture was stirred overnight under a hydrogen atmosphere. The mixture was filtered and concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 80:20) to give 2.6 g of intermediate 22-6.

[0682] MS(ESI, [M+H]) + )m / z:302.20.

[0683] 1 H-NMR (500MHz, DMSO-d6): δ8.21(d,J=7.3Hz,1H),7.99(d,J=1.6Hz,1H),7.26-7.20(m,1H),6.62-6.61(m,2H),4.25(q,J=7.0Hz,2H),3 .73-3.64(m,2H),2.85(tt,J=12.4,3.6Hz,1H),1.72-1.65(m,2H),1.55-1.39(m,2H),1.29(t,J=7.1Hz,3H),1.24(s,3H),1.18(s,3H).

[0684] Step 7: Synthesis of intermediate 22-7

[0685] Intermediate 22-6 (2.35 g), dimethyl sulfoxide (40 mL), iodoacetonitrile (3.91 g), and ferrous sulfate heptahydrate (1.08 g) were mixed and cooled in an ice-water bath. Hydrogen peroxide (4.78 mL) was added dropwise, and the mixture was stirred for 2 hours after the addition was complete. The reaction solution was poured into a saturated sodium sulfite solution (100 mL) and ethyl acetate (100 mL), and the layers were separated. The organic phase was collected and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain 1 g of intermediate 22-7.

[0686] MS(ESI, [M+H]) + )m / z:341.27.

[0687] 1H-NMR (500MHz, DMSO-d6): δ8.26(d,J=7.4Hz,1H),7.35(s,1H),6.85(dd,J=7.4,1.9Hz,1H),6.76(s,1H),4.66(s,2H),4.31(q,J=7.1Hz,2H ),3.76-3.67(m,2H),2.92(tt,J=12.5,3.6Hz,1H),1.74-1.65(m,2H),1.57-1.42(m,2H),1.33(t,J=7.1Hz,3H),1.26(s,3H),1.19(s,3H).

[0688] Step 8: Synthesis of intermediate 22-8

[0689] Intermediate 22-7 (0.31 g), tetrahydrofuran (6 mL), (4R)-4-methyl-1,3,2-dioxathiapentane 2,2-dioxide (0.38 g), and N,N-dimethylpropenylurea (0.23 g) were mixed and cooled to 0 °C in an ice-salt bath under nitrogen protection. Then, a tetrahydrofuran solution (5.46 mL) of 1N bis(trimethylsilylamino)lithium was slowly added dropwise. After the addition was complete, the mixture was stirred at 0 °C for 1 hour. The reaction solution was poured into a saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (20 mL × 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give 0.51 g of the isomer. The obtained isomers were prepared by HPLC (instrument: YMC high-pressure preparative chromatograph; column: UltimateXB-C18, 30×250mm, 10μm; mobile phase: water-acetonitrile (35:65) to obtain 0.19g of intermediate 22-8).

[0690] Compound 22-8: Rt = 2.73 min (UPLC conditions: column: Waters UPLC BEH C18 (50 × 2.1 mm, 1.7 μm), mobile phase: 10 mM ammonium acetate buffer (with 0.1% glacial acetic acid added) - acetonitrile (50:50): acetonitrile = 10:90, flow rate: 0.6 mL / min, column temperature: 40℃)

[0691] MS(ESI, [M+H]) + )m / z:381.34.

[0692] 1H-NMR (500MHz, DMSO-d6): δ8.16(d,J=6.8Hz,1H),7.37(s,1H),6.87(dd,J=7.4,1.8Hz,1H),6.75(s,1H),4.37-4.26(m,2H),3.77- 3.65(m,2H),2.94(tt,J=12.3,3.6Hz,1H),1.70-1.67(m,4H),1.61-1.42(m,6H),1.34(t,J=7.1Hz,3H),1.26(s,3H),1.19(s,3H).

[0693] Step Nine: Synthesis of Intermediate 22-9

[0694] Intermediate 22-8 (0.73 g), dimethyl sulfoxide (5 mL), hydroxylamine hydrochloride (0.67 g), and sodium bicarbonate (0.81 g) were mixed and heated to 65 °C overnight. Heating was stopped, and the mixture was cooled to room temperature. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 0.72 g of intermediate 22-9.

[0695] MS(ESI, [M+H]) + )m / z:414.42.

[0696] Step 10: Synthesis of intermediate 22-10

[0697] Intermediate 22-9 (0.72 g), dimethyl sulfoxide (7 mL), N,N'-carbonyldiimidazole (0.57 g), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.66 g) were mixed and stirred at room temperature for 3 hours. Stirring was stopped, and the reaction mixture was poured into water (50 mL). Extraction was performed with ethyl acetate (20 mL). The aqueous phase was adjusted to pH 6-7 with 2N hydrochloric acid solution and extracted again with ethyl acetate (20 mL × 2). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 0.6 g of intermediate 22-10.

[0698] MS(ESI, [M+H]) + )m / z:440.31.

[0699] Step 11: Synthesis of intermediate 22-11

[0700] Intermediate 22-10 (0.6 g), tetrahydrofuran (6 mL), water (1 mL), and potassium hydroxide (0.31 g) were mixed and heated to 70 °C for 8 hours. Heating was stopped, and the mixture was cooled to room temperature. The reaction solution was poured into water (80 mL) and extracted with ethyl acetate (20 mL). The aqueous phase was collected, the pH was adjusted to 4-5 with 2N hydrochloric acid solution, and extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 0.35 g of intermediate 22-11.

[0701] MS(ESI, [M+H]) + )m / z:412.34.

[0702] 1 H-NMR (500MHz, DMSO-d6): δ12.58-11.62(m,2H),8.06-7.92(m,1H),7.36-7.23(m,1H),6.79-6.73(m,1H),6.72-6.63(m,1H) ),3.75-3.64(m,2H),2.96-2.85(m,1H),1.94-1.78(m,1H),1.76-1.63(m,3H),1.57-1.36(m,3H),1.25(s,6H),1.18(s,3H).

[0703] Step 12: Synthesis of intermediate 22-12 and compounds 22-A and 22-B

[0704] Intermediate 22-11 (0.1 g), intermediate A-1 (0.15 g), N,N-dimethylformamide (3 mL), triethylamine (0.49 g), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.28 g) were mixed and stirred at room temperature for 4 hours after the addition was complete. Stirring was stopped, and the reaction mixture was poured into water (50 mL). Extraction was performed with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (dichloromethane:methanol = 95:5) to obtain 65 mg of intermediate 22-12. The above intermediate 22-12 was prepared by chiral HPLC (column: REGIS IB, 30×250mm, 10μm; mobile phase: carbon dioxide: ethanol (containing 0.1% ammonia) = 65:35; flow rate: 80mL / min) to obtain compound 22-A (25mg) and compound 22-B (22mg).

[0705] Compound 22-A: Rt = 2.06 min (UPCC conditions: column: CHIRALPAK IB-3, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: ethanol: isopropanol (containing 0.1% ammonia) = 50:25:25; flow rate: 2.0 mL / min; column temperature: 40℃)

[0706] HRMS:(ESI, [M+H]) + )m / z:906.4132.

[0707] 1 H-NMR (500MHz, DMSO-d6): δ11.91(s,1H),8.09-8.00(m,1H),7.58-7.48(m,1H),7.36-7.23(m,2H),7 .22-7.03(m,4H),6.98-6.43(m,3H),5.63(q,J=6.6Hz,1H),4.16-4.03(m,1H),3.78-3.64(m,2H),3. 52-3.41(m,1H),3.26-3.19(m,3H),3.02-2.83(m,2H),2.80-2.69(m,1H),2.25-2.13(m,6H),1.76-1 .63(m,4H),1.60-1.49(m,5H),1.38-1.34(m,3H),1.27-1.23(m,5H),1.19(s,3H),1.17-1.12(m,3H).

[0708] Compound 22-B: Rt = 1.74 min (UPCC conditions: column: CHIRALPAK IB-3, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: ethanol: isopropanol (containing 0.1% ammonia) = 50:25:25; flow rate: 2.0 mL / min; column temperature: 40℃)

[0709] HRMS:(ESI, [M+H]) + )m / z:906.4122.

[0710] 1H-NMR (500MHz, DMSO-d6): δ11.95(s,1H),8.10-8.00(m,1H),7.57-7.50(m,1H),7.37-7.24(m,2H),7 .22-6.92(m,5H),6.82-6.41(m,2H),5.63(q,J=6.7Hz,1H),4.19-3.99(m,1H),3.79-3.62(m,2H),3. 54-3.40(m,1H),3.27-3.19(m,3H),3.03-2.84(m,2H),2.83-2.71(m,1H),2.26-2.15(m,6H),1.76-1 .63(m,4H),1.61-1.51(m,5H),1.40-1.35(m,3H),1.28-1.21(m,5H),1.19(s,3H),1.17-1.11(m,3H).

[0711] Example 23

[0712]

[0713] Step 1: Synthesis of Intermediate 23-1

[0714] 4-Bromo-7-fluoroindanone (1 g) and methanol (10 mL) were mixed and cooled in an ice-water bath. Sodium borohydride (0.330 g) was added in portions. After the addition was complete, the ice bath was removed, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water (100 mL) and stirred. A large amount of precipitate was formed. The precipitate was filtered, collected, and dried under vacuum to obtain 0.7 g of intermediate 23-1.

[0715] 1 H-NMR (500MHz, DMSO-d6): δ7.49 (dd, J=8.6, 4.4Hz, 1H), 7.04-6.96 (m, 1H), 5.43-5.38 (m, 1H), 5.36-5.29(m,1H),3.06-2.95(m,1H),2.81-2.66(m,1H),2.38-2.25(m,1H),1.96-1.85(m,1H).

[0716] Step 2: Synthesis of intermediate 23-2

[0717] Intermediate 23-1 (5 g) and dichloromethane (60 mL) were mixed and cooled to -78 °C under nitrogen protection. Then, triethylsilane (7.55 g) and boron trifluoride diethyl ether solution (8.23 mL) were added dropwise. After the addition was complete, the mixture was allowed to rise naturally to room temperature and stirred overnight. The reaction solution was poured into saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (40 mL × 3). The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 100:0) to obtain 4.3 g of intermediate 23-2.

[0718] 1 H-NMR (500MHz, DMSO-d6): δ7.40-7.34(m,1H),7.00-6.94(m,1H),3.01(t,J=7.6Hz,2H),2.90(t,J=7.6Hz,2H),2.09(p,J=7.6Hz,2H).

[0719] Step 3: Synthesis of intermediate 23-3

[0720] Intermediate 23-2 (2 g), tert-butyl hydrazinoate (2.46 g), toluene (10 mL), sodium tert-butoxide (1.79 g), 5-di-tert-butylphosphine-1',3',5'-triphenyl-1'H-[1,4']dipyrazole (0.94 g), and palladium chloride (π-cinnamyl) dimer (0.24 g) were heated to 115 °C for 5 hours under nitrogen protection. Heating was stopped, and the mixture was cooled to room temperature. The reaction solution was poured into water (100 mL), extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain 1.7 g of intermediate 23-3.

[0721] 1 H-NMR (500MHz, DMSO-d6): δ8.75(s,1H),7.02(s,1H),6.77(t,J=8.8Hz,1H),6.52-6.26( m,1H),2.82(t,J=7.5Hz,2H),2.73(t,J=7.5Hz,2H),2.03(p,J=7.6Hz,2H),1.41(s,9H).

[0722] Step 4: Synthesis of intermediate 23-5

[0723] Intermediate 23-3 (1.7 g), dichloromethane (20 mL), and trifluoroacetic acid (8.85 mL) were mixed and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was redissolved in ethanol (20 mL). Then, intermediate 23-4 (1.52 g) and pyridine hydrochloride (0.074 g) were added, and the mixture was heated to 85 °C and stirred for 3 hours. Heating was stopped, and the mixture was cooled to room temperature. The reaction solution was poured into water (100 mL), extracted with ethyl acetate (40 mL × 3), and the organic phase was washed with saturated sodium bicarbonate solution and saturated brine, respectively. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 60:40) to obtain 2.1 g of intermediate 23-5.

[0724] MS(ESI, [M+H]) + )m / z:387.33.

[0725] 1 H-NMR (500MHz, DMSO-d6): δ7.13(dd,J=8.6,4.7Hz,1H),7.04(t,J=8.5Hz,1H),5.17-4.91(m,3H),4.21-3.98(m,1H),3.13 -2.90(m,3H),2.90-2.81(m,1H),2.80-2.69(m,1H),2.48-2.40(m,2H),2.10-2.00(m,2H),1.43(s,9H),1.27-1.20(m,3H).

[0726] Step 5: Synthesis of intermediate 23-6

[0727] Intermediate 23-5 (2.0 g) and tetrahydrofuran (60 mL) were mixed, cooled in an ice-water bath, and triethylamine (2.62 g) and triphosgene (1.55 g) were added. After the addition was complete, the mixture was allowed to rise naturally to room temperature and stirred for 1 hour. The mixture was then cooled in an ice-water bath, and aminoacetaldehyde dimethyl acetal (2.72 g) was added. The mixture was allowed to rise naturally to room temperature and stirred for 2 hours. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (40 mL × 3), and the organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 60:40) to obtain 1.38 g of intermediate 23-6.

[0728] MS(ESI, [M+H]) + )m / z:518.4.

[0729] Step Six: Synthesis of Intermediate 23-7

[0730] Intermediate 23-6 (1.38 g), tetrahydrofuran (30 mL), and methanesulfonic acid (0.13 g) were mixed and heated to 60 °C for 6 hours. The reaction mixture was poured into water (50 mL), extracted with ethyl acetate (50 mL × 3), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (dichloromethane:methanol = 95:5) to give 0.9 g of intermediate 23-7.

[0731] MS(ESI, [M+H]) + )m / z:454.38.

[0732] Step 7: Synthesis of intermediate 23-8

[0733] Intermediate 23-7 (0.4 g), intermediate 1-2 (0.33 g), N-methylpyrrolidone (4 mL), potassium carbonate (0.37 g), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (0.063 g), and cuprous iodide (0.067 g) were mixed and heated to 130 °C for 3 hours under nitrogen protection. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mL × 3), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (dichloromethane:methanol = 95:5) to give 0.56 g of intermediate 23-8.

[0734] MS(ESI, [M+H]) + )m / z:625.42.

[0735] Step 8: Synthesis of intermediate 23-9

[0736] Intermediate 23-8 (0.56 g), dichloromethane (5 mL), and 4N dioxane hydrochloride solution (4 mL) were mixed. The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to obtain 0.56 g of intermediate 23-9.

[0737] MS(ESI, [M+H]) + )m / z:525.35.

[0738] Step Nine: Synthesis of Intermediates 23-10 and Compound 23

[0739] Intermediate B-1 (0.2 g), N,N-dimethylformamide (5 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.55 g), and triethylamine (0.98 g) were mixed and stirred at room temperature for 5 minutes. Then, a solution of intermediate 23-9 (0.31 g) in N,N-dimethylformamide (1 mL) was added. After the addition was complete, the mixture was stirred at room temperature overnight. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane:methanol = 95:5) to obtain 65 mg of intermediate 23-10. The above intermediate 23-10 was prepared and separated by chiral HPLC (column: REGIS IB, 30×250mm, 10μm; mobile phase: n-hexane-ethanol (70:30): dichloromethane = 2:1; flow rate: 40mL / min) to obtain compound 23 (23mg).

[0740] Compound 23: Rt = 3.31 min (UPCC conditions: column: CHIRALPAK IB-3, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: methanol (containing 0.1% ammonia) = 50:50; flow rate: 2.0 mL / min; column temperature: 40℃)

[0741] HRMS:(ESI, [M+H]) + )m / z:918.4122.

[0742] 1 H-NMR (500MHz, DMSO-d6): δ11.74(s,1H),7.59-7.22(m,5H),7.20-7.04(m,3H),7.02-6.93(m,1H),6.92-6. 65(m,2H),5.66-5.52(m,1H),4.44-4.31(m,1H),3.81-3.58(m,3H),3.26-3.16(m,3H),3.08-2.99(m,1H),2 0.97-2.88 (m, 2H), 2.88-2.81 (m, 2H), 2.76-2.69 (m, 1H), 2.59-2.53 (m, 1H), 2.10-1.89 (m, 3H), 1.83-1.44 (m, 11H), 1.39-1.37 (m, 1H), 1.34-1.33 (m, 2H), 1.25-1.23 (m, 4H), 1.20-1.17 (m, 2H), 1.16-1.12 (m, 2H). Example 24

[0743]

[0744] Intermediate 22-11 (0.1 g), intermediate 6-2 (0.15 g), N,N-dimethylformamide (3 mL), triethylamine (0.49 g), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.28 g) were added and stirred overnight at room temperature. After stirring was stopped, the reaction mixture was poured into water (50 mL), extracted with ethyl acetate (20 mL × 3), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (dichloromethane:methanol = 95:5) to obtain 65 mg of intermediate 24-1. The above intermediate 24-1 was prepared and separated by chiral HPLC (column: REGIS IB, 30×250mm, 10μm; mobile phase: n-hexane:ethanol = 56:44; flow rate: 40mL / min) to give compound 24 (21mg).

[0745] Compound 24: Rt = 1.28 min (UPCC conditions: column: CHIRALPAK IB-3, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: ethanol: isopropanol (containing 0.1% ammonia) = 30:35:35; flow rate: 2.0 mL / min; column temperature: 40℃)

[0746] HRMS:(ESI, [M+H]) + )m / z:918.4085.

[0747] 1 H-NMR (500MHz, DMSO-d6): δ11.97(s,1H),8.13-7.97(m,1H),7.60-7.51(m,1H),7.36-7.09(m,6H),7.07 -6.50(m,4H),5.78-5.54(m,1H),4.31-4.05(m,1H),3.83-3.65(m,2H),3.53-3.41(m,1H),3.27-3.18(m, 3H),3.04-2.88(m,2H),2.85-2.73(m,1H),2.10-1.98(m,1H),1.72-1.64(m,3H),1.61-1.51(m,5H),1.3 9-1.33(m,3H),1.28-1.22(m,6H),1.19(s,3H),1.17-1.11(m,3H),1.01-0.90(m,2H),0.64-0.51(m,2H).

[0748] Example 25

[0749]

[0750] Step 1: Synthesis of Intermediate 25-1

[0751] Pyridine-N-oxide (2 g) and dichloromethane (15 mL) were mixed, and benzoyl chloride (2.96 g) was added under ice bath conditions. The mixture was stirred for 30 minutes, and then 1-morpholinocyclopentene (4.19 g) was added. The mixture was heated to 40 °C and reacted for 12 hours. After the reaction was completed, the reaction solution was poured into a 20% hydrochloric acid aqueous solution. The pH of the aqueous phase was adjusted to 8-9 with 5N sodium hydroxide aqueous solution. Dichloromethane (100 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to give 1.56 g of intermediate 25-1.

[0752] MS(ESI, [M+H]) + )m / z:162.12.

[0753] Step 2: Synthesis of intermediate 25-2

[0754] Intermediate 25-1 (1.37 g), methanol (60 mL), hydroxylamine hydrochloride (0.95 g), and potassium acetate (1.67 g) were mixed and stirred at 70 °C for 1 hour. After the reaction was completed, the reaction solution was poured into a saturated sodium bicarbonate solution, extracted with ethyl acetate (100 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 1.43 g of intermediate 25-2.

[0755] MS(ESI, [M+H]) + )m / z:177.32.

[0756] 1 H-NMR (500MHz, DMSO-d6): δ10.35(s,1H),8.49-8.45(m,1H),7.71-7.68(m,1H),7.28-7.26(m,1H),7.21-7.18(m,1H),3.85-3 .84(m,1H),2.55-2.52(m,1H),2.41-2.34(m,1H),2.18-2.09(m,1H),2.07-2.01(m,1H),1.93-1.89(m,1H),1.73-1.67(m,1H).

[0757] Step 3: Synthesis of intermediate 25-3

[0758] Intermediate 25-2 (1.43 g) and dichloromethane (20 mL) were mixed, and p-toluenesulfonyl chloride (1.70 g) and triethylamine (1.23 g) were added under ice bath conditions. The mixture was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was poured into water, and dichloromethane (100 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give 0.68 g of intermediate 25-3.

[0759] MS(ESI, [M+H]) + )m / z:159.12.

[0760] 1 H-NMR (500MHz, DMSO-d6): δ8.54-8.51(m,1H),7.46-7.42(m,1H),7.12-7.07(m,1H),6.70-6.66(m,1H),2.85-2.77(m,4H),2.48-2.42(m,2H).

[0761] Step 4: Synthesis of intermediate 25-4

[0762] Intermediate 25-3 (0.6 g), chloroform (12 mL), and liquid bromine (0.67 g) were mixed and reacted at 50 °C for 12 hours. After the reaction was completed, the reaction solution was poured into a saturated sodium sulfite solution, and dichloromethane (100 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 40:1) to give 0.10 g of intermediate 25-4.

[0763] MS(ESI, [M+H]) + )m / z:237.14.

[0764] 1 H-NMR (500MHz, DMSO-d6): δ8.89(s,1H),7.46(d,J=9.5Hz,1H),7.21(dd,J=9.5,2Hz,1H),2.83-2.74(m,4H),2.48-2.43(m,2H).

[0765] Step 5: Synthesis of intermediate 25-5

[0766] Intermediate A-1 (170 mg), intermediate 25-4 (100 mg), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (27.4 mg), potassium carbonate (160 mg), cuprous iodide (14.67 mg), and N-methylpyrrolidone (5 mL) were mixed and reacted at 120 °C for 12 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was poured into water, and ethyl acetate (50 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give 0.183 g of intermediate 25-5.

[0767] 1 H-NMR (500MHz, DMSO-d6): δ8.96 (s, 1H), 7.59 (d, J = 9.5Hz, 1H), 7.39-7.37 (m, 1H ),7.31(d,J=3.5Hz,1H),7.11(d,J=6.5Hz,2H),6.98(s,1H),5.24-5.05(m,1H), 4.38-4.14(m,1H),3.24-2.98(m,1H),2.86-2.81(m,4H),2.76-2.72(m,1H),2.6 9-2.62(m,1H),2.49-2.44(m,2H),2.19(s,6H),1.44(s,9H),1.23-1.19(m,3H).

[0768] Step Six: Synthesis of Intermediate 25-6

[0769] Intermediate 25-5 (0.18 g), dichloromethane (2 mL), and 4N dioxane hydrochloride solution (2 mL) were mixed and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain 0.15 g of intermediate 25-6.

[0770] MS(ESI, [M+H]) + )m / z:498.38.

[0771] Step 7: Synthesis of intermediate 25-7 and compound 25

[0772] Intermediate B-1 (0.1 g), N,N-dimethylformamide (5 mL), triethylamine (0.68 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.28 g) were mixed and stirred at room temperature for 5 minutes. Intermediate 25-6 (0.13 g) was then added, and the mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction solution was poured into water, and ethyl acetate (50 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give 0.12 g of intermediate 25-7. The above intermediate 25-7 was prepared and separated by chiral HPLC (column: CHIRALART Cellulose-SB, 30×250mm, 5μm; mobile phase: ethanol: n-hexane = 43:57; flow rate: 40mL / min) to obtain 26mg of compound 25.

[0773] Compound 25: Rt = 4.57 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6 x 100 mm, 3 μm); mobile phase: carbon dioxide: methanol (containing 0.1% ammonia) = 60:40; flow rate: 2.0 ml / min; column temperature: 40℃)

[0774] HRMS:(ESI, [M+H]) + )m / z:891.4098.

[0775] 1 H-NMR (500MHz, DMSO-d6): δ11.74(s,1H),8.98(s,1H),7.60(d,J=9.5Hz,1H),7.53(s,1H),7.44-7.39(m,2H),7. 35-7.33(m,1H),7.26(d,J=8.5Hz,1H),7.18-7.14(m,2H),7.02-6.93(m,2H),5.63-5.56(m,1H),4.41-4.35(m,1H ),3.73-3.69(m,2H),3.22-3.15(m,1H),3.07-3.02(m,1H),2.87-2.80(m,6H),2.48-2.42(m,2H),2.23(s,6H),1. 70-1.66(m,2H),1.60-1.56(m,2H),1.43-1.39(m,3H),1.28(s,3H),1.24(s,3H),1.18(s,3H),1.16-1.13(m,3H).

[0776] Example 26

[0777]

[0778] Step 1: Synthesis of Intermediate 26-1

[0779] Cuprous iodide (42.0 mg), potassium carbonate (229 mg), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (39.2 mg), intermediate A-2 (250 mg), intermediate 9-2 (196 mg), and N-methylpyrrolidone (4 mL) were mixed. The reaction mixture was heated to 130 °C and stirred for 5 hours. The reaction solution was poured into ethyl acetate (30 mL) and water (30 mL), and the two phases were separated. The aqueous phase was extracted with ethyl acetate (2 × 20 mL). The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 50:50) to give 190 mg of intermediate 26-1.

[0780] MS(ESI, [M+H]) + m / z:610.41

[0781] Step 2: Synthesis of intermediate 26-2

[0782] Intermediate 26-1 (190 mg) was mixed with 10 mL of 4N dioxane hydrochloride solution and reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain 130 mg of intermediate 26-2.

[0783] MS(ESI, [M+H]) + )m / z:510.34

[0784] Step 3: Synthesis of intermediate 26-3 and compound 26

[0785] Intermediate B-1 (100 mg), N,N-dimethylformamide (5 mL), triethylamine (492 mg), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (277 mg) were stirred for 5 minutes, and then 26-3 (130 mg) was added. The mixture was stirred at room temperature for 4 hours. The reaction solution was poured into water (50 mL), and the resulting solution was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was preparatively separated using a C18 column (column: Ultimate C18, 21.2 × 250 mm, 5 μm; mobile phase: water (0.1% acetic acid): acetonitrile = 25:75, isocratic elution) to obtain 70 mg of intermediate 26-4. The above intermediate 26-4 was prepared and separated by chiral HPLC (column: CHIRALART Cellulose-SB, 30×250mm, 5μm; mobile phase: ethanol-dichloromethane (1:1):n-hexane = 27:73, isocratic elution) to obtain 30mg of compound 26.

[0786] Compound 26: Rt = 2.98 min (UPCC conditions: column: CHIRALPAK IB, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: isopropanol (containing 0.1% ammonia): ethanol = 50:25:25; flow rate: 0.5 mL / min; column temperature: 40 °C).

[0787] HRMS:(ESI, [M+H]) + )m / z:903.4006.

[0788] 1 H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),8.03(s,1H),7.88(d,J=8.4Hz,1H),7.78(d,J=8.4Hz,1H),7.5 4(s,1H),7.42-7.35(m,2H),7.32-7.21(m,4H),6.97-6.88(m,2H),5.58(d,J=6.7Hz,1H),4.39(s,1H),3. 72(d,J=10.2Hz,2H),3.24-3.17(m,2H),3.03-3.01(m,1H),2.91(d,J=15.4Hz,1H),2.74(t,J=7.5Hz,1H) ,2.10-1.96(m,2H),1.75-1.47(m,9H),1.44-1.09(m,13H),0.96(d,J=8.4Hz,2H),0.85(t,J=6.9Hz,3H).

[0789] Example 27

[0790]

[0791] Step 1: Synthesis of intermediates 27-1, 27-2, and 27-3

[0792] Intermediate A-3 (800 mg), intermediate 5-2 (548 mg), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (258 mg), potassium carbonate (751 mg), cuprous iodide (173 mg), and N-methylpyrrolidone (12 mL) were mixed and reacted at 100 °C for 4 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was poured into water, and ethyl acetate (50 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give 940 mg of intermediate 27-1. Intermediate 27-1 was prepared and separated by chiral HPLC (column: CHIRALART Cellulose-SB, 30×250mm, 5μm; mobile phase: ethanol: n-hexane = 43:57; flow rate: 40mL / min) to obtain 450mg intermediate 27-2 and 460mg intermediate 27-3.

[0793] Intermediate 27-2: Rt = 3.73 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6 × 100 mm, 3 μm); mobile phase: carbon dioxide: methanol (containing 0.1% ammonia) = 40:60; flow rate: 2.0 ml / min; column temperature: 40℃)

[0794] MS(ESI, [M+H]) + )m / z:613.44.

[0795] 1 H-NMR (500MHz, DMSO-d6): δ7.46(d,J=2.1Hz,1H),7.38(dd,J=8.1,2.0Hz,1H),7.33(d,J=3 .2Hz,1H),7.19(d,J=7.0Hz,2H),7.12(d,J=8.1Hz,1H),6.85(d,J=3.1Hz,1H),5.27(d,J=6 .0Hz,1H),4.31(s,1H),4.27-4.21(m,1H),4.11-4.03(m,1H),3.51(s,1H),3.24(s,3H),2. 17(d,J=2.1Hz,6H),1.66-1.62(m,2H),1.55-1.52(m,2H),1.45(s,9H),1.29-1.26(m,3H).

[0796] Intermediate 27-3: Rt = 4.78 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6 × 100 mm, 3 μm); mobile phase: carbon dioxide: methanol (containing 0.1% ammonia) = 40:60; flow rate: 2.0 ml / min; column temperature: 40℃)

[0797] MS(ESI, [M+H]) + )m / z:613.43.

[0798] 1 H-NMR (500MHz, DMSO-d6): δ7.46(d,J=2.0Hz,1H),7.38(dd,J=8.1,2.0Hz,1H),7.33(d,J=3.2Hz ,1H),7.19(d,J=7.0Hz,2H),7.12(d,J=7.9Hz,1H),6.85(d,J=3.2Hz,1H),5.27(d,J=6.3Hz,1H) ,4.31(s,1H),4.24(dd,J=12.7,3.5Hz,1H),4.12-4.03(m,1H),3.51(d,J=1.1Hz,1H),3.24(s,3 H),2.17(d,J=2.1Hz,6H),1.67-1.62(m,2H),1.56-1.51(m,2H),1.45(s,9H),1.29-1.26(m,3H).

[0799] Step 2: Synthesis of intermediate 27-4

[0800] Intermediate 27-2 (0.2 g), dichloromethane (5 mL), and 4N dioxane hydrochloride solution (5 mL) were mixed and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain 0.16 g of intermediate 27-4.

[0801] MS(ESI, [M+H]) + )m / z:513.34

[0802] Step 3: Synthesis of intermediate 27-5 and compounds 27-A and 27-B

[0803] Intermediate B-1 (0.12 g), N,N-dimethylformamide (5 mL), triethylamine (0.393 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.22 g) were mixed and stirred at room temperature for 5 minutes. Intermediate 27-4 (0.16 g) was then added, and the mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction solution was poured into water, and ethyl acetate (50 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give 0.2 g of intermediate 27-5. The above intermediate 27-5 was prepared and separated by chiral HPLC (column: CHIRALART Cellulose-SB, 30×250mm, 5μm; mobile phase: ethanol-dichloromethane (1:3):n-hexane = 40:60; flow rate: 40mL / min) to obtain 78mg of compound 27-A and 80mg of compound 27-B.

[0804] Compound 27-A: Rt = 1.09 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6 × 100 mm, 3 μm); mobile phase: carbon dioxide: methanol / acetonitrile (1:1) (containing 0.1% ammonia) = 30:70; flow rate: 2.0 ml / min; column temperature: 40℃)

[0805] HRMS:(ESI, [M+H]) + )m / z:906.4119.

[0806] 1 H-NMR (500MHz, DMSO-d6): δ12.16(s,1H),7.56-7.34(m,6H),7.30-7.17(m, 5H),7.12(d,J=7.2Hz,1H),6.95-6.81(m,3H),4.59-4.33(m,3H),3.89(s,1 H),3.77-3.63(m,3H),3.27-3.22(m,3H),3.11-2.98(m,2H),2.19(s,6H),1 .56-1.49(m,5H),1.46-1.38(m,4H),1.28(s,3H),1.23(s,3H),1.18(s,3H).

[0807] Compound 27-B: Rt = 1.44 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6 × 100 mm, 3 μm); mobile phase: carbon dioxide: methanol / acetonitrile (1:1) (containing 0.1% ammonia) = 30:70; flow rate: 2.0 ml / min; column temperature: 40℃)

[0808] HRMS:(ESI, [M+H]) + )m / z:906.4116.

[0809] 1 H-NMR (500MHz, DMSO-d6): δ12.15(s,1H),7.53-7.34(m,6H),7.31-7.18(m,5H),7.16-7.08(m,1H),6.96-6.78(m,3H),4.59-4.31(m,3H),3.89( s,1H),3.71(s,3H),3.25(s,3H),3.11-2.94(m,2H),2.19(s,6H),1.57- 1.49(m,5H),1.47-1.39(m,4H),1.30(s,3H),1.28(s,3H),1.26(s,3H).

[0810] Step 4: Synthesis of intermediate 27-6

[0811] Intermediate 27-3 (0.2 g), dichloromethane (5 mL), and 4N dioxane hydrochloride solution (5 mL) were mixed and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain 0.16 g of intermediate 27-6.

[0812] Step 5: Synthesis of intermediate 27-7 and compounds 27-C and 27-D

[0813] Intermediate B-1 (0.12 g), N,N-dimethylformamide (5 mL), triethylamine (0.39 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.22 g) were mixed and stirred at room temperature for 5 minutes. Intermediate 27-6 (0.16 g) was then added, and the mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction solution was poured into water, and ethyl acetate (50 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give 0.2 g of intermediate 27-7. The above intermediate 27-7 was prepared and separated by chiral HPLC (column: CHIRALART Cellulose-SB, 30×250mm, 5μm; mobile phase: ethanol-dichloromethane (1:3):n-hexane = 40:60; flow rate: 40mL / min) to obtain 74mg of compound 27-C and 78mg of compound 27-D.

[0814] Compound 27-C: Rt = 1.10 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6 × 100 mm, 3 μm); mobile phase: carbon dioxide: methanol / acetonitrile (1:1) (containing 0.1% ammonia) = 30:70; flow rate: 2.0 ml / min; column temperature: 40℃)

[0815] HRMS:(ESI, [M+H]) + )m / z:906.4132.

[0816] 1 H-NMR (500MHz, DMSO-d6): δ12.15(s,1H),7.47(d,J=5.8Hz,2H),7.44-7.32(m, 4H),7.31-7.18(m,5H),7.12(d,J=5.8Hz,1H),7.00-6.81(m,3H),4.58-4.31(m, 3H),3.95-3.82(m,1H),3.71(s,3H),3.25(s,3H),3.14-2.99(m,2H),2.19(s,6H ),1.59-1.51(m,5H),1.46-1.38(m,4H),1.28(s,3H),1.26(s,3H),1.23(s,3H).

[0817] Compound 27-D: Rt = 1.20 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6 × 100 mm, 3 μm); mobile phase: carbon dioxide: methanol / acetonitrile (1:1) (containing 0.1% ammonia) = 30:70; flow rate: 2.0 ml / min; column temperature: 40℃)

[0818] HRMS:(ESI, [M+H]) + )m / z:906.4144.

[0819] 1 H-NMR (500MHz, DMSO-d6): δ11.68(s,1H),7.54-7.46(m,2H),7.42-7.34(m, 4H),7.29-7.16(m,5H),7.14-7.01(m,2H),6.90-6.82(m,2H),4.59(s,2H), 4.40(s,1H),4.14(s,1H),3.71(s,3H),3.25(s,3H),3.04(s,2H),2.19(s,6 H),1.66-1.59(m,5H),1.54(s,4H),1.35(s,3H),1.30(s,3H),1.26(s,3H).

[0820] Experimental Example 1: Assay of cAMP Expression Activity at the In Vitro Cellular Level

[0821] HEK293 / CRE-Luc / GLP1R cells (manufacturer: GenScript Biotech Inc.) in good growth condition were washed with PBS, digested with trypsin, and the culture was terminated with complete medium. The cells were collected into centrifuge tubes and the cell density was adjusted to 4 × 10⁶ cells / mL using DMEM + 2% FBS medium. 5 Cells were seeded at a concentration of 100 μL / well in 96-well plates and incubated at 37°C for 1 h. After 1 h, the compound was added using a nanoparticle pipette to achieve a final concentration of 10 nM - 0.0006 nM, with two replicates and a control. After culturing for another 6 hours in a cell culture incubator, Luciferase (manufacturer: Novizan Biosciences, 50 μL / well) was added, and the cells were incubated at room temperature for 3 min to allow for complete cell lysis. Luminescence was measured using a PerkinElmer Envision microplate reader, and four-parameter analysis was performed to fit a dose-response curve and calculate EC50. 50 .

[0822] Some of the compounds disclosed herein exhibit good in vitro cell cAMP expression activity, as shown in Table 1.

[0823] Table 1. In vitro cAMP expression activity of some compounds in cells

[0824]

[0825]

[0826] Experimental Example 2: In vitro liver microsomal stability assay

[0827] Liver microsomal incubation samples were prepared by incubating liver microsomal solution (0.5 mg / ml) in mixed PBS buffer (pH 7.4), along with the test compound and NADPH + MgCl2 solution at 37°C and 300 rpm for 1 hour. Samples at 0 hours were prepared by incubating liver microsomal solution (0.5 mg / ml) in mixed PBS buffer (pH 7.4), along with the test compound. After adding acetonitrile solution containing an internal standard, protein precipitation was performed to prepare the supernatant, which was then diluted for LC / MS / MS analysis. The in vitro liver microsomal stability of some compounds is shown in Table 2.

[0828] Table 2 In vitro liver microsomal stability

[0829]

[0830] Some of the compounds disclosed herein exhibit good in vitro liver microsomal stability.

[0831] Experimental Example 3: Pharmacokinetic Evaluation in Mice

[0832] ICR mice, weighing 18-22g, were randomly divided into 4 groups of 9 mice each after acclimatization for 3-5 days. The test compound was administered by gavage (IG) at a dose of 10mg / kg or by intravenous injection (IV) at a dose of 1mg / kg.

[0833] The test animals (ICR mice) were fasted for 12 hours before administration and given food 4 hours after administration. They had free access to water before, during, and after the experiment.

[0834] Following oral administration, approximately 0.1 mL of blood was collected from the orbital sinus at 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, and 24 h. Following intravenous administration, approximately 0.1 mL of blood was collected from the orbital sinus at 5 min, 10 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h. Blood was collected from each mouse at 3-4 time points, with 3 mice at each time point. Whole blood was collected and placed in centrifuge tubes containing EDTA-K2, stored at 4°C, and centrifuged at 4°C and 4000 rpm for 10 min within 1 hour to separate plasma. All collected plasma was immediately stored at -20°C for analysis.

[0835] Take 30 μL of the plasma sample to be tested and the standard sample, add 300 μL of acetonitrile solution containing internal standard (diazepam 20 ng / mL), shake to mix for 5 min, centrifuge at 13000 rpm for 10 min, take 80 μL of supernatant, add 80 μL of ultrapure water to dilute, mix well, take 2 μL for liquid chromatography-mass spectrometry determination, and record the chromatogram.

[0836] The pharmacokinetic properties of some compounds in mice are shown in Table 3.

[0837] Table 3. Pharmacokinetic properties in mice

[0838]

[0839] Some of the compounds disclosed herein exhibit good pharmacokinetic properties in mice.

[0840] Example 4: Evaluation of the hypoglycemic effect in mice

[0841] The experiment used GLP-1R humanized C57BL / 6J mice, weighing 20-22g. After 3 days of acclimatization, the experiment was conducted. All animals were fasted but allowed free access to water until the end of the experiment. Blood was collected from the tip of the mouse tail.

[0842] Animals were fasted the night before the experiment but allowed free access to water. Blood was collected from all animals the following day for blood glucose testing. Animals were randomly divided into a normal control group, a positive drug control group, and a test drug group, with six animals in each group, based on blood glucose and body weight. The drugs were then administered via gavage according to their group classification. Five hours after administration, a glucose solution (2 g / kg) was injected intraperitoneally. Blood glucose concentrations were measured at 0.25 h, 0.5 h, 1 h, 2 h, and 3 h after glucose administration. Blood glucose levels were recorded throughout the experiment, and the area under the blood glucose-time curve (AUC0-180min Glu) was calculated.

[0843] The hypoglycemic effects of some compounds in mice are shown in Table 4.

[0844] Table 4 Evaluation of hypoglycemic efficacy in mice

[0845]

[0846] Some of the compounds disclosed herein have good hypoglycemic effects in mice.

Claims

1. The following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof:

2. Use of the compound of claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diseases related to GLP-1.

3. The use as described in claim 2, wherein the GLP-1-related disease is selected from diabetes.

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