Compounds containing polycondensed ring structures

Abstract

This disclosure belongs to the field of medicinal chemistry and relates to compounds containing polycondensed ring structures, specifically to compounds represented by formula (I), their stereoisomers or pharmaceutically acceptable salts, methods for producing the same, or pharmaceutical compositions thereof, as well as their use in the manufacture of pharmaceuticals for the treatment of diseases associated with diabetes or obesity. [Formula 1] TIFF2026522678000165.tif70170

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority and interest in the Chinese patent application filed with the State Intellectual Property Administration on June 30, 2023, with application number 202310802212.0, the Chinese patent application filed with the State Intellectual Property Administration on November 3, 2023, with application number 202311497217.3, and the Chinese patent application filed with the State Intellectual Property Administration on June 20, 2024, with application number 202410808056.3, the entire contents of which these applications are incorporated herein by reference.

[0002] (Technical field) This disclosure relates to the field of medicinal chemistry and to compounds containing polycondensed ring structures, their stereoisomers or pharmaceutically acceptable salts thereof, methods for producing the same, or pharmaceutical compositions thereof, as well as their use in the manufacture of pharmaceuticals for the treatment of diseases associated with diabetes or obesity. [Background technology]

[0003] Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by elevated blood glucose levels and has high morbidity and mortality rates. 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 from L cells in the small intestine as nutrients pass through the digestive tract. GLP-1 is known to exert various physiological effects via the GLP-1 receptor, including promoting glucose-dependent insulin secretion, inhibiting glucagon secretion, delaying gastric emptying, and suppressing appetite. GLP-1 analogs are commercially available as diabetes medications and are considered one of the most effective diabetes treatments due to their ability to lower HbA1c and reduce weight. However, GLP-1 analogs require subcutaneous injection, resulting in low patient compliance. Therefore, the development of non-peptide GLP-1 receptor small molecule agonists is crucial for improving patient compliance and is a research topic attracting attention in the field of diabetes. [Overview of the project]

[0004] This application provides a compound represented by formula (I), its stereoisomers or its pharmaceutically acceptable salts.

[0005] [Chemical formula]

[0006] (In the formula, X 1 , X 2 are each independently selected from C or N, Y 1 , Y 2 , Y 3 or Y 4 are each independently selected from CH, C or N, R 1 is selected from C 11-15 Cycloalkyl, C 11-15 Aryl, 11-15 member heteroaryl, 11-15 member heterocyclyl, wherein the C 11-15 Cycloalkyl, C 11-15 Aryl, 11-15 member heteroaryl, 11-15 member heterocyclyl are tricyclic rings, and the C 11-15 Cycloalkyl, C 11-15 Aryl, 11-15 member heteroaryl, 11-15 member heterocyclyl may each independently be substituted with one or more R [[ID=A]] a 11-15 Aryl, 11-15 member heteroaryl, 11-15 member heterocyclyl are tricyclic rings, and the C 11-15 Cycloalkyl, C <00A0013>Aryl, 11-15 member heteroaryl, 11-15 member heterocyclyl may each independently be substituted with one or more R a ; Alternatively, R 1 is selected from C 3-7 Cycloalkyl, phenyl, 5-6 member heteroaryl or 3-7 member heterocyclyl, and the R 1 is substituted with one C 2-4 Alkynyl, and R [[ID=A]] 1 may further be independently substituted with one or more R a ; the C 2-4 Alkynyl may be substituted with one or more R b 2-4 Alkynyl may be substituted with one or more R b ; Each R a is independently deuterium, halogen, =O, deuterated C 1-6 It should be noted that there seems to be an error in the original text where "C <00A0013> " is likely a misrepresentation and might be a formatting or encoding issue. This has been left as is in the translation for the sake of maintaining the integrity of the original text. Also, the tags <00A0013> and <00A0019> might be incorrect in the original and should be double-checked. If they are meant to be something else, the translation would need to be adjusted accordingly.Alkyl, -OH, -CN, NH2, -COOH, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-,C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 3-6 Selected from cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl, the deuterated C 1-6 Alkyl, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-,C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-3 Alkylenes independently have one or more R c1 It may be replaced by the above C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl can independently be one or more R d1 It may also be replaced with Each R 2 These are, independently, halogen, -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 Alkenil, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 3-6 Selected from cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl, the C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-,C 1-6 alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenil, C 2-6Alkynyl, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-3 Alkylene is independently optionally substituted with one or more R c2 wherein the C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl is independently optionally substituted with one or more R d2 or two adjacent R on carbon atoms together with the carbon atoms to which they are attached form a C Cycloalkyl, phenyl, 5- to 6-membered heteroaryl or 4- to 6-membered heterocyclyl, and the C 2 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl or 4- to 6-membered heterocyclyl is independently optionally substituted with one or more R 4-6 wherein the C 4-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl or 4- to 6-membered heterocyclyl is independently optionally substituted with one or more R d3 or two adjacent R on carbon atoms together with the carbon atoms to which they are attached form a C Each R 3 is independently deuterium, halogen, -OH, -CN, NH2, -COOH, 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, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl, and the C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C​​​​​​​​​​​​​​​Cycloalkyl, phenyl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl may each independently be substituted with one or more R d4 and may be substituted with R 4 is H, deuterium, halogen, -CN, NH2, -COOH, C 1-6 alkylNH-, (C 1-6 alkyl)2N-, C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkoxyC 1-3 [[ID=2G]]alkylen, and the C 1-6 alkylNH-, (C 1-6 alkyl)2N-, C[[ID=CC]] 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkoxyC 1-3 alkylen may each independently be substituted with one or more R c4 and may be substituted with Each R 5 is independently halogen, -CN, -OH, -SH, -NH2, C 1-6 alkylNH-, (C 1-6 alkyl)2N-, C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-3 alkylen, C 1-6 alkylthio group, -CONH2, -CONHC 1-3 alkyl, -NHCOC 1-3 alkyl, -SO2NH2, -SO2NHC 1-3 alkyl or -NHSO2C 1-3 alkyl, and the C 1-6 alkylNH-, (C 1-6 alkyl)2N-, C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-3 alkylen, C 1-6Alkylthio group, -CONH2, -CONHC 1-3 Alkyl, -NHCOC 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl or -NHSO2C 1-3 Alkyl molecules can be one or more R groups independently. c5 It may also be replaced with R' and R'' are independently H, halogen, -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 group, -CONH2, -CONHC 1-3 Alkyl, -NHCOC 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl or -NHSO2C 1-3 Selected from 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 group, -CONH2, -CONHC 1-3 Alkyl, -NHCOC 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl or -NHSO2C 1-3 Alkyl molecules can be one or more R groups independently. c6 It may also be replaced with Alternatively, R' and R'', together with the carbon atom to which they are bonded, are C 3-6 Forming a cycloalkyl or 3-6 member heterocycloalkyl, the C 3-6 Cycloalkyl or 3-6 member heterocycloalkyl groups independently contain one or more R d5 It may also be replaced with each

[0007] [ka]

[0008] Each of these is independently selected from a single bond or a double bond. Each R b These are, independently, deuterium, halogen, -CN, -OH, -NH2, and C. 1-3 Alkyl or C 1-3 Selected from alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy may be independently substituted with one or more substituents selected from deuterium, halogen, OH, CN, or NH2. Each R c1 , R c2 , R c3 , R c4 , R c5 and R c6 Each of these is independently selected from deuterium, halogen, -CN, -OH, or -NH2. Each R d1 , R d2 , R d3 , R d4 and R d5 These are, independently, deuterium, halogen, -CN, -OH, =O, -NH2, and C. 1-3 Alkyl or C 1-3 Selected from alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy may be independently substituted with one or more substituents selected from deuterium, halogen, OH, CN, or NH2. q is selected from 0, 1, 2, 3, or 4. n is selected from 0, 1, 2, 3, or 4. m is selected from 0, 1, 2, 3, or 4.

[0009] In some embodiments, "replaced by one or more circles" is independently selected from being replaced by 1, 2, 3, 4, 5, or 6 circles.

[0010] In some embodiments, "replaced by one or more circles" is independently selected from being replaced by 1, 2, 3, 4, or 5 circles.

[0011] In some embodiments, "replaced by one or more circles" is independently selected from being replaced by 1, 2, 3, or 4 circles.

[0012] In some embodiments, "replaced by one or more circles" is independently selected from being replaced by one, two, or three circles.

[0013] In some embodiments, the "hetero" in heteroaryl or heterocyclyl is independently selected from heteroatoms of oxygen, sulfur, and nitrogen, the nitrogen atom may be quaternized or oxidized to N(O), the sulfur atom may be oxidized to S(O) or S(O)2, and the other variables are as defined herein.

[0014] In some embodiments, the tricyclic ring is selected from a fused ring of a monocyclic ring and a fused dicyclic ring, a fused ring of a monocyclic ring and a spirodic ring, or a fused ring of a monocyclic ring and a bridging dicyclic ring.

[0015] In some embodiments, the tricyclic ring is selected from a fused ring of a monocyclic ring and a fused dicyclic ring, or a fused ring of a monocyclic ring and a spirodicyclic ring.

[0016] In some embodiments, the tricyclic ring is selected from a fused ring of a monocyclic ring and a fused dicyclic ring, a fused ring of a monocyclic ring and a spirodicyclic ring, or a fused ring of a monocyclic ring and a bridging dicyclic ring, wherein the monocyclic ring is a constituent unit

[0017] [ka]

[0018] It is connected to In some embodiments, in the tricyclic ring, the aromatic ring is a structural unit.

[0019] [ka]

[0020] It is connected to In some other embodiments, the tricyclic ring is selected from a fused ring of a monocyclic ring and a fused dicyclic ring, a fused ring of a monocyclic ring and a spirodicyclic ring, or a fused ring of a monocyclic ring and a bridging dicyclic ring, wherein the monocyclic ring is an aromatic ring, and the monocyclic ring is a constituent unit

[0021] [ka]

[0022] It is connected to In some other embodiments, the tricyclic ring is selected from a fused ring of a monocyclic ring and a fused dicyclic ring, a fused ring of a monocyclic ring and a spirodicyclic ring, or a fused ring of a monocyclic ring and a bridging dicyclic ring, wherein the monocyclic ring is a benzene ring or a 5-6 membered heteroaromatic ring, and the monocyclic ring is a constituent unit

[0023] [ka]

[0024] It is connected to In some other embodiments, the tricyclic ring is selected from a fused ring of a monocyclic ring and a fused dicyclic ring, a fused ring of a monocyclic ring and a spirodicyclic ring, or a fused ring of a monocyclic ring and a bridging dicyclic ring, wherein the monocyclic ring is a benzene ring or a 5-6 membered heteroaromatic ring containing 1-2 N atoms, and the monocyclic ring is a constituent unit

[0025] [ka]

[0026] It is connected to In some other embodiments, the tricyclic ring is selected from a fused ring of a monocyclic ring and a fused dicyclic ring, a fused ring of a monocyclic ring and a spirodicyclic ring, or a fused ring of a monocyclic ring and a bridging dicyclic ring, wherein the monocyclic ring is a benzene ring or a 6-membered heteroaromatic ring containing 1 to 2 N atoms, and the monocyclic ring is a constituent unit

[0027] [ka]

[0028] It is connected to In some other embodiments, the tricyclic ring is selected from a fused ring of a monocyclic ring and a fused dicyclic ring, a fused ring of a monocyclic ring and a spirodicyclic ring, or a fused ring of a monocyclic ring and a bridging dicyclic 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 a constituent unit

[0029] [ka]

[0030] It is connected to In some other embodiments, the tricyclic ring is selected from a fused ring of a monocyclic ring and a fused dicyclic ring, a fused ring of a monocyclic ring and a spirodicyclic ring, or a fused ring of a monocyclic ring and a bridging dicyclic ring, wherein the monocyclic ring is a benzene ring or a pyridine ring, and the monocyclic ring is a constituent unit

[0031] [ka]

[0032] It is connected to In this application, R 1 Middle, constituent unit

[0033] [ka]

[0034] If the ring bonded to it is an aromatic ring, R 1It is defined as an aryl or heteroaryl.

[0035] In some embodiments, R 1 C 11-15 Selected from aryl or 11-15 member heteroaryl, the C 11-15 The aryl or 11-15 member heteroaryl is a tricyclic ring, and the C 11-15 An aryl or 11-15 member heteroaryl independently contains one or more R a It may be replaced with .

[0036] In some embodiments, R 1 Benzo C 7-11 Condensed bicycloalkyl, benzo-7-11 member condensed heterobicyclyl, benzo-7-11 member condensed heterobiaryl, pyride C 7-11 Condensed bicycloalkyl, pyride 7-11 member condensed heterobicyclyl, pyride 7-11 member condensed heterobiaryl, pyride C 7-11 Condensed bicycloalkyl, 7-11 member pyrimide condensed heterobicyclyl, 7-11 member pyrimide condensed heterobiaryl, pyridazino C 7-11 Condensed bicycloalkyl, pyridazino 7-11 member condensed heterobicycloalkyl, pyridazino 7-11 member condensed heterobiaryl, pyrazino C 7-11 Condensed bicycloalkyl groups, pyrazino 7-11 member condensed heterobicycloalkyl groups, pyrazino 7-11 member condensed heterobiaryl groups, benzoC 7-11 Spirobicycloalkyl, BenzoC 7-11 Spiroheterobicyclyl, Pyrido C 7-11 Spirobicycloalkyl, Pyrid C 7-11 Spiroheterobicyclyl, Pyrimide C 7-11 Spirobicycloalkyl, Pyrimide C 7-11 Spiroheterobicyryl, Pyridazino C 7-11 Spirobicycloalkyl, pyridadino C 7-11 Spiroheterobicyryl, Pyrazino C 7-11 Spirobicycloalkyl or pyrazino C 7-11 Selected from spiroheterobicyclyl, the R 1These are, independently, one or more R a It may be replaced with .

[0037] In some embodiments, R 1 Benzo C 7-9 Condensed bicycloalkyl, benzo-7-9 member condensed heterobicyclyl, benzo-7-9 member condensed heterobiaryl, pyride C 7-9 Condensed bicycloalkyl, pyride 7-9 member condensed heterobicyclyl, pyride 7-9 member condensed heterobiaryl, pyride C 7-9 Condensed bicycloalkyl, 7-9 member pyrimide condensed heterobicyclyl, 7-9 member pyrimide condensed heterobiaryl, pyridazino C 7-9 Condensed bicycloalkyl, pyridazino 7-9 member condensed heterobicycloalkyl, pyridazino 7-9 member condensed heterobiaryl, pyrazino C 7-9 Condensed bicycloalkyl groups, pyrazino 7-9 member condensed heterobicycloalkyl groups, pyrazino 7-9 member condensed heterobiaryl groups, benzoC 7-9 Spirobicycloalkyl, BenzoC 7-9 Spiroheterobicyclyl, Pyrido C 7-9 Spirobicycloalkyl, Pyrid C 7-9 Spiroheterobicyclyl, Pyrimide C 7-9 Spirobicycloalkyl, Pyrimide C 7-9 Spiroheterobicyryl, Pyridazino C 7-9 Spirobicycloalkyl, pyridadino C 7-9 Spiroheterobicyryl, Pyrazino C 7-9 Spirobicycloalkyl or pyrazino C 7-9 Selected from spiroheterobicyclyl, the R 1 These are, independently, one or more R a It may be replaced with .

[0038] In some embodiments, R 1 These are benzo-7-9 member condensed heterobicyclyls, benzo-7-9 member condensed heterobiaryls, and benzo-C 7-9 Spirobicycloalkyl, BenzoC 7-9 Spiroheterobicyclyl or pyridoC 7-9Selected from spirobicycloalkyl, the R 1 These are, independently, one or more R a It may be replaced with .

[0039] In some embodiments, R 1 These are benzo-7-9 member condensed heterobicyclyls, benzo-7-9 member condensed heterobiaryls, and benzo-C 7-9 Spirobicycloalkyl, BenzoC 7-9 Spiroheterobicyclyl or pyridoC 7-9 Selected from spirobicycloalkyl, the R 1 Middle, constituent unit

[0040] [ka]

[0041] The ring bonded to is a benzene ring or a pyridine ring, and the R 1 These are, independently, one or more R a It may be replaced with .

[0042] In some embodiments, R 1 This is a benzo-7-9 member condensed heterobicyclyl, benzo-C 7-9 Spirobicycloalkyl or benzoC 7-9 Selected from spiroheterobicyclyl, the R 1 These are, independently, one or more R a It may be replaced with .

[0043] In some embodiments, R 1 This is a benzo-7-9 member condensed heterobicyclyl, benzo-C 7-9 Spirobicycloalkyl or benzoC 7-9 Selected from spiroheterobicyclyl, the R 1 Middle, constituent unit

[0044] [ka]

[0045] The ring bonded to is a benzene ring, and the R 1 These are, independently, one or more R a It may be replaced with .

[0046] In some embodiments, R 1This includes a benzo-5 member cycloalkyl condensed into a 3-member cycloalkyl, a benzo-5 member cycloalkyl condensed into a 4-member cycloalkyl, a benzo-5 member cycloalkyl condensed into a 5-member cycloalkyl, a benzo-6 member cycloalkyl condensed into a 4-member cycloalkyl, a benzo-6 member cycloalkyl condensed into a 5-member cycloalkyl, a benzo-5 member cycloalkyl condensed into a 3-member heterocyclyl, a benzo-5 member cycloalkyl condensed into a 4-member heterocyclyl, a benzo-5 member cycloalkyl condensed into a 5-member heterocyclyl, a benzo-6 member cycloalkyl condensed into a 4-member heterocyclyl, and a benzo-6 member cycloalkyl 5-membered heterocyclyl with quill condensation, 3-membered cycloalkyl with benzo-5-membered heterocyclyl condensation, 4-membered cycloalkyl with benzo-5-membered heterocyclyl condensation, 5-membered cycloalkyl with benzo-5-membered heterocyclyl condensation, 4-membered cycloalkyl with benzo-6-membered heterocyclyl condensation, 5-membered cycloalkyl with benzo-6-membered heterocyclyl condensation, 3-membered heterocyclyl with benzo-5-membered heterocyclyl condensation, 4-membered heterocyclyl with benzo-5-membered heterocyclyl condensation, 5-membered heterocyclyl with benzo-6-membered heterocyclyl condensation, 4-membered heterocyclyl with benzo-6-membered heterocyclyl condensation , benzo-6 member heterocyclyl condensation 5 member heterocyclyl, benzo-5 member heteroaryl condensation 3 member cycloalkyl, benzo-5 member heteroaryl condensation 4 member cycloalkyl, benzo-5 member heteroaryl condensation 5 member cycloalkyl, benzo-5 member heteroaryl condensation 6 member cycloalkyl, benzo-6 member heteroaryl condensation 4 member cycloalkyl, benzo-6 member heteroaryl condensation 5 member cycloalkyl, benzo-5 member heteroaryl condensation 3 member heterocyclyl, benzo-5 member heteroaryl condensation 4 member heterocyclyl, benzo-5 member heteroaryl 5-membered heterocyclyl condensed with benzoyl, 6-membered heterocyclyl condensed with benzoyl, 4-membered heterocyclyl condensed with benzoyl, 5-membered heterocyclyl condensed with benzoyl, 5-membered heteroaryl condensed with benzoyl, 5-membered heteroaryl condensed with benzoyl, 5-membered heteroaryl condensed with benzoyl, 5-membered heteroaryl condensed with benzoyl, 5-membered heterocyclyl condensed with benzoyl, 5-membered heterocyclyl condensed with benzoyl, 5-membered heterocyclyl condensed with benzoyl,Pyridone 5-membered cycloalkyl condensed 3-membered cycloalkyl, pyrido 5-membered cycloalkyl condensed 4-membered cycloalkyl, pyrido 5-membered cycloalkyl condensed 5-membered cycloalkyl, pyrido 6-membered cycloalkyl condensed 4-membered cycloalkyl, pyrido 6-membered cycloalkyl condensed 5-membered cycloalkyl, pyrido 5-membered cycloalkyl condensed 3-membered heterocyclyl, pyrido 5-membered cycloalkyl condensed 4-membered heterocyclyl, pyrido 5-membered cycloalkyl condensed 5-membered heterocyclyl, pyrido 6-membered cycloalkyl condensed 4-membered heterocyclyl Condensed 5-membered heterocyclyl, pyrido 5-membered heterocyclyl condensed 3-membered cycloalkyl, pyrido 5-membered heterocyclyl condensed 4-membered cycloalkyl, pyrido 5-membered heterocyclyl condensed 5-membered cycloalkyl, pyrido 6-membered heterocyclyl condensed 4-membered cycloalkyl, pyrido 6-membered heterocyclyl condensed 5-membered cycloalkyl, pyrido 5-membered heterocyclyl condensed 3-membered heterocyclyl, pyrido 5-membered heterocyclyl condensed 4-membered heterocyclyl, pyrido 5-membered heterocyclyl condensed 5-membered heterocyclyl, pyrido 6-membered heterocyclyl condensed 4-membered heterocyclyl, Pyridone 6-membered heterocyclyl condensation 5-membered heterocyclyl, pyrido 5-membered heteroaryl condensation 3-membered cycloalkyl, pyrido 5-membered heteroaryl condensation 4-membered cycloalkyl, pyrido 5-membered heteroaryl condensation 5-membered cycloalkyl, pyrido 5-membered heteroaryl condensation 6-membered cycloalkyl, pyrido 6-membered heteroaryl condensation 4-membered cycloalkyl, pyrido 6-membered heteroaryl condensation 5-membered cycloalkyl, pyrido 5-membered heteroaryl condensation 3-membered heterocyclyl, pyrido 5-membered heteroaryl condensation 4-membered heterocyclyl, pyrido 5-membered heteroaryl Condensed 5-membered heterocyclyl, pyrido 5-membered heteroaryl condensed 6-membered heterocyclyl, pyrido 6-membered heteroaryl condensed 4-membered heterocyclyl, pyrido 6-membered heteroaryl condensed 5-membered heterocyclyl, pyrido 5-membered cycloalkyl condensed 5-membered heteroaryl, pyrido 6-membered cycloalkyl condensed 5-membered heteroaryl, pyrido 5-membered cycloalkyl condensed 6-membered heteroaryl, pyrido 5-membered heterocyclyl condensed 5-membered heteroaryl, pyrido 6-membered heterocyclyl condensed 5-membered heteroaryl, pyrido 5-membered heterocyclyl condensed 6-membered heteroaryl,Benzone 5-membered cycloalkyl spiro 3-membered cycloalkyl, Benzone 5-membered cycloalkyl spiro 4-membered cycloalkyl, Benzone 5-membered cycloalkyl spiro 5-membered cycloalkyl, Benzone 6-membered cycloalkyl spiro 4-membered cycloalkyl, Benzone 6-membered cycloalkyl spiro 5-membered cycloalkyl, Benzone 5-membered cycloalkyl spiro 3-membered heterocyclyl, Benzone 5-membered cycloalkyl spiro 4-membered heterocyclyl, Benzone 5-membered cycloalkyl spiro 5-membered heterocyclyl, Benzone 6-membered cycloalkyl spiro 4-membered heterocyclyl, Benzone 6-membered Cycloalkyl spiro 5-membered heterocyclyl, benzo 5-membered heterocyclyl spiro 3-membered cycloalkyl, benzo 5-membered heterocyclyl spiro 4-membered cycloalkyl, benzo 5-membered heterocyclyl spiro 5-membered cycloalkyl, benzo 6-membered heterocyclyl spiro 4-membered cycloalkyl, benzo 6-membered heterocyclyl spiro 5-membered cycloalkyl, benzo 5-membered heterocyclyl spiro 3-membered heterocyclyl, benzo 5-membered heterocyclyl spiro 4-membered heterocyclyl, benzo 5-membered heterocyclyl spiro 5-membered heterocyclyl, benzo 6-membered heterocyclyl 4-membered spiro heterocyclyl, 6-membered benzo heterocyclyl, 5-membered spiro heterocyclyl, 5-membered benzo heteroaryl, 3-membered spiro cycloalkyl, 5-membered pyrido cycloalkyl, 3-membered spiro cycloalkyl, 5-membered pyrido cycloalkyl, 4-membered spiro cycloalkyl, 5-membered pyrido cycloalkyl, 5-membered pyrido cycloalkyl, 4-membered pyrido cycloalkyl, 6-membered pyrido cycloalkyl, 5-membered pyrido cycloalkyl, 3-membered pyrido heterocyclyl, 5-membered pyrido cycloalkyl, 4-membered spiro Terocyclyl, pyrido 5-membered cycloalkyl spiro 5-membered heterocyclyl, pyrido 6-membered cycloalkyl spiro 4-membered heterocyclyl, pyrido 6-membered cycloalkyl spiro 5-membered heterocyclyl, pyrido 5-membered heterocyclyl spiro 3-membered cycloalkyl, pyrido 5-membered heterocyclyl spiro 4-membered cycloalkyl, pyrido 5-membered heterocyclyl spiro 5-membered cycloalkyl, pyrido 6-membered heterocyclyl spiro 4-membered cycloalkyl, pyrido 6-membered heterocyclyl spiro 5-membered cycloalkyl, pyrido 5-membered heterocyclyl spiro 3-membered heterocyclyl,Selected from a pyrido 5-membered heterocyclylspiro 4-membered heterocyclyl, pyrido 5-membered heterocyclylspiro 5-membered heterocyclyl, pyrido 6-membered heterocyclylspiro 4-membered heterocyclyl, pyrido 6-membered heterocyclylspiro 5-membered heterocyclyl, or pyrido 5-membered heteroarylspiro 3-membered cycloalkyl, and the above R, 1 These are, independently, one or more R a It may be replaced with .

[0047] In some other embodiments, R 1 This is selected from a benzo-5 member heteroaryl condensed 5-member heterocyclyl, a benzo-5 member heteroaryl condensed 6-member heterocyclyl, a benzo-5 member heterocyclyl condensed 5-member heteroaryl, a benzo-5 member cycloalkyl spiro-3 member cycloalkyl, a benzo-5 member heterocyclyl spiro-3 member cycloalkyl, a benzo-5 member heterocyclyl spiro-4 member cycloalkyl, a benzo-5 member cycloalkyl spiro-4 member heterocyclyl, a pyrido-5 member heteroaryl condensed 5-member cycloalkyl, or a pyrido-5 member cycloalkyl spiro-3 member cycloalkyl, and the R 1 These are, independently, one or more R a It may be replaced with .

[0048] In some other embodiments, R 1 This is selected from a benzo-5 member heteroaryl condensed 5-member heterocyclyl, a benzo-5 member heteroaryl condensed 6-member heterocyclyl, a benzo-5 member heterocyclyl condensed 5-member heteroaryl, a benzo-5 member cycloalkyl spiro-3 member cycloalkyl, a benzo-5 member heterocyclyl spiro-3 member cycloalkyl, a benzo-5 member heterocyclyl spiro-4 member cycloalkyl, a benzo-5 member cycloalkyl spiro-4 member heterocyclyl, a pyrido-5 member heteroaryl condensed 5-member cycloalkyl, or a pyrido-5 member cycloalkyl spiro-3 member cycloalkyl, and the R 1 Middle, constituent unit

[0049] [ka]

[0050] The ring bonded to is a benzene ring or a pyridine ring, and the R 1 These are, independently, one or more R a It may be replaced with .

[0051] In some embodiments, R 1 This is selected from a benzo-5 member heteroaryl condensed 5-member cycloalkyl, a benzo-5 member heteroaryl condensed 5-member heterocyclil, a benzo-5 member heteroaryl condensed 6-member heterocyclil, a benzo-5 member heterocyclil condensed 5-member heteroaryl, a benzo-5 member cycloalkyl spiro 3-member cycloalkyl, a benzo-5 member heterocyclil spiro 3-member cycloalkyl, a benzo-5 member heterocyclil spiro 4-member cycloalkyl, a benzo-5 member cycloalkyl spiro 4-member heterocyclil, or a pyrido-5 member cycloalkyl spiro 3-member cycloalkyl, and the R 1 These are, independently, one or more R a It may be replaced with .

[0052] In some embodiments, R 1 This is selected from a benzo-5 member heteroaryl condensed 5-member cycloalkyl, a benzo-5 member heteroaryl condensed 5-member heterocyclil, a benzo-5 member heteroaryl condensed 6-member heterocyclil, a benzo-5 member heterocyclil condensed 5-member heteroaryl, a benzo-5 member cycloalkyl spiro 3-member cycloalkyl, a benzo-5 member heterocyclil spiro 3-member cycloalkyl, a benzo-5 member heterocyclil spiro 4-member cycloalkyl, a benzo-5 member cycloalkyl spiro 4-member heterocyclil, or a pyrido-5 member cycloalkyl spiro 3-member cycloalkyl, and the R 1 Middle, constituent unit

[0053] [ka]

[0054] The ring bonded to is a benzene ring or a pyridine ring, and the R 1 These are, independently, one or more R a It may be replaced with .

[0055] In some embodiments, R 1 The R is selected from a benzo-5 membered cycloalkyl spiro-3 membered cycloalkyl or a benzo-5 membered heterocyclyl spiro-3 membered cycloalkyl, and the R 1 These are, independently, one or more R a It may be replaced with .

[0056] In some embodiments, R 1 The R is selected from a benzo-5 membered cycloalkyl spiro-3 membered cycloalkyl or a benzo-5 membered heterocyclyl spiro-3 membered cycloalkyl, and the R 1 internal constituent units

[0057] [ka]

[0058] The ring bonded to is a benzene ring, and the R 1 These are, independently, one or more R a It may be replaced with .

[0059] In some embodiments, R 1 teeth,

[0060] [ka]

[0061] [ka]

[0062] [ka]

[0063] [ka]

[0064] Selected from, the R 1 These are, independently, one or more R a It may be replaced with . In some embodiments, R 1 teeth,

[0065] [ka]

[0066] [ka]

[0067] [ka]

[0068] Selected from, the R 1 These are, independently, one or more R a It may be replaced with . In some other embodiments, R 1 teeth,

[0069] [ka]

[0070] Selected from, the R 1 These are, independently, one or more R a It may be replaced with . In some embodiments, R 1 teeth,

[0071] [ka]

[0072] Selected from, the R 1 These are, independently, one or more R a It may be replaced with . In some other embodiments, R 1 teeth,

[0073] [ka]

[0074] Selected from, the R 1 These are, independently, one or more R a It may be replaced with . In some other embodiments, R 1 teeth,

[0075] [ka]

[0076] Selected from, the R 1 These are, independently, one or more R a It may be replaced with . In some embodiments, R 1 is selected from phenyl or a 5-6 member heteroaryl, and the R 1 is one C 2-4 It is substituted with alkynyl, R 1 Furthermore, independently, one or more R a It may be replaced by the above C 2-4 Alkinyl contains one or more R b It may be replaced with .

[0077] In some embodiments, R 1 is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and the R 1 is one C 2-4 It is substituted with alkynyl, R 1 Furthermore, independently, one or more R aIt may be replaced by the above C 2-4 Alkinyl contains one or more R b It may be replaced with .

[0078] In some embodiments, R 1 is selected from phenyl or pyridyl, and the R 1 is one C 2-4 It is substituted with alkynyl, R 1 Furthermore, independently, one or more R a It may be replaced by the above C 2-4 Alkinyl contains one or more R b It may be replaced with .

[0079] In some embodiments, R 1 is selected from phenyl or pyridyl, and the R 1 It is substituted with one ethynyl or propynyl molecule, R 1 Furthermore, independently, one or more R a The ethynyl or propynyl may be substituted with one or more R b It may be replaced with .

[0080] In some embodiments, R 1 is selected from phenyl or pyridyl, and the R 1 It is substituted with one ethynyl or 1-propynyl, R 1 Furthermore, independently, one or more R a The ethynyl or propynyl may be substituted with one or more R b It may be replaced with .

[0081] In some embodiments, each R a These are, independently, halogen, =O, and deuterium C. 1-5 Alkyl, -OH, -CN, NH2, C 1-5 Alkyl, C 2-4 Alkenil, C 2-4 Alkinyl, C 1-5 Alkoxy, C 1-5 Alkoxy C1-3 Alkylene, C 3-6 Selected from cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl, the deuterated C 1-5 Alkyl, C 1-5 Alkyl, C 2-4 Alkenil, C 2-4 Alkinyl, C 1-5 Alkoxy or C 1-5 Alkoxy C 1-3 Alkylenes independently have one or more R c1 It may be replaced by the above C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl can independently be one or more R d1 It may be replaced with .

[0082] In some embodiments, each R a These are, independently, halogen, =O, and deuterium C. 1-3 Alkyl, -OH, -CN, NH2, C 1-3 Alkyl, C 2-4 Alkenil, C 2-4 Alkinyl, C 1-3 Alkoxy, C 1-3 Selected from alkoxymethylene, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, 5-6 membered heteroaryl, or 3-5 membered heterocyclyl, the deuterated C 1-3 Alkyl, C 1-3 Alkyl, C 2-4 Alkenil, C 2-4 Alkinyl, C 1-3 Alkoxy or C 1-3 Alkoxymethylenes are independently one or more R c1 The cyclopropyl, cyclobutyl, cyclopentyl, phenyl, 5-6 membered heteroaryl, or 3-5 membered heterocyclyl may be substituted with one or more R d1 It may be replaced with .

[0083] In some embodiments, each R a These are, independently, halogen, =O, and deuterium C.1-3 Alkyl, C 1-3 Alkyl or C 3-6 Selected from cycloalkyl, the deuterated C 1-3 Alkyl or C 1-3 Alkyl molecules can be one or more R groups independently. c1 It may be replaced by the above C 3-6 Cycloalkyls independently have one or more R d1 It may be replaced with .

[0084] In some embodiments, each R a Each of these 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, and the methyl, ethyl, propyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, methoxymethylene, or ethoxymethylene is independently one or more R c1 The cyclopropyl, cyclobutyl, cyclopentyl, or phenyl may be substituted with one or more R d1 It may be replaced with .

[0085] In some embodiments, each R a Each of these is independently selected from F, Cl, Br, I, =O, -CD3, -C2D5, -OH, -CN, methyl, ethyl, propyl, methoxymethylene, ethoxymethylene, cyclopropyl, cyclobutyl, or cyclopentyl, and the methyl, ethyl, propyl, methoxymethylene, or ethoxymethylene is independently one or more R c1 The cyclopropyl, cyclobutyl, or cyclopentyl may be substituted with one or more R d1 It may be replaced with .

[0086] In some embodiments, each R aEach is independently selected from F, Cl, Br, =O, -CD3, -C2D5, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, or cyclopentyl, and the methyl, ethyl, and propyl are independently one or more R c1 The cyclopropyl, cyclobutyl, or cyclopentyl may be substituted with one or more R d1 It may be replaced with .

[0087] In some embodiments, each R a Each of these is independently selected from F, methyl, =O, -CD3, or cyclopropyl.

[0088] In some embodiments, each R a Each of these is independently selected from methyl or =O.

[0089] In some embodiments, each R a Each of these is independently selected from F or methyl.

[0090] In some embodiments, R 1 teeth,

[0091] [ka]

[0092] [ka]

[0093] [ka]

[0094] Selected from, The aforementioned R 1 R may be independently substituted with one, two, or three substituents selected from F, methyl, =O, -CD3, or cyclopropyl. In some other embodiments, R1 teeth,

[0095] [ka]

[0096] Selected from, the R 1 These may be independently substituted with one, two, or three substituents selected from F, methyl, =O, -CD3, or cyclopropyl.

[0097] In some other embodiments, R 1 teeth,

[0098] [ka]

[0099] Selected from, the R 1 These may be independently substituted with one, two, or three substituents selected from F, methyl, =O, -CD3, or cyclopropyl.

[0100] In some other embodiments, R 1 teeth,

[0101] [ka]

[0102] Selected from, the R 1 These may be independently substituted with one, two, or three substituents selected from F, methyl, =O, -CD3, or cyclopropyl.

[0103] In some embodiments, R 1 teeth,

[0104] [ka]

[0105] [ka]

[0106] [ka]

[0107] Selected from. In some other embodiments, R 1 teeth,

[0108] [ka]

[0109] [ka]

[0110] Selected from. In some embodiments, R 1 teeth,

[0111] [ka]

[0112] Selected from. In some other embodiments, R 1 teeth,

[0113] [ka]

[0114] Selected from. In some other embodiments, R 1 teeth,

[0115] [ka]

[0116] Selected from. In some embodiments, each R b Each of these is independently selected from halogen, -CN, -OH, -NH2, methyl, ethyl, methoxy, or ethoxy, and the methyl, ethyl, methoxy, or ethoxy may be independently substituted with one or more substituents selected from deuterium, halogen, OH, CN, or NH2.

[0117] In some embodiments, each R b Each of them is independent of C 1-3 Selected from alkoxy, the C 1-3 The alkoxy may be independently substituted with one or more substituents selected from deuterium, halogens, OH, CN, or NH2.

[0118] In some embodiments, each R b Each of these is independently selected from F, Cl, Br, I, or methoxy.

[0119] In some embodiments, each R b Each is independently selected from methoxy.

[0120] In some embodiments, R 1 is selected from phenyl or pyridyl, and the R 1 It is substituted with one ethynyl or propynyl molecule, R 1 The substituents may further be independently substituted with one, two, or three substituents selected from F or methyl, and the ethynyl or propynyl substituents may be substituted with one, two, or three methoxy substituents.

[0121] In some embodiments, R 1 is selected from phenyl or pyridyl, and the R 1 It is substituted with one 1-propynyl molecule, R 1Furthermore, may be independently substituted with one, two, or three F molecules, and the 1-propynyl may be substituted with one methoxy molecule.

[0122] In some embodiments, R 1 teeth,

[0123] [ka]

[0124] [ka]

[0125] Selected from. In some embodiments, R 1 teeth,

[0126] [ka]

[0127] Selected from. In some embodiments, each R 2 These are, independently, halogen, -OH, -CN, and C. 1-5 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-5 Alkoxy, C 3-6 Selected from cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl, the C 1-5 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl or C 1-5 Alkoxy can be one or more R independently. c2 It may be replaced by the above C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl can independently be one or more R d2 It may be replaced with .

[0128] In some embodiments, each R 2 These are, independently, halogen, -OH, -CN, and C. 1-3 Alkyl, C 2-4 Alkenil, C 2-4 Alkinyl, C 1-3 Alkoxy, C 3-5 Selected from cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-5 membered heterocyclyl, the C 1-3 Alkyl, C 2-4 Alkenil, C 2-4 Alkinyl or C 1-3 Alkoxy can be one or more R independently. c2 It may be replaced by the above C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl can independently be one or more R d2 It may be replaced with .

[0129] In some embodiments, each R 2 These are, independently, halogen and C 1-3 Alkyl, or C 3-5 Selected from cycloalkyl, the C 1-3 Alkyl molecules can be one or more R groups independently. c2 It may be replaced by the above C 3-6 Cycloalkyls independently have one or more R d2 It may be replaced with .

[0130] In some embodiments, each R 2 Each is independently selected from F, Cl, Br, I, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, or cyclopentyl, and the methyl, ethyl, or propyl is independently one or more R c2 The cyclopropyl, cyclobutyl, or cyclopentyl may be substituted with one or more R d2 It may be replaced with .

[0131] In some embodiments, each R 2Each is independently selected from F, methyl, or cyclopropyl, and the methyl is independently one or more R c2 The cyclopropyl may be substituted with one or more R d2 It may be replaced with .

[0132] In some embodiments, each R 2 Each of these is independently selected from F, methyl, or cyclopropyl.

[0133] In some embodiments, R on two adjacent carbon atoms 2 C 5-6 Forming a cycloalkyl, phenyl, 5-6 membered heteroaryl or 5-6 membered heterocycline, the C 5-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl can independently have one or more R d3 It may be replaced with .

[0134] In some embodiments, R on two adjacent carbon atoms 2 C 5-6 Forming a cycloalkyl or 5-6 membered heterocycline, the C 5-6 Cycloalkyl or 5-6 membered heterocyclyls independently have one or more R d3 It may be replaced with .

[0135] In some embodiments, R on two adjacent carbon atoms 2 C 5-6 Form a cycloalkyl group, and the C 5-6 Cycloalkyls independently have one or more R d3 It may be replaced with .

[0136] In some embodiments, R on two adjacent carbon atoms 2Together with the carbon atom bonded to it, it forms cyclopentyl, pyrrolyl, tetrahydrofuranyl, or tetrahydrothienyl, and the cyclopentyl, pyrrolyl, tetrahydrofuranyl, or tetrahydrothienyl independently forms one or more R d3 It may also be substituted with R on two adjacent carbon atoms. In some embodiments, R on two adjacent carbon atoms 2 Together with the carbon atoms bonded to it, it forms a cyclopentyl, and the cyclopentyl independently has one or more R d3 It may be replaced with .

[0137] In some embodiments, R on two adjacent carbon atoms 2 It forms cyclopentyl with the carbon atom bonded to it.

[0138] In this application, R on two adjacent carbon atoms 2 The fact that it forms cyclopentyl with the carbon atoms bonded to it means that the constituent units formed are,

[0139] [ka]

[0140] It should be understood that R on two adjacent carbon atoms 2 Regarding the formation of pyrrolyl with the carbon atoms bonded to it, the constituent units that are formed are,

[0141] [ka]

[0142] It should be understood that this is the case. In some embodiments, R on two adjacent carbon atoms 2 Together with the carbon atoms bonded to it, it forms cyclopentyl, and the constituent units that are formed are

[0143] [ka]

[0144] That is the case. In some embodiments, q is selected from 0, 1, 2, or 3.

[0145] In some embodiments, q is selected from 1, 2, or 3.

[0146] In some embodiments, q is selected from 2.

[0147] In some embodiments, q is selected from 3.

[0148] In some embodiments, the constituent units

[0149] [ka]

[0150] teeth,

[0151] [ka]

[0152] Selected from. In some embodiments, the constituent units

[0153] [ka]

[0154] teeth,

[0155] [ka]

[0156] Selected from. In some embodiments, the constituent units

[0157] [ka]

[0158] teeth,

[0159] [ka]

[0160] Selected from. In some embodiments, the constituent units

[0161] [ka]

[0162] teeth,

[0163] [ka]

[0164] Selected from. In some embodiments, the constituent units

[0165] [ka]

[0166] teeth,

[0167] [ka]

[0168] Selected from. In some embodiments, the constituent units

[0169] [ka]

[0170] teeth,

[0171] [ka]

[0172] Selected from. In some embodiments, X 1 , X 2 One of them is selected from C, and the other is selected from N.

[0173] In some embodiments, the constituent units

[0174] [ka]

[0175] teeth,

[0176] [ka]

[0177] Selected from. In some embodiments, the constituent units

[0178] [ka]

[0179] teeth,

[0180] [ka]

[0181] Selected from. In some embodiments, Y 1 , Y 2 , Y 3Each is independently selected from C or N, and Y 4 It is selected from CH.

[0182] In some embodiments, Y 1 , Y 2 , Y 3 At least one of is selected from N and Y 4 It is selected from CH.

[0183] In some embodiments, Y 1 is selected from C, Y 2 is selected from N, Y 3 is selected from C, Y 4 It is selected from CH.

[0184] In some embodiments, Y 1 is selected from C, Y 2 is selected from C, Y 3 is selected from N, Y 4 It is selected from CH.

[0185] In some embodiments, Y 1 is selected from N, Y 2 is selected from C, Y 3 is selected from C, Y 4 It is selected from CH.

[0186] In some embodiments, the constituent units

[0187] [ka]

[0188] teeth,

[0189] [ka]

[0190] [ka]

[0191] Selected from. In some embodiments, the constituent units

[0192] [ka]

[0193] teeth,

[0194] [ka]

[0195] Selected from. In some embodiments, each R 3 Each of these is independently deuterium, halogen, and C 1-3 Alkyl, C 2-4 Alkenil, C 2-4 Alkinyl, C 3-6 Selected from cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl, the C 1-3 Alkyl, C 2-4 Alkenil, C 2-4 Alkinyl independently contains one or more R c3 It may be replaced by the above C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl can independently be one or more R d4 It may be replaced with .

[0196] In some embodiments, each R 3 Each of these is independently deuterium, halogen, or C 1-3 Selected from alkyl, the C 1-3 Alkyl molecules can be one or more R groups independently. c3 It may be replaced with .

[0197] In some embodiments, each R 3Each is independent of C 1-3 Selected from alkyl, the C 1-3 Alkyl molecules can be one or more R groups independently. c3 It may be replaced with .

[0198] In some embodiments, each R 3 Each is independently selected from deuterium, F, Cl, Br, I, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, or cyclopentyl, and the methyl, ethyl, or propyl is independently one or more R c3 The cyclopropyl, cyclobutyl, or cyclopentyl may be substituted with one or more R d4 It may be replaced with .

[0199] In some embodiments, each R 3 Each is independently selected from methyl, ethyl, or propyl, and the methyl, ethyl, or propyl is one or more R c3 It may be replaced with .

[0200] In some embodiments, the R 3 It is selected from methyl.

[0201] In some embodiments, n is selected from 0, 1, 2, or 3.

[0202] In some embodiments, n is selected from 1, 2, or 3.

[0203] In some embodiments, n is selected from 1.

[0204] In some embodiments, R 4 H, deuterium, halogen, -CN, C 1-3 alkyl, deuterated C 1-3 Alkyl or C 1-3 Selected from alkoxy, the C 1-3 alkyl, deuterated C 1-3 Alkyl or C 1-3Alkoxy can be one or more R independently. c4 It may be replaced with .

[0205] In some embodiments, R 4 is H or C 1-3 Selected from alkyl, the C 1-3 Alkyl molecules can be one or more R groups independently. c4 It may be replaced with .

[0206] In some embodiments, R 4 is selected from H or methyl, and the methyl is one or more R c4 It may be replaced with .

[0207] In some embodiments, R 4 This is selected from H or methyl.

[0208] In some embodiments, R 4 It is selected from H.

[0209] In some embodiments, R 4 It is selected from methyl.

[0210] In some embodiments, R 5 Halogen, -CN, C 1-3 alkyl, deuterated C 1-3 Alkyl or C 1-3 Selected from alkoxy, the C 1-3 alkyl, deuterated C 1-3 Alkyl or C 1-3 Alkoxy can be one or more R independently. c5 It may be replaced with .

[0211] In some embodiments, R 5 C 1-3 Selected from alkyl, the C 1-3 Alkyl molecules can be one or more R groups independently. c5 It may be replaced with .

[0212] In some embodiments, R 5 It is selected from methyl.

[0213] In some embodiments, m is selected from 0, 1, 2, or 3.

[0214] In some embodiments, m is selected from 0, 1, or 2.

[0215] In some embodiments, m is selected from 0.

[0216] In some embodiments, m is selected from 1.

[0217] In some embodiments, R' and R'' are independently H, deuterium, halogen, -CN, and C. 1-3 alkyl, deuterated C 1-3 Alkyl or C 1-3 Selected from alkoxy, the C 1-3 alkyl, deuterated C 1-3 Alkyl or C 1-3 Alkoxy can be one or more R independently. c6 It may be replaced with .

[0218] In some embodiments, R' and R'' are independently H or C 1-3 Selected from alkyl, the C 1-3 Alkyl molecules can be one or more R groups independently. c6 It may be replaced with .

[0219] In some embodiments, R' and R'' are each independently selected from H or methyl, and the methyl is one or more R c6 It may be replaced with .

[0220] In some embodiments, both R' and R'' are selected from methyl.

[0221] In some embodiments, R' and R'', along with the carbon atom to which they are bonded, are C 3-4 Forming a cycloalkyl or a 3-4 member heterocycloalkyl, the C 3-4 Cycloalkyl or 3-4 membered heterocycloalkyl groups independently have one or more R d5 It may be replaced with .

[0222] In some embodiments, R' and R'', together with the carbon atoms to which they are bonded, form a cyclopropyl, and the cyclopropyl is independently one or more R d5 It may be replaced with .

[0223] In some embodiments, R' and R'', together with the carbon atoms to which they are bonded, form a cyclopropyl group.

[0224] In some embodiments, each R c1 , R c2 , R c3 , R c4 , R c5 and R c6 Each of these is independently selected from halogen, -CN, -OH, or -NH2.

[0225] In some embodiments, each R c1 , R c2 , R c3 , R c4 , R c5 and R c6 Each of these is independently selected from F, -CN, -OH, or -NH2.

[0226] In some embodiments, each R c1 , R c2 , R c3 , R c4 , R c5 and R c6 Each of these is independently selected from F or OH.

[0227] In some embodiments, each R c1 , R c2, R c3 , R c4 , R c5 and R c6 Each of these is selected independently from F.

[0228] In some embodiments, each R d1 , R d2 , R d3 , R d4 and R d5 These are, independently, halogen, -CN, -OH, -NH2, and C. 1-3 Alkyl or C 1-3 Selected from alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy may be independently substituted with one or more substituents selected from halogens, OH, CN, or NH2.

[0229] In some embodiments, each R d1 , R d2 , R d3 , R d4 and R d5 Each of these is independently selected from F, -CN, -OH, -NH2, methyl, or methoxy, and the methyl or methoxy may be independently substituted with one or more substituents selected from F, OH, CN, or NH2.

[0230] In some embodiments, each R d1 , R d2 , R d3 , R d4 and R d5 Each of these is independently selected from F, -CN, -OH, -NH2, methyl, or methoxy.

[0231] In some embodiments, each R d1 , R d2 , R d3 , R d4 and R d5 Each of these is independently selected from F or methyl.

[0232] In some embodiments, each R d1, R d2 , R d3 , R d4 and R d5 Each of these is selected independently from F.

[0233] The compound represented by formula (I) of this application, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from the compounds represented by formulas (IA), (IB), (IC), or (ID), their stereoisomers, or pharmaceutically acceptable salts thereof.

[0234] [ka]

[0235] In the formula, R 1 , R 2 , R 3 , R 4 , R 5 The definitions of R', R'', q, n, or m are as described in the compound represented by formula (I).

[0236] The compound represented by formula (I) of this application, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from the compounds represented by formulas (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.

[0237] [ka]

[0238] [ka]

[0239] During the ceremony,

[0240] [ka]

[0241] , 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 represented by formula (I), r is selected from 0, 1, 2, 3, or 4. X is selected from C or N. X 3 , X 4 , X 5 or X 6 Each is independently selected from C or N, X 7 , X 8 , X 9 , X 10 or X 11 Each of these is independently selected from C, CH, or N.

[0242] In some embodiments, X is selected from C. In some embodiments, X is selected from N.

[0243] In some embodiments, X 3 It is selected from N, X 4 , X 5 or X 6 Each of these is independently selected from C or N.

[0244] In some embodiments, X 3 , X 6 It is selected from N, X 4 , X 5 It is selected from C.

[0245] In some embodiments, X 3 , X 4 It is selected from N, X 5 , X 6 It is selected from C.

[0246] In some embodiments, X 7and X 11 One of them is selected from N, and the other is selected from C.

[0247] In some embodiments, X 7 and X 9 It is selected from N, X 11 It is selected from C, X 8 and X 10 It is selected from CH.

[0248] In some embodiments, r is selected from 0, 1, or 2.

[0249] In some embodiments, r is selected from 0 or 2.

[0250] The present invention further provides a compound represented by formula (I'), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0251] [ka]

[0252] In the formula, X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 ,

[0253] [ka]

[0254] , R 1 , R 2 , R 3 , R 4 , R 5 The definitions of R', R'', q, n, or m are as described in the compound represented by formula (I).

[0255] The compound represented by formula (I) of this application, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from the compounds represented by formulas (I-A'), (I-B'), (I-C'), or (I-D'), their stereoisomers, or pharmaceutically acceptable salts thereof.

[0256] [ka]

[0257] In the formula, R 1 , R 2 , R 3 , R 4 , R 5 The definitions of R', R'', q, n, or m are as described in the compound represented by formula (I).

[0258] The compound represented by formula (I) of this application, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from the compounds represented by formulas (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'), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0259] [ka]

[0260] [ka]

[0261] During the ceremony,

[0262] [ka]

[0263] , R 1 , R 2 , R 3 , R 4 , R5 ,R',R'',R a The definitions of , q, n, or m are as described in the compound represented by formula (I), r is selected from 0, 1, 2, 3, or 4. X is selected from C or N. X 3 , X 4 , X 5 or X 6 Each is independently selected from C or N, X 7 , X 8 , X 9 , X 10 or X 11 Each of these is independently selected from C, CH, or N.

[0264] In some embodiments, 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 the compounds represented by formulas (II-D), (II-F), and (II-J).

[0265] The compound represented by formula (I) of this application, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (III-A), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0266] [ka]

[0267] In the formula, X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 ,

[0268] [ka]

[0269] , R 1 , R 2 , R 3 , R 4 , R 5 The definitions of R', R'', and q are as described in the compound represented by formula (I).

[0270] The compound represented by formula (I) of this application, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from the compounds represented by formula (III-A'), formula (III-B'), or formula (III-C'), their stereoisomers, or pharmaceutically acceptable salts thereof.

[0271] [ka]

[0272] [ka]

[0273] In the formula, X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 ,

[0274] [ka]

[0275] , R 1 , R 2 , R 3 , R 4 , R 5 The definitions of R', R'', and q are as described in the compound represented by formula (I).

[0276] The compound represented by formula (I) of this application, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from the compound of formula (IV-A), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0277] [ka]

[0278] In the formula, X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 ,

[0279] [ka]

[0280] , R 1 , R 2 , R 3 , R 4 The definitions of R', R'', and q are as described in the compound represented by formula (I).

[0281] The compound represented by formula (I) of this application, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (IV-A'), formula (IV-B'), or formula (IV-C'), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0282] [ka]

[0283] In the formula, X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 ,

[0284] [ka]

[0285] , R 1 , R 2 , R 3 , R4 The definitions of R', R'', and q are as described in the compound represented by formula (I).

[0286] In some embodiments, this disclosure includes the variables defined above and their embodiments, as well as any combination thereof.

[0287] In another aspect, this disclosure provides the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0288] [ka]

[0289] [ka]

[0290] [ka]

[0291] [ka]

[0292] [ka]

[0293] [ka]

[0294] In another aspect, the Disclosure further provides pharmaceutical compositions comprising the above-mentioned compounds of the Disclosure, their stereoisomers, or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions of the Disclosure further comprise pharmaceutically acceptable additives.

[0295] In another aspect, the Disclosure further provides a method for treating various GLP-1-related diseases, comprising administering a therapeutically effective amount of the above-mentioned compounds of the Disclosure, their stereoisomers, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof to a mammal, preferably a human, that is in need of such treatment.

[0296] In another aspect, the Disclosure further provides the use of the above-mentioned compounds, their stereoisomers, their pharmaceutically acceptable salts, or their pharmaceutical compositions in the manufacture of pharmaceuticals for the treatment of various GLP-1-related diseases.

[0297] In another aspect, the Disclosure further provides the use of the above-mentioned compounds of the Disclosure, their stereoisomers, their pharmaceutically acceptable salts, or their pharmaceutical compositions for the treatment of various diseases associated with GLP-1.

[0298] In another aspect, the Disclosure further provides the above-mentioned compounds of the Disclosure, their stereoisomers, their pharmaceutically acceptable salts, or their pharmaceutical compositions for treating a variety of GLP-1-related diseases.

[0299] In some embodiments, the various diseases associated with GLP-1 are selected from diabetes or obesity.

[0300] The compounds disclosed herein possess good in vivo and in vitro agonist activity related to GLP-1 (e.g., GLP-1 in vitro enzyme agonist activity) and metabolic stability (e.g., metabolic stability in liver microsomes). [Modes for carrying out the invention]

[0301] [Definition] Unless otherwise specified, the following terms used in this disclosure have the following meanings. Certain terms, unless otherwise defined, should not be interpreted as meaningless or unclear, but rather as having the common sense of the industry. Trademark names used herein refer to the corresponding products or their active ingredients.

[0302] If a covalent bond within a structural unit or group in this disclosure is not bonded to a specific atom, it means that such covalent bond could be bonded to any atom within that structural unit or group, provided that it does not violate the valence bond law.

[0303] The term "substituted" refers to the substitution of one or more hydrogen atoms on a particular atom by a substituent, provided that the valence state of that atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted. Oxo substitution does not occur in aromatic groups.

[0304] The terms "may" or "optionally" mean that the events or conditions described below may or may not occur, and that such descriptions include both the occurrence and non-occurrence of such events or conditions. For example, "may" ethyl be substituted with a halogen means that ethyl can be unsubstituted (CH2CH3), monosubstituted (e.g., CH2CH2F), polysubstituted (e.g., CHFCH2F, CH2CHF2, etc.), or completely substituted (CF2CF3). Those skilled in the art will understand that for any group containing one or more substituents, no substitutions or substitutional modes that cannot exist spatially and / or be synthesized will be introduced.

[0305] C in this specification m-n This means that the part in question has an integer number of carbon atoms within a predetermined range. For example, "C 1-6 " means that the group may have one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, or six carbon atoms. For example, C 1-3 This means that the group may have one carbon atom, two carbon atoms, or three carbon atoms.

[0306] If any variable (e.g., R) appears one or more times in the composition or structure of a compound, the definition for each case is independent. Therefore, for example, if one group is substituted with two Rs, each R has an independent choice.

[0307] When the number of linking groups is 0, for example, -(CH2)0-, it means that the linking group is a covalent bond.

[0308] When one variable is selected from a covalent bond, it means that the two groups connected to it are directly linked. For example, if L' in A-L'-Z represents a covalent bond, it means that this structure is actually A-Z.

[0309] When the bonds of a substituent intersect and connect to two atoms in a ring, such a substituent can bond to any atom in that ring. For example, the above ring A represents that the bonds on both sides can bond to any two different atoms in ring A.

[0310] The term "halo" or "halogen" refers to fluorine, chlorophyll, bromo, and iodine.

[0311] The term "alkyl" is a general term with the formula C n H 2n+1 This refers to a hydrocarbon group, which 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. This alkyl group may be linear or branched, for example, "C 1-12 "Alkyl" or "C 1-6 It could be "alkyl," etc. For example, the term "C 1-12 "Alkyl" refers to alkyl groups containing 1 to 12 carbon atoms, such as C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 and C 12 This includes alkyl groups, as well as any combination of these. For example, the term "C 1-6"Alkyl" refers to alkyl groups 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 as above. Also, for example, the term "C 1-3 "Alkyl" refers to alkyl groups containing 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl, and isopropyl).

[0312] 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 exist in the alkyl group itself, and the substitution positions are arbitrary. For example, the term "deuterated C" 1-3 "Alkyl" refers to alkyl groups containing 1 to 3 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl) that are substituted with 1 to 7 deuterium atoms, where the methyl group can be substituted with 1, 2, or 3 deuterium atoms. Ethyl groups can be substituted with 1, 2, 3, 4, or 5 deuterium atoms. n-propyl and isopropyl groups can be substituted with 1, 2, 3, 4, 5, 6, or 7 deuterium atoms.

[0313] The term "alkenyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one double bond, and typically containing 2-12, 2-8, 2-6, 2-4, or 2-3 carbon atoms. For example, "C 2-12 "Alkenil" or "C 2-6 This could be an "alkenyl," etc. Non-limiting examples of alkenyls include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc.

[0314] The term "alkynyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond, and typically containing 2-12, 2-8, 2-6, 2-4, or 2-3 carbon atoms. For example, "C 2-12 "Alkinyl" or "C 2-6 This could be an "alkynyl," etc. Non-restrictive examples of alkynyls include, but are not limited to, ethynnyl (-C≡CH), propynyl (e.g., 1-propynyl (-C≡C-CH3), 2-propynyl (-CH2-C≡CH)), butynyl (e.g., 1,3-butadiinyl (-C≡CC≡CH)), etc.

[0315] The term "alkoxy" refers to -O-alkyl groups.

[0316] The term "alkylthio group" refers to -S-alkyl groups.

[0317] The term "cycloalkyl" refers to a fully or partially saturated cyclic hydrocarbon that may exist as a monocyclic, bridging, fused, or spirocyclic ring. Unless otherwise specified, this carbocyclic 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 cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, and dicyclo[1.1.1]penta-1-yl. For example, C 3-4 Cycloalkyls include cyclopropyl and cyclobutyl.

[0318] The term "heterocyclyl" refers to a fully saturated or partially saturated aromatic or partially aromatic ring that may exist as a monocyclic, bridging, fused, or spiro-ring. Unless otherwise specified, this heterocycline is typically a 3- to 13-membered ring (e.g., a 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 (preferably 1 or 2) heteroatoms independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and / or boron. Non-exclusive examples of heterocyclyls include spiro[cyclopropane-1,3'-dihydroindole]-yl, 1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyradinyl, 2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazolyl, 1',3'-dihydrospiro[cyclopropane-1,2'-inden]-yl, phenyl, pyridyl, and 1,3-dihydrospiro[inden-2,3'-oxetane]-yl This includes, but is not limited to, spiro[cyclobutan-1,3'-dihydroindole]-yl, spiro[cyclopropane-1,1'-isoindoline]-yl, spiro[cyclopenta[c]pyridine-5,1'-cyclopropane]-yl, spiro[cyclopropane-1,3'-indole]-yl, 5H-imidazo[5,1-a]isoindolyl, or 2,3-dihydro-1H-cyclopenta[3,4]pyrzolo[1,5-a]pyridyl, etc.

[0319] The term "aryl" refers to an aromatic carbocyclic group, which may include an aromatic moiety as well as a non-aromatic moiety. The ring may be monocyclic, or it may be bicyclic or tricyclic, formed from a benzene ring and an aromatic or non-aromatic moiety. For example, an aryl may have 6 to 20 carbon atoms, 6 to 15 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 11 carbon atoms. Non-limiting examples of aryls include, but are not limited to, phenyl, naphthyl, anthracenyl, 1,2,3,4-tetrahydronaphthalene, isochromanyl, 2,4-dihydro-1H-isoquinoline-3-one group, or spirocyclic [cyclopropane-1,2'-indene]-1'(3'H)-one group.

[0320] The term "heteroaryl" refers to a monocyclic or polycyclic system having 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, a non-aromatic moiety may also be included. The ring may be monocyclic, or it may be a bicyclic or tricyclic ring formed from a benzene ring or monocyclic heteroaryl ring and an aromatic or non-aromatic moiety. Preferred heteroaryls have a monocyclic ring with 5 to 8 members (e.g., 5-membered, 6-membered, 7-membered, or 8-membered) or a plurality of fused rings containing 6 to 15, particularly 6 to 12, ring atoms (e.g., 6, 7, 8, 9, 10, 11, or 12 ring atoms). Non-exclusive examples of heteroaryls include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazole, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, pyridopyrrolyl, or a spiro-ring [cyclopropane-1,3'-indoline]-2'-one group.

[0321] The term "alkylene" refers to a divalent group formed by removing one hydrogen atom from any position in an alkyl group. For example, the term "C 1-3 "Alkylene" refers to alkylenes containing 1 to 3 carbon atoms, including, but not limited to, methylene (-CH2-), ethylene (-CH2CH2-), and propylene (-CH2CH2CH2- or -CH2CH(CH3)-).

[0322] The compounds of this disclosure may exist as specific geometric isomers or stereoisomers. All compounds and mixtures thereof envisioned in this application, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers and their racemic mixtures, and other mixtures such as enantiomer or diastereomer-rich mixtures, are within the scope of this disclosure. Other chiral carbon atoms may be present in substituents such as alkyl groups. All these isomers and mixtures thereof are included within the scope of this disclosure.

[0323] Unless otherwise specified, wedge-shaped solid line connections

[0324] [ka]

[0325] and wedge-shaped dashed line connections

[0326] [ka]

[0327] This shows the absolute arrangement of the center of a solid, and the solid lines represent the connections.

[0328] [ka]

[0329] and dashed line connections

[0330] [ka]

[0331] The wavy line indicates the relative arrangement of the center of the solid.

[0332] [ka]

[0333] wedge-shaped solid line connection

[0334] [ka]

[0335] Or a wedge-shaped dashed line connection.

[0336] [ka]

[0337] Indicates, or a wavy line

[0338] [ka]

[0339] Linear solid line combination

[0340] [ka]

[0341] and dashed line connections

[0342] [ka]

[0343] This indicates. Unless otherwise specified, if 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 on the double bond is bonded to two different substituents (in a double bond containing a nitrogen atom, the lone pair of electrons of the nitrogen atom is considered as one of the bonded substituents), then if the atoms on the double bond and their substituents in the compound are connected by a wavy line, it indicates that the compound is a (Z) isomer, an (E) isomer, or a mixture of two isomers.

[0344] The term “treatment” means administering the compounds or formulations relating to this disclosure in order to improve or resolve a disease or one or more symptoms associated with the disease, and includes the following: (i) To suppress a disease or condition, that is, to prevent its progression. (ii) To alleviate a disease or condition, that is, to reduce or eliminate the disease or condition.

[0345] The term “therapeutic or preventive dose” means the amount of a compound of the Disclosure that (i) treats or prevents a particular disease, condition or disorder; (ii) reduces, improves or eliminates one or more symptoms of a particular disease, condition or disorder; or (iii) prevents or delays a particular disease, condition or disorder as described herein. The amount of a compound of the Disclosure that constitutes a “therapeutic dose” will vary depending on the compound, the disease and its severity, the method of administration, and the age of the mammal being treated, but can generally be determined by a person skilled in the art based on their own knowledge and the content of the Disclosure.

[0346] The term "pharmaceutically acceptable" means that, within the bounds of sound medical judgment, a compound, material, composition, and / or dosage form is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problems or complications, and that the benefits / risks are in line with a reasonable ratio.

[0347] Examples of pharmaceutically acceptable salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids.

[0348] The term "pharmaceutical composition" refers to a mixture comprising one or more compounds or salts thereof of the present disclosure and pharmaceutically acceptable additives. The pharmaceutical composition is intended to contribute to the administration of the compounds of the present disclosure to a living organism.

[0349] The term "pharmaceutically acceptable additive" refers to an additive that does not cause significant irritation to the body and does not impair the biological activity and properties of the active compound. Suitable additives are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, and water.

[0350] The terms "comprise" or "comprise," and their English variations such as "comprises" or "comprising," should be understood in an open and non-exclusive sense, meaning "to include, but not to limit."

[0351] The compounds and intermediates of this disclosure may also exist in different tautomerized forms, all of which are included within the scope of this disclosure. The term “tautomer” or “tautomerized form” refers to structural isomers of different energies that can be interconverted across a low energy barrier. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is an imidazole moiety in which a proton can move between two ring nitrogen atoms. Valence tautomers include interconversions via the recombination of some of the bonding electrons.

[0352] This disclosure also includes isotope-labeled compounds of this disclosure that are identical to those described herein, except that one or more atoms are substituted with atoms having atomic weights or mass numbers different from those commonly found in nature. Examples of isotopes that may be incorporated into the compounds of this disclosure are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, for example, respectively 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 Examples include Cl, etc.

[0353] Compounds of the present disclosure labeled with a predetermined isotope (e.g.) 3 H and 14 Those labeled with 1C can be used for tissue distribution analysis of compounds and / or substrates. Tritiation (i.e., 3 H) and carbon-14 (i.e., 14 C) Isotopes are particularly preferred because they are easy to produce and detect. 15 O, 13 N, 11 C and 18 Positron-emitting isotopes such as F can be used in positron emission tomography (PET) studies to measure substrate occupancy. The isotope-labeled compounds of this disclosure can typically be prepared by replacing the non-isotope labeling reagent with the isotope labeling reagent by the following procedure, similar to that in the schemes and / or examples disclosed below.

[0354] Also, heavier isotopes (deuterium ( 2 Substitutions such as H) can offer certain therapeutic advantages due to higher metabolic stability (e.g., extended half-life or reduced dose in vivo) and may be preferable in specific circumstances. Deuterium substitution can be partial or complete, with partial deuterium substitution meaning that at least one hydrogen atom is replaced by at least one deuterium atom. All such compounds are included within the scope of this disclosure.

[0355] The compounds of this disclosure may be asymmetric, such as having one or more stereoisomers. Unless otherwise noted, all stereoisomers include, for example, enantiomers and diastereomers. Compounds containing an asymmetric carbon atom of this disclosure can be isolated in optically active pure form or in racemic form. The optically active pure form can be separated from a racemic mixture or synthesized using chiral starting materials or chiral reagents.

[0356] The pharmaceutical compositions of this disclosure can be prepared by combining the compounds of this disclosure with appropriate pharmaceutically acceptable additives. For example, the pharmaceutical compositions of this disclosure can be prepared in solid, semi-solid, liquid, or gaseous forms, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, and aerosols.

[0357] Typical routes of administration of the compounds of this disclosure or pharmaceutically acceptable salts thereof or pharmaceutically acceptable compositions thereof include, but are not limited to, oral administration, rectal administration, topical administration, inhalation administration, parenteral administration, sublingual administration, vaginal administration, intranasal administration, intraocular administration, intraperitoneal administration, intramuscular administration, subcutaneous administration, and intravenous administration.

[0358] The pharmaceutical compositions disclosed herein can be manufactured using methods well known in the industry, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated tablet manufacturing methods, grinding methods, emulsification methods, and freeze-drying methods.

[0359] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be prepared by mixing the active compound with pharmaceutically acceptable additives known in the art. These additives allow the compounds of this disclosure to be formulated for oral administration to patients in the form of tablets, pills, lozenges, sugar-coated tablets, capsules, liquids, gels, syrups, suspensions, etc.

[0360] Solid oral compositions can be manufactured by conventional mixing, filling, or tableting methods. For example, they can be obtained by grinding a mixture of the active compound and a solid additive component as desired, adding other suitable additive components as needed, and then processing the mixture into granules to obtain a tablet or sugar-coated tablet core. Suitable additive components include, but are not limited to, binders, diluents, disintegrants, lubricants, flow enhancers, sweeteners, or flavoring agents.

[0361] The pharmaceutical composition can be applied to parenteral administration in the form of a suitable unit dosage form, such as a sterile liquid, suspension, or lyophilized product.

[0362] The therapeutic dose of the compounds disclosed herein may be determined, for example, based on the specific therapeutic use, the method of administering the compound, the patient's health condition, and the judgment of the prescribing physician. The proportion or concentration of the compounds disclosed herein in a pharmaceutical composition is not fixed and depends on various factors, including the dose, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compounds of this application may be provided for parenteral administration in a physiologically buffered aqueous solution containing the compound at a concentration of about 0.1 to 10% w / v. A typical dose range is about 1 μg / kg to about 1 g / kg body weight per day. In some embodiments, the dose range is about 0.01 mg / kg to about 100 mg / kg body weight per day. The dose is thought to depend on variations in the type and progression of the disease or condition, the general health condition of the particular patient, the relative biological potency of the selected compound, the formulation of the excipients, and the route of administration. The effective dose can be obtained by extrapolating dose-response curves obtained from in vitro or animal model test systems.

[0363] The compounds of this disclosure can be produced by various synthesis methods well known to those skilled in the art, including specific embodiments illustrated below, embodiments formed in combination with other chemical synthesis methods, and equivalent alternative embodiments well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of this disclosure.

[0364] The chemical reactions in the specific embodiments of this disclosure are completed in a suitable solvent, which must be suitable for the chemical changes of this disclosure and the necessary reagents and materials. To obtain the compounds of this disclosure, those skilled in the art may, as applicable, modify or select synthesis steps or reaction schemes based on existing embodiments.

[0365] One important consideration in designing synthetic routes in this industry is the selection of suitable protecting groups for reactive functional groups (e.g., amino groups in this disclosure). For example, Greene's Protective Groups in OrganiCSynthesis (4th HEd). Hoboken, New Jersey: John Wile & Sons, Inc. can be referenced.

[0366] In some embodiments, the compounds of the present disclosure can be prepared by those skilled in the art of organic synthesis with reference to the following scheme.

[0367] [ka]

[0368] The following abbreviations are used in this disclosure.

[0369] 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, where Z is a leaving group and includes, but is not limited to, F, Cl, Br, I, etc.

[0370] The following abbreviations are used in this disclosure.

[0371] NaHMDS represents sodium bis(trimethylsilyl)amide, DCM represents dichloromethane, and MeOH represents methanol.

[0372] For clarity, the present disclosure will be further illustrated by examples, but these examples will not limit the scope of the present disclosure. All reagents used in the present disclosure are commercially available and can be used without further purification. [Examples]

[0373] Example 1

[0374] [ka]

[0375] Step 1: Synthesis of Intermediate 1-2 5'-Bromo-1',2'-dihydrospiro[cyclopropan-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. The mixture was then stirred for 30 minutes to allow it to react. 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), and after combining with the organic phase, the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, and concentrated under reduced pressure to obtain intermediate 1-2, 450 mg. MS(ESI,[M+H] + )m / z:252.05. 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).

[0376] Step 2: Synthesis of Intermediates 1-3 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 the protection of nitrogen gas. 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 sequentially washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated and purified by column chromatography (petroleum ether:ethyl acetate = 3:2) to obtain intermediate 1-3 0.3 g. MS(ESI,[M+H] + )m / z:613.37. 1 H-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).

[0377] Step 3: Synthesis of Intermediates 1-4 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 to allow the reaction to proceed. After stopping the stirring, the mixture was concentrated under reduced pressure to obtain intermediate 1-4 (0.24 g). MS(ESI,[M+H] + )m / z:513.1.

[0378] Step 4: Synthesis of Compound 1 and Compound 1-A Intermediate B-1 (0.1 g), N,N-dimethylformamide (5 mL), triethylamine (0.576 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium 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 to allow the reaction to proceed. The reaction mixture was poured into water (50 mL), the resulting solution was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated and purified by column chromatography (DCM:MeOH=95:5) to obtain compound 1. Compound 1 was 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). 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°C) HRMS:(ESI,[M+H] + )m / z:906.4130. 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).

[0379] Example 2

[0380] [ka]

[0381] Step 1: Synthesis of Intermediate 2-1 5'-Bromo-1',2'-dihydrospiro[cyclopropan-1,3'-dihydroindole]-2'-one (500 mg) and N,N-dimethylformamide (8 mL) were mixed, sodium hydrogen (126 mg, 60% dispersed in mineral oil) was added under ice bath, and the mixture was stirred for 10 minutes. Then, deuterated iodomethane (457 mg) was added, and the mixture was allowed to react for 2 hours at room temperature. After the reaction was complete, the reaction mixture was poured into saturated ammonium chloride solution (20 mL), ethyl acetate (20 mL) was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 2-1, 400 mg. MS(ESI,[M+H] + )m / z:255.08. 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).

[0382] Step 2: Synthesis of Intermediate 2-2 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 under a nitrogen atmosphere at 120°C for 12 hours. After the reaction was complete, the reaction mixture was poured into water, ethyl acetate (50 mL) was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, the filtrate was concentrated under reduced pressure, and the residue was separated and purified using a silica gel column (petroleum ether:ethyl acetate = 70:30) to obtain intermediate 2-2 260 mg. MS(ESI,[M+H] +)m / z:616.39. 1 HNMR(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).

[0383] Step 3: Synthesis of Intermediate 2-3 Intermediate 2-2 (260 mg) and 4N dioxane hydrochloride solution (5 mL) were mixed and reacted at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain intermediate 2-3 (230 mg).

[0384] Step 4: Synthesis of intermediates 2-4 and compound 2 Intermediate B-1 (0.1 g), N,N-dimethylformamide (5 mL), triethylamine (0.678 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.277 g) were mixed and stirred at room temperature for 5 minutes to react. Intermediate 2-3 (0.148 g) was added and stirred at room temperature for 5 hours to react. After the reaction was complete, the reaction mixture was poured into water, ethyl acetate (50 mL) was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, the filtrate was concentrated under reduced pressure, and the residue was separated and purified using a silica gel column (dichloromethane:methanol = 20:1) to obtain intermediate 2-4 70 mg. Intermediates 2-4 were separated by chiral HPLC (column: CHIRAL ART Cellulose-SB, 30 × 250 mm, 5 μm; mobile phase: ethanol-dichloromethane (1:1):n-hexane = 30:70; flow rate: 38 mL / min) to obtain compound 2 (35 mg). Compound 2: Rt=2.80min (UPCC conditions: KARALA: CHIRALPAK IB-3 (4.6×100mm, 3μm); mobile phase: carbon dioxide: メタノール (containing 0.1% アンモニアwater) = 50:50; flow rate: 2.0mL / min; カラム temperature: 40℃) HRMS:(ESI,[M+H] + )m / z:909.4328. 1 HNMR(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. 20(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,2 H),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).

[0385] Example 3

[0386]

change

[0387] ステップ1:Synthesis of intermediate 3-1 5'-Bromo-1',2'-dihydrospiro[cyclopropan-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 tetrahydrofuran solution of 2 M sodium bis(trimethylsilyl)amide (1.1 mL) were added sequentially. The mixture was heated to 95°C and stirred for 16 hours to allow the reaction to proceed. The reaction solution was diluted with ethyl acetate, filtered by suction, concentrated, and separated and purified by column chromatography (petroleum ether:ethyl acetate = 3:2) to obtain intermediate 3-1 0.5 g. MS(ESI,[M+H] + )m / z:278.09. 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).

[0388] Step 2: Synthesis of Intermediate 3-2 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 gas 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 sequentially washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated and purified by column chromatography (petroleum ether:ethyl acetate = 3:2) to obtain intermediate 3-2 0.3 g. MS(ESI,[M+H] + )m / z:639.33. 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).

[0389] Step 3: Synthesis of Intermediate 3-3 Intermediate 3-2 (0.3 g) and 4N dioxane hydrochloride solution (3 mL) were mixed and stirred at room temperature for 1 hour to allow the reaction to proceed. After stopping the stirring, the mixture was concentrated under reduced pressure to obtain intermediate 3-3 (0.26 g). MS(ESI,[M+H] + )m / z:539.32.

[0390] Step 4: Synthesis of intermediates 3-4 and compound 3 Intermediate B-1 (0.12 g), N,N-dimethylformamide (4 mL), triethylamine (0.068 g), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium 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 to allow it to react. The reaction mixture was poured into water (50 mL), the resulting solution was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated and purified by column chromatography (DCM:MeOH=95:5) to obtain intermediate 3-4. The above intermediates 3-4 were separated by chiral HPLC (column: Pre-packed DREGIS IB, 30 × 250 mm, 10 μm; mobile phase: ethanol-dichloromethane (1:3):n-hexane = 30:70; flow rate: 40 mL / min) to obtain compound 3 85 mg. Compound 3: Rt=2.02min (UPCC conditions: KARALA: CHIRALPAK IB-3 (4.6×100mm, 3μm); mobile phase: carbon dioxide: メタノール (containing 0.1% アンモニアwater) = 30:70; flow rate: 2.0mL / min; カラム temperature: 40℃) HRMS:(ESI,[M+H] + )m / z:932.4280. 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).

[0391] Example 4 Synthesis of compound 4:

[0392]

change

[0393] Intermediate 1-4 (133 mg), N,N-dimethylformamide (5 mL), triethylamine (492 mg), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium 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), 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 separated and purified by silica gel column (DCM:MeOH=95:5) to obtain intermediate 4-1. The above intermediate 4-1 was 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. 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% aqueous ammonia) = 60:40; Flow rate: 2.0 mL / min; Column temperature: 40°C) HRMS:(ESI,[M+H] + )m / z:892.3949. 1 HNMR(500MHz,DMSO-d6)δ12.08(s,1H),7.57-7.38(m,3H),7.34-7.05(m,6H),7.0 0-6.90(m,1H),6.85-6.71(m,1H),5.50(s,1H),4.47-4.30(m,1H),3.72(d,J=8.9H z,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).

[0394] Example 5

[0395] [ka]

[0396] Step 1: Synthesis of Intermediate 5-2 6'-bromospiro[cyclopropane-1,3'-dihydroindole]-2'-one (0.5 g) was dissolved in N,N-dimethylformamide (10 mL), and cesium carbonate (1.38 g) and iodomethane (0.17 mL) were added sequentially. The mixture was heated to 80°C and stirred for 1 hour to allow it to react. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The mixture was filtered by suction, concentrated, and separated and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 5-2, 0.51 g. MS(ESI,[M+H+2] + )m / z:254.02. 1 H-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).

[0397] Step 2: Synthesis of Intermediate 5-3 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 gas protection, the mixture was heated to 130°C and stirred for 6 hours to react. Water and ethyl acetate were added to dilute the mixture, and it was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated NaCl aqueous solution, and dried over anhydrous sodium sulfate. The mixture was filtered by suction, concentrated, and separated and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 5-3 0.18 g. MS(ESI,[M+H] + )m / z:613.38. 1H-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).

[0398] Step 3: Synthesis of Intermediate 5-4 Intermediate 5-3 (0.17 g) and 6N dioxane hydrochloride solution (1 mL) were mixed and reacted by stirring at room temperature for 1 hour. After concentrating and removing the solvent by distillation, saturated sodium bicarbonate aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The mixture was filtered by suction and concentrated to obtain intermediate 5-4 (0.11 g). MS(ESI,[M+H] + )m / z:513.36.

[0399] Step 4: Synthesis of Intermediate 5-5 Intermediate B-1 (0.08 g) and N,N-dimethylformamide (2 mL) were mixed, and triethylamine (44 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (110 mg) were added sequentially. After stirring for 10 minutes, intermediate 5-4 (0.082 g) was added and the mixture was stirred at 40°C for 2 hours. The mixture was diluted with water and ethyl acetate, extracted with ethyl acetate, and the organic layer was sequentially washed with water and saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The filtrate was concentrated and separated and purified by column chromatography (dichloromethane:methanol = 98:2) to obtain intermediate 5-5 60 mg. The above intermediate 5-5 was separated by chiral HPLC (column: CHIRALART Cellulose-SB, 30 × 250 mm, 10 μm; mobile phase: n-hexane:dichloromethane:ethanol = 72:21:7; flow rate: 40 mL / min) to obtain 17 mg of compound 5. 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% aqueous ammonia) = 30:70; Flow rate: 2.0 mL / min; Column temperature: 40°C) HRMS:(ESI,[M+H] + )m / z:906.4103. 1 H-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).

[0400] Example 6

[0401] [ka]

[0402] Step 1: Synthesis of Intermediate 6-1 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 under a nitrogen atmosphere at 120°C for 12 hours. After the reaction was complete, the reaction mixture was poured into water, ethyl acetate (50 mL) was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, the filtrate was concentrated under reduced pressure, and the residue was separated and purified using a silica gel column (dichloromethane:methanol = 20:1) to obtain intermediate 6-1 0.75 g. MS(ESI,[M+H] + )m / z:625.42

[0403] Step 2: Synthesis of Intermediate 6-2 Intermediate 6-1 (0.75 g) and 4N dioxane hydrochloride solution (10 mL) were mixed and reacted at room temperature with stirring for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain intermediate 6-2 (0.65 g).

[0404] Step 3: Synthesis of intermediate 6-3 and compound 6 Intermediate B-1 (0.1 g), N,N-dimethylformamide (5 mL), triethylamine (0.678 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.277 g) were mixed and stirred at room temperature for 5 minutes to react. Intermediate 6-2 (0.15 g) was added and stirred at room temperature for 5 hours to react. After the reaction was complete, the reaction mixture was poured into water, ethyl acetate (50 mL) was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, the filtrate was concentrated under reduced pressure, and the residue was separated and purified using a silica gel column (dichloromethane:methanol = 20:1) to obtain intermediate 6-3 90 mg. The above intermediate 6-3 was separated by chiral HPLC (column: CHIRALART Cellulose-SB, 30 × 250 mm, 5 μm; mobile phase: ethanol-dichloromethane (1:1):n-hexane = 30:70; flow rate: 40 mL / min) to obtain compound 6 (40 mg). 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% aqueous ammonia) = 60:40; Flow rate: 2.0 mL / min; Column temperature: 40°C) HRMS:(ESI,[M+H] + )m / z:918.4083. 1H-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).

[0405] Example 7

[0406] [ka]

[0407] Step 1: Synthesis of Intermediate 7-2 3-Oxopiperazine-1-carboxylate 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 an ice bath. The mixture was stirred at room temperature for 10 minutes to allow the reaction to proceed. 2-Fluoro-4-bromonitrobenzene (3.52 g) was added, and the mixture was stirred at room temperature for 12 hours to allow the reaction to proceed. After the reaction was complete, the reaction solution was poured into saturated ammonium chloride solution (100 mL), ethyl acetate (100 mL) was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, the filtrate was concentrated under reduced pressure, and the residue was separated and purified using a silica gel column (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 7-2 2.29 g. 1H-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).

[0408] Step 2: Synthesis of Intermediate 7-3 Intermediate 7-2 (1.7 g), acetic acid (34 mL), and iron powder (1.2 g) were mixed, and the mixture was heated to 120°C under nitrogen gas protection and reacted for 1 hour. After the reaction was complete, the reaction solution was cooled to room temperature, filtered by suction using diatomaceous earth, and the filtrate was concentrated as is. The residue was dissolved in ethyl acetate (100 mL), washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure to obtain intermediate 7-3 (1.26 g). MS(ESI,[M+H] + )m / z:352.14.

[0409] Step 3: Synthesis of Intermediate 7-4 Intermediate 7-3 (1.26 g) and 4N hydrochloric acid aqueous solution (12 mL) were mixed, and the mixture was heated to 100°C under nitrogen gas protection and reacted for 1 hour. After the reaction was complete, the reaction solution was poured into saturated sodium bicarbonate solution, the pH was adjusted 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 by suction, and the filtrate was concentrated under reduced pressure. The residue was separated and purified using a silica gel column (dichloromethane:methanol = 15:1) to obtain intermediate 7-4 0.64 g. MS(ESI,[M+H] + )m / z:252.13. 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).

[0410] Step 4: Synthesis of Intermediate 7-5 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 to react. Sodium triacetoxyborohydride (0.925 g) was added and the mixture was stirred at room temperature for 12 hours to react. After the reaction was complete, the reaction mixture was poured into a saturated sodium bicarbonate solution, and dichloromethane (100 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure. The residue was separated and purified using a silica gel column (dichloromethane:methanol = 20:1) to obtain intermediate 7-5 0.2 g. MS(ESI,[M+H] + )m / z:266.13. 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).

[0411] Step 5: Synthesis of Intermediate 7-6 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 under a nitrogen atmosphere at 120°C for 12 hours. After the reaction was complete, the reaction mixture was poured into water, ethyl acetate (50 mL) was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column (dichloromethane:methanol = 20:1) to obtain intermediate 7-6 0.245 g. MS(ESI,[M+H] + )m / z:627.48. 1H-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).

[0412] Step 6: Synthesis of Intermediate 7-7 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 to allow the reaction to proceed. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain intermediate 7-7 0.2 g. MS(ESI,[M+H] + )m / z:527.34.

[0413] Step 7: Synthesis of intermediates 7-8 and compound 7 Intermediate B-1 (0.1 g), N,N-dimethylformamide (5 mL), triethylamine (0.678 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.277 g) were mixed and stirred at room temperature for 5 minutes to react. Intermediate 7-7 (0.151 g) was added and stirred at room temperature for 5 hours to react. After the reaction was complete, the reaction mixture was poured into water, ethyl acetate (50 mL) was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column (dichloromethane:methanol = 20:1) to obtain intermediate 7-8 0.12 g. The above intermediates 7-8 were separated chirally by supercritical fluid chromatography (column: CHIRALART Cellulose-SB, 20×100 mm, 5 μm; mobile phase: carbon dioxide:ethanol (0.1% aqueous ammonia) = 68:32; flow rate: 60 mL / min) to obtain compound 7, 54 mg. 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% aqueous ammonia) = 50:50; Flow rate: 2.0 mL / min; Column temperature: 40°C) HRMS:(ESI,[M+H] + )m / z:920.4379. 1HNMR(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).

[0414] Example 8

[0415] [ka]

[0416] Step 1: Synthesis of Intermediate 8-2 2-Pyrrolidone (0.426 g) and N,N-dimethylformamide (15 mL) were mixed, and sodium hydride (0.273 g, 60% dispersed in mineral oil) was added under an ice bath. The mixture was stirred at room temperature for 10 minutes to allow the reaction to proceed. 2-Fluoro-4-bromonitrobenzene (1 g) was added, and the mixture was stirred at room temperature for 2 hours to allow the reaction to proceed. After the reaction was complete, the reaction solution was poured into saturated ammonium chloride solution (100 mL), and ethyl acetate (100 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure. The residue was separated and purified using a silica gel column (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 8-2, 0.83 g. MS(ESI,[M+H] + )m / z:285.02. 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).

[0417] Step 2: Synthesis of Intermediate 8-3 Intermediate 8-2 (0.7 g), acetic acid (20 mL), and iron powder (0.7 g) were mixed, and the mixture was heated to 120°C under nitrogen gas protection and reacted for 4 hours. After the reaction was complete, the reaction solution was cooled to room temperature, filtered by suction using diatomaceous earth, and the filtrate was concentrated as is. The residue was dissolved in ethyl acetate (100 mL), washed with saturated sodium bicarbonate solution and saturated brine, dried with anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure to obtain intermediate 8-3 0.5 g. MS(ESI,[M+H] + )m / z:237.12. 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).

[0418] Step 3: Synthesis of Intermediate 8-4 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 under a nitrogen atmosphere at 120°C for 12 hours. After the reaction was complete, the reaction mixture was poured into water, ethyl acetate (50 mL) was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, the filtrate was concentrated under reduced pressure, and the residue was separated and purified using a silica gel column (dichloromethane:methanol = 20:1) to obtain intermediate 8-4 0.25 g. MS(ESI,[M+H] +)m / z:598.39. 1 H-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).

[0419] Step 4: Synthesis of Intermediate 8-5 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 to allow the reaction to proceed. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain intermediate 8-5 (0.2 g). MS(ESI,[M+H] + )m / z:498.40.

[0420] Step 5: Synthesis of intermediates 8-6 and compound 8 Intermediate B-1 (0.1 g), N,N-dimethylformamide (5 mL), triethylamine (0.678 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.277 g) were mixed and stirred at room temperature for 5 minutes to react. Intermediate 8-5 (0.130 g) was added and stirred at room temperature for 5 hours to react. After the reaction was complete, the reaction mixture was poured into water, ethyl acetate (50 mL) was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column (dichloromethane:methanol = 20:1) to obtain intermediate 8-6 0.12 g. The above intermediates 8-6 were separated chirally by supercritical fluid chromatography (column: CHIRALART Cellulose-SB, 20×100 mm, 5 μm; mobile phase: carbon dioxide:ethanol (0.1% aqueous ammonia) = 53:47; flow rate: 60 mL / min) to obtain 30 mg of compound 8. 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% aqueous ammonia) = 50:50; Flow rate: 2.0 mL / min; Column temperature: 40°C) HRMS:(ESI,[M+H] + )m / z:891.4119. 1HNMR(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, 2H),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. 75(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).

[0421] Example 9

[0422] [ka]

[0423] Step 1: Synthesis of Intermediate 9-2 Sodium hydride (0.995 g, 60% dispersed in mineral oil) and N,N-dimethylformamide (10 mL) were mixed and stirred in an ice bath for 10 minutes under nitrogen gas 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 mixture was stirred while maintaining the temperature to allow the reaction to proceed. The reaction was stopped, 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 separated and purified by column chromatography (petroleum ether:ethyl acetate = 95:5) to obtain intermediate 9-2 0.69 g. 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).

[0424] Step 2: Synthesis of Intermediate 9-3 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. Under nitrogen gas protection, the mixture was placed in an oil bath at 120°C and stirred overnight to allow the reaction to proceed. 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 sequentially washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated and purified by column chromatography (petroleum ether:ethyl acetate = 85:15) to obtain intermediate 9-3 0.27 g. MS(ESI,[M+H] + )m / z:598.34. 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).

[0425] Step 3: Synthesis of Intermediate 9-4 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 to allow the reaction to proceed. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain intermediate 9-4 (0.21 g). MS(ESI,[M+H]+ )m / z:498.0.

[0426] Step 4: Synthesis of intermediate 9-5, compound 9-A, and compound 9-B 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 to allow the reaction to proceed. The reaction mixture was poured into water (50 mL), 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 separated and purified by column chromatography (DCM:MeOH=95:5) to obtain intermediate 9-5 130 mg. The above intermediate 9-5 was separated by chiral HPLC (column: REFLECT I-Cellulose B, 30 × 250 mm, 10 μm; mobile phase: ethanol-dichloromethane (1:4):n-hexane = 25:75; flow rate: 40 mL / min) to obtain compound 9-A (26 mg) and compound 9-B (30 mg), respectively. 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°C) HRMS:(ESI,[M+H] + )m / z:891.4030. 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). Compound 9-B:R t =2.03min (UPCC conditions: Column: CHIRALPAK IB-3, 4.6×100mm, 3μm; Mobile phase: Carbon dioxide:Ethanol:Isopropanol = 40:30:30; Flow rate: 2.0mL / min; Column temperature: 40℃) HRMS:(ESI,[M+H] + )m / z:891.4026. 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).

[0427] Example 10

[0428] [ka]

[0429] Step 1: Synthesis of intermediate 10-2 1-Bromo-2-fluoro-4-iodobenzene (2g), cuprous iodide (0.076g), bis(triphenylphosphine)palladium dichloride (0.140g), diisopropylamine (20mL), and tert-butyldimethyl(propa-2-in-1-yloxy)silane (1.359g) were mixed and stirred overnight at room temperature. The reaction mixture was added to a mixture of ethyl acetate (30mL) and water (40mL) to separate the two phases. The aqueous phase was extracted with ethyl acetate (2×30mL), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. Separation and purification were performed by column chromatography (petroleum ether:ethyl acetate = 98:2) to obtain intermediate 10⁻² 1.8g. 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).

[0430] Step 2: Synthesis of intermediate 10-3 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 then dried by rotary evaporation, and separated and purified by column chromatography (dichloromethane:methanol = 100:0) to obtain intermediate 10-3 (1.67 g). MS(ESI,[M+H] + )m / z:228.23. 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).

[0431] Step 3: Synthesis of intermediate 10-4 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 bath, iodomethane (372 mg) was added dropwise to the reaction mixture, and the reaction mixture was transferred to room temperature and stirred for 2 hours. After quenching the reaction mixture with water, it was added to a mixture of ethyl acetate (30 mL) and water (40 mL), the two phases were separated, the aqueous phase was extracted with ethyl acetate (2 × 30 mL), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to obtain intermediate 10-4 320 mg. 1H-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)

[0432] Step 4: Synthesis of intermediate 10-5 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 mixed. The reaction system was protected with nitrogen gas, and then reacted in an oil bath at 130°C for 3 hours. The reaction solution was added to a mixture of ethyl acetate (30 mL) and water (40 mL), and two phases were separated. The aqueous phase was extracted with ethyl acetate (2 × 30 mL), and after combining with the organic phase, the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. Separation and purification were performed by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain intermediate 10-5 220 mg. MS(ESI,[M+H] + )m / z:604.33.

[0433] Step 5: Synthesis of intermediate 10-6 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 intermediate 10-6 (190 mg). MS(ESI,[M+H] + )m / z:504.26.

[0434] Step 6: Synthesis of intermediate 10-7 and compounds 10-A and 10-B 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 mixture was poured into water (50 mL), 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 to obtain compound 10-7 80 mg. Compound 10-7 was 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). Compound 10-A:R t =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) HRMS:(ESI,[M+H] + )m / z:897.3933. 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). Compound 10-B:R t =2.169min (UPCC conditions: カラム:CHIRALPAK IB-3, 4.6 × 100mm, 3μm; mobile phase: carbon dioxide: ethanoic acid: ethanoic acid = 50:25:25; flow rate: 2.0mL / min; temperature: 40℃) HRMS:(ESI,[M+H] + )m / z:897.3928. 1 H-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).

[0435] Example 11

[0436]

change

[0437] ステップ1:Synthesis of intermediate 11-2 2-Bromo-5-iodopyridine (2g), cuprous iodide (0.040g), bistrisphenylphosphine dipalladium chloride (0.198g), tetrahydrofuran (30mL), triethylamine (10.86g), and propyne (0.367g) were mixed, and the reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was poured into a mixture of ethyl acetate (30mL) and water (40mL) to separate the two phases. The aqueous phase was extracted with ethyl acetate (2×30mL), and after combining with the organic phase, the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. Separation and purification were performed by column chromatography (petroleum ether:ethyl acetate = 97:3) to obtain intermediate 11-2, 1.2g. MS(ESI,[M+H] + )m / z:196.05. 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).

[0438] Step 2: Synthesis of Intermediate 11-3 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. After purging with nitrogen, the mixture was 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 washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The mixture was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain intermediate 11-3 420 mg.

[0439] Step 3: Synthesis of Intermediate 11-4 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 to allow the reaction to proceed. After stopping the stirring, the mixture was concentrated under reduced pressure to obtain intermediate 11-4 (347 mg). MS(ESI,[M+H] + )m / z:457.30.

[0440] Step 4: Synthesis of intermediate 11-5, compound 11-A, and compound 11-B Intermediate 11-4 (132 mg), intermediate B-1 (100 mg), triethylamine (492 mg), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium 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), 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 separated and purified by column chromatography (dichloromethane:methanol = 95:5) to obtain intermediate 11-5 70 mg. The above intermediate 11-5 was separated by chiral HPLC (column: REFLECT I-Cellulose B, 30 × 250 mm, 10 μm; mobile phase: ethanol-dichloromethane (1:3):n-hexane = 20:80; flow rate: 40 mL / min) to obtain compound 11-A (15 mg) and compound 11-B (12 mg), respectively. 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°C). HRMS:(ESI,[M+H] + )m / z:850.3866 1H-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). Compound 11-B:R t =1.31min (UPCC conditions: カラム:CHIRALPAK IB-3, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: ethanoic acid: ethanoic acid = 40:30:30; flow rate: 2.0 mL / min; temperature: 40°C). HRMS:(ESI,[M+H] + m / z:850.3867 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).

[0441] Example 12

[0442]

change

[0443] ステップ1:Synthesis of intermediate 12-2 Sodium hydride (1.167 g, 60% dispersed in mineral oil) was added at 0°C to a mixed solvent of tetrahydrofuran (60 mL) and ethanol (20 mL), and the mixture was stirred for 10 minutes. Intermediate 12-1 (5 g) and diethyl malonate (2.336 g) were added to the reaction mixture, and the mixture was reacted at room temperature for 4 hours. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried and concentrated. Separation and purification were performed by column chromatography (petroleum ether:ethyl acetate = 90:10) to obtain intermediate 12-2 (4.3 g). 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).

[0444] Step 2: Synthesis of Intermediate 12-3 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 mixture was poured into saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and separated and purified by column chromatography (dichloromethane:methanol = 95:5) to obtain intermediate 12-3 0.24 g. 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).

[0445] Step 3: Synthesis of Intermediate 12-4 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 the mixture was reacted for 0.5 hours. Then, p-toluenesulfonyl chloride (0.741 g) was added and the mixture was reacted for a further 1.5 hours. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, the organic phase was dried and concentrated, and separated and purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain intermediate 12-4 (1.2 g). 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).

[0446] Step 4: Synthesis of Intermediate 12-5 Intermediate 12-4 (500 mg) and tetrahydrofuran (10 mL) were mixed, sodium hydride (97 mg, 60% dispersed in mineral oil) was added at 0°C, and the mixture was reacted overnight in an oil bath at 70°C. Saturated ammonium chloride solution was added to the reaction mixture to quench it, ethyl acetate was added for extraction, the organic phase was dried and concentrated, and separated and purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain intermediate 12-5 0.19 g. 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).

[0447] Step 5: Synthesis of Intermediate 12-6 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 intermediate 12-6 0.1 g. MS(ESI,[M+H] +)m / z:342.19.

[0448] Step 6: Synthesis of Intermediate 12-7 Intermediate 12-6 (0.25 g), N,N-dimethylformamide (4 mL), intermediate B-1 (0.251 g), N,N-diisopropylethylamine (0.358 g), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium 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 x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and separated and purified by column chromatography (dichloromethane:methanol = 95:5) to obtain intermediate 12-7 0.2 g. MS(ESI,[M+H] + )m / z:735.44.

[0449] Step 7: Synthesis of intermediate 12-8, compound 12-A, and compound 12-B 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 mixed. Under nitrogen gas protection, the mixture was heated to 130°C and reacted for 3 hours. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting crude product was separated and purified by column chromatography (dichloromethane:methanol = 95:5) to obtain intermediate 12-8 80 mg. The above intermediate 12-8 was 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 compound 12-A (29 mg) and compound 12-B (25 mg), respectively. Compound 12-A:R t=2.22min (UPCC conditions: カラム:CHIRALPAK IB-3, 4.6 × 100mm, 3μm; mobile phase: carbon dioxide: ethanoic acid: ethanoic acid = 40:30:30; flow rate: 2.0mL / min; temperature: 40℃) HRMS:(ESI,[M+H] + )m / z:893.4172. 1 H-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). Compound 12-B:R t =1.76min (UPCC conditions: カラム:CHIRALPAK IB-3, 4.6 × 100mm, 3μm; mobile phase: carbon dioxide: ethanoic acid: ethanoic acid = 40:30:30; flow rate: 2.0mL / min; temperature: 40℃) HRMS:(ESI,[M+H] + )m / z:893.4167. 1 H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),7.58-7.28(m,5H),7.27-7.07(m,4H),6 .99-6.75(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).

[0450] Example 13

[0451] [ka]

[0452] Step 1: Synthesis of Intermediate 13-1 6'-bromo-1',2'-dihydrospiro[cyclopropan-1,3'-indole]-2'-one (0.5 g) and N,N-dimethylformamide (5 mL) were mixed, and sodium hydrogen (0.13 g, 60% dispersed in mineral oil) was added in portions while the mixture was cooled in an ice bath. 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. Next, the mixture was cooled in an ice bath, and deuterated iodomethane (0.46 g) 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 saturated ammonium chloride solution (50 mL), extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, concentrated under reduced pressure, and the resulting crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain intermediate 13-1 0.53 g. 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).

[0453] Step 2: Synthesis of Intermediate 13-2 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 under nitrogen gas protection for 2 hours. The reaction mixture was poured into water (50 mL), extracted with ethyl acetate, combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, concentrated under reduced pressure, and the resulting crude product was separated and purified by column chromatography (dichloromethane:methanol = 95:5) to obtain intermediate 13-2 0.13 g. MS(ESI,[M+H] + )m / z:616.42. 1 H-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).

[0454] Step 3: Synthesis of Intermediate 13-3 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 concentrated under reduced pressure to obtain intermediate 13-3 (0.11 g). MS(ESI,[M+H] + )m / z:516.36.

[0455] Step 4: Synthesis of intermediate 13-4 and compound 13 Intermediate B-1 (0.08 g), N,N-dimethylformamide (2 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.22 g), and triethylamine (0.39 g) were mixed and stirred at room temperature for 5 minutes. Then, a solution of intermediate 1-3 (0.12 g) in NN-dimethylformamide (1 mL) was added, and after the addition was complete, the mixture was stirred at room temperature overnight. The reaction mixture was poured into water (50 mL), extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, and concentrated under reduced pressure. The resulting crude product was separated and purified by column chromatography (dichloromethane:methanol = 95:5) to obtain intermediate 13-4 80 mg. Intermediate 13-4 was separated by chiral HPLC (column: REGIS IB, 30 × 250 mm, 10 μm; mobile phase: n-hexane-ethanol (80:20):dichloromethane = 1:1; flow rate: 40 mL / min) to obtain compound 13 (38 mg). Compound 13:R t =2.077min (UPCC conditions: Column: CHIRALPAK IB-3, 4.6×100mm, 3μm; Mobile phase: Carbon dioxide:Methanol = 30:70; Flow rate: 2.0mL / min; Column temperature: 40℃) HRMS:(ESI,[M+H] + )m / z:909.4308. 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).

[0456] Example 14

[0457] [ka]

[0458] Step 1: Synthesis of Intermediate 14-1 6-bromo-7-fluorodihydroindole-2,3-dione (8.4 g), ethanol (150 mL), and 85% hydrazine hydrate solution (1.5 mL) were mixed and heated to 85°C under nitrogen gas protection for 1 hour. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The cake, ethanol (150 mL), and tert-butoxide potassium (12 g) were mixed and heated to 85°C under nitrogen gas protection for 2 hours. After the reaction was complete, the reaction solution was poured into water, 2N hydrochloric acid aqueous solution (50 mL) was added to adjust the pH to 2-3, filtered, and the cake was dried to obtain intermediate 14-1 4.2 g. MS(ESI,[MH] - )m / z:227.95. 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).

[0459] Step 2: Synthesis of Intermediate 14-2 At -40°C, 8.69 ml of 2N diisopropylaminolithium tetrahydrofuran solution was added to a mixture of intermediate 14-1 (1 g) and tetrahydrofuran (20 ml), and the mixture was stirred for 30 minutes. 1,2-dibromoethane (2.45 g) was added to the reaction mixture, and the mixture was reacted at room temperature for 12 hours. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, the organic phase was dried and concentrated, and the residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 90:10) to obtain 0.27 g of intermediate 14-2. 1H-NMR(500MHz, DMSO-d6): δ 11.24 (s, 1H), 7.24 - 7.19 (m, 1H), 6.81 (d, J = 8.0 Hz, 1H), 1.66 - 1.64 (m, 2H), 1.56 - 1.52 (m, 2H).

[0460] Step 3: Synthesis of Intermediate 14-3 Intermediate 14-2 (0.27 g), N,N-dimethylformamide (5 mL), iodomethane (0.19 g), and cesium carbonate (0.68 g) were mixed. Under the protection of nitrogen gas, the mixture was heated to 80 °C and reacted for 1 hour. After the reaction, the reaction solution was poured into water, ethyl acetate (50 mL) was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate = 90:10) to obtain 0.13 g of Intermediate 14-3. 1 H-NMR(500MHz, DMSO-d6): δ 7.29 - 7.26 (m, 1H), 6.85 (d, J = 8.0 Hz, 1H), 3.38 (d, J = 3.0 Hz, 3H), 1.70 - 1.68 (m, 2H), 1.59 - 1.57 (m, 2H).

[0461] Step 4: Synthesis of Intermediate 14-4 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. Under a nitrogen atmosphere, the reaction was carried out at 100 °C for 12 hours. After the reaction, the reaction solution was poured into water, ethyl acetate (50 mL) was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column (dichloromethane:methanol = 20:1) to obtain 0.14 g of Intermediate 14-4. MS(ESI, [M + H] + ) m / z: 631.39. 1H-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).

[0462] Step 5: Synthesis of Intermediate 14-5 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 to allow the reaction to proceed. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain intermediate 14-5 (0.11 g). MS(ESI,[M+H] + )m / z:531.31.

[0463] Step 6: Synthesis of Compound 14 Intermediate B-3 (0.07 g), N,N-dimethylformamide (4 mL), triethylamine (0.47 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.19 g) were mixed and stirred at room temperature for 5 minutes to react. Intermediate 14-5 (0.1 g) was added and stirred at room temperature for 5 hours to react. After the reaction was complete, the reaction mixture was poured into water, ethyl acetate (50 mL) was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, the filtrate was concentrated under reduced pressure, and the residue was separated and purified using a silica gel column (dichloromethane:methanol = 20:1) to obtain compound 14 0.048 g. HRMS:(ESI,[M+H] + )m / z:924.4014. 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).

[0464] Example 15

[0465] [ka]

[0466] Step 1: Synthesis of Intermediate 15-1 At -60°C, a 15.7 mL solution of 2N diisopropylaminolithium in tetrahydrofuran was added to a mixture of 6-bromo-5-fluorodihydroindole-2-one (1.8 g) and tetrahydrofuran (6 mL), and the mixture was stirred for 30 minutes. Then, 4.41 g of 1,2-dibromoethane was added to the reaction mixture, and the mixture was reacted at room temperature for 12 hours. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, the organic phase was dried and concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:2) to obtain intermediate 15-1, 0.72 g. MS(ESI,[MH] - )m / z:253.96. 1H-NMR(500MHz, DMSO-d6): δ 10.64 (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).

[0467] Step 2: Synthesis of Intermediate 15-2 Intermediate 15-1 (0.7 g) and N,N-dimethylformamide (15 mL) were mixed. Sodium hydride (0.33 g, 60% dispersion in mineral oil) was added under an ice bath, and the mixture was continuously stirred for 30 minutes to react. Iodomethane (1.94 g) was added dropwise to the reaction solution, and the reaction mixture was transferred to room temperature and stirred for 2 hours. After the reaction was completed, the reaction solution was poured into a saturated ammonium chloride aqueous solution (100 mL), ethyl acetate (100 mL) was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by a silica gel column (petroleum ether:ethyl acetate = 1:4) to obtain 0.40 g of Intermediate 15-2. MS(ESI, [M + H] + ) m / z: 269.87. 1 H-NMR(500MHz, DMSO-d6): δ 7.41 (d, J = 6.0 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 3.20 (s, 3H), 1.73 - 1.66 (m, 2H), 1.59 - 1.53 (m, 2H).

[0468] Step 3: Synthesis of Intermediate 15-3 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, ethyl acetate (50 mL) was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by a silica gel column (petroleum ether:ethyl acetate = 3:2) to obtain 0.52 g of Intermediate 15-3. MS(ESI, [M + H]+ )m / z:631.43. 1 H-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).

[0469] Step 4: Synthesis of Intermediate 15-4 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 to allow the reaction to proceed. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain intermediate 15-4 (0.22 g). MS(ESI,[M+H] + )m / z:531.32.

[0470] Step 5: Synthesis of Compound 15 Intermediate B-3 (0.07 g), N,N-dimethylformamide (3 mL), triethylamine (0.47 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.2 g) were mixed and stirred at room temperature for 5 minutes to react. Intermediate 15-4 (0.1 g) was added and stirred at room temperature for 5 hours to react. After the reaction was complete, the reaction mixture was poured into water, ethyl acetate (50 mL) was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column (dichloromethane:methanol = 20:1) to obtain compound 15 0.06 g. HRMS:(ESI,[M+H] + )m / z:924.4020. 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).

[0471] Example 16

[0472] [ka]

[0473] Step 1: Synthesis of Intermediate 16-1 At -78°C, a 9 mL solution of 2N diisopropylaminolithium in tetrahydrofuran was added to a mixed solution of 6-bromo-4-fluorodihydro-2-one (1 g) and tetrahydrofuran (5 mL). The mixture was stirred for 30 minutes while maintaining this temperature, and a 5 mL solution of 1,2-dibromoethane (2.44 g) in tetrahydrofuran was added dropwise. After the addition was complete, the mixture was slowly heated to room temperature and stirred overnight. The reaction was stopped, and the reaction solution was poured into a 100 mL solution of saturated ammonium chloride. The resulting solution was extracted with ethyl acetate (50 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, concentrated under reduced pressure, and separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain intermediate 16-1 0.54 g. MS(ESI,[MH] - )m / z:253.91. 1H-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).

[0474] Step 2: Synthesis of Intermediate 16-2 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. The mixture was then stirred for 30 minutes to allow it to react. Iodomethane (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), and after combining with the organic phase, the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, and concentrated under reduced pressure to obtain intermediate 16-2 500 mg. MS(ESI,[M+H] + )m / z:269.98. 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).

[0475] Step 3: Synthesis of Intermediate 16-3 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. Under nitrogen gas protection, the mixture was stirred and reacted at 150°C under microwave 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 sequentially washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain intermediate 16-3 0.4 g. MS(ESI,[M+H] + )m / z:631.44. 1 H-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).

[0476] Step 4: Synthesis of Intermediate 16-4 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 to allow the reaction to proceed. After stopping the stirring, the mixture was concentrated under reduced pressure to obtain intermediate 16-4 (0.2 g). MS(ESI,[M+H] + )m / z:531.32

[0477] Step 5: Synthesis of Compound 16 Intermediate B-3 (0.15 g), N,N-dimethylformamide (4 mL), triethylamine (0.72 g), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium 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), the resulting solution was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated and purified by column chromatography (dichloromethane:methanol = 95:5) to obtain compound 16 80 mg. HRMS:(ESI,[M+H] + )m / z:924.4023. 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).

[0478] Example 17

[0479] [ka]

[0480] Step 1: Synthesis of Intermediate 17-1 6'-bromo-1',2'-dihydrospiro[cyclopropan-1,3'-indole]-2'-one (0.72 g), copper acetate (0.80 g), 4-dimethylamine pyridine (1.54 g), and toluene (20 mL) were mixed. Then, a solution of 2N sodium bis(trimethylsilyl)amide in tetrahydrofuran (2.21 mL) 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 ethyl acetate (30 mL) and water (70 mL) to separate the two phases. The aqueous phase was extracted with ethyl acetate (30 mL x 2), and the organic phases were combined. The mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered by suction, and concentrated under reduced pressure. The resulting crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 90:10) to obtain intermediate 17-1, 350 mg. 1H-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).

[0481] Step 2: Synthesis of Intermediate 17-2 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 under a nitrogen atmosphere at 125°C for 16 hours and then allowed to cool naturally to room temperature. The reaction mixture was poured into ethyl acetate (20 mL) and water (30 mL) to separate the two phases. The aqueous phase was extracted with (20 mL x 2) of water, and the organic phases were combined. The mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered by suction, and concentrated under reduced pressure. The resulting crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain intermediate 17-2 210 mg. MS(ESI,[M+H] + )m / z:639.48.

[0482] Step 3: Synthesis of Intermediate 17-3 Intermediate 17-2 (200 mg), dichloromethane (2 mL), and 4N dioxane hydrochloride solution (4 mL) were mixed, stirred at room temperature for 1.5 hours, and concentrated under reduced pressure to obtain intermediate 17-3 (180 mg). MS(ESI,[M+H] + )m / z:539.35.

[0483] Step 4: Synthesis of intermediate 17-4 and compound 17 Intermediate B-1 (114 mg), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium 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 mixture was poured into water (50 mL), 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 resulting residue was separated and purified by column chromatography (dichloromethane:methanol = 95:5) to obtain intermediate 17-4 60 mg. Intermediate 17-4 was separated by chiral HPLC (column: CHIRALART Cellulose-SB, 30 × 250 mm, 5 μm; mobile phase: ethanol / 0.1% aqueous ammonia:n-hexane = 30:70, isocratic elution) to obtain compound 17 (18 mg). Compound 17:R t =2.01 min (UPCC conditions: Column: CHIRALPAK IB, 4.6 × 100 mm, 3 μm; Mobile phase: Carbon dioxide: Methanol / 0.1% aqueous ammonia = 30:70; Flow rate: 0.5 mL / min; Column temperature: 40°C) HRMS:(ESI,[M+H] + )m / z:932.4291. 1HNMR(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. 17(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),1.5 0(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).

[0484] Example 18

[0485] [ka]

[0486] Step 1: Synthesis of Intermediate 18-1 Intermediate A-2 (400mg), Intermediate 5-2 (320mg), (1S,2S)-N 1 ,N 2 -Dimethylcyclohexane-1,2-diamine (64 mg), potassium carbonate (400 mg), cuprous iodide (38 mg), and N-methylpyrrolidone (8 mL) were mixed and reacted at 140°C under microwave protection 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 sequentially washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain intermediate 18-1 0.45 g. MS(ESI,[M+H] + )m / z:625.43. 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).

[0487] Step 2: Synthesis of Intermediate 18-2 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 to allow the reaction to proceed. After stopping the stirring, the mixture was concentrated under reduced pressure to obtain intermediate 18-2 (0.33 g). MS(ESI,[M+H] + )m / z:525.23. 1 H-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).

[0488] Step 3: Synthesis of intermediate 18-3 and compound 18 Intermediate B-1 (0.155 g), N,N-dimethylformamide (4 mL), triethylamine (0.075 g), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium 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 to allow it to react. The reaction mixture was poured into water (50 mL), the resulting solution was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated and purified by column chromatography (dichloromethane:methanol = 95:5) to obtain intermediate 18-3. The above intermediate 18-3 was 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°C; column: CHIRALART Cellulose-SB) to obtain 80 mg of compound 18. Compound 18:R t =2.08min (UPCC conditions: Column: CHIRALPAK IB-3 (4.6×100mm, 3μm), Mobile phase: Carbon dioxide:Methanol (0.1% aqueous ammonia) = 30:70; Flow rate: 2ml / min, Column temperature: 40℃) HRMS:(ESI,[M+H] + )m / z:918.4135. 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).

[0489] Example 19

[0490]

change

[0491] ステップ1: Synthesis of intermediate 19-1 and び compound 19 Intermediate B-2 (0.07 g) and N,N-dimethylformamide (2 mL) were mixed, and triethylamine (178 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (134 mg) were added sequentially. After stirring for 10 minutes, intermediate 5-4 (0.09 g) was added, and the mixture was stirred overnight at room temperature to allow it to react. The mixture was diluted with water and ethyl acetate, extracted with ethyl acetate, and the organic layer was sequentially washed with water and saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The filtrate was concentrated and separated and purified by column chromatography (dichloromethane:methanol = 98:2) to obtain intermediate 19-1 60 mg. The above intermediate 19-1 was separated by chiral HPLC (mobile phase: n-hexane:ethanol = 80:20; flow rate: 40 mL / min; column temperature: 25°C; column: YMCCHIRALART Cellulose-SB 30×250) to obtain 20 mg of compound 19. Compound 19:R t =3.55min (UPCC conditions: Column: CHIRALPAK IB-3 (4.6×100mm, 3μm), Mobile phase: Carbon dioxide:Methanol (0.1% aqueous ammonia) = 60:40; Flow rate: 2ml / min, Column temperature: 40℃) HRMS:(ESI,[M+H] + )m / z:892.3960. 1H-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).

[0492] Example 20

[0493]

change

[0494] ステップ1: Synthesis of intermediate 20-1 and び compound 20 Intermediate B-2 (0.083 g), N,N-dimethylformamide (2 mL), triethylamine (0.265 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.109 g) were mixed and stirred at room temperature for 5 minutes to react. Intermediate 6-3 (0.10 g) was added and stirred at room temperature for 5 hours to react. After the reaction was complete, the reaction mixture was poured into water, ethyl acetate (50 mL) was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column (dichloromethane:methanol = 20:1) to obtain intermediate 20-1 0.12 g. The above intermediate 20-1 was separated by chiral HPLC (column: Pre-packe DREGIS IB, 30 × 250 mm, 10 μm; mobile phase: ethanol-dichloromethane (1:1):n-hexane = 30:70; flow rate: 40 mL / min) to obtain compound 20, 33 mg. Compound 20:R t =7.47min (UPCC conditions: Column: CHIRALPAK IB-3 (4.6×100mm, 3μm); Mobile phase: Carbon dioxide:Methanol (containing 0.1% aqueous ammonia) = 30:70; Flow rate: 2.0 ml / min; Column temperature: 40℃) HRMS:(ESI,[M+H] + )m / z:904.3973. 1H-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).

[0495] Example 21

[0496] [ka]

[0497] Step 1: Synthesis of Intermediate 21-1 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 the mixture was stirred for 30 minutes. 1,3-dibromopropane (14.28 g) was added to the reaction mixture, and the mixture was reacted at room temperature for 12 hours. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, the organic phase was dried and concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 21-1, 1.9 g. MS(ESI,[M+H] + )m / z:251.98. 1HNMR(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).

[0498] Step 2: Synthesis of Intermediate 21-2 Intermediate 21-1 (0.7 g) and N,N-dimethylformamide (10 mL) were mixed, and sodium hydrogen (0.14 g, 60% dispersed in mineral oil) was added under ice bath. The mixture was then stirred for 10 minutes to allow the reaction to proceed. Iodomethane (0.51 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 complete, the reaction mixture was poured into saturated ammonium chloride aqueous solution (100 mL), ethyl acetate (100 mL) was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate = 88:12) to obtain intermediate 21-2 0.58 g. MS(ESI,[M+H] + )m / z:266.06. 1 HNMR(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).

[0499] Step 3: Synthesis of intermediates 21-3 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 under a nitrogen atmosphere at 130°C for 12 hours. After the reaction was complete, the reaction mixture was poured into water, ethyl acetate (50 mL) was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate = 55:45) to obtain intermediate 21-3 0.26 g. MS(ESI,[M+H] + )m / z:627.45. 1 HNMR(500MHz,DMSO-d6):δ7.81(d,J=2.2Hz,1H),7.50(dd,J=8.4,2.2Hz,1H),7.27(d,J=3. 2Hz,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).

[0500] Step 4: Synthesis of intermediates 21-4 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 to allow the reaction to proceed. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain intermediate 21-4 (0.21 g). MS(ESI,[M+H] + )m / z:527.35.

[0501] Step 5: Synthesis of intermediate 21-5 and compound 21 Intermediate B-1 (100 mg), N,N-dimethylformamide (5 mL), triethylamine (0.678 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (277 mg) were mixed and stirred at room temperature for 5 minutes to react. Intermediate 21-5 (151 mg) was added and stirred at room temperature for 5 hours to react. After the reaction was complete, the reaction mixture was poured into water, ethyl acetate (50 mL) was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column (dichloromethane:methanol = 97:3) to obtain 0.18 g of intermediate 21-5. The above intermediates 21-5 were separated by chiral HPLC (column: CHIRAL ART Cellulose-SB, 30 × 250 mm, 5 μm; mobile phase: ethanol-dichloromethane (3:2):n-hexane = 27:73; flow rate: 40 mL / min) to obtain 60 mg of compound 21. Compound 21:R t =2.78min (UPCC conditions: Column: CHIRALPAK IB-3 (4.6×100mm, 3μm); Mobile phase: Carbon dioxide:Methanol (containing 0.1% aqueous ammonia) = 50:50; Flow rate: 2.0ml / min; Column temperature: 40℃) HRMS:(ESI,[M+H] + )m / z:920.4281. 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).

[0502] Example 22

[0503] [ka]

[0504] Step 1: Synthesis of Intermediate 22-1 4-bromopyridine-2-carboxyaldehyde (25 g), ethyl acrylate (26.9 g), and triethylenediamine (9.8 g) were mixed, stirred overnight at room temperature, concentrated under reduced pressure, and the resulting residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain intermediate 22-1, 34.2 g. MS(ESI,[M+H] + )m / z:286.04. 1H-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).

[0505] Step 2: Synthesis of Intermediate 22-2 Intermediate 22-1 (33.2 g) and dichloromethane (300 mL) were mixed, cooled in an ice bath, pyridine (9.18 g) was added, and 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 mixture 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 intermediate 22-2 (35 g). MS(ESI,[M+H+2] + )m / z:330.04. 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).

[0506] Step 3: Synthesis of intermediate 22-3 Intermediate 22-2 (39 g) and toluene (250 mL) were mixed, and the mixture was heated to 120°C and reacted overnight. Heating was stopped, the mixture was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain intermediate 22-3 6.4 g. MS(ESI,[M+H+2] + )m / z:270.05. 1H-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).

[0507] Step 4: Synthesis of intermediate 22-4 Intermediate 22-3 (3.6g), 1,4-dioxane (50mL), bis(pinacolato)diborone (4.43g), potassium acetate (2.64g), and 1,1-bis(diphenylphosphin)ferrocenepalladium dichloride (0.49g) were mixed and heated to 90°C under nitrogen gas protection and reacted overnight. Heating was stopped, the mixture was cooled to room temperature, the reaction solution was poured into water (100mL), extracted with ethyl acetate (50mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain intermediate 22-4 4.1g. MS(ESI,[M+H] + )m / z:316.19. 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).

[0508] Step 5: Synthesis of Intermediate 22-5 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(diphenylphosphin)ferrocenepalladium dichloride (0.48 g) were mixed and heated to 90°C under nitrogen gas protection for 3 hours. The reaction solution was poured into water (100 mL), extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain intermediate 22-5 3.6 g. MS(ESI,[M+H] + )m / z:300.19.

[0509] Step 6: Synthesis of intermediates 22-6 Intermediate 22-5 (4.1 g) was mixed with methanol (80 mL), 10% Pd / C (1.46 g) was added, and the mixture was stirred overnight under a hydrogen atmosphere. The mixture was filtered and concentrated, and the residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain intermediate 22-6 2.6 g. MS(ESI,[M+H] + )m / z:302.20. 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).

[0510] Step 7: Synthesis of intermediates 22-7 Intermediate 22-6 (2.35 g), dimethyl sulfoxide (40 mL), iodoacetonitrile (3.91 g), and ferrous sulfate heptahydrate (1.08 g) were mixed, cooled in an ice bath, and hydrogen peroxide (4.78 mL) was added dropwise. After the addition was complete, the mixture was stirred for 2 hours. The reaction mixture was poured into saturated sodium sulfite solution (100 mL) and ethyl acetate (100 mL), separated, the organic phase was recovered and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain intermediate 22-7 1 g. MS(ESI,[M+H] + )m / z:341.27. 1 H-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).

[0511] Step 8: Synthesis of intermediates 22-8 Intermediate 22-7 (0.31 g), tetrahydrofuran (6 mL), (4R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (0.38 g), and N,N-dimethylpropylene urea (0.23 g) were mixed. Under nitrogen gas protection, the mixture was cooled to 0°C in an ice salt bath, and then 5.46 mL of tetrahydrofuran solution of 1N lithium bis(trimethylsilyl)amide was slowly added dropwise. After the addition was complete, the mixture was stirred at 0°C for 1 hour. The reaction mixture was poured into saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (20 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 0.51 g of isomer. The obtained isomers were separated by HPLC (apparatus: YMC high-pressure preparative chromatograph; column: Ultimate XB-C18, 30 × 250 mm, 10 μm; mobile phase: water-acetonitrile (35:65), yielding 0.19 g of intermediate 22-8). Compound 22-8:R t =2.73min (UPLC conditions: Column: Waters UPLCBEHC18 (50×2.1mm, 1.7μm), Mobile phase: 10mM ammonium acetate buffer (with 0.1% glacial acetic acid) - acetonitrile (50:50):acetonitrile = 10:90, Flow rate: 0.6mL / min, Column temperature: 40℃) MS(ESI,[M+H] + )m / z:381.34. 1 H-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).

[0512] Step 9: Synthesis of Intermediate 22-9 Intermediate 22-8 (0.73 g), dimethyl sulfoxide (5 mL), hydroxylamine hydrochloride (0.67 g), and sodium hydrogen carbonate (0.81 g) were mixed and heated to 65 °C for overnight reaction. The heating was stopped and the mixture was cooled to room temperature. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 0.72 g of Intermediate 22-9. MS(ESI,[M+H] + ) m / z: 414.42.

[0513] Step 10: Synthesis of Intermediate 22-10 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. The stirring was stopped and the reaction solution was poured into water (50 mL) and extracted with ethyl acetate (20 mL). The aqueous phase was adjusted to pH 6 - 7 with 2N hydrochloric acid solution and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 0.6 g of Intermediate 22-10. MS(ESI,[M+H] + ) m / z: 440.31.

[0514] Step 11: Synthesis of Intermediate 22-11 Intermediate 22-10 (0.6 g), tetrahydrofuran (6 mL), water (1 mL), and potassium hydroxide (0.31 g) were mixed and the mixture was heated to 70 °C for 8 hours of reaction. The 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 recovered, adjusted to pH 4 - 5 with 2N hydrochloric acid solution and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 0.35 g of Intermediate 22-11. MS(ESI,[M+H] + ) m / z: 412.34. 1H-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).

[0515] Step 12: Synthesis of intermediate 22-12 and compounds 22-A and 22-B Intermediate 22-11 (0.1 g), intermediate A-1 (0.15 g), N,N-dimethylformamide (3 mL), triethylamine (0.49 g), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.28 g) were mixed, and after mixing, the mixture was stirred at room temperature for 4 hours. After stopping the stirring, the reaction mixture was poured into water (50 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting residue was separated and purified by column chromatography (dichloromethane:methanol = 95:5) to prepare intermediate 22-12 65 mg. The above intermediate 22-12 was separated by chiral HPLC (column: REGIS IB, 30 × 250 mm, 10 μm; mobile phase: carbon dioxide:ethanol (containing 0.1% aqueous ammonia) = 65:35; flow rate: 80 mL / min) to prepare compound 22-A (25 mg) and compound 22-B (22 mg). 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% aqueous ammonia) = 50:25:25; Flow rate: 2.0 mL / min; Column temperature: 40°C) HRMS:(ESI,[M+H]+)m / z:906.4132. 1H-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). Compound 22-B:R t =1.74min (UPCC conditions: カラム:CHIRALPAK IB-3, 4.6×100mm, 3μm; mobile phase: diacid carbon: エタノール: イソプロパノール (0 .1% アンモニアwater content)=50:25:25; flow rate: 2.0mL / min; カラム temperature: 40℃) HRMS:(ESI,[M+H] + )m / z:906.4122. 1 H-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).

[0516] Example 23

[0517] [ka]

[0518] Step 1: Synthesis of Intermediate 23-1 4-bromo-7-fluoroindanone (1 g) and methanol (10 mL) were mixed and cooled in an ice bath. Sodium borohydride (0.330 g) was added in portions, and 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 water (100 mL) and stirred, and a large amount of precipitate was formed. The mixture was filtered, the cake was collected and vacuum-dried to obtain intermediate 23-1 0.7 g. 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).

[0519] Step 2: Synthesis of Intermediate 23-2 Intermediate 23-1 (5 g) and dichloromethane (60 mL) were mixed and cooled to -78°C under nitrogen gas protection. Triethylsilane (7.55 g) and boron trifluoride diethyl ether solution (8.23 mL) were added dropwise, and the mixture was allowed to rise naturally to room temperature and stirred overnight. The reaction mixture was poured into saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (40 mL x 3). The organic phases were washed with saturated sodium bicarbonate solution and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 100:0) to obtain intermediate 23-2 4.3 g. 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).

[0520] Step 3: Synthesis of Intermediate 23-3 Intermediate 23-2 (2g), tert-butyl carbacate (2.46g), toluene (10mL), sodium tert-butoxide (1.79g), 5-di-tert-butylphosphine-1',3',5'-triphenyl-1'H-[1,4']dipyrazole (0.94g), and palladium (π-cinnamyl) chloride dimer (0.24g) were mixed and heated to 115°C under nitrogen gas protection for 5 hours. Heating was stopped, the mixture was cooled to room temperature, the reaction solution was poured into water (100mL), extracted with ethyl acetate (50mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain intermediate 23-3 1.7g. 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).

[0521] Step 4: Synthesis of intermediates 23-5 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 resulting residue was redissolved in ethanol (20 mL). 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, the mixture was cooled to room temperature, and the reaction solution was poured into water (100 mL). Extraction was performed with ethyl acetate (40 mL x 3). The organic phases were washed with saturated sodium bicarbonate solution and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 60:40) to obtain intermediate 23-5 2.1 g. MS(ESI,[M+H] + )m / z:387.33. 1H-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).

[0522] Step 5: Synthesis of intermediates 23-6 Intermediate 23-5 (2.0 g) and tetrahydrofuran (60 mL) were mixed, cooled in an ice 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 cooled in an ice bath, aminoacetaldehyde dimethyl acetal (2.72 g) was added, and 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 x 3), and the organic phases were washed with saturated sodium bicarbonate solution and saturated brine, respectively. The mixture was dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 60:40) to obtain intermediate 23-6 1.38 g. MS(ESI,[M+H]+)m / z:518.4.

[0523] Step 6: Synthesis of Intermediate 23-7 Intermediate 23-6 (1.38 g), tetrahydrofuran (30 mL), and methanesulfonic acid (0.13 g) were mixed, and the mixture was heated to 60°C and reacted for 6 hours. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting crude product was separated and purified by column chromatography (dichloromethane:methanol = 95:5) to obtain intermediate 23-7 0.9 g. MS(ESI,[M+H] + )m / z:454.38.

[0524] Step 7: Synthesis of intermediates 23-8 Intermediate 23-7 (0.4g), intermediate 1-2 (0.33g), N-methylpyrrolidone (4mL), potassium carbonate (0.37g), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (0.063gl), and cuprous iodide (0.067g) were mixed and heated to 130°C under nitrogen gas protection for 3 hours. The reaction solution was poured into water (50mL), extracted with ethyl acetate (50mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting crude product was separated and purified by column chromatography (dichloromethane:methanol = 95:5) to obtain intermediate 23-8 0.56g. MS(ESI,[M+H] + )m / z:625.42.

[0525] Step 8: Synthesis of intermediates 23-9 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 intermediate 23-9 (0.56 g). MS(ESI,[M+H] + )m / z:525.35.

[0526] Step 9: Synthesis of intermediates 23-10 and compound 23 Intermediate B-1 (0.2 g), N,N-dimethylformamide (5 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium 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, and after the addition was complete, the mixture was stirred at room temperature overnight. The reaction mixture was poured into water (50 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting crude product was separated and purified by column chromatography (dichloromethane:methanol = 95:5) to obtain intermediate 23-10 65 mg. The above intermediates 23-10 were separated by chiral HPLC (column: REGIS IB, 30 × 250 mm, 10 μm; mobile phase: n-hexane-ethanol (70:30):dichloromethane = 2:1; flow rate: 40 mL / min) to obtain compound 23 (23 mg). Compound 23:R t =3.31 min (UPCC conditions: Column: CHIRALPAK IB-3, 4.6 × 100 mm, 3 μm; Mobile phase: Carbon dioxide: Methanol (containing 0.1% aqueous ammonia) = 50:50; Flow rate: 2.0 mL / min; Column temperature: 40°C) HRMS:(ESI,[M+H] + )m / z:918.4122. 1H-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) ,2.97-2.88(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),1.83-1.4 4(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).

[0527] Example 24

[0528] [ka]

[0529] Intermediate 22-11 (0.1 g), intermediate 6-2 (0.15 g), N,N-dimethylformamide (3 mL), triethylamine (0.49 g), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.28 g) were mixed, and after mixing, the mixture was stirred overnight at room temperature. After stopping the stirring, the reaction mixture was poured into water (50 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting residue was separated and purified by column chromatography (dichloromethane:methanol = 95:5) to obtain intermediate 24-1 65 mg. The above intermediate 24-1 was separated by chiral HPLC (column: REGIS IB, 30 × 250 mm, 10 μm; mobile phase: n-hexane:ethanol = 56:44; flow rate: 40 mL / min) to obtain compound 24 (21 mg). Compound 24:R t=1.28min (UPCC conditions: CHIRALPAK IB-3, 4.6 × 100mm, 3μm; mobile phase: carbon dioxide: Elastomerアンモニアwater contains)=30:35:35; flow rate: 2.0mL / min; カラム temperature: 40℃) HRMS:(ESI,[M+H] + )m / z:918.4085. 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).

[0530] Example 25

[0531]

change

[0532] ステップ1:Synthesis of intermediate 25-1 Pyridine-N-oxide (2 g) and dichloromethane (15 mL) were mixed, benzoyl chloride (2.96 g) was added under ice bath, and the mixture was stirred and reacted for 30 minutes. Then 1-morpholinocyclopentene (4.19 g) was added, and the mixture was heated to 40°C and reacted for 12 hours. After the reaction was complete, the reaction solution was poured into a 20% hydrochloric acid aqueous solution, the aqueous phase was adjusted to pH 8-9 with a 5N sodium hydrogen oxide aqueous solution, and dichloromethane (100 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column (petroleum ether:ethyl acetate = 15:1) to obtain intermediate 25-1 1.56 g. MS(ESI,[M+H] + )m / z:162.12.

[0533] Step 2: Synthesis of Intermediate 25-2 Intermediate 25-1 (1.37 g), methanol (60 ml), hydroxyamine hydrochloride (0.95 g), and potassium acetate (1.67 g) were mixed and reacted by stirring at 70°C for 1 hour. After the reaction was complete, the reaction mixture was poured into a saturated sodium bicarbonate solution, ethyl acetate (100 mL) was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure to obtain intermediate 25-2 (1.43 g). MS(ESI,[M+H] + )m / z:177.32. 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).

[0534] Step 3: Synthesis of Intermediate 25-3 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 an ice bath. The mixture was stirred and reacted at room temperature for 12 hours. After the reaction was complete, 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 by suction, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column (petroleum ether:ethyl acetate = 20:1) to obtain intermediate 25-3 0.68 g. MS(ESI,[M+H] + )m / z:159.12. 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).

[0535] Step 4: Synthesis of Intermediate 25-4 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 complete, the reaction mixture was poured into a saturated sodium sulfite solution, dichloromethane (100 mL) was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, the filtrate was concentrated under reduced pressure, and the residue was separated and purified using a silica gel column (petroleum ether:ethyl acetate = 40:1) to obtain intermediate 25-4 0.10 g. MS(ESI,[M+H] + )m / z:237.14. 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).

[0536] Step 5: Synthesis of intermediate 25-5 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 under a nitrogen atmosphere at 120°C for 12 hours. After the reaction was complete, the reaction mixture was poured into water, ethyl acetate (50 mL) was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column (dichloromethane:methanol = 20:1) to obtain intermediate 25-5 0.183 g. 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).

[0537] Step 6: Synthesis of intermediates 25-6 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 to allow the reaction to proceed. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain intermediate 25-6 (0.15 g). MS(ESI,[M+H] + )m / z:498.38.

[0538] Step 7: Synthesis of intermediate 25-7 and compound 25 Intermediate B-1 (0.1 g), N,N-dimethylformamide (5 mL), triethylamine (0.68 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.28 g) were mixed and stirred at room temperature for 5 minutes to react. Intermediate 25-6 (0.13 g) was added and stirred at room temperature for 5 hours to react. After the reaction was complete, the reaction mixture was poured into water, ethyl acetate (50 mL) was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column (dichloromethane:methanol = 20:1) to obtain intermediate 25-7 0.12 g. The above intermediates 25-7 were separated by chiral HPLC (column: CHIRALART Cellulose-SB, 30 × 250 mm, 5 μm; mobile phase: ethanol:n-hexane = 43:57; flow rate: 40 mL / min) to obtain compound 25, 26 mg. Compound 25:R t =4.57min (UPCC conditions: Column: CHIRALPAK IB-3 (4.6×100mm, 3μm); Mobile phase: Carbon dioxide:Methanol (containing 0.1% aqueous ammonia) = 60:40; Flow rate: 2.0 ml / min; Column temperature: 40℃) HRMS:(ESI,[M+H] + )m / z:891.4098. 1H-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).

[0539] Example 26

[0540] [ka]

[0541] Step 1: Synthesis of Intermediate 26-1 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, and the reaction mixture was heated to 130°C and stirred for 5 hours. The reaction mixture was poured into ethyl acetate (30 mL) and water (30 mL) to separate the two phases. The aqueous phase was extracted with ethyl acetate (2 × 20 mL), and after combining the organic phases, the mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered by suction, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 50:50) to obtain intermediate 26-1 190 mg. MS(ESI,[M+H] + )m / z:610.41

[0542] Step 2: Synthesis of Intermediate 26-2 Intermediate 26-1 (190 mg) and 4N dioxane hydrochloride solution (10 mL) were mixed and reacted at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain intermediate 26-2 (130 mg). MS(ESI,[M+H] + )m / z:510.34

[0543] Step 3: Synthesis of intermediate 26-3 and compound 26 Intermediate B-1 (100 mg), N,N-dimethylformamide (5 mL), triethylamine (492 mg), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (277 mg) were stirred for 5 minutes, then 26-3 (130 mg) was added, and the mixture was stirred at room temperature for 4 hours to allow it to react. The reaction mixture was poured into water (50 mL), 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 separated by preparative separation using a C18 column (column: Xtimate C18, 21.2 × 250 mm, 5 μm; mobile phase: water (0.1% acetic acid):acetonitrile = 25:75, isocratic elution) to obtain intermediate 26-4 70 mg. The above intermediate 26-4 was separated by chiral HPLC (column: CHIRALART Cellulose-SB, 30 × 250 mm, 5 μm; mobile phase: ethanol-dichloromethane (1:1):n-hexane = 27:73, isocratic elution) to obtain 30 mg of compound 26. Compound 26:R t =2.98 min (UPCC conditions: Column: CHIRALPAK IB, 4.6 × 100 mm, 3 μm; Mobile phase: Carbon dioxide: Isopropanol (containing 0.1% aqueous ammonia): Ethanol = 50:25:25; Flow rate: 0.5 mL / min; Column temperature: 40°C). HRMS:(ESI,[M+H] + )m / z:903.4006. 1H-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).

[0544] Example 27

[0545] [ka]

[0546] Step 1: Synthesis of intermediates 27-1, 27-2, and 27-3 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 complete, the reaction solution was poured into water, ethyl acetate (50 mL) was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate = 1:1) to obtain intermediate 27-1 940 mg. The above intermediate 27-1 was separated by chiral HPLC (column: CHIRALART Cellulose-SB, 30 × 250 mm, 5 μm; mobile phase: ethanol:n-hexane = 43:57; flow rate: 40 mL / min) to obtain intermediate 27-2 450 mg and intermediate 27-3 460 mg. Intermediate 27-2: Rt=3.73min (UPCC conditions: KARALA: CHIRALPAK IB-3 (4.6×100mm, 3μm); mobile phase: carbon dioxide: メタノール (containing 0.1% アンモニアwater) = 40:60; flow rate: 2.0ml / min; カラム temperature: 40℃) MS(ESI,[M+H) + )m / z:613.44. 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). Intermediate 27-3:R t =4.78min (UPCC conditions: カラム:CHIRALPAK IB-3 (4.6×100mm, 3μm); mobile phase: carbon dioxide: メタノール (containing 0.1% アンモニアwater) = 40:60; flow rate: 2.0ml / min; カラム temperature: 40℃) MS(ESI,[M+H) + )m / z:613.43. 1H-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).

[0547] Step 2: Synthesis of intermediate 27-4 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 complete, the reaction mixture was concentrated under reduced pressure to obtain intermediate 27-4 (0.16 g). MS(ESI,[M+H] + )m / z:513.34

[0548] Step 3: Synthesis of intermediate 27-5 and compounds 27-A and 27-B Intermediate B-1 (0.12 g), N,N-dimethylformamide (5 mL), triethylamine (0.393 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.22 g) were mixed and stirred at room temperature for 5 minutes to react. Intermediate 27-4 (0.16 g) was added and stirred at room temperature for 5 hours to react. After the reaction was complete, the reaction mixture was poured into water, ethyl acetate (50 mL) was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column (dichloromethane:methanol = 20:1) to obtain intermediate 27-5 0.2 g. The above intermediate 27-5 was separated by chiral HPLC (column: CHIRALART Cellulose-SB, 30 × 250 mm, 5 μm; mobile phase: ethanol-dichloromethane (1:3):n-hexane = 40:60; flow rate: 40 mL / min) to obtain 78 mg of compound 27-A and 80 mg of compound 27-B. Compound 27-A:R t =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% aqueous ammonia) = 30:70; Flow rate: 2.0 ml / min; Column temperature: 40°C) HRMS:(ESI,[M+H] + )m / z:906.4119. 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). Compound 27-B:R t=1.44min (UPCC conditions: Column: CHIRALPAK IB-3 (4.6×100mm, 3μm); Mobile phase: Carbon dioxide:Methanol / Acetonitrile (1:1) (containing 0.1% aqueous ammonia) = 30:70; Flow rate: 2.0 ml / min; Column temperature: 40℃) HRMS:(ESI,[M+H] + )m / z:906.4116. 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).

[0549] Step 4: Synthesis of intermediate 27-6 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 complete, the reaction mixture was concentrated under reduced pressure to obtain intermediate 27-6 (0.16 g).

[0550] Step 5: Synthesis of intermediate 27-7 and compounds 27-C and 27-D Intermediate B-1 (0.12 g), N,N-dimethylformamide (5 mL), triethylamine (0.39 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.22 g) were mixed and stirred at room temperature for 5 minutes to react. Intermediate 27-6 (0.16 g) was added and stirred at room temperature for 5 hours to react. After the reaction was complete, the reaction mixture was poured into water, ethyl acetate (50 mL) was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column (dichloromethane:methanol = 20:1) to obtain intermediate 27-7 0.2 g. The above intermediate 27-7 was separated by chiral HPLC (column: CHIRALART Cellulose-SB, 30 × 250 mm, 5 μm; mobile phase: ethanol-dichloromethane (1:3):n-hexane = 40:60; flow rate: 40 mL / min) to obtain 74 mg of compound 27-C and 78 mg of compound 27-D. Compound 27-C:R t =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% aqueous ammonia) = 30:70; Flow rate: 2.0 ml / min; Column temperature: 40°C) HRMS:(ESI,[M+H] + )m / z:906.4132. 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). Compound 27-D:R t=1.20min (UPCC conditions: Column: CHIRALPAK IB-3 (4.6×100mm, 3μm); Mobile phase: Carbon dioxide:Methanol / Acetonitrile (1:1) (containing 0.1% aqueous ammonia) = 30:70; Flow rate: 2.0ml / min; Column temperature: 40℃) HRMS:(ESI,[M+H] + )m / z:906.4144. 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).

[0551] Test Example 1: Measurement of in vitro cAMP expression activity at the cellular level HEK293 / CRE-Luc / GLP1R cells (manufacturer: GenScript Biotech) in a good growth state were collected, washed with PBS, digested with pancreatin, and cultured in complete medium. The cells were collected in a centrifuge tube and the cell density was adjusted to 4 × 10⁶ using DMEM + 2% FBS medium. 5 The cells were adjusted to a concentration of 100 μL / well and seeded into a 96-well plate. The cells were incubated at 37°C for 1 hour. After 1 hour, the compound was added using a nanoliter pipette to achieve a final concentration of 10 nM to 0.0006 nM. Two duplicate wells were prepared, and a control was also placed. After continuing to culture in a cell culture incubator for 6 hours, the detection reagent Luciferase (manufacturer: Vazyme Biotech, 50 μL / well) was added, and the cells were left at room temperature for 3 minutes to completely lyse. Luminescence was detected using a PerkinElmer Envision microplate reader, and a 4-parameter analysis was performed. The dose-response curve was fitted, and the EC (Emission Control Value) was measured. 50 The result was calculated.

[0552] Some of the compounds disclosed herein exhibit good in vitro cellular cAMP expression activity. Details are shown in Table 1.

[0553] [Table 1]

[0554] Test Example 2: Measurement of in vitro stability in liver microsomes Liver microsome incubation samples were prepared by mixing PBS buffer (pH 7.4), liver microsome solution (0.5 mg / ml), the test compound, and NADPH + MgCl2 solution, and incubating at 37°C and 300 rpm for 1 hour. The 0-hour sample was prepared by mixing PBS buffer (pH 7.4), liver microsome solution (0.5 mg / ml), and the test compound. The sample was added to an acetonitrile solution containing an internal standard, and the supernatant was prepared by protein precipitation. The supernatant was then diluted and used for LC / MS / MS analysis. The in vitro stability of some compounds in liver microsomes is shown in Table 2.

[0555] [Table 2]

[0556] Some of the compounds disclosed herein exhibit good in vitro stability in liver microsomes.

[0557] Test Example 3: Evaluation of in vivo pharmacokinetics in mice ICR mice weighing 18-22g were acclimated for 3-5 days, then randomly divided into 4 groups of 9 mice each.

[0558] The test compounds were administered at a dose of 10 mg / kg for intragastric administration (IG) and 1 mg / kg for intravenous administration (IV).

[0559] The test animals (ICR mice) were fasted for 12 hours prior to administration and fed 4 hours after administration. They were allowed to freely drink water before, during, and after the experiment.

[0560] Approximately 0.1 mL of blood was collected from the orbit at 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 24 hours after intragastric administration. Approximately 0.1 mL of blood was also collected from the orbit at 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 24 hours after intravenous administration. Blood was collected from each mouse 3 to 4 times, with blood collected from 3 mice at each time point. Whole blood was collected, placed in a centrifuge tube containing EDTA-K2, and stored at 4°C. Plasma was centrifuged within 1 hour at 4°C at 4000 rpm for 10 minutes. After all plasma was recovered, it was immediately stored at -20°C and used for measurement.

[0561] 30 μL of plasma sample to be measured and standard curve sample were collected, 300 μL of acetonitrile solution containing an internal standard (diazepam 20 ng / mL) was added, and the mixture was shaken for 5 minutes to ensure homogeneity. The mixture was then centrifuged at 13,000 rpm for 10 minutes. 80 μL of the supernatant was taken, diluted with 80 μL of ultrapure water, and mixed homogeneously. 2 μL was then collected and used for liquid chromatography-mass spectrometry, and the chromatogram was recorded.

[0562] The in vivo pharmacokinetic properties of some compounds in mice are shown in Table 3.

[0563] [Table 3]

[0564] Some of the compounds disclosed herein have good in vivo pharmacokinetic properties in mice.

[0565] Example 4: Evaluation of blood glucose-lowering effect in mice GLP-1R humanized C57BL / 6J mice weighing 20-22g were used in the experiment. After a 3-day acclimatization period, the experiment was conducted. All animals were kept fasted until the end of the experiment, but they were allowed to drink water freely. Blood was collected from the tip of the mouse's tail in all cases.

[0566] The experimental animals were fasted the night before the experiment, but were allowed to drink water freely. The following day, blood was collected from all animals and their blood glucose levels were measured. Based on blood glucose levels and body weight, the animals were randomly divided into a normal control group, a positive control group, and a test drug group, with 6 animals in each group. Subsequently, the test drug was administered intragastricly to each group. Five hours after administration, a glucose solution (2 g / kg) was administered intraperitoneally. Blood glucose concentrations were measured at 0.25 hours, 0.5 hours, 1 hour, 2 hours, and 3 hours after administration. Blood glucose levels were recorded throughout the experiment, and the area under the blood glucose-time curve (AUC0-180 min⁻¹Glu) was calculated.

[0567] The blood glucose-lowering effects of some compounds in mice are shown in Table 4.

[0568] [Table 4]

[0569] Some of the compounds disclosed herein have a good in vivo blood glucose-lowering effect in mice.

Claims

1. A compound represented by formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (In the formula, X １ , X ２ Each is independently selected from C or N, Y １ , Y ２ , Y ３ or Y ４ Each is independently selected from CH, C, or N. R １ is selected from C １１－１５ cycloalkyl, C １１－１５ aryl, 11- to 15-membered heteroaryl, 11- to 15-membered heterocyclyl, wherein the C １１－１５ cycloalkyl, C １１－１５ aryl, 11- to 15-membered heteroaryl, 11- to 15-membered heterocyclyl is a tricyclic ring, and the C １１－１５ cycloalkyl, C １１－１５ aryl, 11- to 15-membered heteroaryl, 11- to 15-membered heterocyclyl may be independently substituted with one or more R ａ and may be substituted, Alternatively, R １ C ３－７ Selected from cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-7 membered heterocyclyl, the R １ is one C ２－４ It is substituted with alkynyl, R １ Furthermore, independently, one or more R ａ It may be replaced by the above C ２－４ Alkinyl contains one or more R ｂ It may also be replaced with Each R ａ These are independently deuterium, halogen, =O, and deuterated carbon. １－６ Alkyl, -OH, -CN, NH ２ , -COOH, C １－６ Alkyl NH-, (C １－６ Alkyl) ２ N-, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Alkoxy, C １－６ Alkoxy C １－３ Alkylene, C ３－６ Selected from cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl, the deuterated C １－６ Alkyl, C １－６ Alkyl NH-, (C １－６ Alkyl) ２ N-, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Alkoxy or C １－６ Alkoxy C １－３ Alkylene independently comprises one or more R ｃ１ It may be replaced by the above C ３－６ Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl can independently have one or more R ｄ１ It may also be replaced with Each R ２ These are, independently, halogen, -OH, -CN, and NH. ２ , -COOH, C １－６ Alkyl NH-, (C １－６ Alkyl) ２ N-, C １－６ Alkyl, deuterated C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Alkoxy, C １－６ Alkoxy C １－３ Alkylene, C ３－６ Selected from cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl, the C １－６ Alkyl NH-, (C １－６ Alkyl) ２ N-, C １－６ Alkyl, deuterated C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Alkoxy or C １－６ Alkoxy C １－３ Alkylene independently comprises one or more R ｃ２ It may be replaced by the above C ３－６ Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl can independently have one or more R ｄ２ It may also be replaced with Alternatively, R on two adjacent carbon atoms ２ C ４－６ Forming cycloalkyl, phenyl, 5-6 membered heteroaryl or 4-6 membered heterocyclyl, the C ４－６ Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-6 membered heterocyclyl can independently have one or more R ｄ３ It may also be replaced with Each R ３ is independently selected from deuterium, halogen, -OH, -CN, NH ２ , -COOH, C １－６ alkylNH-, (C １－６ alkyl) ２ N-, C １－６ alkyl, deuterated C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ alkoxy, C １－６ alkoxyC １－３ alkylene, C ３－６ cycloalkyl, phenyl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl, and the C １－６ alkylNH-, (C １－６ alkyl) ２ N-, C １－６ alkyl, deuterated C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ alkoxy or C １－６ alkoxyC １－３ alkylene may be independently substituted with one or more R ｃ３ , and the C ３－６ cycloalkyl, phenyl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl may be independently substituted with one or more R ｄ４ . R ４ H, deuterium, halogen, -CN, NH ２ , -COOH, C １－６ Alkyl NH-, (C １－６ Alkyl) ２ N-, C １－６ Alkyl, deuterated C １－６ Alkyl, C １－６ Alkoxy or C １－６ Alkoxy C １－３ Selected from alkylene, C １－６ Alkyl NH-, (C １－６ Alkyl) ２ N-, C １－６ Alkyl, deuterated C １－６ Alkyl, C １－６ Alkoxy or C １－６ Alkoxy C １－３ Alkylene independently comprises one or more R ｃ４ It may also be replaced with Each R ５ These are, independently, halogen, -CN, -OH, -SH, and -NH ２ , C １－６ Alkyl NH-, (C １－６ Alkyl) ２ N-, 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 group, -CONH ２ , -CONHC １－３ Alkyl, -NHCOC １－３ Alkyl, -SO ２ NH ２ , -SO ２ NHC １－３ Alkyl or -NHSO ２ C １－３ Selected from alkyl, the C １－６ Alkyl NH-, (C １－６ Alkyl) ２ N-, 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 group, -CONH ２ , -CONHC １－３ Alkyl, -NHCOC １－３ Alkyl, -SO ２ NH ２ , -SO ２ NHC １－３ Alkyl or -NHSO ２ C １－３ Alkyl molecules can be one or more R groups independently. ｃ５ It may also be replaced with R' and R'' are independently H, halogen, -CN, -OH, -SH, and -NH, respectively. ２ , C １－６ Alkyl NH-, (C １－６ Alkyl) ２ N-, 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 group, -CONH ２ , -CONHC １－３ Alkyl, -NHCOC １－３ Alkyl, -SO ２ NH ２ , -SO ２ NHC １－３ Alkyl or -NHSO ２ C １－３ Selected from alkyl, the C １－６ Alkyl NH-, (C １－６ Alkyl) ２ N-, 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 group, -CONH ２ , -CONHC １－３ Alkyl, -NHCOC １－３ Alkyl, -SO ２ NH ２ , -SO ２ NHC １－３ Alkyl or -NHSO ２ C １－３ Alkyl molecules can be one or more R groups independently. ｃ６ It may also be replaced with Alternatively, R' and R'', together with the carbon atom to which they are bonded, are C ３－６ Forming a cycloalkyl or 3-6 member heterocycloalkyl, the C ３－６ A cycloalkyl or a 3- to 6-membered heterocycloalkyl independently contains one or more R ｄ５ It may also be replaced with each 【Chemistry 2】 Each of these is independently selected from a single bond or a double bond. Each R ｂ These are, independently, deuterium, halogen, -CN, -OH, and -NH. ２ , C １－３ Alkyl or C １－３ Selected from alkoxy, the C １－３ Alkyl or C １－３ Alkoxy are independently deuterium, halogen, OH, CN, or NH ２ It may be substituted with one or more substituents selected from the following: Each R ｃ１ , R ｃ２ , R ｃ３ , R ｃ４ , R ｃ５ and R ｃ６ These are, independently, deuterium, halogen, -CN, -OH, or -NH ２ Selected from, Each R ｄ１ , R ｄ２ , R ｄ３ , R ｄ４ and R ｄ５ These are, independently, deuterium, halogen, -CN, -OH, =O, and -NH. ２ , C １－３ Alkyl or C １－３ Selected from alkoxy, the C １－３ Alkyl or C １－３ Alkoxy are independently deuterium, halogen, OH, CN, or NH ２ It may be substituted with one or more substituents selected from the following: q is selected from 0, 1, 2, 3, or 4. n is selected from 0, 1, 2, 3, or 4. m is selected from 0, 1, 2, 3, or 4.

2. The aforementioned R １ C １１－１５ Selected from aryl or 11-15 member heteroaryl, C １１－１５ The aryl or 11-15 membered heteroaryl is a tricyclic ring, and the C １１－１５ An aryl or an 11-15 membered heteroaryl independently contains one or more R ａ It may also be replaced with Alternatively, R １ Benzo C ７－１１ Condensed bicycloalkyl, 7-11 member benzo-condensed heterobicyclyl, 7-11 member benzo-condensed heterobiaryl, pyrido C ７－１１ Condensed bicycloalkyl, pyride 7-11 member condensed heterobicyclyl, pyride 7-11 member condensed heterobiaryl, pyride C ７－１１ Condensed bicycloalkyl, 7-11 member pyrimide condensed heterobicyclyl, 7-11 member pyrimide condensed heterobiaryl, pyridazino C ７－１１ Condensed bicycloalkyl, pyridazino 7-11 member condensed heterobicycloalkyl, pyridazino 7-11 member condensed heterobiaryl, pyrazino C ７－１１ Condensed bicycloalkyl groups, pyrazino 7-11 member condensed heterobicycloalkyl groups, pyrazino 7-11 member condensed heterobiaryl groups, benzoC ７－１１ Spirobicycloalkyl, Benzo C ７－１１ Spiroheterobicyclyl, Pyrido C ７－１１ Spirobicycloalkyl, Pyrid C ７－１１ Spiroheterobicyclyl, Pyrimide C ７－１１ Spirobicycloalkyl, Pyrimide C ７－１１ Spiroheterobicyclyl, Pyridazino C ７－１１ Spirobicycloalkyl, pyridadino C ７－１１ Spiroheterobicyryl, Pyrazino C ７－１１ Spirobicycloalkyl or pyrazino C ７－１１ Selected from spiroheterobicyclyl, the R １ These are, independently, one or more R ａ It may also be replaced with Alternatively, R １ Benzo C ７－９ Condensed bicycloalkyl, benzo-7-9 member condensed heterobicyclyl, benzo-7-9 member condensed heterobiaryl, pyrido C ７－９ Condensed bicycloalkyl, pyride 7-9 member condensed heterobicyclyl, pyride 7-9 member condensed heterobiaryl, pyride C ７－９ Condensed bicycloalkyl, 7-9 member pyrimide condensed heterobicyclyl, 7-9 member pyrimide condensed heterobiaryl, pyridazino C ７－９ Condensed bicycloalkyl, pyridazino 7-9 member condensed heterobicycloalkyl, pyridazino 7-9 member condensed heterobiaryl, pyridazino C ７－９ Condensed bicycloalkyl groups, pyrazino 7-9 member condensed heterobicycloalkyl groups, pyrazino 7-9 member condensed heterobiaryl groups, benzoC ７－９ Spirobicycloalkyl, Benzo C ７－９ Spiroheterobicyclyl, Pyrido C ７－９ Spirobicycloalkyl, Pyrid C ７－９ Spiroheterobicyclyl, Pyrimide C ７－９ Spirobicycloalkyl, Pyrimide C ７－９ Spiroheterobicyclyl, Pyridazino C ７－９ Spirobicycloalkyl, pyridadino C ７－９ Spiroheterobicyryl, Pyrazino C ７－９ Spirobicycloalkyl or pyrazino C ７－９ Selected from spiroheterobicyclyl, the R １ These are, independently, one or more R ａ It may also be replaced with Alternatively, R １ These are benzo-7-9 member condensed heterobicyclyls, benzo-7-9 member condensed heterobiaryls, and benzo-C ７－９ Spirobicycloalkyl, Benzo C ７－９ Spiroheterobicyclyl or pyridoC ７－９ Selected from spirobicycloalkyl, the R １ These are, independently, one or more R ａ It may also be replaced with Alternatively, R １ These are benzo-7-9 member condensed heterobicyclyls, benzo-7-9 member condensed heterobiaryls, and benzo-C ７－９ Spirobicycloalkyl, Benzo C ７－９ Spiroheterobicyclyl or pyridoC ７－９ Selected from spirobicycloalkyl, the R １ Middle, constituent unit 【Transformation 3】 The ring bonded to is a benzene ring or a pyridine ring, and the R １ These are, independently, one or more R ａ It may also be replaced with Alternatively, R １ These are benzo-7-9 member condensed heterobicyclyls, benzo-C ７－９ Spirobicycloalkyl or benzoC ７－９ Selected from spiroheterobicyclyl, the R １ These are, independently, one or more R ａ It may also be replaced with Alternatively, R １ These are benzo-7-9 member condensed heterobicyclyls, benzo-C ７－９ Spirobicycloalkyl or benzoC ７－９ Selected from spiroheterobicyclyl, the R １ Middle, constituent unit 【Chemistry 4】 The ring bonded to is a benzene ring, and the R １ These are, independently, one or more R ａ It may also be replaced with Alternatively, R １ This is selected from a benzo-5 member heteroaryl condensed 5-member heterocyclyl, a benzo-5 member heteroaryl condensed 6-member heterocyclyl, a benzo-5 member heterocyclyl condensed 5-member heteroaryl, a benzo-5 member cycloalkyl spiro 3-member cycloalkyl, a benzo-5 member heterocyclyl spiro 3-member cycloalkyl, a benzo-5 member heterocyclyl spiro 4-member cycloalkyl, a benzo-5 member cycloalkyl spiro 4-member heterocyclyl, a pyrido-5 member heteroaryl condensed 5-member cycloalkyl, or a pyrido-5 member cycloalkyl spiro 3-member cycloalkyl, and the above R １ These are, independently, one or more R ａ It may also be replaced with Alternatively, R １ This is selected from a benzo-5 member heteroaryl condensed 5-member heterocyclyl, a benzo-5 member heteroaryl condensed 6-member heterocyclyl, a benzo-5 member heterocyclyl condensed 5-member heteroaryl, a benzo-5 member cycloalkyl spiro 3-member cycloalkyl, a benzo-5 member heterocyclyl spiro 3-member cycloalkyl, a benzo-5 member heterocyclyl spiro 4-member cycloalkyl, a benzo-5 member cycloalkyl spiro 4-member heterocyclyl, a pyrido-5 member heteroaryl condensed 5-member cycloalkyl, or a pyrido-5 member cycloalkyl spiro 3-member cycloalkyl, and the above R １ Middle, constituent unit 【Transformation 5】 The ring bonded to is a benzene ring or a pyridine ring, and the R １ These are, independently, one or more R ａ It may also be replaced with Alternatively, R １ This is selected from a benzo-5 member heteroaryl condensed 5-member cycloalkyl, a benzo-5 member heteroaryl condensed 5-member heterocyclil, a benzo-5 member heteroaryl condensed 6-member heterocyclil, a benzo-5 member heterocyclil condensed 5-member heteroaryl, a benzo-5 member cycloalkyl spiro 3-member cycloalkyl, a benzo-5 member heterocyclil spiro 3-member cycloalkyl, a benzo-5 member heterocyclil spiro 4-member cycloalkyl, a benzo-5 member cycloalkyl spiro 4-member heterocyclil, or a pyrido-5 member cycloalkyl spiro 3-member cycloalkyl, and the above R １ These are, independently, one or more R ａ It may also be replaced with Alternatively, R １ This is selected from a benzo-5 member heteroaryl condensed 5-member cycloalkyl, a benzo-5 member heteroaryl condensed 5-member heterocyclil, a benzo-5 member heteroaryl condensed 6-member heterocyclil, a benzo-5 member heterocyclil condensed 5-member heteroaryl, a benzo-5 member cycloalkyl spiro 3-member cycloalkyl, a benzo-5 member heterocyclil spiro 3-member cycloalkyl, a benzo-5 member heterocyclil spiro 4-member cycloalkyl, a benzo-5 member cycloalkyl spiro 4-member heterocyclil, or a pyrido-5 member cycloalkyl spiro 3-member cycloalkyl, and the above R １ Middle, constituent unit 【Transformation 6】 The ring bonded to is a benzene ring or a pyridine ring, and the R １ These are, independently, one or more R ａ It may also be replaced with Alternatively, R １ The R is selected from a benzo-5 membered cycloalkylspiro-3 membered cycloalkyl or a benzo-5 membered heterocyclylspiro-3 membered cycloalkyl, １ These are, independently, one or more R ａ It may also be replaced with Alternatively, R １ The R is selected from a benzo-5 membered cycloalkylspiro-3 membered cycloalkyl or a benzo-5 membered heterocyclylspiro-3 membered cycloalkyl, １ Middle, constituent unit 【Transformation 7】 The ring bonded to is a benzene ring, and the R １ These are, independently, one or more R ａ It may also be replaced with Alternatively, R １ teeth, 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 Selected from, The aforementioned R １ These are, independently, one or more R ａ It may also be replaced with Alternatively, R １ teeth, 【Chemistry 11】 Selected from, The aforementioned R １ These are, independently, one or more R ａ It may also be replaced with Alternatively, R １ teeth, 【Chemistry 12】 Selected from, The aforementioned R １ This is one or more R ａ It may also be replaced with Alternatively, R １ teeth, 【Chemistry 13】 Selected from, The aforementioned R １ These are, independently, one or more R ａ It may also be replaced with Alternatively, R １ is selected from phenyl or a 5-6 member heteroaryl, and the R １ is one C ２－４ It is substituted with alkynyl, R １ Furthermore, independently, one or more R ａ It may be replaced by the above C ２－４ Alkinyl contains one or more R ｂ It may also be replaced with Alternatively, R １ is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and the R １ is one C ２－４ It is substituted with alkynyl, R １ Furthermore, independently, one or more R ａ It may be replaced by the above C ２－４ Alkinyl contains one or more R ｂ It may also be replaced with Alternatively, R １ is selected from phenyl or pyridyl, and the R １ is one C ２－４ It is substituted with alkynyl, R １ Furthermore, independently, one or more R ａ It may be replaced by the above C ２－４ Alkinyl contains one or more R ｂ It may also be replaced with Alternatively, R １ is selected from phenyl or pyridyl, and the R １ It is substituted with one ethynyl or propynyl, R １ Furthermore, independently, one or more R ａ The ethynyl or propynyl may be substituted with one or more R ｂ It may also be replaced with Alternatively, R １ is selected from phenyl or pyridyl, and the R １ R is substituted with one ethynyl or 1-propynyl molecule. １ Furthermore, independently, one or more R ａ The ethynyl or propynyl may be substituted with one or more R ｂ It may also be replaced with Alternatively, R １ is selected from phenyl or pyridyl, and the R １ It is substituted with one ethynyl or propynyl, R １ Furthermore, the ethynyl or propynyl may be independently substituted with one, two, or three substituents selected from F or methyl, and the ethynyl or propynyl may be substituted with one, two, or three methoxy groups. Alternatively, R １ is selected from phenyl or pyridyl, and the R １ It is substituted with one 1-propynyl molecule, R １ The compound described in claim 1, its stereoisomer, or its pharmaceutically acceptable salt, wherein the compound may be independently substituted with one, two, or three F atoms, and the 1-propynyl may be substituted with one methoxy atom.

3. Each R ａ These are, independently, halogen, =O, and deuterium C. １－５ Alkyl, -OH, -CN, NH ２ , C １－５ Alkyl, C ２－４ Alkenil, C ２－４ Alkinyl, C １－５ Alkoxy, C １－５ Alkoxy C １－３ Alkylene, C ３－６ Selected from cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl, the deuterated C １－５ Alkyl, C １－５ Alkyl, C ２－４ Alkenil, C ２－４ Alkinyl, C １－５ Alkoxy or C １－５ Alkoxy C １－３ Alkylene independently comprises one or more R ｃ１ It may be replaced by the above C ３－６ Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl can independently have one or more R ｄ１ It may also be replaced with each R ｂ These are, independently, halogen, -CN, -OH, and -NH ２ Selected from methyl, ethyl, methoxy, or ethoxy, the methyl, ethyl, methoxy, or ethoxy is independently deuterium, halogen, OH, CN, or NH ２ It may be substituted with one or more substituents selected from the following: Alternatively, each R ａ These are, independently, halogen, =O, and deuterium C. １－３ Alkyl, -OH, -CN, NH ２ , C １－３ Alkyl, C ２－４ Alkenil, C ２－４ Alkinyl, C １－３ Alkoxy, C １－３ Selected from alkoxymethylene, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, 5-6 membered heteroaryl, or 3-5 membered heterocyclyl, the deuterated C １－３ Alkyl, C １－３ Alkyl, C ２－４ Alkenil, C ２－４ Alkinyl, C １－３ Alkoxy or C １－３ Alkoxymethylenes are independently one or more R ｃ１ The cyclopropyl, cyclobutyl, cyclopentyl, phenyl, 5-6 membered heteroaryl, or 3-5 membered heterocyclyl may be substituted with one or more R ｄ１ It may also be replaced with Alternatively, each R ａ These are, independently, halogen, =O, and deuterium C. １－３ Alkyl, C １－３ Alkyl or C ３－６ Selected from cycloalkyl, the deuterated C １－３ Alkyl or C １－３ Alkyl molecules can be one or more R groups independently. ｃ１ It may be replaced by the above C ３－６ Cycloalkyl groups may independently contain one or more R groups. ｄ１ It may also be replaced with Alternatively, each R ａ Each of these is independent of F, Cl, Br, I, =O, -CD. ３ , -C ２ D ５ -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 may be independently one or more R ｃ１ The cyclopropyl, cyclobutyl, cyclopentyl, or phenyl may be substituted with one or more R ｄ１ It may also be replaced with Alternatively, each R ａ Each of these is independent of F, Cl, Br, I, =O, -CD. ３ , -C ２ D ５ Selected from -OH, -CN, methyl, ethyl, propyl, methoxymethylene, ethoxymethylene, cyclopropyl, cyclobutyl, or cyclopentyl, wherein the methyl, ethyl, propyl, methoxymethylene, or ethoxymethylene is independently one or more R ｃ１ The cyclopropyl, cyclobutyl, or cyclopentyl may be substituted with one or more R ｄ１ It may also be replaced with Alternatively, each R ａ These are F, Cl, Br, =O, -CD, and are independent of each other. ３ , -C ２ D ５ Selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, or cyclopentyl, wherein methyl, ethyl, and propyl are independently one or more R ｃ１ The cyclopropyl, cyclobutyl, or cyclopentyl may be substituted with one or more R ｄ１ It may also be replaced with Alternatively, each R ａ These are F, methyl, =O, and -CD, respectively, independently. ３ or selected from cyclopropyl, Alternatively, each R ａ Each is independently selected from methyl or =O, Alternatively, each R ａ Each is independently selected from F or methyl, Alternatively, each R ｂ Each of them is independent of C １－３ Selected from alkoxy, the C １－３ Alkoxy are independently deuterium, halogen, OH, CN, or NH ２ It may be substituted with one or more substituents selected from the following: Alternatively, each R ｂ Each of these is independently selected from F, Cl, Br, I, or methoxy. Alternatively, each R ｂ Each of these is independently selected from methoxy, a compound according to claim 1 or 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

4. Each of the aforementioned R ２ These are, independently, halogen, -OH, -CN, and C. １－５ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－５ Alkoxy, C ３－６ Selected from cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl, the C １－５ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl or C １－５ Alkoxy can be one or more R independently. ｃ２ It may be replaced by the above C ３－６ Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl can independently have one or more R ｄ２ It may also be replaced with Alternatively, each R ２ These are, independently, halogen, -OH, -CN, and C. １－３ Alkyl, C ２－４ Alkenil, C ２－４ Alkinyl, C １－３ Alkoxy, C ３－５ Selected from cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-5 membered heterocyclyl, the C １－３ Alkyl, C ２－４ Alkenil, C ２－４ Alkinyl or C １－３ Alkoxy can be one or more R independently. ｃ２ It may be replaced by the above C ３－６ Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl can independently have one or more R ｄ２ It may also be replaced with Alternatively, each R ２ These are halogen and C, respectively, independently. １－３ Alkyl, or C ３－５ Selected from cycloalkyl, the C １－３ Alkyl molecules can be one or more R groups independently. ｃ２ It may be replaced by the above C ３－６ Cycloalkyl groups may independently contain one or more R groups. ｄ２ It may also be replaced with Alternatively, each R ２ Each is independently selected from F, Cl, Br, I, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, or cyclopentyl, and the methyl, ethyl, or propyl is independently one or more R ｃ２ The cyclopropyl, cyclobutyl, or cyclopentyl may be substituted with one or more R ｄ２ It may also be replaced with Alternatively, each R ２ Each is independently selected from F, methyl, or cyclopropyl, and the methyl is independently one or more R ｃ２ The cyclopropyl may be substituted with one or more R ｄ２ It may also be replaced with Alternatively, each R ２ Each is independently selected from F, methyl, or cyclopropyl. Alternatively, R on two adjacent carbon atoms ２ C ５－６ Forming a cycloalkyl, phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocycline, the C ５－６ Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl can independently have one or more R ｄ３ It may also be replaced with Alternatively, R on two adjacent carbon atoms ２ C ５－６ Forming a cycloalkyl or 5-6 membered heterocycline, the C ５－６ Cycloalkyl or 5-6 membered heterocyclyl independently have one or more R ｄ３ It may also be replaced with Alternatively, R on two adjacent carbon atoms ２ C ５－６ Form a cycloalkyl group, and the C ５－６ Cycloalkyl groups may independently contain one or more R groups. ｄ３ It may also be replaced with Alternatively, R on two adjacent carbon atoms ２ Together with the carbon atom bonded to it, it forms cyclopentyl, pyrrolyl, tetrahydrofuranyl, or tetrahydrothienyl, and the cyclopentyl, pyrrolyl, tetrahydrofuranyl, or tetrahydrothienyl independently forms one or more R ｄ３ It may be substituted with, or R on two adjacent carbon atoms ２ Together with the carbon atoms bonded to it, it forms a cyclopentyl, and the cyclopentyl independently has one or more R ｄ３ It may also be replaced with Alternatively, R on two adjacent carbon atoms ２ The compound according to any one of claims 1 to 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein together with a carbon atom bonded thereto, it forms a cyclopentyl compound.

5. The aforementioned X １ , X ２ One is selected from C, and the other is selected from N, Y １ , Y ２ , Y ３ Each is independently selected from C or N, and Y ４ It is selected from CH, Or, Y １ , Y ２ , Y ３ At least one of is selected from N, and Y ４ It is selected from CH, Or, Y １ is selected from C, Y ２ is selected from N, Y ３ is selected from C, Y ４ It is selected from CH, Or, Y １ is selected from C, Y ２ is selected from C, Y ３ is selected from N, Y ４ It is selected from CH, Or, Y １ is selected from N, Y ２ is selected from C, Y ３ is selected from C, Y ４ is a compound selected from CH, according to any one of claims 1 to 4, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

6. Each of the aforementioned R ３ Each of these is independently deuterium, halogen, and C １－３ Alkyl, C ２－４ Alkenil, C ２－４ Alkinyl, C ３－６ Selected from cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl, the C １－３ Alkyl, C ２－４ Alkenil, C ２－４ Alkinyl independently has one or more R ｃ３ It may be replaced by the above C ３－６ Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl can independently have one or more R ｄ４ It may be replaced by the above R ４ H, deuterium, halogen, -CN, C １－３ Alkyl, deuterated C １－３ Alkyl or C １－３ Selected from alkoxy, the C １－３ Alkyl, deuterated C １－３ Alkyl or C １－３ Alkoxy can be one or more R independently. ｃ４ It may be replaced by the above R ５ is halogen, -CN, C １－３ Alkyl, deuterated C １－３ Alkyl or C １－３ Selected from alkoxy, the C １－３ Alkyl, deuterated C １－３ Alkyl or C １－３ Alkoxy can be one or more R independently. ｃ５ It may also be replaced with Alternatively, each R ３ Each of these is independently deuterium, halogen, or C １－３ Selected from alkyl, the C １－３ Alkyl molecules can be one or more R groups independently. ｃ３ It may also be replaced with Alternatively, each R ３ Each is independent of C １－３ Selected from alkyl, the C １－３ Alkyl molecules can be one or more R groups independently. ｃ３ It may also be replaced with Alternatively, each R ３ Each of these is independently selected from deuterium, F, Cl, Br, I, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, or cyclopentyl, and the methyl, ethyl, or propyl is independently one or more R ｃ３ The cyclopropyl, cyclobutyl, or cyclopentyl may be substituted with one or more R ｄ４ It may also be replaced with Alternatively, each R ３ Each is independently selected from methyl, ethyl, or propyl, and the methyl, ethyl, or propyl is one or more R ｃ３ It may also be replaced with Alternatively, the aforementioned R ３ It is selected from methyl, Alternatively, R ４ is H or C １－３ Selected from alkyl, the C １－３ Alkyl molecules can be one or more R groups independently. ｃ４ It may also be replaced with Alternatively, R ４ is selected from H or methyl, and the methyl is one or more R ｃ４ It may also be replaced with Alternatively, R ４ is selected from H or methyl, Alternatively, R ４ It is selected from H, Alternatively, R ４ It is selected from methyl, Alternatively, R ５ C １－３ Selected from alkyl, the C １－３ Alkyl molecules can be one or more R groups independently. ｃ５ It may also be replaced with Alternatively, R ５ is a compound selected from methyl, according to any one of claims 1 to 5, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

7. R' and R'' are each independently H, deuterium, halogen, -CN, and C １－３ Alkyl, deuterated C １－３ Alkyl or C １－３ Selected from alkoxy, the C １－３ Alkyl, deuterated C １－３ Alkyl or C １－３ Alkoxy can be one or more R independently. ｃ６ It may also be replaced with Alternatively, R' and R'' can be H or C independently. １－３ Selected from alkyl, the C １－３ Alkyl molecules can be one or more R groups independently. ｃ６ It may also be replaced with Alternatively, R' and R'' are each independently selected from H or methyl, and the methyl is one or more R ｃ６ It may also be replaced with Alternatively, R' and R'' are both selected from methyl, Alternatively, R' and R'', together with the carbon atom to which they are bonded, are C ３－４ Forming a cycloalkyl or a 3-4 member heterocycloalkyl, the C ３－４ A cycloalkyl or a 3-4 membered heterocycloalkyl independently contains one or more R ｄ５ It may also be replaced with Alternatively, R' and R'', together with the carbon atoms to which they are bonded, form a cyclopropyl group, and the cyclopropyl group independently consists of one or more R ｄ５ It may also be replaced with Alternatively, R' and R'', together with the carbon atoms to which they are bonded, form a cyclopropyl compound, the stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 6.

8. The aforementioned q is selected from 0, 1, 2, or 3, or q is selected from 1, 2, or 3, or q is selected from 2, or q is selected from 3, If desired, m may be selected from 0, 1, 2, or 3, or m may be selected from 0, 1, or 2, or m may be selected from 0, or m may be selected from 1. The compound according to any one of claims 1 to 7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein n is optionally selected from 0, 1, 2, or 3, or n is selected from 1, 2, or 3, or n is selected from 1.

9. Each of the aforementioned R ｃ１ , R ｃ２ , R ｃ３ , R ｃ４ , R ｃ５ and R ｃ６ These are, independently, halogen, -CN, -OH, or -NH ２ Selected from, Alternatively, each R ｃ１ , R ｃ２ , R ｃ３ , R ｃ４ , R ｃ５ and R ｃ６ These are, independently, F, -CN, -OH, or -NH ２ Selected from, Alternatively, each R ｃ１ , R ｃ２ , R ｃ３ , R ｃ４ , R ｃ５ and R ｃ６ Each is independently selected from F or OH. Alternatively, each R ｃ１ , R ｃ２ , R ｃ３ , R ｃ４ , R ｃ５ and R ｃ６ Each is independently selected from F, If desired, each of the above R ｄ１ , R ｄ２ , R ｄ３ , R ｄ４ and R ｄ５ These are, independently, halogen, -CN, -OH, and -NH ２ , C １－３ Alkyl or C １－３ Selected from alkoxy, the C １－３ Alkyl or C １－３ Alkoxy compounds are independently halogens, OH, CN, or NH ２ It may be substituted with one or more substituents selected from the following: Alternatively, each R ｄ１ , R ｄ２ , R ｄ３ , R ｄ４ and R ｄ５ These are F, -CN, -OH, and -NH, respectively, independently. ２ Selected from methyl or methoxy, wherein the methyl or methoxy is independently F, OH, CN, or NH ２ It may be substituted with one or more substituents selected from the following: Alternatively, each R ｄ１ , R ｄ２ , R ｄ３ , R ｄ４ and R ｄ５ These are F, -CN, -OH, and -NH, respectively, independently. ２ Selected from methyl or methoxy, Alternatively, each R ｄ１ , R ｄ２ , R ｄ３ , R ｄ４ and R ｄ５ Each is independently selected from F or methyl, Alternatively, each R ｄ１ , R ｄ２ , R ｄ３ , R ｄ４ and R ｄ５ Each of these is independently selected from F, a compound according to any one of claims 1 to 8, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

10. A compound according to any one of claims 1 to 9, selected from a compound represented by formula (I-A), (I-B), (I-C), or (I-D), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 【Chemistry 14】

11. A compound according to any one of claims 1 to 10, selected from compounds represented by formulas (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), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 【Chemistry 15】 【Chemistry 16】 (In the formula, r is selected from 0, 1, 2, 3 or 4, and X is selected from C or N, X ３ , X ４ , X ５ or X ６ Each is independently selected from C or N, and X ７ , X ８ , X ９ , X １０ or X １１ Each is independently selected from C, CH, or N. Alternatively, X is selected from C, or X is selected from N. Or, X ３ It is selected from N, X ４ , X ５ or X ６ Each is independently selected from C or N, Or, X ３ , X ６ It is selected from N, X ４ , X ５ It is selected from C, Or, X ３ , X ４ It is selected from N, X ５ , X ６ It is selected from C, Or, X ７ and X １１ One is selected from N, and the other is selected from C. Or, X ７ and X ９ It is selected from N, X １１ It is selected from C, X ８ and X １０ It is selected from CH, Alternatively, r is selected from 0, 1, or 2. Alternatively, r is selected from 0 or 2.

12. A compound according to any one of claims 1 to 11, selected from a compound represented by formula (I'), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 【Chemistry 17】

13. A compound according to any one of claims 1 to 12, selected from a compound represented by formula (I-A'), (I-B'), (I-C'), or (I-D'), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. [Chemistry 18]

14. A compound according to any one of claims 1 to 13, selected from a compound represented by 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'), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 【Chemistry 19】 【Chemistry 20】 (In the formula, r is selected from 0, 1, 2, 3 or 4, and X is selected from C or N, X ３ , X ４ , X ５ or X ６ Each is independently selected from C or N, and X ７ , X ８ , X ９ , X １０ or X １１ Each is independently selected from C, CH, or N. Alternatively, 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 claim 11 for the compounds represented by formulas (II-D), (II-F), and (II-J).

15. A compound according to any one of claims 1 to 14, selected from a compound represented by formula (IV-A), a compound represented by formula (IV-A'), formula (IV-B'), or formula (IV-C'), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 【Chemistry 21】 【Chemistry 22】

16. The following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof. 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and further comprising a pharmaceutically acceptable additive.

18. Use of a compound according to any one of claims 1 to 16, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17, in the manufacture of a pharmaceutical for treating a disease related to GLP-1.

19. A method for treating or preventing a GLP-1-related disease, comprising administering a therapeutically effective amount of the compound described in any one of claims 1 to 16, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in claim 17, to a mammal in need of treatment, preferably a human.

20. Use of a compound according to any one of claims 1 to 16, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17, for the treatment of a disease related to GLP-1.

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