Macrocyclic compound

Abstract

Provided in the present invention are a macrocyclic compound as represented by formula (I'), or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof. Further provided in the present invention are a method for preparing the compound, a pharmaceutical composition containing the compound, and the use of the compound in the prevention and treatment of KRAS-mediated diseases such as tumors.

Description

macrocyclic compounds

[0001] This application claims priority to PCT International Application PCT / CN2024 / 128551 filed on October 30, 2024, PCT International Application PCT / CN2025 / 091299 filed on April 25, 2025, and Chinese Application CN202511544174.9 filed on October 27, 2025, all of which are incorporated herein by reference in their entirety. Technical Field

[0002] This invention relates to a macrocyclic compound, or its isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate, or a pharmaceutically acceptable salt thereof. The invention also relates to methods for preparing said compound, pharmaceutical compositions comprising said compound, and the use of said compound in the prevention and treatment of KRAS-mediated diseases such as tumors. Background Technology

[0003] Studies show that approximately 25% of human malignancies are associated with mutations in the RAS family of genes (including NRAS, HRAS, and KRAS), causing nearly one million deaths worldwide each year. KRAS mutations are the most common, accounting for about 85% of all RAS mutations. KRAS has a high mutation rate in pancreatic ductal carcinoma (over 90%), followed by colorectal cancer (about 40%) and lung cancer (about 30%). The most common type of KRAS gene mutation is point mutation, with common mutations including KRAS G12D (about 40%), G12V (about 30%), and G12C (about 15%).

[0004] KRAS protein exists in two forms: an inactive form bound to GDP (guanosine diphosphate) and an activated form bound to GTP (guanosine triphosphate). Under normal physiological conditions, it can be transiently activated by upstream growth factors or tyrosine kinases. Activated KRAS can activate downstream signaling pathways, including RAF-MEK-ERK and PI3K-AKT-mTOR, affecting cell growth and differentiation. In KRAS-mutated tumor cells, the balance between the inactive and activated forms is disrupted, with KRAS primarily existing in the activated state. The molecular switch remains continuously open, leading to sustained activation of downstream signals and resulting in continuous tumor cell proliferation.

[0005] For a long time, KRAS has been considered an untreatable target because it has a high affinity for GTP, which is present in high concentrations in vivo. Secondly, the KRAS catalytic site protein has a flat surface, making it difficult for small molecule drugs to target. However, in recent years, the entry of allosteric inhibitors targeting KRAS reported by Mirati et al. and the KRAS-small molecule-CYPA ternary complex inhibitor reported by Revolution into clinical trials signifies that KRAS-mutant tumors are gradually entering the era of precision medicine. Summary of the Invention

[0006] This invention targets KRAS and develops a new class of small molecule inhibitors that can be used to treat various diseases, such as tumors, especially tumors with KRAS mutations.

[0007] In one aspect, the present invention also provides compounds of formula (I'), or isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates, or pharmaceutically acceptable salts thereof:

[0008] The variables are as defined in this paper.

[0009] In another aspect, the present invention provides a compound of formula (I), or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof:

[0010] The variables are as defined herein. In another aspect, the present invention provides a pharmaceutical composition comprising the compounds of the present invention and optionally pharmaceutically acceptable excipients, such as carriers, adjuvants, or mediators.

[0011] In another aspect, the present invention provides the use of the compounds of the present invention in the preparation of medicaments for treating and / or preventing KRAS-mediated diseases.

[0012] In another aspect, the present invention provides a method for treating and / or preventing KRAS-mediated diseases in a subject, comprising administering the subject a compound of the present invention or a pharmaceutical composition of the present invention.

[0013] In another aspect, the present invention provides compounds or pharmaceutical compositions of the present invention for the treatment and / or prevention of KRAS-mediated diseases.

[0014] In another aspect, the diseases for which the present invention is used to treat and / or prevent are tumors (preferably with KRAS mutations); preferably solid tumors; preferably selected from pancreatic cancer, non-small cell lung cancer and gastrointestinal tumors (e.g., rectal cancer and colorectal cancer).

[0015] definition

[0016] Chemical definition

[0017] The definitions of specific functional groups and chemical terms are described in more detail below.

[0018] When listing a range of values, it is assumed that each value and the subranges within that range are included. For example, "C 1-6 Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3- 5. C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0019] “C 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl, C 1-3 Alkyl and C 1-2 Alkyl groups are preferred. In some embodiments, methyl groups are preferred. C 1-6 Examples of alkyl groups include: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term "C" is used in conjunction with the preceding text. 1-6 "Alkyl" also includes heteroalkyl, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3) or i-Bu(-CH2CH(CH3)2).

[0020] “C 2-6"Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 Alkenyl groups are preferred. In some embodiments, C 2-3 Alkenyl groups are preferred. C 2-6 Examples of alkenyl groups include: vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and so on. The term "C" is used in conjunction with these groups. 2-6 "Alkenyl" also includes heteroalkenyl groups, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkenyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0021] “C 2-6 "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 The alkynyl group is preferred. In some embodiments, C 2-3 Alkyne groups are preferred. C 2-6 Examples of alkynyl groups include, but are not limited to: ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentyynyl (C5), hexynyl (C6), etc. The term "C" is used in conjunction with other alkynyl groups. 2-6 "Alkyne" also includes heteroyne, wherein one or more (e.g., 1, 2, 3 or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkynyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0022] “C 1-6 "Alkylene" refers to the removal of C 1-6 The alkyl group is a divalent group formed by another hydrogen atom, and can be substituted or unsubstituted. In some embodiments, C 1-4 Alkylene, C 2-4 Alkylene, C 1-3 Alkylene, C 1-2Alkylenes and methylene groups are preferred. Unsubstituted alkylenes include, but are not limited to: methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2-), and so on. Exemplary substituted alkylenes, for example, those substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylidenes (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc.

[0023] “C 2-6 "Alkenyl" refers to the group that has been de-carbonied. 2-6 The other hydrogen atom of the alkenyl group forms a divalent group, which can be substituted or unsubstituted. In some embodiments, C 2-4 Alkenyl groups are particularly preferred. In some embodiments, C 2-3 Alkenyl groups are particularly preferred. In some embodiments, vinylidene (-CH=CH-) is particularly preferred. Exemplary unsubstituted alkenyl groups include, but are not limited to, vinylidene (-CH=CH-) and propenylidene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenyl groups, such as alkenyl groups substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted ethylidene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylidene (-C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), etc.

[0024] “C 2-6 "Iso-ynyl group" refers to the group with the C group removed. 2-6 The other hydrogen atom of the alkynyl group forms a divalent group, which can be substituted or unsubstituted. In some embodiments, C 2-4 The acetylinyl group is particularly preferred. In some embodiments, C 2-3The ethynyl group is particularly preferred. Exemplary ethynyl groups include, but are not limited to: ethynyl group (-C≡C-), substituted or unsubstituted propynyl group (-C≡CCH2-), etc.

[0025] “C 0-6 "alkylene" refers to chemical bonds and the aforementioned "C" 1-6 Alkylene", "C" 0-4 "alkylene" refers to chemical bonds and the aforementioned "C" 1-4 Alkylene".

[0026] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0027] Therefore, "C" 1-6 "Halogenated alkyl" refers to the above "C 1-6 "alkyl" is substituted with one or more halogen groups. In some embodiments, C 1-4 Haloalkyl groups are particularly preferred, and C4 groups are more preferred. 1-3 Halogenated alkyl, more preferably C 1-2 Halogenated alkyl groups. Exemplary halogenated alkyl groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CH2CF3, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. In some embodiments, -CH2CF3 is preferred. The halogenated alkyl group can be substituted at any available connection point, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0028] “C 3-10 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 cyclic carbon atoms and zero heteroatoms, wherein it optionally contains 1, 2 or 3 double or triple bonds (e.g., ...). In some implementations, C 5-10 cycloalkyl, C 3-7 cycloalkyl and C 3-6 Cycloalkyl groups are particularly preferred, and C10 is more preferred. 5-7 cycloalkyl and C 5-6 Cycloalkyl. In some embodiments, cyclopropyl is preferred. Cycloalkyl also includes a ring system in which the aforementioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the linking point is on the cycloalkyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Cycloalkyl also includes a cycloalkyl ring in which substituents on any adjacent carbon atoms are linked to form a fused ring, together forming a polycyclic alkane sharing two carbon atoms, for example... Cycloalkyl groups also include the aforementioned cycloalkyl ring, wherein substituents on any non-adjacent carbon atoms are linked to form a bridged ring, together forming a polycyclic alkane sharing two or more carbon atoms, for example... The cycloalkyl group further includes the aforementioned cycloalkyl ring, wherein substituents on the same carbon atom are linked together to form a ring, together forming a polycyclic alkane sharing a single carbon atom. Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), etc. The cycloalkyl group may be optionally substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0029] “C 3-10 "Cycloalkylene" refers to the alkylene group after removing C24. 3-10 The cycloalkyl group is a divalent group formed by another hydrogen atom, and can be substituted or unsubstituted. In some embodiments, C 3-7 Cycloalkylene, C 5-7 Cycloalkylene, C 3-6 Cycloalkylene and C 3-4 Cycloalkylene compounds are particularly preferred, such as cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene, with cyclopropylene being especially preferred.

[0030] "3-10 membered heterocyclic groups" refer to saturated or unsaturated groups of 3- to 10 membered non-aromatic ring systems having a ring carbon atom and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, and optionally contains 1, 2, or 3 double or triple bonds. In heterocyclic groups containing one or more nitrogen atoms, the linkage may be a carbon or nitrogen atom, provided the valence allows. In some embodiments, a 5-10 membered heterocyclic group is preferred, which is a 5-10 membered non-aromatic ring system having a cyclic carbon atom and 1 to 5 cyclic heteroatoms; in some embodiments, a 3-7 membered heterocyclic group is preferred, which is a 3-7 membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms; a 5-7 membered heterocyclic group is preferred, which is a 5-7 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; a 3-6 membered heterocyclic group is preferred, which is a 3-6 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; a 4-6 membered heterocyclic group is preferred, which is a 4-6 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; and a 5-6 membered heterocyclic group is preferred, which is a 5-6 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms. Heterocyclic groups also include ring systems in which the aforementioned heterocyclic ring is fused with one or more cycloalkyl groups, wherein the connection point is on the heterocyclic ring; or ring systems in which the aforementioned heterocyclic ring is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the heterocyclic ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclic ring system. Heterocyclic groups also include the aforementioned heterocyclic ring in which substituents on any adjacent carbon or nitrogen atom are linked to form a fused ring, together forming a polycyclic heteroalkane sharing two carbon or nitrogen atoms. Heterocyclic groups also include the aforementioned heterocyclic ring in which substituents on any non-adjacent carbon or nitrogen atom are linked to form a bridged ring, together forming a polycyclic heteroalkane sharing two or more carbon or nitrogen atoms. Heterocyclic groups also include the aforementioned heterocyclic ring in which substituents on the same carbon atom are linked to form a ring, together forming a polycyclic heteroalkane sharing one carbon atom. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirropropyl, oxadicyclopropyl, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirrobutyl, oxacyclobutyl, and thioheterobutyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolidinyl, and pyrrolidin-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: pyrazolyl, dioxacyclopentyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl.Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithianyl, and dioxane. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirheptanyl, oxaheptanyl, and thianyl. Exemplary 5-membered heterocyclic groups fused with a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to: dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinoneyl, etc. Exemplary 6-membered heterocyclic groups fused with a C6 aryl ring (also referring herein to 6,6-bicyclic heterocyclic groups) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc. Heterocyclic groups also include those that share one or two atoms with a cycloalkyl, heterocyclic, aryl, or heteroaryl group to form a bridged or spirocyclic ring, wherein the shared atom may be a carbon or nitrogen atom, provided the valence allows. Heterocyclic groups also include those that can be optionally substituted with one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0031] "3-10 membered heterocyclic group" refers to a divalent group formed by removing another hydrogen atom from a 3-10 membered heterocyclic group, and can be substituted or unsubstituted. In some embodiments, 3-7 membered heterocyclic groups, 5-7 membered heterocyclic groups, 3-6 membered heterocyclic groups, and 3-4 membered heterocyclic groups are particularly preferred, such as tetrahydrofuranyl and pyranyl. In some embodiments, 3-7 membered heterocyclic groups are preferred, and 5-7 membered heterocyclic groups are more preferred, such as morpholinyl, for example...

[0032] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 shared π electrons arranged in a ring) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). Aryl also includes a ring system in which the above-mentioned aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the connection point is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The aryl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0033] "5-14 membered heteroaryl" refers to a 4n+2 aromatic ring system of a 5-14 membered monocyclic or bicyclic ring (e.g., having 6, 10, or 14 shared π electrons arranged in a ring) having a ring carbon atom and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, provided the valence allows. A heteroaryl bicyclic system may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the bonding point is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-10 membered heteroaryl is preferred, which is a 4n+2 aromatic ring system of a 5-10 membered monocyclic or bicyclic ring having a ring carbon atom and 1-4 ring heteroatoms. In other embodiments, 5-6 membered heteroaryl groups are particularly preferred, which are 4n+2 aromatic ring systems of 5-6 membered monocyclic or bicyclic rings having a cyclic carbon atom and 1-4 cyclic heteroatoms. In other embodiments, 5 membered heteroaryl groups are particularly preferred. Exemplary 5 membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrole, furanyl, and thiophene. Exemplary 5 membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, imidazolidenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5 membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiazolyl. Exemplary 5 membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6 membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridinyl or pyridinoneyl, preferably pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl, and pyrazinyl, preferably pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to: triazinyl and tetraazinyl. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azirmonoheptatrienyl, oxazirmonoheptatrienyl, and thioheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazoleyl, benzotriazolyl, benzothiopheneyl, isobenzothiopheneyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphridinyl, pteridinyl, quinolinyl, isoquinolinyl, zenolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. The heteroaryl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0034] “C 6-10"Asyl" refers to the group that has been depleted of C. 6-10 The aryl group is a divalent group formed by the other hydrogen atom, and can be substituted or unsubstituted. In some embodiments, phenylene is particularly preferred.

[0035] "5-10-membered heteroaryl" refers to a divalent group formed by removing another hydrogen atom from a 5-10-membered heteroaryl group, and can be substituted or unsubstituted. In some embodiments, 5-6-membered heteroaryl groups are particularly preferred, with pyridine groups being the most preferred.

[0036] "Oxytochemical" means "=O".

[0037] The term "two adjacent R4 atoms linked together to form a carbon-carbon double bond" refers to, for example... The two R4s in the middle are connected to form The structure shown is similar to that of the others.

[0038] The divalent groups formed by removing one hydrogen atom from the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups defined above are collectively referred to as "subunits". Cyclic groups such as cycloalkyl, heterocyclic, aryl, and heteroaryl are collectively referred to as "cyclogroups".

[0039] The alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups defined in this article are optional substituted groups.

[0040] Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa -ON(R) bb )2、-N(R bb )2、-N(R bb )3 + X - -N(OR) cc )R bb -SH, -SR aa -SSR cc -C(=O)R aa -CO2H, -CHO, -C(OR) cc )2、-CO2R aa -OC(=O)R aa -OCO2R aa -C(=O)N(R) bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa -NR bb CO2R aa -NR bb C(=O)N(Rbb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bbP(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa 2. -B(OR) cc )2、-BR aa (OR cc ), alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0041] Or the two hydrogen-bearing groups on the carbon atom: =O, =S, =NN(R) bb )2、=NNR bb C(=O)R aa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa =NR bb or = NOR cc replace;

[0042] R aa Each of them is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R aa Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0043] R bb Each is independently selected from: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa-C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, or two R bb Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0044] R cc Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R cc Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0045] R dd Each is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee -ON(R) ff )2、-N(R ff )2,、-N(R ff )3 + X - -N(OR) ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee -OCO2R ee -C(=O)N(R) ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee -NR ff CO2R ee -NR ff C(=O)N(R ff )2、-C(=NR ff ORee -OC(=NR) ff )R ee -OC(=NR) ff OR ee -C(=NR) ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee -SO2N(R) ff )2、-SO2R ee -SO2OR ee -OSO2R ee -S(=O)R ee 、-Si(R ee 3. -OSi(R) ee 3. -C(=S)N(R) ff )2、-C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee -P(=O)2R ee -P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee 2. Alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently marked by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two geminal radicals dd Substituents can combine to form =O or =S;

[0046] R ee Each is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently surrounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0047] R ff Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R ffThe groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0048] R gg Each of these is independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C) 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - -NH(C 1-6 Alkyl)2 + X - -NH2(C 1-6 alkyl) + X - -NH3 + X - -N(OC) 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl groups, -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl group, -CO2H, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1- 6-alkyl), -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2、-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 Alkyl)2、-NHC(=O)NH(C 1-6 Alkyl groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC (=NH)(C 1-6 Alkyl group), -OC (=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6 Alkyl groups, -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C 1-6 Alkyl groups, -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C) 1-6 Alkyl)3、-OSi(C 1-6 Alkyl)3, -C(=S)N(C 1-6 Alkyl)2、C(=S)NH(C 1-6 Alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1- 6-alkyl, -SC(=S)SC 1-6 Alkyl group, -P(=O)2(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2、-OP(=O)(C 1-6 Alkyl)2、-OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two ethryl groups gg Substituents can combine to form =O or =S; where X - It is a counterion.

[0049] Exemplary substituents on the nitrogen atom include, but are not limited to: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) bb )R aa -C(=NR) cc OR aa-C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R atoms attached to a nitrogen atom. cc The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, wherein R aa R bb R cc and R dd As stated above.

[0050] Other definitions

[0051] The terms "tumor" or "cancer" include, but are not limited to, the following diseases: Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, hamartoma, mesothelioma; Gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, hemangioma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor), Kaposi's sarcoma, leiomyosarcoma, hemangioma, lipoma, neurofibroma, fibroma); Large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyosarcoma). Urogenital tract: Kidneys (adenocarcinoma, Wilms' tumor, lymphoma, leukemia), Bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), Prostate (adenocarcinoma, sarcoma), Testes (seminomatous sarcoma, teratoma, embryonal carcinoma, teratoma), Choriocarcinoma, Sarcoma, Stromal cell carcinoma, Fibroma, Fibroadenoma, Adenomatous tumor, Lipoma); Liver: Hepatocellular carcinoma, Bile duct carcinoma, Hepatoblastoma, Angiosarcoma, Hepatocellular adenoma, Hemangioma; Bile tract: Gallbladder carcinoma, Ampullary carcinoma, Bile duct carcinoma; Bone: Osteosarcoma, Fibrosarcoma, Malignant fibrous histiocytoma, Chondrosarcoma, Ewing's sarcoma, Malignant lymphoma (reticular cell sarcoma), Multiple myeloma, Malignant giant cell tumor chordoma, Chronic osteocartilaginous osteophytes. Exostoses, benign chondromas, chondroblastomas, fibrochondromas, chondromyxomas, osteoid osteomas, and giant cell tumors; Nervous system: Skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningeal sarcomas, gliomas), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pineal tumors), glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors); Spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecology: Uterus (endometrial cancer), Cervix (cervical cancer, precancerous cervical dysplasia, etc.), Ovary (ovarian cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), Granulosarcoma, Sertoli stromal cell tumor, dysgerminoma, malignant teratoma), Vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), Vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), Fallopian tube (cancer);Hematology: Blood disorders (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma (MCL), follicular lymphoma, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin disorders: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal gland disorders: neuroblastoma.

[0052] As used herein, the term “treatment” refers to reversing, alleviating, inhibiting, or preventing the progression of an obstacle or condition to which the term applies, or one or more symptoms of such an obstacle or condition. The noun “treatment” as used herein also refers to the action of the verb “to treat,” as defined above.

[0053] As used herein, the term "pharmaceutically acceptable salt" refers to carboxylates and amino acid addition salts of the compounds of the present invention that are suitable for contact with patient tissues within the limits of reliable medical judgment, without producing undue toxicity, irritation, allergic reactions, etc., and are effective for their intended use in proportion to a reasonable benefit / risk ratio, including (where possible) zwitterionic forms of the compounds of the present invention.

[0054] Pharmaceutically acceptable base addition salts are those formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, and calcium. Suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucosamine, and procaine.

[0055] The base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the required base in a conventional manner to form a salt. The free acid can be regenerated by contacting the salt form with an acid in a conventional manner and then separating the free acid. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents; however, for the purposes of this invention, the salts are equivalent to their respective free acids.

[0056] Salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, and iodides prepared from inorganic acids, such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid. Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthate, methanesulfonate, gluconate, lactobionate, laurylsulfonate, and hydroxyethanesulfonate. Salts can also be prepared from organic acids, such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkyl acids, hydroxyalkyl acids, alkyl diacids, aromatic acids, and aliphatic and aromatic sulfonic acids. Representative salts include acetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, caprylates, sebacic acid salts, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, naphthates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartrates, and methanesulfonates. Pharmaceutically acceptable salts may include alkali metal and alkaline earth metal-based cations, such as sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. Salts of amino acids are also included, such as arginine salts, gluconates, and galacturonic acids (see, for example, Berge S. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66:1-19, incorporated herein by reference).

[0057] The term "subject" in the administration includes, but is not limited to: humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0058] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0059] Unless otherwise stated, the term “treatment” as used herein includes effects that occur when a subject has a specific disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or delay or slow the development of the disease, disorder, or condition (“therapeutic treatment”), and also includes effects that occur before a subject begins to have a specific disease, disorder, or condition (“preventive treatment”).

[0060] Generally, the "effective amount" of a compound refers to the amount sufficient to elicit a target biological response. As will be understood by those skilled in the art, the effective amount of the compounds of the present invention can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the administration method, and the age, health status, and symptoms of the subject. Effective amounts include therapeutic effective amounts and prophylactic effective amounts.

[0061] Unless otherwise stated, the term "therapeuticly effective amount" of a compound as used herein is an amount sufficient to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. Therapeuticly effective amount of a compound refers to the amount of a therapeutic agent, used alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeuticly effective amount" may include amounts that improve overall treatment, reduce or prevent symptoms or causes of a disease or condition, or enhance the therapeutic effects of other therapeutic agents.

[0062] Unless otherwise stated, the “preventively effective amount” of a compound as used herein is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or an amount sufficient to prevent recurrence of a disease, disorder, or condition. The preventively effective amount of a compound refers to the amount of a therapeutic agent, used alone or in combination with other agents, that provides preventive benefit in the prevention of a disease, disorder, or condition. The term “preventively effective amount” may include amounts that improve overall prevention or enhance the preventive effect of other preventive agents.

[0063] The term "combination" and related terms refer to the simultaneous or sequential administration of the compounds of the present invention and other therapeutic agents. For example, the compounds of the present invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or simultaneously with other therapeutic agents in a single unit dosage form. Detailed Implementation Plan

[0064] In this document, “compounds of the present invention” refers to compounds of formulas (I), (II), (III), (IV-1), (IV-2) and (IV-3), their isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates, and pharmaceutically acceptable salts thereof.

[0065] In this document, compounds are named using standard nomenclature. For compounds with asymmetric centers, it should be understood (unless otherwise stated) that all optical isomers and mixtures thereof are included. Furthermore, unless otherwise specified, all isomers included in this invention may have carbon-carbon double bonds in the forms of Z and E. Regarding compounds existing in different tautomeric forms, a single compound is not limited to any particular tautomer, but is intended to encompass all tautomeric forms.

[0066] In one embodiment, the present invention provides a compound of formula (I'), or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate, or a pharmaceutically acceptable salt thereof:

[0067] in,

[0068] m and n are independently 0, 1, 2 or 3;

[0069] X1, X2, and X3 are independently selected from -CH2-, -CHF-, -CF2-, -C(O)-, and -O-;

[0070] L1 and L2 are independently selected from -CH2-, -O-, -S-, and -NH-;

[0071] Ring A is selected from C 3-10 Cycloalkylene, 3-10 membered heterocyclic alkylene, C 6-10 aryl and 5-10 heteroaryl compounds, which are optionally replaced by 1, 2, 3 or 4 R1s;

[0072] Ring B is selected from C 3-7 Cycloalkylene, 3-7-membered heterocyclic alkylene, phenylene and 5-6-membered heteroaryl alkylene, which are optionally substituted with 1, 2, 3 or 4 R2 groups;

[0073] Ring C is selected from C 3-7 Cycloalkylene, 3-7-membered heterocyclic alkylene, phenylene and 5-6-membered heteroaryl alkylene, which are optionally substituted with 1, 2, 3 or 4 R3s;

[0074] R1, R2, and R3 are each independently selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups;

[0075] Or R2 and R3 can be connected to form C.1-6 Alkylene, which optionally contains a carbon-carbon double bond, and wherein one or two methylene units are optionally and independently replaced by -O-, -S- or -NR-;

[0076] R is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl and 3-7 membered heterocyclic groups;

[0077] Ring D is selected from C 6-10 arylene and 5-10 quinone heteroarylene;

[0078] R D Selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, which are optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 R4 groups;

[0079] R4 is independently selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic groups; optionally surrounded by 1, 2 or 3 R groups. 4s replace;

[0080] Or two adjacent R4 bonds can be linked together to form a carbon-carbon double bond;

[0081] Or two R4s connected together form C 1-6 Alkylene or C 2-6 The alkenyl group forms a fused ring, bridged ring, or spiro ring structure, wherein one or two methylene units are optionally and independently replaced by -O-, -S-, or -NR-.

[0082] R 4s Independently selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0083] a can be 0, 1, 2, or 3;

[0084] R' D Independently selected from H, D, halogen, CN, -L-OR a -L-SR a-L-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl and 3-7 membered heterocyclic groups;

[0085] R5 is selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally bounded by 1, 2, 3 or 4 R groups. 5s replace;

[0086] R 5s Independently selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0087] Or two Rs 5s They connect to form carbon-carbon double bonds;

[0088] Or two Rs 5s Connect to form C 1-6 The alkylene group forms a fused, bridged, or spirocyclic structure (preferably a fused or bridged ring structure), wherein the alkylene group optionally contains a carbon-carbon double bond, and one or two methylene units therein are optionally and independently replaced by -O-, -S-, or -NR-.

[0089] r is 1, 2, 3, 4, 5, or 6;

[0090] R6 is independently selected from H, D, halogen, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 3-7 cycloalkyl and 3-7 membered heterocyclic groups;

[0091] Or two R6s connected together form C. 1-6The alkylene group forms a fused ring, bridged ring, or spiro ring structure, wherein the alkylene group optionally contains a carbon-carbon double bond, and one or two methylene units therein are optionally and independently replaced by -O-, -S-, or -NR-.

[0092] R7 and R8 are independently selected from H, D, halogen, and C. 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0093] Or CR7R8 forms C 3-7 Cycloalkylene or 3-7 membered heterocyclic alkylene;

[0094] R9 is selected from -L-OR 9a -L-SR 9a -L-NR 9b R 9c ;

[0095] R 9a R 9b and R 9c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclic groups; or R 9b R 9c Together with the atoms they connect, they form 3-7 membered heterocyclic groups;

[0096] R 10 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl and C 2-6 alkynyl group;

[0097] R 11 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups;

[0098] L is independently selected from chemical bonds and C. 1-6 Alkylene;

[0099] R a R b and R c Independently selected from H and C 1-6 Alkyl and C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups; or R b R cTogether with the atoms they connect, they form 3-10 membered heterocyclic groups;

[0100] R 12 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, C 1- 2-alkyl substituted C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl and C 2-6 alkynyl group;

[0101] The aforementioned groups are optionally deuterated, up to and including complete deuteration.

[0102] In a more specific embodiment, the present invention provides a compound of formula (I), or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate, or a pharmaceutically acceptable salt thereof:

[0103] in,

[0104] m and n are independently 0, 1, 2 or 3;

[0105] X1, X2, and X3 are independently selected from -CH2-, -CHF-, -CF2-, -C(O)-, and -O-;

[0106] L1 and L2 are independently selected from -CH2-, -O-, -S-, and -NH-;

[0107] Ring A is selected from C 3-10 Cycloalkylene, 3-10 membered heterocyclic alkylene, C 6-10 aryl and 5-10 heteroaryl compounds, which are optionally replaced by 1, 2, 3 or 4 R1s;

[0108] Ring B is selected from C 3-7 Cycloalkylene, 3-7-membered heterocyclic alkylene, phenylene and 5-6-membered heteroaryl alkylene, which are optionally substituted with 1, 2, 3 or 4 R2 groups;

[0109] Ring C is selected from C 3-7 Cycloalkylene, 3-7-membered heterocyclic alkylene, phenylene and 5-6-membered heteroaryl alkylene, which are optionally substituted with 1, 2, 3 or 4 R3s;

[0110] R1, R2, and R3 are each independently selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NRb R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups;

[0111] Or R2 and R3 can be connected to form C. 1-6 Alkylene, which optionally contains a carbon-carbon double bond, and wherein one or two methylene units are optionally and independently replaced by -O-, -S- or -NR-;

[0112] R is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl and 3-7 membered heterocyclic groups;

[0113] Ring D is selected from C 6-10 arylene and 5-10 quinone heteroarylene;

[0114] R D Selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, which are optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 R4 groups;

[0115] R4 is independently selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic groups; optionally surrounded by 1, 2 or 3 R groups. 4s replace;

[0116] Or two adjacent R4 bonds can be linked together to form a carbon-carbon double bond;

[0117] Or two R4s connected together form C 1-6 Alkylene or C 2-6 The alkenyl group forms a fused ring, bridged ring, or spiro ring structure, wherein one or two methylene units are optionally and independently replaced by -O-, -S-, or -NR-.

[0118] R 4s Independently selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6Alkyl and C 1-6 Halogenated alkyl groups;

[0119] a can be 0, 1, 2, or 3;

[0120] R' D Independently selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl and 3-7 membered heterocyclic groups;

[0121] R5 is selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally bounded by 1, 2, 3 or 4 R groups. 5s replace;

[0122] R 5s Independently selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0123] Or two Rs 5s They connect to form carbon-carbon double bonds;

[0124] Or two Rs 5s Connect to form C 1-6 The alkylene group forms a fused, bridged, or spirocyclic structure (preferably a fused or bridged ring structure), wherein the alkylene group optionally contains a carbon-carbon double bond, and one or two methylene units therein are optionally and independently replaced by -O-, -S-, or -NR-.

[0125] r is 1, 2, 3, 4, 5, or 6;

[0126] R6 is independently selected from H, D, halogen, -L-OR a -L-SR a -L-NR b R c C 1-6Alkyl, C 1-6 Halogenated alkyl, -C 3-7 cycloalkyl and 3-7 membered heterocyclic groups;

[0127] Or two R6s connected together form C. 1-6 The alkylene group forms a fused ring, bridged ring, or spiro ring structure, wherein the alkylene group optionally contains a carbon-carbon double bond, and one or two methylene units therein are optionally and independently replaced by -O-, -S-, or -NR-.

[0128] R7 and R8 are independently selected from H, D, halogen, and C. 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0129] Or CR7R8 forms C 3-7 Cycloalkylene or 3-7 membered heterocyclic alkylene;

[0130] R9 is selected from -L-OR 9a -L-SR 9a -L-NR 9b R 9c ;

[0131] R 9a R 9b and R 9c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclic groups; or R 9b R 9c Together with the atoms they connect, they form 3-7 membered heterocyclic groups;

[0132] R 10 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl and C 2-6 alkynyl group;

[0133] R 11 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups;

[0134] L is independently selected from chemical bonds and C. 1-6 Alkylene;

[0135] R a R b and R c Independently selected from H and C 1-6 Alkyl and C1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups; or R b R c Together with the atoms they connect, they form 3-10 membered heterocyclic groups;

[0136] The aforementioned groups are optionally deuterated, up to and including complete deuteration.

[0137] In a more specific embodiment, the present invention provides the above-described compounds, or isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates thereof, or pharmaceutically acceptable salts thereof, having the structures of formulas (II), (III), (IV-1), (IV-2) and (IV-3):

[0138] in,

[0139] T1, T2, T3, T4, and T5 are independently CH or N;

[0140] s and t are independently 0, 1, or 2;

[0141] q can be 0, 1, 2, 3, 4, 5, or 6;

[0142] Y is selected from CR 4d Or N;

[0143] R 4a R 4b and R 4d Independently selected from H, D, halogens, and C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R 4b With R 4d They connect to form carbon-carbon double bonds;

[0144] Or R 4a and R 4b Connect to form C 1-4 Alkylene or C 2-4 The imide group, wherein one or two methylene units are optionally and independently replaced by -O-, -S- or -NR-;

[0145] R4 is independently selected from H, D, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl group; optionally marked with 1, 2 or 3 R groups 4s replace;

[0146] Alternatively, two adjacent R4 groups may connect to form a carbon-carbon double bond; or an R4 group located adjacent to the Y group may connect with an R4 group. 4dThey connect to form carbon-carbon double bonds;

[0147] Or two R4s connected together form C 1-4 Alkylene or C 2-4 The alkenyl group forms a fused ring, bridged ring, or spiro ring structure (preferably a fused ring or bridged ring structure), wherein one or two methylene units are optionally and independently replaced by -O-, -S-, or -NR-.

[0148] R 4c Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups; optionally surrounded by 1, 2 or 3 R groups. 4s replace;

[0149] p is 1, 2, 3 or 4;

[0150] The remaining variables are as defined in this invention.

[0151] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, having the structure of formula (II):

[0152] in,

[0153] m and n are independently 0, 1, 2 or 3;

[0154] L1 and L2 are independently selected from -CH2-, -O-, -S-, and -NH-;

[0155] Ring A is selected from 3-7-membered heterocyclic groups and 5-6-membered heterocyclic groups, preferably 3-7-membered heterocyclic groups, preferably morpholino groups, which are optionally substituted by 1, 2, 3 or 4 R1s;

[0156] T1, T2, T3, T4, and T5 are independently CH or N; preferably, T3 is N.

[0157] R1 is independently selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl and 3-7 membered heterocyclic groups;

[0158] R2 is selected from H, D, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0159] R3 is selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0160] Or R2 and R3 can be connected to form C. 1-6 Alkylene, which optionally contains a carbon-carbon double bond, and wherein one or two methylene units are optionally and independently replaced by -O-, -S- or -NR-;

[0161] R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0162] s and t are independently 0, 1, or 2;

[0163] q can be 0, 1, 2, 3, 4, 5, or 6;

[0164] Y is selected from CR 4d Or N;

[0165] R 4d Selected from H, D, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0166] R4 is independently selected from H, D, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl group; optionally marked with 1, 2 or 3 R groups 4s replace;

[0167] Alternatively, two adjacent R4 groups may connect to form a carbon-carbon double bond; or an R4 group located adjacent to the Y group may connect with an R4 group. 4d They connect to form carbon-carbon double bonds;

[0168] Or two R4s connected together form C 1-4 Alkylene or C 2-4 The alkenyl groups form fused, bridged, or spirocyclic structures (preferably fused or bridged), or R4 and R 4c Connect to form C 1-4 Alkylene or C 2-4 The alkenyl group forms a fused or bridged ring structure (preferably a fused ring structure), wherein one or two methylene units are optionally and independently replaced by -O-, -S- or -NR-.

[0169] R 4c Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups; optionally surrounded by 1, 2 or 3 R groups. 4s replace;

[0170] R 4sIndependently selected from H, D, halogens, and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0171] R5 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7-membered heterocyclic, phenyl, and 5-6-membered heteroaryl groups, optionally surrounded by 1, 2, 3, or 4 R groups. 5s replace;

[0172] R 5s Independently selected from H, D, halogen, CN, -OR a -SR a -NR b R c C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0173] Or two Rs 5s They connect to form carbon-carbon double bonds;

[0174] Or two Rs 5s Connect to form C 1-6 Alkylene (preferably C) 1-4 Alkylenes are used to form fused, bridged, or spirocyclic structures (preferably fused or bridged), wherein the alkylene optionally contains a carbon-carbon double bond and one or two methylene units therein are optionally and independently replaced by -O-, -S-, or -NR-.

[0175] r is 2, 3, 4, 5 or 6; preferably 2 or 3;

[0176] R6 is independently selected from H, D, halogen, and -OR. a -SR a -NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl groups and 3-7 membered heterocyclic groups; and

[0177] There are two R6 connected to form C 1-6 Alkylene (preferably C) 1-4 Alkylene, preferably C 1-2 Alkylenes, preferably methylene, are used to form fused, bridged, or spirocyclic structures (preferably fused or bridged, especially bridged), wherein the alkylene optionally contains a carbon-carbon double bond and one or two methylene units are optionally and independently replaced by -O-, -S-, or -NR-.

[0178] R7 and R8 are independently selected from H, D, halogen, and C. 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0179] Or CR7R8 forms C 3-7 Cycloalkylene or 3-7 membered heterocyclic alkylene;

[0180] R9 is selected from -OR 9a -SR 9a -NR 9b R 9c Preferred - OR 9a ;

[0181] R 9a R 9b and R 9c Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0182] R 10 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl and C 2-6 alkynyl group;

[0183] R 11 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups;

[0184] L is independently selected from chemical bonds and C. 1-6 Alkylene;

[0185] R a R b and R c Independently selected from H and C 1-6 Alkyl and C 1-6 Haloalkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups; or R b R c Together with the atoms they connect, they form 3-7 membered heterocyclic groups;

[0186] The aforementioned groups are optionally deuterated, up to and including complete deuteration.

[0187] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, having the structure of formula (III):

[0188] in,

[0189] m and n are independently 0, 1, 2 or 3; preferably 1;

[0190] L1 is selected from -CH2-, -O-, -S-, and -NH-; preferably -CH2- and -O-; preferably -CH2-;

[0191] T1 is CH or N;

[0192] R2 is selected from H, D, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0193] R3 is selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0194] Or R2 and R3 can be connected to form C. 1-6 Alkylene, preferably C 1-4 Alkylene, which optionally contains a carbon-carbon double bond, and wherein one or two methylene units are optionally and independently replaced by -O-, -S- or -NR-;

[0195] R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0196] Y is selected from CR 4d and N;

[0197] R 4a R 4b and R 4d Independently selected from H, D, halogens, and C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably H or D; or R 4b With R 4d They connect to form carbon-carbon double bonds;

[0198] Or R 4a and R 4b Connect to form C 1-4 Alkylene or C 2-4 Ideonyl groups, preferably forming C 2-3 The alkenyl group, wherein one or two methylene units are optionally and independently replaced by -O-, -S- or -NR-; preferably forming -CH=CH-;

[0199] R 4c Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups; preferably C3-7 Cycloalkyl and 3-7 membered heterocyclic groups; preferably C 3-7 Cycloalkyl; preferably cyclopropyl; optionally marked with 1, 2 or 3 R's 4s replace;

[0200] R 4s Independently selected from H, D, halogens, and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0201] R5 is selected from C 3-7 Cycloalkyl, 3-7-membered heterocyclic, phenyl, and 5-6-membered heteroaryl groups, optionally surrounded by 1, 2, 3, or 4 R groups. 5s replace;

[0202] R 5s Independently selected from H, D, halogens, CN, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0203] Or two Rs 5s They connect to form carbon-carbon double bonds;

[0204] Or two Rs 5s Connect to form C 1-4 The alkylene group forms a fused, bridged, or spirocyclic structure (preferably a fused or bridged ring structure), wherein the alkylene group optionally contains a carbon-carbon double bond, and one or two methylene units therein are optionally and independently replaced by -O-, -S-, or -NR-.

[0205] p is 1, 2, 3 or 4; preferably 1 or 2; preferably 1;

[0206] R6 is selected from H, D, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl group; preferably H or D;

[0207] R7 and R8 are independently selected from H, D, halogen, and C. 1-3 Alkyl and C 1-3 Halogenated alkyl; preferably C 1-3 Alkyl and C 1-3 Halogenated alkyl; preferably C 1-3 Alkyl; preferably Me;

[0208] Or CR7R8 forms C 3-7 Cycloalkylene; preferably C 3-4 Cycloalkylene; preferably cyclopropylene;

[0209] R 10 Selected from C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated alkyl, C2-3 alkenyl and C 2-3 alkynyl group;

[0210] R 11 Selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0211] The aforementioned groups are optionally deuterated, up to and including complete deuteration.

[0212] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ⅳ-1), (Ⅳ-2) or (Ⅳ-3):

[0213] in,

[0214] T1 is CH or N;

[0215] R2 is selected from H, D, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl group; preferably H or D;

[0216] R3 is selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably C 1-6 Halogenated alkyl groups;

[0217] Or R2 and R3 can be connected to form C. 1-6 Alkylene, preferably C 1-4 Alkylene, which optionally contains a carbon-carbon double bond, and wherein one or two methylene units are optionally and independently replaced by -O-, -S- or -NR-;

[0218] R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0219] R5 is selected from C 3-7 Cycloalkyl, 3-7 membered heterocyclic, phenyl and 5-6 membered heteroaryl, preferably C 3-7 Cycloalkyl, 3-7-membered heterocyclic and 5-6-membered heteroaryl groups, optionally surrounded by 1, 2, 3 or 4 R groups. 5s replace;

[0220] R 5s Independently selected from H, D, halogens, CN, C 1-6 Alkyl and C 1-6 Haloalkyl; preferably H, D and halogen (e.g. F);

[0221] Or two Rs5s They connect to form carbon-carbon double bonds;

[0222] Or two Rs 5s Connect to form C 1-4 Alkylene (preferably C) 1-2 Alkylenes, preferably methylene, are used to form fused, bridged, or spirocyclic structures (preferably fused or bridged), wherein the alkylene optionally contains a carbon-carbon double bond, and one or two methylene units are optionally and independently replaced by -O-, -S-, or -NR-.

[0223] R 10 Selected from C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated alkyl, C 2-3 alkenyl and C 2-3 Alkyne group; preferably C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 2-3 alkynyl group;

[0224] R 11 Selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably C 1-6 alkyl;

[0225] The aforementioned groups are optionally deuterated, up to and including complete deuteration;

[0226] Preferably,

[0227] T1 is CH or N;

[0228] R2 is H;

[0229] R3 is -CH2CF3;

[0230] Or R2 and R3 can be connected to form -CH2CH2CH2-;

[0231] R5 is selected from

[0232] R 10 It can be Me, -CD3, or ethynyl.

[0233] R 11 For Me.

[0234] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ⅳ-1), (Ⅳ-2) or (Ⅳ-3), wherein: T1 is CH or N; preferably T1 is CH;

[0235] R2 is selected from H, D, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl group; preferably H or D;

[0236] R3 is selected from C 1-3 Alkyl and C 1-3 Halogenated alkyl; preferably C 1-3 Halogenated alkyl; more preferably -CH2CF3;

[0237] Or R2 and R3 can be connected to form -CH2CH2CH2-;

[0238] R5 is selected from C 5-7 Cycloalkyl group, which optionally contains a carbon-carbon double bond; preferably R5 is selected from C. 5-6 cycloalkyl groups, which optionally contain a carbon-carbon double bond;

[0239] R 10 Selected from C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 2-3 Alkyne group; preferably R 10 For Me;

[0240] R 11 Selected from C 1-3 Alkyl and C 1-3 Halogenated alkyl; preferably R 11 For Me;

[0241] The aforementioned groups are optionally deuterated, up to and including complete deuteration;

[0242] Preferably,

[0243] T1 is CH;

[0244] R2 is H;

[0245] R3 is -CH2CF3;

[0246] R5 is selected from R5 is preferably selected from

[0247] R 10 For Me;

[0248] R 11 For Me.

[0249] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0250] m and n are independently 1;

[0251] X1, X2, and X3 are independently selected from -CH2-;

[0252] L1 and L2 are independently selected from -CH2-;

[0253] Ring A is selected from 3-10 member subheterocyclic groups; preferably...

[0254] Ring B is selected from phenylene; it is optionally substituted with 1, 2, 3 or 4 R2 groups;

[0255] Cyclic C is selected from 5-6 member heteroaryl groups; preferably...

[0256] R2 is selected from -CH2CF3;

[0257] Ring D is selected from 5-10 heteroaryl groups; preferably...

[0258] R D Selected from 3-10 membered heterocyclic groups, which are optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 R4 groups; preferably, R4 is a heterocyclic group. D Selected from

[0259] R4 is independently selected from cyclopropyl;

[0260] a is 0;

[0261] R5 is selected from C 3-10 cycloalkyl;

[0262] r is 2, and two R6s are connected to form C. 1-6 Alkyl groups are used to form fused ring, bridged ring, or spiro ring structures; preferably, r is 2, and two R6 groups are linked to form a methylene group to form a 4-membered bridged ring.

[0263] R7 and R8 are independently selected from Me;

[0264] R9 is selected from -O-CH3;

[0265] R 10 Selected from Me;

[0266] R 11 Selected from Me;

[0267] R12 Selected from cyclopropyl or vinyl;

[0268] The aforementioned groups are optionally deuterated, up to and including complete deuteration.

[0269] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0270] Ring D is selected from 5-10 heteroaryl groups; preferably...

[0271] R D Selected from 3-10 membered heterocyclic groups, which are optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 R4 groups; preferably, R4 is a heterocyclic group. D Selected from Preferred

[0272] R4 is selected from cyclopropyl;

[0273] R 10 Selected from methyl, CD3 and acetylene;

[0274] R 12 Selected from C 1-4 Cyclopropyl groups substituted with alkyl, vinyl, cyclopropyl, and methyl groups; preferably cyclopropyl groups substituted with ethyl, n-propyl, isopropyl, tert-butyl, vinyl, cyclopropyl, and methyl groups; preferably cyclopropyl groups not substituted with methyl groups.

[0275] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0276] m and n are independently 1;

[0277] X1, X2, and X3 are independently selected from -CH2-;

[0278] L1 and L2 are independently selected from -CH2-;

[0279] Ring A is selected from 3-10 member subheterocyclic groups; preferably...

[0280] Ring B is selected from phenylene; it is optionally substituted with 1, 2, 3 or 4 R2 groups;

[0281] Cyclic C is selected from 5-6 member heteroaryl groups; preferably...

[0282] R2 is selected from -CH2CF3;

[0283] a is 0;

[0284] R5 is selected from C 3-10 Cycloalkyl or 5-10 heteroaryl; preferably C 3-10 cycloalkyl;

[0285] r is 2, and two R6s are connected to form C. 1-6 Alkyl groups are used to form fused ring, bridged ring, or spiro ring structures; preferably, r is 2, and two R6 groups are linked to form a methylene group to form a 4-membered bridged ring.

[0286] R7 and R8 are independently selected from Me;

[0287] R9 is selected from -O-CH3;

[0288] R 11 Selected from Me.

[0289] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0290] R5 is selected from C 3-7 Cycloalkyl, 3-7-membered heterocyclic or 5-6-membered heteroaryl; preferably selected from...

[0291] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0292] R5 is C 3-7 cycloalkyl; preferably selected from More

[0293] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R5 is selected from...

[0294] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R5 is selected from...

[0295] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R5 is selected from...

[0296] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein in formula (Ⅳ-1), formula (Ⅳ-2) or formula (Ⅳ-3):

[0297] T1 is CH;

[0298] R2 is H;

[0299] R3 is -CH2CF3;

[0300] R5 is C 3-7 cycloalkyl; preferably selected from

[0301] R 10 For Me;

[0302] R 11 For Me.

[0303] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein in formula (Ⅳ-1), formula (Ⅳ-2) or formula (Ⅳ-3):

[0304] R5 is selected from

[0305] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein in formula (Ⅳ-1), formula (Ⅳ-2) or formula (Ⅳ-3): R5 is selected from...

[0306] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein in formula (Ⅳ-1), formula (Ⅳ-2) or formula (Ⅳ-3): R5 is selected from...

[0307] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the following compounds:

[0308] Preferably, the compound is selected from one of the following compounds:

[0309] In a more specific embodiment, the present invention also provides pharmaceutical compositions comprising the above-described compound, or isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates thereof, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients, and optionally other therapeutic agents.

[0310] In a more specific embodiment, the present invention also provides the use of the above-described compound, or isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates thereof, or pharmaceutically acceptable salts thereof, in the preparation of medicaments for the treatment or prevention of KRAS-mediated diseases.

[0311] In a more specific embodiment, the present invention also provides the use of the above-described pharmaceutical composition in the preparation of a medicament for treating or preventing KRAS-mediated diseases.

[0312] In a more specific embodiment, the present invention also provides a method for treating or preventing KRAS-mediated disease in a subject, comprising administering to the subject a compound of the present invention, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

[0313] In a more specific embodiment, the present invention also provides the above-described compounds, or isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates thereof, or pharmaceutically acceptable salts thereof, or the above-described pharmaceutical compositions of the present invention, for the treatment or prevention of KRAS-mediated diseases.

[0314] In a more specific embodiment, the invention also provides for use in the preparation of a medicament for treating or preventing KRAS-mediated diseases, wherein the disease is a tumor (preferably with a KRAS mutation); preferably a solid tumor; preferably selected from pancreatic cancer, non-small cell lung cancer, and gastrointestinal tumors (e.g., rectal cancer, colorectal cancer). The tumor is further preferably pancreatic cancer, non-small cell lung cancer, or colorectal cancer.

[0315] In a more specific embodiment, the present invention also provides a method for treating or preventing KRAS-mediated diseases, wherein the disease is a tumor (preferably with a KRAS mutation); preferably a solid tumor; preferably selected from pancreatic cancer, non-small cell lung cancer, and gastrointestinal tumors (e.g., rectal cancer, colorectal cancer). The tumor is further preferably pancreatic cancer, non-small cell lung cancer, or colorectal cancer.

[0316] In a more specific embodiment, the present invention also provides the use of the above-described compounds or pharmaceutical compositions as medicines for the treatment or prevention of KRAS-mediated diseases, wherein said disease is a tumor (preferably with a KRAS mutation); preferably a solid tumor; preferably selected from pancreatic cancer, non-small cell lung cancer, and gastrointestinal tumors (e.g., rectal cancer, colorectal cancer). The tumor is further preferably pancreatic cancer, non-small cell lung cancer, or colorectal cancer.

[0317] In a more specific embodiment, the tumor of the present invention is preferably pancreatic cancer.

[0318] In a more specific embodiment, the tumor of the present invention is preferably non-small cell lung cancer.

[0319] In a more specific embodiment, the tumor of the present invention is preferably colorectal cancer.

[0320] In a more specific embodiment, the present invention also provides the following synthesis method:

[0321] (1) Synthesis of intermediate 1

[0322] (2) Synthesis of intermediate 2

[0323] (3) Synthesis of intermediate 3

[0324] (4) Synthesis of the compounds of the present invention

[0325] The reaction conditions for the above synthetic routes can be determined and selected by those skilled in the art based on existing technology, or the reaction conditions disclosed in WO2023060253A1 can be referred to.

[0326] The proportions or percentages of eluents, rinsing solutions, mobile phases, or mobile phase components mentioned in the reference examples and embodiments of the present invention, or the proportions or percentages between them, all refer to volume ratios.

[0327] Reference Example 1: Compound INT-3

[0328] Step 1

[0329] At room temperature, lithium hydroxide (38.1 g, 907 mmol) and water (200 L) were added to a tetrahydrofuran (1 L) solution of compound INT-3-1 (100 g, 226 mmol). The reaction mixture was stirred at 25 °C for 2 hours. After dilution with water (500 mL), the reaction mixture was extracted with ethyl acetate (500 mL x 3), and the organic phases were combined. The combined organic layers were then washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the target compound INT-3-2. LC-MS: m / z: 431.0 [M+23] + .

[0330] Step 2

[0331] To a solution of compound INT-3-2 (13.1 g, 32.0 mmol) in dichloromethane (200 mL), compounds INT-3-3 (5.00 g, 32.0 mmol), N,N-diisopropylethylamine (DIEA) (15.8 mL, 96.0 mmol), and 2-(7-azobenzotriazole)-tetramethylurea hexafluorophosphate (HATU) (14.6 g, 38.4 mmol) were added. The reaction mixture was stirred at 25 °C for 2 hours. After dilution with water (100 mL), the reaction mixture was extracted with dichloromethane (250 mL x 3), and the organic phases were combined. The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (water / acetonitrile = 3 / 2) to give the target compound INT-3-4. LC-MS: m / z: 547.0 [M+1] + .

[0332] Step 3

[0333] A solution of dichloromethane (50 mL) containing 14.1 g (25.8 mmol) of compound INT-3-4 was added to a solution of dioxane hydrochloride (20 mL, 4 M), and the reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give the target compound INT-3. LC-MS: m / z: 447.2 [M+1] + .

[0334] Reference Example 2: Compound INT-4

[0335] Step 1

[0336] Under nitrogen protection, compound INT-4-1 (100 g, 250 mmol) was dissolved in 2-methyltetrahydrofuran (1000 mL), and pinacol diboronate (190 g, 749 mmol), potassium neopentanoate (87.6 g, 625 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (Pd(dppf)Cl2) (5.48 g, 7.49 mmol) were added. The mixture was stirred at 90 °C for 0.5 h. The reaction solution was diluted with water (2000 mL) and extracted with ethyl acetate (1500 mL x 3). The organic phases were combined. The combined organic layers were then washed with brine (1000 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was slurried overnight in n-heptane (1000 mL), filtered, and the collected solid was evaporated to dryness on a rotary evaporator to obtain compound INT-4-2. LC-MS: m / z: 448.2 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ: 8.31 (d, J = 3.2Hz, 1H), 7.42 (d, J = 3.2Hz, 1H), 4.80 (q, J = 6.4Hz, 1H), 3.60-3.56(m,4H),3.23(s,3H),3.17-3.12(m,4H),1.47(s,9H),1.46(s,3H),1.36(s,12H).

[0337] Step 2

[0338] Under nitrogen protection, compounds INT-4-2 (40.0 g, 89.4 mmol) and INT-4-3 (57.8 g, 89.4 mmol) were dissolved in 1,4-dioxane (800 mL) and water (160 mL). Potassium carbonate (30.9 g, 224 mmol) and Pd(dppf)Cl2 (3.27 g, 4.47 mmol) were added, and the mixture was stirred at 70 °C for 18 hours. The reaction solution was diluted with water (500 mL) and extracted with ethyl acetate (800 mL x 3). The organic phases were combined. The combined organic layers were then washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent: ethyl acetate / petroleum ether, where ethyl acetate accounted for 0-50% by volume) to give compound INT-4-4. LC-MS: m / z: 839.8, 841.4 [M+1] + .

[0339] Step 3

[0340] To a mixture of compound INT-4-4 (50.0 g, 59.5 mmol) and cesium carbonate (58.2 g, 179 mmol) in N,N-dimethylformamide DMF (250 mL), 2,2,2-trifluoroethyltrifluoromethanesulfonate (41.5 g, 179 mmol) was added, and the mixture was stirred at 25 °C for 16 hours. The mixture was then poured into water, extracted with ethyl acetate (EtOAc), concentrated, and purified by column chromatography (PE / EtOAc = 3 / 1) to give compound INT-4-5. 1 H NMR(400MHz, CDCl3)δ:8.43(d,J=2.8Hz,1H),7.86(d,J=1.8Hz,1H),7.64-7.55(m,4H),7.45-7.32(m,7 H),7.28(s,1H),7.12(d,J=1.6Hz,1H),4.46(d,J=8.8Hz,2H),3.89(d,J=6.4Hz,1H),3.63-3.50(m,4H) ,3.40(d,J=9.6Hz,1H),3.30(d,J=9.6Hz,1H),3.16-3.04(m,4H),2.94(s,3H),2.70(d,J=14.1Hz,1H), 2.41(d,J=14.0Hz,1H),1.48(s,9H),1.43-1.41(m,3H),1.02(d,J=8.3Hz,9H),0.75(d,J=13.8Hz,6H).

[0341] Step 4

[0342] Compound INT-4-5 (500 mg, 0.542 mmol) was dissolved in dioxane hydrochloride (5 mL), and then stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure to give compound INT-4-6. LC-MS: m / z: 821.4 [M+1] + 823.4[M+1] + .

[0343] Step 5

[0344] Compound INT-4-7 (212 mg, 1.22 mmol) and sodium cyanoborohydride (76.5 mg, 1.22 mmol) were added to a solution of compound INT-4-6 (500 mg, 0.608 mmol) in isopropanol (5 mL) at 25 °C. The mixture was stirred at 50 °C for 18 hours. The mixture was quenched with H₂O (50 mL) and extracted with EtOAc (50 mL x 3). The organic phases were combined. The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give compound INT-4-8. LC-MS: m / z: 861.2, 863.2 [M+1] + .

[0345] Step 6

[0346] A 1M solution of TBAF in THF was added to a 5 mL solution of compound INT-4-8 (500 mg, 0.580 mmol) in tetrahydrofuran (THF). The reaction mixture was stirred at 50 °C for 18 hours. The mixture was quenched with NH4Cl and extracted with EtOAc (15 mL x 3). The organic phases were combined. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give compound INT-4-9. LC-MS: m / z: 623.2, 625.2 [M+1] + .

[0347] Step 7

[0348] At 25 °C, imidazole (43.7 mg, 0.641 mmol) and TBSCl (72.5 mg, 0.481 mmol) were added to a DCM (5 mL) solution of compound INT-4-9 (200 mg, 0.321 mmol). The reaction mixture was stirred at 25 °C for 18 hours. The reaction mixture was extracted with EtOAc and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (80% EA / PE) to give compound INT-4-10. LC-MS: (ESI) m / z: 737.2, 739.2 [M+1] + .

[0349] Step 8

[0350] Compounds INT-4-11 (35.0 mg, 0.108 mol), [2'-(amino)[1,1'-biphenyl]-2-yl][[2',6'-di(1-methylethoxy)[1,1'-biphenyl]-2-yl]dicyclohexylphosphine]palladium chloride (RuPhos Pd G2) (8.42 mg, 0.011 mmol), Pd(OAc)2 (2.43 mg, 0.011 mmol), 2-dicyclohexylphosphine-2′,6′-diisopropoxy-1,1′-biphenyl (RuPhos) (10.2 mg, 0.022 mmol), and Cs2CO3 (177 mg, 0.542 mmol) were added to a dioxane (1 mL) solution of compound INT-4-10 (80 mg, 0.108 mmol). The reaction mixture was stirred at 100 °C for 2 hours. The reaction mixture was extracted with EtOAc and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% DCM / MeOH) to give compound INT-4-12. LC-MS: m / z: 490.6 [M+2] 2+ .

[0351] Step 9

[0352] Compound INT-4-12 (3.0 g, 3.06 mmol) was dissolved in tetrahydrofuran (30 mL) and water (6 mL), and lithium hydroxide monohydrate (0.3 g, 7.66 mmol) was added. The mixture was stirred at 25 °C for 3 hours. The reaction solution was acidified to pH 5–6 with 6 M hydrochloric acid solution under ice bath conditions. The reaction solution was extracted with ethyl acetate (50 mL x 3). The mixture was then washed with brine (50 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give compound INT-4-13. LC-MS: m / z: 965.4 [M+1] + .

[0353] Step 10

[0354] Compounds INT-4-13 (1.40 g, 1.40 mmol) and INT-3-3 (300 mg, 1.68 mmol) were dissolved in dichloromethane (14 mL), and HATU (0.8 g, 2.10 mmol) and N,N-diisopropylethylamine (DIEA) (0.69 mL, 4.20 mmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with water (50 mL) and ethyl acetate (80 mL x 3). The extract was then washed with brine (50 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent: ethyl acetate / petroleum ether, where ethyl acetate accounted for 0-70% by volume) to give compound INT-4-14. LC-MS: m / z: 1103.6 [M+1] + .

[0355] Step 11

[0356] Compound INT-4-14 (1.4 g, 1.27 mmol) was dissolved in tetrahydrofuran (14 mL) and water (3 mL), acidified with concentrated hydrochloric acid to pH 2, stirred for 10 minutes, extracted with EtOAc, and concentrated to obtain compound INT-4-15.

[0357] Step 12

[0358] Compound INT-4-15 (1.2 g, 1.21 mmol) was dissolved in THF (12 mL) and water (3 mL), and lithium hydroxide monohydrate (0.2 g, 3.03 mmol) was added. The mixture was stirred at 25 °C for 1.5 hours. The reaction mixture was acidified to pH 2 with concentrated hydrochloric acid, and tetrahydrofuran was removed by concentration. The residue was purified by reversed-phase chromatography to give compound INT-4-16. LC-MS: m / z: 975.6 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ: 9.45 (s, 1H), 8.53 (d, J = 2.6Hz, 1H), 7.60 (d, J = 8.0Hz, 1H), 7.39 (t, J = 17.8Hz, 6H), 7.27 (dd, J = 19.6, 12.0Hz, 1H), 7.22-7. 14(m,1H),7.08(d,J=8.6Hz,1H),6.04(s,1H),5.25(s,2H),5.20-4.85(m ,2H),4.54(d,J=17.6Hz,2H),4.12-3.85(m,4H),3.75(d,J=38.4Hz,2H),3 .61(t,J=6.6Hz,2H),3.45(d,J=10.2Hz,4H),3.04(s,3H),2.97(s,5H),2 .65(d,J=4.0Hz,1H),2.57(d,J=13.8Hz,1H),2.42-2.14(m,4H),2.08(s,2 H),1.92(d,J=9.8Hz,1H),1.87-1.74(m,1H),1.68(dd,J=21.0,9.8Hz,2H ), 1.35 (t, J = 5.2Hz, 3H), 0.99 (s, 2H), 0.86 (d, J = 7.0Hz, 2H), 0.63 (s, 6H).

[0359] Step 13

[0360] Compound INT-4-16 (200 mg, 0.18 mmol) was dissolved in anhydrous dichloromethane (15 mL), and 1-hydroxybenzotriazole (HOBt) (37.0 mg, 0.28 mmol), 4-dimethylaminopyridine (DMAP) (113 mg, 0.92 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (71 mg, 0.37 mmol) were added. The reaction mixture was stirred at 20 °C for 18 hours. The mixture was concentrated and purified by column chromatography (MeOH / DCM = 1 / 10) to give compound INT-4-17. LC-MS: m / z: 957.6 [M+1] + . 1 H NMR (400MHz, CDCl3) δ: 8.46 (d, J = 2.8Hz, 1H), 8.08 (d, J = 7.6Hz, 1H), 7.42-7.27 (m, 7H), 7.12 (d, J = 14.2Hz, 2H), 5.49 (d, J = 11.2Hz, 1 H),5.38(d,J=8.4Hz,1H),5.30(s,1H),5.06(q,J=12.2Hz,2H),4.86(s,2H),4.54(d,J=8.8Hz,2H),3.98(d,J=11.2Hz,2H),3.74(d, J=25.6Hz,1H),3.65(d,J=10.6Hz,4H),3.35-3.16(m,7H),2.99(d,J=25.0Hz,2H),2.82(d,J=21.0Hz,7H),2.61(d,J=9.0Hz,2H),2. 41(s,1H),2.22-2.06(m,1H),2.01(d,J=12.4Hz,2H),1.74(d,J=8.8Hz,2H),1.47(t,J=7.8Hz,3H),0.92(s,3H),0.66-0.32(m,6H).

[0361] Step 14

[0362] Compound INT-4-17 (20 mg, 0.02 mmol) was dissolved in anhydrous methanol (2 mL), and Pd / C (10 mg, 10% purity, 55% water) was added to displace hydrogen gas. The mixture was stirred at 20 °C for 6 hours. The mixture was filtered, and the filter cake was washed with anhydrous methanol. The organic phases were combined and concentrated to give compound INT-4. LC-MS: 823.4 [M+1] + .

[0363] Reference Example 3: Synthesis of intermediate INT-5

[0364] Step 1

[0365] At -60°C, a solution of dimethyl sulfoxide (120 mL, 1681 mmol) in dichloromethane (200 mL) was slowly added dropwise to a solution of oxaloyl chloride (94.8 mL, 1121 mmol) in dichloromethane (200 mL). After 30 minutes, a solution of compound INT-5-1 (55 g, 560 mmol) in dichloromethane (200 mL) was added dropwise at -60°C. After 1 hour, triethylamine (312 mL, 2242 mmol) was added dropwise at -60°C. The mixture was stirred at -60°C for 30 minutes, then heated to 0°C. The mixture was quenched dropwise with water and extracted with dichloromethane (200 mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give compound INT-5-2. 1 H NMR (400 MHz, CDCl3) δ9.72 (s, 1H), 5.67-5.51 (m, 2H), 2.63-2.25 (m, 3H), 2.24-2.02 (m, 2H).

[0366] Step 2

[0367] At 0 °C, lithium chloride (0.22 g, 5.31 mmol) and trimethylsilane nitrile (27.0 g, 281 mmol) were slowly added to a tetrahydrofuran (500 mL) solution of compound INT-5-2 (27.0 g, 281 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was filtered to obtain a filtrate, which was then concentrated under reduced pressure to obtain compound INT-5-3. 1 H NMR (400MHz, CDCl3) δ5.44-5.42(m,2H),4.10(J=4.4Hz,1H),2.43-2.19(m,3H),2.09-1.88(m,2H),0.00(s,9H).

[0368] Step 3

[0369] At 0 °C, thionyl chloride (20.0 mL, 276 mmol) was slowly added to a methanol (100 mL) solution of compound INT-5-3 (27.0 g, 138 mmol). The mixture was stirred at 65 °C for 3 hours. The mixture was quenched with 10% potassium carbonate and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give compound INT-5-4. 1H NMR (400MHz, CDCl3) δ5.59-5.78(m,2H),4.11(d,J=4.8Hz,1H),3.71(s,3H),2.62-2.42(m,1H),2.39-2.23(m,4H).

[0370] Step 4

[0371] At 0 °C, 2,6-dimethylpyridine (1.37 g, 12.8 mmol) was added to a solution of compound INT-5-4 (1.00 g, 6.40 mmol) in dichloromethane (30 mL), followed by the slow addition of trifluoromethanesulfonic anhydride (2.17 g, 7.68 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give compound INT-5-5.

[0372] Step 5

[0373] At 0 °C, a mixture of N,N-diisopropylethylamine (2.47 g, 19.2 mmol) and (S)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester (1 g, 4.42 mmol) in acetonitrile (15 mL) was slowly added to a solution of compound INT-5-5 (1.84 g, 6.38 mmol) in acetonitrile (20 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel, eluent petroleum ether / ethyl acetate, ethyl acetate ratio: 0-30%) to give compound INT-5-6. LC-MS: m / z: 365.2 [M+1] + .

[0374] Step 6

[0375] To a solution of compound INT-5-6 (700 mg, 1.92 mmol) in tetrahydrofuran (50 mL), lithium hydroxide monohydrate (403 mg, 9.60 mmol), methanol (50 mL), and water (50 mL) were added. The reaction mixture was stirred at 45 °C for 16 hours. The mixture was concentrated under reduced pressure to give a crude product. The crude product was dissolved in THF, filtered, and the filtrate was concentrated under reduced pressure to give compound INT-5-7 (600 mg, yield 89%). LC-MS: m / z: 351.2 [M+23] + .

[0376] Step 7

[0377] Compound INT-5-7 (88 g, 241 mmol) was resolved by SFC forward chromatography (column type: Ultimate YMC K-Prep-LAB 100G, Daicel ChiralPak IJ 40 mm I D 250 mm x 10 μm; elution gradient: 0-30% B, mobile phase A: Hexane (10% DCM); mobile phase B: Ethanol; flow rate: 100 mL / min) to obtain compound INT-5-8 (retention time: 3.908 min) and compound INT-5-9 (retention time: 6.123 min).

[0378] Step 8

[0379] Compound INT-5-9 (1 g, 2.85 mmol) was dissolved in DMF (10 mL), and cesium carbonate (1.12 g, 3.42 mmol) and allyl bromo (0.380 g, 3.14 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was quenched with water (30 mL) and extracted with ethyl acetate (30 mL * 2). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was subjected to silica gel column chromatography (petroleum ether / ethyl acetate, 0-20% ethyl acetate) to give compound INT-5-10. LC-MS: m / z: 391.4 [M+1] + .

[0380] Step 9

[0381] Compound INT-5-10 (5.5 g, 35.4 mmol) was dissolved in ethyl acetate (2.5 mL), followed by the addition of ethyl acetate hydrochloride solution (2.5 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to give compound INT-5-11. LC-MS: m / z: 291.2 [M+1] + .

[0382] Step 10

[0383] At room temperature, lithium (2R,3R)-3-cyclopropyl-1-methylaziridine-2-carboxylate (0.61 g, 4.14 mmol), ethyl diisopropylamine (3.43 mL, 20.7 mmol), and HATU (2.05 g, 5.38 mmol) were added to a DMF (4 mL) solution of compound INT-5-11 (1.2 g, 4.14 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give compound INT-5-12. LC-MS: m / z: 414.2 [M+1] + .

[0384] Step 11

[0385] At room temperature, dioxane (0.52 mL, 7.98 mmol) and tetrakis(triphenylphosphine)palladium (0.15 g, 0.133 mmol) were added to a 10 mL solution of compound INT-5-12 (1.1 g, 2.66 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at 25 °C for 2 hours. The mixture was concentrated directly under reduced pressure to give a crude product. The crude product was purified by C18 reversed-phase column chromatography (H2O:CAN = 10:1) to give compound INT-5. LC-MS: m / z: 374.4 [M+1] + .

[0386] Example 1

[0387] Step 1

[0388] Compound 1-1A (5.00 g, 34.9 mmol) was dissolved in water (200 mL), and sulfuric acid (140 mL, 70.0 mmol) was added. The mixture was then cooled to 0 °C, and an aqueous solution of sodium nitrite (7.23 g, 105 mmol) (200 mL) was slowly added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined. The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude target compound 1-2A. LC-MS: m / z: 145.2 [M+1] + .

[0389] Step 2

[0390] Compounds 1-2A (4.50 g, 31.2 mmol) were dissolved in N,N-dimethylformamide (40 mL), and benzyl bromide (5.34 g, 31.2 mmol) and cesium carbonate (11.19 g, 34.3 mmol) were added. The mixture was stirred at room temperature for 18 hours. The reaction solution was diluted with water (200 mL) and then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate volume percentage: 0-10%) to give the target compound 1-3A. LC-MS: m / z: 257.4 [M+23] + .

[0391] Step 3

[0392] Compound 1-3A (3.00 g, 12.8 mmol) was dissolved in dichloromethane (30 mL) and 2,6-dimethylpyridine (2.74 g, 25.6 mmol) was added. The mixture was then cooled to 0 °C, and trifluoromethanesulfonic anhydride (5.42 g, 19.2 mmol) was slowly added. The reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the crude product was subjected to column chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate volume percentage: 0-5%) to give target compound 1-4A. LC-MS: m / z: 389.0 [M+23] + .

[0393] Step 4

[0394] Compound 1-4A (3.40 g, 9.28 mmol) was dissolved in acetonitrile (ACN) (7 mL), and compound 1-5A (2.10 g, 9.28 mmol) and N,N-diisopropylethylamine (3.59 g, 27.8 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the crude product was subjected to column chromatography (silica gel, eluent: ethyl acetate / petroleum ether, where ethyl acetate accounted for 0-10% by volume) to give compound 1-6A. LC-MS: m / z: 443.4 [M+1] + .

[0395] Step 5

[0396] Compound 1-6A (600 mg, 1.36 mmol) was dissolved in methanol (12 mL), and palladium on carbon (120 mg, 0.11 mmol) was added. The mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere (15 psi). The reaction solution was filtered and concentrated to give compound 1-7A. LC-MS: m / z: 353.8 [M+1] + .

[0397] Step 6

[0398] Compounds 1-7A (34.26 mg, 0.097 mmol) and INT-4 (80.0 mg, 0.10 mmol) were dissolved in N,N-dimethylformamide (2 mL). (2-oxime-cyanoethyl acetate)-N,N-dimethylmorpholinourea hexafluorophosphate (COMU) (62.4 mg, 0.15 mmol) and N,N-diisopropylethylamine (37.6 mg, 0.29 mmol) were added, and the reaction was stirred at room temperature for 2 hours. The reaction mixture was extracted with water (30 mL) and ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent: methanol / dichloromethane, methanol volume percentage: 0-10%) to give compounds 1-8A. LC-MS: m / z: 579.6 [M+2] 2+ .

[0399] Step 7

[0400] Compound 1-8A (70.0 mg, 0.06 mmol) was dissolved in dichloromethane (1 mL), and 4 M hydrochloric acid / 1,4-dioxane (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give compound 1-9A. LC-MS: m / z: 529.2 [M+2] 2+ .

[0401] Step 8

[0402] Compounds 1-9A (60.0 mg, 0.06 mmol) and 1-10A (16.7 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (32.4 mg, 0.09 mmol) and N,N-diisopropylethylamine (36.6 mg, 0.28 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (30 mL), extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent: methanol / dichloromethane, methanol volume percentage: 0-10%) and special preparation (column type: Ultimate YMC-Triart Prep C18, 50 x 250 mm x 10 μm; elution phase: mobile phase A / mobile phase B, elution gradient: 50-90% mobile phase B, mobile phase A: 1% ammonium acetate / water; mobile phase B: acetonitrile; flow rate: 25 mL / min) to obtain compound 1.

[0403] LC-MS: m / z: 591.2 [M+2H] 2+ . 1 H NMR(400MHz, CD3OD)δ:8.42(d,J=2.8Hz,1H),7.49(d,J=8.8Hz,1H),7.32-7.26(m,2H),7.15(dd,J=9.1,2.0Hz,1H),5.52(t,J=6.0Hz,1H) ,5.05-4.94(m,1H),4.70(dd,J=10.0,4.8Hz,2H),4.59(s,1H),4.48(s,1H),4.07(d,J=6.0Hz,1H),3.97(d,J=11.2Hz,1H),3.85-3.76(m, 3H),3.72-3.62(m,3H),3.52-3.40(m,3H),3.29(s,4H),3.19(s,3H),2.97-2.57(m,16H),2.48(dd,J=10.7,5.2Hz,1H),2.39-2.20(m,6H) ,2.15-1.73(m,10H),1.61(dd,J=29.8,20.4Hz,7H),1.45(t,J=5.6Hz,4H),0.87(s,3H),0.68-0.40(m,11H),0.27(dd,J=5.0,2.8Hz,1H).

[0404] Example 2

[0405] Step 1

[0406] Compound 2-1A (3.50 g, 27.1 mmol) was dissolved in 100 mL of 0.5 M sulfuric acid aqueous solution, and 36.1 mL of 163 mmol sodium nitrite aqueous solution was added at 0 °C. The reaction mixture was stirred at 0 °C for 3 h, followed by stirring at 25 °C for 24 h. The reaction mixture was filtered through diatomaceous earth, and the pH of the filtrate was adjusted to 1-2 with 2 M sulfuric acid aqueous solution, followed by extraction with ethyl acetate (200 mL x 2). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 2-2A. LC-MS: m / z: 131.2 [M+1] + .

[0407] Step 2

[0408] Compound 2-2A (1.70 g, 63.2 mmol) and Cs₂CO₃ (5.11 g, 15.7 mmol) were dissolved in 200 mL of DMF, and benzyl bromide (2.46 g, 14.4 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction solution was quenched with 10 mL of water and extracted with ethyl acetate (10 mL x 2). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel, eluent: tetrahydrofuran / dipetroleum ether, tetrahydrofuran volume percentage: 0-5%) to give compound 2-3A. LC-MS: m / z: 243.2 [M+23] + .

[0409] Step 3

[0410] Compound 2-3A (1.00 g, 4.54 mmol) and 2,6-dimethylpyridine (0.97 g, 9.08 mmol) were dissolved in 10 mL of dichloromethane. Trifluoromethanesulfonic anhydride (1.92 g, 6.81 mmol) was added dropwise at 0 °C, and the reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with water and extracted with dichloromethane (20 mL x 2). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude compound 2-4A. The crude product was used directly as a starting material for the next step.

[0411] Step 4

[0412] Crude compounds 2-4A (1.50 g, 4.26 mmol) and 1-5A (1.06 g, 4.68 mmol) were dissolved in 20 mL of acetonitrile, and DIEA (1.06 mL, 6.39 mmol) was added. The reaction mixture was stirred at 80 °C for 3 hours. The reaction mixture was quenched with 10 mL of water and extracted with ethyl acetate (10 mL x 2). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel, eluent: tetrahydrofuran / dipetroleum ether, tetrahydrofuran volume percentage: 0-15%) to give compound 2-5A. LC-MS: m / z: 429.6 [M+1] + .

[0413] Step 5

[0414] Compound 2-5A (700 mg, 1.63 mmol) was dissolved in 20 mL of methanol, and Pd / C (20 mg, 10% purity, 55% water) was added. The mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere (15 psi). The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give compound 2-6A. LC-MS: m / z: 339.6 [M+1] + .

[0415] Step 6

[0416] Compounds 2-6A (40.0 mg, 0.118 mmol) and INT-4 (97.3 mg, 0.118 mmol) were dissolved in N,N-dimethylformamide (2 mL). (2-oxime-cyanoethyl acetate)-N,N-dimethylmorpholinourea hexafluorophosphate (COMU) (75.9 mg, 0.177 mmol) and N,N-diisopropylethylamine (45.7 mg, 0.355 mmol) were added, and the reaction was stirred at room temperature for 2 hours. The reaction mixture was extracted with water (30 mL) and ethyl acetate (10 mL x 3), and the organic layers were combined. The mixture was then washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent: methanol / dichloromethane, methanol volume percentage: 0-10%) to give compound 2-7A. LC-MS: m / z: 572.4 [M+2] 2+ .

[0417] Step 7

[0418] Compound 2-7A (80.0 mg, 0.070 mmol) was dissolved in dichloromethane (2 mL), and 4 M hydrochloric acid / 1,4-dioxane (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give crude compound 2-8A. LC-MS: m / z: 522.6 [M+2] 2+ .

[0419] Step 8

[0420] Compounds 2-8A (70.0 mg, 0.067 mmol) and 1-10A (19.7 mg, 0.134 mmol) were dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (38.2 mg, 0.101 mmol) and N,N-diisopropylethylamine (25.9 mg, 0.201 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with water (30 mL) and ethyl acetate (10 mL x 3), the combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent: methanol / dichloromethane, methanol volume percentage: 0-10%) and special preparation (column type: Ultimate YMC-Triart Prep C18, 50 x 250 mm x 10 μm; elution phase: mobile phase A / mobile phase B, elution gradient: 50-90% mobile phase B; mobile phase A: 1% ammonium acetate / water, mobile phase B: acetonitrile; flow rate: 25 mL / min) to obtain compound 2.

[0421] LC-MS: m / z: 583.3 [M+2] 2+ . 1 H NMR(400MHz,CD3OD)δ:8.34(d,J=2.8Hz,1H),7.41(d,J=8.8Hz,1H),7.25(s, 1H),7.19(d,J=5.8Hz,1H),7.08(dd,J=9.0,2.0Hz,1H),5.45(q,J=6.4Hz,1H) ,4.92(dd,J=16.3,8.4Hz,1H),4.63(d,J=4.4Hz,2H),4.41(s,1H),3.99(d,J =5.6Hz,1H),3.91(d,J=10.8Hz,1H),3.79-3.70(m,3H),3.66-3.57(m,3H),3. 50-3.32(m,4H),3.22(s,4H),3.13-3.07(m,3H),2.88(dd,J=13.2,8.4Hz,1H ),2.81-2.62(m,12H),2.60-2.37(m,5H),2.31(d,J=2.4Hz,3H),2.26(d,J=6. 4Hz,1H),2.16(dd,J=16.7,10.0Hz,1H),2.08-1.66(m,14H),1.57(t,J=9.6Hz ,1H),1.43-1.35(m,4H),0.79(s,3H),0.61-0.36(m,11H),0.27-0.18(m,1H).

[0422] Example 3

[0423] Step 1

[0424] At 0 °C, a solution of compound 3-1A (12 g, 88.2 mmol) in tetrahydrofuran (50 mL) was slowly added to a solution of sodium borohydride (3.50 g, 92.6 mmol) in tetrahydrofuran (50 mL). After 1 hour, a boron trifluoride diethyl ether complex (12.5 g, 88.2 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. The mixture was quenched with 95% ethanol and extracted with dichloromethane (100 mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give compound 3-2A. 1 H NMR (400MHz, CDCl3)3.65-3.58(m,2H),3.55-3.53(m,2H),2.28-2.25(m,3H).

[0425] Step 2

[0426] At 25°C, a solution of pyridine chlorochromate PCC (28.2 g, 131 mmol) in dichloromethane (40 mL) was slowly added to a solution of compound 3-2A (10 g, 81.9 mmol) in dichloromethane (40 mL). The mixture was stirred at room temperature for 1 hour, and then ether (50 mL) was added. The reaction mixture was filtered through silica gel powder and diatomaceous earth to obtain a filtrate, which was concentrated under reduced pressure to obtain compound 3-3A. 1 H NMR (400MHz, CDCl3)9.78(s,1H),3.05-2.89(m,1H),2.87-2.61(m,4H).

[0427] Step 3

[0428] A solution of lithium chloride (29 mg, 0.683 mmol) was added to a tetrahydrofuran (15 mL) solution of compound 3-3A (8.2 g, 68.3 mmol), and trimethylsilane nitrile (7112 mg, 71.7 mmol) was slowly added dropwise at 0 °C. The mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered to obtain a filtrate, which was then concentrated under reduced pressure to give compound 3-4A. 1 H NMR (400MHz, CDCl3) 4.27 (d, J = 5.6Hz 1H), 2.59-2.48 (m, 1H), 2.47-2.23 (m, 4H), 0.00 (s, 9H).

[0429] Step 4

[0430] Concentrated hydrochloric acid (5 mL) was added to a concentrated solution of compound 3-4A (7.35 g, 33.5 mmol), and the reaction mixture was stirred at 70 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give compound 3-5A. 1 H NMR (400MHz, CDCl3) 4.25 (d, J = 4Hz 1H), 2.93-2.52 (m, 5H).

[0431] Step 5

[0432] Compound 3-5A (4.10 g, 24.7 mmol) was dissolved in N,N-dimethylformamide (40 mL), and benzyl bromide (4.22 g, 24.7 mmol) and cesium carbonate (8.85 g, 27.15 mmol) were added. The mixture was stirred at room temperature for 18 hours. The reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined. The combined organic layers were then washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate volume percentage: 0-10%) to give compound 3-6A. LC-MS: m / z: 279.0 [M+23] + .

[0433] Step 6

[0434] Compound 3-6A (1.10 g, 4.29 mmol) was added to a solution in dichloromethane (20 mL) with 2,6-dimethylpyridine (1.5 mL, 12.9 mmol), and the mixture was cooled to 0 °C. Trifluoromethanesulfonic anhydride (1.82 g, 6.44 mmol) was then slowly added. The reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated to give compound 3-7A. LC-MS: m / z: 411.0 [M+23] + .

[0435] Step 7

[0436] Compound 3-7A (1.50 g, 3.86 mmol) was dissolved in acetonitrile (20 mL), and compound 1-5A (0.87 g, 3.86 mmol) and N,N-diisopropylethylamine (1.49 g, 11.6 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the crude product was subjected to column chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate volume percentage: 0-10%) to give the target compound 3-8A. LC-MS: m / z: 464.6 [M+1] + .

[0437] Step 8

[0438] Compound 3-8A (1.3 g, 2.71 mmol) was resolved by supercritical fluid chromatography (SFC) in a forward direction (column: Ultimate YMC K-Prep-LAB 100G, Daicel ChiralPak IJ 40 mm I D 250 mm x 10 μm; elution phase: mobile phase A / mobile phase B, elution gradient: 0-2% mobile phase B, wherein mobile phase A: hexane; mobile phase B: ethanol; flow rate: 80 mL / min) to give compound 3-9A (LC-MS: m / z: 465.4 [M+1]). +SFC: 100% ee, Rt = 6.308 min (Column: Daicel Chiral PAK-IJS 150 x 4.6 mm - 5 μm, AO043; Mobile phase: Phase A is hexane, Phase B is ethanol; Elution gradient: 2% Phase B (Phase B to Phase A volume ratio); Flow rate: 1 mL / min, 12.5 min; Column temperature: 35 °C) and compound 4-1A (LC-MS: , (ESI) m / z: 465.3 [M+1) + SFC: 100% ee, Rt = 7.923 min (Column: Daicel Chiral PAK-IJS 150 x 4.6 mm - 5 μm, AO043; Mobile phase: Phase A is hexane, Phase B is ethanol; Elution gradient: 2% Phase B (Volume ratio of Phase B to Phase A); Flow rate: 1 mL / min, 12.5 min; Column temperature: 35℃).

[0439] Step 9

[0440] Compound 3-9A (60 mg, 0.125 mmol) was dissolved in methanol (2 mL), and palladium on carbon (20.0 mg) was added. The reaction mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere (15 psi). The reaction solution was filtered and concentrated to give the target compound 3-10A. LC-MS: (ESI) m / z: 374.2 [M+1] + .

[0441] Step 10

[0442] Compound 3-10A (50.0 mg, 0.134 mmol) and compound INT-4 (110 mg, 0.134 mmol) were dissolved in N,N-dimethylformamide (2 mL), and (2-oxime-cyanoethyl acetate)-N,N-dimethylmorpholinourea hexafluorophosphate (85.7 mg, 0.2 mmol) and N,N-diisopropylethylamine (51.68 mg, 0.401 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with water (30 mL) and ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent: methanol / dichloromethane, methanol volume percentage: 0-10%) to give the target compound 3-11A. LC-MS: m / z: 590.4 [M+2] 2+ .

[0443] Step 11

[0444] Compound 3-11A (70.0 mg, 0.059 mmol) was dissolved in dichloromethane (2 mL), and 4 M hydrochloric acid / 1,4-dioxane (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give the target compound 3-12A. LC-MS: m / z: 540.4 [M+2] 2+ .

[0445] Step 12

[0446] Compound 3-12A (60.0 mg, 0.056 mmol) and lithium (2R,3R)-3-cyclopropyl-1-methylaziridine-2-carboxylate (16.4 mg, 0.111 mmol) were dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (31.7 mg, 0.083 mmol) and N,N-diisopropylethylamine (21.5 mg, 0.167 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with water (30 mL) and ethyl acetate (10 mL x 3), and the combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent: methanol / dichloromethane, methanol volume percentage: 0-10%) and special preparation (column type: Ultimate YMC-Triart Prep C18, 50 x 250 mm x 10 μm; eluent: mobile phase A / mobile phase B, elution gradient: 50-90% mobile phase B; mobile phase A: 1% ammonium acetate / water, mobile phase B: acetonitrile; flow rate: 25 mL / min) to obtain compound 3.

[0447] LC-MS:m / z:602.0[M+2] 2+ . 1H NMR(400MHz, CD3OD)δ:8.34(d,J=2.8Hz,1H),7.42-7.39(m,1H),7.25(s,1H),7.15-7.03(m,2H),5.41(s,1H),4.92(d,J=8.0Hz, 1H),4.62(s,2H),4.41(s,1H),4.01(d,J=6.0Hz,1H),3.93-3.72(m,4H),3.63(d,J=11.2Hz,2H),3.53-3.36(m,5H),3.22(s,4H) ,3.13(s,3H),3.08(s,1H),2.90(dd,J=24.0,7.2Hz,2H),2.82-2.62(m,13H),2.57-2.37(m,8H),2.32(d,J=3.6Hz,3H),2.29-2. 14(m,2H),1.94-1.66(m,7H),1.56(t,J=9.2Hz,1H),1.42-1.34(m,4H),0.80(s,3H),0.53-0.33(m,10H),0.20(d,J=4.8Hz,1H).

[0448] Example 4

[0449] Step 1

[0450] Compound 4-1A (60.0 mg, 0.125 mmol) was dissolved in methanol (2 mL), and palladium on carbon (20 mg, 10% purity, 55% water) was added. The reaction mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere (15 psi). The reaction solution was filtered and concentrated to give the target compound 4-2A. LC-MS: m / z: 375.2 [M+1] + .

[0451] Step 2

[0452] Compound 4-2A (45.0 mg, 0.120 mmol) and compound INT-4 (98.9 mg, 0.120 mmol) were dissolved in N,N-dimethylformamide (2 mL), and (2-oxime-cyanoethyl acetate)-N,N-dimethylmorpholinourea hexafluorophosphate (61.7 mg, 0.144 mmol) and N,N-diisopropylethylamine (0.06 mL, 0.361 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (30 mL) and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-10%) to give the target compound 4-3A. LC-MS: (ESI) m / z: 590.6 [M+2H] 2+ .

[0453] Step 3

[0454] Compound 4-3A (100 mg, 0.085 mmol) was dissolved in dichloromethane (2 mL), and 4 M hydrochloric acid / 1,4-dioxane (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give the target compound 4-4A. LC-MS: m / z: 540.4 [M+2] 2+ .

[0455] Step 4

[0456] Compound 4-4A (70 mg, 0.065 mmol) and lithium (2R,3R)-3-cyclopropyl-1-methylaziridine-2-carboxylate (19.1 mg, 0.130 mmol) were dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (29.6 mg, 0.078 mmol) and N,N-diisopropylethylamine (0.054 mL, 0.324 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with water (30 mL) and ethyl acetate (10 mL x 3), the combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent: methanol / dichloromethane, methanol volume percentage: 0-10%) and special preparation (column type: Ultimate YMC-Triart Prep C18, 50 x 250 mm x 10 μm; eluent: mobile phase A / mobile phase B, elution gradient: 50-90% mobile phase B; mobile phase A: 1% ammonium acetate / water, mobile phase B: acetonitrile; flow rate: 25 mL / min) to obtain compound 4.

[0457] LC-MS:m / z:602.0[M+2] 2+ . 1 H NMR (400MHz, CDCl3) δ: 8.45 (s, 1H), 7.90-7.75 (m, 1H), 7.56 (d, J = 8.4Hz, 1H), 7.18-7.10 (m, 3H), 6.2 4(s,1H),5.37(s,2H),4.68(s,1H),4.54(s,1H),4.40(s,1H),3.97(s,1H),3.82(s,1H),3.72-3.40( m,7H),3.19(s,6H),3.07(s,4H),2.95-2.85(m,4H),2.67(s,11H),2.34-2.04(m,8H),1.99-1.61(m, 9H), 1.50 (s, 1H), 1.34 (d, J = 6.0Hz, 4H), 0.78 (s, 3H), 0.58 (s, 2H), 0.45-0.35 (m, 10H), 0.16 (s, 1H).

[0458] Example 5

[0459] Step 1

[0460] At -60°C, a solution of dimethyl sulfoxide (120 mL, 1681 mmol) in dichloromethane (200 mL) was slowly added dropwise to a solution of oxaloyl chloride (94.8 mL, 1121 mmol) in dichloromethane (200 mL). After 30 minutes, a solution of compound 5-1A (55 g, 560 mmol) in dichloromethane (200 mL) was added dropwise at -60°C. After 1 hour, triethanolamine (TEA) (312 mL, 2242 mmol) was added dropwise at -60°C. The mixture was stirred at -60°C for 30 minutes, then heated to 0°C. The mixture was quenched with water and extracted with dichloromethane (200 mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the target compound 5-2A. 1 H NMR (400MHz, CDCl3) δ: 9.72 (s, 1H), 5.67-5.51 (m, 2H), 2.63-2.25 (m, 3H), 2.24-2.02 (m, 2H).

[0461] Step 2

[0462] At 0 °C, lithium chloride (0.22 g, 5.31 mmol) and trimethylsilane nitrile (27.0 g, 281 mmol) were slowly added to a tetrahydrofuran (500 mL) solution of compound 5-2A (27.0 g, 281 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was filtered to obtain a filtrate, which was then concentrated under reduced pressure to obtain compound 5-3A.

[0463] 1 H NMR (400MHz, CDCl3) δ: 5.44-5.42 (m, 2H), 4.10 (J = 4.4Hz, 1H), 2.43-2.19 (m, 3H), 2.09-1.88 (m, 2H), 0.00 (s, 9H).

[0464] Step 3

[0465] At 0 °C, thionyl chloride (20.0 mL, 276 mmol) was slowly added to a methanol (100 mL) solution of compound 5-3A (27.0 g, 138 mmol). The mixture was stirred at 65 °C for 3 hours. The mixture was quenched with 10% potassium carbonate and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give compound 5-4A.

[0466] 1 H NMR (400MHz, CDCl3) δ: 5.59-5.78 (m, 2H), 4.11 (d, J = 4.8Hz, 1H), 3.71 (s, 3H), 2.62-2.42 (m, 1H), 2.39-2.23 (m, 4H).

[0467] Step 4

[0468] At 0 °C, 2,6-dimethylpyridine (1.37 g, 12.8 mmol) was added to a solution of compound 5-4A (1.00 g, 6.40 mmol) in dichloromethane (30 mL), followed by the slow addition of trifluoromethanesulfonic anhydride (2.17 g, 7.68 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude target compound 5-5A. The crude compound was used directly in the next reaction.

[0469] Step 5

[0470] At 0 °C, N,N-diisopropylethylamine (2.47 g, 19.2 mmol) and an aqueous solution of compound 5-5A (1.84 g, 6.38 mmol) in acetonitrile (20 mL) were slowly added to a solution of compound 1-5A (1.84 g, 6.38 mmol) in acetonitrile (15 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel, eluent: petroleum ether / ethyl acetate, ethyl acetate volume percentage: 0-30%) to give target compound 5-7A. LC-MS: m / z: 365.2 [M+1] + .

[0471] Step 6

[0472] To a solution of compound 5-7A (700 mg, 1.92 mmol) in tetrahydrofuran (50 mL), lithium hydroxide (403 mg, 9.60 mmol), methanol (50 mL), and water (50 mL) were added. The reaction mixture was stirred at 45 °C for 16 hours. The mixture was concentrated under reduced pressure to give a crude product. The crude product was dissolved in THF, filtered, and the filtrate was concentrated under reduced pressure to give compound 5-8A. LC-MS (ESI) m / z: 351.2 [M+1] + .

[0473] Step 7

[0474] Compounds INT-4 (188 mg, 0.228 mmol), N,N-diisopropylethylamine (0.11 mL, 0.685 mmol), and COMU (146 mg, 0.342 mmol) were added to a solution of compound 5-8A (80.0 mg, 0.228 mmol) in N,N-dimethylformamide (2 mL) at 25 °C. The reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with water and extracted with ethyl acetate (50 mL x 3), and the organic layers were combined. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified using a specialized column (Ultimate YMC-Triart Prep C18, 50 x 250 mm x 10 μm; eluent: mobile phase A / mobile phase B, elution gradient: 50-90% mobile phase B; mobile phase A: 1% trifluoroacetic acid (TFA) aqueous solution; mobile phase B: acetonitrile; flow rate: 25 mL / min) to obtain the target compound 5-9A (LC-MS: retention time Rt = 3.571 min, m / z: 578.5 [M+2]). 2+，Mobile phase A: 0.01% trifluoroacetic acid aqueous solution; Mobile phase B: 0.01% trifluoroacetic acid acetonitrile solution; Elution gradient: Mobile phase B increased from 5% to 58% within 5 minutes, then from 58% to 95% within 2 minutes; Flow rate: 1.8 ml / min; Column type: Waters XBridge C18, 3.5 μm, 4.6 x 50 mm; Column temperature: 45 °C) and 6-1A (LC-MS: retention time Rt = 3.696 min, m / z: 578.5 [M+2]) 2+ Mobile phase A: 0.01% trifluoroacetic acid aqueous solution; Mobile phase B: 0.01% trifluoroacetic acid acetonitrile solution; Elution gradient: Mobile phase B increased from 5% to 58% within 5 minutes, then from 58% to 95% within 2 minutes; Flow rate: 1.8 ml / min; Column type: Waters XBridge C18, 3.5 μm, 4.6 x 50 mm; Column temperature: 45 °C.

[0475] Step 8

[0476] At 0 °C, a solution of dioxane in hydrochloric acid (2.5 mL, 4 M) was added to a solution of compound 5-9A (65.0 mg, 0.056 mmol) in dichloromethane (2.5 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the target compound 5-10A. LC-MS: m / z: 528.4 [M+2] 2+ .

[0477] Step 9

[0478] At 0 °C, compounds 1-10A (16.7 mg, 0.114 mmol), N,N-diisopropylethylamine (0.047 mL, 0.284 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (26.0 mg, 0.068 mmol) were added to N,N-dimethylformamide (3 mL) containing compound 5-10A (60.0 mg, 0.057 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (26.0 mg, 0.068 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel, elution phase: dichloromethane / methanol, elution gradient: 0–7% methanol) and preparative chromatography (column type: Ultimate YMC-Triart Prep C18, 50 x 250 mm x 10 μm; elution phase: mobile phase A / mobile phase B, elution gradient: 50–90% mobile phase B, mobile phase A: 1% ammonium acetate aqueous solution; mobile phase B: acetonitrile; flow rate: 25 mL / min) to give compound 5.

[0479] LC-MS:m / z:590.0[M+2] 2+ . 1 H NMR(400MHz, DMSO-d6)δ:8.45(d,J=2.8Hz,1H),7.95-7.80(m,1H),7.57(d,J=8.8Hz,1H),7.22-7.06(m,3H),6 .14(s,1H),5.63(d,J=7.4Hz,2H),5.37(s,2H),4.68(s,1H),4.56(s,1H),4.39(s,1H),3.97(d,J=6.0Hz,1H), 3.83(d,J=9.6Hz,1H),3.69-3.39(m,7H),3.20(s,6H),3.12-2.90(m,5H),2.85-2.56(m,13H),2.38-2.12(m,9 H),1.95-1.57(m,9H),1.50(s,1H),1.34(d,J=6.1Hz,4H),0.79(s,3H),0.65-0.22(m,12H),0.15-0.12(m,1H).

[0480] Example 6

[0481] Step 1

[0482] Compound 6-1A (65.0 mg, 0.056 mmol) was dissolved in dichloromethane (2 mL), and 4 M hydrochloric acid / 1,4-dioxane (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give compound 6-2A. LC-MS: m / z: 528.4 [M+2] 2+ .

[0483] Step 2

[0484] Compounds 6-2A (60.0 mg, 0.057 mmol) and 1-10A (16.7 mg, 0.114 mmol) were dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (32.4 mg, 0.085 mmol) and N,N-diisopropylethylamine (22.0 mg, 0.171 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with water (30 mL) and ethyl acetate (10 mL x 3), and the combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-10%) and special preparation (column type: Ultimate YMC-Triart Prep C18, 50 x 250 mm x 10 μm; elution phase: mobile phase A / mobile phase B, elution gradient: 50-90% mobile phase B, mobile phase A: 1% aqueous trifluoroacetic acid; mobile phase B: acetonitrile; flow rate: 25 mL / min) to give compound 6.

[0485] LC-MS: (ESI) m / z: 590.0 [M+2] 2+ . 1 H NMR (400MHz, CD3OD) δ: 8.42 (d, J = 2.8Hz, 1H), 7.49 (d, J = 9.2Hz, 1H), 7.33 (s, 1H), 7.26 (d, J = 6.0Hz, 1H), 7.15 (d, J = 7.6Hz, 1H), 5.67 (s, 2H), 5 .53(d,J=8.0Hz,1H),4.71(d,J=4.8Hz,2H),4.60(s,1H),4.50(s,1H),4.08(d,J=6.4Hz,1H),4.00(d,J=12.0Hz,1H),3.88-3.78(m,3H),3.70( d,J=9.2Hz,2H),3.61(d,J=10.6Hz,2H),3.52-3.43(m,3H),3.19-3.10 (m,6H),2.96(s,3H),2.86-2.61(m,16H),2.46(s,3H),2.40-2.32(m,5 H),2.26(s,2H),2.16-1.90(m,6H),1.76(s,3H),1.65(t,J=9.6Hz,1H) ,1.50-1.44(m,4H),0.88(s,3H),0.62-0.47(m,9H),0.30-0.25(s,1H).

[0486] Example 7

[0487] Step 1

[0488] Compound 7-2A (280 mg, 0.78 mmol) was dissolved in tetrahydrofuran (100 mL), and NaH (3.12 g, 78.0 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then, compound 7-1A (5.00 g, 52.0 mmol) was added to the mixture and stirred at 0 °C for 1 h. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The organic phases were combined. The organic phases were then washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was subjected to column chromatography (elution phase: 0-10% tetrahydrofuran / petroleum ether) to give compound 7-3A.

[0489] 1 H NMR(400MHz, CDCl3)δ:5.75(dd,J=10.0,1.2Hz,1H),4.20–4.06(m,2H),3.22(dt,J=18.8,2.0Hz,1H),2.86-2.4 2(m,3H),1.41(ddd,J=8.8,5.2,2.4Hz,1H),1.31-1.20(m,4H),0.63-0.49(m,1H),-0.24(dd,J=8.8,4.0Hz,1H).

[0490] Step 2

[0491] Compound 7-3A (6.50 g, 39.1 mmol) was dissolved in ethanol (50 mL), and 10% palladium / carbon (416 mg, 3.91 mmol) was added. The reaction was stirred for 2 hours at room temperature under a hydrogen atmosphere (1 atm). The reaction solution was filtered through diatomaceous earth. The filtrate was concentrated to give compound 7-4A. 1 H NMR(400MHz, CDCl3)δ:4.23-3.97(m,2H),2.33-2.11(m,2H),1.96-1.85(m,1H),1.70(s,2H),1.41( qt,J=10.8,5.6Hz,1H),1.30-1.15(m,5H),0.80-0.60(m,1H),0.32-0.12(m,1H),0.10-0.01(m,1H).

[0492] Step 3

[0493] Compound 7-4A (5.00 g, 29.7 mmol) was dissolved in methanol (20 mL) and water (4 mL), and lithium hydroxide (3.74 g, 89.2 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was poured into a 2 M hydrochloric acid aqueous solution (30 mL) and extracted with ethyl acetate (50 mL x 2). The mixed organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 7-5A. The product was used directly in the next reaction.

[0494] Step 4

[0495] Compound 7-5A (4.00 g, 28.5 mmol) was dissolved in DMF (50 mL), and cesium carbonate (14.0 g, 42.8 mmol) and benzyl bromide (5.86 g, 34.2 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 2). The mixed organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was subjected to column chromatography (elution phase: 0-5% tetrahydrofuran / petroleum ether) to give compound 7-6A. LC-MS: m / z: 231.4 [M+1] + .

[0496] Step 5

[0497] Potassium bis(trimethylsilylamino)amide (18.2 mL, 18.2 mmol, 1 M) was added to tetrahydrofuran (20 mL) at -78 °C, followed by a tetrahydrofuran (30 mL) solution of compound 7-6A (3.50 g, 15.2 mmol). After stirring at -78 °C for 0.5 hours, a tetrahydrofuran (30 mL) solution of compound 7-7A (4.77 g, 18.2 mmol) was added to the reaction mixture, and the mixture was stirred at -78 °C for 1 hour. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 2). The organic phases were combined. The organic phases were then washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (elution phase: 0-10% tetrahydrofuran / petroleum ether) and preparative separation (master column: Ultimate C18, 50x250mm, 10µm; elution phase: mobile phase A / mobile phase B, elution gradient: 45-75% mobile phase B; mobile phase A: 0.1% trifluoroacetic acid aqueous solution; mobile phase B: acetonitrile; flow rate: 70mL / min) to give compounds 7-8A. LC-MS: m / z: 269.4 [M+23] + .

[0498] Step 6

[0499] Compounds 7-8A (1.30 g, 5.28 mmol) and 2,6-dimethylpyridine (1.13 g, 10.6 mmol) were dissolved in dichloromethane (10 mL). Trifluoromethanesulfonic anhydride (2.23 g, 7.92 mmol) was added at -25 °C, and the reaction was stirred at -25 °C for 1 hour. The reaction mixture was poured into water (10 mL) and extracted with dichloromethane (20 mL x 2). The mixed organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 7-9A. The product was used directly in the next reaction.

[0500] Step 7

[0501] Compounds 7-9A (2.00 g, 5.29 mmol) and 1-5A (1.20 g, 5.29 mmol) were dissolved in acetonitrile (50 mL), and diisopropylethylamine (1.31 mL, 7.93 mmol) was added. The reaction mixture was stirred at 80 °C for 3 hours. The reaction solution was concentrated to give crude compound 7-10A.

[0502] Step 8

[0503] The crude compound 7-10A was purified by a chiral column (column type: Daicel ChiralPak IG, 50mm IDx 250mm, 10µm; elution phase: mobile phase A / mobile phase B, elution gradient: 5% mobile phase B, mobile phase A: n-hexane; mobile phase B: ethanol; flow rate: 90mL / min) to obtain a mixture of compounds 7-11A and 8-1A, as well as compounds 9-1A and 10-1A. The mixture of compounds 7-11A and 8-1A was further purified by SFC (column type: Daicel ChiralPak OJ, 40mm IDx 250mm, 10µm; elution phase: mobile phase A / mobile phase B, elution gradient: 15% mobile phase B, mobile phase A: supercritical CO2; mobile phase B: methanol; flow rate: 120mL / min) to obtain compounds 7-11A and 8-1A.

[0504] Compound 7-11A: LC-MS: RT = 0.690 min, (ESI) m / z: 455.2 [M+1] + ,

[0505] Compound 8-1A: LC-MS: RT = 0.687 min, (ESI) m / z: 455.2 [M+1] + ,

[0506] Compound 9-1A: LC-MS: RT = 0.694 min, (ESI) m / z: 455.2 [M+1] + ,

[0507] Compound 10-1A: LC-MS: RT = 0.703 min, (ESI) m / z: 455.2 [M+1] + .

[0508] LC-MS method: Mobile phase: A: 0.01% trifluoroacetic acid aqueous solution, B: 0.01% trifluoroacetic acid acetonitrile solution; Elution gradient: mobile phase B, increasing from 5% to 95% within 0.5 minutes; Flow rate: 1.8 ml / min; Column type: Shim-pack Scepter C18-120_33x3mm_3μm A-RP-1525; Column temperature: 45℃.

[0509] Step 9

[0510] Compound 7-11A (80.0 mg, 0.176 mmol) was dissolved in methanol (5 mL), and platinum carbon (Pt / C) (24.0 mg, 30% w / w) was added. The mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere (15 psi). The reaction solution was filtered and concentrated to give the target compound 7-12A. LC-MS: (ESI) m / z: 365.2 [M+1] + .

[0511] Step 10

[0512] Compound 7-12A (80.0 mg, 0.097 mmol), compound INT-4 (62.4 mg, 0.146 mmol), and N,N-diisopropylethylamine (37.6 mg, 0.29 mmol) were reacted at room temperature with stirring for 2 hours. The reaction mixture was extracted with water (30 mL) and ethyl acetate (10 mL x 3), and the organic phases were combined. The organic layer was then washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent: methanol / dichloromethane, methanol volume percentage: 0-10%) to give the target compound 7-13A. LC-MS: m / z: 585.4 [M+2] 2+ .

[0513] Step 11

[0514] Compound 7-13A (50.0 mg, 0.043 mmol) was dissolved in dichloromethane (2 mL), and 4 M hydrochloric acid / 1,4-dioxane (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give compound 7-14A. LC-MS: m / z: 535.4 [M+2] 2+ .

[0515] Step 12

[0516] Compound 7-14A (50.0 mg, 0.047 mmol) and lithium (2R,3R)-3-cyclopropyl-1-methylaziridine-2-carboxylate (13.8 mg, 0.094 mmol) were dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (26.7 mg, 0.07 mmol) and N,N-diisopropylethylamine (18.1 mg, 0.14 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (30 mL) and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent: methanol / dichloromethane, methanol volume percentage: 0-10%) and preparative separation (column type: JB-C235-03 Prime C18, 30 x 150 mm x 5 μm; elution phase: mobile phase A / mobile phase B, elution gradient: 57-83% mobile phase B, mobile phase A: 1% ammonium bicarbonate aqueous solution; mobile phase B: acetonitrile; flow rate: 25 mL / min) to obtain compound 7.

[0517] LC-MS: m / z: 1192.6 [M+1] + . 1 H NMR(400MHz, CD3OD)δ:8.38(d,J=2.8Hz,1H),7.45(d,J=8.8Hz,1H),7.29(s,1H),7.22(s,1H),7.12(d,J=9.2Hz,1H),5.44(d,J=6.8Hz,1H),5.03-4 .89(m,1H),4.68(d,J=5.2Hz,2H),4.56(s,1H),4.45(s,1H),4.04(d,J=6 .4Hz,1H),3.93(s,1H),3.82-3.72(m,3H),3.68-3.58(m,3H),3.47-3.34( m,4H),3.16(s,3H),3.13-3.09(m,1H),2.96-2.65(m,14H),2.60-2.53(m ,2H),2.49-2.42(m,1H),2.34(s,1H),2.30(s,2H),2.28-2.17(m,2H),2.0 5-1.83(m,5H),1.80-1.55(m,6H),1.41(d,J=6.2Hz,4H),1.37-1.20(m,5H ),0.84(s,3H),0.68-0.37(m,12H),0.26-0.23(m,1H),0.05-0.03(m,1H).

[0518] Example 8

[0519] Step 1

[0520] Pt / C (10%, 25 mg) was added to a methanol (5 mL) solution of compound 8-1A (50 mg, 0.110 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere (15 psi). The reaction mixture was filtered to obtain a filtrate, which was then concentrated under reduced pressure to give the target compound 8-2A. LC-MS: m / z: 365.3 [M+1] + .

[0521] Step 2

[0522] Compounds 8-2A (26.5 mg, 0.073 mmol), DIPEA (28.3 mg, 0.219 mmol), and COMU (37.5 mg, 0.087 mmol) were added to a DMF (3 mL) solution of compound INT-4 (60 mg, 0.073 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with water and extracted with ethyl acetate (50 mL x 3). The organic phases were combined. The organic layer was then washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-7%) to give the target compound 8-3A as a yellow solid. LC-MS: m / z: 1169.2 [M+1] + .

[0523] Step 3

[0524] At room temperature, a solution of dioxane hydrochloride (1 mL, 4 M) was added to a solution of compound 8-3A (60 mg, 0.051 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated under reduced pressure to give compound 8-4A. LC-MS: m / z: 535.3 [M+2] 2+ .

[0525] Step 4

[0526] Compounds 1-10A (13.8 mg, 0.094 mmol), diisopropylethylamine (0.039 mL, 0.234 mmol), and HATU (21.3 mg, 0.056 mmol) were added to a DMF (2 mL) solution of compound 8-4A (50 mg, 0.047 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was subjected to column chromatography (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-10%) and preparative chromatography (column type: Prime C18, 30 x 150 mm x 5 μm; elution phase: mobile phase A / mobile phase B, elution gradient: 58-80% mobile phase B, mobile phase A: 1% ammonium acetate aqueous solution; mobile phase B: acetonitrile; flow rate: 25 mL / min) to obtain target compound 8.

[0527] LC-MS: m / z: 1192.2 [M+1] + . 1 H NMR (400MHz, CDCl3) δ: 8.46 (d, J = 2.8Hz, 1H), 7.34-7.27 (m, 2H), 7.14-7.08 (m, 2H), 6.90-6.77 (m, 1H), 5.60-5.42 (m, 2H), 4.94-4. 74(m,2H),4.59-4.39(m,2H),4.15-4.06(m,1H),3.98(d,J=10.6Hz,1H),3.83-3.77(m,1H),3.74-3.35(m,9H),3.21(s,8H),3.04- 2.71(m,10H),2.70-2.49(m,5H),2.43-2.36(m,4H),2.24-1.93(m,6H),1.87-1.79(m,3H),1.72-1.66(m,4H),1.47(d,J=6.0Hz,3H ),1.34-1.25(m,3H),1.24-1.13(m,2H),0.89(s,3H),0.82-0.72(m,1H),0.52-0.37(m,9H),0.30-0.17(m,2H),0.16-0.09(m,1H).

[0528] Example 9

[0529] Step 1

[0530] Compound 9-1A (100 mg, 0.22 mmol) was dissolved in methanol (10 mL), and platinum carbon (40.0 mg, 40% w / w) was added. The reaction mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere (15 psi). The reaction solution was filtered and concentrated to give the target compound 9-2A. LC-MS: m / z: 365.2 [M+1] + .

[0531] Step 2

[0532] Compound INT-4 (100 mg, 0.122 mmol) and compound 9-2A (53.2 mg, 0.146 mmol) were dissolved in N,N-dimethylformamide (2 mL), and (2-oxime-cyanoethyl acetate)-N,N-dimethylmorpholinourea hexafluorophosphate (85.7 mg, 0.200 mmol) and N,N-diisopropylethylamine (51.7 mg, 0.401 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with water (30 mL) and ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-10%) to give the target compound 9-3A. LC-MS: m / z: 585.4 [M+2] 2+ .

[0533] Step 3

[0534] Compound 9-3A (60.0 mg, 0.051 mmol) was dissolved in dichloromethane (2 mL), and 4 M hydrochloric acid / 1,4-dioxane (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give compound 9-4A. LC-MS: m / z: 535.2 [M+2] 2+ .

[0535] Step 4

[0536] Compounds 9-4A (60.0 mg, 0.056 mmol) and 1-10A (16.51 mg, 0.112 mmol) were dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (32.0 mg, 0.084 mmol) and N,N-diisopropylethylamine (21.7 mg, 0.168 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with water (30 mL) and ethyl acetate (10 mL x 3), the combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-10%) and HPLC preparation (column type: Ultimate YMC-Triart Prep C18, 50 x 250 mm x 10 μm; elution phase: mobile phase A / mobile phase B, gradient elution: 50-90% mobile phase B, mobile phase A: 1% ammonium acetate aqueous solution; mobile phase B: acetonitrile; flow rate: 25 mL / min) to obtain target compound 9.

[0537] LC-MS: m / z: 1193.2 [M+1] + . 1H NMR (400MHz, CD3OD) δ: 8.22 (d, J = 2.8Hz, 1H), 7.29 (d, J = 8.8Hz, 1H), 7.13 (s, 1H), 7.05 (d, J = 6. 2Hz,1H),6.95(d,J=7.6Hz,1H),5.31-5.27(m,1H),4.85-4.73(m,1H),4.52(s,2H),4.40(s,2H) ,4.29(s,1H),3.88(d,J=6.0Hz,1H),3.81(d,J=11.6Hz,1H),3.67-3.57(m,3H),3.52–3.42(m, 3H),3.36(d,J=6.8Hz,1H),3.32-3.23(m,3H),3.00(s,3H),2.95(s,1H),2.79-2.71(m,3H),2.6 7-2.63(m,5H),2.61-2.54(m,5H),2.48(d,J=9.2Hz,1H),2.41(s,1H),2.29(s,1H),2.18(d,J= 2.0Hz,3H),2.16-2.12(m,1H),2.09-2.02(m,1H),1.87(d,J=7.6Hz,1H),1.82-1.70(m,5H),1.6 5(d,J=8.0Hz,1H),1.57(d,J=6.8Hz,4H),1.44(t,J=9.6Hz,3H),1.26(t,J=8.4Hz,4H),1.09(d ,J=24.4Hz,5H),0.68(s,3H),0.42-0.23(m,10H),0.10(d,J=5.6Hz,2H),0.00(d,J=4.0Hz,1H).

[0538] Example 10

[0539] Step 1

[0540] Pt / C (10%, 25 mg) was added to a methanol (5 mL) solution of compound 10⁻¹A (50 mg, 0.110 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere (15 psi). The reaction mixture was filtered to obtain a filtrate, which was then concentrated under reduced pressure to give the target compound 10⁻²A. LC-MS: m / z: 365.3 [M+1] + .

[0541] Step 2

[0542] Compound 10⁻²A (28.4 mg, 0.078 mmol), N,N-diisopropylethylamine (DIPEA) (32.9 mg, 0.255 mmol), and COMU (43.7 mg, 0.102 mmol) were added to a DMF (3 mL) solution of compound INT-4 (70 mg, 0.085 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was subjected to column chromatography (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-10%) to give compound 10⁻³A. LC-MS: m / z: 1169.2 [M+1] + .

[0543] Step 3

[0544] At room temperature, a solution of dioxane hydrochloride (1 mL, 4 M) was added to a solution of compound 10⁻³A (75 mg, 0.064 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated under reduced pressure to give compound 10⁻⁴A. LC-MS: m / z: 535.4 [M+2] 2+ .

[0545] Step 4

[0546] Compounds 1-10A (13.8 mg, 0.094 mmol), diisopropylethylamine (0.039 mL, 0.234 mmol), and HATU (21.3 mg, 0.056 mmol) were added to a 2 mL DMF solution of compound 10-4A (50 mg, 0.047 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-10%) and then purified by HPLC (column type: Prime C18, 30 x 150 mm x 5 μm; elution gradient: 58-80% B, mobile phase A: 1% ammonium acetate aqueous solution; mobile phase B: acetonitrile; flow rate: 25 mL / min) to obtain the target compound 10.

[0547] LC-MS: m / z: 1192.6 [M+1] + . 1H NMR (400MHz, CDCl3) δ: 8.46 (d, J = 2.8Hz, 1H), 7.35-7.28 (m, 2H), 7.13-7.06 (m, 2H), 6.55-6.35 (m, 1H), 5.61-5.39 (m, 2H), 4.95-4.75 (m, 2H) ,4.57-4.40(m,2H),4.14-4.05(m,1H),3.97(d,J=10.2Hz,1H),3.85- 3.76(m,1H),3.71-3.38(m,9H),3.27-3.10(m,8H),3.02-2.88(m,2H), 2.83-2.71(m,8H),2.68-2.56(m,5H),2.46-2.40(m,1H),2.38(s,3H) ,2.21-1.82(m,9H),1.79-1.68(m,4H),1.48(d,J=6.2Hz,3H),1.34-1. 21(m,5H),0.90(s,3H),0.82-0.73(m,1H),0.72-0.65(m,1H),0.53-0. 44(m,8H),0.42-0.36(m,1H),0.28-0.13(m,1H),-0.01–-0.09(m,1H).

[0548] Example 11

[0549] Step 1

[0550] Compound 11-1A (20 g, 127 mmol) was dissolved in 100 mL of 0.5 M sulfuric acid solution, and 170 mL of 763 mmol sodium nitrite solution was added at 0 °C. The reaction mixture was stirred at 0 °C for 3 h, followed by stirring at 25 °C for 24 h. The reaction mixture was filtered through diatomaceous earth, and the pH of the filtrate was adjusted to 1-2 with 2 M sulfuric acid solution, followed by extraction with ethyl acetate (200 mL x 2). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 11-2A. LC-MS: m / z: 159.2 [M+1] + .

[0551] Step 2

[0552] Compound 11-2A (10.0 g, 63.2 mmol) and Cs₂CO₃ (24.7 g, 75.9 mmol) were dissolved in 200 mL of DMF, and benzyl bromide (11.9 g, 69.5 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction solution was quenched with 100 mL of water and extracted with ethyl acetate (100 mL x 2). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel, eluent: tetrahydrofuran / dipetroleum ether, tetrahydrofuran ratio: 0-5%) to give compound 11-3A. LC-MS: m / z: 271.2 [M+23] + .

[0553] Step 3

[0554] Compound 11-3A (5.00 g, 20.1 mmol) and 2,6-dimethylpyridine (4.32 g, 40.3 mmol) were dissolved in 100 mL of dichloromethane. Trifluoromethanesulfonic anhydride (8.52 g, 30.2 mmol) was added dropwise at 0 °C, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (silica gel, eluent: tetrahydrofuran / dipetroleum ether, tetrahydrofuran ratio: 0-5%) to give compound 11-4A.

[0555] Step 4

[0556] Compounds 11-4A (1.00 g, 2.63 mmol) and 1-5A (0.59 g, 2.63 mmol) were dissolved in 20 mL of acetonitrile, and DIEA (0.87 mL, 5.26 mmol) was added. The reaction mixture was stirred at 80 °C for 3 hours. The reaction mixture was quenched with 10 mL of water and extracted with ethyl acetate (10 mL x 2). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel, eluent: tetrahydrofuran / dipetroleum ether, tetrahydrofuran ratio: 0-15%) to give compound 11-5A. LC-MS: m / z: 457.5 [M+1] + .

[0557] Step 5

[0558] Compound 11-5A (1.00 g, 2.19 mmol) was dissolved in 20 mL of methanol, and palladium on carbon (20 mg, 10% purity, 55% water) was added. The mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere (15 psi). The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give compound 11-6A. LC-MS: m / z: 367.3 [M+1] + .

[0559] Step 6

[0560] Compound INT-4 (100 mg, 0.122 mmol) and compound 11-6A (67.1 mg, 0.183 mmol) were dissolved in 3 mL of N,N-dimethylformamide. COMU (67.7 mg, 0.158 mmol) and N,N-diisopropylethylamine (0.803 mL, 4.860 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The solution was diluted with dichloromethane (20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-10%) to give the target compound 11-7A. LC-MS: m / z: 1172.6 [M+1] + .

[0561] Step 7

[0562] Compound 11-7A (72.0 mmol, 0.061 mmol) was dissolved in 1 mL of dichloromethane, and 1 mL of 4M hydrochloric acid / 1,4-dioxane was added. The mixture was stirred at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure to give compound 11-8A. LC-MS: m / z: 1071.6 [M+1] + .

[0563] Step 8

[0564] Compounds 11-8A (65.0 mg, 0.061 mmol) and 1-10A (17.9 mg, 0.121 mmol) were dissolved in 2 mL of N,N-dimethylformamide. HATU (25.0 mg, 0.067 mmol) and N,N-diisopropylethylamine (39.0 mg, 0.303 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The solution was diluted with 20 mL of dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was prepared by column chromatography (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-10%) and HPLC (column type: Boston Prime C18, 30.0*150mm, 5um; elution phase: mobile phase A / mobile phase B, elution gradient: 60-90% mobile phase B; mobile phase A: 10mM ammonium acetate aqueous solution, mobile phase B: acetonitrile; flow rate: 25mL / min) to obtain compound 11.

[0565] LC-MS: m / z: 1194.6 [M+1] + . 1H NMR(400MHz,CD3OD)δ:8.40(d,J=2.8Hz,1H),7.47(d,J=8.8Hz,1H),7.31(s,1H),7.24( s,1H),7.13(dd,J=9.0,2.0Hz,1H),5.53(t,J=6.0Hz,1H),4.97(dd,J=16.4,8.4Hz,1H) ,4.69(dd,J=9.8,4.8Hz,2H),4.52(d,J=42.5Hz,2H),4.06(d,J=6.0Hz,1H),3.97(d,J= 9.6Hz,1H),3.86-3.76(m,3H),3.65(dd,J=18.6,10.6Hz,3H),3.56–3.36(m,4H),3.15( d,J=17.2Hz,3H),2.97(d,J=10.4Hz,1H),2.77(ddd,J=15.2,10.8,5.6Hz,12H),2.61(d dd,J=16.2,12.8,7.6Hz,3H),2.50-2.43(m,1H),2.38-2.27(m,4H),2.27-2.20(m,1H), 2.08(dd,J=14.6,7.4Hz,1H),1.97(s,3H),1.90-1.59(m,11H),1.44(dd,J=15.0,6.6Hz ,4H),1.31-1.03(m,6H),0.85(s,3H),0.66-0.38(m,11H),0.26(dd,J=7.0,3.6Hz,1H).

[0566] Example 12

[0567] Step 1

[0568] Trimethylsilane nitrile (5.68 g, 57.2 mmol) was slowly added dropwise to a tetrahydrofuran (70 mL) solution of compound 12-1A (5.00 g, 52.0 mmol) and LiCl (0.02 g, 0.520 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated to give compound 12-2A, which was used directly in the next step of the reaction.

[0569] 1 H NMR (400MHz, CDCl3) δ: 7.32 (d, J = 0.8 Hz, 1H), 7.20 (d, J = 1.6 Hz, 1H), 6.25 (d, J = 1.2 Hz, 1H), 5.24 (s, 1H).

[0570] Step 2

[0571] At 0 °C, SOCl2 (34.9 mL, 481 mmol) was slowly added to a methanol (470 mL) solution of compound 12-2A (47.0 g, 241 mmol). The reaction mixture was stirred at 65 °C for 3 hours. The mixture was concentrated to give a crude product. The crude product was washed with aqueous potassium carbonate and sodium chloride solutions. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 12-3A.

[0572] 1 H NMR (400MHz, CDCl3) δ7.48 (d, J = 0.8 Hz, 1H), 7.39 (d, J = 1.2 Hz, 1H), 6.42 (d, J = 1.2 Hz, 1H), 5.17 (d, J = 3.6 Hz, 1H), 3.81 (s, 1H).

[0573] Step 3

[0574] At 0 °C, thionyl chloride (0.571 mL, 7.88 mmol) and N,N-dimethylformamide (0.020 mL, 0.263 mmol) were added dropwise to a THF (5 mL) solution of compound 12-3A (820 mg, 5.25 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated to give compound 12-4A.

[0575] 1 H NMR (400MHz, CDCl3) δ: 7.56 (d, J = 0.8 Hz, 1H), 7.42 (d, J = 1.2 Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H), 5.35 (s, 1H), 3.82 (s, 1H).

[0576] Step 4

[0577] Compound 1-5A (1.54 g, 8.84 mmol) and N,N-diisopropylethylamine (855 mg, 6.63 mmol) were added to a 10 mL solution of acetonitrile containing 500 mg (2.21 mmol) of compound 12-4A. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with water (30 mL) and ethyl acetate (30 mL x 3), and the combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent: petroleum ether / ethyl acetate, ethyl acetate ratio: 0-30%) to give compound 12-5A. LC-MS: m / z: 365.4 [M+1] + .

[0578] Step 5

[0579] At 25 °C, lithium hydroxide (259 mg, 6.17 mmol) and methanol (4.5 mL) were added to a tetrahydrofuran (4.5 mL) solution of compound 12-5A (450 mg, 1.24 mmol). The reaction mixture was stirred at room temperature for 2 hours. The pH of the mixture was adjusted to 5–6, and the mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give compound 12-6A. LC-MS: m / z: 351.2 [M+1] + .

[0580] Step 6

[0581] Compound 12-6A (400 mg, 1.13 mmol) was purified by SFC (instrument: Waters PrepSFC 150 mg / mL; column type: Regis Whelk O1(R,R); 40 mm ID × 250 mm, 10 μm; gradient elution: 35% 0.1% ammonia solution / supercritical CO2; flow rate: 120 mL / min) to obtain compound 12-7A (SFC: 100% ee, Rt = 2.279 min (column type: Regis WHELK(R,R) 150 x 4.6)). The column model is Regis WHELK(R,R)150x4.6 mm_5μm; mobile phase: mobile phase A is supercritical CO2, mobile phase B is a 0.1% diethylamine methanol solution; gradient elution: 30% mobile phase B in mobile phase A; flow rate: 2 mL / min, 6.0 min; column temperature: 35℃) and compound 13-1A (SFC: 100% ee, Rt = 3.199 min (column model: Regis WHELK(R,R)150x4.6 mm_5μm; mobile phase: mobile phase A is supercritical CO2, mobile phase B is a 0.1% diethylamine methanol solution; gradient elution: 30% mobile phase B in mobile phase A; flow rate: 2 mL / min, 6.0 min; column temperature: 35℃).

[0582] Step 7

[0583] Compound 12-7A (40.0 mg, 0.114 mmol) and INT-4 (93.9 mg, 0.114 mmol) were dissolved in N,N-dimethylformamide (2 mL). (2-oxime-cyanoethyl acetate)-N,N-dimethylmorpholinourea hexafluorophosphate (73.3 mg, 0.171 mmol) and N,N-diisopropylethylamine (44.12 mg, 0.342 mmol) were added, and the reaction was stirred at room temperature for 2 hours. The reaction mixture was extracted with water (30 mL) and ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-10%) to give compound 12-8A. LC-MS: m / z: 577.8 [M+2] 2+ .

[0584] Step 8

[0585] Compound 12-8A (90.0 mg, 0.078 mmol) was dissolved in dichloromethane (2 mL), and 4 M hydrochloric acid / 1,4-dioxane (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give crude compound 12-9A. LC-MS: m / z: 527.6 [M+2] 2+ .

[0586] Step 9

[0587] Compounds 12-9A (80.0 mg, 0.076 mmol) and 1-10A (22.3 mg, 0.152 mmol) were dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (43.2 mg, 0.114 mmol) and N,N-diisopropylethylamine (29.3 mg, 0.227 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with water (30 mL) and ethyl acetate (10 mL x 3), and the combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-10%), and then prepared by HPLC (column type: Ultimate Prime C18, 30 x 150 mm x 5 μm; elution phase: mobile phase A / mobile phase B, gradient: 52-70% mobile phase B, mobile phase A: 1% aqueous acetic acid; mobile phase B: acetonitrile; flow rate: 25 mL / min) to obtain compound 12.

[0588] LC-MS: m / z: 589.9 [M+2] 2+ .1 1H NMR (400 MHz, CD3OD) δ: 8.17 (d, J = 2.8 Hz, 1H), 7.35 (s, 1H), 7.23 (d, J = 4.2 Hz, 2H), 7.08 (s, 1H), 7.00 (d, J = 10.4 Hz, 1H), 6.89 (d, J = 9.2 Hz, 1H), 6.32 (s, 1H), 5.32 (d, J = 5.2 Hz, 1H), 4.72 (d, J = 9.2 Hz, 1H), 4.46 (d, J = 4.4 Hz, 2H), 4.35 (s, 1H), 4.24 (s, 1H), 3.81 (d, J = 4.8 Hz, 1H), 3.73 (d, J = 11.2 Hz, 1H), 3.59 (dd, J = 19.3, 9.6 Hz, 4H), 3.47 - 3.39 (m, 3H), 3.22 (dd, J = 25.3, 8.4 Hz, 4H), 3.05 (s, 2H), 2.95 - 2.89 (m, 4H), 2.70 (d, J = 10.0 Hz, 2H), 2.62 - 2.46 (m, 10H), 2.39 - 2.30 (m, 3H), 2.23 (t, J = 7.5 Hz, 2H), 2.13 (s, 3H), 2.11 - 2.06 (m, 1H), 2.00 (d, J = 6.4 Hz, 1H), 1.92 - 1.86 (m, 1H), 1.77 (d, J = 9.2 Hz, 2H), 1.75 - 1.70 (m, 1H), 1.68 - 1.57 (m, 2H), 1.55 - 1.45 (m, 1H), 1.41 (t, J = 9.6 Hz, 1H), 1.29 - 1.21 (m, 1H), 1.19 (d, J = 6.4 Hz, 3H), 0.65 - 0.55 (m, 3H), 0.35 - 0.15 (m, 11H), 0.20 - 0.10 (m, 1H).

[0589] Example 13

[0590] Step 1

[0591] Compound 13-1A (47.9 mg, 0.137 mmol) and compound INT-4 (75.0 mg, 0.091 mmol) were dissolved in N,N-dimethylformamide (2 mL). (2-oxime-cyanoethyl acetate)-N,N-dimethylmorpholinourea hexafluorophosphate (58.5 mg, 0.137 mmol) and N,N-diisopropylethylamine (0.045 mL, 0.273 mmol) were added, and the reaction was stirred at room temperature for 2 hours. The reaction mixture was extracted with water (30 mL) and ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-10%) to give compound 13-2A.

[0592] LC-MS: m / z: 577.8 [M+2] 2+ .

[0593] Step 2

[0594] Compound 13-2A ​​(75.0 mg, 0.065 mmol) was dissolved in dichloromethane (2 mL), and 4 M hydrochloric acid / 1,4-dioxane (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give crude compound 13-3A. LC-MS: m / z: 527.6 [M+2] 2+ .

[0595] Step 3

[0596] Compounds 13-3A (65.0 mg, 0.062 mmol) and 1-10A (17.4 mg, 0.123 mmol) were dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (70.3 mg, 0.185 mmol) and N,N-diisopropylethylamine (0.020 mL, 0.123 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with water (30 mL) and ethyl acetate (10 mL x 3), and the combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-10%), and then prepared by HPLC (column type: Ultimate Prime C18, 30 x 150 mm x 5 μm; elution phase: mobile phase A / mobile phase B, gradient: 52-70% mobile phase B, mobile phase A: 1% aqueous acetic acid; mobile phase B: acetonitrile; flow rate: 25 mL / min) to obtain compound 13.

[0597] LC-MS: m / z: 590.0 [M+2] 2+ . 1 H NMR (400 MHz, CD3OD) δ: 8.39 (d, J = 2.8 Hz, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.48 - 7.42 (m, 2H), 7.31 (s, 1H), 7.21 (d, J = 24.0 Hz, 1H), 7.11 (t, J = 9.2 Hz, 1H), 6.55 (d, J = 17.2 Hz, 1H), 5.56 (d, J = 14.0 Hz, 1H), 4.95 (s, 1H), 4.69 (s, 2H), 4.47 (s, 1H), 4.05 (s, 1H), 3.92 (s, 1H), 3.90 - 3.80 (m, 3H), 3.80 - 3.70 (m, 3H), 3.62 (s, 2H), 3.58 - 3.36 (m, 4H), 3.20 - 3.10 (m, 4H), 2.99 (s, 1H), 2.90 (d, J = 9.4 Hz, 1H), 2.84 - 2.81 (m, 4H), 2.72 (s, 4H), 2.64 (d, J = 7.2 Hz, 2H), 2.61 - 2.55 (m, 1H), 2.50 - 2.40 (m, 2H), 2.37 (d, J = 1.6 Hz, 3H), 2.33 (d, J = 8.4 Hz, 1H), 2.20 (dd, J = 16.4, 9.2 Hz, 2H), 2.09 - 1.95 (m, 3H), 1.94 (d, J = 5.2 Hz, 2H), 1.90 - 1.75 (m, 3H), 1.74 - 1.70 (m, 1H), 1.64 (d, J = 9.6 Hz, 1H), 1.46 (d, J = 7.3 Hz, 1H), 1.41 (d, J = 6.4 Hz, 4H), 0.84 (s, 3H), 0.62 - 0.39 (m, 11H), 0.25 (d, J = 5.4 Hz, 1H).

[0598] Example 14

[0599] Step 1

[0600] At room temperature, 2-methylpropionaldehyde (3.53 mL, 38.7 mmol) and tetraethyl titanate (17.6 g, 77.3 mmol) were added to a tetrahydrofuran (60 mL) solution of compound 14-1A (4.0 g, 25.8 mmol). The reaction mixture was heated to 60 °C and stirred for 3 hours. The reaction was quenched with water (100 mL), filtered, and the mixture was extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was subjected to column chromatography (silica gel, eluent: petroleum ether / ethyl acetate, ethyl acetate ratio: 0-10%) to give compound 14-2A. LC-MS: m / z: 210.0 [M+1] + .

[0601] Step 2

[0602] At -60 °C, lithium bis(trimethylsilylaminolithium) (LiHMDS) (13.7 mL, 1 M in THF) was slowly added to a tetrahydrofuran (50 mL) solution of compound 14-2A (3.13 g, 13.7 mmol). The reaction mixture was stirred at -60 °C for 1.5 h. After dilution with water (100 mL), the reaction mixture was extracted with ethyl acetate (100 mL x 3), and the organic phases were combined. The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was subjected to column chromatography (silica gel, eluent: petroleum ether / ethyl acetate, ethyl acetate ratio: 0-10%) to give compound 14-3A. LC-MS: m / z: 358.2 [M+1] + .

[0603] Step 3

[0604] At 0 °C, methanol (5 mL), water (5 mL), and trifluoroacetic acid (3.83 g, 33.6 mmol) were added to a solution of compound 14-3A (2.4 g, 6.71 mmol) in acetone (24 mL). The reaction mixture was stirred at 0 °C for 1 hour. The pH of the reaction mixture was adjusted to 8 with a 25% ammonia solution. The mixture was quenched with water and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate-free solution. After filtration, the filtrate was concentrated under reduced pressure. The crude product was subjected to column chromatography (silica gel, eluent: petroleum ether / ethyl acetate, ethyl acetate ratio: 0-50%) to give compound 14-4A. LC-MS: m / z: 220.2 [M+1] + .

[0605] Step 4

[0606] At 25 °C, silver carbonate (753 mg, 2.73 mmol) and methyl iodide (388 mg, 2.73 mmol) were added to a tetrahydrofuran (10 mL) solution of compound 14-4A (200 mg, 0.91 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: petroleum ether / ethyl acetate, ethyl acetate ratio: 0-30%) to give the target compound 14-5A. LC-MS: m / z: 234.2 [M+1] + .

[0607] Step 5

[0608] A solution of lithium hydroxide hydrate (24.8 mg, 0.579 mmol) in water (0.1 mL) was added to a solution of compound 14-5A (90 mg, 0.386 mmol) in tetrahydrofuran (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to give compound 14-6A. LC-MS: m / z: 144.2 [M+1] + .

[0609] Step 6

[0610] Compound 14-6A (6.22 mg, 0.062 mmol), ethyl diisopropylamine (0.017 mL, 0.104 mmol), and HATU (9.51 mg, 0.025 mmol) were added to a DMF (1 mL) solution of compound 5-10A (22 mg, 0.021 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: dichloromethane / methanol, methanol ratio: 0-10%), and then prepared by HPLC (column type: Prime C18, 30 x 150 mm x 5 μm; elution phase: mobile phase A / mobile phase B, gradient: 58-80% mobile phase B, mobile phase A: 1% ammonium acetate aqueous solution; mobile phase B: acetonitrile; flow rate: 25 mL / min) to obtain compound 14.

[0611] LC-MS: m / z: 1180.6 [M+1] + . 1H NMR (400MHz, CDCl3) δ: 8.46 (d, J = 2.8Hz, 1H), 7.35-7.28 (m, 2H), 7.15-7.09 (m, 2 H),6.97-6.83(m,1H),5.67-5.58(m,2H),5.56-5.38(m,2H),5.39-5.30(m,1H),4 .91-4.76(m,2H),4.61-4.43(m,2H),4.13-4.07(m,1H),3.99-3.92(m,1H),3.82 -3.76(m,1H),3.69-3.58(m,5H),3.50-3.42(m,2H),3.26--3.18(m,6H),3.00-2. 94(m,1H),2.83-2.76(m,6H),2.67-2.63(m,1H),2.61-2.55(m,2H),2.49-2.41( m,5H),2.37-2.30(m,2H),2.26-2.18(m,1H),2.17-2.08(m,2H),2.06-2.00(m,2H ),1.99-1.88(m,3H),1.87-1.75(m,3H),1.72-1.68(m,2H),1.47(d,J=6.2Hz,3H) ,1.31-1.25(m,7H),1.08(d,J=6.8Hz,3H),0.92-0.80(m,7H),0.57-0.39(m,7H).

[0612] Example 15

[0613] Step 1

[0614] Compounds 15-2A (5 g, 32.2 mmol) and 15-1A (1.87 g, 32.2 mmol) were added to tetrahydrofuran (60 mL), followed by tetraethyl titanate (22.04 g, 96.6 mmol). The mixture was heated to 70 °C and reacted for 3 hours. After cooling to room temperature, the reaction was quenched with water, filtered, and the filtrate was collected. The filtrate was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 15-3A. LC-MS: (ESI) m / z: 196.0 [M+1] + . 1 H NMR (400MHz, CDCl3) δ: 8.25 (t, J = 4.4Hz, 1H), 7.61-7.50 (m, 2H), 7.30 (d, J = 8.0Hz, 2H), 2.61-2.43 (m, 2H), 2.39 (d, J = 6.2Hz, 3H), 1.16 (t, J = 7.4Hz, 3H).

[0615] Step 2

[0616] Compound 15-3A (2.10 g, 10.8 mmol) and compound 15-4A (3.20 g, 14.0 mmol) were added to tetrahydrofuran (21 mL), purged with nitrogen, cooled to -60 °C, and LiHMDS (14.0 mL) was added dropwise. The reaction mixture was then slowly heated to -40 °C and reacted for 1.5 hours. The reaction was quenched with water at -40 °C, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent: petroleum ether / ethyl acetate, ethyl acetate ratio: 0-30%) to give the target compound 15-5A. LC-MS: m / z: 344.2 [M+1] + . 1 H NMR(400MHz, CDCl3)δ:7.66-7.55(m,2H),7.44-7.27(m,4H),7.24(s,1H),7.21-7.10(m,2H),5.04(dd,J=27.1,12.3Hz,2H),3. 22(d,J=7.2Hz,1H),2.73(dd,J=13.8,7.2Hz,1H),2.46-2.33(m,3H),1.89-1.70(m,1H),1.73-1.56(m,2H),1.06-0.99(m,3H).

[0617] Step 3

[0618] Compound 15-5A (500 mg, 1.46 mmol) was added to a mixed solution of acetone (5 mL), methanol (1 mL), and water (1 mL). The mixture was cooled to 0 °C, and trifluoroacetic acid (TFA) (0.557 mL, 7.279 mmol) was added dropwise. The mixture was stirred at 0 °C for 1.5 hours. The reaction was quenched with ammonia, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product was subjected to column chromatography (silica gel, eluent: petroleum ether / ethyl acetate, ethyl acetate ratio: 0-80%) to give the target compound 15-6A. LC-MS: m / z: 206.0 [M+1] + .

[0619] Step 4

[0620] Compound 15-6A (100 mg, 0.487 mmol) was dissolved in tetrahydrofuran (5 mL), and disilver carbonate (335 mg, 1.22 mmol) and methyl iodide (172.88 mg, 1.22 mmol) were added. The reaction mixture was stirred at room temperature for 18 hours. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent: petroleum ether / ethyl acetate, ethyl acetate ratio: 0-20%) to give the target compound 15-7A. LC-MS: m / z: 220.2 [M+1] + .

[0621] Step 5

[0622] Compound 15-7A (70.0 mg, 0.319 mmol) was dissolved in tetrahydrofuran (1 mL) and water (1 mL), and lithium hydroxide monohydrate (10.80 mg, 0.257 mmol) was added. The reaction was stirred at room temperature for 2 hours. The pH was adjusted to approximately 8 with 0.5 M hydrochloric acid solution, and then lyophilized to obtain the target compound 15-8A. LC-MS: m / z: 130.4 [M+1] + .

[0623] Step 6

[0624] Compounds 5-10A (50.0 mg, 0.047 mmol) and 15-8A (19.20 mg, 0.142 mmol) were dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (27.01 mg, 0.071 mmol) and N,N-diisopropylethylamine (18.34 mg, 0.142 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with water (30 mL) and ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-10%) and then preparatively separated by HPLC (column type: JB-C235-03 Prime C18, 30 x 150 mm x 5 μm; elution phase: mobile phase A / mobile phase B, elution gradient: 57-76% mobile phase B, mobile phase A: 1% ammonium bicarbonate aqueous solution; mobile phase B: acetonitrile; flow rate: 25 mL / min) to obtain the target compound 15.

[0625] LC-MS: m / z: 1166.6 [M+1] + . 1H NMR(400MHz, CD3OD)δ:8.42(d,J=2.8Hz,1H),7.49(d,J=8.8Hz,1H),7.33(s,1H),7.27(s, 1H),7.15(d,J=10.8Hz,1H),5.65(s,2H),5.51(s,1H),4.72(d,J=5.6Hz,2H),4.60(s,1H), 4.49(s,1H),4.08(s,1H),3.98(d,J=11.2Hz,1H),3.85-3.77(m,3H),3.65(dd,J=31.2,10 .8Hz,4H),3.54-3.42(m,4H),3.19(s,3H),3.16-3.14(m,2H),3.05(d,J=9.6Hz,1H),2.85( dd,J=11.8,6.8Hz,8H),2.77(d,J=9.5Hz,3H),2.68(dd,J=18.6,8.8Hz,3H),2.47(s,3H), 2.41(s,1H),2.38(s,2H),2.34(dd,J=10.4,6.8Hz,2H),2.28-2.21(m,2H),1.99(d,J=52.2 Hz,4H),1.90-1.74(m,5H),1.65(s,1H),1.44(d,J=6.4Hz,3H),1.42-1.36(m,2H),1.32(s ,4H),1.00(t,J=7.5Hz,3H),0.87(s,3H),0.61(s,2H),0.55(d,J=6.8Hz,2H),0.50(s,2H).

[0626] Example 16

[0627] Step 1

[0628] (R)-(4-methylphenyl)(oxo)-λ4-sulfanilamide (5.0 g, 32.2 mmol) and compound 16-1A (5.25 mL, 48.3 mmol) were dissolved in tetrahydrofuran (100 mL), and tetraisopropyl titanate (22.0 g, 96.637 mmol) was added. The reaction mixture was stirred at 25 °C for 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was subjected to column chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-10%) to give compound 16-2A. LC-MS: m / z: 224.2 [M+1] + .

[0629] Step 2

[0630] Compound 16-2A (3.5 g, 15.7 mmol) and benzyl 2-bromoacetate (4.67 g, 20.4 mmol) were dissolved in tetrahydrofuran (70 mL). The reaction solution was cooled to -60 °C, and lithium bis(trimethylsilylamino)lithium (20.4 mL, 20.4 mmol) was slowly added dropwise. The reaction was stirred at -60 °C for 2 hours. The reaction solution was extracted with water (100 mL) and ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-50%) to give the target compound 16-3A. LC-MS: m / z: 372.2 [M+1] + .

[0631] Step 3

[0632] Compound 16-3A (2.0 g, 5.38 mmol) was dissolved in acetone (20 mL), methanol (4 mL), and water (4 mL). The reaction mixture was cooled to 0 °C, and trifluoroacetic acid (3.07 g, 26.9 mmol) was slowly added. The reaction mixture was stirred at 0 °C for 2 hours. Ammonia was slowly added dropwise to adjust the pH to 8, and the mixture was then extracted with water (100 mL) and ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-50%) to give compound 16-4A. LC-MS: m / z: 234.0 [M+1] + .

[0633] Step 4

[0634] Compound 16-4A (50.0 mg, 0.214 mmol) was dissolved in tetrahydrofuran (2 mL), and silver carbonate (147.7 mg, 0.536 mmol) and methyl iodide (76.05 mg, 0.536 mol) were added. The mixture was stirred at room temperature for 18 hours. The reaction solution was extracted with water (100 mL) and ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent: petroleum ether / ethyl acetate, ethyl acetate ratio: 0-20%) to give the target compound 16-5A. LC-MS: m / z: 248.2 [M+1] + .

[0635] Step 5

[0636] Compound 16-5A (30.0 mg, 0.129 mmol) was dissolved in tetrahydrofuran (1 mL) and water (0.5 mL), and lithium hydroxide monohydrate (10.80 mg, 0.257 mmol) was added. The reaction was stirred at room temperature for 2 hours. The pH was adjusted to approximately 8 with 0.5 M hydrochloric acid solution, and then lyophilized to obtain the target compound 16-6A. LC-MS: m / z: 158.2 [M+1] + .

[0637] Step 6

[0638] Compounds 5-10A (60.0 mg, 0.057 mmol) and 16-6A (18.6 mg, 0.114 mmol) were dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (32.41 mg, 0.085 mmol) and N,N-diisopropylethylamine (22.0 mg, 0.171 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (30 mL) and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-10%), followed by purification by rapid silica gel column chromatography (methanol / dichloromethane, methanol ratio: 0-85%) to obtain compound 16.

[0639] LC-MS: m / z: 1194.5 [M+1] + . 1H NMR(400MHz,CD3OD)δ:8.30(d,J=2.8Hz,1H),7.37(d,J=8.8Hz,1H),7.22(s,1H ),7.15(s,1H),7.04(d,J=8.8Hz,1H),5.53(s,2H),5.39(s,1H),4.91-4.84(m, 1H),4.60(d,J=5.2Hz,2H),4.48(s,1H),4.37(s,1H),3.96(d,J=6.4Hz,1H),3. 86(d,J=10.1Hz,1H),3.73-3.65(m,3H),3.61-3.46(m,4H),3.41-3.26(m,4H),3 .05(d,J=17.2Hz,4H),2.95(d,J=9.6Hz,1H),2.85-2.71(m,10H),2.69-2.46(m ,8H),2.37-2.25(m,6H),2.20-2.08(m,3H),2.03-1.79(m,6H),1.78-1.61(m,4 H),1.53(t,J=9.4Hz,1H),1.47-1.42(m,1H),1.33(d,J=6.2Hz,3H),0.81(d,J= 4.8Hz, 9H), 0.76 (s, 3H), 0.49 (s, 2H), 0.46-0.41 (m, 2H), 0.38 (d, J = 3.6Hz, 2H).

[0640] Example 17

[0641] Step 1

[0642] To a solution of compound 17-1A (2.22 g, 25.8 mmol) in tetrahydrofuran (50 mL), (R)-(4-methylphenyl)(oxo)-λ4-sulfanilamide (4.00 g, 25.8 mol) and tetraethyl titanate (14.7 g, 64.4 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours. The mixture was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was subjected to column chromatography (silica gel, eluent: petroleum ether / ethyl acetate, ethyl acetate ratio: 0-50%) to give compound 17-2A. LC-MS: m / z: 224.0 [M+1] + .

[0643] Step 2

[0644] At -78 °C, LiHMDS (11 mL, 1 M, 11.1 mmol) was slowly added to a tetrahydrofuran (20 mL) solution of compound 17-2A (1.9 g, 8.51 mmol) and benzyl bromoacetate (2.53 g, 11.1 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was subjected to column chromatography (silica gel, eluent: petroleum ether / ethyl acetate, ethyl acetate ratio: 0-30%) to give compound 17-3A. LC-MS: m / z: 372.2 [M+1] + .

[0645] Step 3

[0646] At 0 °C, methanol (2 mL), water (2 mL), and trifluoroacetic acid (2.76 g, 24.2 mmol) were slowly added to a solution of compound 17-3A (1.8 g, 4.85 mmol) in acetone (10 mL). The reaction mixture was stirred at 0 °C for 1 hour. The pH was adjusted to 8 with ammonia (25%). Extraction was performed with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: petroleum ether / ethyl acetate, ethyl acetate ratio: 0-100%) to give compound 17-4A. LC-MS: m / z: 234.3 [M+1] + .

[0647] Step 4

[0648] Silver carbonate (887 mg, 3.22 mmol) and methyl iodide (548 mg, 3.86 mmol) were added to a tetrahydrofuran (3 mL) solution of compound 17-4A (300 mg, 1.29 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was subjected to column chromatography (silica gel, eluent: dichloromethane / methanol, methanol ratio: 0-10%) to give the target compound 17-5A. LC-MS: RT = 0.628 min, (ESI) m / z: 248.2 [M+H] + .

[0649] Step 5

[0650] To a solution of compound 17-5A (150 mg, 0.607 mmol) in tetrahydrofuran (2 mL), water (2 mL) and lithium hydroxide (38.2 mg, 0.910 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give a crude product. The residue was lyophilized to give the target compound 17-6A. LC-MS: m / z: 156.2 [M+1] + .

[0651] Step 6

[0652] To a DMF (2 mL) solution of compound 5-10A (50 mg, 0.047 mmol), 17-6A (15.5 mg, 0.095 mmol), diisopropylethylamine (0.039 mL, 0.237 mmol), and HATU (21.6 mg, 0.057 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude residue was subjected to column chromatography (silica gel, eluent: dichloromethane / methanol, methanol ratio: 0-7%) and preparation (column type: Prime C18, 30 x 150 mm x 5 μm; elution phase: mobile phase A / mobile phase B, gradient elution: 58-80% mobile phase B, mobile phase A: 1% ammonium acetate aqueous solution; mobile phase B: acetonitrile; flow rate: 25 mL / min) to give compound 17.

[0653] LC-MS: m / z: 1194.2 [M+1] + . 1H NMR(400MHz, CD3OD)δ:8.42(d,J=2.8Hz,1H),7.49(d,J=8.8Hz,1H),7.33(s,1H),7.27(s,1H),7.16(d,J=9.2Hz,1H),5.66(s,2H),5.55-5.46(m,1H) ,5.11-4.95(m,1H),4.78-4.70(m,4H),4.65-4.48(m,4H),4.14-4.05(m,1 H),3.98(d,J=11.2Hz,1H),3.90-3.72(m,4H),3.72-3.55(m,3H),3.53-3. 49(m,2H),3.46-3.38(m,2H),3.23-3.18(m,3H),3.16-3.12(m,1H),3.08- 3.02(m,1H),2.97-2.82(m,10H),2.79-2.60(m,7H),2.52-2.41(m,7H),2. 37-2.22(m,4H),2.16-1.82(m,6H),1.81-1.73(m,2H),1.67-1.59(m,1H), 1.45(d,J=6.2Hz,3H),1.34-1.29(m,1H),0.88(s,3H),0.63-0.46(m,7H).

[0654] Example 18

[0655] Step 1

[0656] A mixture of compound 18-1A (200 mg, 1.79 mmol), 2,2-dihydroxyacetic acid (197 mg, 2.14 mmol), and 1-5A (404 mg) in hexafluoroisopropanol (HFIP) (5 mL) was stirred at 50 °C under a nitrogen atmosphere for 1 hour. The mixture was concentrated and purified by reversed-phase column chromatography (ACN / H2O = 50%) to give the target compound 18-2A.

[0657] 1 H NMR (400MHz, CDCl3) δ: 5.93 (s, 1H), 4.10 (s, 1H), 3.58-2.93 (m, 8H), 2.47-2.31 (m, 4H), 2.11-1.69 (m, 6H), 1.38 (s, 9H).

[0658] Step 2

[0659] Compound INT-4 (200 mg, 0.243 mmol) and compound 18-2A (85.2 mg, 0.243 mmol) were dissolved in N,N-dimethylformamide (5 mL), and (2-oxime-cyanoethyl acetate)-N,N-dimethylmorpholinourea hexafluorophosphate (156 mg, 0.365 mmol) and N,N-diisopropylethylamine (94.1 mg, 0.729 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with water (30 mL) and ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-10%), followed by preparative separation by HPLC (column type: JB-C235-03 Prime C18, 30 x 150 mm x 5 μm; elution phase: mobile phase A / mobile phase B, elution gradient: 46-76% mobile phase B, mobile phase A: 1% ammonium acetate aqueous solution; mobile phase B: acetonitrile; flow rate: 25 mL / min) to obtain the target compound 18-3A (LC-MS: RT = 1.721 min, (ESI) m / z: 578.4 [M+2)). 2+ Method information: Mobile phase A: 5 mM ammonium bicarbonate aqueous solution; Mobile phase B: acetonitrile; Elution gradient: Mobile phase B increased from 5% to 95% within 1.3 min; Flow rate: 1.8 ml / min; Column type: Waters XBridge C18, 4.6*50 mm, 3.5 μm A-RP-1850; Column temperature: 45 °C) and compound 19-1A (LC-MS: RT = 1.744 min, (ESI) m / z: 578.4 1 / 2 [M+2] 2+ Method information: Mobile phase A: 5 mM ammonium bicarbonate aqueous solution; Mobile phase B: acetonitrile; Elution gradient: Mobile phase B increased from 5% to 95% within 1.3 min; Flow rate: 1.8 ml / min; Column type: Waters XBridge C18, 4.6*50 mm, 3.5 μm A-RP-1850; Column temperature: 45℃.

[0660] Step 3

[0661] Compound 18-3A (50.0 mg, 0.043 mmol) was dissolved in dichloromethane (2 mL), and 4 M hydrochloric acid / 1,4-dioxane (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give compound 18-4A. LC-MS: m / z: 528.3 [M+2] 2+ .

[0662] Step 4

[0663] Compound 18-4A (50.0 mg, 0.047 mmol) and compound 1-10A (13.9 mg, 0.095 mmol) were dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (27.0 mg, 0.071 mmol) and N,N-diisopropylethylamine (18.3 mg, 0.142 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined. The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-10%), and then preparatively separated by HPLC (column type: JB-C235-03 Prime C18, 30 x 150 mm x 5 μm; elution phase: mobile phase A / mobile phase B, elution gradient: 57-83% mobile phase B, mobile phase A: 1% ammonium bicarbonate aqueous solution; mobile phase B: acetonitrile; flow rate: 25 mL / min) to obtain the target compound 18.

[0664] LC-MS: m / z: 589.8 [M+2] 2+ . 1 H NMR(400MHz,CD3OD)δ:8.42(d,J=2.8Hz,1H),7.51-7.45(m,1H),7.33(s,1 H),7.23(d,J=24.4Hz,1H),7.17-7.10(m,1H),5.82(s,1H),5.61-5.52(m, 1H),5.05-4.93(m,1H),4.74-4.67(m,2H),4.49(s,1H),4.08(s,1H),3.97 (d,J=11.6Hz,1H),3.82(d,J=8.4Hz,3H),3.76-3.45(m,9H),3.19(d,J=5. 6Hz,3H),3.17-3.13(m,1H),3.03-2.90(m,2H),2.87-2.82(m,5H),2.81-2 .54(m,8H),2.51-2.43(m,2H),2.43-2.23(m,10H),2.19-1.97(m,4H),1.9 4–1.83(m,5H),1.79-1.74(m,1H),1.65(t,J=8.4Hz,1H),1.50-1.42(m,4H ),0.87(s,3H),0.73-0.67(m,1H),0.62-0.44(m,10H),0.31-0.25(m,1H).

[0665] Example 19

[0666] Step 1

[0667] Compound 19-1A (40.0 mg, 0.035 mmol) was dissolved in dichloromethane (2 mL), and 4 M hydrochloric acid / 1,4-dioxane (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give crude compound 19-2A, which was used directly in the next reaction. LC-MS: m / z: 528.4 [M+2] 2+ .

[0668] Step 2

[0669] Compound 19-2A (40 mg, 0.038 mmol) and compound 1-10A (11.2 mg, 0.076 mmol) were dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (21.61 mg, 0.057 mmol) and N,N-diisopropylethylamine (14.7 mg, 0.114 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined. The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-10%), and then further purified by preparative chromatography (column type: JB-C235-03 Prime C18, 30 x 150 mm x 5 μm; elution phase: mobile phase A / mobile phase B, elution gradient: 57-83% mobile phase B, mobile phase A: 1% ammonium bicarbonate aqueous solution; mobile phase B: acetonitrile; flow rate: 25 mL / min) to obtain compound 19.

[0670] LC-MS: m / z: 589.8 [M+2] 2+ . 1H NMR(400MHz,CD3OD)δ:8.42(d,J=2.8Hz,1H),7.49(d,J=8.8Hz,1H),7.33(s,1 H),7.26(d,J=10.0Hz,1H),7.15(dd,J=2.0,1.6Hz,1H),5.83(d,J=2.0Hz,1H), 5.55(d,J=6.4Hz,1H),5.06-4.91(m,1H),4.71(dd,J=10.0,4.8Hz,2H),4.49(d ,J=9.8Hz,1H),4.06(d,J=6.0Hz,1H),3.97(d,J=10.4Hz,1H),3.87-3.61(m,7H ),3.53-3.39(m,4H),3.29(s,4H),3.21-3.14(m,3H),2.96(d,J=5.4Hz,1H),2. 86-2.69(m,10H),2.64-2.58(m,3H),2.52-2.30(m,11H),2.24(d,J=10.4Hz,1H ),2.09-1.81(m,8H),1.79-1.73(m,1H),1.65(t,J=9.6Hz,1H),1.52-1.47(m,1 H), 1.44 (d, J = 6.4Hz, 3H), 0.86 (s, 3H), 0.67-0.42 (m, 11H), 0.31-0.25 (m, 1H).

[0671] Example 20

[0672] Step 1

[0673] A mixture of 20-1A (50 g, 287 mmol), 2-methylpropyl-2-ylpiperazine-1-carboxylate (56.2 g, 301 mmol), and DIEPA (74.1 g, 574 mmol) in acetonitrile (500 mL) was stirred at room temperature for 1 hour. The mixture was poured into water, and the solid was filtered to give 20-2A as a white solid. LC-MS: RT = 0.774 min, (ESI) m / z: 345.7 [M+23] + .

[0674] Step 2

[0675] To a solution of 20-2A (70.0 g, 216 mmol) in THF (700 mL), the mixture was cooled to 0 °C, and MeMgBr (144 mL, 432 mmol) was slowly added. The reaction mixture was stirred for 2 hours. The reaction mixture was extracted with water (1000 mL) and ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (1000 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (PE / EA = 10 / 1) to give 20-3A as a white solid. LC-MS: RT = 1.430 min, (ESI) m / z: 363.3 [M+23] + .

[0676] Step 3

[0677] The triethylamine solution (489 mL, 3521 mmol) was cooled to 0 °C, and formic acid (64.8 g, 1408 mmol) was added dropwise. Then, a solution of Ru-L(S,S) (7.42 g, 11.7 mmol) and 20-3A (40.0 g, 117 mmol) in THF (400 mL) was added. The reaction mixture was heated to 40 °C and stirred for 18 hours. The reaction mixture was extracted with H₂O (100 mL) and EtAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (PE / EA = 1 / 1) to give 20-4A. LC-MS: (ESI) m / z: 343.2 [M+1] + .

[0678] Step 4

[0679] A solution of 20-4A (35.0 g, 102.094 mmol) in N,N-dimethylformamide (350 mL) was cooled to 0 °C, and sodium hydride (4.90 g, 204.189 mmol) was slowly added. After 0.5 hours, iodomethane (21.7 g, 153 mmol) was added dropwise, and the reaction mixture was stirred for 2 hours. The reaction mixture was extracted with water (1000 mL) and ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (PE / EA = 1 / 1) to give 20-5A. LC-MS: (ESI) m / z: 379.2 [M+23] + .

[0680] Step 5

[0681] Under nitrogen protection at 25 °C, hexamethyldiselenes (21 g, 56.4 mmol), hexamethyldiselenes (14.0 mL, 67.7 mmol), Pd(dppf)Cl₂ (4.13 g, 5.64 mmol), and lithium chloride (3.59 g, 84.7 mmol) were added to a solution of 20-5A (21 g, 56.4 mmol) in 210 mL of dioxane. The reaction mixture was stirred at 100 °C for 16 hours. The reaction product was detected by LC-MS. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 20-6A. LC-MS: (ESI) m / z: 487.2 [M+1] + .

[0682] Step 6

[0683] Under an argon atmosphere, 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-2-iodo-1H-indole (33.9 g, 52.5 mmol), tetrakis(triphenylphosphine)palladium (8.10 g, 7.00 mmol), and cuprous iodide (3.34 g, 17.5 mmol) were added to a solution of 20-6A (17 g, 35.03 mmol) in 150 mL of dioxane. The reaction mixture was stirred at 120 °C for 6 hours. The reaction product was detected by LC-MS. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 20-7A. LC-MS: (ESI) m / z: 840.4 [M+1] + .

[0684] Step 7

[0685] Cesium carbonate (35.2 g, 108 mol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (25.1 g, 108 mmol) were added fractionally to a solution of 20-7A (13 g, 15.4 mmol) in 100 mL of N,N-dimethylformamide. The mixture was heated to 25 °C and stirred for 18 hours. Brine was added to the residue, and the mixture was extracted with ethyl acetate (500 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified on silica gel using a mixture of ethyl acetate and hexane (1:1) as the eluent to give 20-8A. LC-MS: (ESI) m / z: 922.6 [M+1] + .

[0686] Step 8

[0687] Zinc bromide (2.44 g, 10.8 mmol) was added to a solution of 20-8A (2 g, 2.16 mmol) in dichloromethane (20 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 18 hours. LC-MS showed detection of the reaction product. The reaction mixture was extracted with ethyl acetate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 20-9A. LC-MS: (ESI) m / z: 822.3 [M+1] + .

[0688] Step 9

[0689] At 25 °C, glacial acetic acid (0.410 mL, 7.29 mmol), 1-ethoxy-1-[(trimethylsilyl)oxy]cyclopropane (0.42 g, 2.43 mmol), and sodium cyanoborohydride (0.31 g, 4.86 mmol) were added to a solution of 20-9A (2.0 g, 2.43 mmol) in 20 mL of isopropanol. The reaction mixture was stirred at 50 °C for 18 hours. LC-MS showed detection of the reaction product. The reaction mixture was extracted with ethyl acetate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% DCM / MeOH) to give 20-10A. LC-MS: (ESI) m / z: 862.3 [M+1] + .

[0690] Step 10

[0691] Under nitrogen atmosphere, a mixture of 20-10A (1501 mg, 1.74 mmol) and TBAF (1823 mg, 6.97 mmol) in 30 mL of THF was stirred overnight at 50 °C. The reaction mixture was poured into water, extracted with EtOAc, and concentrated to give 20-11A. LC-MS: (ESI) m / z: 624.0 [M+1] + .

[0692] Step 11

[0693] TBSCl (361 mg, 2.40 mmol) was added to a mixture of 20-11A (1000 mg, 1.60 mmol) and imidazole (327 mg, 4.80 mmol) in dichloromethane (20 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated and purified by column chromatography (DCM / MeOH = 30 / 1) to give 20-12A. LC-MS: (ESI) m / z: 738.0 [M+1] + .

[0694] Step 12

[0695] 20-12A (725 mg, 1.62 mmol), RuPhos (101 mg, 0.217 mmol), RuPhos Pd G2 (168 mg, 0.227 mmol), Pd(OAc)2 (24.3 mg, 0.108 mmol), and Cs2CO3 (1412 mg, 4.33 mmol) were added to dioxane (12 mL). The mixture was stirred at 80 °C for 2 hours under nitrogen. The mixture was then concentrated and purified by column chromatography (DCM / MeOH = 20 / 1) to obtain 20-13A. LC-MS: (ESI) m / z: 553.0 [M+2] 2+ .

[0696] Step 13

[0697] A solution of LiOH (0.06 g, 1.36 mmol) in H₂O (10 mL) was added to a mixture of 20-13A (1.5 g, 1.36 mmol) and 20 mL of THF. The mixture was stirred at 25 °C for 1 hour, then the pH of the mixture was adjusted to 2 with 1 M HCl, concentrated, and purified by a C18 reversed-phase column (acetonitrile / water = 50%) to obtain 20-14A.

[0698] Step 14

[0699] EDCI (162 mg, 0.845 mmol) was added to a DCM (40 mL) solvent containing 20-15A (550 mg, 0.563 mmol), HOBt (114 mg, 0.845 mmol), and DMAP (344 mg, 2.82 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and purified by C18 chromatography (acetonitrile / water = 60%) to give 20-16A. LC-MS: (ESI) m / z: 480.0 [M+2] 2+ .

[0700] Step 15

[0701] 20-16A (300 mg, 0.313 mmol) was dissolved in isopropanol (10 mL), and palladium on carbon (150 mg, 50% w / w) was added. The reaction mixture was stirred for 2 hours at room temperature under a hydrogen atmosphere (1 atm). The reaction solution was filtered and concentrated to give 20-17A. LC-MS: (ESI) m / z: 413.3 [M+2] 2+ .

[0702] Step 16

[0703] 20-17A (150 mg, 0.182 mmol), 2-((S)-7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]non-2-yl)-2-(cyclopent-3-en-1-yl)acetic acid (76.6 mg, 0.218 mmol) were dissolved in N,N-dimethylformamide (5 mL), and (2-oxime-cyanoethyl acetate)-N,N-dimethylmorpholinourea hexafluorophosphate (117 mg, 0.273 mmol) and N,N-diisopropylethylamine (70.5 mg, 0.546 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with water (30 mL) and ethyl acetate (10 mL * 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent methanol / dichloromethane, methanol ratio: 0-10%) to give 20-18A. LC-MS: (ESI) m / z: 579.0 [M+2] 2+ .

[0704] Step 17

[0705] 20-18A (100 mg, 0.086 mmol) was dissolved in dichloromethane (2 mL), and 4 M hydrochloric acid / 1,4-dioxane (0.5 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to give compound 20-19A. LC-MS: (ESI) m / z: 529.0 [M+2] 2+ .

[0706] Step 18

[0707] 20-19A (100 mg, 0.095 mmol) and lithium (2R,3R)-3-cyclopropyl-1-methylaziridine-2-carboxylate (13.8 mg, 0.094 mmol) were dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (26.7 mg, 0.07 mmol) and N,N-diisopropylethylamine (27.9 mg, 0.189 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with water (30 mL) and ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent methanol / dichloromethane, methanol ratio: 0-10%) to give the crude target compound 20. LC-MS: (ESI) m / z: 1180.7 [M+1] +Compound 20 crude was purified by chiral column (column type: Daicel ChiralPak IBN-5S, 4.6 mm ID x 150 mm, 5 μm; elution gradient: 5% B, mobile phase A: n-Hexane; mobile phase B: ethanol; flow rate: 1.0 mL / min), 20-P1: RT = 2.413 min, 20-P2: RT = 6.263 min, and preparatively separated by high performance liquid chromatography (column type: JB-C235-03 Prime C18, 30 x 150 mm x 5 μm; elution gradient: 57-83% B, mobile phase A: 1% ammonium bicarbonate / water; mobile phase B: acetonitrile; flow rate: 25 mL / min) to obtain compound 20.

[0708] The characterization information for compound 20 is as follows:

[0709] LC-MS: RT=1.046min, (ESI)m / z:1179.4[M+1] + . 11H NMR (400 MHz, MeOD) δ 8.35 (s, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.30 (s, 1H), 7.22 (d, J = 8.8 Hz, 1H), 6.11 (t, J = 11.6 Hz, 1H), 5.66 (s, 2H), 5.47 (t, J = 6.4 Hz, 1H), 5.08 - 5.00 (m, 1H), 4.73 (d, J = 5.0 Hz, 1H), 4.62 (d, J = 11.4 Hz, 2H), 4.27 (d, J = 6.3 Hz, 1H), 3.97 (d, J = 11.2 Hz, 1H), 3.81 (t, J = 10.0 Hz, 2H), 3.68 (d, J = 5.6 Hz, 5H), 3.58 (d, J = 11.0 Hz, 2H), 3.51 - 3.49 (m, 1H), 3.44 - 3.38 (m, 3H), 3.36 (s, 4H), 3.17 - 3.02 (m, 3H), 2.98 - 2.87 (m, 4H), 2.80 - 2.76 (m, 7H), 2.72 - 2.60 (m, 3H), 2.49 (d, J = 11.0 Hz, 3H), 2.39 (s, 1H), 2.37 - 2.31 (m, 4H), 2.21 (d, J = 11.6 Hz, 2H), 2.14 - 2.08 (m, 1H), 1.98 - 1.85 (m, 3H), 1.80 (s, 1H), 1.76 - 1.66 (m, 2H), 1.47 (t, J = 7.0 Hz, 1H), 1.26 (d, J = 6.2 Hz, 3H), 0.99 (s, 3H), 0.65 (s, 1H), 0.56 - 0.49 (m, 6H), 0.36 (s, 3H), 0.29 (d, J = 4.4 Hz, 1H).

[0710] Or

[0711] LC-MS: RT = 1.028 min, (ESI) m / z: 1179.4 [M+1] + . 1H NMR(400MHz,MeOD)δ8.35(s,1H),7.48(d,J=9.0Hz,1H),7.27(s,1H),7.14(d,J= 7.6Hz,1H),5.66(s,2H),5.54(d,J=6.4Hz,1H),5.03(d,J=17.0Hz,1H),4.71(d,J =5.6Hz,2H),4.60(s,2H),4.42(s,1H),4.23(d,J=6.0Hz,1H),3.97(s,1H),3.81( s,4H),3.73-3.67(m,5H),3.66-3.58(m,2H),3.53-3.48(m,3H),3.45-3.38(m,2H ),3.15(d,J=1.6Hz,4H),3.08(d,J=10.0Hz,2H),2.99-2.87(m,4H),2.79-2.65( m,8H),2.59(s,2H),2.47(s,3H),2.38(s,1H),2.36-2.29(m,4H),2.26(d,J=9.2H z,2H),2.05(s,2H),1.98-1.83(m,3H),1.73(s,1H),1.62(s,1H),1.52-1.47(m,3 H),1.46-1.38(m,1H),1.31(s,1H),0.72(s,3H),0.57-0.48(m,6H),0.27(s,1H).

[0712] Example 21

[0713] Step 1

[0714] Under an argon atmosphere, tert-butyl piperazine-1-carboxylate (77.8 g, 417 mmol) and triethylamine (48.4 mL, 348 mmol) were added to a stirred solution of 21-1A (70.0 g, 348 mmol) in tetrahydrofuran (150 mL). The reaction mixture was stirred at 60 °C for 18 hours. The reaction solution was diluted with water (200 mL), extracted with ethyl acetate (250 mL x 3), the organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated. The resulting crude product was added to petroleum ether (1000 mL), filtered, and the filter cake was dried to give 21-2A. LC-MS: (ESI) m / z: 367.2 [M+1] + . 1H NMR (400MHz, DMSO) δ 8.37 (d, J=2.8Hz, 1H), 7.63 (d, J=2.8Hz, 1H), 3.49-3.44 (m, 8H), 1.41 (s, 9H).

[0715] Step 2

[0716] Under an argon atmosphere, methyl magnesium bromide (272 mL, 816 mmol, 3 M) was added to a cooled and stirred solution of 21-2A (100 g, 272 mmol) in ultradry tetrahydrofuran (1000 mL). The reaction was stirred at 0 °C for 1 h. The reaction solution was quenched with ammonium chloride (600 mL) and extracted with ethyl acetate (600 mL x 3). The combined organic layers were washed with sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, concentrated, and purified on silica gel using a mixture of ethyl acetate / hexane as the eluent to give 21-3A. LC-MS: (ESI) m / z: 384.2 [M+1] + . 1 H NMR (400MHz, DMSO) δ8.36(d,J=2.8Hz,1H),7.53(d,J=2.8Hz,1H),3.44(s,8H),2.53(s,3H),1.42(s,9H).

[0717] Step 3

[0718] Under an argon atmosphere, 2,3,4,6,7,8-hexahydro-1H-pyrimidino[1,2-a]pyrimidine (0.83 g, 5.98 mmol) was added to a 5 mL deuterated chloroform solution of 21-3A (23 g, 59.8 mmol), and the mixture was stirred at 25 °C for 30 minutes. The mixture was then concentrated, and this process was repeated more than twice to obtain crude product 21-4A, which was used directly in the next reaction. 1 H NMR (400MHz, CDCl3) δ8.18(d,J=2.86Hz,1H),7.30(d,J=2.8Hz,1H),3.61-3.56(m,4H),3.37-3.32(m,4H),1.47(s,9H).

[0719] Step 4

[0720] Sodium borohydride (4.49 g, 118 mmol) was added in portions to a cooled, stirred solution of 21-4A (23 g, 59.3 mmol) in deuterated methanol (10 mL) at 0 °C. The mixture was stirred at 25 °C for 2 hours. Brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified on silica gel using an ethyl acetate / hexane (1:1) mixture as eluent to give 21-5A. LC-MS: (ESI) m / z: 389.2 [M+1] + .

[0721] Step 5

[0722] At 0 °C, NaH (4.02 g, 100 mmol) was added in portions to a cooled and stirred solution of 21-5A (19.5 g, 50.2 mmol) in N,N-dimethylformamide (200 mL). The mixture was stirred at 0 °C for 30 min, followed by the addition of CH3I (14.3 g, 100 mmol) in portions. The mixture was heated to 25 °C and stirred for 18 h. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate (300 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified on silica gel using an ethyl acetate / hexane (1:1) mixture as eluent to give 21-6A. LC-MS: (ESI) m / z: 403.0 [M+1] + .

[0723] Step 6

[0724] Under an argon atmosphere, 1,1-bis(diphenylphosphine)diberyl palladium dichloride (1.47 g, 2.01 mmol) and potassium 2,2-dimethylpropionate (23.4 g, 167 mmol) were added to a stirred solution of 21-6A (27 g, 66.9 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-4-tetramethyl-1,3,2-dioxaborane-2-yl)-1,3,2-dioxaborane (51.0 g, 200 mmol) in 150 mL of 2-methyltetrahydrofuran. The reaction mixture was stirred at 90 °C for 30 min. The reaction solution was concentrated under reduced pressure and purified on neutral alumina using a mixture of ethyl acetate / hexane (1:1) as the eluent to give 21-7A. LC-MS: (ESI) m / z: 451.2 [M+1] + .

[0725] Step 7

[0726] Under an argon atmosphere, 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-2-iodo-1H-indole (26.2 g, 40.6 mmol), 1,1-bis(diphenylphosphine)dimerferropalladium dichloride (1.49 g, 2.03 mmol), and potassium carbonate (5.62 g, 40.6 mmol) were added fractionally to a solution of 21-7A (18.3 g, 40.6 mmol) in 200 mL of dioxane and 40 mL of water. The mixture was heated to 70 °C and stirred for 18 hours. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate (500 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified on silica gel using an ethyl acetate / hexane (1:1) mixture as eluent to give 21-8A. LC-MS: (ESI) m / z: 841.4 [M+1] + .

[0727] Step 8

[0728] Cesium carbonate (56.8 g, 174 mmol) was added to a solution of 21-8A (21 g, 24.9 mmol) in 200 mL of N,N-dimethylformamide, and the mixture was stirred at room temperature for 30 min. Then, 2,2,2-difluoroethyltrifluoromethanesulfonate (40.5 g, 174 mmol) was added. The reaction mixture was stirred at 25 °C for 18 h. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with further saturated saline solution, and concentrated under vacuum. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 8:1) to give 21-9A. LC-MS: (ESI) m / z: 924.4 [M+1] + .

[0729] Step 9

[0730] 21-9A (18.6 g, 20.1 mmol) was dissolved in 4 M dioxane hydrochloride (20 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure to give crude 21-10A. LC-MS: (ESI) m / z: 824.2 [M+1] + .

[0731] Step 10

[0732] Sodium cyanoboronate (2.44 g, 38.8 mmol) was added to a solution of 21-10A (16 g, 19.4 mmol) in isopropanol (160 mL), and the mixture was stirred at room temperature for 30 min. Then, 1-ethoxy-1-[(trimethylsilyl)oxy]cyclopropane (6.76 g, 38.8 mmol) was added. The reaction mixture was stirred at 50 °C for 18 h. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with further saturated saline solution, and concentrated under vacuum. The residue was purified by silica gel column chromatography to give 21-11A. LC-MS: (ESI) m / z: 863.2 [M+1] + .

[0733] Step 11

[0734] Under nitrogen protection, tetrabutylammonium fluoride (24.5 g, 93.6 mmol) was added to tetrahydrofuran (180 mL) containing 21-11A (18.0 g, 20.8 mmol). The reaction mixture was stirred at 50 °C for 18 hours. LC-MS showed detection of the reaction product. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give crude product 21-12A, which was used directly for the next step. LC-MS: (ESI) m / z: 625.3 [M+1] + .

[0735] Step 12

[0736] Under nitrogen protection, imidazole (2.61 g, 38.3 mmol) and tert-butyldimethylchlorosilane (5.77 g, 38.3 mmol) were added to a 170 mL solution of 21-12A. The reaction mixture was stirred at 25 °C for 18 hours. LC-MS showed the detection of the reaction product. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 21-13A. LC-MS: (ESI) m / z: 739.7 [M+1] + .

[0737] Step 13

[0738] A solution of 21-13A (1000 mg, 1.35 mmol), INT-3 (904 mg, 2.025 mmol), RuPhos (125 mg, 0.27 mmol), RuPhos Pd G2 (209 mg, 0.290 mmol), Pd(OAc)2 (30.3 mg, 0.135 mmol), and Cs2CO3 (1979 mg, 6.07 mmol) was added to dioxane (15 mL), and stirred at 80 °C for 1 hour under nitrogen. The mixture was concentrated and purified by column chromatography (DCM / MeOH = 30 / 1) to obtain 21-14A. LC-MS: (ESI) m / z: 1106.2 [M+1] + .

[0739] Step 14

[0740] A solution of LiOH·H₂O (189 mg, 4.52 mmol) in H₂O (5 mL) was added to 10 mL of THF containing 1000 mg (0.904 mmol) of 21-14A. The mixture was stirred at room temperature for 1 hour. The pH of the mixture was adjusted to 5 with 1 M HCl, extracted with EtOAc, and concentrated to obtain 21-15A. LC-MS: (ESI) m / z: 1092.2 [M+1] + .

[0741] Step 15

[0742] 1 mL of 6 M dilute hydrochloric acid was added to a 10 mL solution of 21-15A (1000 mg, 0.824 mmol) in THF, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated and purified by C18 reverse-phase column chromatography (ACN / H2O = 50%) to give 21-16A. LC-MS: (ESI) m / z: 978.0 [M+1] + .

[0743] Step 16

[0744] To a solution of 21-16A (500 mg, 0.511 mmol) in DCM (50 mL), add HOBt (103 mg, 0.767 mmol) and DMAP (312 mg, 2.56 mmol), then add EDCI (195 mg, 1.02 mmol). Stir the mixture at room temperature for 1 hour. Concentrate the mixture and purify it by column chromatography (DCM / MeOH = 20 / 1) to obtain a white solid product. LC-MS: RT = 0.676 min, (ESI) m / z: 960.1 [M+1] + The product was then purified by SFC to obtain 21-17A.

[0745] Step 17

[0746] 21-17A (110 mg, 0.115 mmol) was dissolved in isopropanol (5 mL), and 10% aqueous palladium on carbon (55.0 mg, 50% w / w) was added. The reaction mixture was stirred at room temperature for 2 hours under a hydrogen pressure of 15 psi. The reaction solution was filtered and concentrated to give 21-18A. LC-MS: (ESI) m / z: 826.4 [M+1] + .

[0747] Step 18

[0748] 21-18A (50.0 mg, 0.061 mmol) and 2-((S)-7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]non-2-yl)-2-(cyclopent-3-en-1-yl)acetic acid (25.5 mg, 0.073 mmol) were dissolved in N,N-dimethylformamide (2 mL), and (2-oxime-cyanoethyl acetate)-N,N-dimethylmorpholinourea hexafluorophosphate (38.9 mg, 0.091 mmol) and N,N-diisopropylethylamine (23.4 mg, 0.182 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with water (30 mL) and ethyl acetate (10 mL * 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent methanol / dichloromethane, methanol ratio: 0-10%) to give the target compound 21-19A. LC-MS: (ESI) m / z: 579.8 1 / 2 [M+1] + .

[0749] Step 19

[0750] 21-19A (50.0 mg, 0.043 mmol) was dissolved in dichloromethane (2 mL), and 4M hydrochloric acid / 1,4-dioxane (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give the target compound 21-20A. LC-MS: (ESI) m / z: 529.7 1 / 2 [M+1] + .

[0751] Step 20

[0752] 21-20A (50.0 mg, 0.047 mmol) and lithium (2R,3R)-3-cyclopropyl-1-methylaziridine-2-carboxylate (13.9 mg, 0.094 mmol) were dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (26.9 mg, 0.071 mmol) and N,N-diisopropylethylamine (18.3 mg, 0.142 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with water (30 mL) and ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent methanol / dichloromethane, ratio: 0-10%) and preparative separation (column type: JB-C235-03 Prime C18, 30 x 150 mm x 5 μm; gradient: 57-83% B, mobile phase A: 1% NH4HCO3 / H2O; mobile phase B: ACN; flow rate: 25 mL / min) to obtain target compound 21.

[0753] LC-MS: (ESI)m / z:591.1 1 / 2[M+1]+. 1H NMR (400MHz, CD3OD) δ8.42(d,J=2.8Hz,1H),7.49(d,J=8.8Hz,1H),7.33(s ,1H),7.27(s,1H),7.16(d,J=8.8Hz,1H),5.66(s,2H),5.51(s,1H),4.99(s ,1H),4.72(d,J=5.6Hz,2H),4.60(s,1H),4.49(s,1H),4.07(s,1H),3.98( d,J=10.6Hz,1H),3.86-3.77(m,3H),3.72-3.64(m,3H),3.53-3.48(m,2H), 3.47-3.38(m,3H),3.19(s,3H),3.16-3.14(m,1H),3.05(t,J=10.4Hz,1H) ,2.99-2.81(m,9H),2.80-2.56(m,8H),2.48(s,3H),2.39(s,1H),2.37-2.3 0(m,4H),2.25(s,2H),2.14-1.83(m,5H),1.81-1.71(m,2H),1.64(d,J=9. 2Hz,1H),1.47-1.41(m,1H),0.88(s,3H),0.61-0.50(m,10H),0.27(s,1H).

[0754] Example 22

[0755] Step 1

[0756] Lithium aluminum hydride solid (5.69 g, 150 mmol) and ultra-dry tetrahydrofuran (80 mL) were added to a dry 250 mL three-necked flask. The mixture was cooled to 0 °C under nitrogen protection. A tetrahydrofuran solution (60 mL) of 22-1A (10.0 g, 99.9 mmol) was slowly added dropwise to the above mixture under nitrogen protection at 0 °C. After the addition was complete, the reaction solution was raised to 20 °C and stirred overnight. The reaction was confirmed by TLC. The reaction solution was cooled to 0 °C, and cold water (5.7 mL), 15% sodium hydroxide aqueous solution (5.7 mL), and cold water (17.1 mL) were added slowly in sequence. Then, magnesium sulfate (20 g) was added, and stirring was continued for half an hour. The mixture was filtered, concentrated, and dried to obtain 22-2A. 1 H NMR (400MHz, CD3Cl3) δ3.38(s,2H),1.15(s,3H),0.41-0.38(m,2H),0.34-0.31(m,2H).

[0757] Step 2

[0758] Add 3.70 g (43.0 mmol) of 22-2A and 150 mL of ultra-dry dichloromethane to a 250 mL three-necked flask and cool to 0 °C under nitrogen protection. Then add 19.3 g (43.0 mmol) of PCC to the mixture under nitrogen protection at 0 °C. After the addition is complete, raise the temperature to 20 °C and stir overnight. Filter, concentrate, and dry the mixture to obtain 22-3A. 1 H NMR (400MHz, CD3Cl3) δ8.65(s,1H),1.17(s,2H),0.76-0.74(m,2H),0.34-0.31(m,2H).

[0759] Step 3

[0760] (R)-(-)-4-methylbenzenesulfinamide (2.80 g, 18.0 mol) and tetraethyl titanate (30.1 g, 36.1 mmol) were added to a solution of 22-3A (2.28 g, 27.1 mmol) in 50 mL of tetrahydrofuran at room temperature. The reaction mixture was stirred at 75 °C for 18 hours. The reaction was detected by LC-MS. The reaction mixture was cooled to room temperature, quenched by pouring ice water (100 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to give 22-4A. LC-MS: (ESI) m / z: 222.0 [M+1] + .

[0761] Step 4

[0762] At -70°C, LiHMDS (5.29 mL, 5.29 mmol) was slowly added to a tetrahydrofuran (22 mL) solution of 22-4A (900 mg, 4.07 mmol) and benzyl 2-bromoacetate (1.21 g, 5.29 mmol). After the addition was complete, the reaction mixture was heated to -40°C and stirred for 1.5 hours. The reaction was confirmed by LC-MS. The mixture was quenched with ice water (40 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 6:1) to give 22-5A. LC-MS: RT = 1.52 min, (ESI) m / z: 370.2 [M+1] + .

[0763] Step 5

[0764] At 0 °C, trifluoroacetic acid (1.54 g, 13.5 mmol) was slowly added to a solution of 22-5A (1.0 g, 2.71 mmol) in acetone (10 mL), methanol (2 mL), and water (2 mL). The reaction was stirred at 0 °C for 2 hours, and the pH of the reaction solution was adjusted to 8 at 0 °C with ammonia (25%). Extraction was performed with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give 22-6A. LC-MS: (ESI) m / z: 232.1 [M+1] + .

[0765] Step 6

[0766] A dry molecular sieve (500 mg) was added to a solution of 22-6A (500 mg, 2.16 mmol) and silver carbonate (1.79 g, 6.49 mmol) in 10 mL of tetrahydrofuran at room temperature. After stirring the reaction solution for 5 minutes, iodomethane (1.53 g, 10.8 mmol) was added. The reaction solution was stirred at room temperature for 18 hours. The reaction solution was filtered and concentrated, and the crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain 22-7A. LC-MS: (ESI) m / z: 246.2 [M+1] + .

[0767] Step 7

[0768] At 0 °C, water (0.5 mL) and lithium hydroxide (25.7 mg, 0.61 mmol) were added to a 2 mL solution of tetrahydrofuran containing 100 mg (0.41 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction was confirmed by LC-MS. The solution was concentrated under reduced pressure, and the crude product was lyophilized to obtain 22-8A. LC-MS: (ESI) m / z: 156.2 [M+1] + .

[0769] Step 8

[0770] Diisopropylethylamine (0.034 mL, 0.24 mmol) was added to a DMF (1 mL) solution of compounds 5-10A (50 mg, 0.05 mmol) and 22-8A (23.2 mg, 0.14 mmol) at 0 °C. After addition, the mixture was stirred for 5 minutes. HATU (21.9 mg, 0.06 mmol) was added to the reaction mixture under nitrogen protection. After addition, the reaction mixture was stirred at 15 °C for 2 hours. The reaction was confirmed by LC-MS. The reaction mixture was poured into ice water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated brine (5 mL) and dried over anhydrous sodium sulfate. The mixture was then filtered and concentrated. The crude product was obtained by column chromatography (dichloromethane:methanol = 94:6) and preparative HPLC ([column type: Prime C18, 30 x 150 mm x 5 μm; gradient: 58-80% B, mobile phase A: 1% NH4OAc / H2O; mobile phase B: ACN; flow rate: 25 mL / min]) to approximately 14 mg of crude product. The crude product was then subjected to special preparative HPLC ([column type: JB-C235-03 Prime C18, 30 x 150 mm x 5 μm; gradient: 45-70% B, mobile phase A: 1% NH4HCO3 / H2O; mobile phase B: acetonitrile; flow rate: 25 mL / min]) to obtain compound 22.

[0771] LC-MS: (ESI) m / z: 1192.7 [M+1] + . 1H NMR (400MHz, CD3OD) δ8.40(d,J=2.8Hz,1H),8.40(d,J=2.4Hz,1H),7.47(d,J=8.8Hz,1H),7.31(d,J=2 .4Hz,1H),7.25(s,1H),7.18-7.09(m,1H),5.71-5.59(m,2H),5.48(dd,J=9.2,3.2Hz,1H),5.04-4.93 (m,1H),4.72-4.67(m,2H),4.58(s,6H),4.46(s,1H),4.09-4.02(m,1H),3.99-3.94(m,1H),3.81-3.7 6(m,3H),3.70-3.63(m,2H),3.46-3.39(m,2H),3.17(s,2H),3.06-2.99(m,1H),2.90-2.85(m,2H),2.8 5-2.78(m,6H),2.76-2.71(m,2H),2.70-2.57(m,4H),2.52-2.42(m,3H),2.32(s,1H),2.29(s,2H)2.2 4-2.12(m,3H),2.10-1.97(m,3H),1.96-1.87(m,2H),1.86-1.76(m,3H),1.76-1.70(m,1H),1.62(s,1H ),1.42(d,J=6.0Hz,3H),1.30(brs,4H),1.07(d,J=1.2Hz,3H),0.85(s,3H),0.70-0.64(m,1H),0.59( s,2H),0.56-0.51(m,2H),0.50-0.45(m,2H),0.41-0.31(m,1H),0.28-0.20(m,1H),0.12-0.02(m,1H).

[0772] Example 23

[0773] Step 1

[0774] 23-1A (500 mg, 8.92 mmol) and (R)-(4-methylphenyl)(oxo)-λ4-sulfanilamide (692 mg, 4.46 mmol) were dissolved in tetrahydrofuran (10 mL), and tetraisopropyl titanate (3.80 g, 13.4 mmol) was added. The reaction mixture was stirred at 65 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was subjected to column chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0-10%) to give compound 23-2A.

[0775] LC-MS(ESI) m / z: 194.0 [M+1] + .

[0776] Step 2

[0777] 23-2A (450 mg, 2.33 mmol) and benzyl 2-bromoacetate (693 mg, 3.03 mmol) were dissolved in tetrahydrofuran (10 mL). The reaction solution was cooled to -60 °C, and lithium bis(trimethylsilylamino)lithium (3.03 mL, 3.03 mmol) was slowly added dropwise. The reaction was stirred at -60 °C for 2 hours. The reaction solution was extracted with water (100 mL) and ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0-50%) to give the target compound 23-3A. LC-MS: (ESI) m / z: 342.0 [M+1] + .

[0778] Step 3

[0779] 23-3A (250 mg, 0.732 mmol) was dissolved in acetone (5 mL), methanol (1 mL), and water (1 mL). The reaction mixture was cooled to 0 °C, and trifluoroacetic acid (417 mg, 3.66 mmol) was slowly added. The reaction mixture was stirred at 0 °C for 2 hours. Ammonia was slowly added dropwise to adjust the pH to 8, and the mixture was then extracted with water (100 mL) and ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0-50%) to give the target compound 23-4A. LC-MS: (ESI) m / z: 204.0 [M+1] + .

[0780] Step 4

[0781] 23-4A (120 mg, 0.590 mmol) was dissolved in tetrahydrofuran (5 mL), and silver carbonate (407 mg, 1.48 mmol) and methyl iodide (210 mg, 1.48 mol) were added. The mixture was stirred at room temperature for 18 hours. The reaction solution was extracted with water (100 mL) and ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent petroleum ether / ethyl acetate, ethyl acetate ratio: 0-10%) to give the target compound 23-5A. LC-MS: (ESI) m / z: 218.0 [M+1] + .

[0782] Step 5

[0783] 23-5A (40.0 mg, 0.184 mmol) was dissolved in tetrahydrofuran (2 mL) and water (1 mL), and lithium hydroxide monohydrate (15.5 mg, 0.368 mmol) was added. The reaction was stirred at room temperature for 2 hours. The pH was adjusted to approximately 8 with 0.5 M hydrochloric acid solution, and then lyophilized to obtain the target compound 23-6A. LC-MS: (ESI) m / z: 128.2 [M+1] + .

[0784] Step 6

[0785] Compounds 5-10A (50.0 mg, 0.047 mmol) and 23-6A (12.6 mg, 0.095 mmol) were dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (27.0 mg, 0.071 mmol) and N,N-diisopropylethylamine (18.3 mg, 0.142 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with water (30 mL) and ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by column chromatography (silica gel, eluent methanol / dichloromethane, ratio: 0-10%) and preparative high-performance liquid chromatography (column type: JB-C235-03 Prime C18, 30 x 150 mm x 5 μm; gradient: 57-83% B, mobile phase A: 1% NH4HCO3 / H2O; mobile phase B: acetonitrile; flow rate: 25 mL / min) to give compound 23. LC-MS: (ESI) m / z: 582.8 1 / 2 [M+1] + .

[0786] 1H NMR (400MHz, MeOD) δ8.42(d,J=2.8Hz,1H),7.49(d,J=8.8Hz,1H),7.33(s,1H),7.27(s,1H),7.16(d,J=8.8Hz,1H),5.65(s,2H),5.54-5.37(m,3H) ,5.24-5.19(m,1H),5.03-4.91(m,2H),4.85(s,3H),4.71(s,2H),4.60(s ,1H),4.49(s,1H),4.07(s,1H),3.96(s,1H),3.86-3.76(m,3H),3.70(d,J =10.8Hz,2H),3.58-3.37(m,7H),3.19-3.15(m,4H),3.05-3.00(m,1H),2 .90-2.81(m,8H),2.78-2.58(m,6H),2.46(t,J=13.2Hz,6H),2.25(t,J=1 0.0Hz,2H),2.09-1.99(m,2H),1.92-1.83(m,3H),1.77-1.74(m,2H),1.6 5(t,J=9.6Hz,1H),1.45(d,J=6.0Hz,3H),0.88(s,3H),0.61-0.50(m,7H).

[0787] Example 24

[0788] Step 1

[0789] Under an argon atmosphere, (S)-hexahydropyridazine-3-carboxylic acid methyl ester (0.57 g, 3.97 mmol), N,N-diisopropylethylamine (1.18 g, 9.16 mmol), and (2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.74 g, 4.58 mmol) were added to a solution of 24-1A (2.60 g, 3.05 mmol) in 26 mL of N,N-dimethylformamide and reacted at 25 °C. The reaction mixture was stirred at 25 °C for 2 h. The reaction product was detected by LC-MS. The reaction mixture was extracted with ethyl acetate and concentrated under reduced pressure. The residue was purified by C18 reversed-column chromatography to give 24-2A. LC-MS: (ESI) m / z: 977.8 [M+1] + .

[0790] Step 2

[0791] Under nitrogen protection at 25°C, lithium hydroxide monohydrate (0.43 g, 10.2 mmol) was added to a solution of 24-2A (2.5 g, 2.56 mmol) in tetrahydrofuran (25 mL) and water (5 mL). The reaction mixture was stirred at 25°C for 2 hours. LC-MS showed detection of the reaction product. The reaction mixture was purified by C18 reverse-phase column chromatography to give 24-3A. LC-MS: (ESI) m / z: 963.8 [M+1] + .

[0792] Step 3

[0793] Under argon protection at 25°C, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.98 g, 15.5 mmol), 1-hydroxybenzotriazole (701 mg, 5.19 mmol), and N,N-diisopropylethylamine (2.01 g, 15.5 mmol) were added to a solution of 24-3A (500 mg, 0.519 mmol) in dichloromethane (100 mL). The reaction mixture was stirred at 25°C for 18 hours. LC-MS showed the reaction product was detected. The reaction mixture was extracted with EtOAC and concentrated under reduced pressure. The residue was purified with C18 (ACN / H2O; 0-55%) to give 24-4A. LC-MS: (ESI) m / z: 944.4 [M+1] + .

[0794] Step 4

[0795] Under nitrogen protection, 55% Pd / C (8.39 mg, 0.043 mmol) and potassium carbonate (59.9 mg, 0.434 mmol) were added to a 10 mL solution of 24-4A (410 mg, 0.434 mmol). The reaction mixture was stirred at 25 °C for 2 hours. LC-MS showed the presence of the reaction product. The reaction mixture was filtered and concentrated under reduced pressure to give crude 24-5A. LC-MS: (ESI) m / z: 810.5 [M+1] + .

[0796] Step 5

[0797] Under nitrogen protection at 25°C, 24-5A (200 mg, 0.247 mmol) and 2-(bicyclo[3.1.0]hex-2-en-3-yl)-2-((S)-7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]non-2-yl)-2l3 acetic acid (129 mg, 0.370 mmol) were dissolved in N,N-dimethylformamide (3.00 mL). N,N-diisopropylethylamine (0.123 mL, 0.740 mmol) was added first, followed by (2-oxime-cyanoethyl acetate)-N,N-dimethyl-morpholinourea hexafluorophosphate (95.1 mg, 0.222 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with water (20 mL) and ethyl acetate (10 mL x 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent methanol / dichloromethane, methanol ratio: 0-10%) to give 24-6A. LC-MS: (ESI) m / z: 572.5 [M+2] 2+ .

[0798] Step 6

[0799] Under nitrogen protection at 25°C, 24-6A (100.0 mg, 0.088 mmol) was dissolved in dichloromethane (2.00 mL), and 4M hydrochloric acid / 1,4-dioxane (0.400 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give the target compound 24-7A. LC-MS: (ESI) m / z: 1044.4 [M+1] + .

[0800] Step 7

[0801] Under argon protection at 25°C, 24-7A (90.0 mg, 0.086 mmol) and lithium (2R,3R)-3-cyclopropyl-1-methylaziridine-2-carboxylate (25.4 mg, 0.172 mmol) were dissolved in N,N-dimethylformamide (2.00 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (42.6 mg, 0.112 mmol) and N,N-diisopropylethylamine (0.045 mL, 0.259 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with water (20 mL) and ethyl acetate (10 mL x 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was preparatively separated by high performance liquid chromatography (HPLC) (column type: JB-C235-03 Prime C18, 30 x 150 mm x 5 μm; elution gradient: 57-83% B, mobile phase A: 1% NH4HCO3 / H2O; mobile phase B: ACN; flow rate: 25 mL / min) to obtain compound 24. LC-MS: (ESI) m / z: 1166.6 [M+1] + .

[0802] 1 H NMR (400MHz, CD3OD) δ8.46-8.38(m,1H),7.48(d,J=9.4Hz,1H),7.31(s,1H),7.13(d,J=4.8Hz,2H),5.67(d,J=4.0Hz,3H),5.07-4.91(m,1H), 4.72(s,1H),4.52-4.36(m,1H),4.12-4.01(m,1H),3.92(s,2H),3.87- 3.79(m,2H),3.67(m,5H),3.53-3.48(m,1H),3.48-3.35(m,3H),3.31- 3.27(m,3H),3.21(s,3H),3.12-3.03(m,1H),3.01-2.88(m,3H),2.88- 2.83(m,5H),2.82-2.67(m,6H),2.54-2.42(m,2H),2.38-2.29(m,4H), 2.27-2.07(m,3H),2.03-1.73(m,8H),1.70-1.56(m,1H),1.50-1.39(m ,4H),1.32(s,2H),0.91(s,3H),0.69-0.37(m,10H),0.35-0.21(m,1H).

[0803] Example 25

[0804] Step 1

[0805] Lithium bis(trimethylsilylamino)amine (249 mL, 250 mmol, 1 M) was slowly added dropwise to 25-1A (12 g, 137 mmol) in tetrahydrofuran (100 mL) at -78 °C. After stirring at -78 °C for one hour, a solution of 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (49.0 g, 137 mmol) in tetrahydrofuran (100 mL) was added to the reaction mixture, and the mixture was allowed to react at room temperature for 4 hours. The reaction mixture was extracted with water (200 mL) and ethyl acetate (200 mL x 2). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, 100% petroleum ether) to give 25-2A.

[0806] Step 2

[0807] 25-2A (16 g, 70.12 mmol), bis(boron)pinacol (26.7 g, 105 mmol), potassium acetate (13.8 g, 140 mmol), 1,1-bis(diphenylphosphine)diberberine palladium dichloride (3.08 g, 4.21 mmol), and DPPF (2.37 g, 4.21 mmol) were dissolved in dioxane (100 mL) and reacted at 80 °C for 16 hours under a nitrogen atmosphere. The reaction solution was concentrated to obtain the crude product. The crude product was subjected to column chromatography (silica gel, 100% petroleum ether) to obtain 25-3A.

[0808] 1 H NMR (400MHz, CD3Cl3) δ6.71(q,J=2.0Hz,1H),2.65(dd,J=7.2,1.8Hz,1H),2.44(d,J=17.2Hz,1H),1.92- 1.79(m,1H),1.72-1.61(m,1H),1.25(s,12H),0.87(td,J=8.0,3.6Hz,1H),-0.13(dd,J=7.2,3.6Hz,1H).

[0809] Step 3

[0810] 25-3A (50.0 mg, 0.061 mmol), 2,2-dihydroxyacetic acid (50.0 mg, 0.061 mmol), and tert-butyl(S)-2,7-diazaspiro[4.4]nonane-2-carboxylate (27.6 mg, 0.079 mmol) were dissolved in hexafluoroisopropanol (1.00 mL), and the reaction mixture was stirred at 50 °C for 16 hours. The reaction mixture was extracted with water (20 mL) and ethyl acetate (10 mL x 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The reaction solution was concentrated to obtain a crude product, which was then passed through an SFC (column type: Daicel ChiralPak IK, 40mm IDx 250mm, 10µm; elution gradient: 35% B; mobile phase A: supercritical carbon dioxide; mobile phase B: methanol solution of 0.1% ammonia; flow rate: 150mL / min) to obtain 25-4A-P1, 25-4A-P2, 25-4A-P3 and 25-4A-P4.

[0811] LC-MS: P1:RT=0.593min, (ESI)m / z:363.2[M+1] + SFC:RT = 3.735 min.

[0812] P2:RT=0.592min,(ESI)m / z:363.2[M+1] + SFC:RT = 4.406 min.

[0813] P3:RT=0.592min,(ESI)m / z:363.2[M+1] + SFC:RT = 5.303 min.

[0814] P4:RT=0.592min,(ESI)m / z:363.2[M+1] + SFC:RT = 6.121 min.

[0815] Step 4

[0816] INT-4 (50.0 mg, 0.061 mmol) and 25-4A-P1 (27.6 mg, 0.079 mmol) were dissolved in N,N-dimethylformamide (1.00 mL). N,N-diisopropylethylamine (0.032 mL, 0.182 mmol) was added first, followed by (2-oxime-cyanoethyl acetate)-N,N-dimethylmorpholinourea hexafluorophosphate (31.2 mg, 0.073 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was extracted with water (20 mL) and ethyl acetate (10 mL x 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent methanol / dichloromethane, methanol ratio: 0-10%) to give the target compound 25-5-P1.

[0817] LC-MS: (ESI) m / z: 584.3 [M+2] 2+ .

[0818] Step 5

[0819] 25-5-P1 (30.0 mg, 0.026 mmol) was dissolved in dichloromethane (1.00 mL), and 4 M hydrochloric acid / 1,4-dioxane (0.200 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give the target compound 25-6-P1. LC-MS: (ESI) m / z: 534.4 [M+2] 2+ .

[0820] Step 6

[0821] 25-6-P1 (25.0 mg, 0.023 mmol) and lithium (2R,3R)-3-cyclopropyl-1-methylaziridine-2-carboxylate (6.90 mg, 0.047 mmol) were dissolved in N,N-dimethylformamide (1 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (11.6 mg, 0.03 mmol) and N,N-diisopropylethylamine (9.07 mg, 0.070 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with water (20 mL) and ethyl acetate (10 mL x 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was prepared and separated (column type: JB-C235-03 Prime C18, 30 x 150 mm x 5 μm; elution gradient: 57-83% B, mobile phase A: 1% ammonium bicarbonate aqueous solution; mobile phase B: acetonitrile; flow rate: 25 mL / min) to obtain the target compound 25-P1.

[0822] LC-MS: (ESI) m / z: 595.5 [M+2] 2+ 。

[0823] 1 H NMR (400 MHz, CD3OD) δ 8.45 - 8.38 (m, 1H), 7.52 - 7.41 (m, 1H), 7.32 (s, 1H), 7.26 - 7.16 (m, 1H), 7.16 - 7.08 (m, 1H), 6.00 (s, 1H), 5.56 - 5.46 (m, 1H), 5.05 - 4.92 (m, 1H), 4.75 - 4.62 (m, 2H), 4.59 (s, 1H), 4.48 (s, 1H), 4.07 (s, 1H), 3.98 (d, J = 10.8 Hz, 1H), 3.92 - 3.76 (m, 3H), 3.75 - 3.68 (m, 2H), 3.64 (s, 1H), 3.58 - 3.43 (m, 4H), 3.43 - 3.34 (m, 2H), 3.23 - 3.16 (m, 3H), 3.06 - 2.92 (m, 1H), 2.88 - 2.79 (m, 4H), 2.78 - 2.71 (m, 2H), 2.71 - 2.56 (m, 4H), 2.56 - 2.45 (m, 2H), 2.43 - 2.31 (m, 4H), 2.30 - 2.17 (m, 2H), 2.15 - 2.00 (m, 4H), 2.00 - 1.89 (m, 2H), 1.90 - 1.81 (m, 2H), 1.79 - 1.71 (m, 2H), 1.68 - 1.55 (m, 3H), 1.52 - 1.42 (m, 4H), 1.32 (s, 3H), 0.86 (s, 3H), 0.83 - 0.76 (m, 1H), 0.75 - 0.65 (m, 1H), 0.63 - 0.40 (m, 10H), 0.36 - 0.23 (m, 1H).

[0824] Step 7 [[ID=IO]]

[0825] INT-4 (50.0 mg, 0.061 mmol) and 25-4A-P2 (26.4 mg, 0.073 mmol) were dissolved in N,N-dimethylformamide (2 mL), and (2-oxime-cyanoethyl acetate)-N,N-dimethylmorpholinourea hexafluorophosphate (39.0 mg, 0.091 mmol) and N,N-diisopropylethylamine (23.5 mg, 0.182 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with water (30 mL) and ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent methanol / dichloromethane, methanol ratio: 0-10%) to give the target compound 25-5A-P2. LC-MS: (ESI) m / z: 584.3 1 / 2 [M+1] + .

[0826] Step 8

[0827] 25-5A-P2 (50.0 mg, 0.043 mmol) was dissolved in dichloromethane (2 mL), and 4 M hydrochloric acid / 1,4-dioxane (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give the target compound 25-6A-P2. LC-MS: (ESI) m / z: 534.3 [M+1] 2+ .

[0828] Step 9

[0829] 25-6A-P2 (50.0 mg, 0.047 mmol) and lithium (2R,3R)-3-cyclopropyl-1-methylaziridine-2-carboxylate (13.8 mg, 0.094 mmol) were dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (26.7 mg, 0.07 mmol) and N,N-diisopropylethylamine (18.1 mg, 0.141 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with water (30 mL) and ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent methanol / dichloromethane, ratio: 0-10%) and preparative separation (column type: JB-C235-03 Prime C18, 30 x 150 mm x 5 μm; elution gradient: 57-83% B, mobile phase A: 1% ammonium bicarbonate aqueous solution; mobile phase B: acetonitrile; flow rate: 25 mL / min) to obtain the target compound 25-P2. LC-MS: (ESI) m / z: 596.01 / 2 [M+1] + .1 H NMR (400MHz, CD3OD) δ8.54(d,J=2.8Hz,1H),7.61(d,J=8.8Hz,1H),7.45(s,1H),7 .37(d,J=9.0Hz,1H),7.30-7.25(m,1H),6.14(s,1H),5.68-5.61(m,1H),5.14-5. 08(m,1H),4.82(d,J=5.2Hz,2H),4.72(s,1H),4.60(s,1H),4.21-4.12(m,2H),4. 01-3.92(m,3H),3.85-3.71(m,4H),3.63-3.58(m,2H),3.54-3.51(m,2H),3.42(s ,4H),3.32-3.27(m,3H),3.09(s,1H),3.02-2.84(m,9H),2.76-2.63(m,4H),2.62 -2.54(m,2H),2.51(d,J=2.0Hz,3H),2.49-2.46(m,1H),2.40-2.31(m,1H),2.28- 1.95(m,7H),1.88(t,J=4.8Hz,2H),1.79-1.73(m,1H),1.65-1.59(m,1H),1.56(d ,J=6.4Hz,3H),1.44(s,3H),0.98(s,3H),0.76-0.58(m,10H),0.45-0.37(m,1H).

[0830] Step 10

[0831] INT-4 (50.0 mg, 0.061 mmol) and 25-4A-P3 (26.4 mg, 0.073 mmol) were dissolved in N,N-dimethylformamide (1.00 mL). N,N-diisopropylethylamine (0.030 mL, 0.182 mmol) was added first, followed by (2-oxime-cyanoethyl acetate)-N,N-dimethylmorpholinourea hexafluorophosphate (58.5 mg, 0.137 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was extracted with water (10 mL) and ethyl acetate (10 mL x 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent methanol / dichloromethane, methanol ratio: 0-10%) to give the target compound 25-5A-P3. LC-MS: (ESI) m / z: 584.0 [M+2] 2+ .

[0832] Step 11

[0833] 25-5A-P3 (50 mg, 0.043 mmol) was dissolved in dichloromethane (2.00 mL), and 4 M hydrochloric acid / 1,4-dioxane (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give the target compound 25-6A-P3. LC-MS: (ESI) m / z: 534.2 [M+2] 2+ .

[0834] Step 12

[0835] 25-6A-P3 (50.0 mg, 0.047 mmol) and lithium (2R,3R)-3-cyclopropyl-1-methylaziridine-2-carboxylate (13.8 mg, 0.070 mmol) were dissolved in N,N-dimethylformamide (1 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (26.7 mg, 0.070 mmol) and N,N-diisopropylethylamine (18.2 mg, 0.141 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with water (10 mL) and ethyl acetate (10 mL x 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was prepared and separated (column type: JB-C235-03 Prime C18, 30 x 150 mm x 5 μm; elution gradient: 59-83% B, mobile phase A: 10 mM NH4HCO3 / H2O; mobile phase B: acetonitrile; flow rate: 25 mL / min) to obtain the target compound 25-P3.

[0836] LC-MS: (ESI) m / z: 596.1 [M+2] 2+ . 1H NMR (400MHz, CD3OD) δ8.40(d,J=2.8Hz,1H),7.46(d,J=8.8Hz,1H),7.31(s,1H),7.24(d,J=9. 2Hz,1H),7.13(d,J=7.2Hz,1H),5.98(s,1H),5.52(d,J=6.8Hz,1H),5.10-4.89(m,1H),4.69(d ,J=5.4Hz,2H),4.46(s,1H),4.09-3.96(m,2H),3.80(s,3H),3.68(d,J=11.2Hz,3H),3.54(s, 1H),3.48-3.37(m,3H),3.20-3.09(m,4H),2.94(s,1H),2.86-2.79(m,4H),2.79-2.69(m,4H), 2.69-2.58(m,3H),2.50(dd,J=22.0,8.0Hz,3H),2.37(s,3H),2.32(dd,J=6.8,4.0Hz,3H),2. 22(dd,J=18.8,9.2Hz,2H),1.98(d,J=9.2Hz,4H),1.93-1.78(m,3H),1.74(d,J=3.6Hz,3H),1. 66-1.53(m,3H),1.48(dd,J=14.8,8.0Hz,1H),1.42(d,J=6.4Hz,3H),1.29(s,3H),0.84(s,3H) ,0.65-0.57(m,3H),0.53(d,J=6.8Hz,2H),0.47(s,4H),0.28(s,1H),-0.09(d,J=17.6Hz,1H).

[0837] Step 13

[0838] INT-4 (50.0 mg, 0.061 mmol) and 25-4A-P4 (27.6 mg, 0.079 mmol) were dissolved in N,N-dimethylformamide (1.00 mL). N,N-diisopropylethylamine (0.032 mL, 0.182 mmol) was added first, followed by (2-oxime-cyanoethyl acetate)-N,N-dimethylmorpholinourea hexafluorophosphate (23.4 mg, 0.055 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with water (20 mL) and ethyl acetate (10 mL x 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent methanol / dichloromethane, methanol ratio: 0-10%) to give the target compound 25-5A-P4. LC-MS: (ESI) m / z: 585.2 [M+2]2+ .

[0839] Step 14

[0840] 25-5A-P4 (50.0 mg, 0.043 mmol) was dissolved in dichloromethane (1.00 mL), and 4 M hydrochloric acid / 1,4-dioxane (0.200 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give the target compound 25-6A-P4.

[0841] LC-MS: (ESI) m / z: 534.8 [M+2] 2+ .

[0842] Step 15

[0843] 25-6A-P4 (50.0 mg, 0.047 mmol) and lithium (2R,3R)-3-cyclopropyl-1-methylaziridine-2-carboxylate (13.8 mg, 0.094 mmol) were dissolved in N,N-dimethylformamide (1 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (23.2 mg, 0.061 mmol) and N,N-diisopropylethylamine (0.024 mL, 0.141 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with water (20 mL) and ethyl acetate (10 mL x 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was prepared and separated (column type: JB-C235-03 Prime C18, 30 x 150 mm x 5 μm; gradient: 57-83% B, mobile phase A: 1% ammonium bicarbonate aqueous solution; mobile phase B: acetonitrile; flow rate: 25 mL / min) to obtain the target compound 25-P4.

[0844] LC-MS: (ESI) m / z: 596.0 [M+2] 2+ .

[0845] 1H NMR (400MHz, CD3OD) δ8.44(d,J=2.8Hz,1H),7.50(t,J=8.0Hz,1H),7.35(s,1H),7.32-7. 20(m,1H),7.19-7.11(m,1H),6.01(s,1H),5.67-5.49(m,1H),5.08-4.94(m,1H),4.79-4 .67(m,2H),4.52(s,1H),4.11(s,1H),4.00(d,J=10.8Hz,1H),3.94-3.79(m,3H),3.78-3 .70(m,2H),3.70-3.60(m,2H),3.59-3.51(m,2H),3.50-3.39(m,2H),3.35-3.30(m,6H),3 .25-3.16(m,3H),3.09-2.94(m,1H),2.92-2.84(m,4H),2.85-2.71(m,4H),2.70-2.56(m ,4H),2.56-2.47(m,1H),2.47-2.34(m,5H),2.33-2.23(m,2H),2.23-1.89(m,4H),1.89-1 .72(m,4H),1.71-1.58(m,2H),1.56-1.44(m,4H),0.89(s,3H),0.86-0.77(m,1H),0.77- 0.67(m,1H),0.64-0.55(m,4H),0.54-0.41(m,5H),0.38-0.25(m,1H),0.06-0.08(m,1H).

[0846] Example 26

[0847] Step 1

[0848] Under nitrogen atmosphere, 26-1A (36 g, 166 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,3,2-dioxaborane (127 g, 500 mmol), [(2,2-dimethylpropionyl)oxy]potassium (58.4 g, 417 mmol), and Pd(dppf)Cl2 (6.10 g, 8.33 mmol) were added to dioxane (400 mL), and the mixture was stirred at 100 °C for 2 hours. The mixture was concentrated and purified by column chromatography (PE / EtOAc = 1 / 1) to give 26-2A. LC-MS: (ESI) m / z: 182.4 [M+1] + .

[0849] Step 2

[0850] Pd(dppf)Cl2 (6.95 g, 9.50 mmol) was added to a solution of 26-2A (50 g, 190 mmol), INT-4-3 (110 g, 171 mmol), potassium carbonate (65.6 g, 475 mmol) in dioxane (200 mL), and water (20 mL). The reaction mixture was stirred at 70 °C for 16 hours under N2 protection. The reaction mixture was quenched with water (200 mL) and extracted with ethyl acetate (200 mL x 2). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was subjected to silica gel column chromatography (petroleum ether / ethyl acetate, 0-30% ethyl acetate) to give 26-3A. LC-MS: (ESI) m / z: 655.0 [M+1] + .

[0851] Step 3

[0852] 2,2,2-trifluoroethyl trifluoromethanesulfonic acid (53.1 g, 228 mmol) was added to a DMF solution of 26-3A (50 g, 76.2 mmol) and cesium carbonate (74.5 g, 228 mmol) (250 mL). The reaction mixture was stirred at 30 °C for 16 hours. The reaction mixture was quenched with water (300 mL) and extracted with ethyl acetate (300 mL * 2). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was subjected to silica gel column chromatography (petroleum ether / ethyl acetate, 0-10% ethyl acetate) to give 26-4A. LC-MS: (ESI) m / z: 737.0 [M+1] + .

[0853] Step 4

[0854] Under nitrogen atmosphere, 26-4A (65 g, 88 mmol) was dissolved in tetrahydrofuran (600 mL), and a mixture of tetrabutylammonium fluoride (65 g, 88 mmol) was added. The mixture was stirred at 50 °C for 18 hours. The mixture was washed with saturated ammonium chloride, extracted and concentrated with ethyl acetate, and purified by column chromatography (PE / EtOAc = 1 / 1) to give 26-5A. LC-MS: (ESI) m / z: 499.2 [M+1] + .

[0855] Step 5

[0856] Under nitrogen atmosphere, 26-5A (52 g, 104 mmol), triethylamine (58.4 g, 208 mmol), 4-dimethylaminopyridine (1.2 g, 10 mmol), and acetic anhydride (21 g, 208 mmol) were added to tetrahydrofuran (500 mL), and the mixture was stirred at 25 °C for 18 hours. The mixture was concentrated and purified by column chromatography (PE / EtOAc = 1 / 1) to give 26-6A. LC-MS: (ESI) m / z: 541.4 [M+1] + .

[0857] Step 6

[0858] Under nitrogen atmosphere, 26-6A (52 g, 104 mmol), bis(boron) (9.48 g, 37 mmol), [Ir(cod)Cl]₂ (0.74 g, 1.09 mmol), and dtpby (0.59 g, 2.19 mmol) were added to tetrahydrofuran (120 mL), and the mixture was stirred at 75 °C for 18 hours. The mixture was concentrated and purified by column chromatography (PE / EtOAc = 1 / 1) to give 26-7A. LC-MS: (ESI) m / z: 586.6 [M+1] + .

[0859] Step 7

[0860] A solution of 26-8A (500 mg, 2.52 mmol), 1-ethoxy-1-[(trimethylsilyl)oxy]cyclopropane (879 mg, 5.04 mmol), and AcOH (0.142 mL, 2.52 mmol / L) in MeOH (10 mL) and THF (10 mL) was stirred at 40 °C for 16 hours. The mixture was poured into water, extracted with EtOAc, and concentrated to give 26-9A. LC-MS: (ESI) m / z: 239.2 [M+1] + .

[0861] Step 8

[0862] 26-9A (5000 mg, 21.0 mmol) was added to HCl / dioxane (50 mL) and stirred at room temperature for 1 hour. The mixture was concentrated, diluted with MeOH, and K₂CO₃ was added. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated, diluted with EtOAc, filtered, and concentrated again to obtain 26-10A. LC-MS: (ESI) m / z: 239.2 [M+1] + .

[0863] Step 9

[0864] 26-7A (1600 mg, 2.4 mmol), 26-10A (994 mg, 7.19 mmol), Cu(OAc)₂ (871 mg, 4.80 mmol), TEA (1 mL, 7.19 mmol), and 4A molecular sieve (15000 mg, 2.40 mmol) were added to 20 mL of ACN and stirred overnight at 40 °C under O₂. The mixture was concentrated and purified by column chromatography (DCM / MeOH = 30 / 1) to obtain 26-11A. LC-MS: (ESI) m / z: 677.2 [M+1] + .

[0865] Step 10

[0866] 26-11A (889 mg, 1.99 mmol), RuPhos (124 mg, 0.266 mmol), RuPhos PdG2 (206 mg, 0.266 mmol), Pd(OAc)2 (29.8 mg, 0.133 mmol), and Cs2CO3 (1947 mg, 5.98 mmol) were added to dioxane (0.5 mL), and the mixture was stirred at 80 °C for 1 hour under nitrogen. The mixture was concentrated and purified by column chromatography (DCM / MeOH = 30 / 1) to obtain 26-12A. LC-MS: (ESI) m / z: 1043.2 [M+1] + .

[0867] Step 11

[0868] To 26-12A (450 mg, 0.431 mmol) in THF (5 mL), a solution of LiOH (90.5 mg, 2.16 mmol) in H₂O (3 mL) was added, and the mixture was stirred at room temperature for 1 hour. The pH of the mixture was adjusted to 4 with 1 M HCl solution. The mixture was purified by passing it through a C18 column (ACN / H₂O = 40%) to give 26-13A. LC-MS: (ESI) m / z: 494.5 1 / 2 [M+2] + .

[0869] Step 12

[0870] To a mixture of 26-13A (240 mg, 0.243 mmol), EDCI (93.2 mg, 0.486 mmol) was added to HOBt (49.3 mg, 0.365 mmol) and DMAP (148 mg, 1.22 mmol) in DCM (0.5 mL). The mixture was stirred at room temperature for 3 hours. The mixture was concentrated and purified by C18 reverse-phase column chromatography (ACN / H2O = 60%) to give 26-14A. LC-MS: (ESI) m / z: 969.2 [M+1]+.

[0871] Step 13

[0872] At room temperature, 50.00 mg (10% palladium content) of palladium catalyst on carbon containing 55% water was added to a 4 mL solution of 26-14A (120 mg, 0.144 mmol) in isopropanol. The reaction mixture was stirred under a hydrogen balloon for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 26-15A. LC-MS: (ESI) m / z: 835.3 [M+1] + .

[0873] Step 14

[0874] At 25 °C, 2-((S)-7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]non-2-yl)-2-(cyclopent-3-en-1-yl)acetic acid (20.2 mg, 0.06 mmol), DIEA (23.2 mg, 0.180 mmol), and COMU (30.8 mg, 0.072 mmol) were added to a DMF (3 mL) solution of 26-15A (50 mg, 0.06 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with water and extracted with ethyl acetate (50 mL * 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give compound 26-16A. LC-MS: (ESI) m / z: 584.4 [M+2] 2+ .

[0875] Step 15

[0876] Hydrogen chloride (4 M in dioxane, 1 mL) was added to a solution of 26-16A (65 mg, 0.056 mmol) in 1 mL of dichloromethane at 25 °C. The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give yellow compound 26-17A. LC-MS: (ESI) m / z: 1067.2 [M+1] + .

[0877] Step 16

[0878] At 25 °C, lithium ({[(2R,3R)-3-cyclopropyl-1-methylaziridin-2-yl]carbonyl}oxy) (11.2 mg, 0.076 mmol), DIEA (24.2 mg, 0.187 mmol), and HATU (17.1 mg, 0.045 mmol) were added to a 5 mL solution of DMF containing 40 mg of 26-17A (0.037 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) and high performance liquid chromatography (principal C18 column, 30 x 150 mm x 5 μm; elution gradient: 58-80% B, mobile phase A: 1% NH4OAc / H2O; mobile phase B: acetonitrile; flow rate: 25 mL / min) to obtain compound 26.

[0879] LC-MS: (ESI) m / z: 596.5 [M+2] 2+ . 1H NMR(400MHz,MeOD)δ8.32(d,J=2.8Hz,1H),7.49(d,J=8.4Hz,1H),7.28(s,1H),7.21- 7.07(m,2H),5.81-5.57(m,2H),5.56-5.41(m,1H),5.08-4.97(m,1H),4.75-4.66(m,2 H),4.63-4.54(m,1H),4.53-4.43(m,1H),4.13-4.04(m,1H),4.02-3.94(m,1H),3.89- 3.74(m,6H),3.73-3.65(m,3H),3.62-3.48(m,4H),3.47-3.38(m,3H),3.19(s,3H),3. 16-3.13(m,1H),3.09-3.02(m,1H),2.96-2.79(m,5H),2.78-2.67(m,3H),2.64-2.55 (m,2H),2.53-2.45(m,3H),2.44-2.31(m,4H),2.30-2.17(m,2H),2.13-1.85(m,6H),1 .84-1.76(m,1H),1.72(d,J=9.2Hz,1H),1.69-1.60(m,1H),1.55-1.47(m,1H),1.46(d ,J=6.3Hz,4H),0.88(s,3H),0.70-0.56(m,4H),0.55-0.41(m,7H),0.35-0.22(m,1H).

[0880] Example 27

[0881] Step 1

[0882] Compound 27-1A (50 g, 248 mmol) and tert-butylpiperazine-1-carboxylic acid ester (48.6 g, 261 mmol) were dissolved in tetrahydrofuran (300 mL), and triethylamine (34.5 mL, 248 mmol) was added. The reaction mixture was heated to 60 °C and stirred for 16 hours under nitrogen atmosphere. The reaction solution was quenched with water (500 mL), extracted with ethyl acetate (500 mL * 3), and the combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 27-2A. LC-MS: RT = 0.77 min, (ESI) m / z: 367.3 [M+1] + .

[0883] Step 2

[0884] 27-2A (60 g, 163 mmol) was dissolved in tetrahydrofuran (300 mL), and DIBAL-H (1 M, 163 mL) was added at -78 °C. The reaction mixture was reacted at -78 °C for 1 hour. The reaction mixture was quenched with 10% acetic acid aqueous solution (200 mL), extracted with ethyl acetate (500 mL * 3), and the combined organic layers were neutralized with sodium bicarbonate aqueous solution, washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 27-3A. LC-MS: RT = 0.67 min, (ESI) m / z: 370.2 [M+1] + .

[0885] Step 3

[0886] At -78 °C, 129 mL of butyllithium (324 mmol, 2.5 M) was added to a solution of triisopropylsilylacetylene (44.3 g, 243 mmol) in tetrahydrofuran (300 mL). After stirring at -78 °C for one hour, 27-3A (60 g, 162.0 mmol) was added to the reaction mixture, and stirring was continued at -78 °C for another hour. The reaction mixture was slowly added to ice water (300 mL), extracted with ethyl acetate (300 mL x 2), the combined organic phases were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 0-20% ethyl acetate) to give 27-4A. LC-MS: RT = 0.994 min, (ESI) m / z: 552.3 [M+1] + .

[0887] Step 4

[0888] 27-4A (32 g, 56.5 mmol) was dissolved in DMF (200 mL), and NaH (2.78 g, 69.5 mmol) was added under ice-water bath conditions. After stirring at 0 °C for one hour, iodomethane (12.3 g, 86.9 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for one hour. The reaction mixture was slowly added to ice water (300 mL), extracted with ethyl acetate (300 mL x 2), and the combined organic phases were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was subjected to normal-phase column chromatography (petroleum ether / ethyl acetate, 0-20% ethyl acetate) to give 27-5A. LC-MS: RT = 1.064 min, (ESI) m / z: 566.2 [M+1] + .

[0889] Step 5

[0890] To a solution of 27-5A (32 g, 56.5 mmol) in 300 mL of 2-methyltetrahydrofuran, diboronpinacol ester (43.0 g, 169 mmol), potassium neopentate (19.8 g, 141 mmol), and Pd(dppf)Cl2 (2.07 g, 2.82 mmol) were added. The reaction mixture was reacted at 90 °C for 0.5 h under nitrogen protection. The reaction mixture was cooled to room temperature and purged with water (300 mL). Extraction was performed with ethyl acetate (300 mL x 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was subjected to reversed-phase column chromatography (pure water / acetonitrile, 5-100% acetonitrile) to give 27-6A. LC-MS: RT = 0.788 min, (ESI) m / z: 532.3 [M+1-82] + .

[0891] Step 6

[0892] The mixture of 27-7A (20 g, 30.9 mmol) and TBAF·3H2O (29.3 g, 92.8 mmol) in THF (200 mL) was stirred overnight at 50 °C. The reaction mixture was cooled to room temperature and purged with water (1 L), extracted with ethyl acetate (300 mL x 3), washed with brine (200 mL x 3), dried over MgSO4, filtered, and concentrated to give 27-8A, which was used directly in the next step.

[0893] Step 7

[0894] DMAP (0.33 g, 2.70 mmol) was added to a mixture of 27-8A (22 g, 26.9 mmol) and triethylamine (7.5 mL, 53.9 mmol) in THF (100 mL) at 15 °C. The mixture was stirred for 5 minutes, and then acetic anhydride (2.53 mL, 27.0 mmol) was added. After the addition, the reaction mixture was stirred at 20 °C for 18 hours. The reaction mixture was diluted with water (200 mL), extracted with ethyl acetate (100 mL x 3), the combined organic phases were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated, and the residue was purified by rapid silica gel column chromatography (SiO2, ethyl acetate: petroleum ether from 0 to 10%) to give 27-9A. 1 H NMR (400MHz, CDCl3) δ8.10(s,1H),7.68(s,1H),7.31(s,1H),7.26-7.15(m,2H),3.85(s,3H),2.66(s,2H),2.16(s,3H),1.02(s,6H).

[0895] Step 8

[0896] To a mixture of 27-9A (6424 mg, 14.3 mmol) and 27-6A (7300 mg, 11.89 mmol) in 1,4-dioxane (75 mL) and H₂O (15 mL), K₂CO₃ (4931 mg, 35.7 mmol) and Pd(dppf)Cl₂ (870 mg, 1.19 mmol) were added. The reaction mixture was heated to 70 °C and reacted for 4 hours. The reaction mixture was cooled to room temperature, and the combined mixture was poured into water (300 mL), extracted with ethyl acetate (300 mL x 3), washed with brine (300 mL), dried, filtered, and concentrated. The residue was purified by silica chromatography (0 to 25% EtOAc in PE) to give 27-10A. LC-MS: RT = 3.953 min, (ESI) m / z: 809.2 [M+1] + .

[0897] Step 9

[0898] At 20°C, under nitrogen atmosphere, Cs₂CO₃ (7240 mg, 22.2 mmol) was added to a 50 mL solution of 27-10A (6000 mg, 7.40 mmol) in DMF, and the mixture was stirred for 30 minutes. Then, 2,2,2-trifluoroethyl trifluoromethanesulfonate (5157 mg, 22.2 mmol) was added to the mixture and stirred overnight. The reaction liquid was poured into water (100 mL), extracted with ethyl acetate (50 mL x 3), and the combined organic phases were concentrated under reduced pressure to give the crude compound 27-11A, which was purified by column chromatography (SiO₂, PE, 0 to 20% EA).

[0899] Step 10

[0900] 27-11A (3.60 g, 4.04 mmol) was dissolved in dichloromethane (40 mL), and trifluoroacetic acid (4 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give compound 27-12A. LC-MS: RT = 2.701 min, (ESI) m / z: 791.2 [M+1] + .

[0901] Step 11

[0902] Compound 27-12A (3.60 g, 4.55 mmol) and [(2-methoxycyclopropyl)oxy]trimethylsilane (2.19 g, 13.6 mmol) were dissolved in isopropanol (40 mL), and sodium cyanoborohydride (0.86 g, 13.64 mmol) and acetic acid (0.27 g, 4.55 mmol) were added. The reaction mixture was heated to 40 °C and stirred for 18 hours under nitrogen. The reaction solution was extracted with water (50 mL) and ethyl acetate (30 mL x 3), and the combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid silica gel chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 27-13A. LC-MS: RT = 4.680 min, (ESI) m / z: 831.2 [M+1] + .

[0903] Step 12

[0904] 27-13A (1.20, 1.44 mmol), INT-3 (0.89 mg, 2.16 mmol), Ruphos Pd G2 (0.22 g, 0.29 mmol), Pd(OAc)2 (0.06 g, 0.29 mmol), Ruphos (0.34 g, 0.72 mmol), and cesium carbonate (1.88 g, 5.77 mmol) were dissolved in 1,4-dioxane (20 mL). The reaction mixture was stirred at 80 °C for 3 hours. The reaction mixture was filtered and extracted with water (20 mL) and ethyl acetate (10 mL x 3). The combined organic layers were washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid silica gel chromatography (petroleum ether / ethyl acetate = 1 / 5) to give the target compound 27-14A. LC-MS: RT=1.538min, (ESI)m / z:1163.2[M+1] + .

[0905] Step 13

[0906] 27-14A (900 mg, 0.774 mmol) was dissolved in tetrahydrofuran (15 mL) and water (5 mL), and lithium hydroxide monohydrate (325 mg, 7.74 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The pH of the reaction mixture was adjusted to 6 by adding 1 N dilute hydrochloric acid dropwise, and the mixture was extracted with water (10 mL) and ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by C18 reverse column chromatography (water / acetonitrile = 1 / 1: 0-50%) to give compound 27-15A.

[0907] LC-MS: RT=1.347min, (ESI)m / z:1107.4[M+1] + .

[0908] Step 14

[0909] TCFH (304 mg, 1.08 mmol) and NMI (148 mg, 1.81 mmol) were dissolved in N,N-dimethylformamide (1 mL). Then, 27-15A (400 mg, 0.361 mmol) dissolved in N,N-dimethylformamide (4 mL) was slowly added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was extracted with water (30 mL) and ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to preparative separation (column type: JB-C235-03 Prime C18, 30 x 150 mm x 5 μm; gradient: 57-83% B, mobile phase A: 1% NH4HCO3 / H2O; mobile phase B: ACN; flow rate: 25 mL / min) to obtain the target compound 27-16A.

[0910] LC-MS: RT=1.616min, (ESI)m / z:1089.4[M+1] + .

[0911] Step 15

[0912] 27-16A (100 mg, 0.092 mmol) was purified by chiral column to obtain target compounds 27-16A-P1 and 27-16A-P2. Separation conditions: Instrument: SHIMADZU NEXERA XR-20ADXR; Column: YMC Amylose-SA 250x4.6mm_5μm; Column temperature: 35℃; Flow rate: 1.0 ml / min; Detection wavelength: 254 nm; Mobile phase A: hexane; Mobile phase B: ethanol; Elution gradient: A:B = 60:40 (V / V).

[0913] 27-16A-P1: LC-MS: RT=1.600min, (ESI)m / z:1089.4[M+1] + .

[0914] 27-16A-P2: LC-MS: RT=1.627min, (ESI)m / z:1089.4[M+1] + .

[0915] Step 16

[0916] 27-16A-P1 (25.0 mg, 0.023 mmol) was dissolved in acetonitrile (2 mL), and cesium fluoride (41.8 mg, 0.275 mmol) was added. The reaction mixture was stirred at 70 °C for 1 hour. The reaction solution was filtered and concentrated to give compound 27-17A-P1. LC-MS: RT = 1.608 min, (ESI) m / z: 933.4 [M+1] + .

[0917] Step 17

[0918] 27-17A-P1 (25.0 mg, 0.027 mmol) was dissolved in dichloromethane (2 mL), and 4 M hydrochloric acid / 1,4-dioxane (0.5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give compound 27-18A-P1. LC-MS: RT = 1.027 min, (ESI) m / z: 833.3 [M+1]+.

[0919] Step 18

[0920] 27-18A-P1 (16.8 mg, 0.045 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (15.4 mg, 0.036 mmol) and N,N-diisopropylethylamine (11.6 mg, 0.090 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with water (30 mL) and ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was preparatively separated (column type: JB-C235-03 Prime C18, 30 x 150 mm x 5 μm; elution gradient: 57-83% B, mobile phase A: 1% NH4HCO3 / H2O; mobile phase B: ACN; flow rate: 25 mL / min) to obtain the target compound 27-P1. LC-MS: RT = 1.090 min, (ESI) m / z: 1188.4 [M+1] + .

[0921] 1H NMR (400MHz, MeOD) δ8.40(d,J=2.8Hz,1H),7.47(d,J=9.2Hz,1H),7.31(s,1H),7.25(s,1H),7.15(d,J=9.6Hz,1H),5.64(s,2H),5.34(t,J=4.6 Hz,1H),4.71(d,J=14.8Hz,6H),3.94(s,1H),3.78(s,2H),3.65(d,J=10.4Hz,3H),3.38(s,6H),3.05(d,J=9.8Hz,2H),2.85–2.79(m,6H),2.77 –2.68(m,5H),2.45(s,3H),2.36(s,1H),2.32(s,2H),2.20(dd,J=14.8,7.6Hz,4H),2.08–2.00(m,5H),1.93(s,3H),1.84(d,J=7.6Hz,2H),1.7 5(s,2H),1.62(d,J=9.2Hz,4H),1.46–1.39(m,2H),1.17(t,J=7.2Hz,1 H),0.90(t,J=6.8Hz,3H),0.85(s,3H),0.58–0.44(m,9H),0.25(s,1H).

[0922] Step 19

[0923] 27-16A-P2 (30.0 mg, 0.028 mmol) was dissolved in acetonitrile (2 mL), and cesium fluoride (41.8 mg, 0.275 mmol) was added. The reaction mixture was stirred at 70 °C for 1 hour. The reaction solution was filtered and concentrated to give compound 27-17A-P2.

[0924] LC-MS: RT=1.283min, (ESI)m / z:933.3[M+1] + .

[0925] Step 20

[0926] 27-17A-P2 (30.0 mg, 0.032 mmol) was dissolved in dichloromethane (2 mL), and 4 M hydrochloric acid / 1,4-dioxane (0.5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give compound 27-18A-P2. LC-MS: RT = 1.061 min, (ESI) m / z: 833.4 [M+1] + .

[0927] Step 21

[0928] 27-18A-P2 (30.0 mg, 0.036 mmol), 2-(cyclopent-3-en-1-yl)-2-((S)-7-((2R,3R)-3-cyclopropyl-1-methylaziridin-2-carbonyl)-2,7-diazaspiro[4.4]non-2-yl)-2l3acetic acid (20.2 mg, 0.054 mmol) were dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (18.5 mg, 0.043 mmol) and N,N-diisopropylethylamine (13.9 mg, 0.108 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with water (30 mL) and ethyl acetate (10 mL * 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to preparative separation (column type: JB-C235-03 Prime C18, 30 x 150 mm x 5 μm; elution gradient: 57-83% B, mobile phase A: 1% NH4HCO3 / H2O; mobile phase B: ACN; flow rate: 25 mL / min) to obtain the target compound 27-P2.

[0929] LC-MS: RT=1.035min, (ESI)m / z:1188.4[M+1] + .

[0930] 1H NMR(400MHz,MeOD)δ8.40(d,J=2.8Hz,1H),7.47–7.38(m,2H),7.21–7.13(m,2H),5.64(s,2H),5.48(s,1H),4.70(d,J=5.2Hz,3H),4.63(d,J= 2.0Hz,1H),4.58(s,1H),4.52(s,1H),4.43(s,1H),3.94(s,1H),3.85– 3.64(m,6H),3.55(s,1H),3.50–3.46(m,3H),3.40(d,J=6.6Hz,1H),3. 13(s,4H),3.03(dd,J=7.2,5.2Hz,3H),2.87(s,3H),2.84–2.80(m,5H) ,2.77–2.53(m,7H),2.46(s,4H),2.37(s,1H),2.32(s,2H),2.31–2.20 (m,3H),2.11(s,2H),1.93–1.64(m,7H),1.66(d,J=9.4Hz,1H),1.45–1 .42(m,1H),0.89(s,3H),0.62(s,3H),0.55–0.40(m,7H),0.27(s,1H).

[0931] Example 28

[0932] Step 1

[0933] INT-9 (6 g, 8.99 mmol), 28-1A (3.57 g, 18.0 mmol), Cu(OAc)₂ (3.59 g, 18.0 mmol), TEA (3.64 g, 35.96 mmol), and 4A molecular sieve (3 g) were added to ACN (20 mL) and stirred overnight at 50 °C under O₂. The mixture was concentrated and purified by column chromatography (mobile phase DCM / MeOH = 30 / 1) to obtain 28-2A. LC-MS: RT = 2.038 min, (ESI) m / z: 737.3 [M+1] + .

[0934] Step 2

[0935] ZnBr2 (3.05 g, 13.5 mmol) was added to a 20 mL solution of DCM containing 28-2A (2.00 g, 2.71 mmol) at 25 °C, and the mixture was stirred at 25 °C for 16 hours under a N2 atmosphere. The mixture was concentrated under vacuum, and the residue was purified by column chromatography (SiO2, 0 to 15% methanol solution of DCM) to give 28-3A. LC-MS: RT = 2.494 min, (ESI) m / z: 637.2 [M+1] + .

[0936] Step 3

[0937] Sodium cyanoborate (0.89 g, 14.1 mmol) and AcOH (0.3 mL) were added to a solution of 28-3A (3 g, 4.706 mmol) and 1-ethoxy-1-[(trimethylsilyl)oxy]cyclopropane (2.46 g, 14.1 mmol) in i-PrOH (30 mL). The mixture was stirred at 40 °C for 16 hours under N2 atmosphere. The reactants were filtered and concentrated under vacuum. The crude product was purified by column chromatography (SiO2, PE, 0 to 50% EtOAc), then concentrated under vacuum and purified by C18 reverse-phase column (ACN / H2O = 70%) to give 28-4A. LC-MS: RT = 3.359 min, (ESI) m / z: 677.2 [M+1] + .

[0938] Step 4

[0939] To a solution of 28-4A (350 mg, 0.517 mmol) and INT-3 (345 mg, 0.775 mmol) in dioxane (1 mL), RuPhos Pd G2 (120 mg, 0.155 mmol), RuPhos (72.3 mg, 0.155 mL), and Cs₂CO₃ (504 mg, 1.55 mmol) were added, and the mixture was stirred at 90 °C for 2 hours under a N₂ atmosphere. The reaction mixture was filtered and concentrated under vacuum to obtain a crude product. The crude product was purified by column chromatography (SiO₂, 0 to 10% dichloromethane in methanol) to obtain 28-5A. LC-MS: RT = 0.894 min, (ESI) m / z: 522.2 [M+2] 2+ .

[0940] Step 5

[0941] Lithium hydroxide hydrate (40.2 mg, 0.959 mmol) was added to 28-5A (200 mg, 0.192 mmol) in 1 mL of THF and 0.3 mL of H₂O, and the mixture was stirred at 25 °C for 6 hours under a nitrogen atmosphere. The mixture was acidified to pH 3 with 1 N HCl solution, and the residue was purified by C18 reverse-phase column chromatography (mobile phase: acetonitrile / water = 60%) to give 28-6A. LC-MS: RT = 1.181 min, (ESI) m / z: 494.4 [M+2] 2+ .

[0942] Step 6

[0943] DMAP (123 mg, 1.01 mmol), HOBt (54.8 mg, 0.405 mmol), and EDCI (77.7 mg, 0.405 mmol) were added to 20 mL of a DCM solution containing 28-6A (200 mg, 0.203 mmol). The mixture was stirred at 25 °C for 18 hours under a nitrogen atmosphere. The mixture was diluted with 20 mL of H₂O, extracted with EtOAc (10 mL x 2), the organic layer was washed with saturated NaCl solution (10 mL), and concentrated under vacuum. The residue was purified by C18 reverse-phase column chromatography (mobile phase: acetonitrile / water = 70%) to give 28-7A. LC-MS: RT = 3.359 min, (ESI) m / z: 969.4 [M+1] + .

[0944] Step 7

[0945] 28-7A (50.0 mg, 0.052 mmol) was dissolved in isopropanol (5 mL), and palladium on carbon (25.0 mg, 50% w / w) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was filtered and concentrated to give 28-8A. LC-MS: RT = 1.086 min, (ESI) m / z: 835.4 [M+1] + .

[0946] Step 8

[0947] 28-8A (35.0 mg, 0.042 mmol) and INT-5 (23.5 mg, 0.063 mmol) were dissolved in N,N-dimethylformamide (2 mL), and COMU (21.5 mg, 0.050 mmol) and N,N-diisopropylethylamine (16.2 mg, 0.126 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with water (30 mL) and ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (silica gel, eluent methanol / dichloromethane, methanol ratio: 0-10%) and preparative separation (column type: JB-C235-03 Prime C18, 30 x 150 mm x 5 μm; gradient: 57-83% mobile phase B, mobile phase A: 1% ammonium bicarbonate / water; mobile phase B: acetonitrile; flow rate: 25 mL / min) to obtain the target compound 28.

[0948] LC-MS: RT=1.049min, (ESI)m / z:1191.4[M+1] + .

[0949] 1H NMR(400MHz,CD3OD)δ7.98(d,J=2.4Hz,1H),7.48(d,J=8.8Hz,1H),7.24(s,1H),7.1 5(d,J=8.8Hz,1H),6.90(s,1H),5.64(s,2H),5.48(s,1H),4.75–4.67(m,2H),4.58( s,6H),4.51(s,1H),4.37(d,J=5.4Hz,2H),4.07(d,J=6.2Hz,1H),3.95(d,J=11.4Hz ,1H),3.80(d,J=9.6Hz,2H),3.71–3.57(m,4H),3.52–3.34(m,7H),3.23(s,3H),3.06 –2.84(m,8H),2.79–2.69(m,4H),2.66–2.57(m,3H),2.46(s,2H),2.36(s,1H),2.33 –2.28(m,3H),2.23(d,J=9.0Hz,2H),2.13–2.01(m,2H),1.97–1.92(m,3H),1.83(t,J =7.0Hz,1H),1.77(t,J=7.0Hz,1H),1.70–1.61(m,2H),1.43(t,J=6.8Hz,4H),0.92( s,3H),0.62(d,J=6.4Hz,1H),0.50–0.44(m,5H),0.34(d,J=6.0Hz,2H),0.27(s,2H).

[0950] In a more specific embodiment, the present invention also provides the following test method:

[0951] AsPC-1CTG Experiment

[0952] Experimental objective: This experiment aims to verify the inhibitory effect of the compound of the present invention on the proliferation of KRASG12D-mutant AsPC-1 human metastatic pancreatic cancer cells.

[0953] Experimental materials: AsPC-1 cell line was purchased from ATCC, RPMI-1640 Medium was purchased from HyClone, penicillin / streptomycin antibiotics were purchased from Gibco, and fetal bovine serum was purchased from Solarbio. CellCounting-lite 2.0 Luminescent Cell Viability Assay reagents were purchased from Vazyme.

[0954] Experimental methods:

[0955] 1. Cell Culture

[0956] 1) The ASPC-1 cell line was cultured in the corresponding cell culture medium in an incubator at a temperature of 37°C and a CO2 concentration of 5%.

[0957] 2) When the adherent cells reach 70%-90% confluence, discard the culture medium, gently shake with an appropriate amount of PBS to cover the adherent cells, then aspirate the PBS, add an appropriate amount of 0.25% Trypsin-EDTA (1×) solution, incubate at 37℃ until the cells are completely separated, add the appropriate cell culture medium to stop cell digestion, transfer the cell suspension to a sterile centrifuge tube, centrifuge at 1000 rpm for 5 min to collect the cells, remove the supernatant, resuspend and count, and transfer to a new culture medium for continued culture.

[0958] 3) All operations follow the standard operating procedures for cell culture of Guizhou Zhongyue Biotechnology Co., Ltd.

[0959] 2. Experimental Procedure

[0960] 1) Once the adherent cells have reached the logarithmic growth phase, centrifuge at 1000 rpm for 5 min to collect the cells and discard the supernatant. Resuspend the cells in fresh complete culture medium and count them. Prepare a cell suspension according to the number of cells to be plated in Table 3.1, and seed the cells in 384-well plates at a ratio of 300 cells / 40 μL / well. Incubate the plates overnight at 37°C in a 5% CO2 incubator.

[0961] 2) The test substance was diluted with serial DMSO and added at 40 nL / well using an IDOT instrument to obtain the final working concentration.

[0962] 3) Place the cell culture plate in an incubator at 37°C and 5% CO2 for 7 days.

[0963] 4) After incubation, add 20 μL of Cell Counting-Lite 2.0 Luminescent Cell Viability Assay reagent to each well, centrifuge at 1000 rpm for 1 min, shake for 2 min, and then incubate at room temperature for 28 min.

[0964] 5) Use BMG to read the Luminescence value.

[0965] Data analysis: The readings of the DMSO-treated wells (high-value control) were set to 0% inhibition rate, and the readings of the culture medium (low-value control) were set to 100% inhibition rate. The inhibition rate of each test solution was calculated.

[0966] Inhibition%=(Ave_H-Sample) / (Ave_H-Ave_L)

[0967] Z': Factor calculation equation: Z=1-3(SD_H+SD_L) / (AVE_H–AVE_L)

[0968] L: Chemiluminescence value of culture medium well

[0969] H: DMSO solvent control treatment chemiluminescence value of cell pores

[0970] SD is the standard error, and AVE is the mean.

[0971] The IC of the compound is obtained using the following nonlinear fitting formula. 50 (Half-maximal inhibitory concentration):

[0972] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0973] X: Compound concentration

[0974] Y: Compound inhibition rate (% inhibition)

[0975] R_IC 50 For relative IC 50 A_IC 50 For absolute IC 50 .

[0976] Calculate the relative IC of the test compound 50 .

[0977] Example 29

[0978] Compounds 1-2, 4-7, 9, 11, and 15 from the compounds 1-19 obtained in Examples 1-19 were selected for in vitro cell proliferation inhibition activity experiments according to the AsPC-1CTG assay method described above, and the experimental results are shown in Table 1.

[0979] Table 1: Experimental results of the in vitro cell proliferation inhibition activity of the compounds of the present invention

[0980] Conclusion: The compounds of this invention have significant inhibitory activity on the cell proliferation of RAS mutant AsPC-1 cell lines.

[0981] In a more specific embodiment, the present invention also provides the following test method:

[0982] GP2D CTG Experimental Method 1

[0983] Experimental Objective: This experiment aims to verify the effect of the compound of this invention on KRAS. G12DInhibitory effect on the proliferation of mutant GP2D human colon cancer cells.

[0984] Experimental materials: GP2D cell line, DMEM medium, penicillin / streptomycin antibiotics were purchased from Vicente, and fetal bovine serum was purchased from Biosera. The Cell Viability Assay reagent (3D cell viability chemiluminescence assay) was purchased from Promega.

[0985] Experimental Methods: GP2D cells were seeded in 96-well U-bottom cell culture plates, with 80 μL of cell suspension per well containing 2000 GP2D cells. The cell culture plates were incubated overnight in a CO2 incubator. The test compound was diluted 5-fold to the 8th concentration using a multi-channel pipette, from 200 μM to 2.56 nM, in duplicate. 78 μL of culture medium was added to the intermediate plate, and then 2 μL of serially diluted compound was transferred to each well of the intermediate plate according to the corresponding position. After mixing, 20 μL of the compound was transferred to each well of the cell culture plate. The concentration range of the compound transferred to the cell culture plate was 1 μM to 0.0128 nM. The cell culture plates were incubated in a CO2 incubator for 5 days. After the cell culture plates with added compounds had finished incubating, 100 μL of chemiluminescent cell viability assay reagent was added to each well of the cell culture plate, and incubated at room temperature for 10 minutes to stabilize the luminescence signal. The readings were obtained using a multi-label analyzer.

[0986] Data analysis: The raw data were converted into inhibition rate (IC) using the equation (Sample-Min) / (Max-Min)*100%. 50 The value can be obtained by curve fitting using four parameters (obtained in the "log(inhibitor) vs. response-variable slope" mode of GraphPad Prism).

[0987] Calculate the relative IC of the test compound 50 .

[0988] Technical effect: The compound of the present invention has good anti-cell proliferation activity.

[0989] GP2D CTG Experimental Method 2

[0990] Experimental objective: This experiment aims to verify the inhibitory effect of the compound of the present invention on the proliferation of KRAS G12D mutant GP2D human colon cancer cells.

[0991] Experimental materials: GP2D cell line was purchased from Cobioer, DMEM medium was purchased from HyClone, penicillin / streptomycin antibiotics were purchased from Gibco, and fetal bovine serum was purchased from Solarbio. CellCounting-lite 2.0 Luminescent Cell Viability Assay reagents were purchased from Vazyme.

[0992] Experimental methods:

[0993] 1. Cell Culture

[0994] 1) The GP2D cell line was cultured in the corresponding cell culture medium in an incubator at a temperature of 37°C and a CO2 concentration of 5%.

[0995] 2) When the adherent cells reach 70%-90% confluence, discard the culture medium, gently shake with an appropriate amount of PBS to cover the adherent cells, then aspirate the PBS, add an appropriate amount of 0.25% Trypsin-EDTA (1×) solution, incubate at 37℃ until the cells are completely separated, add the appropriate cell culture medium to stop cell digestion, transfer the cell suspension to a sterile centrifuge tube, centrifuge at 1000 rpm for 5 min to collect the cells, remove the supernatant, resuspend and count, and transfer to a new culture medium for continued culture.

[0996] 3) All operations follow the standard operating procedures for cell culture of Guizhou Zhongyue Biotechnology Co., Ltd.

[0997] 2. Experimental Procedure

[0998] 1) Once the adherent cells have reached the logarithmic growth phase, centrifuge at 1000 rpm for 5 min to collect the cells and discard the supernatant. Resuspend the cells in fresh complete culture medium and count them. Prepare a cell suspension according to the plating layout and seed 500 cells / 195 μL / well in a 96-well plate. Incubate the plate overnight at 37°C in a 5% CO2 incubator.

[0999] 2) The test substances SPR-A003, SPR-A006, SPR-A000 and RMC-6236 were first serially diluted with DMSO, then diluted 25 times with culture medium, and finally added at 5 μL / well to obtain the final working concentration.

[1000] 3) Place the cell culture plate in an incubator at 37°C and 5% CO2 for 7 days.

[1001] 4) After incubation, discard 100 μL of culture medium. Add 60 μL of Cell Counting-Lite 2.0 Luminescent Cell Viability Assay reagent to each well, centrifuge at 1000 rpm for 1 min, vortex for 2 min, and then incubate at room temperature for 28 min.

[1002] 5) Use BMG to read the Luminescence value.

[1003] 3. Data Analysis: Set the readings of the DMSO-treated wells (high-value control) to 0% inhibition rate and the readings of the culture medium (low-value control) to 100% inhibition rate, and calculate the inhibition rate of each test solution.

[1004] Inhibition%=(Ave_H-Sample) / (Ave_H-Ave_L)

[1005] Z': Factor calculation equation: Z=1-3(SD_H+SD_L) / (AVE_H–AVE_L)

[1006] L: Chemiluminescence value of culture medium well

[1007] H: DMSO solvent control treatment chemiluminescence value of cell pores

[1008] SD is the standard error, and AVE is the mean.

[1009] The IC50 (half-maximal inhibitory concentration) of the compound was obtained using the following nonlinear fitting formula:

[1010] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[1011] X: Compound concentration

[1012] Y: Compound inhibition rate (% inhibition)

[1013] R_IC 50 For relative IC 50 A_IC 50 For absolute IC 50 .

[1014] Calculate the relative IC of the test compound 50 .

[1015] Technical effect: The compound of the present invention has good anti-cell proliferation activity.

[1016] Example 30

[1017] Compound 1 obtained in Example 1 was subjected to an in vitro cell proliferation inhibition activity experiment according to the above-described GP2D CTG experimental method 2, and the experimental results are shown in Table 2.

[1018] Table 2: Results of in vitro cell proliferation inhibition activities of the compounds of the present invention

[1019] Conclusion: The compounds of this invention have significant inhibitory activity on the cell proliferation of the RAS mutant GP2D cell line.

[1020] In a more specific embodiment, the present invention also provides the following test method:

[1021] GP2D p-ERK experiment

[1022] Experimental objective: To screen compounds that can effectively inhibit p-ERK in GP2D cells using the HTRF method.

[1023] Experimental methods:

[1024] 1) GP2D cells were seeded in 96-well cell culture plates with 80 μL of cell suspension per well, containing 8000 cells per well. The cell culture plates were placed in a CO2 incubator and incubated overnight at 37°C.

[1025] 2) Add 2 μL of the compound to 78 μL of cell culture medium, mix well, and then add 20 μL of the compound solution to the corresponding wells of the cell plate. Place the cell plate back into the carbon dioxide incubator and continue incubation for 1 hour.

[1026] 3) After incubation, discard the cell supernatant, add 50 μL of 1X cell lysis buffer to each well, and incubate at room temperature with shaking for 30 minutes.

[1027] 4) Dilute Phospho-ERK1 / 2 Eu Cryptate antibody and Phospho-ERK1 / 2d2 antibody 20-fold using detection buffer.

[1028] 5) Take 16 μL of cell lysate supernatant into each well of a new 384 white microplate, then add 2 μL of Phospho-ERK1 / 2 Eu Cryptate antibody dilution and Phospho-ERK1 / 2 d2 antibody dilution, and incubate at room temperature for at least 4 hours.

[1029] 6) After incubation, use a multi-label analyzer to read HTRF excitation: 320nm, emission: 615nm, 665nm.

[1030] Calculate IC of the test compound50 .

[1031] Technical effect: The compound of the present invention has good anti-cell proliferation activity.

[1032] The drug RMC-9805 involved in the embodiments of the present invention is Zoldonrasib, a drug from Revolution Medicines Inc. that targets KRAS G12D.

[1033] Example 31: Pharmacokinetic Study in Mice

[1034] Experimental objective:

[1035] The pharmacokinetic behavior of the compounds of this invention in male mice was evaluated.

[1036] Experimental methods:

[1037] The test compounds were dissolved in a solvent (10% DMSO / 10% Solutol / 80% water, volume percentage). Eight male BALB / c mice were randomly divided into four groups of two. Groups 1 and 3 received a single intravenous bolus (iv) injection of RMC-9805 and compound 5, respectively, at a dose of 3 mg / kg. Groups 2 and 4 received a single oral gavage (po) injection of RMC-9805 and compound 5, respectively, at a dose of 10 mg / kg. Four additional male BALB / c mice were randomly divided into two groups of two. Group 5 received a combined intravenous bolus (iv) injection of RMC-9805 and compound 5, each at a dose of 3 mg / kg. Group 6 received a combined oral gavage (po) injection of RMC-9805 and compound 5, each at a dose of 10 mg / kg. Whole blood and plasma samples were collected at 0.083 (IV injection group only), 0.25, 1, 2, 4, 8, and 24 hours post-administration. The concentrations of compounds in whole blood and plasma samples were determined using LC-MS / MS.

[1038] Experimental results:

[1039] The specific experimental results of the mouse pharmacokinetic assays for RMC-9805 and compound 5 are shown in Table 3:

[1040] Table 3. Pharmacokinetic results of RMC-9805 and compound 5 in mice.

[1041] ND: Not Determined

[1042] Conclusion: Compound 5 of this invention exhibits higher exposure levels and a longer half-life in whole blood samples compared to the reference compound RMC-9805, and demonstrates favorable pharmacokinetic properties. Combined dosing experiments showed that the exposure level of RMC 9805 in whole blood decreased compared to monotherapy, while the exposure level of compound 5 remained largely unchanged.

[1043] Example 32: Pharmacokinetic Study in Rats

[1044] Experimental objective:

[1045] The pharmacokinetic behavior of the compounds of this invention in male rats was evaluated.

[1046] Experimental methods:

[1047] The test compounds were dissolved in a solvent (10% DMSO / 10% Solutol / 80% water, volume percentage). Eight male SD rats were randomly divided into four groups of two. Groups 1 and 3 received a single intravenous bolus (iv) injection of RMC-9805 and compound 5, respectively, at a dose of 3 mg / kg. Groups 2 and 4 received a single oral gavage (po) injection of RMC-9805 and compound 5, respectively, at a dose of 100 mg / kg. Whole blood samples were collected at 0.083 hours (IV injection group only), 0.25 hours, 1, 2, 4, 8, and 24 hours post-administration, and plasma samples were collected at 2 and 4 hours post-administration. The concentrations of the compounds in whole blood and plasma samples were determined using LC-MS / MS.

[1048] Experimental results:

[1049] The specific experimental results of the rat pharmacokinetic assays for RMC-9805 and compound 5 are shown in Table 4.

[1050] Table 4. Pharmacokinetic results of RMC-9805 and compound 5 in rats.

[1051] Conclusion: Compound 5 of the present invention has a higher exposure level and longer half-life in whole blood samples than the reference compound RMC-9805, and exhibits good pharmacokinetic properties.

[1052] Example 33: Pharmacokinetic Study of Beagle Dogs

[1053] Experimental objective:

[1054] The pharmacokinetic behavior of the compounds of this invention in male beagle dogs was evaluated.

[1055] Experimental methods:

[1056] The test compounds were dissolved in a solvent (10% DMSO / 10% Solutol / 80% water, volume percentage). Eight male beagle dogs were divided into four groups of two. Groups 1 and 3 received a single intravenous bolus (iv) injection of RMC-9805 and compound 5, respectively, at a dose of 1 mg / kg. Groups 2 and 4 received a single oral gavage (po) injection of RMC-9805 and compound 5, respectively, at a dose of 10 mg / kg. Whole blood and plasma samples were collected at 0.083 (IV injection group only), 0.25, 1, 2, 4, 8, and 24 hours post-administration. The concentrations of the compounds in whole blood and plasma samples were determined using LC-MS / MS.

[1057] Experimental results:

[1058] The specific experimental results of the beagle dog pharmacokinetic assays for RMC-9805 and compound 5 are shown in Table 5:

[1059] Table 5. Pharmacokinetic results of RMC-9805 and compound 5 in beagle dogs.

[1060] Conclusion: Compound 5 of the present invention has a higher exposure level and longer half-life in whole blood samples than the reference compound RMC-9805, and exhibits good pharmacokinetic properties.

[1061] Example 34: In vivo pharmacodynamic study of RMC-9805 and compound 5 in a subcutaneous xenograft tumor model of human pancreatic cancer HPAC cells in BALB / c nude mice

[1062] Experimental Objective

[1063] The in vivo efficacy of compound 5 of this invention in a BALB / c nude mouse subcutaneous xenograft model of human pancreatic cancer HPAC cells was investigated.

[1064] Experimental methods and procedures

[1065] Experimental animals: female BALB / c nude mice, 6-8 weeks old, weighing 18-22 grams; Supplier: Jiangsu Jicui Biotechnology Co., Ltd.

[1066] (1) Cell Culture: Human pancreatic cancer HPAC cells (American Type Culture Collection Center (ATCC), catalog number: CRL-2119) were cultured in vitro in a monolayer. Culture conditions were as follows: DMEM / F12 medium supplemented with 5% fetal bovine serum, 1.2 g / L sodium bicarbonate, 2.5 mM L-glutamine, 15 mM 4-hydroxyethylpiperazine ethanesulfonic acid, 0.5 mM sodium pyruvate, 0.002 mg / mL insulin, 0.005 mg / mL transferrin, 40 ng / mL hydrocortisone, 10 ng / mL mouse epidermal growth factor, and 1% penicillin-streptomycin solution; cultured at 37°C in a 5% CO2 incubator. Cells were passaged twice a week using trypsin-EDTA digestion. When cell saturation reached 80%-90% and the required number was achieved, cells were harvested, counted, and seeded.

[1067] (2) Tumor cell inoculation and grouping: 0.1 mL (3 × 10⁻⁶) of the tumor cells were inoculated and grouped. 6 HPAC tumor cells were subcutaneously inoculated into the right posterior dorsal region of each mouse. The average tumor volume in the efficacy experiment reached approximately 201 mmHg. 3 The animals were divided into groups of 6 for administration.

[1068] The solvent was 10% DMSO + 10% Solutol + 80% double-distilled water (volume percentage). Control group: The solvent was administered once daily by gavage at a volume of 10 μL / g; Treatment group: The test compound was dissolved in the solvent and administered once daily by gavage. The administration regimen is shown in Table 6.

[1069] Table 6. Grouping and Dosing Regimens of Experimental Animals

[1070] Note: 1. N is the number of mice in each group.

[1071] 2. Dosage volume: 10 μL / g based on mouse body weight.

[1072] 3.PO: Oral administration.

[1073] 4. Dosage frequency: QD x 28D, once a day for 28 consecutive days.

[1074] (3) Measure the tumor diameter twice a week using calipers and calculate the tumor volume (V). The calculation formula is: V = 0.5a × b 2 Where a and b are the long and short diameters of the tumor, respectively. The antitumor efficacy of the test compound is evaluated by the tumor growth inhibition rate (TGI), calculated as follows: TGI(%) = [1 - (mean tumor volume at the end of treatment in a certain treatment group - mean tumor volume at the start of treatment in that treatment group) / (mean tumor volume at the end of treatment in the solvent control group - mean tumor volume at the start of treatment in the solvent control group)] × 100%

[1075] Experimental results

[1076] The body weight of mice in each treatment group remained good after administration. The TGI was calculated based on the average tumor volume on day 28 after administration. The specific experimental results are shown in Table 7.

[1077] Table 7. Evaluation of the antitumor efficacy of the compounds of this invention in a human pancreatic cancer HPAC model.

[1078] Note: SEM: Standard Error.

[1079] Conclusion: Compound 5 of the present invention exhibited excellent tumor-suppressing effects in the HPAC tumor model.

[1080] The compounds of this invention may include one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of this invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. The isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[1081] The compounds of this invention can exist as tautomers. Tautomers are functional group isomers that arise from the rapid movement of an atom between two positions in a molecule. Tautomers are a special type of functional group isomer. A pair of tautomers can interconvert, but usually the more stable isomer is the dominant form. Examples include enol and keto tautomers.

[1082] Those skilled in the art will understand that organic compounds can form complexes with solvents, react in the solvent, or precipitate or crystallize out of the solvent. These complexes are called "solvates." When the solvent is water, the complex is called a "hydrate." This invention covers all solvates of the compounds of this invention.

[1083] The term "solvent" refers to a compound or its salt that is bound to a solvent and formed typically by a solvent decomposition reaction. This physical association may include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be separable, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvent" includes solvates in solution and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[1084] The term "hydrate" refers to a compound that is bound to water. Typically, it is determined by the ratio of the number of water molecules contained in the hydrate to the number of molecules of the compound in the hydrate. Therefore, a hydrate of a compound can be represented, for example, by the general formula R·xH₂O, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, e.g., hemihydrates (R·0.5H₂O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R·2H₂O) and hexahydrates (R·6H₂O)).

[1085] The compounds of this invention can be in amorphous or crystalline forms (polymorphs). Furthermore, the compounds of this invention can exist in one or more crystalline forms. Therefore, this invention encompasses all amorphous or crystalline forms of the compounds of this invention within its scope. The term "polymorph" refers to the crystalline form of a compound (or its salts, hydrates, or solvates) with a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, photoelectric properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can lead to the dominance of one crystalline form. Various polymorphs of the compounds can be prepared by crystallization under different conditions.

[1086] The present invention also includes isotopically labeled compounds (isotopic variants) that are equivalent to those described in formula (I), etc., but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, for example... 2 H, 3 H, 13 C 11 C 14 C15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Other isotopes of the present invention containing the aforementioned isotopes and / or other atoms, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of this invention. Certain isotope-labeled compounds of the present invention, for example, those incorporating radioactive isotopes (e.g.,...) 3 H and 14 Those in category C) can be used for drug and / or substrate tissue distribution determination. Tritium, i.e. 3 H and carbon-14, i.e. 14 Carbon isotopes are particularly preferred because they are easy to prepare and detect. Subsequently, they are replaced by heavier isotopes, such as deuterium, i.e., 2 H, because higher metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, may be preferred in some cases. Isotope-labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by using readily available isotope-labeled reagents instead of non-isotope-labeled reagents when performing the processes described below and / or the techniques disclosed in the examples and preparation examples.

[1087] Furthermore, prodrugs are also included in the context of this invention. As used herein, the term "prodrug" refers to a compound which is converted in vivo, for example, by hydrolysis in the blood, into its active form having a medical effect. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACSSymposium Series, Vol. 14; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; and D. Fleisher, S. Ramon, and H. Barbra, "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs," Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each of which is incorporated herein by reference.

[1088] A prodrug is any covalently bonded compound of the present invention that, when administered to a patient, releases the parent compound in vivo. Prodrugs are typically prepared by modifying functional groups in a manner that allows the modification to produce the parent compound through conventional operation or in vivo cleavage. Prodrugs include, for example, compounds of the present invention in which a hydroxyl, amino, or thiol group is bonded to any group, which, when administered to a patient, can cleave to form a hydroxyl, amino, or thiol group. Thus, representative examples of prodrugs include (but are not limited to) acetate / amide, formate / amide, and benzoate / amide derivatives of formula (I) with hydroxyl, thiol, and amino functional groups. Additionally, in the case of carboxylic acids (-COOH), esters, such as methyl esters, ethyl esters, etc., can be used. The ester itself may be active and / or hydrolyzable under in vivo conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those groups that readily decompose in the body to release the parent acid or its salt.

[1089] The present invention also provides pharmaceutical formulations comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, or excipient thereof. All such forms are subject to the pres...

Claims

Compounds of formula (I'), or isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates, or pharmaceutically acceptable salts thereof: in, m and n are independently 0, 1, 2 or 3; X1, X2, and X3 are independently selected from -CH2-, -CHF-, -CF2-, -C(O)-, and -O-; L1 and L2 are independently selected from -CH2-, -O-, -S-, and -NH-; Ring A is selected from C 3-10 Cycloalkylene, 3-10 membered heterocyclic alkylene, C 6-10 aryl and 5-10 heteroaryl compounds, which are optionally replaced by 1, 2, 3 or 4 R1s; Ring B is selected from C 3-7 Cycloalkylene, 3-7-membered heterocyclic alkylene, phenylene and 5-6-membered heteroaryl alkylene, which are optionally substituted with 1, 2, 3 or 4 R2 groups; Ring C is selected from C 3-7 Cycloalkylene, 3-7-membered heterocyclic alkylene, phenylene and 5-6-membered heteroaryl alkylene, which are optionally substituted with 1, 2, 3 or 4 R3s; R1, R2, and R3 are each independently selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; Or R2 and R3 can be connected to form C. 1-6 Alkylene, which optionally contains a carbon-carbon double bond, and wherein one or two methylene units are optionally and independently replaced by -O-, -S- or -NR-; R is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl and 3-7 membered heterocyclic groups; Ring D is selected from C 6-10 arylene and 5-10 quinone heteroarylene; R D Selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, which are optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 R4 groups; R4 is independently selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic groups; optionally surrounded by 1, 2 or 3 R groups. 4s replace; Or two adjacent R4 bonds can be linked together to form a carbon-carbon double bond; Or two R4s connected together form C 1-6 Alkylene or C 2-6 The alkenyl group forms a fused ring, bridged ring, or spiro ring structure, wherein one or two methylene units are optionally and independently replaced by -O-, -S-, or -NR-. R 4s Independently selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; a can be 0, 1, 2, or 3; R' D Independently selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl and 3-7 membered heterocyclic groups; R5 is selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally bounded by 1, 2, 3 or 4 R groups. 5s replace; R 5s Independently selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Or two Rs 5s They connect to form carbon-carbon double bonds; Or two Rs 5s Connect to form C 1-6 The alkylene group forms a fused, bridged, or spirocyclic structure (preferably a fused or bridged ring structure), wherein the alkylene group optionally contains a carbon-carbon double bond, and one or two methylene units therein are optionally and independently replaced by -O-, -S-, or -NR-. r is 1, 2, 3, 4, 5, or 6; R6 is independently selected from H, D, halogen, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 3-7 cycloalkyl and 3-7 membered heterocyclic groups; Or two R6s connected together form C. 1-6 The alkylene group forms a fused ring, bridged ring, or spiro ring structure, wherein the alkylene group optionally contains a carbon-carbon double bond, and one or two methylene units therein are optionally and independently replaced by -O-, -S-, or -NR-. R7 and R8 are independently selected from H, D, halogen, and C. 1-3 Alkyl and C 1-3 Halogenated alkyl groups; Or CR7R8 forms C 3-7 Cycloalkylene or 3-7 membered heterocyclic alkylene; R9 is selected from -L-OR 9a -L-SR 9a -L-NR 9b R 9c ; R 9a R 9b and R 9c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclic groups; or R 9b R 9c Together with the atoms they connect, they form 3-7 membered heterocyclic groups; R 10 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl and C 2-6 alkynyl group; R 11 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups; L is independently selected from chemical bonds and C. 1-6 Alkylene; R a R b and R c Independently selected from H and C 1-6 Alkyl and C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups; or R b R c Together with the atoms they connect, they form 3-10 membered heterocyclic groups; R 12 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, C 1- 2-alkyl substituted C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl and C 2-6 alkynyl group; The aforementioned groups are optionally deuterated, up to and including complete deuteration. The compound of claim 1, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate, or a pharmaceutically acceptable salt thereof: is a compound of formula (I). in, m and n are independently 0, 1, 2 or 3; X1, X2, and X3 are independently selected from -CH2-, -CHF-, -CF2-, -C(O)-, and -O-; L1 and L2 are independently selected from -CH2-, -O-, -S-, and -NH-; Ring A is selected from C 3-10 Cycloalkylene, 3-10 membered heterocyclic alkylene, C 6-10 aryl and 5-10 heteroaryl compounds, which are optionally replaced by 1, 2, 3 or 4 R1s; Ring B is selected from C 3-7 Cycloalkylene, 3-7-membered heterocyclic alkylene, phenylene and 5-6-membered heteroaryl alkylene, which are optionally substituted with 1, 2, 3 or 4 R2 groups; Ring C is selected from C 3-7 Cycloalkylene, 3-7-membered heterocyclic alkylene, phenylene and 5-6-membered heteroaryl alkylene, which are optionally substituted with 1, 2, 3 or 4 R3s; R1, R2, and R3 are each independently selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; Or R2 and R3 can be connected to form C. 1-6 Alkylene, which optionally contains a carbon-carbon double bond, and wherein one or two methylene units are optionally and independently replaced by -O-, -S- or -NR-; R is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl and 3-7 membered heterocyclic groups; Ring D is selected from C 6-10 arylene and 5-10 quinone heteroarylene; R D Selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, which are optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 R4 groups; R4 is independently selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic groups; optionally surrounded by 1, 2 or 3 R groups. 4s replace; Or two adjacent R4 bonds can be linked together to form a carbon-carbon double bond; Or two R4s connected together form C 1-6 Alkylene or C 2-6 The alkenyl group forms a fused ring, bridged ring, or spiro ring structure, wherein one or two methylene units are optionally and independently replaced by -O-, -S-, or -NR-. R 4s Independently selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; a can be 0, 1, 2, or 3; R' D Independently selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl and 3-7 membered heterocyclic groups; R5 is selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally bounded by 1, 2, 3 or 4 R groups. 5s replace; R 5s Independently selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Or two Rs 5s They connect to form carbon-carbon double bonds; Or two Rs 5s Connect to form C 1-6 The alkylene group forms a fused, bridged, or spirocyclic structure (preferably a fused or bridged ring structure), wherein the alkylene group optionally contains a carbon-carbon double bond, and one or two methylene units therein are optionally and independently replaced by -O-, -S-, or -NR-. r is 1, 2, 3, 4, 5, or 6; R6 is independently selected from H, D, halogen, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 3-7 cycloalkyl and 3-7 membered heterocyclic groups; Or two R6s connected together form C. 1-6 The alkylene group forms a fused ring, bridged ring, or spiro ring structure, wherein the alkylene group optionally contains a carbon-carbon double bond, and one or two methylene units therein are optionally and independently replaced by -O-, -S-, or -NR-. R7 and R8 are independently selected from H, D, halogen, and C. 1-3 Alkyl and C 1-3 Halogenated alkyl groups; Or CR7R8 forms C 3-7 Cycloalkylene or 3-7 membered heterocyclic alkylene; R9 is selected from -L-OR 9a -L-SR 9a -L-NR 9b R 9c ; R 9a R 9b and R 9c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclic groups; or R 9b R 9c Together with the atoms they connect, they form 3-7 membered heterocyclic groups; R 10 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl and C 2-6 alkynyl group; R 11 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups; L is independently selected from chemical bonds and C. 1-6 Alkylene; R a R b and R c Independently selected from H and C 1-6 Alkyl and C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups; or R b R c Together with the atoms they connect, they form 3-10 membered heterocyclic groups; The aforementioned groups are optionally deuterated, up to and including complete deuteration. The compound of claim 2, or its isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates, or pharmaceutically acceptable salts thereof, having the structure of formula (II), (III), (IV-1), (IV-2) and (IV-3): in, T1, T2, T3, T4, and T5 are independently CH or N; s and t are independently 0, 1, or 2; q can be 0, 1, 2, 3, 4, 5, or 6; Y is selected from CR 4d Or N; R 4a R 4b and R 4d Independently selected from H, D, halogens, and C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R 4b With R 4d They connect to form carbon-carbon double bonds; Or R 4a and R 4b Connect to form C 1-4 Alkylene or C 2-4 The imide group, wherein one or two methylene units are optionally and independently replaced by -O-, -S- or -NR-; R4 is independently selected from H, D, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl group; optionally marked with 1, 2 or 3 R groups 4s replace; Alternatively, two adjacent R4 groups may connect to form a carbon-carbon double bond; or an R4 group located adjacent to the Y group may connect with an R4 group. 4d They connect to form carbon-carbon double bonds; Or two R4s connected together form C 1-4 Alkylene or C 2-4 The alkenyl group forms a fused ring, bridged ring, or spiro ring structure (preferably a fused ring or bridged ring structure), wherein one or two methylene units are optionally and independently replaced by -O-, -S-, or -NR-. R 4c Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups; optionally surrounded by 1, 2 or 3 R groups. 4s replace; p is 1, 2, 3 or 4; The remaining variables are as defined in claim 1. The compound of claim 2 or 3, or its isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates, or pharmaceutically acceptable salts thereof, having the structure of formula (II): in, m and n are independently 0, 1, 2 or 3; L1 and L2 are independently selected from -CH2-, -O-, -S-, and -NH-; Ring A is selected from 3-7-membered heterocyclic groups and 5-6-membered heterocyclic groups, preferably 3-7-membered heterocyclic groups, preferably morpholino groups, which are optionally substituted by 1, 2, 3 or 4 R1s; T1, T2, T3, T4, and T5 are independently CH or N; preferably, T3 is N. R1 is independently selected from H, D, halogen, CN, -L-OR a -L-SR a -L-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl and 3-7 membered heterocyclic groups; R2 is selected from H, D, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R3 is selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Or R2 and R3 can be connected to form C. 1-6 Alkylene, which optionally contains a carbon-carbon double bond, and wherein one or two methylene units are optionally and independently replaced by -O-, -S- or -NR-; R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; s and t are independently 0, 1, or 2; q can be 0, 1, 2, 3, 4, 5, or 6; Y is selected from CR 4d Or N; R 4d Selected from H, D, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R4 is independently selected from H, D, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl group; optionally marked with 1, 2 or 3 R groups 4s replace; Alternatively, two adjacent R4 groups may connect to form a carbon-carbon double bond; or an R4 group located adjacent to the Y group may connect with an R4 group. 4d They connect to form carbon-carbon double bonds; Or two R4s connected together form C 1-4 Alkylene or C 2-4 The alkenyl groups form fused, bridged, or spirocyclic structures (preferably fused or bridged), or R4 and R 4c Connect to form C 1-4 Alkylene or C 2-4 The alkenyl group forms a fused or bridged ring structure (preferably a fused ring structure), wherein one or two methylene units are optionally and independently replaced by -O-, -S- or -NR-. R 4c Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups; optionally surrounded by 1, 2 or 3 R groups. 4s replace; R 4s Independently selected from H, D, halogens, and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R5 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7-membered heterocyclic, phenyl, and 5-6-membered heteroaryl groups, optionally surrounded by 1, 2, 3, or 4 R groups. 5s replace; R 5s Independently selected from H, D, halogen, CN, -OR a -SR a -NR b R c C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Or two Rs 5s They connect to form carbon-carbon double bonds; Or two Rs 5s Connect to form C 1-6 Alkylene (preferably C) 1-4 Alkylenes are used to form fused, bridged, or spirocyclic structures (preferably fused or bridged), wherein the alkylene optionally contains a carbon-carbon double bond and one or two methylene units therein are optionally and independently replaced by -O-, -S-, or -NR-. r is 2, 3, 4, 5 or 6; preferably 2 or 3; R6 is independently selected from H, D, halogen, and -OR. a -SR a -NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl groups and 3-7 membered heterocyclic groups; and There are two R6 connected to form C 1-6 Alkylene (preferably C) 1-4 Alkylene, preferably C 1-2 Alkylenes, preferably methylene, are used to form fused, bridged, or spirocyclic structures (preferably fused or bridged, especially bridged), wherein the alkylene optionally contains a carbon-carbon double bond and one or two methylene units are optionally and independently replaced by -O-, -S-, or -NR-. R7 and R8 are independently selected from H, D, halogen, and C. 1-3 Alkyl and C 1-3 Halogenated alkyl groups; Or CR7R8 forms C 3-7 Cycloalkylene or 3-7 membered heterocyclic alkylene; R9 is selected from -OR 9a -SR 9a -NR 9b R 9c Preferred - OR 9a ; R 9a R 9b and R 9c Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 10 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl and C 2-6 alkynyl group; R 11 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups; L is independently selected from chemical bonds and C. 1-6 Alkylene; R a R b and R c Independently selected from H and C 1-6 Alkyl and C 1-6 Haloalkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups; or R b R c Together with the atoms they connect, they form 3-7 membered heterocyclic groups; The aforementioned groups are optionally deuterated, up to and including complete deuteration. The compound of claim 2 or 3, or its isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates, or pharmaceutically acceptable salts thereof, having the structure of formula (III): in, m and n are independently 0, 1, 2 or 3; preferably 1; L1 is selected from -CH2-, -O-, -S-, and -NH-; preferably -CH2- and -O-; preferably -CH2-; T1 is CH or N; R2 is selected from H, D, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R3 is selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Or R2 and R3 can be connected to form C. 1-6 Alkylene, preferably C 1-4 Alkylene, which optionally contains a carbon-carbon double bond, and wherein one or two methylene units are optionally and independently replaced by -O-, -S- or -NR-; R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Y is selected from CR 4d and N; R 4a R 4b and R 4d Independently selected from H, D, halogens, and C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably H or D; or R 4b With R 4d They connect to form carbon-carbon double bonds; Or R 4a and R 4b Connect to form C 1-4 Alkylene or C 2-4 Ideonyl groups, preferably forming C 2-3 The alkenyl group, wherein one or two methylene units are optionally and independently replaced by -O-, -S- or -NR-; preferably forming -CH=CH-; R 4c Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups; preferably C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups; preferably C 3-7 Cycloalkyl; preferably cyclopropyl; optionally marked with 1, 2 or 3 R's 4s replace; R 4s Independently selected from H, D, halogens, and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R5 is selected from C 3-7 Cycloalkyl, 3-7-membered heterocyclic, phenyl, and 5-6-membered heteroaryl groups, optionally surrounded by 1, 2, 3, or 4 R groups. 5s replace; R 5s Independently selected from H, D, halogens, CN, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Or two Rs 5s They connect to form carbon-carbon double bonds; Or two Rs 5s Connect to form C 1-4 The alkylene group forms a fused, bridged, or spirocyclic structure (preferably a fused or bridged ring structure), wherein the alkylene group optionally contains a carbon-carbon double bond, and one or two methylene units therein are optionally and independently replaced by -O-, -S-, or -NR-. p is 1, 2, 3 or 4; preferably 1 or 2; preferably 1; R6 is selected from H, D, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl group; preferably H or D; R7 and R8 are independently selected from H, D, halogen, and C. 1-3 Alkyl and C 1-3 Halogenated alkyl; preferably C 1-3 Alkyl and C 1-3 Halogenated alkyl; preferably C 1-3 Alkyl; preferably Me; Or CR7R8 forms C 3-7 Cycloalkylene; preferably C 3-4 Cycloalkylene; preferably cyclopropylene; R 10 Selected from C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated alkyl, C 2-3 alkenyl and C 2-3 alkynyl group; R 11 Selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; The aforementioned groups are optionally deuterated, up to and including complete deuteration. The compound of claim 2 or 3, or its isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates, or pharmaceutically acceptable salts thereof, having the structure of formula (Ⅳ-1), (Ⅳ-2) or (Ⅳ-3): in, T1 is CH or N; R2 is selected from H, D, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl group; preferably H or D; R3 is selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably C 1-6 Halogenated alkyl groups; Or R2 and R3 can be connected to form C. 1-6 Alkylene, preferably C 1-4 Alkylene, which optionally contains a carbon-carbon double bond, and wherein one or two methylene units are optionally and independently replaced by -O-, -S- or -NR-; R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R5 is selected from C 3-7 Cycloalkyl, 3-7 membered heterocyclic, phenyl and 5-6 membered heteroaryl, preferably C 3-7 Cycloalkyl, 3-7-membered heterocyclic and 5-6-membered heteroaryl groups, optionally surrounded by 1, 2, 3 or 4 R groups. 5s replace; R 5s Independently selected from H, D, halogens, CN, C 1-6 Alkyl and C 1-6 Haloalkyl; preferably H, D and halogen (e.g. F); Or two Rs 5s They connect to form carbon-carbon double bonds; Or two Rs 5s Connect to form C 1-4 Alkylene (preferably C) 1-2 Alkylenes, preferably methylene, are used to form fused, bridged, or spirocyclic structures (preferably fused or bridged), wherein the alkylene optionally contains a carbon-carbon double bond, and one or two methylene units are optionally and independently replaced by -O-, -S-, or -NR-. R 10 Selected from C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated alkyl, C 2-3 alkenyl and C 2-3 Alkyne group; preferably C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 2-3 alkynyl group; R 11 Selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably C 1-6 alkyl; The aforementioned groups are optionally deuterated, up to and including complete deuteration; Preferably, T1 is CH or N; R2 is H; R3 is -CH2CF3; Or R2 and R3 can be connected to form -CH2CH2CH2-; R5 is selected from R 10 It is Me, -CD3, or ethynyl; R 11 For Me. The compound of claim 6, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein in formula (Ⅳ-1), (Ⅳ-2), or (Ⅳ-3): T1 is CH or N; preferably T1 is CH. R2 is selected from H, D, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl group; preferably H or D; R3 is selected from C 1-3 Alkyl and C 1-3 Halogenated alkyl; preferably C 1-3 Halogenated alkyl; more preferably -CH2CF3; Or R2 and R3 can be connected to form -CH2CH2CH2-; R5 is selected from C 5-7 Cycloalkyl group, which optionally contains a carbon-carbon double bond; preferably R5 is selected from C. 5-6 cycloalkyl groups, which optionally contain a carbon-carbon double bond; R 10 Selected from C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 2-3 Alkyne group; preferably R 10 For Me; R 11 Selected from C 1-3 Alkyl and C 1-3 Halogenated alkyl; preferably R 11 For Me; The aforementioned groups are optionally deuterated, up to and including complete deuteration; Preferably, T1 is CH; R2 is H; R3 is -CH2CF3; R5 is selected from R5 is preferably selected from R 10 For Me; R 11 For Me. The compound of claim 1 or 2, or its isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates, or pharmaceutically acceptable salts thereof, wherein: m and n are independently 1; X1, X2, and X3 are independently selected from -CH2-; L1 and L2 are independently selected from -CH2-; Ring A is selected from 3-10 member subheterocyclic groups; preferably... Ring B is selected from phenylene; it is optionally substituted with 1, 2, 3 or 4 R2 groups; Cyclic C is selected from 5-6 member heteroaryl groups; preferably... R2 is selected from -CH2CF3; Ring D is selected from 5-10 heteroaryl groups; preferably... R D Selected from 3-10 membered heterocyclic groups, which are optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 R4 groups; preferably, R4 is a heterocyclic group. D Selected from R4 is independently selected from cyclopropyl; a is 0; R5 is selected from C 3-10 cycloalkyl; r is 2, and two R6s are connected to form C. 1-6 Alkyl groups are used to form fused ring, bridged ring, or spiro ring structures; preferably, r is 2, and two R6 groups are linked to form a methylene group to form a 4-membered bridged ring. R7 and R8 are independently selected from Me; R9 is selected from -O-CH3; R 10 Selected from Me; R 11 Selected from Me; R 12 Selected from cyclopropyl or vinyl; The aforementioned groups are optionally deuterated, up to and including complete deuteration. The compound of claim 1, or its isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates, or pharmaceutically acceptable salts thereof, wherein: Ring D is selected from 5-10 heteroaryl groups; preferably... R D Selected from 3-10 membered heterocyclic groups, which are optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 R4 groups; preferably, R4 is a heterocyclic group. D Selected from Preferred R4 is selected from cyclopropyl; R 10 Selected from methyl, CD3 and acetylene; R 12 Selected from C 1-4 Cyclopropyl groups substituted with alkyl, vinyl, cyclopropyl, and methyl groups; preferably cyclopropyl groups substituted with ethyl, n-propyl, isopropyl, tert-butyl, vinyl, cyclopropyl, and methyl groups; preferably cyclopropyl groups not substituted with methyl groups. The compound of claim 1 or 9, or its isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates, or pharmaceutically acceptable salts thereof, wherein: m and n are independently 1; X1, X2, and X3 are independently selected from -CH2-; L1 and L2 are independently selected from -CH2-; Ring A is selected from 3-10 member subheterocyclic groups; preferably... Ring B is selected from phenylene; it is optionally substituted with 1, 2, 3 or 4 R2 groups; Cyclic C is selected from 5-6 member heteroaryl groups; preferably... R2 is selected from -CH2CF3; a is 0; R5 is selected from C 3-10 Cycloalkyl or 5-10-membered heteroaryl; preferably C 3-10 cycloalkyl; r is 2, and two R6s are connected to form C. 1-6 Alkyl groups are used to form fused ring, bridged ring, or spiro ring structures; preferably, r is 2, and two R6 groups are linked to form a methylene group to form a 4-membered bridged ring. R7 and R8 are independently selected from Me; R9 is selected from -O-CH3; R 11 Selected from Me. The compound of any one of claims 1-7 and 9-10, or its isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates, or pharmaceutically acceptable salts thereof, wherein: R5 is selected from C 3-7 Cycloalkyl, 3-7-membered heterocyclic or 5-6-membered heteroaryl; preferably selected from... The compound of any one of claims 1-11, or its isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates, or pharmaceutically acceptable salts thereof, wherein: R5 is C 3-7 cycloalkyl; preferably selected from More The compound of claim 12, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R5 is selected from The compound of claim 13, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R5 is selected from The compound of claim 13, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R5 is selected from The compound of claim 11, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein in formula (Ⅳ-1), (Ⅳ-2), or (Ⅳ-3): T1 is CH; R2 is H; R3 is -CH2CF3; R5 is C 3-7 cycloalkyl; preferably selected from R 10 For Me; R 11 For Me. The compound of claim 16, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein in formula (Ⅳ-1), (Ⅳ-2), or (Ⅳ-3): R5 is selected from The compound of claim 17, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein in formula (Ⅳ-1), (Ⅳ-2), or (Ⅳ-3): R5 is selected from... The compound of claim 17, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein in formula (Ⅳ-1), (Ⅳ-2), or (Ⅳ-3): R5 is selected from... The compound of any one of claims 1-19, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from one of the following compounds: Preferably, the compound is selected from one of the following compounds: A pharmaceutical composition comprising a compound of any one of claims 1-20, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, and optionally comprising other therapeutic agents. Use of any compound of claims 1-20, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 21, in the preparation of a medicament for the treatment or prevention of KRAS-mediated diseases. A method of treating or preventing KRAS-mediated disease in a subject, comprising administering to the subject a compound of any one of claims 1-20, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 21. The compound of any one of claims 1-20, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 21, for the treatment or prevention of KRAS-mediated diseases. The use of claim 22, the method of claim 23, or the use of the compound or pharmaceutical composition of claim 24, wherein the disease is a tumor (preferably with a KRAS mutation); preferably a solid tumor; preferably selected from pancreatic cancer, non-small cell lung cancer, and gastrointestinal tumors; the tumor is preferably selected from pancreatic cancer, non-small cell lung cancer, rectal cancer, or colorectal cancer.

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