Tricyclic compounds and their use

Abstract

The present invention relates to a tricyclic compound of formula (I) (wherein each variable is as defined herein), a pharmaceutical composition containing the same, a method for preparing the same, and the use thereof. TIFF2026519454000385.tif57170

Description

[Technical Field]

[0001] This invention relates to a tricyclic compound, a pharmaceutical composition containing the same, a method for preparing the same, and the use thereof. [Background technology]

[0002] The RAS (rat sarcoma virus) protein is a type of membrane-bound guanosine triphosphate hydrolase (GTP hydrolase), and currently, there are three known genes in the RAS family: KRAS, NRAS, and HRAS. The RAS protein functions as a molecular switch; it is activated and becomes "ON" when it binds to GTP, and inactivated and becomes "OFF" when GTP is hydrolyzed. This process is regulated by guanosine nucleotide exchange factors (GEFs) or GTPase-activating proteins (GAPs): GEFs promote the exchange of guanosine triphosphate (GTP) to guanosine diphosphate (GDP), while GAPs promote the hydrolysis of GTP. Studies have shown that the RAS gene has a high frequency of missense mutations in tumors, with three mutation hotspots: G12, G13, and Q61, respectively. These mutations allow the RAS protein to bind to GTP for extended periods, which leads to sustained activation of downstream effector signals and promotes tumor formation and growth. KRAS is an important member of the RAS family, and its main downstream signaling pathways include PI3K / AKT and RAF / MEK / ERK, which regulate various biological functions such as cell proliferation, apoptosis, and differentiation.

[0003] Abnormal activation of the RAS protein is closely associated with tumorigenesis, with KRAS mutations being the most common, accounting for approximately 85% of all cases, while NRAS and HRAS mutations account for 12% and 3%, respectively. KRAS mutations are predominant in pancreatic, colorectal, and lung cancers, NRAS mutations are more common in melanoma and acute myeloid leukemia, and HRAS mutations are more common in bladder and head and neck cancers. The most common KRAS mutation is the G12 mutation at codon 12, with G12C being the most common KRAS mutation in NSCLC patients, and KRAS G12D and KRAS G12V being the most common mutations in colorectal and pancreatic cancers. Amplification of the KRAS gene is also observed in various tumors, with an incidence of approximately 15% in esophageal adenocarcinoma and chromosomally unstable gastric cancer.

[0004] The close relationship between KRAS and tumors has drawn much attention to this target, but it took scientists over 30 years of research to make it a targetable protein. In May 2021, Amgen's KRAS G12C inhibitor Lumakras received early approval from the US FDA, marking a significant breakthrough in overcoming the "difficulty of treating" KRAS. However, the KRAS G12C patient population represents only a small fraction of KRAS mutation patients, and the majority of patients require drugs that target other KRAS mutations. Currently, there are no drugs that target mutations other than KRAS G12C approved worldwide. Therefore, the development of KRAS-targeted drugs, especially pan-KRAS-targeted drugs, is expected to have broad applications. [Overview of the project] [Means for solving the problem]

[0005] The present invention addresses the aforementioned needs in the art. The present invention provides a KRAS inhibitor that can significantly inhibit KRAS mutations or KRAS gene amplification. In some embodiments, the compound of the present invention is a mutant KRAS G12C inhibitor. In some embodiments, the compound of the present invention is a mutant KRAS G12D inhibitor. In some embodiments, the compound of the present invention is a mutant KRAS G12V inhibitor. In some embodiments, the compound of the present invention is a mutant KRAS G13D inhibitor. In some embodiments, the compound of the present invention is a mutant KRAS Q61H inhibitor. In some embodiments, the compound of the present invention is a KRAS gene amplification inhibitor. In some embodiments, the compound of the present invention is a pan-KRAS inhibitor. The compounds of the present invention can be used for the treatment or prevention of diseases having KRAS mutations or KRAS gene amplification, particularly cancer.

[0006] The present invention relates to a compound of formula (I):

Chemical formula

[0007] The aforementioned compounds and the active compounds disclosed in connection with the present invention (including compounds of general formulas and specific compounds), as well as their pharmaceutically acceptable salts, solvates, racemic mixtures, enantiomers, diastereomers or tautomers, are collectively referred to herein as "compounds of the present invention."

[0008] Furthermore, the present invention provides a pharmaceutical composition comprising the compound of the present invention and optionally comprising a pharmaceutically acceptable excipient.

[0009] The present invention also provides a method for inhibiting the activity of mutant KRAS protein in vivo or in vitro, which comprises contacting the mutant KRAS protein with an effective amount of the compound of the present invention.

[0010] The present invention also provides a method for treating or preventing diseases, particularly cancer, that have KRAS mutations or KRAS gene amplifications, which comprises administering an effective amount of the compound of the present invention to a subject in need.

[0011] The present invention also provides a method for treating or preventing cancer, particularly cancers having KRAS mutations or KRAS gene amplification, which comprises administering an effective amount of the compound of the present invention to a subject in need.

[0012] The present invention also provides for the use of the compounds of the present invention in the treatment or prevention of diseases having KRAS mutations or KRAS gene amplification, particularly cancer.

[0013] The present invention also provides for the use of the compounds of the present invention in the treatment or prevention of cancer, particularly cancers having KRAS mutations or KRAS gene amplification.

[0014] The present invention also provides for the use of the compounds of the present invention in the manufacture of pharmaceuticals for treating or preventing diseases having KRAS mutations or KRAS gene amplification, particularly cancer.

[0015] The present invention also provides for the use of the compounds of the present invention in the manufacture of pharmaceuticals for treating or preventing cancer, particularly cancers having KRAS mutations or KRAS gene amplification.

[0016] The present invention also provides compounds for inhibiting the activity of mutant KRAS proteins in vivo or in vitro.

[0017] The present invention also provides compounds of the present invention for use as pharmaceuticals.

[0018] The present invention also provides compounds of the present invention that are used as pharmaceuticals for treating or preventing diseases having KRAS mutations or KRAS gene amplification, particularly for treating or preventing cancer.

[0019] The present invention also provides a pharmaceutical composition comprising the compound of the present invention and at least one additional therapeutic agent, wherein the additional therapeutic agent is preferably selected from an antitumor agent, an anti-inflammatory agent, or an immunomodulator, wherein the antitumor agent includes chemotherapeutic agents, immune checkpoint inhibitors or agonists, and targeted therapeutic agents.

[0020] The present invention also provides a kit for treating or preventing diseases, particularly cancer, that have KRAS mutations or KRAS gene amplifications. The kit may include a pharmaceutical composition and instructions for use of the present invention, the pharmaceutical composition comprising a compound of the present invention. [Modes for carrying out the invention]

[0021] definition When used in this application, the following words, phrases, and symbols are intended to have the meanings described below, unless otherwise indicated by the context in which they are used.

[0022] A dash ("-") without a space between two letters or symbols is used to indicate a substituent bond. For example, -O(C 1~6 Alkyl) is C 1~6 This shows that the alkyl group is bonded to the rest of the molecule via the oxygen atom.

[0023] As used herein, the term "alkyl" refers to a group of 1 to 18 carbon atoms (C 1~18 This refers to a linear or branched saturated hydrocarbon group containing 1 to 10 carbon atoms (C 1~10 ), more preferably 1 to 6 carbon atoms (C 1~6 ), more preferably 1 to 4 carbon atoms (C1~4 ) or 1 to 3 carbon atoms (C 1~3 This refers to a straight-chain or branched saturated hydrocarbon group containing ). The term "alkyl" is preceded by the prefix "C". a~b If a is included, it means the number of carbon atoms in the alkyl group, where a is the minimum number of carbon atoms in the alkyl group and b is the maximum number of carbon atoms in the alkyl group. For example, "C 1~6 "Alkyl" refers to alkyl groups containing 1 to 6 carbon atoms. 1~3 "Alkyl" refers to an alkyl group containing 1 to 3 carbon atoms. 1~6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl, i-propyl), butyl (e.g., n-butyl, i-butyl, s-butyl, and t-butyl), pentyl (e.g., n-pentyl, i-pentyl, neopentyl), and hexyl. When used between two dashes ("-"), for example, -(C 1~6 Alkyl)-OH), where alkyl refers to alkylene.

[0024] As used herein, the term "alkylidene" refers to a divalent alkyl group as defined above, which is a linear or branched divalent hydrocarbon group having the formula :=CR'R'', bonded to the rest of the molecule by two single bonds on the same carbon atom, i.e., R' and R'' may be the same or different. In one embodiment, the alkylidene group has 1 to 6 carbon atoms (C 1~6 Alkylidene). In another embodiment, the alkylidene group is C 1~3 Alkyridene, C 1~2 It is an alkylidene, or a C1 alkylidene. 1~6 Examples of alkylidenes include, but are not limited to, methylidene (=CH2), ethylidene (=CHCH3), and propylidene (=CH-CH2-CH3).

[0025] As used herein, the term "alkylene" refers to the divalent group of an alkyl group as defined above, which is bonded to the rest of the molecule by two single bonds on the same or different carbon atoms, respectively. In one embodiment, the alkylene group has 1 to 6 carbon atoms (C 1~6 Alkylene). In another embodiment, the alkylene group is C 1~3 Alkylene, C 1~2 It is an alkylene or a C1 alkylene. 1~6 Examples of alkylenes include methylene (-CH2-), 1,2-ethylene (-CH2CH2-), 1,1-ethylene (-CH(CH3)-), 1,3-propylene (-CH2-CH2-CH2-), 1,1-propylene (-CH(CH2CH3)-), 2,2-propylene (-C(CH3)2-), 1,2-propylene (-CH(CH3)CH2-), and 1,4-butylene (-CH2-CH2-CH2-CH2-).

[0026] As used herein, the term "alkenyl" refers to a compound comprising one or more, for example, one, two, or three carbon-carbon double bonds (C=C) and two to 18 carbon atoms (C=C). 2~18 ), preferably 2 to 10 carbon atoms (C 2~10 ), more preferably 2 to 6 carbon atoms (C 2~6 ), more preferably 2 to 4 carbon atoms (C 2~4 This refers to a linear or branched unsaturated hydrocarbon group containing ). The term "alkenyl" is prefixed with "C". a~b If a is enclosed in quotation marks, this indicates the number of carbon atoms in the alkenyl, where a is the minimum number of carbon atoms in the alkenyl and b is the maximum number of carbon atoms in the alkenyl. For example, "C 2~6 "Alkenyl" refers to an alkenyl containing 2 to 6 carbon atoms. 2~4 "Alkenyl" refers to an alkenyl containing 2 to 4 carbon atoms. 2~6 Examples of alkenyls include, but are not limited to, vinyl, propenyl (e.g., 2-propenyl), and butenyl (e.g., 2-butenyl). The alkenyl bond may be located on or outside a double bond.

[0027] As used herein, the term "alkynyl" refers to a group consisting of one or more carbon-carbon triple bonds (C≡C) and 2 to 18 carbon atoms (C≡C). 2~18 ), preferably 2 to 10 carbon atoms (C 2~10 ), more preferably 2 to 6 carbon atoms (C 2~6 ), more preferably 2 to 4 carbon atoms (C 2~4 Refers to a linear or branched unsaturated hydrocarbon group containing ). The term "alkynyl" is prefixed with "C". a~b If a is included, it means the number of carbon atoms in the alkynyl, where a is the minimum number of carbon atoms in the alkynyl and b is the maximum number of carbon atoms in the alkynyl. For example, "C 2~6 "Alkynyl" refers to an alkynyl compound containing 2 to 6 carbon atoms. 2~4 "Alkynyl" refers to an alkynyl compound containing 2 to 4 carbon atoms. 2~6 Examples of alkynyls include, but are not limited to, ethynyl, propynyl (e.g., 2-propynyl), and butynyl (e.g., 2-butynyl). The alkynyl bond may be located either on or outside a triple bond.

[0028] As used herein, the terms "halogen" or "halo" mean fluoro, chloro, bromo, and iodine, preferably fluoro, chloro, and bromo, more preferably fluoro and chloro.

[0029] As used herein, the term “haloalkyl” refers to an alkyl group as defined herein, wherein one or more hydrogen atoms, e.g., 1, 2, 3, 4, 5, or all hydrogen atoms, are substituted with halogen atoms, and if one or more hydrogen atoms are substituted with halogen atoms, the halogen atoms may be the same or different. In one embodiment, the term “haloalkyl” as used herein refers to an alkyl group as defined herein, wherein two or more hydrogen atoms, e.g., 2, 3, 4, or 5, or all hydrogen atoms, are substituted with halogen atoms, where the halogen atoms are the same. In another embodiment, the term “haloalkyl” as used herein refers to an alkyl group as defined herein, wherein two or more hydrogen atoms, e.g., 2, 3, 4, or 5, or all hydrogen atoms, are substituted with halogen atoms, where the halogen atoms are different. The term “haloalkyl” is prefixed with “C a~b If a is included, it means the number of carbon atoms in the haloalkyl, where a is the minimum number of carbon atoms in the haloalkyl and b is the maximum number of carbon atoms in the haloalkyl. For example, "C 1~6 "Haloalkyl" refers to a haloalkyl as defined herein, containing 1 to 6 carbon atoms. 1~4 "Haloalkyl" refers to a haloalkyl group containing 1 to 4 carbon atoms as defined herein. 1~6 Examples of haloalkyl groups, though not limited to them, include -CF3, -CHF2, -CH2F, -CH2CH2F, -CH2CHF2, -CH2CF3, and -CH(CF3)2.

[0030] As used herein, the term "cycloalkyl" refers to a ring of 3 to 12 carbon atoms (C) 3~12 ), for example, 3 to 10 ring carbon atoms (C 3~10 ), 3 to 8 ring carbon atoms (C 3~8 ), 5-7 ring carbon atoms (C 5~7 ), 4-7 ring carbon atoms (C 4~7 ), or 3 to 6 ring carbon atoms (C 3~6This refers to a saturated or partially unsaturated cyclic hydrocarbon group having ) which may have one or more rings, for example, 1, 2, or 3 rings, preferably 1 or 2 rings. The term "cycloalkyl" is prefixed with "C". a~b If a is included, it means the number of carbon atoms in the cycloalkyl group, where a is the minimum number of carbon atoms in the cycloalkyl group and b is the maximum number of carbon atoms in the cycloalkyl group. For example, "C 3~8 "Cycloalkyl" or "3-8 membered cycloalkyl" refers to a cycloalkyl group containing 3 to 8 ring carbon atoms; "C 3~6 A “cycloalkyl” or “3- to 6-membered cycloalkyl” refers to a cycloalkyl group containing 3 to 6 ring carbon atoms. Cycloalkyls may include fused or bridging rings, or spiro rings. The rings of a cycloalkyl group are either saturated or have one or more (e.g., one or two) double bonds (i.e., partially unsaturated), but are not fully conjugated and are not aryl groups as defined herein. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2.2]pentyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl.

[0031] As used herein, the term "cycloalkylene" refers to the divalent group of a cycloalkyl group as defined above, which is bonded to the rest of the molecule via two single bonds on the same or different carbon atoms. Examples of cycloalkylenes include, but are not limited to, cyclopropylene (e.g., 1,1-cyclopropylene, 1,2-cyclopropylene), cyclobutylene (e.g., 1,1-cyclobutylene, 1,3-cyclobutylene), cyclopentylene, cyclohexylene, cyclopentenylene, cyclopentadienylene, and cyclohexenylene.

[0032] As used herein, the terms “heterocyclyl” and “heterocyclic” are interchangeable and refer to a saturated or partially unsaturated cyclic group having 3 to 14 ring atoms, e.g., 4 to 14 ring atoms (4 to 14-membered heterocyclyl), 4 to 12 ring atoms (4 to 12-membered heterocyclyl), 4 to 10 ring atoms (4 to 10-membered heterocyclyl), 3 to 8 ring atoms (3 to 8-membered heterocyclyl), 4 to 8 ring atoms (4 to 8-membered heterocyclyl), 3 to 6 ring atoms (3 to 6-membered heterocyclyl), or 4 to 5 ring atoms (4 to 5-membered heterocyclyl), and containing one or more heteroatoms (selected independently from N, O, and S) in the ring, with the remaining ring atoms being carbon; a heterocyclyl may have one or more rings, e.g., 1, 2, or 3, preferably 1 or 2 rings. Furthermore, heterocyclyls also include those in which the N or S heteroatom is oxidized to various arbitrary oxidation states. The bond site of the heterocyclyl may be on either the N heteroatom or the carbon. For example, “4-10 membered heterocyclil” refers to a heterocyclil having 4-10 (4, 5, 6, 7, 8, 9, or 10) ring atoms and containing at least one heteroatom independently selected from N, O, and S, for example, 1, 2, 3, or 4, preferably 1, 2, or 3; “3-8 membered heterocyclil” refers to a heterocyclil having 3-8 (3, 4, 5, 6, 7, or 8) ring atoms and containing at least one heteroatom independently selected from N, O, and S, for example, 1, 2, or 3, preferably 1 or 2; and “3-6 membered heterocyclil” refers to a heterocyclil having 3-6 (3, 4, 5, or 6) ring atoms and containing at least one heteroatom independently selected from N, O, and S (preferably N and O), preferably 1 or 2, which is preferably a monocyclic ring. Heterocyclils also include fused or bridging rings, or spirorings. The heterocyclyl ring may be saturated or have one or more (e.g., one or two) double bonds (i.e., partially unsaturated), but not fully conjugated, and is not a heteroaryl as defined herein.Examples of heterocyclines, though not limited to them, include: 4-10 member heterocyclines, 3-8 member heterocyclines, 3-6 member heterocyclines, and 4-5 member heterocyclines, e.g., oxetanil, azetidinil, pyrrolidinil, tetrahydrofuranil, dioxolanil, tetrahydropyranil, morpholinil, thiomorpholinil, piperidinil, piperazinil, tetrahydropyridyl, dihydropyrimidinil, dihydropyradinil, pyrazolidinil, hexahydro-1H-pyrrolidinil, hexahydrospiro[cyclopropane-pyrrolidinil] (e.g., tetrahydro-1'H,3 'H-spiro[cyclopropane-1,2'-pyrrolidinil], hexahydrospiro[cyclopropane-1,3'-pyrrolidinil], and hexahydrospiro[cyclopropane-1,1'-pyrrolidinil]), octahydrocyclopropa[a]pyrrolidinil, and oxaspiro[3,3]heptyl, preferably oxetanil, azetidinil, pyrrolidinil, tetrahydropyranil, morpholinil, piperidinil, piperazinil, hexahydro-1H-pyrrolidinil, tetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidinil], octahydrocyclopropa[a]pyrrolidinil.

[0033] As used herein, the terms “aryl” and “aromatic hydrocarbon” are interchangeable and refer to a carboncyclic hydrocarbon group having 6 to 14 carbon atoms (e.g., 6 to 14 carbon atoms (6-14 membered aryl), 6 to 12 carbon atoms (6-12 membered aryl), 6 to 10 carbon atoms (6-10 membered aryl)), which consists of one or more rings (e.g., two fused rings), where at least one ring is an aromatic ring. Examples of aryls include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, phenanthryl, indenyl, indanyl, azlenyl, and benzocyclobutenyl, with phenyl and naphthyl being preferred.

[0034] As used herein, the terms “heteroaryl” and “heteroaromatic ring” are interchangeable and refer to monocyclic, dicyclic, or tricyclic systems having 5 to 15 ring atoms (e.g., 5 to 14 ring atoms (5 to 14-membered heteroaryl), 5 to 13 ring atoms (5 to 13-membered heteroaryl), 5 to 12 ring atoms (5 to 12-membered heteroaryl), 5 to 6 ring atoms (5 to 6-membered heteroaryl), 8 to 13 ring atoms (8 to 13-membered heteroaryl), and 9 to 12 ring atoms (9 to 12-membered heteroaryl)), and containing one or more heteroatoms independently selected from N, O, and S, for example, 1, 2, 3, or 4, preferably 1, 2, or 3, with the remaining ring atoms being carbon, where at least one ring is an aromatic ring, and S and N may be optionally oxidized to various oxidation states. If the total number of S and O atoms in the heteroaryl group is greater than 1, the S and O heteroatoms are not adjacent to each other. Preferably, the heteroaryl is a heteroaryl ring with 5 to 13 members. For example, the heteroaryl includes: 5-6 membered monocyclic heteroaryls, i.e., monocyclic cyclic aromatic heterocyclic radicals having 5 or 6 ring atoms, wherein the ring atoms contain one or more heteroatoms independently selected from N, O, and S (preferably N), for example, 1, 2, or 3, and the remaining ring atoms are carbon atoms; and 8-13 membered bicyclic or tricyclic heteroaryl groups, i.e., bicyclic or tricyclic heteroaryl groups having 8, 9, 10, 11, 12, or 13 ring atoms, wherein the ring atoms include one or more heteroatoms independently selected from N, O, and S (preferably N), for example, 1, 2, 3, or 4, preferably 1, 2, or 3 heteroatoms, the remaining ring atoms are carbon atoms, and at least one ring is an aromatic ring.

[0035] Examples of heteroaryls include, but are not limited to, the following: 5-6 membered monocyclic heteroaryls, e.g., pyridyl, N-oxidepyridyl, pyrazinyl, pyrimidinyl, triazinyl (e.g., 1,2,4-triazinyl, 1,3,5-triazinyl), pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl), thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, triazolyl, thienyl, Franyl, pyranyl, pyrrolyl, pyridazinyl, preferably triazolyl, pyridyl, N-oxidepyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, imidazolyl, isoxazolyl, triazinyl (e.g., 1,2,4-triazinyl), oxazolyl, thiadiazolyl, more preferably pyridyl (e.g., pyridine-4-yl, pyridine-3-yl), pyrazinyl, pyridazinyl, pyrimidinyl; and 8-13 membered bicyclic or tricyclic heteroaryls, e.g., benzoxazolyl, benzoisoxazolyl, benzothienyl, Benzothiazolyl, benzoisothiazolyl, imidazopyrimidinil (e.g., imidazo[1,2-c]pyrimidinil), imidazopyrazinon (imidazo[1,2-a]pyrazinon and imidazo[1,5-a]pyrazinon), imidazopyridyl (imidazo[1,2-a]pyridyl, etc.), imidazopyridazinil (e.g., imidazo[1,2-b]pyridazinil), pyrrolopyrazinil (e.g., pyrroro[1,2-a]pyrazinon), pyrrolopyridyl (e.g., 1H-pyroro[2,3-b]pyridyl), pyrrolopyrimidinil (e.g., pyrroro[3,4-d]pyridyl) Limidinil), pyrazolopyrazine (e.g., pyrazolo[1,5-a]pyrazine), pyrazolopyridinil (e.g., 1H-pyrazolo[3,4-b]pyridinil), pyrazolopyrimidinil (e.g., pyrazolo[1,5-a]pyrimidinil), triazolopyrimidinil (e.g., [1,2,4]triazolo[4,3-c]pyrimidinil and [1,2,4]triazolo[1,5-c]pyrimidinil), triazolopyrazine (e.g., [1,2,4]triazolo[1,5-a]pyrazine), triazolopyridyl (e.g., [1,2,4]triazolo[4,[3-a]pyridyl and [1,2,4]triazolo[1,5-a]pyridyl), tetrazolopyridyl (e.g., tetrazolo[1,5-a]pyridyl), benzofuranil, benzimidazolyl, indolyl, indazolyl, prinyl, quinolyl, quinolinolyl (i.e., oxoquinolyl, e.g., 2-oxoquinolyl), tetrahydroquinolyl (e.g., 1,2,3,4-tetrahydroquinolyl), isoquinolinyl, tetrahydroisoquinolyl (e.g., 5,6,7,8-tetrahydroisoquinolyl), tetrahydronaphthilidinyl (e.g., 1,2 ,3,4-tetrahydro-2,7-naphthilidinyl), dihydro-cyclopentapyridyl (e.g., 6,7-dihydro-5H-cyclopenta[c]pyridyl), dihydro-pyrrolopyridyl (e.g., 2,3-dihydro-1H-pyrrolo[3,4-c]pyridyl), 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 1,2,3,4-tetrahydro-1,5-naphthilidinyl, benzoindazolyl (e.g., 1H-benzo[f]indazolyl), tetrahydrobenzoindazolyl (e.g., 5,6,7,8-tetrahydro-1H -benzo[f]indazolyl), pyrazoloquinolyl (e.g., 1H-pyrazolo[4,3-g]quinolyl), tetrahydrocyclopentaindazolyl (e.g., 1,5,6,7-tetrahydrocyclopenta[f]indazolyl), dihydrocyclopentaindazolyl (e.g., 1,7-dihydrocyclopenta[f]indazolyl), dihydroindenothiazolyl (e.g., 6,7-dihydro-5H-indeno[5,6-d]thiazolyl), hexahydroindenoxadinyl (e.g., 2,3,4,6,7,8-hexahydroindeno[5,6-b][1 ,4]oxazinyl), tetrahydrocyclopentaindolyl (e.g., 1,5,6,7-tetrahydrocyclopenta[f]indolyl), tetrahydroindenoimidazolyl (e.g., 1,5,6,7-tetrahydroindeno[5,6-d]imidazolyl), preferably indazolyl, indolyl, benzimidazolyl, benzothiazolyl, quinolyl, 2-oxoquinolyl, 1,2,3,4-tetrahydroquinolyl, isoquinolinyl, 5,6,7,8-tetrahydroisoquinolyl, 1,2,3,4-tetrahydro-2,7-naphthilidinyl, 6,7-Dihydro-5H-cyclopenta[c]pyridyl, 2,3-Dihydro-1H-pyrrolo[3,4-c]pyridyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-a]pyridyl, 1H-pyrrolo[2,3-b]pyridyl, [1,2,4]triazolo[1,5-a]pyridyl, 1,2,3,4-tetrahydro-1,5-naphthilidinyl, 1H-benzo[f]indazolyl, 5,6,7,8-tetrahydro-1H-benzo[f]indazolyl, 1H -Pyrazolo[4,3-g]quinolyl, 1,5,6,7-tetrahydrocyclopenta[f]indazolyl, 1,7-dihydrocyclopenta[f]indazolyl, 6,7-dihydro-5H-indeno[5,6-d]thiazolyl, 2,3,4,6,7,8-hexahydroindeno[5,6-b][1,4]oxazinyl), 1,5,6,7-tetrahydrocyclopenta[f]indolyl, 1,5,6,7-tetrahydroindeno[5,6-d]imidazolyl.

[0036] As used herein, the term "-OH" refers to a hydroxyl group.

[0037] As used herein, the term "-CN" refers to a cyano group.

[0038] As used herein, the term "oxo" refers to =O.

[0039] As used herein, the terms “any” or “optionally” mean that the events or situations described thereafter may or may not occur, and such descriptions include both cases in which such events or situations occur and cases in which they do not. For example, “may be optionally substituted with one or more substituents” includes both cases in which the group is not substituted with the substituents described. Those skilled in the art will understand that for any group containing one or more substituents, such group is not intended to introduce substitutions or substitution patterns that are sterically unrealizable, chemically inappropriate, synthetically unrealizable, and / or inherently unstable.

[0040] As used herein, the terms “substituted” or “substituted with…” mean that one or more (e.g., 1, 2, 3, or 4) hydrogen atoms on a designated atom or group are substituted with one or more (e.g., 1, 2, 3, or 4) substituents, preferably selected from the group of substituents or radicals shown, provided that the substituents do not exceed the normal valence of the designated atom. The substituents may be the same or different from each other. As used herein, the terms “substituted with a group selected from one or more…” or “substituted with one or more…” mean that one or more hydrogen atoms on a designated atom or group are independently substituted with one or more radicals from the group of substituents or radicals shown, in which case the radicals may be the same or different from each other. Preferably, “substituted with one or more groups selected from…” or “substituted with one or more groups” means that the specified atom or group is substituted with one, two, three, or four radicals independently selected from the group of substituents or radicals shown, in which case the radicals may be the same or different from each other. In some embodiments, when the substituent is oxo (i.e., =O), two hydrogen atoms on a single atom are substituted with oxo. Any substituent may be any radical, as long as the combination of substituent and / or variables results in a chemically correct and stable compound. A chemically correct and stable compound means a compound that withstands sufficient separation from the reaction mixture and is robust enough to allow identification of the chemical structure of the compound. Preferably, the substituents are those exemplified in the compounds of the examples of this application.

[0041] Unless otherwise specified, substituents are named in the form of the core structure. For example, if (cycloalkyl)alkyl is listed as a possible substituent, it should be understood that the bonding site of this substituent to the core structure is on the alkyl portion.

[0042] In this specification, where a structural formula is marked with an asterisk "*", it means that the chiral center at the position of the "*" in the compound is in a single configuration of (R) or (S) configuration; where the content of the single-configuration compound marked with "*" is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100%, or any value between these values). For example, some compounds of the present invention, such as the compound of formula (a) below, and their structural formulas contain an asterisk "*", which means that the compound is in a single configuration of the compound of formula (b) or the compound of formula (c). [ka]

[0043] A person skilled in the art ("POSITA") will recognize that a portion of the compounds of formula (I) may contain one or more chiral centers and therefore may exist in two or more stereoisomeric forms. Racemates of these isomers, individual isomers, and mixtures enriched with one enantiomer, as well as diastereomers in the case of two chiral centers, and mixtures partially enriched with a particular diastereomer, are included in the scope of the present invention. Furthermore, a POSITA will recognize that the present invention also includes all individual stereoisomers (e.g., enantiomers, diastereomers), racemic mixtures, or partially divided mixtures of the compounds of formula (I), and, where appropriate, their individual tautomeric forms.

[0044] As used herein, the term "stereoisomer" refers to a compound that has the same chemical composition but differs in the arrangement of atoms or groups in space. Stereoiomers include enantiomers, diastereomers, and the like.

[0045] As used herein, the terms “enantiomer” and “enantiomer form” are interchangeable and refer to two stereoisomers of a compound that cannot be superimposed on each other.

[0046] As used herein, the terms “diastereomer” and “diastereomer form” are interchangeable and refer to stereoisomers having two or more chiral centers whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectroscopic properties, or biological activity. Mixtures of diastereomers can be separated by high-resolution analytical methods such as electrophoresis or chromatography such as HPLC.

[0047] In some embodiments, the present invention provides compounds having various stereoisomer purities, i.e., enantiomer purities or diastereomer purities expressed by different "ee" or "de" values. In some embodiments, the compounds of formula (I) described herein have an enantiomer purity of at least 60% ee (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100% ee, or any value between these values). In some embodiments, the compounds of formula (I) described herein have an enantiomer purity greater than 99.9% ee. In some embodiments, the compounds of formula (I) described herein have a diastereomer purity of at least 60% de (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100% de, or any value between these values). In some embodiments, the compounds of formula (I) described herein have a diastereomer purity greater than 99.9% de.

[0048] "Enantiomer excess" or "ee" refers to the proportion of one enantiomer relative to the other. In the case of a mixture of R-type and S-type enantiomers, the percentage of enantiomer excess is defined as |RS|*100, where R and S are the mole fraction or weight fraction of each enantiomer in the mixture, and R+S=1. If the optical rotation of the chiral substance is known, the percentage of enantiomer excess is defined as ([a]obs / [a]max)*100, where [a]obs is the optical rotation of the enantiomer mixture and [a]max is the optical rotation of the pure enantiomer.

[0049] The term "diastereomer excess" or "de" refers to the amount of one diastereomer in excess of the other, and is defined by analogy based on the enantiomer excess. Thus, in the case of a mixture of diastereomers D1 and D2, the percentage of the diastereomer excess is defined as |D1-D2|*100, where D1 and D2 are the mole fraction or weight fraction of each diastereomer in the mixture, and D1+D2=1.

[0050] The diastereomer excess and enantiomer excess can be measured by several analytical techniques (such as nuclear magnetic resonance spectroscopy, chiral column chromatography, and / or optical polarization measurement) according to conventional protocols well known to those skilled in the art.

[0051] Racemates can be used as is or separated into individual isomers. This separation yields stereochemically pure compounds or mixtures enriched with one or more isomers. Methods for isomer separation are known (see Allinger NL and Eliel ELin, “Topics in Stereochemistry”, Vol. 6, Wiley Interscience, 1971), including physical methods such as chromatography using chiral adsorbents. Individual isomers can be prepared in chiral form from chiral precursors. Alternatively, individual isomers can be chemically separated from a mixture by forming diastereomer salts using chiral acids (e.g., 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), fractionating and crystallizing the salts, liberating one or both of the separated bases, and optionally repeating this process to obtain one or both of the isomers substantially free of the other (i.e., in a form with optical purity >95%). Alternatively, a racemic mixture can be covalently bonded to a chiral compound (auxiliary agent) to produce a diastereomer, which can then be separated by chromatography or fractional crystallization. After that, the chiral auxiliary agent can be chemically removed to obtain a pure enantiomer.

[0052] As used herein, the term "tautomer" refers to a structural isomer of a compound produced by the rapid motion of atoms at two positions within the molecule. Tautomers readily interconvert with each other; for example, enol and ketone forms are typical tautomers.

[0053] "Pharmacologically acceptable salt" is intended to mean a salt of a free acid or base of the compound of formula (I) that is nontoxic, bioacceptable, or otherwise biosuitable for administration to the target of treatment or prevention. For example, acid addition salts include salts obtained from inorganic and organic acids. For an overview, see, for example, SMBerge et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002.

[0054] Furthermore, if the compounds described herein are obtained as acid addition salts, free bases can also be obtained by basicizing the solution of the acid addition salt. Conversely, if the product is a free base, an acid chloride salt, particularly a pharmaceutically acceptable acid chloride salt, can be produced by dissolving the free base in a suitable solvent and then treating the solution with an acid, following conventional procedures for preparing acid addition salts from base compounds. POSITA will recognize a variety of synthetic methods that can be used without excessive experimentation to prepare non-toxic, pharmaceutically acceptable acid chloride salts or base addition salts.

[0055] A "solvate" refers to a solvation form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap solvent molecules in a fixed molar ratio in the solid state, thus forming solvates. If the solvent is water, the solvate formed is a hydrate; if the solvent is alcohol, the solvate formed is an alcolate. Hydrates are formed by one or more molecules of water, or a combination of less than one molecule of water and one molecule of another substance, where water retains its molecular state as H2O. Such combinations can form one or more hydrates, such as hemihydrates, monohydrates, and dihydrates.

[0056] The compounds of the present invention also include isotope-labeled compounds in which one or more atoms are substituted with atoms having atomic weights or mass numbers different from those normally found in nature. This specification envisions all isotopes of the specified atoms or elements, and their use. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, for example, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I is an example of a specific isotope-labeled compound of the present invention (for example, 3 H and 14 Tritium (labeled with 1C) is useful in compound and / or substrate tissue distribution assays. 3 H) and carbon 14 (i.e., 14 C) Isotopes are particularly useful for this purpose because they are easy to prepare and detect. Furthermore, deuterium (i.e., 2 Substitution with heavier isotopes such as H) may be preferable in some situations because it can result in certain therapeutic benefits due to improved metabolic stability (e.g., increased in vivo half-life or reduced dose). 1 H) atom deuterium ( 2 It will be understood that substitution with H atoms yields deuterated compounds. Any number of hydrogen atoms in any compound of formula (I) may be substituted with an equal number of deuterium atoms. The isotope-labeled compounds of formula (I) can generally be prepared by the prior art well known to those skilled in the art, or by a process similar to that described in the following examples, using a suitable isotope-labeling reagent instead of an unlabeled reagent.

[0057] As used herein, the terms “group” and “radical” are synonymous and are intended to refer to a functional group or molecular fragment that can be bound to other molecular fragments.

[0058] The term "active ingredient" is used to refer to a chemical substance that has biological activity. In some embodiments, the "active ingredient" is a chemical substance that has pharmaceutical utility.

[0059] As used herein, the term “pharmaceutical combination” means a product obtained by mixing or combining two or more active ingredients, and includes immobilized and non-immobilized combinations of active ingredients (e.g., kits) and pharmaceutical compositions. “Immobilized combination” means that two or more active ingredients (e.g., the compound of the present invention and an additional therapeutic agent) are administered simultaneously to a patient in the form of a single entity or dose. “Non-immobilized combination” means that two or more active ingredients (e.g., the compound of the present invention and an additional therapeutic agent) are administered simultaneously, in parallel, or sequentially to a patient as separate entities, thereby providing the patient with a therapeutically effective level of the compound.

[0060] The terms “treating,” “treating,” or “preventing” a disease or disorder refer to administering one or more pharmaceutical substances, particularly the compounds of the present invention, to a subject having a disease or disorder, a subject having symptoms of a disease or disorder, or a subject having a predisposition to a disease or disorder, for the purpose of curing, promoting healing, alleviating, reducing, improving, modifying, enhancing, or influencing the disease or disorder, the symptoms of a disease or disorder, or the predisposition to a disease or disorder, in connection with achieving a therapeutic effect. In some embodiments, the disease or disorder is cancer, such as a solid tumor or hematological malignancy.

[0061] In relation to chemical reactions, the terms “treat,” “contact,” and “react” mean adding or mixing two or more reagents under appropriate conditions to produce the indicated and / or desired product. It should be noted, however, that the reaction producing the indicated and / or desired product does not necessarily result directly from the combination of the two reagents initially added; rather, one or more intermediates may be formed in the mixture, ultimately leading to the formation of the indicated and / or desired product.

[0062] As used herein, the term “effective dose” refers to a quantity or dosage of a KRAS inhibitor that is generally sufficient to provide a therapeutic benefit in patients requiring treatment or prevention of a disease or disorder involving a KRAS mutation or KRAS gene amplification. The effective dose or dosage of the active ingredient in this disclosure may be determined by methods such as modeling, dose escalation studies, or clinical trials, and by taking into account factors such as the method or route of administration or drug delivery, the pharmacokinetics of the drug, the severity and course of the disease or disorder, the patient’s treatment history or ongoing treatment, the patient’s health status and response to the drug, and the judgment of the attending physician.

[0063] Exemplary dosages range from approximately 0.0001 to 200 mg of the active ingredient per kg of body weight per day, for example, in single or divided dose units (e.g., BID, TID, QID), approximately 0.001 to 100 mg / kg / day, or approximately 0.01 to 35 mg / kg / day, or approximately 0.1 to 10 mg / kg / day. For a 70 kg person, an exemplary range of appropriate dosages is approximately 0.05 to 7 g / day, or approximately 0.2 to 5 g / day. Once improvement in the patient's disease or disorder is observed, the dosage may be adjusted for maintenance treatment. For example, depending on the symptoms, the dosage, frequency of administration, or both may be reduced to a level that maintains the desired therapeutic effect. Of course, treatment can be discontinued once symptoms have subsided to an appropriate level. However, if symptoms recur, the patient may require long-term intermittent treatment.

[0064] The terms “inhibition” or “inhibiting” refer to a decrease in baseline activity of a biological activity or process. The term “inhibition of mutant KRAS protein activity” is a practical pharmaceutically active activity for the purposes of this disclosure and refers to a decrease in the activity of mutant KRAS protein as a direct or indirect response to the presence of the compound of the present invention, compared to the activity of mutant KRAS protein in the absence of the compound of the present invention. This decrease in activity may be due to a direct interaction between the compound of the present invention and mutant KRAS protein, or to an interaction between the compound of the present invention and one or more other factors that consequently affect the activity of mutant KRAS protein. For example, the presence of the compound of the present invention may reduce the activity of mutant KRAS protein by directly binding to the mutant KRAS protein, by another factor causing a decrease in mutant KRAS protein activity, or by (directly or indirectly) reducing the amount of mutant KRAS protein present in a cell or organism.

[0065] As used herein, the terms “subject” or “patient” mean mammals and non-mammals. Mammals mean all members of the class Mammalia, including, but not limited to, humans; non-human primates such as chimpanzees or other apes and monkey species; domestic animals such as cattle, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; and laboratory animals including rodents such as rats, mice, and guinea pigs. Examples of non-mammals include, but not limited to, birds. The terms “subject” or “patient” do not indicate a specific age or sex. In some embodiments, the subject or patient is human.

[0066] Generally, the term "approximately" in this specification is used to correct for a range of variation of up to 20% above or below the stated figures.

[0067] Technical and scientific terms used herein, unless otherwise defined, have the meanings generally understood by POSITA in relation to this disclosure.

[0068] All numerical ranges in this specification, unless otherwise stated, shall be interpreted as disclosing each numerical value and subset of numerical values ​​within that range. For example, when referring to any range of values, it shall be considered to refer to all values ​​within that range, for example, all integers within that range. For example, C as used herein 1~6 This represents the inclusion of 1, 2, 3, 4, 5, or 6 Cs. The present invention relates to all values ​​included within a range, all smaller ranges, and upper or lower limits of numerical ranges.

[0069] Detailed description of the embodiment Embodiment 1. Formula (I): [ka] (In the formula, X is O, NR 11 , CR 15 R 16 , C(O), S, S(O), or S(O)2; R 11 These are, independently, hydrogen and C 1~6 Alkyl, C 1~6 Haloalkyl, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-CN,-CO(C 1~6 Alkyl), -CONH2, -CONH(C 1~6 Alkyl), -CON(C 1~6 Alkyl)2, C 3~8 Selected from cycloalkyl and 3- to 8-membered heterocyclines; R 15 and R 16 These are, independently, hydrogen, deuterium, halogen, -CN, -OH, -NH2, and C. 1~6 Alkyl, C 1~6 Haloalkyl, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-CN,-O(C1~6 Alkyl), -O(C 1~6 Haloalkyl), -NH(C 1~6 Alkyl), -N(C 1~6 Alkyl)2,-CO(C 1~6 Alkyl), -CONH2, -CONH(C 1~6 Alkyl), -CON(C 1~6 Alkyl)2, C 3~8 Selected from cycloalkyls and 3- to 8-membered heterocyclines; or R 15 and R 16 C 3~6 Forming cycloalkyl or 3-6 membered heterocyclines; Y is N and Z is N; or Y is C-CN and Z is N, or Z is CR2; [ka] This represents a double bond or a single bond, [ka] When R6 represents a double bond, R6 and R8 do not exist; p is 0, 1, or 2; R1 is -L1-R 18 and; L1 does not exist, or L1 is NR 11 , O, C(O), S, S(O), or S(O)2; R 18 These are 6-14 member aryls, 5-14 member heteroaryls, and C 3~10 Selected from cycloalkyls and 4- to 14-membered heterocyclines, each of which can optionally be: halogen, -CN, -OH, -SH, -SF5, oxo, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C1~6 Alkyl)-CN,-O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -O(C 3~8 Cycloalkyl), -O (3-8 member heterocyclyl), -S (C 1~6 Alkyl), -S(C 1~6 Haloalkyl), -S(C 3~8 Cycloalkyl, -S (3-8 member heterocyclyl), -OC(O)NR a R b , -NR a C(O)OR c , -NR a C(O)R d , -NR a R b -C(O)NR a R b , -C(O)OR c , -C(O)R d -S(O)2R f , and -S(O)2NR a R b It may be substituted with one or more elements selected independently from; where C 1~6 The alkyl group may optionally be substituted with one or more deuterium atoms, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~8 The cycloalkyl and 3- to 8-membered heterocyclyl compounds may each be optionally substituted with one or more halogens; R2 is hydrogen, halogen, -CN, -OH, -SH, oxo, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 Alkyl)-CN,-O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -O(C 3~8Cycloalkyl), -O (3-8 member heterocyclyl), -S (C 1~6 Alkyl), -S(C 1~6 Haloalkyl), -S(C 3~8 Cycloalkyl, -S (3-8 member heterocyclyl), -OC(O)NR a R b , -NR a C(O)OR c , -NR a C(O)R d , -NR a R b -C(O)NR a R b , -C(O)OR c , -C(O)R d -S(O)2R f , and -S(O)2NR a R b Selected from; where C 1~6 The alkyl group may optionally be substituted with one or more deuterium atoms, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~8 The cycloalkyl and 3- to 8-membered heterocyclyl compounds may each be optionally substituted with one or more halogens; R3 is hydrogen, -OH, -SH, -NH2, C 1~6 Alkyl, C 1~6 Haloalkyl, -O(C) 1~6 Alkyl), -O(C 1~6 Alkyl), -S(C 1~6 Alkyl), -S(C 1~6 Haloalkyl), -NH(C 1~6 Alkyl), -N(C 1~6 Alkyl)2, C 3~8 Cycloalkyl, 4-10 membered heterocyclyl, and -O-L2-R 12 Selected from; where C 3~8 Cycloalkyls and 4-10 membered heterocyclines can be optionally: deuterium, halogen, -CN, -OH, -SH, oxo, -NH2, C 1~6 Alkyl, C 1~6 Alkyridene, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6Haloalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 Alkyl)-CN,-O(C 1~6 Alkyl), and -S(C 1~6 It may be substituted with one or more groups independently selected from alkyl, where C 1~6 Alkylidene may optionally be substituted with one or more halogens; L2 does not exist, or L2 is C 1~6 Alkylene or C 3~8 It is a cycloalkylene, and here, C 1~6 Alkylene and C 3~8 Each cycloalkylene may optionally be substituted with one or more deuterium atoms or halogens; R 12 C 3~10 A cycloalkyl or 4-12 member heterocycline, each optionally comprising: deuterium, halogen, -CN, -OH, -SH, oxo, C 1~6 Alkyl, C 1~6 Alkyridene, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -O(C 3~8 Cycloalkyl), -O (3-8 member heterocyclyl), -S (C 1~6 Alkyl), -S(C 1~6 Haloalkyl), -S(C 3~8 Cycloalkyl, -S (3-8 member heterocyclyl), -OC(O)NR a R b , -NR a C(O)OR c , -NR a C(O)R d, -NR a R b -C(O)NR a R b , -C(O)OR c , -C(O)R d -S(O)2R f , and -S(O)2NR a R b It may be substituted with one or more elements selected independently from; where C 1~6 Alkyl, C 1~6 Alkyridene, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~8 Cycloalkyls and 3- to 8-membered heterocyclines may each optionally contain one or more R groups. 17 It may also be replaced with; R 17 Deuterium, halogen, -CN, -OH, -SH, oxo, C 1~6 Alkyl, C 1~6 Alkyridene, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 Alkyl)-CN,-O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -S(C 1~6 Alkyl), -S(C 1~6 Haloalkyl), -NR a R b ,-NHCO(C 1~6 Alkyl), -CO(C 1~6 Alkyl), -CONH2, -CONH(C 1~6 Alkyl), -CON(C 1~6 Alkyl)2,-S(O)2(C 1~6 Alkyl), -S(O)2NH(C 1~6 Alkyl, and S(O)2N(C 1~6Selected from alkyl)2; where 3- to 8-membered heterocyclyl, optionally: deuterium, halogen, -CN, -OH, oxo, -NH2, C 1~6 Alkyl, C 1~6 Alkyridene, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 Alkyl)-CN,-O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -S(C 1~6 Alkyl), -S(C 1~6 Haloalkyl), -CO(C 1~6 Alkyl), and -S(O)2(C 1~6 It may be substituted with one or more groups independently selected from alkyl groups; R4 is C 1~6 Alkyl, C 2~6 Alkenil, C 3~10 Selected from cycloalkyl, 4-12 membered heterocyclyl, and 5-12 membered heteroaryl, each optionally containing one or more R 13 It may also be replaced with; R 13 Deuterium, halogen, -CN, -OH, -SH, oxo, -NH2, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 Alkyl)-CN,-O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -S(C 1~6 Alkyl), -S(C1~6 Haloalkyl), -NHCO(C 1~6 Alkyl), -NH(C 1~6 Alkyl), -N(C 1~6 Alkyl)2,-CO(C 1~6 Alkyl), -CONH2, -CONH(C 1~6 Alkyl), -CON(C 1~6 Alkyl)2,-S(O)2(C 1~6 Alkyl), -S(O)2NH(C 1~6 Alkyl), and -S(O)2N(C 1~6 Selected from alkyl)2; where C 3~8 Cycloalkyls, 3-8 membered heterocyclines, 6-10 membered aryls, and 5-10 membered heteroaryls may each optionally contain one or more R 14 It may also be replaced with; R 14 These are independently deuterium, halogen, -CN, -OH, -SH, oxo, and C. 1~6 Alkyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 Alkyl)-CN,-O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -O(C 3~8 Cycloalkyl), -O (3-8 member heterocyclyl), -S (C 1~6 Alkyl), -S(C 1~6 Haloalkyl), -S(C 3~8 Cycloalkyl, -S (3-8 member heterocyclyl), -NR a C(O)R d , -NR a R b -C(O)NR a R b , -C(O)OR c , -C(O)R d -S(O)2R f , and -S(O)2NR a R bSelected from; where C 1~6 The alkyl group may be optionally substituted with one or more deuterium atoms, C 3~8 Cycloalkyls, 3- to 8-membered heterocyclines, phenyls, and 5- to 6-membered heteroaryls may each be optionally substituted with one or more halogens; R5, R6, R7, R8, R9 and R 10 These are, independently, hydrogen, deuterium, halogen, -CN, -OH, -SH, oxo, -NH2, and C. 1~6 Alkyl, C 1~6 Haloalkyl, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-CN,-O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -NH(C 1~6 Alkyl), -N(C 1~6 Alkyl)2,-CO(C 1~6 Alkyl), -CONH2, -CONH(C 1~6 Alkyl), -CON(C 1~6 Alkyl)2, C 3~8 Selected from cycloalkyls and 3- to 8-membered heterocyclines; or R5 and R6, R7 and R8, R9 and R 10 R5 and R7, R7 and R9, or R5 and R9, together with the carbon atom they bond to, C 3~6 Forming cycloalkyl or 3-6 membered heterocyclines; Alternatively, R4 and R5, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 12-membered heteroaryl, which can optionally contain one or more R 14 It may also be replaced with; Alternatively, R4 and R5, together with the nitrogen and carbon atoms to which they bond, form a 4- to 10-membered heterocycline; where a 4- to 10-membered heterocycline is defined as follows: C 3~8They may be substituted with one or more groups independently selected from cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; 4-10 membered heterocyclyls may further be substituted with: deuterium, halogen, -CN, -OH, -SH, oxo, -NH2, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 Alkyl)-CN,-O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -S(C 1~6 Alkyl), -S(C 1~6 Haloalkyl), -NHCO(C 1~6 Alkyl), -NH(C 1~6 Alkyl), -N(C 1~6 Alkyl)2,-CO(C 1~6 Alkyl), -CONH2, -CONH(C 1~6 Alkyl), -CON(C 1~6 Alkyl)2,-S(O)2(C 1~6 Alkyl), -S(O)2NH(C 1~6 Alkyl), and -S(O)2N(C 1~6 The alkyl group may be optionally substituted with one or more groups independently selected from the alkyl group; where C 3~8 Cycloalkyls, 3-8 membered heterocyclines, 6-10 membered aryls, and 5-10 membered heteroaryls may each optionally contain one or more R 14 It may also be replaced with; R a , R b , R c , R d and R f These are, independently, hydrogen and C 1~6 Alkyl, C 3~8 Selected from cycloalkyl, 3-8 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl; where C 1~6 Alkyl, C 3~8Cycloalkyls, 3-8 membered heterocyclines, phenyls, and 5-6 membered heteroaryls can be optionally: halogens, -CN, -OH, -O(C) 1~6 Alkyl), C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, -NR g R h -C(O)NR g R h , and -NR g C(O)R i It may be substituted with one or more elements independently selected from; where R g , R h and R i These are, independently, hydrogen and C 1~6 Alkyl, C 1~6 Haloalkyl, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-CN,-(C 1~6 Alkyl)-NH2,-(C 1~6 Alkyl)-NH(C 1~6 Alkyl), -(C 1~6 Alkyl)-N(C 1~6 Alkyl)2, C 3~8 Independently selected from cycloalkyl, 3-8 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl; or R a and R b (These, along with the nitrogen atom to which they bond, form 3- to 8-membered heterocyclines.) Compounds thereof or pharmaceutically acceptable salts thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers thereof.

[0070] Embodiment 2.X is O, NR 11 , CR 15 R 16 , C(O), S, S(O), or S(O)2; R 11 These are, independently, hydrogen and C 1~6 Alkyl, C 1~6 Haloalkyl, -(C 1~6 Alkyl)-O-(C1~6 Alkyl), -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-CN,-CO(C 1~6 Alkyl), -CONH2, -CONH(C 1~6 Alkyl), -CON(C 1~6 Alkyl)2, C 3~8 Selected from cycloalkyl and 3- to 8-membered heterocyclines; R 15 and R 16 These are, independently, hydrogen, deuterium, halogen, -CN, -OH, -NH2, and C. 1~6 Alkyl, C 1~6 Haloalkyl, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-CN,-O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -NH(C 1~6 Alkyl), -N(C 1~6 Alkyl)2,-CO(C 1~6 Alkyl), -CONH2, -CONH(C 1~6 Alkyl), -CON(C 1~6 Alkyl)2, C 3~8 Selected from cycloalkyls and 3- to 8-membered heterocyclines; or R 15 and R 16 C 3~6 Forming cycloalkyl or 3-6 membered heterocyclines; Y is N and Z is N; or Y is C-CN and Z is N, or Z is CR2; [ka] This represents a double bond or a single bond, [ka] When R6 represents a double bond, R6 and R8 do not exist; p is 0, 1, or 2; R1 is -L1-R 18 and; L1 does not exist, or L1 is NR 11 , O, C(O), S, S(O), or S(O)2; R 18 These are 6-12 member aryls, 5-12 member heteroaryls, and C 3~10 Selected from cycloalkyls and 4- to 12-membered heterocyclines, each optionally consisting of: halogen, -CN, -OH, -SH, oxo, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 Alkyl)-CN,-O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -O(C 3~8 Cycloalkyl), -O (3-8 member heterocyclyl), -S (C 1~6 Alkyl), -S(C 1~6 Haloalkyl), -S(C 3~8 Cycloalkyl, -S (3-8 member heterocyclyl), -OC(O)NR a R b , -NR a C(O)OR c , -NR a C(O)R d , -NR a R b -C(O)NR a R b , -C(O)OR c , -C(O)R d -S(O)2R f , and -S(O)2NR a R b It may be substituted with one or more elements selected independently from; where C 1~6 The alkyl group may optionally be substituted with one or more deuterium atoms, C 2~6 Alkenil, C 2~6Alkinyl, C 3~8 The cycloalkyl and 3- to 8-membered heterocyclyl compounds may each be optionally substituted with one or more halogens; R2 is hydrogen, halogen, -CN, -OH, -SH, oxo, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 Alkyl)-CN,-O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -O(C 3~8 Cycloalkyl), -O (3-8 member heterocyclyl), -S (C 1~6 Alkyl), -S(C 1~6 Haloalkyl), -S(C 3~8 Cycloalkyl, -S (3-8 member heterocyclyl), -OC(O)NR a R b , -NR a C(O)OR c , -NR a C(O)R d , -NR a R b -C(O)NR a R b , -C(O)OR c , -C(O)R d -S(O)2R f , and -S(O)2NR a R b Selected from; where C 1~6 The alkyl group may optionally be substituted with one or more deuterium atoms, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~8 The cycloalkyl and 3- to 8-membered heterocyclyl compounds may each be optionally substituted with one or more halogens; R3 is hydrogen, -OH, -SH, -NH2, C 1~6 Alkyl, C 1~6Haloalkyl, -O(C) 1~6 Alkyl), -O(C 1~6 Haloalkyl), -S(C 1~6 Alkyl), -S(C 1~6 Haloalkyl), -NH(C 1~6 Alkyl), -N(C 1~6 Alkyl)2, C 3~8 Cycloalkyl, 4-10 membered heterocyclyl, and -O-L2-R 12 Selected from; where C 3~8 Cycloalkyls and 4-10 membered heterocyclines can be optionally: deuterium, halogen, -CN, -OH, -SH, oxo, -NH2, C 1~6 Alkyl, C 1~6 Alkyridene, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 Alkyl)-CN,-O(C 1~6 Alkyl), and -S(C 1~6 It may be substituted with one or more groups independently selected from alkyl, where C 1~6 Alkylidene may optionally be substituted with one or more halogens; L2 does not exist, or L2 is C 1~6 Alkylene or C 3~8 It is a cycloalkylene, and here, C 1~6 Alkylene and C 3~8 Each cycloalkylene may optionally be substituted with one or more deuterium atoms or halogens; R 12 C 3~10 The cycloalkyl or 4-12 member heterocycline, each optionally comprising: deuterium, halogen, -CN, -OH, -SH, oxo, C 1~6 Alkyl, C 1~6 Alkyridene, C 2~6 Alkenil, C 2~6Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, 3- to 8-membered heterocyclyl, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -O(C 3~8 Cycloalkyl), -O(3- to 8-membered heterocyclyl), -S(C 1~6 Alkyl), -S(C 1~6 Haloalkyl), -S(C 3~8 Cycloalkyl), -S(3- to 8-membered heterocyclyl), -OC(O)NR a R b , -NR a C(O)OR c , -NR a C(O)R d , -NR a R b , -C(O)NR a R b , -C(O)OR c , -C(O)R d , -S(O)2R f , and -S(O)2NR a R b may be substituted with one or more groups independently selected from; wherein, C 1~6 Alkyl, C 1~6 Alkylidene, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl and 3- to 8-membered heterocyclyl may each optionally be substituted with one or more R 17 ; R 17 is deuterium, halogen, -CN, -OH, -SH, oxo, C 1~6 Alkyl, C 1~6 Alkylidene, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, 3- to 8-membered heterocyclyl, -(C 1~6 Alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6alkyl), -(C 1~6 alkyl)-CN, -O(C 1~6 alkyl), -O(C 1~6 haloalkyl), -S(C 1~6 alkyl), -S(C 1~6 haloalkyl), -NR a R b , -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CONH2, -CONH(C 1~6 alkyl), -CON(C 1~6 alkyl)2, -S(O)2(C 1~6 alkyl), -S(O)2NH(C 1~6 alkyl), and S(O)2N(C 1~6 alkyl)2; is selected from R4 is C 1~6 alkyl, C 2~6 alkenyl, C 3~10 cycloalkyl, 4- to 12-member heterocyclyl and 5- to 12-member heteroaryl, each of which may optionally be substituted with one or more R 13 ; R 13 is deuterium, halogen, -CN, -OH, -SH, oxo, -NH2, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 haloalkyl, C 3~8 cycloalkyl, 3- to 8-member heterocyclyl, 6- to 10-member aryl, 5- to 10-member heteroaryl, -(C 1~6 alkyl)-OH, -(C 1~6 alkyl)-O-(C 1~6 alkyl), -(C 1~6 alkyl)-CN, -O(C 1~6 alkyl), -O(C 1~6 haloalkyl), -S(C 1~6 alkyl), -S(C 1~6 haloalkyl), -NHCO(C 1~6 alkyl), -NH(C 1~6 alkyl), -N(C 1~6 alkyl)2, -CO(C 1~6Alkyl), -CONH2, -CONH(C 1~6 Alkyl), -CON(C 1~6 Alkyl)2,-S(O)2(C 1~6 Alkyl), -S(O)2NH(C 1~6 Alkyl), and -S(O)2N(C 1~6 Selected from alkyl)2; where C 3~8 Cycloalkyls, 3-8 membered heterocyclines, 6-10 membered aryls, and 5-10 membered heteroaryls may each optionally contain one or more R 14 It may also be replaced with; R 14 These are independently deuterium, halogen, -CN, -OH, -SH, oxo, and C. 1~6 Alkyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 Alkyl)-CN,-O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -O(C 3~8 Cycloalkyl), -O (3-8 member heterocyclyl), -S (C 1~6 Alkyl), -S(C 1~6 Haloalkyl), -S(C 3~8 Cycloalkyl), -S (3-8 member heterocyclyl), -NHCO(C 1~6 Alkyl), -NR a R b -C(O)NR a R b , -C(O)OR c , -C(O)R d -S(O)2R f , and -S(O)2NR a R b Selected from; where C 1~6 The alkyl group may be optionally substituted with one or more deuterium atoms, and C 3~8Cycloalkyls, 3- to 8-membered heterocyclines, phenyls, and 5- to 6-membered heteroaryls may each be optionally substituted with one or more halogens; R5, R6, R7, R8, R9 and R 10 These are, independently, hydrogen, deuterium, halogen, -CN, -OH, -SH, oxo, -NH2, and C. 1~6 Alkyl, C 1~6 Haloalkyl, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-CN,-O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -NH(C 1~6 Alkyl), -N(C 1~6 Alkyl)2,-CO(C 1~6 Alkyl), -CONH2, -CONH(C 1~6 Alkyl), -CON(C 1~6 Alkyl)2, C 3~8 Selected from cycloalkyls and 3- to 8-membered heterocyclines; or R5 and R6, R7 and R8, R9 and R 10 R5 and R7, R7 and R9, or R5 and R9, together with the carbon atom they bond to, C 3~6 Forming cycloalkyl or 3-6 membered heterocyclines; Alternatively, R4 and R5, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 12-membered heteroaryl, which can optionally contain one or more R 14 It may also be replaced with; Alternatively, R4 and R5, together with the nitrogen and carbon atoms to which they bond, form a 4- to 10-membered heterocycline; where a 4- to 10-membered heterocycline is defined as follows: C 3~8 They may be substituted with one or more groups independently selected from cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; 4-10 membered heterocyclyl may further be: deuterium, halogen, -CN, -OH, -SH, oxo, -NH2, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6Alkinyl, C 1~6 Haloalkyl, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 Alkyl)-CN,-O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -S(C 1~6 Alkyl), -S(C 1~6 Haloalkyl), -NHCO(C 1~6 Alkyl), -NH(C 1~6 Alkyl), -N(C 1~6 Alkyl)2,-CO(C 1~6 Alkyl), -CONH2, -CONH(C 1~6 Alkyl), -CON(C 1~6 Alkyl)2,-S(O)2(C 1~6 Alkyl), -S(O)2NH(C 1~6 Alkyl), and -S(O)2N(C 1~6 The alkyl group may be optionally substituted with one or more groups independently selected from the alkyl group; where C 3~8 Cycloalkyls, 3-8 membered heterocyclines, 6-10 membered aryls, and 5-10 membered heteroaryls may each optionally contain one or more R 14 It may also be replaced with; R a , R b , R c , R d and R f These are, independently, hydrogen and C 1~6 Alkyl, C 3~8 Selected from cycloalkyl, 3-8 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl; where C 1~6 Alkyl, C 3~8 Cycloalkyls, 3-8 membered heterocyclyls, phenyls, and 5-6 membered heteroaryls can be optionally: halogens, -CN, -OH, -O(C) 1~6 Alkyl), C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, -NR g R h , and -NR g C(O)R iIt may be substituted with one or more elements independently selected from; where R g , R h and R i These are, independently, hydrogen and C 1~6 Alkyl, C 1~6 Haloalkyl, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-CN,-(C 1~6 Alkyl)-NH2,-(C 1~6 Alkyl)-NH(C 1~6 Alkyl), -(C 1~6 Alkyl)-N(C 1~6 Alkyl)2, C 3~8 Compounds described in Embodiment 1 or pharmaceutically acceptable salts thereof, independently selected from cycloalkyl, 3-8 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, or solvates, racemic mixtures, enantiomers, diastereomers, or tautomers thereof.

[0071] Embodiment 3. A compound described in Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein X is O.

[0072] Embodiment 4. A compound according to Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein Y is N and Z is N.

[0073] Embodiment 5. The compound is of formula (II): [ka] A compound of the compound described in Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof.

[0074] Embodiment 6. A compound according to any one of Embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein P is 0 or 1; preferably, p is 0.

[0075] Embodiment 7.R1 is -L1-R 18 L1 is either not present or L1 is NR 11 And here, R 11 These are, independently, hydrogen and C 1~6 Alkyl and C 1~6 A compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 6, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, selected from haloalkyl groups; preferably, L1 is absent or L1 is NH; more preferably, L1 is absent.

[0076] Embodiment 8.R 18 However, 6-10 membered aryls, 5-14 membered heteroaryls (for example, 5-10 membered heteroaryls), C 3~8 Selected from cycloalkyls and 4-8 membered heterocyclyls, preferably selected from 6-10 membered aryls and 5-13 membered heteroaryls (e.g., 5-10 membered heteroaryls), more preferably selected from 6-10 membered aryls and 8-13 membered heteroaryls, most preferably selected from phenyl, naphthyl, 9-10 membered heteroaryls and 12-13 membered heteroaryls, each optionally consisting of: halogen, -CN, -OH, -SH, -SF5, oxo, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 Alkyl)-CN,-O(C 1~6 Alkyl), -O(C 1~6Haloalkyl), -OC(O)NR a R b , -NR a C(O)OR c , -NR a C(O)R d , -NR a R b , and -C(O)NR a R b It may be substituted with one or more elements selected independently from; where C 1~6 The alkyl group may optionally be substituted with one or more deuterium atoms, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~8 The cycloalkyl and 3-8 membered heterocyclyl compounds described in Embodiment 7, or pharmaceutically acceptable salts thereof, or solvates, racemic mixtures, enantiomers, diastereomers, or tautomers thereof, may each be optionally substituted with one or more halogens.

[0077] Embodiment 9.R 18 The following are selected from phenyl, naphthyl, indanyl, benzocyclobutenyl, pyridyl, pyrimidinyl, pyrazinyl, indazolyl, indolyl, benzothiazolyl, benzothienyl, benzimidazolyl, benzindazolyl, tetrahydrobenzuindazolyl, quinolyl, quinolinonyl, tetrahydroquinolyl, isoquinolyl, pyrazoloquinolyl, pyrrolopyridyl, triazolopyridyl, tetrahydrocyclopentaindazolyl, dihydrocyclopentaindazolyl, dihydroindenothiazolyl, hexahydroindenooxazinyl, tetrahydrocyclopentaindolyl, tetrahydroindenoimidazolyl, cyclohexyl, and cyclohexenyl, each of which may optionally be: halogen, -CN, -OH, -SH, -SF5, oxo, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C1~6 Alkyl), -(C 1~6 Alkyl)-CN,-O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -OC(O)NR a R b , -NR a C(O)R d , -NR a R b , and -C(O)NR a R b It may be substituted with one or more elements selected independently from; where C 1~6 The alkyl group may optionally be substituted with one or more deuterium atoms, and C 2~6 Alkenil, C 2~6 Alkinyl, C 3~8 The cycloalkyl and 3-8 membered heterocyclyl may each be optionally substituted with one or more halogens; preferably, R 18 The following are selected from phenyl, naphthyl, indanyl, benzocyclobutenyl, pyridyl, pyrimidinyl, pyrazinyl, indazolyl, benzothiazolyl, quinolyl, isoquinolyl, cyclohexyl, and cyclohexenyl, each of which may optionally be: halogen, -CN, -OH, -SH, oxo, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 Alkyl)-CN,-O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -NR a C(O)R d , and -NR a R b It may be substituted with one or more elements selected independently from; where C 1~6 The alkyl group may optionally be substituted with one or more deuterium atoms, C 2~6 Alkenil, C2~6 Alkinyl, C 3~8 The cycloalkyl and 3-8 membered heterocyclyl compounds described in Embodiment 8, or pharmaceutically acceptable salts thereof, or solvates, racemic mixtures, enantiomers, diastereomers, or tautomers thereof, may each be optionally substituted with one or more halogens.

[0078] Embodiment 10.R 18 However, the following: [ka] Selected from the following, each of which can be any of the following: halogen, -CN, -OH, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, -O(C 1~6 Alkyl), -OC(O)NR a R b , -NR a C(O)R d and -NR a R b It may be substituted with one or more elements independently selected from; where R a , R b and R d These are, independently, hydrogen and C 1~6 Selected from alkyl; where R a , R b and R d C in 1~6 Alkyl groups are: -OH, -NR g R h -C(O)NR g R h , and -NHC(O)R i It may be substituted with one or more elements independently selected from; where R g , R h and R i These are, independently, hydrogen and C 1~6 Alkyl, and -(C 1~6 Selected from alkyl)-NH2; or R a and Rb They form a 3-6 membered heterocycline together with the nitrogen atom to which they bond; preferably, R 18 The following: [ka] Selected from the following, each of which can be arbitrarily: halogen, -OH, C 1~6 Alkyl, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, -O(C 1~6 Alkyl), -OC(O)NR a R b , -NR a C(O)R d and -NR a R b It may be substituted with one or more elements independently selected from; where R a , R b and R d These are, independently, hydrogen and C 1~6 Selected from alkyl; where R a , R b and R d C in 1~6 Alkyl groups are: -OH, -NR g R h -C(O)NR g R h , and -NHC(O)R i It may be substituted with one or more elements independently selected from; where R g , R h and R i These are, independently, hydrogen and C 1~6 Alkyl and -(C 1~6 Selected from alkyl)-NH2; or R a and R b They, together with the nitrogen atom to which they bond, form 3-6 membered heterocyclines; Comfortable, R 18 The following: [ka] Selected from, Each of these can be arbitrarily selected from the following: halogen, -OH, C 1~6 Alkyl, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, -O(C 1~6 Alkyl), -NR a C(O)R d , and -NR a R b It may be substituted with one or more elements independently selected from; where R a , R b and R d These are, independently, hydrogen and C 1~6 Selected from alkyl; where R a , R b and R d C in 1~6 Alkyl groups are: -OH, -NR g R h and -NHC(O)R i It may be substituted with one or more elements independently selected from; where R g , R h and R i These are, independently, hydrogen and C 1~6 Alkyl, and -(C 1~6 Selected from alkyl)-NH2; More preferably, R 18 teeth, [ka] This is because, optionally, halogen, -OH, C 1~6 Alkyl, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 3~8 It may be substituted with one or more groups independently selected from cycloalkyl and -NH2; or R 18 teeth, [ka] And this is, optionally, halogen, C 1~6 Alkyl, C 2~6 Alkinyl, C 1~6 Haloalkyl, C3~8 It may be substituted with one or more groups independently selected from cycloalkyl and -NH2; or R 18 teeth, [ka] This is because, optionally, halogen, -OH, C 1~6 Alkyl and C 2~6 It may be substituted with one or more groups independently selected from the alkynyl group, or R 18 teeth, [ka] And this is, optionally, halogen, C 1~6 Alkyl and C 3~8 The compounds described in Embodiment 9 or pharmaceutically acceptable salts thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers thereof, which may be substituted with one or more groups independently selected from cycloalkyl groups.

[0079] Embodiment 11. R2 is hydrogen, halogen, -CN, -OH, -SH, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, -O(C 1~6 Alkyl), and -NR a R b Selected independently from; where C 1~6 The alkyl group may optionally be substituted with one or more deuterium atoms, C 2~6 Alkenil, C 2~6 Alkinyl and C 3~8 Each cycloalkyl group may optionally be substituted with one or more halogens; preferably, R2 is hydrogen, halogen, -CN, -OH, C 1~6 Alkyl, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, -O(C 1~6A compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 10, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, selected from alkyl, and -NH2; more preferably, R2 is a halogen, for example, F.

[0080] Embodiment 12. R3 is hydrogen, -OH, -O(C 1~6 Alkyl), -O(C 1~6 Alkyl), -S(C 1~6 Alkyl), -S(C 1~6 Haloalkyl), C 3~8 Cycloalkyl, 4-10 membered heterocyclyl, and -O-L2-R 12 Selected from; where C 3~8 Cycloalkyls and 4-10 membered heterocyclines can be optionally: deuterium, halogen, -CN, -OH, oxo, C 1~6 Alkyl, C 1~6 Alkyridene, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 Alkyl)-CN, and -O(C 1~6 It may be substituted with one or more groups independently selected from alkyl, where C 1~6 Alkylidene may optionally be substituted with one or more halogens; preferably, R3 is hydrogen, -O(C 1~6 Alkyl), -S(C 1~6 Alkyl), 4-10 membered heterocyclyl, and -O-L2-R 12 Selected from; where 4-10 member heterocyclils are deuterium, halogen, and -(C 1~6 It may be optionally substituted with one or more groups independently selected from alkyl)-OH; more preferably, R3 is -O-L2-R 12The compound described in any one of Embodiments 1 to 11, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof.

[0081] Embodiment 13. C may be optionally substituted with one or more deuterium or halogens. 1~6 Alkylene or C 3~8 It is a cycloalkylene; preferably, L2 may be optionally substituted with one or more deuterium or halogens. 1~6 A compound according to Embodiment 12 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, which is alkylene; more preferably, L2 is CH2 which may be optionally substituted with one or more deuterium atoms.

[0082] Embodiment 14.R 12 However, C 3~8 The cycloalkyl or 4-10 membered heterocycline, preferably 4-10 membered heterocycline, more preferably 4-8 membered heterocycline, each of which may optionally be: deuterium, halogen, -CN, -OH, oxo, C 1~6 Alkyl, C 1~6 Alkyridene, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, -O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -NR a C(O)OR d , -NR a R b -C(O)NR a R b , -C(O)OR c , and -C(O)R d It may be substituted with one or more elements selected independently from; where C 1~6 Alkyl, C 1~6 Alkyridene, C 3~8 Cycloalkyls and 3- to 8-membered heterocyclines may each optionally contain one or more R groups. 17The compounds described in Embodiment 12 or 13, or pharmaceutically acceptable salts thereof, or solvates, racemic mixtures, enantiomers, diastereomers, or tautomers thereof, which may be substituted with .

[0083] Embodiment 15.R 12 The compounds are selected from cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranil, hexahydro-1H-pyrrolidinyl, tetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidinyl] and octahydrocyclopropa[a]pyrrolidinyl, each of which may optionally be: deuterium, halogen, -CN, -OH, oxo, C 1~6 Alkyl, C 1~6 Alkyridene, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, -O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -NR a C(O)OR d , -NR a R b -C(O)NR a R b , -C(O)OR c , and -C(O)R d It may be substituted with one or more elements selected independently from; where C 1~6 Alkyl, C 1~6 Alkyridene, C 3~8 Cycloalkyls and 3- to 8-membered heterocyclines may each optionally contain one or more R groups. 17 The compounds described in Embodiment 14, or pharmaceutically acceptable salts thereof, or solvates, racemic mixtures, enantiomers, diastereomers, or tautomers thereof, which may be substituted with .

[0084] Embodiment 16.R 12 However, the following: [ka] Selected from the following, each of which can be any of the following: deuterium, halogen, -CN, -OH, oxo, C 1~6 Alkyl, C 1~6 Alkyridene, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, and -O(C 1~6 It may be substituted with one or more groups independently selected from alkyl; where C 1~6 Alkyl, C 1~6 Alkyridene, C 3~8 Cycloalkyls and 3- to 8-membered heterocyclines may each optionally contain one or more R groups. 17 It may also be replaced with; preferably, R 12 The following: [ka] Selected from; each of them optionally: deuterium, halogen, -CN, oxo, C 1~6 Alkyl, C 1~6 Alkyridene, C 1~6 They may be substituted with one or more groups independently selected from haloalkyls and 3- to 8-membered heterocyclines; where C 1~6 Alkyl, C 1~6 Alkylidenes and 3- to 8-membered heterocyclines may each be optionally composed of one or more R 17 It may also be replaced with; Comfortable, R 12 The following: [ka] Selected from; each of them optionally: deuterium, halogen, -CN, oxo, C 1~6 Alkyl, C 1~6 Alkyridene, C 1~6 They may be substituted with one or more groups independently selected from haloalkyls and 3- to 8-membered heterocyclines; where C 1~6 Alkyl, C 1~6 Alkylidenes and 3- to 8-membered heterocyclines may each be optionally composed of one or more R 17 It may also be replaced with; More preferably, R 12 teeth, [ka] This is because, optionally, -CN and C 1~6 It may be substituted with one or more groups independently selected from alkyl groups; where C 1~6 Alkyl is one or more R 17 It may be arbitrarily replaced with; or R 12 teeth, [ka] And this is, optionally, C 1~6 It may be substituted with one or more groups independently selected from the haloalkyl group; or R 12 teeth, [ka] This is because, optionally, the following: deuterium, halogen, C 1~6 Alkyl, C 1~6 They may be substituted with one or more groups independently selected from haloalkyls and 3- to 8-membered heterocyclines; where C 1~6 Alkyl and 3-8 membered heterocyclyl molecules may each optionally contain one or more R groups. 17 It may also be replaced with; or R 12 teeth, [ka] This is, optionally, deuterium, halogen, and C 1~6 It may be substituted with one or more groups independently selected from alkylidene; where C 1~6 Alkyl is one or more R 17 The compounds described in Embodiment 15, or pharmaceutically acceptable salts thereof, or solvates, racemic mixtures, enantiomers, diastereomers, or tautomers thereof, which may be optionally substituted with.

[0085] Embodiment 17.R 17However, deuterium, halogen, -CN, -OH, oxo, 3-8 member heterocyclyl, -O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -NR a R b , and -NHCO(C 1~6 Selected from alkyl groups, where 3- to 8-membered heterocyclyl groups are optionally: halogen, -CN, -OH, oxo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 Alkyl)-CN,-O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -CO(C 1~6 Alkyl), and S(O)2(C 1~6 It may be substituted with one or more groups independently selected from alkyl groups; preferably, R 17 These include deuterium, halogens, -OH, 3-8 membered heterocyclyl, and -NR a R b Selected from, where 3- to 8-membered heterocyclines are optionally: halogens, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 Alkyl)-CN,-O(C 1~6 Alkyl), -CO(C 1~6 Alkyl), and S(O)2(C 1~6 It may be substituted with one or more groups independently selected from alkyl groups; more preferably, R 17 It is deuterium, halogen, -OH, 3-8 membered heterocycline, -N(C 1~6 Alkyl)2, and -N(C 1~6 Alkyl)(C 3~8Selected from cycloalkyl, where C 1~6 Alkyl groups may be optionally substituted with one or more -OH groups, and 3- to 8-membered heterocyclyl groups may optionally be:C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, and -(C 1~6 It may be substituted with one or more groups independently selected from alkyl)-OH; more preferably, R 17 This includes deuterium and halogens, selected from, for example, F, the compounds described in any one of Embodiments 14 to 16, or pharmaceutically acceptable salts thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers thereof.

[0086] Embodiment 18.R4 is C 1~6 Alkyl, C 3~8 Selected from cycloalkyls, 4-8 membered heterocyclines, and 5-10 membered heteroaryls, each optionally containing one or more R groups. 13 It may also be replaced by; preferably, R4 is C 1~6 Alkyl, C 3~8 Selected from cycloalkyls and 4- to 8-membered heterocyclines, each optionally containing one or more R groups. 13 It may also be replaced by; more preferably, R4 is C 1~6 Alkyl and C 3~8 Selected from cycloalkyls, each optionally containing one or more R 13 It may also be replaced with; more preferably, R4 is C 1~6 It is an alkyl group, which is one or more R 13 It may be optionally replaced by; most preferably, R4 is one or more R 13 C may be arbitrarily replaced with 1~6 A compound described in any one of Embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, which is alkyl.

[0087] Embodiment 19.R 13 However, deuterium, halogen, -OH, oxo, -NH2, C3~8 Cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -O(C 1~6 Alkyl), -NHCO(C 1~6 Alkyl), -NH(C 1~6 Alkyl), and -N(C 1~6 Selected from alkyl)2; where C 3~8 Cycloalkyls, 3-8 membered heterocyclines, 6-10 membered aryls, and 5-10 membered heteroaryls may each optionally contain one or more R 14 It may also be replaced with; preferably, R 13 R is selected from deuterium, oxo, -NH2, and 5-10 membered heteroaryls; where the 5-10 membered heteroaryl is one or more R 14 It may be optionally replaced with; more preferably, R 13 R is selected from deuterium and 5-10 membered heteroaryls; where the 5-10 membered heteroaryl is one or more R 14 It may be optionally replaced with; more preferably, R 13 is one or more R 14 A compound according to Embodiment 18 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, which may be optionally substituted with a 5-6 member heteroaryl.

[0088] Embodiment 20.R 13 The compounds are selected from phenyl, pyrazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, and imidazopyridyl, each of which may optionally contain one or more R compounds. 14 The compounds described in Embodiment 19, or pharmaceutically acceptable salts thereof, or solvates, racemic mixtures, enantiomers, diastereomers, or tautomers thereof, which may be substituted with .

[0089] Embodiment 21.R 13 However, the following: [ka] Selected from, each of which may optionally contain one or more R 14 It may also be replaced with; Preferably, R 13 teeth, [ka] Selected from, each of which may optionally contain one or more R 14 It may also be replaced with; Comfortable, R 13 teeth, [ka] This is one or more R 14 It may be arbitrarily replaced with; or R 13 teeth, [ka] This is one or more R 14 The compounds described in Embodiment 20 or pharmaceutically acceptable salts thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers thereof, which may be optionally substituted with.

[0090] Embodiment 22.R 14 However, independently, deuterium, halogen, -CN, -OH, oxo, C 1~6 Alkyl, C 1~6 Haloalkyl, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 Alkyl)-CN,-O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -NR a C(O)R d , -NR a R b , and -C(O)NR a R b Selected independently from; where C 1~6 The alkyl group may optionally be substituted with one or more deuterium atoms; preferably, R14 Halogen and -NR a R b Selected independently from; more preferably, R 14 The compound is -NH2, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, according to any one of embodiments 19 to 21.

[0091] Embodiment 23. R5, R6, R7, R8, R9 and R 10 However, each is independent of hydrogen, deuterium, and C. 1~6 Alkyl, C 1~6 Haloalkyl and C 3~8 Selected from cycloalkyl groups; or R5 and R6, R7 and R8, R9 and R 10 R5 and R7, R7 and R9, or R5 and R9, together with the carbon atom they bond to, C 3~6 Forms a cycloalkyl or 3-6 membered heterocycline; preferably R5, R6, R7, R8, R9 and R 10 These are, independently, hydrogen, deuterium, and C 1~3 Selected from alkyl groups; or R5 and R6 together with the carbon atoms to which they are bonded form cyclopropyl; or R5 and R7 together with the carbon atoms to which they are bonded form cyclopropyl, cyclopentyl, tetracyclofuranyl, or tetrahydropyranyl; more preferably R5, R6, R7, R8, R9 and R 10 all are hydrogen; or R5 is C 1~3 It is an alkyl group, and R6, R7, R8, R9 and R 10 R5 and R7 are each independently selected from hydrogen and deuterium; or R5 and R7, together with the carbon atoms to which they are bonded, form cyclopentyl, tetrahydrofuranyl, or tetrahydropyranyl, as described in any one of Embodiments 1 to 22, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof.

[0092] Embodiment 24. The compound is of formula (I-2): [ka] (In the formula: R1 is -L1-R 18 and; L1 does not exist; R 18 These are selected from 6-10 membered aryls and 5-14 membered heteroaryls, each of which can optionally be: halogen, -CN, -OH, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, -O(C 1~6 Alkyl), -OC(O)NR a R b , -NR a C(O)OR d , and -NR a R b It may be substituted with one or more groups independently selected from; preferably, R 18 The following: [ka] Selected from the following, each of which can be arbitrarily: halogen, -OH, C 1~6 Alkyl, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, -O(C 1~6 Alkyl), -OC(O)NR a R b , -NR a C(O)OR d , and -NR a R b It may be substituted with one or more groups independently selected from; more preferably, R 18 The following: [ka] Selected from the following, each of which can be arbitrarily: halogen, -OH, C 1~6 Alkyl, C 2~6 Alkinyl, C 1~6 Haloalkyl, C3~8 Cycloalkyl, -O(C 1~6 Alkyl), -NR a C(O)R d , and -NR a R b It may be substituted with one or more groups independently selected from; more preferably, R 18 teeth, [ka] This is because, optionally, the following: halogen, -OH, C 1~6 Alkyl, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 3~8 It may be substituted with one or more groups independently selected from cycloalkyl and -NH2; or, R 18 teeth, [ka] And this is, optionally, below: halogen, C 1~6 Alkyl, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 3~8 It may be substituted with one or more groups independently selected from cycloalkyl and -NH2; or, R 18 teeth, [ka] This is because, optionally, the following: halogen, -OH, C 1~6 Alkyl and C 2~6 It may be substituted with one or more groups independently selected from the alkynyl group; or R 18 teeth, [ka] And this is, optionally, below: halogen, C 1~6 Alkyl and C 3~8 It may be substituted with one or more groups independently selected from the alkynyl group; R2 is hydrogen, halogen, -CN, -OH, C1~6 Alkyl, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, -O(C 1~6 Selected from alkyl and -NH2; preferably, R2 is a halogen; R3 is -O-L2-R 12 and; L2 is C 1~6 Alkylene or C 3~8 It is a cycloalkylene, each of which may optionally be substituted with one or more deuterium or halogens; preferably, L2 is C 1~6 It is an alkylene, which may be optionally substituted with one or more deuterium atoms; more preferably, L2 is CH2, which may be optionally substituted with one or more deuterium atoms; R 12 C 3~8 The compounds are cycloalkyl or 4-10 member heterocyclines, each optionally comprising: deuterium, halogen, -CN, oxo, C 1~6 Alkyl, C 1~6 Alkyridene, C 1~6 They may be substituted with one or more groups independently selected from haloalkyls and 3- to 8-membered heterocyclines; where C 1~6 Alkyl, C 1~6 Alkylidenes and 3- to 8-membered heterocyclines may each be optionally composed of one or more R 17 It may also be replaced with; preferably, R 12 The following: [ka] Selected from the following, each of which can optionally be: deuterium, halogen, -CN, oxo, C 1~6 Alkyl, C 1~6 Alkyridene, C 1~6 They may be substituted with one or more groups independently selected from haloalkyls and 3- to 8-membered heterocyclines; where C 1~6 Alkyl, C 1~6 Alkylidenes and 3- to 8-membered heterocyclines may each be optionally composed of one or more R17 It may also be replaced by; more preferably, R 12 The following: [ka] Selected from the following, each of which can optionally be: deuterium, halogen, -CN, oxo, C 1~6 Alkyl, C 1~6 Alkyridene, C 1~6 They may be substituted with one or more groups independently selected from haloalkyls and 3- to 8-membered heterocyclines; where C 1~6 Alkyl, C 1~6 Alkylidenes and 3- to 8-membered heterocyclines may each be optionally composed of one or more R 17 It may also be replaced with; more preferably, R 12 teeth, [ka] This is, optionally, -CN and C 1~6 It may be substituted with one or more groups independently selected from alkyl groups; where C 1~6 Alkyl is one or more R 17 It may be arbitrarily replaced with; or R 12 teeth, [ka] And this is C 1~6 It may be optionally substituted with one or more groups independently selected from the haloalkyl group; or, R 12 teeth, [ka] This is because, optionally, the following: deuterium, halogen, C 1~6 Alkyl, C 1~6 It may be substituted with one or more groups independently selected from haloalkyl and 3- to 8-membered heterocyclyl groups; where C 1~6 Alkyl and 3- to 8-membered heterocyclyl molecules may each optionally contain one or more R groups. 17It may be replaced with; or, R 12 teeth, [ka] This is because, optionally, the following: deuterium, halogens, and C 1~6 It may be substituted with one or more groups independently selected from alkylidene; where C 1~6 Each alkylidene may optionally contain one or more R 17 It may also be replaced with; R 17 These include deuterium, halogens, -OH, 3-8 membered heterocyclyl, and -NR a R b Selected from, where 3- to 8-membered heterocyclines are optionally halogens, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 Alkyl)-CN,-O(C 1~6 Alkyl), -CO(C 1~6 Alkyl), and S(O)2(C 1~6 It may be substituted with one or more groups independently selected from alkyl groups; preferably, R 17 It is deuterium, halogen, -OH, 3-8 membered heterocycline, -N(C 1~6 Alkyl)2, and -N(C 1~6 Alkyl)(C 3~8 Selected from cycloalkyl, where C 1~6 Alkyl groups may be optionally substituted with one or more -OH groups, and 3- to 8-membered heterocyclyl groups are as follows: C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, and -(C 1~6 It may be substituted with one or more groups independently selected from alkyl)-OH; more preferably, R 17 This is selected from deuterium and halogens, for example, F; R4 is C 1~6 Alkyl, C3~8 Selected from cycloalkyls and 4- to 8-membered heterocyclines, each optionally containing one or more R groups. 13 It may also be replaced by; preferably, R4 is C 1~6 Alkyl and C 3~8 Selected from cycloalkyls, each optionally containing one or more R 13 It may be optionally replaced with; more preferably, R4 is C 1~6 It is an alkyl group, which is one or more R 13 It may be optionally replaced with; more preferably, R4 is C 1~6 It is an alkyl group, which is one or more R 13 It has been replaced with; R 13 R is selected from deuterium and 5-10 membered heteroaryls; where the 5-10 membered heteroaryl is one or more R 14 It may be optionally replaced with; preferably, R 13 The following: [ka] Selected from, each of which can optionally contain one or more R 14 It may also be replaced by; more preferably, R 13 teeth, [ka] This is because one or more R 14 It may be arbitrarily replaced with; or R 13 teeth, [ka] This is because one or more R 14 It may be arbitrarily replaced with: R 14 Halogen and -NR a R b Selected from; preferably, R 14 It is -NH2; R5, R6, R7, and R8 are each independently hydrogen, deuterium, and C 1~6 Alkyl, C 1~6 Haloalkyl and C 3~8 Selected from cycloalkyl groups; or R5 and R6, R7 and R8, or R5 and R7 together with the carbon atom to which they are bonded, C 3~6 They form a cycloalkyl or a 3-6 membered heterocycline; preferably, R5, R6, R7, and R8 each independently consist of hydrogen, deuterium, and C 1~3 Selected from alkyl groups; or R5 and R6, together with the carbon atoms to which they are bonded, form a cyclopropyl group; or R5 and R7, together with the carbon atoms to which they are bonded, form a cyclopropyl group, cyclopentyl group, tetrahydrofuranyl group, or tetrahydropyranyl group; more preferably, R5, R6, R7 and R8 are all hydrogen; or R5 is C 1~3 It is an alkyl group, where R6, R7, and R8 are each independently selected from hydrogen and deuterium; or R5 and R7, together with the carbon atoms to which they are bonded, form cyclopentyl, tetrahydrofuranyl, or tetrahydropyranyl; R a , R b and R d These are, independently, hydrogen and C 1~6 Alkyl and C 3~8 Selected from cycloalkyl; where C 1~6 Alkyl and C 3~8 Cycloalkyl groups can be any of the following: -OH, -NR g R h -C(O)NR g R h , and -NHC(O)R i It may be substituted with one or more elements independently selected from; where R g , R h and R i These are, independently, hydrogen and C 1~6 Alkyl, and -(C 1~6 A compound selected from alkyl)-NH2, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof.

[0093] Embodiment 25.R4 is R 13 C replaced by 1~6 It is alkyl; R 13 The following: [ka] Selected from, each of which may optionally contain one or more R 14 It may also be replaced with; Preferably, R 13 The following: [ka] Selected from, each of which may optionally contain one or more R 14 It may also be replaced with; Comfortable, R 13 teeth, [ka] This is one or more R 14 It may be arbitrarily replaced with; or R 13 teeth, [ka] This is one or more R 14 It may be arbitrarily replaced with; R 14 This is independently a compound described in Embodiment 24 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, selected from halogens and NH2.

[0094] Embodiment 26. Hereafter:

[0095] [Table 1] TIFF2026519454000051.tif232170TIFF2026519454000052.tif226170TIFF2026519454000053.tif255170TIFF2026519454000054.tif255170TIFF2026519454000055.tif226170TIFF2026519454000056.tif237170TIFF2026519454000057.tif255170TIFF2026519454000058.tif226170TIFF2026519454000059.tif226170TIFF2026519454000060.tif189170TIFF2026519454000061.tif255170TIFF2026519454000062.tif232170TIFF2026519454000063.tif226170TIFF2026519454000064.tif216170TIFF2026519454000065.tif226170TIFF2026519454000066.tif237170TIFF2026519454000067.tif226170TIFF2026519454000068.tif194170TIFF2026519454000069.tif237170TIFF2026519454000070.tif226170TIFF2026519454000071.tif237170TIFF2026519454000072.tif248170TIFF2026519454000073.tif242170TIFF2026519454000074.tif226170TIFF2026519454000075.tif232170TIFF2026519454000076.tif255170TIFF2026519454000077.tif237170TIFF2026519454000078.tif189170TIFF2026519454000079.tif237170TIFF2026519454000080.tif255170TIFF2026519454000081.tif242170TIFF2026519454000082.A compound or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, selected from tif253170.

[0096] Embodiment 27. A pharmaceutical composition comprising a compound and / or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 26, and optionally comprising a pharmaceutically acceptable excipient.

[0097] Embodiment 28. A method for inhibiting the activity of a mutant KRAS protein in vivo or in vitro, comprising contacting the mutant KRAS protein in an effective amount of a compound and / or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 26.

[0098] Embodiment 29. A method for treating or preventing a target disease, comprising administering an effective amount of a compound and / or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 26 to a subject in need thereof, characterized in that the disease comprises a KRAS mutation or KRAS gene amplification; the KRAS mutation is preferably a KRAS G12C mutation, a KRAS G12D mutation, a KRAS G12V mutation, a KRAS G13D mutation, and / or a KRAS Q61H mutation; the KRAS gene amplification is preferably a wild-type KRAS gene amplification; the disease is preferably cancer; the cancer is preferably a solid tumor or a hematological malignancy; and the cancer is more preferably lung cancer (e.g., lung adenocarcinoma, non-small cell lung cancer, and small cell lung cancer), colorectal cancer, pancreatic cancer, colon cancer, rectal cancer, thyroid cancer, esophageal cancer (e.g., esophageal adenocarcinoma), bile duct cancer, gallbladder cancer, head and neck cancer, breast cancer, endometrial cancer, prostate cancer, ovarian cancer A method in which cancer is selected from cancer, cervical cancer, neuroblastoma, melanoma, brain tumor, gastric cancer (e.g., chromosomally unstable gastric cancer and gastric adenocarcinoma), bladder cancer, liver cancer, kidney cancer, bone cancer, sarcoma, adrenal cancer, leukemia, lymphoma and myeloma; cancer is more preferably selected from lung cancer (lung adenocarcinoma, non-small cell lung cancer and small cell lung cancer), colorectal cancer, pancreatic cancer, colon cancer, esophageal cancer (e.g., esophageal adenocarcinoma), and gastric cancer (e.g., chromosomally unstable gastric cancer and gastric adenocarcinoma, etc.).

[0099] Embodiment 30. Use of a compound and / or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 26 in the manufacture of a pharmaceutical product for treating or preventing a disease having a KRAS mutation or KRAS gene amplification, wherein the KRAS mutation is preferably a KRAS G12C mutation, a KRAS G12D mutation, a KRAS G12V mutation, a KRAS G13D mutation, and / or a KRAS Q61H mutation; the KRAS gene amplification is preferably a wild-type KRAS gene amplification; the disease is preferably cancer; the cancer is preferably a solid tumor or a hematological malignancy; and the cancer is more preferably lung cancer (e.g., lung adenocarcinoma, non-small cell lung cancer, and small cell lung cancer), colorectal cancer, pancreatic cancer, colon cancer, rectal cancer, thyroid cancer, esophageal cancer (e.g., esophageal adenocarcinoma), bile duct cancer, gallbladder cancer, head and neck cancer, breast cancer, endometrial cancer, prostate cancer, egg cancer Cancers selected from uterine cancer, cervical cancer, neuroblastoma, melanoma, brain tumor, gastric cancer (e.g., chromosomally unstable gastric cancer and gastric adenocarcinoma), bladder cancer, liver cancer, kidney cancer, bone cancer, sarcoma, adrenal cancer, leukemia, lymphoma, and myeloma; cancers are more preferably selected from lung cancer (lung adenocarcinoma, non-small cell lung cancer, and small cell lung cancer), colorectal cancer, pancreatic cancer, colon cancer, esophageal cancer (e.g., esophageal adenocarcinoma), and gastric cancer (e.g., chromosomally unstable gastric cancer and gastric adenocarcinoma, etc.).

[0100] Embodiment 31. A compound and / or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 26, for use as a pharmaceutical.

[0101] Embodiment 32. The disease is preferably cancer; the KRAS mutation is preferably KRAS G12C mutation, KRAS G12D mutation, KRAS G12V mutation, KRAS G13D mutation, and / or KRAS Q61H mutation; the KRAS gene amplification is preferably wild-type KRAS gene amplification; the cancer is preferably a solid tumor or hematological malignancy; the cancer is more preferably lung cancer (e.g., lung adenocarcinoma, non-small cell lung cancer, and small cell lung cancer), colorectal cancer, pancreatic cancer, colon cancer, rectal cancer, thyroid cancer, esophageal cancer (e.g., esophageal adenocarcinoma), bile duct cancer, gallbladder cancer, head and neck cancer, breast cancer, endometrial cancer, prostate cancer, ovarian cancer, cervical cancer, neuroblastoma, melanoma, brain tumor, gastric cancer (e.g., chromosomally unstable gastric cancer, and gastric adenocarcinoma), bladder cancer A compound and / or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of diseases having a KRAS mutation or KRAS gene amplification, selected from bladder cancer, liver cancer, kidney cancer, bone cancer, sarcoma, adrenal cancer, leukemia, lymphoma and myeloma; more preferably, selected from lung cancer (adenocarcinoma, non-small cell lung cancer and small cell lung cancer), colorectal cancer, pancreatic cancer, colon cancer, esophageal cancer (e.g., esophageal adenocarcinoma), and gastric cancer (e.g., chromosomally unstable gastric cancer and gastric adenocarcinoma).

[0102] Embodiment 33. A pharmaceutical combination comprising a compound and / or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 26 and at least one additional therapeutic agent, wherein the additional therapeutic agent is preferably selected from an antitumor agent, an anti-inflammatory agent, or an immunomodulator, and the antitumor agent comprises a chemotherapeutic agent, an immune checkpoint inhibitor or agonist, and a targeted therapeutic agent.

[0103] Embodiment 34. Formula (II): [ka] (In the formula, R2, R4, R5, R6, R7, R8, R9, R 10 X, Y, Z, and p are as defined in any one of Embodiments 1 to 25; X1 is a halogen; X2 is hydrogen, halogen, -S(C1~6 Alkyl) or -S(O)(C 1~6 (Alkyl) Compounds thereof or pharmaceutically acceptable salts thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers thereof.

[0104] Embodiment 35. The compound is of formula (II-1): [ka] (In the formula, X1 is a halogen; preferably, X1 is chlorine; X2 is hydrogen, halogen, -S(C 1~6 Alkyl) or -S(O)(C 1~6 A compound according to Embodiment 34 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein X2 is an alkyl group; preferably, X2 is hydrogen, chlorine, -S(CH3), or -S(O)(CH3); more preferably, X2 is hydrogen, -S(CH3), or -S(O)(CH3).

[0105] Embodiment 36. Hereafter:

[0106] [Table 2] A compound described in Embodiment 35 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, selected from TIFF2026519454000086.tif255170 or TIFF2026519454000087.tif40170.

[0107] Various embodiments of the present invention (including the following embodiments) and features of various embodiments should be interpreted as being arbitrarily combined with each other, and the various solutions obtained from these combinations are all included in the scope of the present invention, just as they are obtained from combinations specifically and individually expressed herein, unless otherwise clearly stated in the context.

[0108] Beneficial Effects of the Present Invention As mentioned above, abnormal activation of the RAS protein is known to be closely related to tumorigenesis, with KRAS mutations being the most common, and KRAS gene amplification also being observed in various tumors. Inhibiting KRAS mutations or KRAS gene amplification can significantly suppress cell proliferation in KRAS-related diseases such as cancer. Surprisingly, the inventors have found that the compound of the present invention can significantly suppress KRAS mutations or KRAS gene amplification.

[0109] In some embodiments, the compounds of the present invention can inhibit intracellular KRAS activity, particularly the activity of mutant KRAS, for example, the activity of one or more mutant KRAS (including, but not limited to, the activity of KRAS G12C, KRAS G12D, KRAS G12V, KRAS G13D and / or KRAS Q61H).

[0110] In some embodiments, the compounds of the present invention can inhibit cell proliferation in cell lines having KRAS mutations. For example, the compounds have cell proliferation inhibitory activity in one or more cell lines having KRAS mutations (including, but not limited to, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G13D, and / or KRAS Q61H mutations).

[0111] In some embodiments, the compounds of the present invention can suppress cell proliferation in cell lines having KRAS gene amplification. For example, these compounds exhibit cell proliferation inhibitory activity in cell lines having wild-type KRAS gene amplification.

[0112] Because the compounds of the present invention possess the above-described KRAS inhibitory activity and cell proliferation inhibitory activity, they have potential value as antiproliferative and / or apoptosis-inducing agents in the prevention and / or treatment of diseases involving KRAS mutations or KRAS gene amplification, such as cancer or tumors as defined herein.

[0113] General synthesis methods The compounds of formula (I) and / or pharmaceutically acceptable salts thereof described herein can be synthesized using commercially available starting materials by methods well known to those skilled in the art or by methods disclosed in this patent application. The synthesis routes shown in Schemes 1 and 2 illustrate general methods for synthesizing the compounds of the present invention.

[0114] Scheme 1: [ka] R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 and p are as defined herein.

[0115] As shown in Scheme 1, the compound of formula IA is reacted with the compound of formula IB under alkaline conditions (e.g., sodium hydride, but not limited) to obtain the compound of formula IC. The compound of formula IC is reacted under alkaline conditions (e.g., DIEA, but not limited) in the presence of a condensing agent (e.g., BOP-Cl, but not limited) to obtain the compound of formula ID. The compound of formula ID is oxidized in the presence of an oxidizing agent (e.g., m-CPBA, but not limited) to obtain the compound of formula IE. The compound of formula IE is reacted with the corresponding alcohol, etc., under alkaline conditions (e.g., LiHMDS, but not limited) to obtain the compound of formula IF. The compound of formula IF is subjected to a palladium-catalyzed coupling reaction with the corresponding borate, boric acid, or alkyltin under alkaline conditions to obtain the compound of formula (I-1). In this case, the alkali used can be selected from Cs2CO3, K2CO3, K3PO4, etc., and the catalyst used can be selected from Pd(dppf)Cl2·CH2Cl2, Pd-G3, Pd(PPh3)4, etc.

[0116] Scheme 2: [ka] R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 and p are as defined herein.

[0117] As shown in Scheme 2, the compound of formula IA is reacted with the compound of formula IB under alkaline conditions (e.g., sodium hydride, but not limited) to obtain the compound of formula IC. The compound of formula IC is reacted under alkaline conditions (e.g., DIEA, but not limited) in the presence of a condensing agent (e.g., BOP-Cl, but not limited) to obtain the compound of formula ID. The compound of formula ID is subjected to a palladium-catalyzed coupling reaction with the corresponding borate, boric acid, or alkyltin under alkaline conditions to obtain the compounds of formula I-E'. In this case, the alkali used can be selected from Cs2CO3, K2CO3, K3PO4, etc., and the catalyst used can be selected from Pd(dppf)Cl2·CH2Cl2, Pd-G3, Pd(PPh3)4, etc. The compounds of formula I-E' are oxidized in the presence of an oxidizing agent (e.g., m-CPBA, but not limited) to obtain the compounds of formula I-F'. The compound of formula I-F' is reacted with the corresponding alcohol under alkaline conditions (for example, LiHMDS, but not limited to LiHMDS) to obtain the compound of formula (I-1).

[0118] The substituents of the compounds obtained in this way can be further modified to obtain other desired compounds. For synthetic chemical transformations, see, for example, the following references: R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, (1995) and subsequent editions.

[0119] Before use, the compounds of the present invention can be purified by column chromatography, high-performance liquid chromatography, crystallization, or other suitable methods.

[0120] Pharmaceutical composition and its usefulness A pharmaceutical composition can be prepared using the compound of the present invention (for example, any of the compounds in the examples described herein) alone or in combination with one or more additional therapeutic agents. The pharmaceutical composition comprises: (a) an effective amount of the compound of the present invention; (b) a pharmaceutically acceptable excipient (for example, one or more pharmaceutically acceptable carriers); and optionally (c) at least one additional therapeutic agent.

[0121] A pharmaceutically acceptable excipient is an excipient that is compatible with the active ingredient of a composition (and, in some embodiments, can stabilize the active ingredient) and is not harmful to the target being treated. For example, solubilizers such as cyclodextrin (which forms a specific, more soluble complex with the compounds of the present invention) can be used as pharmaceutical excipients for delivering the active ingredient. Other examples of excipients include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D&C Yellow #10. Suitable pharmaceutically acceptable excipients are listed in Remington's Pharmaceutical Sciences, A. Osol, a standard reference in the art.

[0122] Pharmaceutical compositions containing the compounds of the present invention can be administered by a variety of known methods, including orally, topically, rectally, parenterally, by inhalation spray, or via an implantable reservoir. As used herein, the term "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intra-synovial, intrasternal, intrathecal, intrafocal, and intracranial injection or infusion techniques.

[0123] The pharmaceutical compositions described herein may be prepared in the form of tablets, capsules, sachets, sugars, powders, granules, lozenges, reconstituted powders, liquids, or suppositories. In some embodiments, the pharmaceutical compositions comprising the compounds of the present invention are formulated for intravenous infusion, topical administration, or oral administration.

[0124] The oral composition may be any orally administered dosage form, including but not limited to tablets, capsules, emulsions, and aqueous suspensions, dispersions, and solutions. Common carriers for tablets include lactose and corn starch. Lubricants such as magnesium stearate are also typically added to tablets. For oral administration in capsule form, lactose and dried corn starch are useful diluents. For oral administration in aqueous suspension or emulsion form, the active ingredient can be suspended or dissolved in an oily phase combined with an emulsifier or suspending agent. Specific sweeteners, flavorings, or colorings may be added as needed.

[0125] In some embodiments, the compounds of the present invention may be present in amounts of 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400, and 500 mg per tablet. In some embodiments, the compounds of the present invention may be present in amounts of 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400, and 500 mg per capsule.

[0126] Sterile injectable compositions (e.g., aqueous or oily suspensions) can be prepared according to techniques known in the art using suitable dispersants or wetting agents (e.g., Tween 80) and suspension agents. Sterile injectable compositions may also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents (e.g., 1,3-butanediol solution). Pharmacovigilantly acceptable vehicles and solvents that can be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils are commonly used as solvents or suspension media (e.g., synthetic monoglycerides or diglycerides). Fatty acids such as oleic acid and its glyceride derivatives, as well as naturally pharmaceutically acceptable oils such as olive oil and castor oil (especially their polyoxyethylated forms), can be used as sterile injectable media. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, or carboxymethylcellulose or similar dispersants.

[0127] The inhalation composition can be prepared according to techniques known in the art of pharmaceutical formulations, and can be prepared as a saline solution using benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, fluorocarbons, and / or other solubilizers or dispersants known in the art.

[0128] Topical compositions can be formulated in the form of oils, creams, lotions, ointments, etc. Suitable carriers for the compositions include vegetable oils or mineral oils, white petrolatum (white soft paraffin), branched-chain fatty acids or oils, animal fats, and high molecular weight alcohols (greater than C12). In some embodiments, pharmaceutically acceptable carriers are those on which the active ingredient dissolves. Emulsifiers, stabilizers, humectants, and antioxidants may be included, and optionally, agents that impart color or fragrance. Furthermore, transdermal absorption enhancers may be used in these topical formulations. Examples of such enhancers are described in U.S. Patent Nos. 3,989,816 and 4,444,762.

[0129] Creams can be formulated from a mixture of mineral oil, self-emulsifying beeswax, and water, to which an active ingredient dissolved in a small amount of oil, such as almond oil, is added. An example of such a cream contains, by weight, approximately 40 parts water, 20 parts beeswax, 40 parts mineral oil, and 1 part almond oil. Ointments can be formulated by mixing a solution of the active ingredient dissolved in a vegetable oil, such as almond oil, with warm soft paraffin, and then cooling it. An example of such an ointment is one containing approximately 30% by weight of almond oil and approximately 70% by weight of white soft paraffin.

[0130] The compounds of the present invention are useful as KRAS inhibitors. In some embodiments, the compounds of the present invention are useful as pan-KRAS inhibitors. As used herein, inhibition of the activity of two or more (e.g., 2, 3, 4, 5, or 6) mutant KRAS proteins is referred to as pan-KRAS inhibition. In such cases, the compounds of the present invention inhibit the activity of two or more (e.g., 2, 3, 4, 5, or 6) mutant KRAS proteins. In some embodiments, the KRAS mutation sites correspond to G12, G13, or Q61. In some embodiments, the KRAS mutations correspond to G12A, G12C, G12D, G12R, G12S, G12V, G13A, G13C, G13D, G13R, G13S, G13V, Q61E, Q61H, Q61K, Q61L, Q61P, or Q61R mutations. In some embodiments, the KRAS mutation corresponds to the G12A, G12C, G12D, G12R, G12S, G12V, G13D, or Q61H mutation.

[0131] Using appropriate in vitro assays, the effect of the compounds of the present invention on inhibiting the activity of mutant KRAS proteins can be evaluated. Furthermore, in vivo assays can be used to verify the compounds of the present invention for additional effects in preventing or treating cancer. For example, the compounds of the present invention can be administered to animals with cancer (e.g., mouse models), and their therapeutic effects can be evaluated. If the results of preclinical trials are favorable, the range of dosages and routes of administration for animals such as humans can be predicted.

[0132] The compounds of the present invention may be shown to have sufficient preclinical utility to warrant the conduct of clinical trials in which beneficial therapeutic or preventive effects are expected to be demonstrated in subjects with cancer, for example.

[0133] In this specification, the term “cancer” refers to a cytotoxicity characterized by uncontrolled or dysregulated cell proliferation, impaired cell differentiation, inadequate ability to invade surrounding tissues, and / or ability to establish new proliferation in ectopic sites. The term “cancer” includes, but is not limited to, solid tumors and hematological malignancies such as leukemia, lymphoma, or myeloma. The term “cancer” encompasses diseases of the skin, tissues, organs, bones, cartilage, blood, and blood vessels. The term “cancer” further includes primary cancers, as well as metastatic cancers, recurrent cancers, and refractory cancers.

[0134] Non-limiting examples of solid tumors include: pancreatic cancer; bladder cancer; colorectal cancer; colon cancer; rectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; testicular cancer; renal cancer, such as metastatic renal cell carcinoma; urothelial carcinoma; liver cancer; hepatocellular carcinoma; lung cancer (e.g., non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), bronchioloalveolar carcinoma (BAC), and lung adenocarcinoma); ovarian cancer (e.g., advanced epithelial or primary peritoneal cancer); cervical cancer; endometrial cancer Gastric cancer (e.g., chromosomally unstable gastric cancer and gastric adenocarcinoma); esophageal cancer (e.g., esophageal adenocarcinoma); head and neck cancer (e.g., head and neck squamous cell carcinoma); skin cancer (e.g., melanoma and basal cell carcinoma); neuroendocrine cancer (e.g., metastatic neuroendocrine tumors); neuroblastoma; brain tumors (e.g., glioblastoma, undifferentiated oligodendrogliocytoma, adult glioblastoma pleomorphonum, and adult undifferentiated astrocytoma); bone cancer; sarcoma (e.g., Kaposi's sarcoma); adrenal cancer; mesothelioma; mesothelial carcinoma; choriocarcinoma; muscle cancer; connective tissue cancer; and thyroid cancer.

[0135] Non-exclusive examples of hematological malignancies include acute myeloid leukemia (AML); juvenile acute myeloid leukemia; chronic myeloid leukemia (CML) (including transitional CML and acute transformation CML (CML-BP)); acute lymphoblastic leukemia (ALL); B-cell acute lymphoblastic leukemia (B-ALL); chronic lymphocytic leukemia (CLL) (including high-risk CLL); human acute monocytic leukemia (M(5)); hairy cell leukemia; lymphocytic leukemia; chronic lymphocytic leukemia; myeloid leukemia; acute lymphoblastic leukemia; small lymphocytic lymphoma (SLL); lymphoblastic lymphoma; Hodgkin lymphoma; non-Hodgkin lymphoma (NHL); mantle cell Lymphoma (MCL); B-cell lymphoma; T-cell lymphoma; diffuse large B-cell lymphoma (DLBCL); large B-cell lymphoma (LBCL); follicular lymphoma; marginal zone lymphoma; Burkitt lymphoma; non-Burkitt high-grade B-cell lymphoma; extranodal marginal zone B-cell lymphoma; multiple myeloma (MM); Waldenström macroglobulinemia; myelodysplastic syndromes (MDS) (including refractory anemia (RA), refractory anemia with ring sideroblasts (RARS), refractory anemia with blast cell proliferation (RAEB), and refractory anemia with blast cell proliferation in the transitional phase (RAEB-T)); and myeloproliferative syndromes.

[0136] In some embodiments, solid tumors include lung cancer (such as lung adenocarcinoma, non-small cell lung cancer, and small cell lung cancer), colorectal cancer, pancreatic cancer, colon cancer, rectal cancer, thyroid cancer, esophageal cancer (such as esophageal adenocarcinoma), bile duct cancer, gallbladder cancer, head and neck cancer, breast cancer, endometrial cancer, prostate cancer, ovarian cancer, cervical cancer, neuroblastoma, melanoma, brain tumor, gastric cancer (such as chromosomally unstable gastric cancer and gastric adenocarcinoma), bladder cancer, liver cancer, kidney cancer, bone cancer, sarcoma, and adrenal cancer. In some embodiments, solid tumors include lung cancer (such as lung adenocarcinoma, non-small cell lung cancer, and small cell lung cancer), colorectal cancer, pancreatic cancer, colon cancer, esophageal cancer (such as esophageal adenocarcinoma), and gastric cancer (such as chromosomally unstable gastric cancer and gastric adenocarcinoma).

[0137] In some embodiments, hematological malignancies include acute myeloid leukemia (AML), juvenile acute myeloid leukemia, chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), B-cell acute lymphoblastic leukemia (B-ALL), acute lymphoblastic leukemia, chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), large B-cell lymphoma (LBCL), B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, follicular lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma, myelodysplastic syndrome, and myeloma (such as multiple myeloma).

[0138] The compounds of the present invention can be used, for example, to achieve beneficial therapeutic or preventive effects in subjects with cancer.

[0139] Furthermore, the compounds of the present invention (for example, any of the compounds in the examples described herein) may be administered in combination with additional therapeutic agents for the treatment of diseases or disorders described herein (for example, cancer). The additional therapeutic agents may be administered separately from the compounds of the present invention, or may be included together with such components in the pharmaceutical compositions described herein, such as fixed-dose combination formulations. In some embodiments, the additional therapeutic agents are known or found to be effective in treating diseases involving KRAS mutations or KRAS gene amplification, for example, another KRAS inhibitor, or a compound active against another target associated with a particular disease. This combination may help increase potency (for example, by including a compound that enhances the potency or effectiveness of the compounds of the present invention in the combination), reduce one or more side effects, or reduce the required dose of the compounds of the present invention.

[0140] In some embodiments, the compounds of the present invention (for example, any of the compounds in the examples described herein) may be administered in combination with additional therapeutic agents such as antitumor agents, anti-inflammatory agents, or immunomodulators, in which case the antitumor agent includes chemotherapeutic agents, immune checkpoint inhibitors or agonists, and targeted therapeutic agents. As used herein, the term “antitumor agent” refers to any agent administered to a cancer-affected subject for the purpose of treating cancer, such as chemotherapeutic agents, immune checkpoint inhibitors or agonists, and targeted therapeutic agents.

[0141] Non-exclusive examples of chemotherapeutic agents include topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin and their analogs or metabolites, and doxorubicin); topoisomerase II inhibitors (e.g., etoposide, teniposide, mitoxantrone, idarubicin, daunorubicin); and alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine, streptozocin, decarbazine, methotrexate, mitomycin C, and cyclophosphamide). Examples include DNA intercalators (e.g., cisplatin, oxaliplatin, and carboplatin); free radical generators such as bleomycin; nucleoside mimetic compounds (e.g., 5-fluorouracil, capecitabine, gemcitabine, fludarabine, cytarabine, azacitidine, mercaptopurine, thioguanine, pentostatin, hydroxyurea); paclitaxel, docetaxel, and related analogs; vincristine, vinblastine, and related analogs; thalidomide and related analogs (e.g., CC-5013, CC-4047).

[0142] Non-exclusive examples of immune checkpoint inhibitors or agonists include PD-1 inhibitors (e.g., anti-PD-1 antibodies such as pembrolizumab, nivolumab, and PDR001 (spartalizumab)); PD-L1 inhibitors (e.g., anti-PD-L1 antibodies such as atezolizumab, durvalumab, and avelumab); CTLA-4 inhibitors (e.g., anti-CTLA-4 antibodies such as ipilimumab); and BTLA inhibitors, LAG-3 inhibitors, TIM3 inhibitors, TIGIT inhibitors, VISTA inhibitors, and OX-40 agonists.

[0143] Targeted therapies include a variety of small molecule or large molecule targeted therapies, and non-limiting examples include: protein tyrosine kinase inhibitors (such as imatinib mesylate and gefitinib); proteasome inhibitors (such as bortezomib); NF-κB inhibitors (such as IκB kinase inhibitors); EGFR inhibitors; SHP2 inhibitors; IGF1R inhibitors; JAK inhibitors; Met inhibitors; SRC inhibitors; ERK inhibitors; CDK4 / 6 inhibitors; PI3K inhibitors; SYK inhibitors; Bcl2 inhibitors; IDO inhibitors; A2AR inhibitors; BRAF inhibitors (such as dabrafenib); MEK inhibitors (such as trametinib); mTOR inhibitors (such as rapamycin); anti-CD40 antibodies ( Examples of inhibitors include antibodies that bind to proteins overexpressed in cancer cells and downregulate cell replication, such as anti-CD20 antibodies (rituximab, ibritumomab tiuxetan, and tocitumomab), anti-Her2 monoclonal antibodies (trastuzumab), anti-EGFR antibodies (cetuximab), and anti-VEGF antibodies (bevacizumab); anti-angiogenic drugs (e.g., lenalidomide); and other protein or enzyme inhibitors. These proteins or enzymes are known to be upregulated, overexpressed, or activated in cancer, and their inhibition can suppress cell proliferation. [Examples]

[0144] The examples given below are for illustrative purposes only and should not be considered limiting in any sense. While efforts have been made to ensure accuracy in the numerical values ​​used (e.g., quantities, temperatures, etc.), those skilled in the art should understand that some degree of experimental error or deviation must be taken into account. Unless otherwise specified, parts are by weight, temperatures are in Celsius, and pressures are atmospheric pressure or approximately atmospheric pressure. All MS data were measured using an Agilent 6120 or Agilent 1100. All NMR data were generated using a Varian 400 MR instrument. All reagents and materials used in this invention, except for synthetic intermediates, are commercially available. All compound names, except for reagents, were generated using Chemdraw 16.0.

[0145] If any of the structures disclosed herein contains an atom with an empty valence, that empty valence is a hydrogen atom, which is omitted for convenience.

[0146] In this application, if there is a discrepancy between the name and structure of a compound, and both are shown in reference to the said compound, the structure of the compound shall prevail unless the context makes it clear that the structure of the compound is incorrect and the name is correct.

[0147] List of abbreviations used in the following examples:

[0148] [Table 3] TIFF2026519454000091.tif254170TIFF2026519454000092.tif89170

[0149] Example 1: Compound Synthesis Intermediate I-A1 2-(3-(ethoxymethoxy)-7,8-difluoronaphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Step 1: 8-Bromo-6-(ethoxymethoxy)-1,2-difluoronaphthalene 4-Bromo-5,6-difluoronaphthalen-2-ol (3.74 g, 14.4 mmol) and DIEA (5.60 g, 43.3 mmol) were dissolved in dichloromethane (50 mL), cooled to 0°C, and then (chloromethoxy)ethane (1.77 g, 18.8 mmol) was added. The reaction solution was stirred at 20°C for 1 hour, then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (3.43 g, yield 75%) as a purple solid.

[0150] Step 2: 2-(3-(ethoxymethoxy)-7,8-difluoronaphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 8-Bromo-6-(ethoxymethoxy)-1,2-difluoronaphthalene (3.43 g, 10.8 mmol), B2Pin2 (5.49 g, 12.6 mmol), potassium acetate (3.19 g, 32.4 mmol), and Pd(dppf)Cl2·CH2Cl2 (883 mg, 1.08 mmol) were dissolved in 1,4-dioxane (60 mL) and stirred at 70°C for 5 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (2.37 g, yield 59%) as a purple oil. [M+H] + 365.2

[0151] By following the preparation steps for intermediate I-A1, the intermediates shown in the table below were prepared from the corresponding starting materials and reagents:

[0152] [Table 4]

[0153] Intermediate I-A3 2-(3-chloro-2-cyclopropyl-5-(ethoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Step 1: 1-Bromo-3-chloro-2-cyclopropylbenzene 1-Bromo-3-chloro-2-iodobenzene (11.0 g, 34 mmol), cyclopropylboronic acid (3.9 g, 45 mmol), potassium phosphate (26.5 g, 125 mmol), and Pd(dppf)Cl2 (1.3 g, 0.05 mmol) were dissolved in 1,4-dioxane (100 mL) and water (25 mL), and then stirred at 100°C for 18 hours under nitrogen protection. The reaction solution was diluted with water and extracted with ethyl acetate (100 mL x 2). The organic phase was recovered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (6.9 g, yield 86%) as a white oil.

[0154] Step 2: 2-(3-bromo-5-chloro-4-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1-Bromo-3-chloro-2-cyclopropylbenzene (2.5 g, 10.8 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.1 g, 32.4 mmol), (Ir(OMe)(cod))2 (357 mg, 0.5 mmol), and 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (173 mg, 0.6 mmol) were dissolved in n-heptane (40 mL), and the mixture was stirred at 60°C for 3 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step of the reaction.

[0155] Step 3: 3-Bromo-5-chloro-4-cyclopropylphenol Crude 2-(3-bromo-5-chloro-4-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was dissolved in tetrahydrofuran (30 mL) and water (15 mL), cooled to 0°C, and then acetic acid (40 mL) and 30% aqueous hydrogen peroxide solution (106 mL) were added and the mixture was stirred for 1 hour. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The organic phase was recovered and concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (methanol / water, 0.1% formic acid) to obtain the target product (1.5 g, 2-step yield 50%) as a gray oil. [MH] - 245.0, 246.9

[0156] Step 4: 1-Bromo-3-chloro-2-cyclopropyl-5-(ethoxymethoxy)benzene 3-Bromo-5-chloro-4-cyclopropylphenol (590 mg, 2.4 mmol) and DIEA (925 mg, 7.2 mmol) were dissolved in dichloromethane (6 mL), cooled to 0°C, and then (chloromethoxy)ethane (450 mg, 4.8 mmol) was added. The reaction solution was stirred at 20°C for 1 hour, then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (670 mg, yield 92%) as a colorless oil.

[0157] Step 5: 2-(3-chloro-2-cyclopropyl-5-(ethoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1-Bromo-3-chloro-2-cyclopropyl-5-(ethoxymethoxy)benzene (674 mg, 2.2 mmol), B2Pin2 (1.1 g, 4.4 mmol), potassium acetate (650 mg, 6.6 mmol), and Pd(dppf)Cl2 (925 mg, 0.02 mmol) were dissolved in 1,4-dioxane (100 mL), and the mixture was stirred at 100°C for 18 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (568 mg, yield 73%) as a colorless oil. [M+H] + 353.1

[0158] By following the preparation steps for intermediate I-A3, the intermediates shown in the table below were prepared from the corresponding starting materials and reagents:

[0159] [Table 5]

[0160] Intermediate I-A9 1-(tributylstylinyl)isoquinoline-3-amine [ka] 1-Bromoisoquinoline-3-amine (200 mg, 0.9 mmol), hexa-n-butylditine (626 mg, 1.08 mmol), Pd2(dba)3 (83 mg, 0.09 mmol), PCy3 (50 mg, 0.18 mmol), and lithium chloride (190 mg, 4.5 mmol) were added to a 1,4-dioxane solution (5 mL), and the mixture was stirred at 115°C for 18 hours under nitrogen protection. After filtration, the cake was washed with ethyl acetate (10 mL). The filtrate was collected and concentrated under reduced pressure to obtain the unpurified target compound. This was used directly in the next step of the reaction. [M+H] + 435.2

[0161] Intermediate I-A10 (2-Methoxy-5-(trifluoromethyl)phenyl)boronic acid [ka] Step 1: 2-Bromo-1-methoxy-4-(trifluoromethyl)benzene At room temperature, potassium carbonate (3.8 g, 27.5 mmol) and iodomethane (0.7 mL, 11.4 mmol) were added to a solution of 2-bromo-4-(trifluoromethyl)phenol (2 g, 8.3 mmol) in DMF (20 mL), and the mixture was stirred for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was recovered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (1.65 g, yield 78%) as oil.

[0162] Step 2: (2-Methoxy-5-(trifluoromethyl)phenyl)boronic acid At -70°C, 2.9 mL (7.2 mmol) of 2.5 M n-butyllithium / n-hexane solution was added dropwise to a solution of 2-bromo-1-methoxy-4-(trifluoromethyl)benzene (1.65 g, 6.5 mmol) in diethyl ether (25 mL), and the mixture was stirred for 30 minutes under nitrogen protection. At -70°C, triisopropyl borate (2.4 g, 12.8 mmol) was added dropwise to the reaction solution, and the mixture was gradually heated to room temperature and stirred for 16 hours. 25 mL (2 M) aqueous hydrochloric acid solution was added to the reaction solution and the mixture was vigorously stirred for 2 hours. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was recovered. The mixture was then vacuum concentrated under reduced pressure, the resulting residue was suspended in petroleum ether, filtered, and the cake was recovered. After drying, the target product (450 mg, 32% yield) was obtained.

[0163] Intermediate I-A12 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline [ka] Step 1: 3-Bromo-4-iodo-5-methylaniline At room temperature, 4.8 g of NIS (21.5 mmol) was added to a solution of 3-bromo-5-methylaniline (4.0 g, 21.5 mmol) in DMF (10 mL) and acetic acid (6 mL), and the mixture was stirred for 2 hours. Water (10 mL) was added to the reaction solution, and after extraction with ethyl acetate (40 mL x 2), the organic phase was recovered, concentrated under reduced pressure, and purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the target product (5.4 g, yield 80%) as a yellow solid. [M+H] + 311.9, 313.9

[0164] Step 2: 3-Bromo-4-iodo-N,N-bis(4-methoxybenzyl)-5-methylaniline At room temperature, sodium carbonate (4.6 g, 43.2 mmol), potassium iodide (1.7 g, 10.4 mmol), and PMB-Cl (6.0 g, 38.0 mmol) were added to a solution of 3-bromo-4-iodo-5-methylaniline (5.4 g, 17.3 mmol) in DMF (20 mL). The reaction solution was stirred at 90 °C for 6 hours, cooled to room temperature, quenched with water (10 mL), extracted with ethyl acetate (50 mL x 2), and the organic phase was recovered. After drying over anhydrous sodium sulfate, the mixture was filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was slurryed in ethanol and filtered. The cake was recovered and dried to obtain the target product (7.3 g, yield 77%) as a white solid. [M+H] + 552.0, 554.0

[0165] Step 3: 3-Bromo-N,N-bis(4-methoxybenzyl)-5-methyl-4-(trifluoromethyl)aniline At room temperature, copper iodide (13 g, 66.0 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (5.0 g, 23.6 mmol) were added to a solution of 3-bromo-4-iodo-N,N-bis(4-methoxybenzyl)-5-methylaniline (7.3 g, 13.2 mmol) in DMF (15 mL). The reaction solution was stirred at 90°C for 18 hours, then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (5.1 g, yield 78%) as a yellow solid. [M+H] + 494.0, 496.0

[0166] Step 4: 3-Bromo-5-methyl-4-(trifluoromethyl)aniline 3-Bromo-N,N-bis(4-methoxybenzyl)-5-methyl-4-(trifluoromethyl)aniline (5.1 g, 13.2 mmol) was dissolved in trifluoroacetic acid (20 mL). The reaction solution was stirred at 50°C for 2 hours and then concentrated under reduced pressure. The resulting residue was diluted with water, adjusted to pH=7 by adding sodium bicarbonate, and extracted with ethyl acetate (50 mL x 2). The organic phase was recovered and concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (acetonitrile / water) to obtain the target product (1.3 g, yield 50%) as a yellow solid. [M+H] + 254.0, 256.0

[0167] Step 5: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline 3-Bromo-5-methyl-4-(trifluoromethyl)aniline (1.3 g, 5.1 mmol), B2Pin2 (1.1 g, 12.8 mmol), potassium acetate (1.5 g, 15.3 mmol), and Pd(dppf)Cl2 (372 mg, 0.05 mmol) were dissolved in 1,4-dioxane (100 mL), and the mixture was stirred at 100°C for 18 hours under nitrogen protection. After vacuum concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (718 mg, yield 47%) as a gray oil. [M+H] + 302.2

[0168] By following the preparation steps for intermediate I-A12, the intermediates shown in the table below were prepared from the corresponding starting materials and reagents:

[0169] [Table 6] TIFF2026519454000101.tif146170

[0170] Intermediate I-A13 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((trimethylsilyl)ethinyl)-1H-indazole [ka] Step 1: 3-Bromo-4-iodo-2-methylaniline At room temperature, 3-bromo-2-methylaniline (11.16 g, 60.0 mmol) was dissolved in DMF (36 mL) and acetic acid (90 mL), to which NIS (13.90 g, 61.8 mmol) was added and the mixture was stirred for 2 hours. After vacuum concentration under reduced pressure, the resulting residue was dissolved in ethyl acetate and washed with water. The organic phase was recovered and vacuum concentrated under reduced pressure to obtain the unpurified target product (18.72 g, 100% yield). This was used directly in the next step of the reaction. [M+H] + 311.9, 313.9

[0171] Step 2: 4-bromo-5-iodo-1H-indazole At 0-5°C, a solution of sodium nitrite (4.74 g, 71.8 mmol) in water (47 mL) was added dropwise to a solution of 3-bromo-4-iodo-2-methylaniline (18.0 g, 57.6 mmol) in acetic acid (270 mL). The reaction solution was stirred at room temperature for 16 hours, and then poured into water (1 L). After filtration, the cake was collected and dried to obtain the unpurified target product (100% yield) as a red solid, which was used directly in the next step of the reaction. [M+H] + 322.9, 324.9

[0172] Step 3: 4-bromo-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole At room temperature, DHP (9.69 g, 115.2 mmol) and p-toluenesulfonic acid monohydrate (1.10 g, 5.76 mmol) were added to a solution of 4-bromo-5-iodo-1H-indazole (57.6 mmol) in dichloromethane (200 mL), and the mixture was stirred for 2 hours. The reaction solution was washed with aqueous sodium bicarbonate, the organic phase was recovered, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the target product (12.1 g, yield 52%) as a brown solid. [M+H] + 406.9, 408.9

[0173] Step 4: 4-Bromo-1-(tetrahydro-2H-pyran-2-yl)-5-((trimethylsilyl)ethinyl)-1H-indazole 4-Bromo-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (4.73 g, 11.6 mmol), trimethylsilylacetylene (23.2 mL), Pd(PPh3)2Cl2 (204 mg, 0.29 mmol), copper iodide (111 mg, 0.59 mmol), and triethylamine (23.2 mL) were added to tetrahydrofuran (23.2 mL) and stirred at 30°C for 2 hours under nitrogen protection. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (3.30 g, yield 75%) as a brown oil. [M+H] + 377.0, 379.0

[0174] Step 5: 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((trimethylsilyl)ethinyl)-1H-indazole 4-Bromo-1-(tetrahydro-2H-pyran-2-yl)-5-((trimethylsilyl)ethynyl)-1H-indazole (3.38 g, 8.94 mmol), B2Pin2 (4.54 g, 17.9 mmol), potassium phosphate trihydrate (7.15 g, 26.8 mmol), cataCXium A Pd-G3 (0.66 g, 0.89 mmol), and Pd(dppf)Cl2·CH2Cl2 (0.73 g, 0.89 mmol) were added to 1,4-dioxane (52 mL), and the mixture was stirred at 80°C for 16 hours under nitrogen protection. After vacuum concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (560 mg, yield 15%) as a red oil. [M+H] + 425.3

[0175] Intermediate I-A15 3-Chloro-4-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline [ka] Step 1: 3-Bromo-5-chloro-4-cyclopropylaniline 3-Bromo-5-chloro-4-iodoaniline (1.30 g, 3.9 mmol), cyclopropylboronic acid (605 mg, 7.0 mmol), cesium carbonate (2.55 g, 7.8 mmol), and Pd(dppf)Cl2·CH2Cl2 (319 mg, 0.39 mmol) were dissolved in 1,4-dioxane (50 mL) and water (5 mL), and then stirred at 110°C for 4 hours under nitrogen protection. After vacuum concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (650 mg, yield 67%) as a white solid.

[0176] Step 2: 3-Chloro-4-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline 3-Bromo-5-chloro-4-cyclopropylaniline (450 mg, 1.8 mmol), B2Pin2 (558 mg, 2.2 mmol), potassium acetate (539 mg, 5.5 mmol), and Pd(dppf)Cl2·CH2Cl2 (149 mg, 0.18 mmol) were dissolved in 1,4-dioxane (100 mL), and the mixture was stirred at 90°C for 18 hours under nitrogen protection. After vacuum concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (280 mg, yield 52%) as a red oil. [M+H] + 294.2

[0177] By following the preparation steps for intermediate I-A15, the intermediates shown in the table below were prepared from the corresponding starting materials and reagents:

[0178] [Table 7]

[0179] Intermediate I-A72 5-Fluoro-1-((trifluoromethyl)sulfonyl)-1H-benzo[f]indazole-4-yltrifluoromethanesulfonate [ka] Step 1: 5-((2-bromo-3-fluorophenyl)(hydroxy)methyl)-N-methoxy-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide Under nitrogen protection at -78°C, 10.5 mL (21.0 mmol) of 2N LDA / tetrahydrofuran solution was added dropwise to 50 mL (50 mL) of N-methoxy-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (6.00 g, 21.0 mmol) in tetrahydrofuran solution. After stirring for 30 minutes, 5 mL (5 mL) of 2-bromo-3-fluorobenzaldehyde (6.40 g, 31.5 mmol) in tetrahydrofuran solution was added dropwise. The reaction solution was stirred at -78°C for 1 hour, then heated to room temperature and stirred overnight. The mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was recovered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (6.00 g, yield 58%) as a white solid. [M+H] + 488.2,490.2

[0180] Step 2: 5-(2-bromo-3-fluorobenzyl)-N-methoxy-N-methyl-1H-pyrazole-4-carboxamide A solution of 5-((2-bromo-3-fluorophenyl)(hydroxy)methyl)-N-methoxy-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (6.00 g, 12.3 mmol), trifluoroacetic acid (20 mL), and triethylsilane (20 mL) in dichloromethane (40 mL) was stirred at 60°C for 16 hours under nitrogen protection. After vacuum concentration under reduced pressure, the resulting residue was diluted with ethyl acetate, adjusted to pH 8 with 2N sodium hydroxide aqueous solution, and extracted with ethyl acetate (30 mL x 3). The organic phase was recovered and combined, vacuum concentrated under reduced pressure, and then purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (3.50 g, yield 83%) as a yellow solid. [M+H] + 342.2,344.2

[0181] Step 3: 5-Fluoro-2,9-dihydro-4H-benzo[f]indazole-4-one At 0°C, a 1.3N isopropylmagnesium chloride-lithium chloride / tetrahydrofuran (31.5 mL, 40.9 mmol) solution was added dropwise to a tetrahydrofuran (35 mL) solution of 5-(2-bromo-3-fluorobenzyl)-N-methoxy-N-methyl-1H-pyrazole-4-carboxamide (3.50 g, 10.2 mmol), and the mixture was stirred under nitrogen protection for 2 hours. The reaction solution was quenched with 1N hydrochloric acid to pH 5, then adjusted to pH 8 with a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate (30 mL x 3). The organic phase was collected, combined, and concentrated under reduced pressure. The resulting residue was washed with ethyl acetate to obtain the target product (1.44 g, yield 70%) as a yellow solid. [M+H] + 203.2

[0182] Step 4: 5-Fluoro-1-((trifluoromethyl)sulfonyl)-1H-benzo[f]indazole-4-yltrifluoromethanesulfonate At -10°C, trifluoromethanesulfonic anhydride (5.86 g, 20.8 mmol) was added dropwise to a solution of 5-fluoro-2,9-dihydro-4H-benzo[f]indazole-4-one (700 mg, 3.5 mmol) and DIEA (2.68 g, 20.8 mmol) in dichloromethane (10 mL), and the mixture was stirred for 1 hour under nitrogen protection. The reaction solution was diluted with dichloromethane and washed with a saturated aqueous solution of sodium chloride. The organic phase was recovered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (1.20 g, yield 74%) as a yellow solid. [M+H] + 467.2

[0183] By following the preparation steps for intermediate I-A72, the intermediates shown in the table below were prepared from the corresponding starting materials and reagents:

[0184] [Table 8]

[0185] Intermediate I-A73 4-Bromo-7-fluoro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazole [ka] Step 1: 6-bromo-3,4-difluoro-2-methylaniline At room temperature, NBS solid (97.61 g, 548 mmol) was added in several portions to a solution of 3,4-difluoro-2-methylaniline (78.5 g, 548 mmol) in DMF (780 mL), and the mixture was stirred for 30 minutes. The reaction solution was poured into water (2.4 L) and extracted twice with petroleum ether / ethyl acetate (400 mL / 400 mL). The organic phases were collected, combined, and then concentrated under reduced pressure to obtain the target product (121 g, 99% yield) as a red oil, which was used directly in the next step of the reaction.

[0186] Step 2: 1-Bromo-4,5-difluoro-2-iodo-3-methylbenzene At 0°C, 12N hydrochloric acid (65 mL, 780 mmol) was added dropwise to a solution of 6-bromo-3,4-difluoro-2-methylaniline (51.9 g, 234 mmol) in acetonitrile (500 mL). While maintaining the internal temperature at 0°C, an aqueous solution of sodium nitrite (19.35 g, 281 mmol) (100 mL) was added dropwise, and the mixture was stirred for 30 minutes. Then, a solution of potassium iodide (46.6 g, 281 mmol) in water (100 mL) was added dropwise, the mixture was heated to room temperature, and stirred for 3 hours. The resulting solution was adjusted to pH 8-9 with 1N sodium hydroxide aqueous solution and extracted with ethyl acetate (400 mL x 2). The organic phase was recovered and combined, washed with aqueous sodium thiosulfate (100 mL), and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (62.7 g, yield 83%) as a white solid. [M+H] + 294.2

[0187] Step 3: 1-Bromo-4,5-difluoro-3-methyl-2-(trifluoromethyl)benzene A mixture of 1-bromo-4,5-difluoro-2-iodo-3-methylbenzene (62.7 g, 188 mmol), copper iodide (305 g, 1.6 mol), 2,2-difluoro-2-(fluorosulfonyl)methyl acetate (307 g, 1.6 mol), and DMF (750 mL) was stirred at 65°C for 16 hours under nitrogen protection. After filtration, the filtrate was diluted with water (2 L) and extracted with ethyl acetate (600 mL x 2). The organic phases were recovered and combined, washed with a saturated aqueous solution of sodium chloride, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (44 g, yield 85%) as a colorless oil.

[0188] Step 4: 2-Bromo-5,6-difluoro-4-methyl-3-(trifluoromethyl)benzaldehyde Under nitrogen protection at -78°C, 176 mL (176 mmol) of 1N LDA / tetrahydrofuran solution was added dropwise to 200 mL of tetrahydrofuran solution of 1-bromo-4,5-difluoro-3-methyl-2-(trifluoromethyl)benzene (44 g, 156 mmol), and the mixture was stirred for 30 minutes. Then, 23.4 g (320 mmol) of DMF was added dropwise, and the mixture was stirred for 2 hours. The reaction solution was poured into 1 L of ice-cold saturated aqueous solution of ammonium chloride and extracted with ethyl acetate (300 mL x 2). The organic phases were collected and combined, and concentrated under reduced pressure to obtain the target product (48.5 g, 100% yield) as a yellow oil, which was used directly in the next step of the reaction.

[0189] Step 5: 4-bromo-7-fluoro-6-methyl-5-(trifluoromethyl)-1H-indazole 2-Bromo-5,6-difluoro-4-methyl-3-(trifluoromethyl)benzaldehyde (48.5 g, 156 mmol) was dissolved in tetrahydrofuran (200 mL), and 98% hydrazine hydrate (24.03 g, 50.06 mmol) was added. The mixture was stirred at 60°C for 2 hours. The reaction solution was diluted with ethyl acetate (300 mL) and washed with a saturated aqueous solution of sodium chloride. The organic phase was collected and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was suspended in dichloromethane (50 mL). After filtration, the resulting solid was collected and dried to obtain the target product (32.7 g, yield 69%) as a yellow solid. [M+H] + 296.8, 298.8.

[0190] Step 6: 4-Bromo-7-fluoro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazole At room temperature, 4-bromo-7-fluoro-6-methyl-5-(trifluoromethyl)-1H-indazole (32.4 g, 109 mmol) and dihydropyran (27.5 g, 327 mmol) were dissolved in 100 mL of dichloromethane, to which p-toluenesulfonic acid monohydrate (2.07 g, 10.9 mmol) was added and the mixture was stirred for 12 hours. The reaction solution was washed with water (50 mL), extracted with dichloromethane (100 mL x 2), and the organic phase was collected and combined. The mixture was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (34.3 g, yield 83%) as a white solid. [M+H] + 381.2, 383.2

[0191] By following the preparation steps for intermediate I-A73, the intermediates shown in the table below were prepared from the corresponding starting materials and reagents:

[0192] [Table 9]

[0193] Intermediate I-A77 4-Bromo-5,5-difluoro-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7-tetrahydrocyclopenta[f]indazole [ka] Step 1: 7-bromo-5-fluoro-2,3-dihydrospiro[indene-1,2'-[1,3]dithiolane] 7-Bromo-5-fluoro-2,3-dihydro-1H-inden-1-one (10.0 g, 43.7 mmol), 1,2-ethanedithiol (4.11 g, 43.7 mmol), and p-toluenesulfonic acid monohydrate (1.66 g, 8.7 mmol) were dissolved in toluene (200 mL) and stirred at 120 °C for 6 hours. The reaction solution was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium chloride. The organic phase was recovered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (12.8 g, yield 96%) as a white solid.

[0194] Step 2: 7-bromo-1,1,5-trifluoro-2,3-dihydro-1H-indene Under nitrogen protection at -78°C, a mixture of 7-bromo-5-fluoro-2,3-dihydrospiro[idden-1,2'-[1,3]dithiolane] (22.5 g, 78.6 mmol) in dichloromethane (100 mL) was mixed with pyridine hydrofluoride (20 mL), stirred for 30 minutes, and then a solution of 1,3-dibromo-5,5-dimethylimidazolidined-2,4-dione (6.0 g, 19.7 mmol) in dichloromethane (100 mL) was added dropwise. The mixture was stirred at -78°C for 2 hours, heated to room temperature, and then stirred for a further 3 hours. The reaction solution was poured into 100 mL of 1N sodium hydroxide aqueous solution and washed with sodium bisulfite aqueous solution. The organic phase was recovered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol / water) to obtain the target product (960 mg, yield 19%) as a colorless solid.

[0195] Step 3: 4-bromo-5,5-difluoro-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7-tetrahydrocyclopenta[f]indazole Following steps 4-6 of the preparation of intermediate I-A73, the target product (630 mg, 3-step yield 47%) was prepared as a colorless oil from 7-bromo-1,1,5-trifluoro-2,3-dihydro-1H-indene (950 mg). [M+H] + 357.0, 359.2

[0196] By following the preparation steps for intermediate I-A77, the intermediates shown in the table below were prepared from the corresponding starting materials and reagents:

[0197] [Table 10]

[0198] Intermediate I-A81 4-Bromo-3,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazole [ka] Step 1: 4-bromo-3-iodo-6-methyl-5-(trifluoromethyl)-1H-indazole At room temperature, iodine (9.50 g, 37.5 mmol) was added to a solution of 4-bromo-6-methyl-5-(trifluoromethyl)-1H-indazole (4.20 g, 15.0 mmol) and potassium hydroxide (2.50 g, 45.0 mmol) in DMF (20 mL), and the mixture was stirred for 16 hours. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium sulfite solution, and the organic phase was recovered. The mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (4.0 g, yield 66%) as a yellow solid. [M+H] + 404.4, 406.4

[0199] Step 2: 4-bromo-3-iodo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazole At room temperature, 4-bromo-3-iodo-6-methyl-5-(trifluoromethyl)-1H-indazole (2.0 g, 4.94 mmol) and dihydropyran (830 mg, 9.88 mmol) were dissolved in dichloromethane (20 mL), to which p-toluenesulfonic acid monohydrate (94 mg, 0.49 mmol) was added and the mixture was stirred for 16 hours. The reaction solution was washed with aqueous sodium bicarbonate (20 mL), extracted with dichloromethane (20 mL x 2), and the organic phase was collected and combined, then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (2.0 g, yield 83%) as a white solid.

[0200] Step 3: 4-Bromo-3,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazole Under nitrogen protection, 1.0 g, 2.04 mmol of 1N dimethylzine / toluene solution (2.2 mL, 2.2 mmol) was added to a solution of 4-bromo-3-iodo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazole (1.0 g, 2.04 mmol) and Pd(dppf)Cl2 (165 mg, 0.204 mmol) in 1,4-dioxane (10 mL). The reaction solution was stirred at 100 °C for 1 hour, then cooled, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution, and the organic phase was recovered. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (500 mg, yield 65%) as a yellow solid. [M+H] + 377.0, 379.0

[0201] By following the preparation steps for intermediate I-A81, the intermediates shown in the table below were prepared from the corresponding starting materials and reagents:

[0202] [Table 11]

[0203] Intermediate I-A83 4-Bromo-3-chloro-7-fluoro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazole [ka] Step 1: 4-Bromo-3-chloro-7-fluoro-6-methyl-5-(trifluoromethyl)-1H-indazole 4-bromo-7-fluoro-6-methyl-5-(trifluoromethyl)-1H-indazole (620 mg, 2.09 mmol) was dissolved in DMF (5 mL) and NCS (279 mg, 2.09 mmol) was added. The mixture was stirred at 60°C for 16 hours under nitrogen protection. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was recovered. The mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol / water, 0.1% formic acid) to obtain the target product (470 mg, 68% yield) as a white solid. [M+H] + 332.0

[0204] Step 2: 4-Bromo-3-chloro-7-fluoro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazole The target product was prepared according to step 2 of the preparation of intermediate I-A81. [M+H] + 416.0

[0205] Intermediate I-B4 (S)-(1-(2,2-difluoroethyl)azetidine-2-yl)methanol [ka] At 0°C, 2,2-difluoroethyltrifluoromethanesulfonate (1.18 g, 5.5 mmol) was added dropwise to a solution of (S)-azetidine-2-ylmethanol (436 mg, 5.0 mmol) and potassium carbonate (1.38 g, 10.0 mmol) in acetonitrile (15 mL). The reaction solution was stirred at room temperature for 5 hours. After filtration, the filtrate was collected and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain the target product (420 mg, yield 56%) as a colorless oil. [M+H] + 152.1

[0206] Intermediate I-B10 ((2S,4R)-4-fluoro-1-methylpyrrolidine-2-yl)methanol [ka] At -10°C, lithium aluminum hydride (461 mg, 12.1 mmol) was added in several portions to a solution of 1-(tert-butyl)2-methyl(2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate (1.0 g, 4.04 mmol) in tetrahydrofuran (15 mL) and the mixture was stirred for 30 minutes. The reaction solution was heated to 70°C and stirred for 3 hours. After cooling to room temperature, a saturated aqueous solution of sodium sulfate was added dropwise, followed by filtration. The filtrate was collected, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain the target product (200 mg, yield 38%) as oil. [M+H] + 134.2. 1 H NMR(400MHz,CDCl3)δ 5.20-4.98(m,1H),3.74-3.66(m,1H),3.57-3.30(m,2H),2.86-2.49(m,3H),2.38(s,3H),2.17-1.93(m,2H)

[0207] Intermediate I-B11 (R)-(1-(2-fluoroethyl)pyrrolidine-2-yl)methanol [ka] Step 1: 2-Fluoroethyl-4-methylbenzenesulfonate At 0°C, triethylamine (1.86 mL, 13.3 mmol), Tos-Cl (2.22 g, 11.7 mmol) in a 4 mL solution of dichloromethane, and DMAP (105 mg, 0.86 mmol) were added to a 2-fluoroethanol (500 mg, 7.8 mmol) in a 10 mL solution of dichloromethane. The reaction solution was stirred at room temperature for 16 hours, then diluted with dichloromethane, sequentially washed with 1 M aqueous hydrochloric acid and aqueous potassium carbonate, and the organic phase was recovered. The mixture was then vacuum concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (1.5 g, yield 59%) as a yellow oil. [M+H] + 219.1

[0208] Step 2: (R)-(1-(2-fluoroethyl)pyrrolidine-2-yl)methanol At room temperature, 2-fluoroethyl 4-methylbenzenesulfonate (1.0 g, 4.58 mmol), D-prolinol hydrochloride (628 mg, 4.58 mmol), and potassium carbonate (1.6 g, 11.4 mmol) were added to acetonitrile (10 mL) and stirred for 16 hours. After filtration, the filtrate was collected and concentrated under reduced pressure. The resulting residue was purified by column chromatography (dichloromethane / methanol) using silicic acid to obtain the target product (120 mg, yield 18%) as a yellow oil. [M+H] + 148.4. 1 H NMR(400MHz,CDCl3)δ 4.65-4.36(m,2H),3.64-3.58(m,1H),3.44-3.36(m,1H),3.28-3.20(m,1H) ,3.12-2.97(m,1H),2.75-2.41(m,3H),2.41-2.30(m,1H),1.92-1.65(m,4H)

[0209] Intermediate I-B15 (S)-(1-(methyl-d3)pyrroridine-2-yl-5,5-d2)methane-d2-ol [ka] At 0°C, lithium aluminum deuteride (2.61 g, 62.1 mmol) was added in several portions to a solution of 1-(tert-butyl)-2-methyl(S)-5-oxopyrrolidine-1,2-dicarboxylate (3.02 g, 12.4 mmol) in tetrahydrofuran (55 mL). The reaction solution was stirred at 70°C for 3 hours. After cooling to 0°C, water (2.6 mL) was added dropwise, followed by 15% sodium hydroxide aqueous solution (2.6 mL) and water (7.8 mL). After filtration, the cake was washed with dichloromethane (100 mL). The filtrate was collected, washed with water, and the organic phase was collected and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under atmospheric pressure to obtain the unpurified target product (758 mg, yield 50%) as oil, which was used directly in the next step of the reaction. [M+H] + 123.2. 1 H NMR(400MHz,CD3OD)δ 2.38-2.29(m,1H),2.02-1.91(m,1H),1.78-1.66(m,2H),1.64-1.53(m,1H)

[0210] By following the preparation steps for intermediate I-B15, the intermediates shown in the table below were prepared from the corresponding starting materials and reagents:

[0211] [Table 12]

[0212] Intermediate I-B18 (S)-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyrrolidine-2-yl)methanol [ka] (S)-Pyrrolidine-2-ylmethanol (250 mg, 2.47 mmol), (2-bromoethoxy)(tert-butyl)dimethylsilane (591 mg, 2.47 mmol), and potassium carbonate (681 mg, 4.94 mmol) were added to acetonitrile (15 mL). The reaction solution was stirred at 60°C for 24 hours. After vacuum concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (water / methanol) to obtain the target product (450 mg, 70% yield) as a yellow oil. [M+H] + 260.2

[0213] Intermediate I-B23 (S)-(1-(oxetan-3-yl)pyrrolidine-2-yl)methanol [ka] At room temperature, (S)-pyrrolidine-2-ylmethanol (1.62 g, 16.0 mmol) and oxetane-3-one (1.61 g, 22.4 mmol) were added to dichloromethane (64 mL) and stirred for 10 minutes. Sodium triacetoxyborohydride (6.60 g, 32.0 mmol) was added to the reaction solution and stirred at room temperature for 2 hours. After vacuum concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain the target product (1.79 g, yield 71%) as a yellow oil. [M+H] + 158.2

[0214] Intermediate I-B26 ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl-2,5,5-dimethyl)methanol [ka] Step 1: Ethyl(7aS)-2-hydroxy-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate-2-d At 0°C, sodium borode deuteride (280 mg, 6.68 mmol) was added in several portions to a 50 mL solution of ethyl(S)-2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (4.7 g, 22.3 mmol) in ethanol, and the mixture was stirred for 10 minutes. The reaction solution was quenched with aqueous ammonium chloride, then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain the target product (3.3 g, yield 69%) as a colorless oil. [M+H] + 215.1

[0215] Step 2: Ethyl(2R,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate-2-d Under nitrogen protection at -70°C, DAST (3.3 g, 21 mmol) was added dropwise to a solution of ethyl(7aS)-2-hydroxy-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate-2-d (3.0 g, 14.0 mmol) in dichloromethane (50 mL). The reaction solution was gradually heated to room temperature and stirred for 16 hours. The reaction solution was quenched with methanol, water was added, and then extracted with dichloromethane. The organic phase was recovered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (800 mg, yield 26%) as oil. [M+H] + 217.1

[0216] Step 3: (6R,7aS)-6-fluoro-7a-(hydroxymethyl)hexahydro-3H-pyrrolidine-3-one-6-d At 0°C, sodium borohydride (168 mg, 4.40 mmol) was added to a solution of ethyl(2R,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate-2-d (800 mg, 3.68 mmol) in anhydrous ethanol (10 mL). The reaction solution was stirred at room temperature for 1 hour. The reaction solution was quenched with aqueous ammonium chloride solution, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain the target product (650 mg, yield 101%) as oil. [M+H] + 175.1

[0217] Step 4: ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl-2,5,5-dimethyl)methanol The target product was prepared from the corresponding intermediate and reagent according to the preparation steps for intermediate I-B15. [M+H] + 163.2

[0218] By following the preparation steps for intermediate I-B26, the intermediates shown in the table below were prepared from the corresponding starting materials and reagents:

[0219] [Table 13]

[0220] Intermediate I-B40 (1-((cyclopropyl(methyl)amino)methyl)cyclopropyl)methanol [ka] Step 1: Methyl 1-(cyclopropyl(methyl)carbamoyl)cyclopropane-1-carboxylate At room temperature, DIEA (3.15 g, 24.4 mmol) was added to a solution of 1,1-cyclopropanedicarboxylic acid monomethyl ester (880 mg, 6.1 mmol), N-methylcyclopropanamine (845 mg, 7.9 mmol), and HATU (3.00 g, 7.9 mmol) in DMF (8 mL), and the mixture was stirred for 1 hour. The reaction solution was purified by silica gel column chromatography (water / methanol) to obtain the target product (1.0 g, yield 83%) as a colorless oil. [M+H] + 184.1

[0221] Step 2: (1-((cyclopropyl(methyl)amino)methyl)cyclopropyl) methanol At 0°C, lithium aluminum hydride (475 mg, 12.5 mmol) was added to a solution of methyl 1-(cyclopropyl(methyl)carbamoyl)cyclopropane-1-carboxylate (1.0 g, 5.07 mmol) in tetrahydrofuran (20 mL). The reaction solution was stirred at 50°C for 3 hours, then cooled to 0°C, quenched with ethyl acetate, and poured into water. After filtration, the filtrate was washed with methanol. The filtrate was collected, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain the target product (700 mg, yield 89%) as a colorless oil. [M+H] + 156.1

[0222] Intermediate I-C1 5,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine-4(3H)-one [ka] Step 1: 2,6-Dichloro-3-fluoropyridine-4-amine At room temperature, Select Fluor (146.7 g, 414 mmol) was added to a methanol / water (500 mL / 100 mL) solution of 2,6-dichloropyridine-4-amine (60.0 g, 368 mmol). The reaction solution was stirred at 50°C for 16 hours, then cooled to room temperature and concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, and the organic phase was recovered. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (42.0 g, yield 63%) as a white solid. [M+H] + 181.0,183.1

[0223] Step 2: tert-butyl(tert-butoxycarbonyl)(2,6-dichloro-3-fluoropyridine-4-yl)carbamate At room temperature, DMAP (1.42 g, 11.6 mmol) and (Boc)2O (126.6 g, 580 mmol) were added to a solution of 2,6-dichloro-3-fluoropyridine-4-amine (42.0 g, 232 mmol) in tetrahydrofuran (100 mL). The reaction solution was stirred at 70°C for 4 hours, then cooled to room temperature and concentrated under reduced pressure. The resulting residue was slurryed in methanol and filtered. The cake was collected and dried to obtain the target product (73.0 g, 83% yield) as a white solid. [M+H] + 381.1,383.1

[0224] Step 3: tert-butyl 4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate Under nitrogen protection at -70°C, 287 mL (574 mmol) of 2.0 M LDA / tetrahydrofuran / n-hexane solution was added dropwise to a solution of tert-butyl(tert-butoxycarbonyl)(2,6-dichloro-3-fluoropyridine-4-yl)carbamate (73.0 g, 191 mmol) in tetrahydrofuran (500 mL), and the mixture was stirred at this temperature for 1 hour. The reaction solution was quenched with acetic acid, diluted with ethyl acetate, and washed with water. The organic phase was recovered, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (51.0 g, yield 70%) as a white solid. [M+H] + 381.1,383.1

[0225] Step 4: 4-amino-2,6-dichloro-5-fluoronicotinate At room temperature, tert-butyl 4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate (51.0 g, 134 mmol) was dissolved in 1,4-dioxane (200 mL) and concentrated hydrochloric acid (50 mL) was added. The reaction solution was stirred at 35 °C for 16 hours, then concentrated under reduced pressure to obtain the unpurified target product (34.9 g, 100% yield), which was used directly in the next reaction. [M+H] + 225.0, 227.0

[0226] Step 5: 5,7-Dichloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidine-4(3H)-one At room temperature, unpurified 4-amino-2,6-dichloro-5-fluoronicotinate (34.9 g, 134 mmol) was dissolved in thionyl chloride (300 mL). The reaction solution was stirred at 50°C for 3 hours, cooled to room temperature, and then concentrated under reduced pressure. The resulting residue was dissolved in acetone (200 mL), and the resulting solution was added dropwise to a solution of ammonium thiocyanate (30.7 g, 403 mmol) in acetone (300 mL), and stirred at room temperature for 1 hour. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was recovered. The crude product (35.0 g, 98% yield) was concentrated under reduced pressure and used directly in the next step. [M+H] + 265.9, 267.9

[0227] Step 6: 5,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine-4(3H)-one At room temperature, a solution of sodium hydroxide (10.5 g, 263 mmol) in 500 mL of water and iodomethane (37.4 g, 263 mmol) were added to a solution of unpurified 5,7-dichloro-8-fluoro-2-mercaptopirido[4,3-d]pyrimidine-4(3H)-one (35.0 g, 132 mmol) in 500 mL of methanol, and the mixture was stirred for 2 hours. The reaction solution was diluted with water (1 L) and adjusted to pH=6 with concentrated hydrochloric acid. After filtration, the cake was washed with water and dried. The resulting solid was suspended in acetonitrile, filtered, and dried to obtain the target product (33.2 g, 90% yield) as a yellow solid. [M+H] + 280.0, 281.9

[0228] Intermediate I-C2 2-((1-(2-aminopyridine-3-yl)ethyl)amino)ethane-1-ol [ka] At room temperature, tetraethyl titanate (1 L) was added to a solution of 1-(2-aminopyridine-3-yl)ethane-1-one (100.0 g, 734 mmol) and 2-aminoethane-1-ol (134.6 g, 2.2 mol) in ethanol (1 L). The reaction solution was stirred at 90°C for 16 hours, then cooled to 15-20°C. Sodium borohydride (38.9 g, 1.03 mol) was slowly added in several portions, and after the addition was complete, the solution was stirred at room temperature for 2 hours. The reaction solution was poured into water (5 L), filtered, and the cake was washed with ethanol (0.5 L). The filtrate was collected and combined, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain the target product (92.0 g, yield 70%) as a yellow solid. [M+H] + 182.2

[0229] Intermediate I-C3 3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)ethyl)pyridine-2-amine [ka] Step 1: 5-(2-((1-(2-aminopyridine-3-yl)ethyl)amino)ethoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine-4-ol At -5 to 0°C, 60% sodium hydride (2.57 g, 107.1 mmol) was added to a solution of intermediate I-C2 (7.76 g, 42.8 mmol) in tetrahydrofuran (200 mL) and the mixture was stirred at 0°C for 40 minutes. At -5 to 0°C, intermediate I-C1 (10.0 g, 35.7 mmol) was added to the reaction solution and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water, adjusted to pH=4 with 1.2 M hydrochloric acid, and extracted twice with dichloromethane. The aqueous phase was collected and adjusted to pH=7 with sodium bicarbonate powder. After filtration, the cake was collected and dried to obtain the unpurified target product (12.0 g, yield 79%) as a yellow solid, which was used directly in the next step of the reaction. [M+H] +424.1

[0230] Step 2: 3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)ethyl)pyridine-2-amine At room temperature, BOP-Cl (8.63 g, 33.9 mmol) and DIEA (10.95 g, 84.7 mmol) were added to a solution of 5-(2-((1-(2-aminopyridine-3-yl)ethyl)amino)ethoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine-4-ol (12.0 g, 28.2 mmol) in chloroform (250 mL). The reaction solution was stirred at 65 °C for 4 hours, then concentrated under reduced pressure. The resulting residue was slurryed in methanol, filtered, and the cake was recovered and dried to obtain the unpurified target product (8.8 g, 76% yield) as a yellow solid, which was used directly in the next step of the reaction. [M+H] + 407.1

[0231] By following the preparation steps for intermediates I-C3, the intermediates shown in the table below were prepared from the corresponding starting materials and reagents:

[0232] [Table 14] TIFF2026519454000128.tif255170

[0233] Intermediate I-C4 3-(1-(5-chloro-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)ethyl)pyridine-2-amine [ka] Step 1: 4-amino-2,6-dichloro-5-fluoronicotinamide At room temperature, DIEA (1.3 mL, 7.95 mmol), HATU (2.0 g, 5.30 mmol), and ammonium chloride (430 mg, 7.95 mmol) were added to a solution of 4-amino-2,6-dichloro-5-fluoronicotinic acid (700 mg, 2.65 mmol) in DMF (7 mL) and stirred for 2 hours. After vacuum concentration under reduced pressure, the residue was purified by silica gel column chromatography (methanol / water) to obtain the target product (660 mg, yield 111%) as a white solid. [M+H] + 224.0

[0234] Step 2: 5,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-ol A mixture of 4-amino-2,6-dichloro-5-fluoronicotinamide (660 mg, 2.95 mmol) and triethyl orthoformate (3 mL) was stirred at 140°C for 18 hours. After cooling to room temperature, ethyl acetate (20 mL) was added to the reaction solution. After filtration, the cake was washed with ethyl acetate and dried to obtain the target product (370 mg, yield 54%) as a yellow solid. [M+H] + 234.0

[0235] Step 3: 3-(1-(5-chloro-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)ethyl)pyridine-2-amine The target product was prepared from the corresponding intermediates and reagents according to the preparation steps for intermediates I-C3. [M+H] + 361.1

[0236] Intermediate I-C5 5-Chloro-4-fluoro-2-(methylthio)-10-(1-(pyridazin-3-yl)ethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene [ka] Step 1: 2-((1-(pyridazine-3-yl)ethyl)amino)ethane-1-ol At room temperature, 34 g of 4A molecular sieve was added to a solution of 1,4-dioxane (102 mL) containing 5.0 g, 41 mmol of 1-(pyridazin-3-yl)ethane-1-one and 7.5 g, 123 mol of 2-aminoethane-1-ol. The reaction solution was stirred at 100°C for 16 hours, then cooled to room temperature, filtered, and the filtrate was collected and concentrated under reduced pressure. At 0-5°C, sodium borohydride (2.63 g, 69 mmol) was slowly added in several portions to a methanol (102 mL) solution of the resulting residue. After the addition was complete, the solution was stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction solution and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain the target product (5.45 g, yield 79%) as a yellow oil. [M+H] + 168.2

[0237] Step 2: 5-Chloro-4-fluoro-2-(methylthio)-10-(1-(pyridazin-3-yl)ethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene The target product was prepared from the corresponding intermediates and reagents according to the preparation steps for intermediates I-C3. [M+H] + 391.3

[0238] Intermediate I-C6 3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl-8,8-d2)ethyl)pyridine-2-amine [ka] Step 1: Ethyl glycinate (1-(2-aminopyridine-3-yl)ethyl) At room temperature, 12 mL of tetraethyl titanate was added to a solution of 1-(2-aminopyridine-3-yl)ethane-1-one (2.6 g, 19.0 mmol) and glycine ethyl hydrochloride (4.0 g, 28.6 mmol) in ethanol (12 mL). The reaction solution was stirred at 90 °C for 10 hours, then cooled to 15-20 °C. Sodium borohydride (2.17 g, 57.0 mmol) was slowly added in several portions, and after the addition was complete, the solution was stirred at room temperature for 2 hours. The reaction solution was poured into water (100 mL), filtered, and the cake was washed with dichloromethane / methanol. The filtrate was collected and combined, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain the target product (1.2 g, yield 28%) as a yellow oil. [M+H] + 224.2

[0239] Step 2: 2-((1-(2-aminopyridine-3-yl)ethyl)amino)ethane-1,1-d2-1-ol The target product was prepared from lithium aluminum deuteride and the corresponding intermediates and reagents according to the preparation steps for intermediate I-B10. [M+H] + 184.2

[0240] Step 3: 3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl-8,8-d2)ethyl)pyridine-2-amine The target product was prepared from the corresponding intermediates and reagents according to the preparation steps for intermediates I-C3. [M+H] + 409.1

[0241] By following the preparation steps for intermediates I-C6, the intermediates shown in the table below were prepared from the corresponding starting materials and reagents:

[0242] [Table 15]

[0243] Intermediates I-C8 and I-C9 3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)ethyl)pyridine-2-amine enantiomer [ka] Step 1: 2-((1-(2-aminopyridine-3-yl)ethyl)amino)ethane-1-ol enantiomer 2-((1-(2-aminopyridine-3-yl)ethyl)amino)ethane-1-ol (60.0 g) was separated by chiral HPLC to obtain a pair of enantiomers. Chiral HPLC analysis conditions: Column: OD-H (0.46 cm ID × 15 cm L); Mobile phase: Carbon dioxide / ethanol (0.05% ethylenediamine) = 70:30; Flow rate: 2.5 mL / min; Detector: UV 254 nm; First eluent (19.0 g, RT = 2.877 min), ee% = 100%; Second eluent (17.5 g, RT = 3.124 min), ee% = 100%.

[0244] Steps 2 and 3: 3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)ethyl)pyridine-2-amine enantiomer Following the preparation steps for intermediates I-C3, the target intermediate was prepared from the corresponding chiral starting materials and reagents. The enantiomers in the table were subjected to chiral HPLC analysis under the following conditions (flow rate: 1 mL / min; detector: UV 254 nm):

[0245] [Table 16]

[0246] Intermediate I-C14 3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)cyclopropyl)-N-(4-methoxybenzyl)pyridine-2-amine [ka] Step 1: Ethyl 1-(2-chloropyridine-3-yl)cyclopropane-1-carboxylate At -5 to 0°C, 60% sodium hydroxide (3.26 g, 81.6 mmol) was added to a solution of 2-(2-chloropyridine-3-yl)ethyl acetate (3.99 g, 20.0 mmol) in DMF (80 mL) and stirred at 0°C for 1 hour. At -5 to 0°C, 1,2-dibromoethane (5.65 g, 30.0 mmol) was added to the reaction solution and stirred at 0°C for 2 hours. The reaction solution was poured into an aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was recovered, washed with a saturated aqueous solution of sodium chloride, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (3.60 g, yield 80%) as a yellow oil. [M+H] + 226.1

[0247] Step 2: 1-(2-chloropyridine-3-yl)cyclopropane-1-carboxylic acid A solution of ethyl 1-(2-chloropyridine-3-yl)cyclopropane-1-carboxylate (3.60 g, 15.9 mmol) and sodium hydroxide (3.18 g, 79.5 mmol) in ethanol (80 mL) and water (40 mL) was stirred at 80°C for 24 hours. The resulting solution was concentrated under reduced pressure and adjusted to pH 7 with 1 M hydrochloric acid. After extraction with ethyl acetate, the organic phase was recovered and washed with a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product (2.90 g, yield 92%) as a yellow solid. [M+H] + 198.1

[0248] Step 3: tert-butyl(1-(2-chloropyridine-3-yl)cyclopropyl)carbamate A solution of 1-(2-chloropyridine-3-yl)cyclopropane-1-carboxylic acid (2.90 g, 14.7 mmol), DPPA (6.05 g, 22.0 mmol), and triethylamine (4.40 g, 44 mmol) in tert-butyl alcohol (50 mL) was stirred at 85 °C for 48 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was recovered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (1.0 g, yield 25%) as a yellow solid. [M+H] + 269.1

[0249] Step 4: tert-butyl(2-((tert-butyldimethylsilyl)oxy)ethyl)(1-(2-chloropyridine-3-yl)cyclopropyl)carbamate At -5 to 0°C, 60% sodium hydride (446 mg, 11.2 mmol) was added to a solution of tert-butyl (1-(2-chloropyridine-3-yl)cyclopropyl) carbamate (1.0 g, 3.72 mmol) in DMF (10 mL) and stirred at room temperature for 1 hour. (2-bromoethoxy)(tert-butyl)dimethylsilane (1.33 g, 5.58 mmol) was added to the reaction solution and stirred at room temperature for 4 hours. The reaction solution was poured into an aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was recovered, washed with a saturated aqueous solution of sodium chloride, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (1.30 g, yield 82%) as a yellow oil. [M+H] + 427.3

[0250] Step 5: tert-butyl(2-((tert-butyldimethylsilyl)oxy)ethyl)(1-(2-((4-methoxybenzyl)amino)pyridine-3-yl)cyclopropyl)carbamate tert-butyl(2-((tert-butyldimethylsilyl)oxy)ethyl)(1-(2-chloropyridine-3-yl)cyclopropyl)carbamate (1.30 g, 3.04 mmol), (4-methoxyphenyl)methanamine (835 mg, 6.08 mmol), Pd2(dba)3 (278 mg, 0.30 mmol), BINAP (378 mg, 0.61 mmol), and sodium tert-butoxide (630 mg, 9.12 mmol) were added to toluene (10 mL) and stirred at 100 °C for 2 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (1.50 g, yield 93%) as a yellow solid. [M+H] + 528.4

[0251] Step 6: tert-butyl(2-hydroxyethyl)(1-(2-((4-methoxybenzyl)amino)pyridine-3-yl)cyclopropyl)carbamate A solution of tert-butyl(2-(tert-butyldimethylsilyl)oxy)ethyl)(1-(2-(4-methoxybenzyl)amino)pyridine-3-yl)cyclopropyl)carbamate (1.50 g, 2.84 mmol) in trifluoroacetic acid (5 mL) was stirred at 50°C for 3 hours, and then concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane, washed with aqueous sodium bicarbonate, and the organic phase was recovered. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target product (0.75 g, yield 84%) as a yellow solid. [M+H] + 314.2

[0252] Step 7: 3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)cyclopropyl)-N-(4-methoxybenzyl)pyridine-2-amine The target product was prepared from the corresponding intermediates and reagents according to the preparation steps for intermediates I-C3. [M+H] + 539.2

[0253] Intermediates I-C29 and I-C30 3-(1-((S)-5-chloro-4-fluoro-9-methyl-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)ethyl)pyridine-2-amine diastereomer [ka] Intermediates I-C29-a and I-C30-a were prepared from their respective chiral starting materials and reagents according to preparation step 1 of intermediates I-C8 and I-C9. Chiral HPLC analysis was performed under the following conditions (flow rate: mL / min; detector: UV254nm):

[0254] [Table 17]

[0255] While maintaining the internal temperature below 40°C, sodium tert-butoxide (126.26 g, 1.3 mol) was slowly added in several batches to a tetrahydrofuran (730 mL) solution of intermediate I-C29-a (80.17 g, 0.41 mol) and intermediate I-C1 (92.0 g, 0.33 mol) and stirred at room temperature for 2 hours. The reaction solution was poured into water (2.1 L), adjusted to pH=7 with 1.2 M hydrochloric acid, and extracted with dichloromethane (2.1 L x 3). The organic phases were recovered and combined, concentrated under reduced pressure, and BOP-Cl (177.1 g, 0.42 mol) and DMAP (128.5 g, 1.05 mol) were added to the resulting DMA solution and stirred at room temperature for 16 hours. After stirring the reaction solution at 100°C for 6 hours, it was poured into water and filtered to recover the cake. The cake was vacuum-dried under reduced pressure, suspended in methanol (400 mL), filtered, the solid was recovered, and dried under reduced pressure to obtain intermediate I-C29 (83.2 g, yield 57%). [M+H] + 421.1.

[0256] Following the preparation steps for intermediate I-C29, intermediate I-C30 was prepared from intermediate I-C30-a and the corresponding reagent.

[0257] Intermediates I-C38 and I-C39 were prepared from the corresponding starting materials and reagents according to the preparation steps for intermediates I-C29 and I-C30: [ka]

[0258] Intermediate I-C32 (*) tert-butyl((2S)-1-((3-(1-((S)-5-chloro-4-fluoro-9-methyl-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)ethyl)pyridine-2-yl)amino)-1-oxopropan-2-yl)carbamate [ka] NMI (0.98 g, 11.88 mmol) and TCFH (2.0 g, 7.13 mmol) were added to a solution of intermediate I-C29 (1.00 g, 2.38 mmol) and (tert-butoxycarbonyl)-L-alanine (0.90 g, 4.75 mmol) in acetonitrile (15 mL), and the mixture was stirred at room temperature for 16 hours under nitrogen protection. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was recovered. The mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (water / methanol) to obtain the target intermediate (1.36 g, 97% yield) as a solid. [M+H] + 592.1.

[0259] compound 1 4-(10-(1-(2-aminopyridine-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-5-yl)-5,6-difluoronaphthalene-2-ol [ka] Step 1: 3-(1-(5-chloro-4-fluoro-2-(methylsulfinyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)ethyl)pyridine-2-amine At 0-5°C, m-CPBA (85% content, 384 mg, 1.89 mmol) was added to a solution of intermediate I-C3 (700 mg, 1.72 mmol) in dichloromethane (10 mL) and stirred for 30 minutes. Water was added to the reaction solution and extracted with dichloromethane (10 mL x 3). The organic phase was recovered and concentrated under reduced pressure to obtain the unpurified target product (700 mg), which was used directly in the next step of the reaction.

[0260] Step 2: 3-(1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)ethyl)pyridine-2-amine At 0-5°C, a 1.3M LiHMDS / THF solution (3.31 mL, 4.3 mmol) was mixed with 3-(1-(5-chloro-4-fluoro-2-(methylsulfinyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)ethyl)pyridine-2-amine (700 mg) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (intermediate I-B1, 821 mg, 5.16 mmol) in anhydrous tetrahydrofuran (8 mL) and stirred for 30 minutes. Water was added to the reaction solution and extracted with dichloromethane (10 mL x 3). The organic phase was recovered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain the target product (210 mg, 2-step yield 24%) as a pale yellow solid. [M+H] + 518.2.

[0261] Step 3: 3-(1-(5-(3-(ethoxymethoxy)-7,8-difluoronaphthalene-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)ethyl)pyridine-2-amine 3-(1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)ethyl)pyridine-2-amine (47 mg, 0.09 mmol), intermediate I-A1 (66 mg, 0.18 mmol), cataCXium A Pd-G3 (7 mg, 0.01 mmol), and anhydrous potassium phosphate (57 mg, 0.27 mmol) were dissolved in acetonitrile / water (5 mL / 1 mL) and stirred at 70°C for 3 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (water / methanol) to obtain the target product as a yellow solid.

[0262] Step 4: 4-(10-(1-(2-aminopyridine-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-5-yl)-5,6-difluoronaphthalene-2-ol At room temperature, a methanol (0.5 mL) solution of 3-(1-(5-(3-(ethoxymethoxy)-7,8-difluoronaphthalene-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)ethyl)pyridine-2-amine was mixed with 4 M hydrogen chloride / 1,4-dioxane solution (4 mL) and stirred for 30 minutes. After vacuum concentration under reduced pressure, water (1 mL) and concentrated aqueous ammonia (0.5 mL) were added to the resulting residue, and it was extracted with dichloromethane to recover the organic phase, which was then vacuum concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain the target product (37 mg, 2-step yield 62.7%) as a pale yellow solid. [M+H] + 662.6. 1 H NMR(400MHz,CD3OD)δ 7.95(d,J=3.9Hz,1H),7.76(d,J=7.3Hz,1H),7.58(dd,J=9.2,5.1Hz,1H),7.38(dd,J=17.4,9 .2Hz,1H),7.29(d,J=2.1Hz,1H),7.19(dd,J=4.5,2.3Hz,1H),6.78(dd,J=7.5,5.1Hz,1H),6. 62(d,J=6.8Hz,1H),5.43-5.21(m,1H),4.49-4.29(m,4H),3.84-3.74(m,1H),3.62-3.51(m,1 H),3.28-3.17(m,3H),3.02(s,1H),2.40-2.13(m,3H),2.02-1.89(m,3H),1.68-1.64(m,3H).

[0263] [Table 18] TIFF2026519454000142.tif255170TIFF2026519454000143.tif255170TIFF2026519454000144.tif255170TIFF202 6519454000145.tif255170TIFF2026519454000146.tif255170TIFF2026519454000147.tif255170TIFF20265194540 00148.tif255170TIFF2026519454000149.tif255170TIFF2026519454000150.tif255170TIFF2026519454000151.t if255170TIFF2026519454000152.tif255170TIFF2026519454000153.tif255170TIFF2026519454000154.tif255170

[0264] The diastereomers in the table were subjected to chiral HPLC analysis under the following conditions (flow rate: 1 mL / min; detector: UV254 nm):

[0265] [Table 19]

[0266] Compounds 2 and 3 3-(1-(5-(5,6-dimethyl-1H-indazole-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)ethyl)pyridine-2-amine and 10-(1-(2-aminopyridine-3-yl)ethyl)-5-(5,6-dimethyl-1H-indazole-4-yl)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene 2-ol [ka] Step 1: 3-(1-(5-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-yl)-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)ethyl)pyridine-2-amine Intermediate I-C3 (186 mg, 0.46 mmol), intermediate I-A2 (328 mg, 0.92 mmol), cataCXium A Pd-G3 (67 mg, 0.092 mmol), and anhydrous potassium phosphate (293 mg, 1.38 mmol) were dissolved in tetrahydrofuran / water (5 mL / 1 mL), and the mixture was stirred at 70°C for 3 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (water / methanol) to obtain the target product (205 mg, yield 74%) as a yellow solid. [M+H] + 601.4

[0267] Step 2: 3-(1-(5-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-yl)-4-fluoro-2-(methylsulfinyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)ethyl)pyridine-2-amine At 0-5°C, m-CPBA (85% content, 37 mg, 0.18 mmol) was added to a solution of 3-(1-(5-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-yl)-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)ethyl)pyridine-2-amine (95 mg, 0.16 mmol) in dichloromethane (10 mL) and stirred for 30 minutes. Water was added to the reaction solution and extracted with dichloromethane (5 mL x 3). The organic phase was recovered and concentrated under reduced pressure to obtain the unpurified target product (99 mg), which was used directly in the next step of the reaction. [M+H] + 617.3

[0268] Step 3: 3-(1-(5-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)ethyl)pyridine-2-amine and 10-(1-(2-aminopyridine-3-yl)ethyl)-5-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-yl)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-2-ol At 0-5°C, 3-(1-(5-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-yl)-4-fluoro-2-(methylsulfinyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)ethyl)pyridine-2-amine (92 mg, 0.15 mmol) and intermediate I-B1 (72 mg, 0.45 mmol) were mixed dropwise with 1.3 M LiHMDS / THF solution (0.34 mL, 0.44 mmol) and stirred for 30 minutes. Water was added to the reaction solution and extracted with dichloromethane (5 mL x 3). The organic phase was recovered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain a mixture of unpurified target products as a pale yellow solid, which was used directly in the next step of the reaction.

[0269] Step 4: 3-(1-(5-(5,6-dimethyl-1H-indazole-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)ethyl)pyridine-2-amine-2-amine and 10-(1-(2-aminopyridine-3-yl)ethyl)-5-(5,6-dimethyl-1H-indazole-4-yl)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-2-ol At room temperature, a 4 M hydrochloric acid / 1,4-dioxane solution (4 mL) was added to a methanol (0.5 mL) solution of the mixture obtained in step 3 (15 mg), and the mixture was stirred for 30 minutes. After vacuum concentration under reduced pressure, water (1 mL) and concentrated aqueous ammonia (0.5 mL) were added to the resulting residue, and after extraction with dichloromethane, the organic phase was recovered and vacuum concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain compound 2 (12 mg) and compound 3 (15 mg) as pale yellow solids. Compound 2, [M+H] + 628.3. 1 H NMR(400MHz,CD3OD)δ 7.99-7.94(m,1H),7.78-7.74(m,1H),7.63(s,1H),7.47(s,1H),6.80-6.76(m,1H),6 .66-6.58(mz,1H),5.41-5.24(m,1H),4.52-4.46(m,1H),4.40-4.32(m,3H),3.86-3. 73(m,1H),3.64-3.58(m,1H),3.24-3.19(m,3H),3.07-3.00(m,1H),2.48(s,3H),2.3 6-2.26(m,1H),2.22(s,3H),2.20-2.13(m,2H),2.02-1.92(m,3H),1.68-1.64(m,3H) Compound 3, [M+H] + 487.2. 1 H NMR(400MHz,CD3OD)δ 7.96-7.92(m,1H),7.70-7.63(m,2H),7.44(s,1H),6.78-6.69(m,2H),4.50- 4.20(m,3H),3.76-3.50(m,2H),2.44(s,3H),2.22(s,3H),1.63-1.59(m,3H)

[0270] The compounds shown in the table below were prepared from the corresponding intermediates and reagents by following the preparation steps for compounds 2 and 3:

[0271] [Table 20] TIFF2026519454000158.tif255170TIFF2026519454000159.tif255170TIFF2026519454000160.tif255170TIFF2026519454000161.t if255170TIFF2026519454000162.tif255170TIFF2026519454000163.tif255170TIFF2026519454000164.tif255170TIFF20265194540 00165.tif255170TIFF2026519454000166.tif255170TIFF2026519454000167.tif255170TIFF2026519454000168.tif255170TIFF202 6519454000169.tif255170TIFF2026519454000170.tif255170TIFF2026519454000171.tif255170TIFF2026519454000172.tif255170 TIFF2026519454000173.tif255170TIFF2026519454000174.tif255170TIFF2026519454000175.tif255170TIFF2026519454000176.t if255170TIFF2026519454000177.tif255170TIFF2026519454000178.tif255170TIFF2026519454000179.tif255170TIFF20265194540 00180.tif255170TIFF2026519454000181.tif255170TIFF2026519454000182.tif255170TIFF2026519454000183.tif255170TIFF202 6519454000184.tif255170TIFF2026519454000185.tif255170TIFF2026519454000186.tif255170TIFF2026519454000187.tif255170

[0272] Compounds 20 and 21 3-(10-((R or S)-1-(2-aminopyridine-3-yl)ethyl)-2-(((S)-1-(2,2-difluoroethyl)azetidine-2-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-5-yl)-5-chloro-4-cyclopropylphenol (diastereomer 1 and diastereomer 2) [ka] Compound 16 was divided by chiral HPLC to obtain a pair of diastereomers. Chiral HPLC division conditions: Column: IC (2 × 25 cm); Mobile phase: Ethanol (0.1% aqueous ammonia); Flow rate: 15 mL / min; Detector: UV 254 nm.

[0273] First eluent (Compound 20, diastereomer 1, chiral HPLC analysis conditions: column: IC (0.46 × 25 cm); mobile phase: ethanol (0.1% diethylamine), RT = 4.775 min), de% = 100%, [M + H] + 642.3. 1 H NMR(400MHz,CD3OD)δ 7.99-7.93(m,1H),7.81-7.72(m,1H),6.92(d,J=2.6Hz,1H),6.82-6.76(m,1H),6. 73(d,J=2.6Hz,1H),6.66-6.58(m,1H),6.04-5.70(m,1H),4.58-4.28(m,4H),3.83- 3.70(m,2H),3.64-3.45(m,2H),3.26-3.09(m,2H),2.92-2.75(m,1H),2.23-2.11( m,2H),1.91-1.79(m,1H),1.72-1.61(m,3H),0.77-0.59(m,2H),0.27-0.05(m,2H).

[0274] Second eluent (Compound 21, diastereomer 2, chiral HPLC analysis conditions: column: IC (0.46 × 25 cm); mobile phase: ethanol (0.1% diethylamine), RT = 5.926 min), de% = 96.36%, [M + H] + 642.3. 1H NMR(400MHz,CD3OD)δ 8.00-7.92(m,1H),7.80-7.72(m,1H),6.96-6.90(m,1H),6.82-6.76(m,1H),6.75 -6.72(m,1H),6.67-6.58(m,1H),6.04-5.66(m,1H),4.62-4.29(m,4H),3.86-3.6 7(m,2H),3.61-3.48(m,2H),3.27-3.09(m,2H),2.92-2.71(m,1H),2.21-2.14(m, 2H),1.90-1.81(m,1H),1.70-1.61(m,3H),0.74-0.61(m,2H),0.20-0.07(m,2H).

[0275] The compounds shown in the table below were prepared using the chiral resolution conditions for compounds 20 and 21:

[0276] [Table 21] TIFF2026519454000190.tif255170TIFF2026519454000191.tif255170TIFF2026519454000192.tif255170TIFF2026519454000193.tif255170TIFF2026519454000194.tif255170TIFF2026519454000195.tif255170TIFF2026519454000196.tif255170TIFF2026519454000197.tif255170TIFF2026519454000198.tif255170TIFF2026519454000199.tif255170TIFF2026519454000200.tif255170TIFF2026519454000201.tif255170TIFF2026519454000202.tif255170TIFF2026519454000203.tif255170TIFF2026519454000204.tif255170TIFF2026519454000205.tif255170TIFF2026519454000206.tif255170TIFF2026519454000207.tif255170TIFF2026519454000208.tif255170TIFF2026519454000209.tif255170TIFF2026519454000210.tif255170TIFF2026519454000211.tif255170TIFF2026519454000212.tif255170TIFF2026519454000213.tif255170TIFF2026519454000214.tif255170TIFF2026519454000215.tif255170TIFF2026519454000216.tif255170TIFF2026519454000217.tif255170TIFF2026519454000218.tif255170TIFF2026519454000219.tif255170TIFF2026519454000220.tif255170TIFF2026519454000221.tif255170TIFF2026519454000222.tif255170TIFF2026519454000223.tif255170TIFF2026519454000224.tif255170TIFF2026519454000225.tif255170TIFF2026519454000226.tif255170TIFF2026519454000227.tif255170TIFF2026519454000228.tif255170TIFF2026519454000229.tif255170TIFF2026519454000230.tif255170TIFF2026519454000231.tif255170TIFF2026519454000232.tif255170TIFF2026519454000233.tif255170TIFF2026519454000234.tif255170TIFF2026519454000235.tif255170TIFF2026519454000236.tif255170TIFF2026519454000237.tif255170TIFF2026519454000238.tif255170TIFF2026519454000239.tif255170TIFF2026519454000240.tif255170TIFF2026519454000241.tif255170TIFF2026519454000242.tif255170TIFF2026519454000243.tif255170TIFF2026519454000244.tif255170TIFF2026519454000245.tif255170TIFF2026519454000246.tif255170TIFF2026519454000247.tif255170TIFF2026519454000248.tif255170TIFF2026519454000249.tif255170TIFF2026519454000250.tif255170TIFF2026519454000251.tif255170TIFF2026519454000252.tif255170TIFF2026519454000253.tif255170TIFF2026519454000254.tif255170TIFF2026519454000255.tif255170TIFF2026519454000256.tif255170.

[0277] The diastereomers in the table were subjected to chiral HPLC analysis under the following conditions (flow rate: 1 mL / min; detector: UV254 nm):

[0278] [Table 22] TIFF2026519454000258.tif255170TIFF2026519454000259.tif255170TIFF2026519454000260.tif255170TIFF2026519454000261.tif13170

[0279] The enantiomers in the table were subjected to chiral HPLC analysis under the following conditions (flow rate: 1 mL / min; detector: UV254 nm):

[0280] [Table 23]

[0281] compound 28 1-(10-(1-(2-aminopyrrolidine-3-yl)ethyl)-4-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-5-yl)isoquinoline-3-amine [ka] Step 1: 1-(10-(1-(2-aminopyridine-3-yl)ethyl)-4-fluoro-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-5-yl)isoquinoline-3-amine Crude intermediate I-A9 (0.9 mmol), intermediate I-C3 (200 mg, 0.5 mmol), Pd(PPh3)4 (58 mg, 0.05 mmol), copper iodide (29 mg, 0.15 mmol), and lithium chloride (84 mg, 2 mmol) were added to DMA (8 mL) and stirred at 120 °C for 2 hours under nitrogen protection. The resulting product was purified by silica gel column chromatography (methanol / water) and preparative thin-layer chromatography (dichloromethane / methanol) to obtain the target product (80 mg, yield 31%) as a yellow solid. [M+H] + 515.2

[0282] Step 2: 1-(10-(1-(2-aminopyrrolidine-3-yl)ethyl)-4-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-5-yl)isoquinoline-3-amine By following preparation steps 2 and 3 of compound 2, target compound 28 was prepared from the corresponding intermediates and reagents. [M+H] + 582.3. 1 H NMR(400MHz,CD3OD)δ 7.94(d,J=5.0Hz,1H),7.74(d,J=7.5Hz,1H),7.64-7.44(m,3H),7.20-7.10(m,1H),6. 92(s,1H),6.82-6.73(m,1H),6.66-6.54(m,1H),4.60-4.41(m,3H),4.40-4.30(m,1H) ,3.80-3.72(m,1H),3.61-3.46(m,1H),3.15-3.00(m,1H),2.85-2.81(m,1H),2.51(s, 3H),2.40-2.32(m,1H),2.15-2.05(m,1H),1.90-1.71(m,3H),1.63(d,J=10.2Hz,3H).

[0283] By following the preparation steps for compound 28, the compounds shown in the table below were prepared from the corresponding intermediates and reagents:

[0284] [Table 24]

[0285] compound 326 (*)6-((9S)-10-(1-(2-aminopyridine-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-5-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine [ka] Step 1: (*)3-(1-((S)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-9-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)ethyl)pyridine-2-amine The target intermediate was prepared from the corresponding intermediate and reagent by following preparation steps 1 and 2 of compound 1. [M+H] + 532.2

[0286] Step 2: (*)3-(1-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-9-methyl-5-(tributylstanyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)ethyl)pyridine-2-amine (*)3-(1-((S)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-9-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)ethyl)pyridine-2-amine (500 mg, 0.94 mmol), hexa-n-butylditine (1.09 g, 1.88 mmol), and Pd(PPh3)4 (217 mg, 0.188 mmol) were added to toluene (6 mL) and stirred at 100°C for 16 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol) to obtain the target product (300 mg, yield 41%) as a yellow solid. [M+H] + 788.4

[0287] Step 3: (*)6-((9S)-10-(1-(2-aminopyridine-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-5-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine The target intermediate was prepared from the corresponding intermediate and reagent by following preparation step 1 of compound 28. [M+H] + 912.4

[0288] Step 4: (*)6-((9S)-10-(1-(2-aminopyridine-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-5-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (*)6-((9S)-10-(1-(2-aminopyridine-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-5-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (20 mg, 0.022 mmol) was added to trifluoroacetic acid (3 mL) and stirred at 55°C for 2 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (methanol / water) and preparative thin-layer chromatography (dichloromethane / methanol) to obtain the target compound (10 mg, yield 68%) as a yellow solid. [M+H] + 672.2. 1 1H NMR (400MHz, CD3OD)δ 7.99-7.94(m,1H),7.83-7.76(m,1H),6.81-6.71(m,2H),6.60-6.54(m,1H),5 .39-5.18(m,1H),4.64-4.56(m,1H),4.36-4.25(m,3H),4.13-3.99(m,1H),3.2 6-3.19(m,2H),3.17-3.12(m,1H),3.03-2.95(m,1H),2.45-2.39(m,3H),2.37 -2.13(m,3H),2.04-1.88(m,3H),1.66(d,J=6.8Hz,3H),0.67(d,J=6.9Hz,3H).

[0289] By following the preparation steps for compound 326, the compounds shown in the table below were prepared from the corresponding intermediates and reagents:

[0290] [Table 25] TIFF2026519454000267.tif227170TIFF2026519454000268.tif240170TIFF2026519454000269.tif234170TIFF2026519454 000270.tif227170TIFF2026519454000271.tif240170TIFF2026519454000272.tif187170TIFF2026519454000273.tif81170

[0291] The diastereomers in the table were obtained by separation using preparative thin-layer chromatography (dichloromethane / methanol / 33% aqueous ammonia = 100 / 8 / 0.75). HPLC analysis was performed under the following conditions (flow rate: 1 mL / min; detector: UV254 nm):

[0292] [Table 26]

[0293] compound 336 (*)1-((9S)-10-(1-(2-aminopyridine-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-5-yl)-1H-indazole-3-amine [ka] (*)3-(1-((S)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-9-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)ethyl)pyridine-2-amine (100 mg, 0.19 mmol; The target intermediate prepared in step 1 of compound 326, 1H-indazole-3-amine (32 mg, 0.24 mmol), Pd2(dba)3 (17 mg, 0.002 mmol), xanthophos (21 mg, 0.004 mmol), and sodium tert-butoxide (36 mg, 0.38 mmol) were added to toluene (5 mL) and stirred at 100 °C for 2 hours under nitrogen protection. The reaction solution was concentrated and purified by silica gel column chromatography (methanol / water) and preparative thin-layer chromatography (dichloromethane / methanol) to obtain the target product (17 mg, yield 14%) as a yellow solid. [M+H] + 629.2. 1 1H NMR (400MHz, CD3OD)δ 8.26-8.17(m,1H),7.99-7.90(m,1H),7.82-7.72(m,2H),7.52-7.40(m,1H) ,7.29-7.17(m,1H),6.82-6.67(m,2H),5.45-5.16(m,1H),4.66-4.56(m,1H) ,4.36-4.22(m,3H),4.08-3.96(m,1H),3.25-3.15(m,2H),3.04-2.95(m,1H) ,2.40-2.11(m,3H),2.0-1.88(m,3H),1.66-1.58(m,3H),0.72-0.63(m,3H).

[0294] By following the preparation steps for compound 336, the compounds shown in the table below were prepared from the corresponding intermediates and reagents:

[0295] [Table 27]

[0296] Compound 394 (*)2-(((1-((((9S)-10-(1-(2-aminopyridine-3-yl)ethyl)-4-fluoro-5-(7-fluoro-6-methyl-5-(trifluoromethyl)-1H-indazole-4-yl)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-2-yl)oxy)methyl)cyclopropyl)methyl)(methyl)amino)ethane-1-ol [ka] Step 1: (*)(1-((((9S)-10-(1-(2-aminopyridine-3-yl)ethyl)-5-chloro-4-fluoro-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-2-yl)oxy)methyl)cyclopropyl)methanol The target intermediate was prepared from the corresponding intermediate and reagent by following preparation steps 1 and 2 of compound 1. [M+H] + 475.2

[0297] Step 2: (*)(1-((((9S)-10-(1-(2-aminopyridine-3-yl)ethyl)-5-chloro-4-fluoro-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-2-yl)oxy)methyl)cyclopropyl)methylmethanesulfonate At 0°C, DIEA (261 mg, 2.02 mmol) and methanesulfonyl chloride (154 mg, 1.35 mmol) were added to (*)(1-((((9S)-10-(1-(2-aminopyridine-3-yl)ethyl)-5-chloro-4-fluoro-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-2-yl)oxy)methyl)cyclopropyl)methanol (320 mg, 0.67 mmol) in dichloromethane (10 mL), and the mixture was stirred for 1.5 hours. The reaction solution was diluted with dichloromethane and washed with a saturated aqueous solution of sodium chloride. The organic phase was collected and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the target product (440 mg, yield 118%) as a yellow solid, which was used directly in the next step of the reaction. [M+H] + 552.6

[0298] Step 3: (*) 2-(((1-((((9S)-10-(1-(2-aminopyridine-3-yl)ethyl)-5-chloro-4-fluoro-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-2-yl)oxy)methyl)cyclopropyl)methyl)(methyl)amino)ethane-1-ol (*)(1-((((9S)-10-(1-(2-aminopyridine-3-yl)ethyl)-5-chloro-4-fluoro-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-2-yl)oxy)methyl)cyclopropyl)methyl)(methyl)amino)ethane-1-ol 10-tetraazacyclohepta[de]naphthalen-2-yl)oxy)methyl)cyclopropyl)methylmethanesulfonate (220 mg, 0.40 mmol), 2-(methylamino)ethane-1-ol (90 mg, 1.19 mmol), and DIEA (206 mg, 1.59 mmol) were added to DMF (3 mL) and stirred at 90°C for 4 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (methanol / water) to obtain the target product (150 mg, 71% yield) as a yellow solid. [M+H]+ 531.8

[0299] Step 4: (*)2-(((1-((((9S)-10-(1-(2-aminopyridine-3-yl)ethyl)-4-fluoro-5-(7-fluoro-6-methyl-5-(trifluoromethyl)-1H-indazole-4-yl)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-2-yl)oxy)methyl)cyclopropyl)methyl)(methyl)amino)ethane-1-ol The target compound was prepared from the corresponding intermediate and reagent by following preparation steps 3 and 4 of compound 1. [M+H] + 713.7. 1 H NMR(400MHz,CD3OD)δ 8.02-7.94(m,1H),7.88-7.69(m,2H),6.83-6.72(m,2H),4.68-4.55(m,1H),4.55-4.29(m,3H),4.14-3.98(m,1H), 3.65(t,J=6.0Hz,2H),2.69-2.46(m,7H),2.35(s,3H),1.68(d,J=6.8Hz,3H),0.81-0.62(m,5H),0.61-0.43(m,2H).

[0300] Compounds 169 and 170 (*)3-(1-(5-(5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2S or 2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl-2-d)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)ethyl)pyridine-2-amine (Diastereomer 1 and Diastereomer 2) [ka] By following the preparation steps for compound 2, the compounds prepared from I-A18, I-B31, and I-C9 were separated by preparative high-performance liquid chromatography to obtain a pair of diastereomers. Preparative HPLC conditions: Column: AQ-C18 (3 × 15 cm); Mobile phase: Methanol / water (0.1% formic acid); Flow rate: 30 mL / min; Detector: UV 254 nm.

[0301] First eluent (Compound 169, diastereomer 1, chiral HPLC analysis conditions: column: ODH (0.46 × 25 cm); mobile phase: n-heptane / ethanol (0.1% diethylamine) = 20 / 80, RT = 5.848 min), de% = 100%, [M+H] + 676.3. 1 H NMR(400MHz,CD3OD)δ 7.96-7.94(m,1H),7.75(d,J=7.4Hz,1H),6.79-6.75(m,1H),6.69-6.48 (m,2H),4.52-4.19(m,4H),3.74-3.68(m,1H),3.52-3.32(m,2H),3.10- 3.05(m,1H),2.96-2.81(m,1H),2.78-2.68(m,1H),2.55-2.42(m,1H),2 .35(s,3H),2.27-2.09(m,1H),2.05-1.77(m,4H),1.63(d,J=6.8Hz,3H).

[0302] Second eluent (Compound 170, diastereomer 2, chiral HPLC analysis conditions: Column: ODH (0.46 × 25 cm); Mobile phase: n-heptane / ethanol (0.1% diethylamine = 20 / 80, RT = 6.277 min), de% = 100%, [M+H] + 676.3. 1H NMR(400MHz,CD3OD)δ 7.95-7.93(m,1H),7.74(d,J=7.5Hz,1H),6.78-6.74(m,1H),6.64-6.48(m,2H),4.50-4.24(m,4H),3.78-3.66(m,1H), 3.58-3.48(m,1H),3.33-3.16(m,3H),3.07-2.98(m,1H),2.41-2.12(m,6H),2.05-1.85(m,3H),1.63(d,J=6.9Hz,3H).

[0303] Compounds 169 and 170 were prepared according to the preparative HPLC conditions shown in the table below:

[0304] [Table 28] TIFF2026519454000280.tif255162TIFF2026519454000281.tif255162TIFF2026519454000282.tif255162TIFF2026519454000283.tif255162TIFF2026519454000284.tif255162Note: Intermediate I-B38 was a commercially available product.

[0305] The diastereomers in the table were subjected to chiral HPLC analysis under the following conditions (flow rate: 15 mL / min; detector: UV254 nm):

[0306] [Table 29]

[0307] compound 293 (*)3-((9S)-10-(1-(2-aminopyridine-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-5-yl)-5-chloro-4-cyclopropylphenylethyl carbamate acetate [ka] At 0-5°C, isocyanoethane (93 mg, 1.3 mmol) was added to a 20 mL DCM solution of compound 268 (312 mg, 0.47 mmol) and DIEA (315 mg, 5.2 mmol), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride (0.2 mL) was added, and the reaction solution was concentrated under reduced pressure. After purification by silica gel column chromatography (water / methanol, 0.2% acetic acid), the target compound (182 mg, yield 49%) was obtained as a white solid. (Free base)[M+H] + 735.3. 1 H NMR(400MHz,CD3OD)δ 8.02-7.92(m,1H),7.84-7.76(m,1H),7.34-7.29(m,1H),7.21-7.13(m,1H),6.83-6.66(m, 2H),5.57-5.27(m,1H),4.67-4.58(m,1H),4.56-4.45(m,2H),4.34-4.25(m,1H),4.17-4.0 2(m,1H),3.71-3.42(m,3H),3.25-3.12(m,3H),2.58-2.23(m,3H),2.19-2.01(m,3H),1.97 -1.87(m,5H),1.70-1.61(m,3H),1.17-1.11(m,3H),0.79-0.64(m,5H),0.26-0.30(m,2H).

[0308] By following the preparation steps for compound 293, the compounds shown in the table below were prepared from the corresponding intermediates and reagents:

[0309] [Table 30] TIFF2026519454000288.tif255170

[0310] compound 310 (*)5,6-difluoro-4-((9S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10-(1-(imidazo[1,2-a]pyridine-8-yl)ethyl)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-5-yl)naphthalene-2-ol [ka] Compound 275 (100 mg, 0.15 mmol) and a 40% aqueous solution of chloroacetaldehyde (0.3 mL) were dissolved in n-butyl alcohol (2 mL) and stirred at 100°C for 2 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (water / methanol) and preparative thin-layer chromatography (dichloromethane / methanol) to obtain the target product (45 mg, yield 43%) as a white solid. [M+H] + 700.3. 1 H NMR(400MHz,CD3OD)δ 8.49(d,J=6.8Hz,1H),7.88(s,1H),7.60-7.47(m,3H),7.41-7.30(m,1H),7.29- 7.08(m,2H),7.05-6.89(m,2H),5.40-5.21(m,1H),4.63-4.56(m,1H),4.47-4.33 (m,2H),4.33-4.15(m,2H),3.38-3.30(m,1H),3.25-3.14(m,2H),3.05-2.95(m, 1H),2.46-2.06(m,3H),2.03-1.89(m,2H),1.89-1.74(m,4H),0.62-0.45(m,3H).

[0311] Compound 334 (*) 5-Chloro-3-(1-((9S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-9-methyl-5-(6-methyl-5-(trifluoromethyl)-1H-indazole-4-yl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)ethyl)pyridine-2-amine [ka] Compound 312 (32 mg, 0.046 mmol) and NCS (9.2 mg, 0.069 mmol) were dissolved in DMF (1 mL) and stirred at room temperature for 4 hours. The reaction solution was purified by silica gel column chromatography (water / methanol) and preparative thin-layer chromatography (dichloromethane / methanol) to obtain the target product (8 mg, 4% yield) as a yellow solid. [M+H] + 730.1. 1 H NMR(400MHz,CD3OD)δ 7.99-7.95(m,1H),7.82-7.78(m,1H),7.74-7.59(m,2H),6.79-6.73(m, 1H),5.38-5.21(m,1H),4.66-4.58(m,1H),4.38-4.30(m,3H),4.15-4.0 8(m,1H),3.25-3.15(m,3H),3.05-2.97(m,1H),2.69-2.66(m,3H),2.37 -2.15(m,3H),2.03-1.91(m,3H),1.69-1.66(m,3H),0.80-0.73(m,3H).

[0312] The compounds shown in the table below were prepared from the corresponding intermediates and reagents by following the compound preparation steps described above, under conditions deemed appropriate by those skilled in the art:

[0313] [Table 31] TIFF2026519454000292.tif253170TIFF2026519454000293.tif255170TIFF2026519454000294.tif55170

[0314] Example 2: Assay of intracellular pERK1 / 2(Thr202 / Tyr204) phosphorylation 1. Reagents and materials: • pERK1 / 2 (Thr202 / Tyr204) HTRF kit, Cisbio, Cat#64ERKPEH; • OptiPlate (trademark) - 384-well plate, PerkinElmer, Cat# 6007299; • 96-well plate, Corning, Cat#353072; • Instruments: EnVision2104, PerkinElmer; ·Cell lines: NCI-H358 (KRAS G12C), ATCC, CRL-5807; PANC-1 (KRAS G12D), ATCC, CRL-1469; NCI-H441 (KRAS G12V), ATCC, HTB-174.

[0315] 2. Preparation of reaction solution The test compound was dissolved in DMSO, diluted to 200.0 μM, and then further diluted threefold to prepare a series of test compounds at concentrations of 66.7, 22.2, 7.4, 2.5, 0.82, 0.27, and 0.09 μM. Next, 10 μL each of the compounds at different dilution concentrations was added to 190 μL of DMEM medium to prepare 10× test compounds. • 1× Cell Lysis Buffer: 4× Cell Lysis Stock Solution (provided by the kit) was diluted four-fold with deionized water, and then 1% 100× Blocking Stock Solution (provided by the kit) was added. • pERK1 / 2 detection solution (prepared immediately before use): pERK1 / 2 d2 antibody (supplied by the kit) and pERK1 / 2 cryptotate antibody (supplied by the kit) were diluted in a ratio of 1:1:38 with the detection solution (supplied by the kit).

[0316] 3. Experiment Steps Cells were inoculated into 96-well plates (100 μL / well) at a density of 10,000–12,000 cells / well. Negative control wells were not inoculated with cells, and only 100 μL / well of cell medium was added. The plates were placed overnight in a cell incubator at 5% CO2 and 37°C. 10 μL of 10× test compound was added to a 100 μL 96-well cell culture plate; 10 μL of 5% DMSO culture solution was packed into both the positive control well (i.e., the control well without chemical compound treatment) and the negative control well; and the plate was cultured for 2 days in a cell incubator with 5% CO2 and at 37°C. The culture medium was removed from the 96-well plate; 50 μL of 1× cell lysis buffer was added to each well; the plate was placed in a microplate shaker; and lysis was performed by shaking at 900 rpm for 1 hour at room temperature. - 16 μL of lysis buffer was taken from a 96-well plate and transferred to a 384-well plate, then centrifuged at 1000 rpm for 30 seconds; then, 4 μL of pERK1 / 2 detection solution was added to each well, followed by centrifuging at 1000 rpm for 30 seconds; the 384-well plate was sealed with a sealing membrane and incubated in a dark place in a low-speed shaker at 100 rpm at 25°C for 2 hours. • The fluorescence intensity (RFU) of each well was detected using EnVision2104, with emission wavelength 1 set to 665 nm and emission wavelength 2 to 615 nm.

[0317] 4. Data Analysis Fluorescence ratio = fluorescence value 665nm / fluorescence value 615nm Inhibition rate (%) = 100 - ((fluorescence ratio of compound well - fluorescence ratio of negative control well) / (fluorescence ratio of positive control well - fluorescence ratio of negative control well)) × 100 Here: • The fluorescence ratio of the compound well refers to the fluorescence ratio of the well containing the test compound; The fluorescence ratio of the negative control well refers to the fluorescence ratio of the control well that does not contain cells; • The fluorescence ratio of the positive control well refers to the fluorescence ratio of the cell wells treated with 0.5% DMSO. I C 50 Values: Obtained by calculation using XL-Fit 5.0 software.

[0318] 5. Test Results

[0319] [Table 32] TIFF2026519454000296.tif255170TIFF2026519454000297.tif255170TIFF2026519454000298.tif255170TIFF20265194540 00299.tif255170TIFF2026519454000300.tif255170TIFF2026519454000301.tif255170TIFF2026519454000302.tif150170

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