Sulfonimidoyl-containing ATR inhibitor compounds

Abstract

The present invention relates to sulfonimidoyl-containing ATR inhibitor compounds of formula (I), processes for their preparation, pharmaceutical compositions containing said compounds, and their use in the treatment of diseases and / or disorders related to or mediated by ATR. [C1] TIFF2024517906000109.tif48156

Description

[Technical Field]

[0001] The present invention relates to sulfonimidoyl-containing ATR inhibitor compounds, methods for producing the same, pharmaceutical compositions comprising the compound, and their use in the treatment of diseases and / or disorders related to or mediated by ATR. [Background technology]

[0002] Rad3-associated kinase (ATR), a mutation gene for ataxia telangiectasia, is a protein kinase that responds to DNA-damaged cells. Upon activation, ATR can regulate cellular life processes, including cell cycle arrest, inhibition of replication origins, initiation of replication forks, and DNA double-strand repair, through various signaling pathways. ATR kinase functions with ATM (ataxia telangiectasia mutation) kinase and many other proteins to regulate the cellular response to DNA damage (commonly referred to as the DNA damage response (DDR)). When cells recognize DNA damage via DDR, they immediately activate the DNA repair program, trigger cell cycle checkpoints, inhibit normal cell cycle progression, and provide time for DNA repair. Without DDR, cells are more susceptible to and more likely to die from endogenous cell damage or DNA damage caused by chemotherapy and radiation therapy for cancer treatment.

[0003] Many cancer cells have defects in their DNA repair pathways and exhibit a high degree of dependence on remaining intact DNA repair proteins, including ATR. ATR is a key member of the DDR involved in the replication response of damaged DNA and is crucial for maintaining genomic stability and integrity and promoting cell survival. Many cancer cells rely more heavily on the ATR pathway than normal cells to regulate the repair of cellular DNA damage and promote cell survival, making ATR a promising target for cancer therapy. Therefore, ATR inhibitors have potential therapeutic effects against these tumor cells.

[0004] Currently, no ATR inhibitors are on the market, making the development of safer and more effective ATR inhibitors of great importance. Summary of the Invention Means for Solving the Problem

[0005] In one aspect, the present invention provides a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0006] Chemical Formula

[0007] In the formula, Chemical Formula is a double bond, and X is selected from CR a , Y is selected from N, or Chemical Formula is a single bond, and X is selected from C=O, Y is selected from NR b , R a is selected from hydrogen, hydroxy, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, or C 3-10 cycloalkyl-C 2-6 alkynyl, provided that said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl and C 3-10 cycloalkyl-C 2-6 alkynyl are optionally substituted with one or more substituents selected from halogen, hydroxy or cyano, R b is selected from hydrogen or C 1-6 alkyl, R 1 and R2 Each of them is independent of C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from 5-membered aryls or 5-10 membered heteroaryls, provided that the C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 5-10 member heteroaryls and 5-10 member heteroaryls can be any one or more R c It may also be replaced with Alternatively, R 1 , R 2 These, together with the sulfur atoms to which they bond, form a 3-10 membered heterocycline, and the 3-10 membered heterocycline is optionally composed of one or more R d It may also be replaced with Each R c and R d These are, independently, halogen, hydroxyl, amino, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-S(O)2-, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from 5-10 member aryls or heteroaryls, R 3 This can be any one or more R e Selected from 5-10 member heteroaryls, which may be substituted with R e is hydroxy, amino, halogen, C 1-6 Alkyl, Halogen C 1-3 Alkyl, C 3-6 Selected from cycloalkyl or 3-6 member heterocycloalkyl.

[0008] In some embodiments, R a is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl or C 3-10 Cycloalkyl-C 2-6Selected from alkynyl, provided that C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl and C 3-10 Cycloalkyl-C 2-6 The alkynyl may be substituted with one or more halogens as desired.

[0009] In some embodiments, R a is hydrogen, hydroxyl, halogen or C 1-6 Selected from alkyl, provided that the C 1-6 The alkyl group may be optionally substituted with one or more halogens. In some embodiments, R a is hydrogen, hydroxyl, halogen or C 1-3 Selected from alkyl, provided that the C 1-3 The alkyl group may be optionally substituted with one or more halogens.

[0010] In some embodiments, R a is hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or C 3-6 Cycloalkyl-C 2-4 Selected from alkynyl, provided that C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and C 3-6 Cycloalkyl-C 2-4 The alkynyl may be substituted with one or more halogens as desired.

[0011] In some embodiments, R aThis is selected from hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylethynyl, or cyclopropylpropynyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylethynyl, and cyclopropylpropynyl may be optionally substituted with one or more halogens.

[0012] In some embodiments, R a This is selected from hydrogen, bromo, methyl, n-propyl, isobutyl, tert-butyl, methoxy, cyclopropyl, or cyclopropylethynyl, wherein the methyl, n-propyl, isobutyl, tert-butyl, methoxy, cyclopropyl, and cyclopropylethynyl may be optionally substituted with one or more halogens.

[0013] In some embodiments, R a This is selected from hydrogen, bromo, methyl, trifluoromethyl, 3,3,3-trifluoropropyl, isobutyl, tert-butyl, difluoromethoxy, cyclopropyl, or cyclopropylethynyl.

[0014] In some embodiments, R a This is selected from hydrogen or halogen.

[0015] In some embodiments, R a This is selected from hydrogen, fluoro, chloro, or bromo.

[0016] In some embodiments, R a This is selected from hydrogen or bromo.

[0017] In some embodiments, R b is hydrogen or C 1-3 Selected from alkyl. In some embodiments, R b It is selected from hydrogen.

[0018] In some embodiments, [ka] It is a double bond, and X is a CR bond. a Y is selected from N.

[0019] In some embodiments, [ka] It is a single bond, and X is selected from C=O, and Y is NR b Selected from.

[0020] In some embodiments, [ka] The bond is a double bond, and X is selected from CH or CBr, and Y is selected from N. In some embodiments, [ka] The bond is a single bond, and X is selected from C=O and Y is selected from NH.

[0021] In some embodiments, R 1 and R 2 Each of them is independent of C 1-6 Alkyl, C 3-8 Selected from cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, provided that the C 3-8 Cycloalkyl, 3-8 member heterocycloalkyl, phenyl, and 5-6 member heteroaryl may be any one or more R c It may be replaced with .

[0022] In some embodiments, R 1 and R 2 are each independently selected from C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl, provided that said C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl and 5- to 6-membered heteroaryl are optionally substituted with one or more R c .

[0023] In some embodiments, R 1 and R 2 are each independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, thienyl, pyridyl, pyrimidinyl or furyl, provided that said cyclopropyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, thienyl, pyridyl, pyrimidinyl and furyl are optionally substituted with one or more R c .

[0024] In some embodiments, R 1 and R 2 are each independently selected from methyl, ethyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl or pyridyl, provided that said cyclopropyl, cyclopentyl, cyclohexyl, phenyl and pyridyl are optionally substituted with one or more R c . In some embodiments, the structural unit

Chemical

[0025] In some embodiments, R 1 and R 2 are each independently C 1-3 alkyl, C 3-4Selected from cycloalkyl, phenyl, or 5-6 member heteroaryl, provided that the C 3-4 Cycloalkyl, phenyl, and 5-6 member heteroaryl may optionally be one or more R c It may be replaced with .

[0026] In some embodiments, R 1 and R 2 Each of these is independently selected from methyl, ethyl, cyclopropyl, phenyl, or pyridyl.

[0027] In some embodiments, the structural unit [ka] Selected from.

[0028] In some embodiments, each R c and R d These are, independently, halogen, hydroxyl, amino, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-C(O)-, C 1-4 Alkyl-S(O)2-, C 3-8 Cycloalkyl, 3-8 member heterocycloalkyl, C 6-8 Selected from a 5-8 member aryl or 5-8 member heteroaryl.

[0029] In some embodiments, each R c and R d These are, independently, halogen, hydroxyl, amino, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkyl-C(O)-, C 1-3 Alkyl-S(O)2-, C 3-6 Selected from cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl.

[0030] In some embodiments, each R c and R dEach of these is independently selected from fluoro, chloro, bromo, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, CH3C(O)-, CH3CH2C(O)-, CH3CH2CH2C(O)-, (CH3)2CH(O)-, CH3S(O)2-, CH3CH2S(O)2-, CH3CH2CH2S(O)2-, (CH3)2CHS(O)2-, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyrrolyl, piperazinyl, piperidinyl, phenyl, furyl, pyrrolyl, thienyl, pyridyl, or pyrimidinyl.

[0031] In some embodiments, each R c and R d These are, independently, halogen, hydroxyl, amino, and C. 1-4 Alkyl or C 1-4 Selected from alkoxys. In some embodiments, each R c and R d These are, independently, halogen, hydroxyl, amino, and C. 1-3 Alkyl or C 1-3 Selected from alkoxys. In some embodiments, each R c and R d These are, independently, halogen or C 1-3 Selected from alkyl groups.

[0032] In some embodiments, R c Halogen, hydroxyl, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkyl-C(O)- or C 1-3 Selected from alkyl-S(O)2-. In some embodiments, R c R is selected from halogen, hydroxyl, or amino. In some embodiments, R c R is selected from fluoro, chloro, or bromo. In some embodiments, c It is selected from Bromo.

[0033] In some embodiments, R 1 , R 2 These, together with the sulfur atoms to which they are bonded, form 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, or 10-membered heterocycloalkyl groups, wherein the heterocycloalkyl group may optionally contain one or more R d It may be replaced with .

[0034] In some embodiments, R 1 , R 2 These, together with the sulfur atoms to which they are bonded, form a 4-6 member monoheterocycloalkyl or a 7-10 member spiroheterocycloalkyl, and the monoheterocycloalkyl and spiroheterocycloalkyl can optionally have one or more R d It may be replaced with .

[0035] In some embodiments, R 1 , R 2 Together with the sulfur atoms to which they are bonded, they form a 4-membered, 5-membered, or 6-membered monoheterocycloalkyl group, or a 7-membered or 9-membered spiroheterocycloalkyl group, and the monoheterocycloalkyl group and spiroheterocycloalkyl group may optionally contain one, two, or three R atoms. d It may be replaced with R 1 , R 2 Along with the sulfur atoms to which they are bonded, [ka] It forms R 1 , R 2 Along with the sulfur atoms to which they are bonded, [ka] It forms.

[0036] In some embodiments, R d Halogen, hydroxyl, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3Alkyl-C(O)-, C 1-3 Alkyl-S(O)2-, C 3-6 Selected from cycloalkyl, 3-6 member heterocycloalkyl (e.g., 3-, 4-, 5-, or 6-membered), phenyl, or 5-6 member heteroaryl. In some embodiments, R d Halogen, hydroxyl, amino, C 1-3 Alkyl or C 1-3 Selected from alkoxys. In some embodiments, R d C 1-3 Alkyl or C 1-3 Selected from alkoxy.

[0037] In some embodiments, R d C 1-6 Selected from alkyl. In some embodiments, R d C 1-3 Selected from alkyl. In some embodiments, R d R is selected from methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R d It is selected from methyl.

[0038] In some embodiments, R 1 and R 2 These are, independently, methyl, ethyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, and phenyl. [ka] Selected from, or R 1 , R 2 Along with the sulfur atoms to which they are bonded, [ka] It forms.

[0039] In some embodiments, R 1 and R 2 These are, independently, methyl, ethyl, cyclopropyl, and phenyl. [ka] Selected from, or R 1 , R 2 Along with the sulfur atoms to which they are bonded, [ka] It forms.

[0040] In some embodiments, the structural unit [ka] Selected from.

[0041] In some embodiments, the structural unit [ka] Selected from.

[0042] In some embodiments, R 3 This can be any one or more R e Selected from 5-6 member heteroaryls, which may be substituted with .

[0043] In some embodiments, R 3 This can be any one or more R e Selected from five-membered heteroaryls, which may be substituted with .

[0044] In some embodiments, R 3 This can be any one or more R e Selected from a 5-membered N-containing heteroaryl which may be substituted with .

[0045] In some embodiments, R 3 This can be any one or more R e Selected from pyrazolyl, which may be substituted with .

[0046] In some embodiments, R 3This is any one R e Selected from pyrazolyl, which may be substituted with .

[0047] In some embodiments, R 3 teeth, [ka] Selected from.

[0048] In some embodiments, R 3 teeth, [ka] Selected from.

[0049] In some embodiments, R e is hydroxy, amino, halogen, C 1-3 Alkyl, Halogen C 1-3 Alkyl, C 3-6 Selected from cycloalkyl or 3-6 member heterocycloalkyl.

[0050] In some embodiments, R e C 1-3 Alkyl, Halogen C 1-3 Alkyl or C 3-6 Selected from cycloalkyl. In some embodiments, R e This is selected from methyl, trifluoromethyl, or cyclopropyl.

[0051] In some embodiments, R 3 teeth, [ka] Selected from.

[0052] In some embodiments, R 3 teeth, [ka] Selected from.

[0053] In some embodiments, the compound of formula (I) of the present invention, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof. [ka] In the formula, R 1 , R 2 and R e The definition is as stated above, n is selected from 0, 1, or 2. In some embodiments, n is selected from 0 or 1.

[0054] In some embodiments, the structural unit [ka] The definition is as stated above.

[0055] In some embodiments, the compound of formula (I) of the present invention, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from the compound of formula (III), its stereoisomer, or a pharmaceutically acceptable salt thereof. [ka] In the formula, R 1 , R 2 , R b and R e The definition is as stated above, n is selected from 0, 1, or 2. In some embodiments, n is selected from 0 or 1.

[0056] In some embodiments, the structural unit [ka] The definition is as stated above.

[0057] In some embodiments, the compound of formula (I) of the present invention, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from the compound of formula (Ia), the compound of formula (Ib), the compound of formula (II-a), the compound of formula (II-b), the compound of formula (III-a) or the compound of formula (III-b), their stereoisomers, or pharmaceutically acceptable salts thereof. [ka] In the formula, X, Y, R 1 , R 2 , R 3 , R b and R e The definition is as stated above, n is selected from 0, 1, or 2. In some embodiments, n is selected from 0 or 1.

[0058] In some embodiments, the structural unit [ka] The definition is as stated above.

[0059] In some embodiments, the heteroatoms in the heterocyclyl, heterocycloalkyl, or heteroaryl are selected from N, O, or S, and the number of heteroatoms may be selected from one, two, or three.

[0060] In some embodiments, the "one or more" is selected from one, two, three, four, five, or six. In some embodiments, the "one or more" is selected from one, two, or three. In some embodiments, the "one or more" is selected from one or two.

[0061] In some embodiments, the present invention includes the variables and embodiments defined above, as well as any combination thereof.

[0062] In some embodiments, the compound of formula (I) of the present invention is selected from the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0063] [ka]

[0064] In some embodiments, the compound of formula (I) of the present invention is selected from the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0065] [ka]

[0066] In another aspect, the present invention provides pharmaceutical compositions comprising the above-mentioned compounds of the present invention, their stereoisomers, or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions of the present invention further comprise pharmaceutically acceptable adjuvants.

[0067] In another aspect, the present invention provides a method for inhibiting ATR kinase in mammals, comprising administering a therapeutically effective amount of the above compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a mammal in need of treatment, preferably a human.

[0068] In yet another aspect, the present invention provides the use of the above-mentioned compound, its stereoisomer, or its pharmaceutically acceptable salt, or a pharmaceutical composition thereof, in the manufacture of a pharmacopoeia for inhibiting ATR kinase.

[0069] In yet another aspect, the present invention provides the use of the above-mentioned compound, its stereoisomer, or its pharmaceutically acceptable salt, or a pharmaceutical composition thereof, in the inhibition of ATR kinase.

[0070] In yet another aspect, the present invention provides the above compound that inhibits ATR kinase, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0071] In yet another aspect, the present invention provides a method for treating a disease and / or disorder associated with ATR or mediated by ATR in a mammal, which comprises administering a therapeutically effective amount of the above compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal in need of treatment, preferably a human.

[0072] In yet another aspect, the present invention provides use of the above compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for treating a disease and / or disorder associated with ATR or mediated by ATR.

[0073] In yet another aspect, the present invention provides use of the above compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment of a disease and / or disorder associated with ATR or mediated by ATR.

[0074] In yet another aspect, the present invention provides the above compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating a disease and / or disorder associated with ATR or mediated by ATR.

[0075] In some embodiments, the disease and / or disorder associated with ATR or mediated by ATR is selected from hyperproliferative diseases, such as cancer. In some embodiments, the cancer is selected from liver cancer, ovarian cancer, breast cancer, skin cancer, colorectal cancer, lung cancer, lymphoma and the like.

[0076] The compound of the present invention has good in vitro kinase inhibitory activity and cell proliferation inhibitory activity, is metabolically stable in vivo and in vitro, and has good in vivo exposure, half-life and bioavailability.

[0077] Definitions Unless otherwise specified, the terms used below in the present invention have the following meanings. Unless specifically defined, a particular term shall not be considered uncertain or unclear, but shall be understood according to the ordinary meaning in the art. When a trade name is mentioned in the present specification, it is intended to refer to the corresponding product or the active ingredient thereof.

[0078] Chemical bond

Chemical Formula

Chemical Formula

Chemical Formula

[0079] The term "substituted" means that any one or more hydrogen atoms on a specified atom are substituted with a substituent, as long as the valence of the specified atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted, and oxo does not occur on an aromatic group.

[0080] The terms “optional” or “optionally” mean that the event or situation described thereafter may or may not occur, and such description includes both the occurrence and non-occurrence of such event or situation. For example, “optionally substituted with a group” means that it is either unsubstituted or substituted with one or more of that group. Specifically, for example, “optionally” substituted with a halogen of ethyl means that ethyl may be unsubstituted (CH2CH3), monosubstituted (e.g., CH2CH2F), polysubstituted (e.g., CHFCH2F, CHCHF2, etc.), or fully substituted (CF2CF3). A person skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern is introduced that is spatially impossible and / or cannot be synthesized.

[0081] C in this specification m-n This means that the part has an integer number of carbon atoms within a specified range. For example, "C 1~6 "This group may have one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, or six carbon atoms, and "C 1-3 This means that the group may have one carbon atom, two carbon atoms, or three carbon atoms.

[0082] If any variable (e.g., R) appears one or more times in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted with two Rs, each R has an independent choice.

[0083] If one variable is selected from covalent bonds, it means that the two groups to which it is joined are directly bonded. For example, if L in ALZ represents a covalent bond, it means that this structure is actually AZ.

[0084] When a bond of one substituent is cross-linked to two atoms on one ring, it means that the substituent may be bonded to any atom on that ring. For example, the structural unit

Chemical formula

[0085] The term "halo" or "halogen" means fluoro, chloro, bromo and iodo.

[0086] The term "hydroxy" means a -OH group.

[0087] The term "amino" means a -NH2 group.

[0088] The term "alkyl" refers to a hydrocarbon group having the general formula C n H 2n+1 . The alkyl may be linear or branched. For example, the term "C 1-6 alkyl" means an alkyl containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl moiety (i.e., alkyl) in alkoxy, alkylamino, dialkylamino, alkylsulfonyl and alkylthio has the same definition as above.

[0089] The term "alkoxy" means -O-alkyl.

[0090] The term "alkylamino" means -NH-alkyl.

[0091] The term "alkynyl" refers to a linear or branched hydrocarbon chain containing 2 to 12 carbon atoms and having one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, propargyl, and 3-hexynyl.

[0092] The term "halogenoalkyl" refers to an alkyl group in which one or more hydrogen atoms are substituted with halogen atoms. Non-exclusive examples of halogenoalkyls include -CH2F, -CHF2, -CF3, -CCl3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CF2CF3, etc.

[0093] The term "cycloalkyl" refers to a carbon ring that can exist as a fully saturated monocycle, bridged ring, or spirocycle. Unless otherwise specified, this carbon ring is generally a 3- to 10-membered ring. Non-exclusive examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, and adamantyl.

[0094] The term "heterocyclyl" means a non-aromatic ring that can exist as a monocycle, bridging ring, or spirocycle, and is either fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic). Unless otherwise specified, this heterocycle is generally a 3-7 membered ring containing 1-3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, phosphorus, and / or nitrogen. Non-limiting examples of heterocyclyls include oxyranil, tetrahydrofuranil, dihydrofuranil, pyrrolidinil, N-methylpyrrolidinil, dihydropyrrolyl, piperidinil, piperazinil, pyrazolidinil, 4H-pyranil, morpholinil, thiomorpholinil, tetrahydrothienyl, or [ka] This includes, among others.

[0095] The term "heterocycloalkyl" refers to a cyclic group that can exist as a fully saturated monocycle, bridged ring, or spirocycle. Unless otherwise specified, this heterocycle is generally a 3- to 7-membered ring containing 1-3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, phosphorus, and / or nitrogen. Examples of 3-membered heterocycloalkyls include, but are not limited to, oxyranyl, thyranyl, and aziranyl. Non-limiting examples of 4-membered heterocycloalkyls include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Examples of 5-membered heterocycloalkyls include tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, [ka] This includes, but is not limited to, the following: Examples of 6-membered heterocycloalkyls include, but are not limited to, piperidinyl, tetrahydropyranil, tetrahydrothiapyranil, morpholinil, piperazinyl, 1,4-oxathianil, 1,4-dioxanil, thiomorpholinil, 1,3-dithianil, and 1,4-dithianil. Examples of 7-membered heterocycloalkyls include, but are not limited to, azepanil, oxepanil, and thiepanil. Preferably, monocyclic heterocycloalkyls having 5 or 6 ring atoms.

[0096] The term "monoheterocycloalkyl" refers to a heterocycloalkyl group that exists as a single ring.

[0097] The term “spiroheterocycloalkyl” refers to a fully saturated 5- to 20-membered polycyclic ring sharing one carbon atom (called a spiro atom) between monocyclic rings, wherein one or more ring atoms in this polycyclic ring are heteroatoms (preferably one or two heteroatoms) selected from sulfur, silicon, phosphorus, oxygen, and / or nitrogen, and the remaining ring atoms are carbon atoms. Preferably 6- to 14 members, more preferably 6- to 10 members. Spiroheterocyclic rings are classified as monospiroheterocyclic rings, dispiroheterocyclic rings, or polyspiroheterocyclic rings depending on the number of spiro atoms shared between the rings, preferably monospiroheterocyclic rings or dispiroheterocyclic rings, more preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclic rings. Non-limiting examples of spiroheterocyclic rings are: [ka] Includes.

[0098] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system. For example, an aryl may have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Non-limiting examples of aryls include phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetrahydronaphthalene.

[0099] The term "heteroaryl" refers to a monocyclic or fused polycyclic system containing at least one ring atom selected from N, O, and S, with the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryls have a single 5- to 8-membered ring, or multiple fused rings containing 6- to 14, particularly 6- to 10, ring atoms. Non-limiting examples of heteroaryls include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, and the like.

[0100] The term "treatment" means administering the compounds or formulations described in the present invention to improve or resolve one or more symptoms of a disease or a disease, and includes the following: (i) To suppress a disease or disease state, that is, to inhibit its progression, (ii) To alleviate a disease or disease state, that is, to cause regression of the disease or disease state.

[0101] The term "prevention" means administering the compounds or formulations described in the present invention to prevent one or more symptoms associated with a disease, and includes preventing the development of a disease or disease condition in a mammal, and in particular includes preventing the development of a disease or disease condition in a mammal that is susceptible to the disease condition but has not been diagnosed with the disease condition.

[0102] The term “therapeutic dose” means the amount of the compound of the present invention used to (i) treat or prevent a particular disease, condition, or disorder, or (ii) alleviate, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder. The amount of the compound of the present invention constituting a “therapeutic dose” varies depending on the compound, the disease condition and its severity, the mode of administration, and the age of the mammal being treated, but can be routinely determined by those skilled in the art based on their own knowledge and this disclosure.

[0103] The term "pharmaceutically acceptable" means that, within the bounds of reliable medical judgment, these compounds, materials, compositions and / or dosage forms are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0104] Examples of pharmaceutically acceptable salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with basic or acidic amino acids, and so on.

[0105] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present invention or salts thereof with pharmaceutically acceptable adjuvants. The pharmaceutical composition is intended to facilitate the administration of the compounds of the present invention to living organisms.

[0106] The term "pharmaceutically acceptable adjuvant" means an adjuvant that does not have a significant irritant effect on the living organism and does not impair the biological activity and performance of the active compound. Suitable adjuvant are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, and water.

[0107] The terms "comprise" or "comprise," and their English variations such as "comprises" or "comprising," should be understood in an open and non-exclusive sense, meaning "to include, but not to limit."

[0108] The compounds of the present invention may exist in specific geometric or stereoisomer forms. The present invention assumes that all compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, and (L)-isomers, as well as all mixtures, including racemic mixtures and other mixtures such as mixtures rich in enantiomers or diastereomers, are within the scope of the present invention. Alkyl substituents may have other chiral carbon atoms. All of these isomers and mixtures thereof are within the scope of the present invention.

[0109] Unless otherwise specified, "(D)" or "(+)" represents a right-handed rotation, "(L)" or "(-)" represents a left-handed rotation, and "(DL)" or "(±)" represents a racemic mixture.

[0110] Unless otherwise specified, [ka] This shows the absolute arrangement of the center of the solid. [ka] This shows the relative arrangement of the center of the solid.

[0111] The optically active (R)- and (S)-isomers, as well as the D and L isomers, can be prepared by chiral synthesis, chiral reagents, or other prior art. If it is desired to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary agent (the resulting diastereomer mixture is separated, and the auxiliary groups are cleaved to obtain the pure enantiomer of the desired type). Alternatively, if the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), a salt of the diastereomer is formed with a suitable optically active acid or base, the diastereomer is then divided by a conventional method known in the art, and the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomers is generally performed by chromatography using a chiral stationary phase and optionally combined with chemical derivatization (e.g., production of carbamates from amines).

[0112] The present invention is identical to that described herein, but also includes isotope-labeled compounds of the present invention in which one or more atoms are substituted with atoms of different atomic weights or mass numbers than those commonly found in nature. Examples of isotopes that can be bonded to the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, for example, respectively. 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36Examples include Cl.

[0113] Several isotope-labeled compounds of the present invention (e.g.) 3 H and 14 Tritiation (i.e., labeled with 1C) is useful in tissue distribution assays of compounds and / or substrates. 3 H), and carbon-14 (i.e.) 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. 15 O, 13 N, 11 C, and 18 Positron-emitting isotopes such as F are useful in positron emission tomography (PET) studies and can be used to determine substrate occupancy. The isotope-labeled compounds of the present invention can generally be prepared by using an isotope-labeled reagent instead of an unlabeled reagent by following a procedure similar to that in the scheme and / or examples disclosed below.

[0114] Furthermore, heavier isotopes (for example, deuterium (i.e., 2 Substitution with H or D may be preferable in certain circumstances because it can provide certain therapeutic benefits due to higher metabolic stability (e.g., increased half-life in vivo or reduced dose required). However, deuterium substitution may be partial or complete, with partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.

[0115] The pharmaceutical compositions of this application can be prepared by combining the compounds of the present invention with appropriate pharmaceutically acceptable adjuvants, and can be prepared in solid, semi-solid, liquid, or gaseous forms, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, and aerosols.

[0116] Typical routes of administration of the compounds of the present invention or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, nasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0117] The pharmaceutical composition of the present invention can be manufactured using methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill production methods, grinding methods, emulsification methods, and freeze-drying methods.

[0118] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable adjuvants known in the art. For oral administration to a patient, these adjuvants allow the compound of the present invention to be formulated into tablets, pills, lozenges, sugar-coated preparations, capsules, liquids, gels, slurries, suspensions, etc.

[0119] Solid oral compositions can be formulated by conventional mixing, filling, or tableting methods. For example, the active compound may be mixed with a solid adjuvant, the resulting mixture may be optionally pulverized, other suitable adjuvants may be added as needed, and then the mixture may be processed into granules to obtain a tablet or sugar-coated core. Suitable adjuvants include, but are not limited to, binders, diluents, disintegrants, lubricants, fluidizers, sweeteners, or flavoring agents.

[0120] The pharmaceutical composition may be a sterile solution, suspension, or lyophilized product in a suitable unit dosage form, and is also applicable for parenteral administration.

[0121] In all administration methods of the compound of formula (I) described herein, the daily dose is 0.01 to 200 mg / kg body weight, either as a single dose or in divided doses.

[0122] The compounds of the present invention can be prepared by various synthesis methods well known to those skilled in the art, including the specific embodiments listed below, embodiments in combination with other chemical synthesis methods, and equivalent alternative forms well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0123] The chemical reactions in specific embodiments of the present invention are carried out in appropriate solvents suitable for the chemical changes and necessary reagents and materials in the present invention. To obtain the compounds of the present invention, those skilled in the art may need to modify or select synthesis steps or reaction schemes based on existing embodiments.

[0124] One of the important considerations in synthetic route planning in this field is the selection of an appropriate protecting group for a reactive functional group (e.g., amino in this invention), for example, see Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc. All references incorporated herein are incorporated collectively.

[0125] In some embodiments, the compounds of the present invention may be prepared by organic synthesis specialists by referring to the following route.

[0126] [ka]

[0127] In the formula, R 1 , R 2 The definition is as stated above.

[0128] This invention uses the following abbreviations.

[0129] HEPES represents 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, MgCl2 represents magnesium chloride, DTT represents dithiothreitol, EGTA represents ethylene glycol-bis(2-aminoethyl ether)tetraacetic acid, DMSO represents dimethyl sulfoxide, EDTA represents ethylenediaminetetraacetic acid, HU represents hydroxyurea, and SEM represents (trimethylsilyl)ethoxymethyl. [Modes for carrying out the invention]

[0130] For clarity, the present invention will be further illustrated by examples, but these examples will not limit the scope of the invention. Various modifications and improvements to specific embodiments of the invention will be obvious to those skilled in the art without departing from the spirit and scope of the invention. All reagents used in the present invention are commercially available and can be used without further purification.

[0131] Synthesis of intermediates: Intermediate 1: Synthesis of Compound A1 and Compound A2 [ka]

[0132] Step 1: Synthesis of Compounds A1-2 Compound A1-1 (20 g) was dissolved in 6 M dilute hydrochloric acid (140 mL), the mixture was cooled to 5°C, 1 M aqueous sodium nitrite solution (241 mL) was added dropwise, and the mixture was reacted for 1 hour. Then, 1 M aqueous tin dichloride hydrochloric acid solution (480 mL) was added dropwise to the mixture and the mixture was reacted overnight at room temperature. The reaction solution was concentrated, ethyl acetate (100 mL) was added to the resulting crude mixture and beaten, then filtered and dried to obtain 62.9 g of crude compound A1-2, which was used directly in the next reaction. MS (ESI, [M+H] + m / z: 99.07. 1H NMR (500 MHz, DMSO-d6) δ 9.88 (s, 3H), 7.64 (d, J=2.4Hz, 1H), 5.82 (d, J=2.4Hz, 1H).

[0133] Step 2: Synthesis of Compounds A1-4 Compound A1-3 (14 g) was mixed with toluene (105 mL) and diethyl ether (105 mL), cooled to -78°C, and 35 mL of a tetrahydrofuran / n-hexane solution of 2 M lithium diisopropylamide was added dropwise. The reaction was allowed to proceed at -78°C for 1 hour. Ethyl formate (6.46 g) was added to the reaction mixture, and the reaction was continued at -78°C for 30 minutes. Next, formic acid (5.35 g) and ethyl acetate (100 mL) were added, and the reaction mixture was raised to room temperature. The organic phase was sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 11.2 g of compound A1-4. 1 H NMR (500 MHz, CDCl3) δ 10.11 (s, 1H), 7.54 (d, J=3.0 Hz, 1H).

[0134] Step 3: Synthesis of Compounds A1-5 Compound A1-2 (15 g), compound A1-4 (6 g), and ethanol (100 mL) were mixed and reacted at room temperature for 30 minutes. The reaction solution was concentrated, the residue was dissolved in ethyl acetate, washed sequentially with saturated sodium bicarbonate, water, and saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 6.02 g of compound A1-5. MS (ESI, [M+H] + ) m / z: 349.87. 1 H NMR (500 MHz, DMSO-d6) δ 12.01 (s, 1H), 10.85 (s, 1H), 7.94 (s, 1H), 7.81 (d, J = 2.7 Hz, 1H), 7.53 (d, J = 1.3 Hz, 1H), 5.97 (s, 1H).

[0135] Step 4: Synthesis of Compounds A1-6 Compound A1-5 (10 g) and N-methylpyrrolidone (140 mL) were mixed and heated to 200°C in a microwave, and the mixture was allowed to react for 20 minutes. Water was added to the reaction solution to precipitate the solid, which was then filtered, washed, and dried to obtain 7.4 g of compound A1-6. MS (ESI, [M+H] + ) m / z: 329.83. 1 H NMR (500 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.27 (s, 1H), 7.93 (d, J = 2.2 Hz, 1H), 7.68 (s, 1H), 6.67 (d, J = 2.3 Hz, 1H).

[0136] Step 5: Synthesis of Compounds A1-7 Compound A1-6 (7 g), (R)-3-methylmorpholine (4.3 g), and dimethyl sulfoxide (30 mL) were mixed and heated to 120°C, where they were reacted for 4 hours. Water was added to the reaction solution to precipitate the solid, which was then filtered, washed, and dried to obtain 6.8 g of compound A1-7. MS (ESI, [M+H] + ) m / z: 411.00. 1 H NMR (500 MHz, DMSO-d6) δ 12.87 (s, 1H), 7.84 (d, J=11.2Hz, 2H), 7.28 (s, 1H), 6.76 (d, J=1.8Hz, 1H), 4.45 (d, J=4.9Hz, 1H), 4.08-3.99 (m, 1H), 3.95 (dd, J=11.4, 3.4Hz, 1H), 3.74 (d, J=11.4Hz, 1H), 3.63 (dd, J=11.4, 2.9Hz, 1H), 3.48 (td, J=11.9, 2.9Hz, 1H), 3.17 (td, J=12.8, 3.6Hz, 1H), 1.19 (d, J=6.7Hz, 3H).

[0137] Step 6: Synthesis of Compound A1 and Compound A2 Compound A1-7 (4 g), diisopropylethylamine (3.78 g), and dichloromethane (60 mL) were mixed, and 2-(trimethylsilyl)ethoxymethyl chloride (3.25 g) was added dropwise. The mixture was reacted at room temperature for 30 minutes. Dichloromethane (20 mL) and saturated sodium bicarbonate (20 mL) were added to the reaction mixture, and the organic phase was separated and concentrated. The resulting crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound A1 (2.02 g) and compound A2 (1.13 g). Compound A1: MS (ESI, [M+H] + ) m / z: 541.02. 1 H NMR (500 MHz, CDCl3) δ 7.83 (s, 1H), 7.64 (d, J = 1.8 Hz, 1H), 7.00 (s, 1H), 6.59 (d, J = 1.8 Hz, 1H), 5.72-5.65 (m, 2H), 4.34-4.27 (m, 1H), 4.01 (dd, J = 11.5, 3.7 Hz, 1H), 3.95 (dd, J = 13.3, 2.5 Hz, 1H), 3.79 (d, J = 11.4 Hz, 1H), 3.71 (dd, J = 11.5, 3.1 Hz, 1H), 3.56 (td, J = 12.0, 3.1 Hz, 1H), 3.47-3.38 (m, 2H), 3.25 (td, J = 12.8, 3.9 Hz, 1H), 1.29 (d, J = 6.8 Hz, 3H), 0.78-0.72 (m, 2H), -0.15 (s, 9H). Compound A2: MS (ESI, [M+H] + ) m / z: 541.02. 1H NMR (500 MHz, DMSO-d6) δ8.02 (d, J = 2.4 Hz, 1H), 7.84 (s, 1H), 7.28 (s, 1H), 6.86 (d, J = 2.4 Hz, 1H), 5.43 (s, 2H), 4.51-4.41 (m, 1H), 4.05-4.01 (m, 1H), 3.94 (dd, J = 11.4, 3.5 Hz, 1H), 3.73 (d, J = 11.4 Hz, 1H), 3.66-3.57 (m, 3H), 3.48 (td, J = 11.9, 3.0 Hz, 1H), 3.17 (td, J = 12.8, 3.7 Hz, 1H), 1.19 (d, J = 6.7 Hz, 3H), 0.88-0.82 (m, 2H), -0.05 (s, 9H).

[0138] Intermediate 2: Synthesis of Compound B1 [ka]

[0139] Compound B1-1 (1 g), iodobenzene diacetate (10.71 g), ammonium carbamate (3.46 g), and methanol (10 mL) were mixed and reacted at room temperature for 1 hour. The reaction mixture was filtered and concentrated, and the crude product was separated and purified by column chromatography (dichloromethane:methanol = 50:1) to obtain compound B1 (750 mg). 1 1H NMR (500 MHz, DMSO-d6): δ 3.01-2.88 (m, 4H), 1.20 (t, J=7.4Hz, 6H).

[0140] Intermediate 3: Synthesis of compound C1 [ka]

[0141] Compound C1-1 (0.8 g), iodobenzene diacetate (10.43 g), ammonium carbamate (3.37 g), and methanol (10 mL) were mixed and reacted at room temperature for 1 hour. The reaction mixture was filtered and concentrated, and the crude product was separated and purified by column chromatography (dichloromethane:methanol = 50:1) to obtain compound C1 (450 mg). 1 1H NMR (500 MHz, DMSO-d6): δ 4.01-3.80 (m, 4H), 2.13-1.96 (m, 2H).

[0142] Intermediate 4: Synthesis of compound D1 [ka]

[0143] Compound D1-1 (1 g), iodobenzene diacetate (3 g), ammonium carbamate (9.28 g), and methanol (20 mL) were mixed and reacted at room temperature for 1 hour. The reaction mixture was filtered and concentrated, and the crude product was separated and purified by column chromatography (dichloromethane:methanol = 20:1) to obtain compound D1 (1.12 g). 1 H NMR (500 MHz, CDCl3) δ 3.15-3.12 (m, 4H), 2.28-2.24 (m, 4H).

[0144] Intermediate 5: Synthesis of Compound E1 [ka]

[0145] Thiocyclopentane (0.5 g), which is compound E1-1, methanol (10 mL), ammonium carbamate (0.57 g), and iodobenzene diacetate (3.31 g) were mixed and reacted at room temperature for 0.5 hours. The reaction mixture was filtered and concentrated, and the resulting crude product was separated and purified by column chromatography (dichloromethane:methanol = 20:1) to obtain compound E1 (0.48 g). 1 H NMR (500 MHz, CDCl3) δ 3.32 (s, 1H), 3.10-3.02 (m, 4H), 2.09-2.06 (m, 4H), 1.64 (qd, J =5.8, 4.9, 3.2Hz, 2H).

[0146] Intermediate 6: Synthesis of Compound F1 [ka]

[0147] Compound F1-1 (0.5 g), methanol (10 mL), ammonium carbamate (0.56 g), and iodobenzene diacetate (3.09 g) were mixed and reacted at room temperature for 1 hour. The reaction mixture was filtered and concentrated, and the resulting crude product was separated and purified by column chromatography (dichloromethane:methanol = 20:1) to obtain compound F1 (0.605 g). 1 H NMR (500 MHz, CDCl3) δ 4.17-4.08 (m, 4H), 3.21-3.12 (m, 4H).

[0148] Intermediate 7: Synthesis of compound G1 [ka]

[0149] Step 1: Synthesis of Compound G1-2 Compound G1-1 (2.064 g) was dissolved in dichloromethane (20 mL), triethylamine (3.04 g) was added, and benzoyl chloride (2.81 g) was added dropwise under ice cooling. After the addition was complete, the mixture was allowed to react overnight at room temperature. The reaction solution was diluted with dichloromethane, washed sequentially with saturated sodium bicarbonate solution, water, and saturated saline solution, and dried over anhydrous sodium sulfate. After filtration and concentration, 4.1 g of compound G1-2 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.45-7.43 (m, 3H), 7.38 (dd, J=6.7, 3.1 Hz, 2H), 3.86-3.54 (m, 4H), 2.72-2.54 (m, 4H).

[0150] Step 2: Synthesis of Compound G1 Compound G1-2 (1 g) was dissolved in methanol (15 mL), ammonium carbamate (0.565 g) and iodobenzene diacetate (3.26 g) were added, and the mixture was reacted at room temperature for 0.5 hours. The reaction mixture was filtered and concentrated, and the resulting crude product was separated and purified by column chromatography (dichloromethane:methanol = 19:1) to obtain 0.82 g of compound G1. 1 H NMR (500 MHz, DMSO-d6) δ 7.56-7.37 (m, 5H), 4.29-4.07 (brs, 1H), 3.86-3.54 (m, 4H), 3.22-2.90 (m, 4H).

[0151] Intermediate 8: Synthesis of compound H1 [ka]

[0152] Step 1: Synthesis of compound H1-2 Compound H1-1 (2 g) was dissolved in pyridine (5 mL), and a solution of p-toluenesulfonyl chloride (5.82 g) in pyridine (56 mL) was added dropwise under ice cooling. The mixture was then allowed to react overnight at room temperature. Dichloromethane was added to the reaction mixture, and it was washed sequentially with 1 M dilute hydrochloric acid, water, and saturated brine. The mixture was dried over anhydrous sodium sulfate. After filtration and concentration, the resulting crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 3.1 g of compound H1-2. 1H NMR (500 MHz, CDCl3) δ 7.73 (d, J=8.3Hz, 4H), 7.35 (d, J=8.0Hz, 4H), 3.83 (s, 4H), 2.46 (s, 6H), 1.32 (s, 10H).

[0153] Step 2: Synthesis of Compound H1-3 Dissolve compound H1-2 (3 g) in N,N-dimethylformamide (50 mL), add sodium sulfide notahydrate (3.18 g), and 100 o The mixture was heated to 14°C and reacted for 7 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the organic phase was sequentially washed with water and saturated brine, then dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the resulting crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 19:1) to obtain 0.22 g of compound H1-3. 1 H NMR (500 MHz, CDCl3) δ 2.90 (s, 4H), 1.68 (s, 4H), 1.40 (q, J=5.7Hz, 4H), 1.35-1.29 (m, 2H).

[0154] Step 3: Synthesis of the compound Compound H1-3 (200 mg) was dissolved in methanol (10 mL), ammonium carbamate (165 mg) and iodobenzene diacetate (951 mg) were added, and the mixture was reacted at room temperature for 0.5 hours. The reaction mixture was filtered and concentrated, and the resulting crude product was separated and purified by column chromatography (dichloromethane:methanol = 19:1) to obtain 0.27 g of compound H1. 1 H NMR (500 MHz, CDCl3) δ 3.84-3.74 (m, 4H), 1.79 (dt, J=19.5, 5.5 Hz, 4H), 1.48-1.42 (m 6H).

[0155] Intermediate 9: Synthesis of Compound I1 [ka]

[0156] Step 1: Synthesis of Compounds I1-2 Compound I1-1 (500 mg) and triethylamine (790 mg) were dissolved in dichloromethane (20 mL). A solution of benzoyl chloride (439 mg) in dichloromethane (2 mL) was added dropwise under ice cooling, and the mixture was allowed to react overnight at room temperature. Dichloromethane was added to the reaction mixture, and the mixture was sequentially washed with saturated sodium bicarbonate aqueous solution, water, and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration, 0.52 g of compound I1-2 was obtained and used directly in the next reaction. 1 H NMR (500 MHz, CDCl3) δ 7.70-7.57 (m, 2H), 7.51-7.45 (m, 1H), 7.41 (dd, J=8.2, 6.6Hz, 2H), 4.34-4.23 (m, 4H), 3.51-3.21 (m, 4H).

[0157] Step 2: Synthesis of Compound I1 Compounds I1-2 were dissolved in methanol (10 mL), ammonium carbamate (160 mg) and iodobenzene diacetate (925 mg) were added, and the mixture was reacted at room temperature for 0.5 hours. The reaction mixture was filtered and concentrated, and the resulting crude product was separated and purified by column chromatography (dichloromethane:methanol = 10:1) to obtain 0.25 g of compound I1. 1 H NMR (500 MHz, CDCl3) δ 7.67-7.57 (m, 2H), 7.55-7.46 (m, 1H), 7.43 (dd, J=8.2, 6.8 Hz, 2H), 4.48 (s, 4H), 4.30 (s, 4H), 3.20 (s, 1H).

[0158] Intermediate 10: Compound J1 [ka]

[0159] Step 1: Synthesis of compound J1-2 Dissolve compound J1-1 (1.5 g) in tetrahydrofuran (30 mL), 0 o The mixture was cooled to 1°C, and 10.27 mL of a tetrahydrofuran solution of 1 M cyclopropylmagnesium bromide was added dropwise under nitrogen protection. The mixture was then allowed to react at room temperature for 0.5 hours. 60 mL of saturated ammonium chloride aqueous solution was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the resulting crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 0:1) to obtain 0.4 g of compound J1-2. 1 H NMR (500 MHz, CDCl3) δ 2.65 (s, 3H), 2.16 (tt, J =8.0, 4.9Hz, 1H), 1.21-1.12 (m, 1H), 1.04-0.91 (m, 2H), 0.88-0.75 (m, 1H).

[0160] Step 2: Synthesis of Compound J1 Compound J1-2 (0.4 g) was dissolved in methanol (10 mL), ammonium carbamate (0.45 g) and iodobenzene diacetate (3.31 g) were added, and the mixture was reacted at room temperature for 0.5 hours. The reaction mixture was filtered and concentrated, and the resulting crude product was separated and purified by column chromatography (dichloromethane:methanol = 19:1) to obtain 0.42 g of compound J1. 1 H NMR (500 MHz, CDCl3) δ 3.04 (s, 3H), 2.81 (brs, 1H), 2.56 (tt, J=7.9, 4.7Hz, 1H), 1.28-1.11 (m, 2H), 1.09-0.97 (m, 2H).

[0161] Intermediate 11: Synthesis of compound K1 [ka]

[0162] Compound K1-1 (1 g), iodobenzene acetate (6.89 g), ammonium carbamate (2.22 g), and methanol (10 mL) were mixed and reacted at room temperature for 1 hour. The reaction mixture was filtered and concentrated, and the resulting crude product was separated and purified by column chromatography (dichloromethane:methanol = 49:1) to obtain 600 mg of compound K1. 1 H NMR (500 MHz, DMSO-d6): δ 7.98-7.88 (m, 2H), 7.66 (t, J=7.3Hz, 1H), 7.60 (t, J=7.4Hz, 2H), 3.06 (s, 3H), 1.91 (s, 1H).

[0163] Intermediate 12: Compound L1 [ka]

[0164] Step 1: Synthesis of Compound L1-2 Compound L1-1 (3.66 g) and potassium carbonate (9.10 g) are dissolved in dichloromethane (15 mL), 0 o The mixture was cooled to 1°C, and methylene iodide (7.01 g) and triethylamine (0.459 mL) were added dropwise. The mixture was reacted at room temperature for 6 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, the aqueous phase was extracted with dichloromethane, and the organic phase was sequentially washed with water and saturated brine. The mixture was then dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the resulting crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 3 g of compound L1-2. 1 HNMR (500 MHz, DMSO-d6) δ 8.37 (dd, J = 4.6, 1.6 Hz, 2H), 7.25 (dd, J = 4.6, 1.6 Hz, 2H), 2.51 (s, 3H).

[0165] Step 2: Synthesis of Compound L1 Compound L1-2 (1 g), iodobenzene acetate (5.15 g), and ammonium carbamate (1.87 g) were dissolved in methanol (10 mL) and reacted at room temperature for 1 hour. The reaction mixture was filtered and concentrated, and the resulting crude product was separated and purified by column chromatography (dichloromethane:methanol = 47:3) to obtain compound L1 (500 mg). 1 HNMR (500 MHz, DMSO-d6) δ 8.86 (dd, J = 4.4, 1.6 Hz, 2H), 7.87 (dd, J = 4.4, 1.6 Hz, 2H), 3.15 (s, 3H).

[0166] Intermediate 13: Compound M1 [ka]

[0167] Compound M1-1 (500 mg) was dissolved in methanol (10 mL), ammonium carbamate (412 mg) and iodobenzene diacetate (2.2 g) were added, and the mixture was reacted at room temperature for 1 hour. The reaction mixture was filtered and concentrated, and the resulting crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 0.31 g of compound M1. 1 H NMR (500 MHz, DMSO-d6) δ 8.00-7.97 (m, 2H), 7.46-7.42 (m, 2H), 4.28 (s, 1H), 3.08 (s, 3H).

[0168] Intermediate 14: Compound N1 [ka]

[0169] Step 1: Synthesis of compound N1-2 Compound N1-1 (150 mg), 1,2-dimethyldisulfone (415 mg), bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium bis(hexafluorophosphate) (49.4 mg), and dichloroethane (22 mL) were mixed and reacted at room temperature under light illumination (5 w, 450 nm) for 16 hours. The reaction mixture was filtered and concentrated, and the resulting crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 3:1). This experimental procedure was repeated twice, and a total of 450 mg of starting material was added to obtain a total of 150 mg of compound N1-2.

[0170] Step 2: Synthesis of Compound N1 Compound N1-2 (150 mg) was dissolved in methanol (5 mL), ammonium carbamate (403 mg) and iodobenzene diacetate (1.24 g) were added, and the mixture was reacted at room temperature for 0.5 hours. The reaction mixture was filtered and concentrated, and the resulting crude product was separated and purified by column chromatography (dichloromethane:methanol = 10:1) to obtain 100 mg of compound N1. 1 HNMR (500 MHz, DMSO-d6) δ 3.48 (dd, J = 15.9, 8.1 Hz, 1H), 2.81 (s, 3H), 1.96-1.80 (m, 4H), 1.71-1.61 (m, 2H), 1.60-1.50 (m, 2H).

[0171] Intermediate 15: Compound O1 [ka]

[0172] Step 1: Synthesis of compound O1-2 Dissolve compound O1-1 (30 g) in methanol (182 mL), and 5 oThe mixture was cooled to 1°C, and sodium borohydride (2.1 g) was added in portions. The mixture was reacted for 1 hour while maintaining the temperature at 5°C. Water (100 mL) was added to the reaction mixture, the aqueous phase was extracted with dichloromethane, and the organic phase was sequentially washed with water and saturated brine. The mixture was then dried over anhydrous sodium sulfate. After filtration and concentration, the resulting crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 28 g of compound O1-2. 1 H-NMR (500 MHz, DMSO-d6): δ 4.46 (d, J = 4.1 Hz, 1H), 3.83 (m, 4H), 3.55 (s, 1H), 1.72 -1.60 (m, 4H), 1.54-1.38 (m, 4H).

[0173] Step 2: Synthesis of Compound O1-3 Compound O1-2 (9 g) was dissolved in dichloromethane (80 mL), cooled to 5°C, and triethylamine (17.27 g) and methanesulfonyl chloride (7.82 g) were added. The mixture was reacted for 30 minutes while maintaining the temperature at 5°C. Water (100 mL) was added to the reaction mixture, the aqueous phase was extracted with dichloromethane, and the organic phase was sequentially washed with water and saturated brine. The mixture was then dried over anhydrous sodium sulfate. After filtration and concentration, the resulting crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain 12 g of compound O1-3. 1 H-NMR (500 MHz, DMSO-d6): δ 4.76 (m, 1H), 3.94 -3.71 (m, 4H), 3.18 (s, 3H), 1.89 (m, 2H), 1.84-1.74 (m, 2H), 1.69 (m, 2H), 1.60 (m, 2H).

[0174] Step 3: Synthesis of Compound O1-4 Compound O1-3 (12.2 g) was dissolved in N,N-dimethylformamide (100 mL), cooled to 5°C, sodium thiomethoxide (4.16 g) was added in portions, and the mixture was gradually heated to room temperature and reacted overnight. Water (200 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was sequentially washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 9 g of compound O1-4. MS (ESI, [M+H] + ) m / z: 189.22.

[0175] Step 4: Synthesis of Compound O1-5 Compound O1-4 (9 g) was dissolved in ethyl acetate (85 mL), 3N hydrochloric acid (9 mL) was added dropwise, and the mixture was reacted at room temperature for 30 minutes. Water (50 mL) was added, the mixture was extracted with ethyl acetate, the organic phase was sequentially washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain 5.6 g of compound O1-5. 1 H NMR (500 MHz, DMSO -d6) δ 3.07 (m, 1H), 2.38 (m, 2H), 2.30 (m, 2H), 2.21-2.14 (m, 2H), 2.10 (s, 3H), 1.73 (m, 2H).

[0176] Step 5: Synthesis of compound O1-6 Compound O1-5 (5 g) was dissolved in dichloromethane (50 mL), cooled to 0°C, and diethylaminosulfatrifluoride (11.18 g) was added dropwise to the reaction mixture. The reaction was allowed to proceed for 3 hours while maintaining the temperature at 0°C, and saturated sodium bicarbonate aqueous solution (50 mL) was added. The mixture was extracted with dichloromethane, the organic phase was sequentially washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 3.5 g of compound O1-6. 1H NMR (500 MHz, DMSO-d6) δ 3.13 (t, J = 10.1 Hz, 1H), 2.06 (s, 3H), 1.93-1.79 (m, 3H), 1.60 (dd, J = 20.3, 10.4 Hz, 3H), 1.13 (m, 2H).

[0177] Step 6: Synthesis of Compound O1 Compound O1-6 (250 mg) was dissolved in methanol (5 mL), ammonium carbamate (470 mg) and iodobenzene diacetate (1.45 g) were added, and the mixture was reacted at room temperature for 1 hour. The reaction mixture was filtered and concentrated, and the resulting crude product was separated and purified by column chromatography (dichloromethane:methanol = 15:1) to obtain 200 mg of compound O1. MS (ESI, [M+H] + ) m / z: 198.02. 1 HNMR (500 MHz, DMSO-d6) δ 3.11 (dd, J = 21.0, 9.2 Hz, 1H), 2.86 (s, 3H), 2.20-2.11 (m, 4H), 1.95 (d, J = 15.0 Hz, 1H), 1.84 (d, J = 21.8 Hz, 1H), 1.74-1.55 (m, 3H).

[0178] Intermediate 16: Synthesis of compound P1 [ka]

[0179] Compound P1-1 (0.5 g), methanol (10 mL), ammonium carbamate (0.56 g), and iodobenzene diacetate (3.09 g) were mixed and reacted at room temperature for 5 hours. The reaction mixture was filtered and concentrated, and the resulting crude product was separated and purified by column chromatography (dichloromethane:methanol = 16:1) to obtain compound P1 (0.416 g). 1H NMR (500 MHz, DMSO-d6) δ 2.77 (s, 3H), 1.90 (s, 1H), 1.30 (s, 9H).

[0180] Intermediate 17: Synthesis of Compound Q1 [ka]

[0181] Compound Q1-1 (54 g) was dissolved in an aqueous hydrochloric acid solution (6 M, 1600 mL), the mixture was cooled to 5°C, and an aqueous sodium nitrite solution (1 M, 45 mL) was added dropwise. The mixture was reacted for 1 hour, and then an aqueous hydrochloric acid solution of tin dichloride (1 M, 74 mL) was added dropwise to the mixture. The mixture was reacted overnight at room temperature. The reaction solution was concentrated, and ethyl acetate (100 mL) was added to the resulting crude mixture and beaten. The mixture was then filtered and dried to obtain the crude hydrochloride salt of compound Q1 (40 g), which was used directly in the next reaction. MS (ESI, [M+H] + ) m / z: 139.10.

[0182] Example 1: Synthesis of Compound 1 [ka]

[0183] Step 1: Synthesis of Compound 1-1 Compound A1 (100 mg), dimethyl sulfoximine (20.68 mg), tris(dibenzylideneacetone)dipalladium (8.47 mg), 4,5-bisdiphenylphosphin-9,9-dimethylxanthene (10.71 mg), cesium carbonate (121 mg), and 1,4-dioxane (5 mL) were mixed and reacted at 80°C for 1 hour under a nitrogen atmosphere. The reaction mixture was filtered, the filtrate was concentrated, and the crude product was separated and purified by column chromatography (dichloromethane:methanol = 9:1) to obtain 71 mg of compound 1-1. 1H NMR (500 MHz, CDCl3): δ 8.07 (s, 1H), 7.63 (d, J=2.0Hz, 1H), 6.60 (d, J=2.0Hz, 1H), 6.26 (s, 1H), 5.76-5.70 (m, 2H), 4.32-4.30 (m, 1H), 4.00-3.91 (m, 2H), 3.78-3.70 (m, 2H), 3.59-3.54 (m, 1H), 3.46-3.42 (m, 2H), 3.28 (d, J=1.5Hz, 6H), 3.25-3.19 (m, 1H), 1.26 (d, J=7.0Hz, 3H), 0.79-0.75 (m, 2H), -0.14 (s, 9H).

[0184] Step 2: Synthesis of Compound 1 Compound 1-1 (350 mg) was dissolved in dichloromethane (4 mL), cooled to 0°C, and triethylsilane (805 mg) and trifluoroacetic acid (1 mL) were added. The mixture was reacted at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane and adjusted to pH 8 with saturated sodium bicarbonate solution. The organic phase was sequentially washed with water and saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the crude product was separated and purified by column chromatography (dichloromethane:methanol = 9:1) to obtain compound 1 (212 mg). MS (ESI, [M+H] + ) m / z: 376.30. 1 H NMR (500 MHz, DMSO-d6): δ 12.73 (s, 1H), 7.89 (s, 1H), 7.80 (s, 1H), 6.78 (s, 1H), 6.18 (s, 1H), 4.33 (d, J=5.5Hz, 1H), 3.97-3.91 (m, 2H), 3.75 (d, J=11.5Hz, 1H), 3.64 (dd, J=11.3, 2.8Hz, 1H), 3.49 (td, J=11.8, 2.8Hz, 1H), 3.41 (s, 6H), 3.13 (td, J=12.5, 3.5Hz, 1H), 1.18 (d, J=7.0Hz, 3H).

[0185] Example 2: Synthesis of Compound 2 [ka]

[0186] Compound 2 (90 mg) was synthesized in the same manner as described in Example 1, using compound B1 instead of dimethyl sulfoximine in step 1. MS (ESI, [M+H] + ) m / z: 404.27. 1 H NMR (500 MHz, DMSO-d6): δ 12.73 (s, 1H), 7.92 (s, 1H), 7.81 (s, 1H), 6.79 (s, 1H), 6.22 (s, 1H), 4.29 (d, J=4.8Hz, 1H), 3.97-3.89 (m, 2H), 3.74 (d, J=11.3Hz, 1H), 3.64 (d, J=11.3Hz, 1H), 3.48 (dd, J=14.7, 7.5Hz, 5H), 3.11 (t, J=12.6Hz, 1H), 1.32 (td, J=7.3, 2.8Hz, 6H), 1.16 (d, J=6.6Hz, 3H).

[0187] Example 3: Synthesis of Compound 3 [ka]

[0188] Compound 3 (80 mg) was synthesized in the same manner as described in Example 1, using compound C1 instead of dimethylsulfoximine in Step 1. MS (ESI, [M+H] + ) m / z: 388.12. 1H NMR (500 MHz, DMSO-d6): δ 12.75 (s, 1H), 7.91 (s, 1H), 7.82 (s, 1H), 6.79 (s, 1H), 6.02 (s, 1H), 4.54-4.39 (m, 2H), 4.39-4.27 (m, 3H), 3.99-3.83 (m, 2H), 3.74 (d, J=11.3Hz, 1H), 3.64 (dd, J=11.3, 2.4Hz, 1H), 3.49 (td, J=11.7, 2.4Hz, 1H), 3.12 (td, J=12.5, 2.8Hz, 1H), 2.45-2.33 (m, 1H), 2.28 (dd, J=18.9, 9.2Hz, 1H), 1.17 (d, J=6.6Hz, 3H).

[0189] Example 4: Synthesis of Compound 4 [ka]

[0190] Compound 4 (46 mg) was synthesized in the same manner as described in Example 1, using compound D1 instead of dimethylsulfoximine in Step 1. MS (ESI, [M+H] + ) m / z: 402.15. 1 H NMR (500 MHz, CDCl3) δ 8.03 (s, 1H), 7.64 (s, 1H), 6.87 (s, 1H), 6.17 (s, 1H), 4.34-4.33 (m, 1H), 4.03-4.00 (m, 1H), 3.93-3.91 (m, 1H), 3.81-3.73 (m, 2H), 3.60-3.58 (m, 1H), 3.52-3.48 (mm, 2H), 3.31-3.25 (m, 3H), 2.36-2.31 (m, 4H), 1.27 (d, J=7.0Hz, 3H).

[0191] Example 5: Synthesis of Compound 5 [ka]

[0192] Compound 5 (94 mg) was synthesized in the same manner as described in Example 1, using compound E1 instead of dimethyl sulfoximine in Step 1. MS (ESI, [M+H] + ) m / z: 416.17. 1 H NMR (500 MHz, CDCl3) δ 11.84 (s, 1H), 8.09 (s, 1H), 7.66 (d, J=2.2Hz, 1H), 6.82 (s, 1H), 6.31 (s, 1H), 4.42-4.31 (m, 1H), 4.04 (dd, J=11.4, 3.7Hz, 1H), 4.00-3.91 (m, 1H), 3.87-3.75 (m, 2H), 3.63 (td, J=11.8, 3.1Hz, 1H), 3.56-3.44 (m, 2H), 3.32 (td, J=12.7, 3.9Hz, 1H), 3.21-3.16 (m, 2H), 2.14-2.10 (m, 4H), 1.84-1.79 (m, 1H), 1.66-1.59 (m, 1H), 1.32 (d, J=6.8Hz, 3H).

[0193] Example 6: Synthesis of Compound 6 [ka]

[0194] Compound 6 (58 mg) was synthesized in the same manner as described in Example 1, using compound F1 instead of dimethylsulfoximine in Step 1. MS (ESI, [M+H] + ) m / z: 418.26. 1H NMR (500 MHz, CDCl3) δ 8.01 (s, 1H), 7.68 (s, 1H), 6.90 (s, 1H), 6.25 (s, 1H), 4.37-4.36 (m, 1H), 4.22-4.19 (m, 2H), 4.05-4.03 (m, 3H), 3.96-3.94 (m, 1H), 3.82-3.80 (m, 1H), 3.76-3.74 (m, 1H), 3.62-3.58 (m, 1H), 3.50-3.47 (m, 2H), 3.33-3.30 (m, 3H), 1.29 (d, J=6.5Hz, 3H).

[0195] Example 7: Synthesis of Compound 7 [ka]

[0196] Step 1: Synthesis of Compound 7-1 Compound A1, Compound G1 (183 mg), Tris(dibenzylideneacetone)dipalladium (27.1 mg), 4,5-bisdiphenylphosphin-9,9-dimethylxanthene (34.3 mg), cesium carbonate (386 mg), and dioxane (10 mL) were mixed and then subjected to a nitrogen atmosphere for 80°C. o The reaction was carried out in 1C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated. The crude product was then separated and purified by column chromatography (dichloromethane:methanol = 19:1) to obtain 0.37 g of compound 7-1. 1H NMR (500 MHz, CDCl3) δ 8.11 (s, 1H), 7.63 (d, J=1.9 Hz, 1H), 7.51-7.43 (m, 5H), 6.60 (d, J=1.9Hz, 1H), 6.27 (s, 1H), 5.82-5.65 (m, 2H), 4.33-4.29 (m, 1H), 3.99 (dd, J=11.4, 3.7Hz, 1H), 3.91 (dd, J=13.3, 2.9Hz, 1H), 3.88-3.82 (m, 2H), 3.78-3.69 (m, 2H), 3.56 (td, J=11.9, 3.2 Hz, 2H), 3.48-3.44 (m, 3H), 3.22 (td, J=12.7, 3.9 Hz, 3H), 1.57 (s, 2H), 1.26 (d, J=6.7 Hz, 3H), 0.77 (dd, J=9.5, 7.2 Hz, 2H), 0.14 (s, 9H).

[0197] Step 2: Synthesis of Compound 7-2 Compound 7-1 (200 mg) was dissolved in tetrahydrofuran (6 mL), and under nitrogen protection, a solution of 2.5 M lithium tetrahydroaluminum in tetrahydrofuran (0.18 mL) was added dropwise, and the mixture was reacted at room temperature for 1 hour. The mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the resulting crude product was separated and purified by column chromatography (dichloromethane:methanol = 10:1) to obtain 0.1 g of compound 7-2. 1H NMR (500 MHz, CDCl3) δ 8.12 (s, 1H), 7.63 (d, J=1.9Hz, 1H), 6.61 (d, J=1.8Hz, 1H), 6.29 (s, 1H), 5.85-5.65 (m, 2H), 4.32 (dd, J=7.2, 2.9Hz, 1H), 3.99 (dd, J=11.4, 3.8Hz, 1H), 3.93 (dd, J=13.2, 2.9Hz, 1H), 3.77 (d, J=11.3Hz, 1H), 3.72 (dd, J=11.3, 3.1Hz, 1H), 3.57 (td, J=11.9, 3.1Hz, 1H), 3.52-3.42 (m, 4H), 3.40-3.36 (m, 2H), 3.34-3.28 (m, 2H), 3.25-3.19 (m, 3H), 1.76 -1.67 (m, 1H), 1.26 (d, J=6.6Hz, 3H), 0.81-0.72 (m, 2H), 0.14 (s, 9H).

[0198] Step 3: Synthesis of Compound 7-3 Compound 7-2 (70 mg) was dissolved in methanol (2 mL), and acetic acid (16.09 mg), 37% formaldehyde aqueous solution (104 mg), and sodium borohydride cyanohydride (16.09 mg) were added sequentially, and the mixture was reacted at room temperature for 1 hour. Triethylamine was added to adjust the pH to approximately 8, and the mixture was concentrated. The resulting crude product was separated and purified by column chromatography (dichloromethane:methanol = 19:1) to obtain 0.096 g of compound 7-3. 1H NMR (500 MHz, CDCl3) δ 8.12 (s, 1H), 7.63 (d, J=1.8Hz, 1H), 6.61 (d, J=1.8Hz, 1H), 6.27 (s, 1H), 5.92-5.63 (m, 2H), 4.32 (dd, J=7.2, 2.8Hz, 1H), 3.99 (dd, J=11.4, 3.7Hz, 1H), 3.97-3.88 (m, 1H), 3.77 (d, J=11.3Hz, 1H), 3.72 (dd, J=11.3, 3.1Hz, 1H), 3.57 (td, J=11.9, 3.1Hz, 1H), 3.50-3.43 (m, 4H), 3.34 (ddd, J=13.6, 9.7, 3.3Hz, 2H), 3.22 (td, J=12.7, 3.9Hz, 1H), 3.08-2.95 (m, 2H), 2.95-2.84 (m, 2H), 2.43 (s, 3H), 1.26 (d, J = 6.7 Hz, 3H), 0.82-0.71 (m, 2H), 0.14 (s, 9H).

[0199] Step 4: Synthesis of Compound 7 Compound 7-3 (70 mg) was dissolved in dichloromethane (5 mL), and triethylsilane (145 mg) and trifluoroacetic acid (2.277 g) were added sequentially. The reaction was allowed to proceed at room temperature for 0.5 hours. The reaction mixture was diluted with dichloromethane, and saturated sodium bicarbonate solution was added under ice cooling to adjust the pH to neutral. The organic phase was sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the resulting crude product was separated and purified by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 7 (0.048 g). MS (ESI, [M+H] + ) m / z: 431.27. 1H NMR (500 MHz, CDCl3) δ 11.56 (brs, 1H), 8.10 (s, 1H), 7.63 (d, J=2.1Hz, 1H), 6.84-6.76 (m, 1H), 6.30 (s, 1H), 4.41-4.33 (m, 1H), 4.05 (dd, J=11.4, 3.7Hz, 1H), 3.95 (dd, J=13.1, 2.9Hz, 1H), 3.85-3.74 (m, 2H), 3.63 (td, J=11.8, 3.1Hz, 1H), 3.51-3.46 (m, 2H), 3.37-3.30 (m, 3H), 3.08-2.97 (m, 2H), 2.93-2.88 (m, 2H), 2.43 (s, 3H), 1.32 (d, J=6.7Hz, 3H).

[0200] Example 8: Synthesis of Compound 8 [ka]

[0201] Compound 8 (68 mg) was synthesized in the same manner as described in Example 1, using compound H1 instead of dimethylsulfoximine in Step 1. MS (ESI, [M+H] + ) m / z: 456.15. 1 H NMR (500 MHz, CDCl3) δ 11.37 (brs, 1H), 8.03 (s, 1H), 7.62 (d, J =2.1Hz, 1H), 6.87-6.70 (m, 1H), 6.14 (s, 1H), 4.42-4.28 (m, 1H), 4.07-3.98 (m, 3H), 3.97-3.89 (m, 3H), 3.86-3.75 (m, 2H), 3.64 (td, J=11.8, 3.1Hz, 1H), 3.33 (td, J=12.6, 3.9Hz, 1H), 1.91-1.80 (m, 4H), 1.51-1.46 (m, 6H), 1.32 (d, J=6.8Hz, 3H).

[0202] Example 9: Synthesis of Compound 9 [ka]

[0203] Step 1: Synthesis of Compound 9-1 Compound A1, Compound I1 (168 mg), Tris(dibenzylideneacetone)dipalladium (28 mg), 4,5-bisdiphenylphosphin-9,9-dimethylxanthene (35.3 mg), cesium carbonate (597 mg), and dioxane (10 mL) were mixed and heated under a nitrogen atmosphere for 80°C. o The reaction was carried out in 1C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was separated and purified by column chromatography (dichloromethane:methanol = 19:1) to obtain 0.39 g of compound 9-1. 1 H NMR (500 MHz, CDCl3) δ 7.99 (s, 1H), 7.67-7.57 (m, 3H), 7.55-7.46 (m, 1H), 7.44 (dd, J =8.2, 6.8Hz, 2H), 6.60 (d, J=1.9Hz, 1H), 6.10 (s, 1H), 5.79-5.66 (m, 2H), 4.60-4.39 (m, 8H), 4.30 (d, J=7.5Hz, 1H), 3.99 (dd, J=11.4, 3.7Hz, 1H), 3.93-3.85 (m, 1H), 3.80-3.68 (m, 2H), 3.56 (td, J=11.8, 3.1Hz, 1H), 3.49-3.42 (m, 2H), 3.22 (td, J=12.7, 3.9Hz, 1H), 1.26 (d, J=6.7Hz, 3H), 0.77 (dd, J=9.5, 7.2Hz, 2H), 0.14 (s, 9H).

[0204] Step 2: Synthesis of Compound 9-2 Compound 9-1 (330 mg) was dissolved in tetrahydrofuran (11 mL). Under nitrogen protection, a solution of 2.5 M lithium tetrahydroaluminum in tetrahydrofuran (0.30 mL) was added dropwise, and the mixture was reacted at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and it was washed sequentially with water and saturated brine, then dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the resulting crude product was separated and purified by column chromatography (dichloromethane:methanol = 9:1) to obtain 0.16 g of compound 9-2. 1 H NMR (500 MHz, CDCl3) δ 8.01 (s, 1H), 7.63 (d, J=1.9 Hz, 1H), 6.60 (d, J=1.9Hz, 1H), 6.11 (s, 1H), 5.76-5.70 (m, 2H), 4.46-4.37 (m, 4H), 4.33-4.30 (m, 1H), 3.99 (dd, J=11.4, 3.7Hz, 1H), 3.93-3.85 (m, 5H), 3.77 (d, J=11.3Hz, 1H), 3.72 (dd, J =11.3, 3.1Hz, 1H), 3.57 (td, J=11.8, 3.1Hz, 1H), 3.49-3.41 (m, 2H), 3.22 (td, J=12.7, 3.8Hz, 1H), 1.26 (d, J=6.6Hz, 3H), 0.81-0.72 (m, 2H), 0.14 (s, 9H).

[0205] Step 3: Synthesis of Compound 9-3 Compound 9-2 (120 mg) was dissolved in methanol (10 mL), and acetic acid (25.8 mg), 37% formaldehyde aqueous solution (174 mg), and sodium borohydride cyanohydride (27 mg) were added sequentially. The mixture was reacted at room temperature for 1 hour. Triethylamine was added to adjust the pH to basic, ethyl acetate was added, and the mixture was washed sequentially with water and saturated brine. After filtration and concentration of the filtrate, compound 9-3 was obtained and used directly in the next reaction.

[0206] Step 4: Synthesis of Compound 9 Compound 9-3 (0.11 g) was dissolved in dichloromethane (5 mL), triethylsilane (0.22 g) and trifluoroacetic acid (3.5 g) were added, and the mixture was reacted at room temperature for 0.5 hours. Dichloromethane was added to the reaction mixture, and saturated sodium bicarbonate aqueous solution was added under ice cooling to adjust the pH to neutral. The organic phase was sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the resulting crude product was separated and purified by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 9 (0.065 g). MS (ESI) m / z: 443.20 [M+H] + . 1 H NMR (500 MHz, CDCl3) δ 7.99 (s, 1H), 7.63 (d, J=2.1Hz, 1H), 6.81 (s, 1H), 6.13 (s, 1H), 4.47-4.25 (m, 5H), 4.04 (dd, J=11.4, 3.8Hz, 1H), 3.94 (dd, J=13.0, 3.0Hz, 1H), 3.86-3.73 (m, 2H), 3.63 (td, J=11.8, 3.1Hz, 1H), 3.43 (s, 4H), 3.32 (td, J=12.6, 3.9Hz, 1H), 2.33 (s, 3H), 1.31 (d, J=6.8Hz, 3H).

[0207] Example 10: Synthesis of Compound 10-A and Compound 10-B [ka]

[0208] (1) Compound 10-2 (110 mg) was synthesized in the same manner as described in Example 1, using compound J1 instead of dimethyl sulfoximine in Step 1. Compound 10-2 was separated by chiral HPLC (mobile phase: n-hexane:ethanol = 70:30; flow rate: 40 mL / min; column temperature: 22 oC; CHIRALART Amylose-SB 30×250), それぞれ compound 10-A (42 mg) and び compound 10-B (39 mg) were obtained in sequence. Compound 10-A:R t = 15.9 min. HRMS: (ESI, [M+H] + m / z: 402.1712. 1 H NMR (500 MHz, CDCl3) δ 11.67 (brs, 1H), 8.06 (s, 1H), 7.64 (d, J=2.1Hz, 1H), 6.79 (s, 1H), 6.29 (s, 1H), 4.43-4.23 (m, 1H), 4.05 (dd, J=11.4, 3.7Hz, 1H), 3.94 (dd, J=12.9, 2.9Hz, 1H), 3.86-3.75 (m, 2H), 3.64 (td, J=11.8, 3.1Hz, 1H), 3.32 (td, J=12.6, 3.9Hz, 1H), 3.23 (s, 3H), 2.70-2.65 (m, 1H), 1.51-1.46 (m, 1H), 1.31 (d, J=6.7Hz, 4H), 1.23-1.18 (m, 1H), 1.18-1.09 (m, 1H). Compound 10-B:R t = 26.3 min. HRMS: (ESI, [M+H] + m / z: 402.1706. 1H NMR (500 MHz, CDCl3) δ 7.99 (s, 1H), 7.71-7.39 (m, 1H), 6.94-6.61 (m, 1H), 6.22 (s, 1H), 4.38-4.16 (m, 1H), 3.97 (dd, J=11.3, 3.7Hz, 1H), 3.91 (dd, J=13.2, 2.9Hz, 1H), 3.79-3.67 (m, 2H), 3.56 (td, J=11.9, 3.1Hz, 1H), 3.24 (td, J=12.7, 3.8Hz, 1H), 3.17 (s, 3H), 2.62-2.59 (m, 1H), 1.44- 1.39 (m, 1H), 1.24 (d, J=6.7Hz, 4H), 1.14-1.10 (m, 1H), 1.07-1.05 (m, 1H).

[0209] Or, (2) Compound 10-2 (110 mg) was synthesized in the same manner as described in Example 1, using compound J1 instead of dimethyl sulfoximine in Step 1. Compound 10-2 was fractionated by SFC (mobile phase: carbon dioxide:ethanol = 65:35; flow rate: 60 mL / min; column temperature: 35 o (C; Chromatography column: CHIRALART Cellulose -SB 30×250), compound 10-A (42 mg) and compound 10-B (39 mg) were obtained sequentially. Compound 10-A:R t = 2.4 min. HRMS: (ESI, [M+H] + ) m / z: 402.1712. 1H NMR (500 MHz, CDCl3) δ 11.67 (brs, 1H), 8.06 (s, 1H), 7.64 (d, J=2.1Hz, 1H), 6.79 (s, 1H), 6.29 (s, 1H), 4.39-4.34 (m, 1H), 4.05 (dd, J=11.4, 3.7Hz, 1H), 3.94 (dd, J=12.9, 2.9Hz, 1H), 3.86-3.75 (m, 2H), 3.64 (td, J=11.8, 3.1Hz, 1H), 3.32 (td, J=12.6, 3.9Hz, 1H), 3.23 (s, 3H), 2.70-2.65 (m, 1H), 1.51-1.46 (m, 1H), 1.33-1.30 (m, 4H), 1.23-1.18 (m, 1H), 1.18-1.09 (m, 1H). Compound 10-B:R t = 3.5 min. HRMS: (ESI, [M+H] + m / z: 402.1706. 1 H NMR (500 MHz, DMSO-d6) δ 12.74 (s, 1H), 7.90 (s, 1H), 7.81 (s, 1H), 6.79 (s, 1H), 6.20 (s, 1H), 4.26-4.24 (m, 1H), 3.98-3.92 (m, 2H), 3.75 (d, J=11.2Hz, 1H), 3.64 (dd, J=11.3, 3.0 Hz, 1H), 3.48 (td, J=11.8, 3.1Hz, 1H), 3.39 (s, 3H), 3.11 (td, J=12.8, 3.9 Hz, 1H), 3.00-2.95 (m, 1H), 1.36-1.31 (m, 1H), 1.22-1.11 (m, 6H).

[0210] Example 11: Synthesis of Compound 11-A and Compound 11-B

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[0211] Compound 11-2 (130 mg) was synthesized in the same manner as described in Example 1, using compound K1 instead of dimethylsulfoximine in Step 1. Compound 11-2 was fractionated by chiral HPLC (mobile phase: (n-hexane:dichloromethane = 7:3):isopropanol = 3:1; flow rate: 40 mL / min; column temperature: 25 o (C; Chromatography column: CHIRALART Amylose-SB 30×250), compound 11-A (40 mg) and compound 11-B (45 mg) were obtained sequentially. Compound 11-A:R t = 13.1 min. MS (ESI, [M+H] + ) m / z: 438.20. 1 H NMR (500 MHz, DMSO-d6): δ 8.03 (d, J=7.6Hz, 2H), 8.00 (s, 1H), 7.76 (d, J=1.9Hz, 1H), 7.72 (t, J=7.3Hz, 1H), 7.65 (t, J=7.6Hz, 2H), 6.73 (s, 1H), 6.02 (s, 1H), 4.06 (d, J=5.0Hz, 1H), 3.90 (dd, J =11.2, 3.0Hz, 1H), 3.80 (d, J=12.4Hz, 1H), 3.69 (d, J=11.3Hz, 1H), 3.59 (s, 3H), 3.54 (dd, J=11.3, 2.6Hz, 1H), 3.42 (td, J=11.7, 2.6Hz, 1H), 2.97 (td, J=12.8, 3.6Hz, 1H), 1.10 (d, J=6.6Hz, 3H). Compound 11-B:R t = 20.8 min. MS (ESI, [M+H] + ) m / z: 438.20. 1H NMR (500 MHz, DMSO-d6): δ 8.12-7.89 (m, 3H), 7.76 (d, J=1.8Hz, 1H), 7.71 (t, J=7.3Hz, 1H), 7.65 (t, J=7.6Hz, 2H), 6.72 (d, J=2.0Hz, 1H), 5.90 (s, 1H), 3.97-3.85 (m, 2H), 3.82 (d, J=12.6Hz, 1H), 3.66 (d, J=11.3Hz, 1H), 3.61 (s, 3H), 3.57 (dd, J=11.4, 2.4Hz, 1H), 3.38 (td, J=11.8, 2.4Hz, 1H), 2.95 (td, J=12.9, 3.6Hz, 1H), 0.79 (d, J=6.6Hz, 3H).

[0212] Example 12: Synthesis of Compound 12-A and Compound 12-B [ka]

[0213] Compound 12-2 (130 mg) was synthesized in the same manner as described in Example 1, using compound L1 instead of dimethylsulfoximine in Step 1. Compound 12-2 was fractionated by chiral HPLC (mobile phase: n-hexane:ethanol = 9:11; flow rate: 40 mL / min; column temperature: 25 o (C; Chromatography column: CHIRALART Cellulose-SB 30×250mm), and compounds 12-A (52 mg) and 12-B (50 mg) were obtained sequentially. Compound 12-A:R t = 14.1 min. MS (ESI, [M+H] + ) m / z: 439.15. 1H NMR (500 MHz, DMSO-d6)δ 12.74 (s, 1H), 8.91 (d, J=4.5Hz, 2H), 8.00 (d, J=6.1Hz, 3H), 7.79 (s, 1H), 6.73 (s, 1H), 6.02 (s, 1H), 4.09 (d, J=5.0Hz, 1H), 3.91 (dd, J=11.3, 3.1Hz, 1H), 3.81 (d, J=13.0Hz, 1H), 3.70 (d, J=8.9Hz, 4H), 3.55 (d, J=14.2Hz, 1H), 3.43 (td, J=11.8, 2.9Hz, 1H), 2.98 (td, J=12.7, 3.4Hz, 1H), 1.10 (d, J=6.7Hz, 3H). Compound 12-B:R t = 18.8 min. MS (ESI, [M+H) + m / z: 439.16. 1 H NMR (500 MHz, DMSO-d6): δ 12.69 (s, 1H), 8.90 (dd, J=4.5, 1.6Hz, 2H), 8.09-7.86 (m, 3H), 7.78 (s, 1H), 6.72 (s, 1H), 5.89 (s, 1H), 3.98-3.82 (m, 3H), 3.70 (d, J=9.0Hz, 3H), 3.67 (d, J=11.4Hz, 1H), 3.58 (dd, J=11.4, 2.9Hz, 1H), 3.40 (dd, J=17.8, 8.8Hz, 1H), 2.96 (td, J=12.9, 3.7Hz, 1H), 0.81 (d, J=6.7Hz, 3H).

[0214] Example 13: Synthesis of Compound 13

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[0215] ステップ1: Synthesis of compound 13-2 Compound 13-1 (3 g) was dissolved in 6 M hydrochloric acid solution (20 mL), cooled to below 5°C, and 1 M sodium nitrite aqueous solution (31 mL) was added dropwise. The mixture was reacted at 5°C for 1 hour. 1 M tin dichloride hydrochloric acid solution (62 mL) was then added dropwise to the mixture and the mixture was reacted at room temperature overnight. The reaction solution was concentrated, and ethyl acetate (30 mL) was added to the resulting crude mixture and beaten. The mixture was then filtered and dried to obtain crude compound 13-2 (9.1 g), which was used directly in the next reaction. 1 H NMR (500 MHz, DMSO-d6) δ 9.87 (s, 2H), 7.47-7.12 (m, 1H), 5.61 (s, 1H), 2.19 (s, 3H).

[0216] Step 2: Synthesis of Compound 13-3 Compound A1-4 (3.7 g), compound 13-2 (6.13 g), and ethanol (80 mL) were mixed and reacted at room temperature for 0.5 hours. The mixture was concentrated, the residue was dissolved in ethyl acetate (200 mL), and washed sequentially with saturated sodium bicarbonate solution, water, and saturated saline solution, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the resulting crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 13-3 (2.1 g). 1 H NMR (500 MHz, DMSO-d6) δ 11.66 (s, 1H), 10.73 (s, 1H), 7.91 (s, 1H), 7.80 (d, J=2.5Hz, 1H), 5.76 (s, 1H), 2.17 (s, 3H).

[0217] Step 3: Synthesis of Compound 13-4 Compound 13-3 (1 g) and N-methylpyrrolidone (15 mL) were mixed and heated to 200°C in a microwave and reacted for 20 minutes. Water (100 mL) was added to the reaction mixture to precipitate the solid, which was then filtered, washed, and dried to obtain compound 13-4 (202 mg). 1H NMR (500 MHz, DMSO-d6) δ 12.76 (s, 1H), 8.24 (s, 1H), 7.67 (s, 1H), 6.43 (s, 1H), 2.33 (s, 3H).

[0218] Step 4: Synthesis of Compound 13-5 Compound 13-4 (200 mg), (R)-3-methylmorpholine (118 mg), and dimethyl sulfoxide (7 mL) were mixed and heated to 120°C, where they were reacted for 6 hours. Water was added to the reaction mixture to precipitate the solid, which was then filtered, washed, and dried to obtain compound 13-5 (160 mg). 1 H NMR (500 MHz, DMSO-d6) δ 12.53 (s, 1H), 7.80 (s, 1H), 7.26 (s, 1H), 6.49 (s, 1H), 4.49-4.39 (m, 1H), 4.04 (d, J=13.0Hz, 1H), 3.95 (dd, J=11.3, 3.0Hz, 1H), 3.74 (d, J=11.4Hz, 1H), 3.63 (dd, J=11.4, 2.6Hz, 1H), 3.48 (td, J=11.9, 2.7Hz, 1H), 3.16 (td, J=13.0, 3.6Hz, 1H), 2.30 (s, 3H), 1.19 (d, J = 6.7Hz, 3H).

[0219] Step 5: Synthesis of Compound 13 Compound 13-5 (140 mg), dimethyl sulfoximine (40 mg), tris(dibenzylideneacetone)dipalladium (15 mg), 4,5-bisdiphenylphosphin-9,9-dimethylxanthene (19 mg), cesium carbonate (215 mg), and dioxane (10 mL) were mixed and heated to 100°C, where the mixture was reacted for 8 hours. The reaction mixture was filtered and concentrated, and the resulting crude product was separated and purified by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 13 (37 mg). MS (ESI, [M+H] + ) m / z: 390.14. 1H NMR (500 MHz, DMSO-d6) δ 12.39 (s, 1H), 7.85 (s, 1H), 6.52 (s, 1H), 6.17 (s, 1H), 4.30 (d, J=5.1Hz, 1H), 4.03-3.86 (m, 2H), 3.75 (d, J=11.2Hz, 1H), 3.64 (dd, J=11.3, 2.5Hz, 1H), 3.49 (td, J=11.8, 2.5Hz, 1H), 3.40 (d, J=1.4Hz, 6H), 3.18-3.05 (m, 1H), 2.29 (s, 3H), 1.17 (d, J=6.6Hz, 3H).

[0220] Example 14: Synthesis of compounds 14-A and 14-B [ka]

[0221] Compound 14-2 (180 mg) was synthesized in the same manner as described in Example 1, using compound M1 instead of dimethylsulfoximine in Step 1. Compound 14-2 was fractionated by chiral HPLC (mobile phase: n-hexane:ethanol = 60:40; flow rate: 1 mL / min; column temperature: 25 o Using chromatography column C (CHIRALART Cellulose-SB), compounds 14-A (67 mg) and 14-B (70 mg) were sequentially obtained. Compound 14-A:R t = 16.5 min. 1¹H NMR (500 MHz, CDCl₃) δ 8.12 (s, 1H), 8.07-7.89 (m, 2H), 7.61 (d, J = 2.1 Hz, 1H), 7.23 (t, J = 8.5 Hz, 2H), 6.77 (s, 1H), 6.13 (s, 1H), 4.24-4.16 (m, 1H), 4.00 (dd, J = 11.4, 3.8 Hz, 1H), 3.87 - 3.84 (m, 1H ), 3.79 - 3.77 (m, 1H), 3.72 - 3.69 (m, 1H), 3.58 (td, J = 11.8, 3.1 Hz, 1H), 3.37 (s, 3H), 3.20 (td, J = 12.6, 3.8 Hz, 1H), 1.26 (d, J = 6.7 Hz, 3H). HRMS: (ESI) calculated for C 21 H 22 FN₇O₂S ([M+H] + ) m / z: 456.1618, found: 456.1613. Compound 14-B: R t = 24.5 min. 1 ¹H NMR (500 MHz, CDCl₃) δ 11.48 (brs, 1H), 8.12 (s, 1H), 8.03-7.90 (m, 2H), 7.60 (d, J = 2.1 Hz, 1H), 7.22 (t, J = 8.4 Hz, 2H), 6.76 (s, 1H), 6.04 (s, 1H), 4.13-4.04 (m, 1H), 3.99 (dd, J = 11.4, 3.8 Hz, 1H), 3.88 (dd, J = 13.1, 2.9 Hz, 1H), 3.79-3.69 (m, 2H), 3.56 (td, J = 11.9, 3.1 Hz, 1H), 3.39 (s, 3H), 3.19 (td, J = 12.7, 3.9 Hz, 1H), 1.01 (d, J = 6.7 Hz, 3H). HRMS: (ESI) calculated for C 21 H 22FN7O2S ([M+H] + ) m / z: 456.1618 , found: 456.1612 .

[0222] Example 15: Synthesis of compounds 15-A and 15-B [ka]

[0223] Compound 15-2 (90 mg) was synthesized in the same manner as described in Example 1, using compound N1 instead of dimethylsulfoximine in Step 1. Compound 15-2 was fractionated by chiral HPLC (mobile phase: n-hexane:ethanol = 3:2; flow rate: 40 mL / min; column temperature: 25°C; chromatography column: CHIRALART Cellulose-SB) to sequentially obtain compound 15-A (35 mg) and compound 15-B (32 mg), respectively. Compound 15-A:R t = 10.6 min. MS (ESI, [M+H] + ) m / z: 430.19. 1 H-NMR (500 MHz, DMSO-d6)δ 12.68 (s, 1H), 7.89 (s, 1H), 7.74 (s, 1H), 6.78 (s, 1H), 6.20 (s, 1H), 4.29 (d, J = 5.0 Hz, 1H), 4.03-3.89 (m, 3H), 3.74 (d, J = 11.2 Hz, 1H), 3.64 (dd, J = 11.3, 2.8 Hz, 1H), 3.48 (td, J = 11.8, 2.9 Hz, 1H), 3.27 (s, 3H), 3.18-3.05 (m, 1H), 2.16-2.00 (m, 4H), 1.81-1.69 (m, 2H), 1.68-1.56 (m, 2H), 1.17 (d, J = 6.7 Hz, 3H). Compound 15-B:R t = 17.5 min. MS (ESI, [M+H]+ ) m / z: 430.19. 1 H-NMR (500 MHz, DMSO-d6): δ 12.68 (s, 1H), 7.89 (s, 1H), 7.80 (s, 1H), 6.79 (s, 1H), 6.18 (s, 1H), 4.32 (s, 1H), 3.96 (dd, J = 15.5, 7.3 Hz, 2H), 3.90 (d, J = 12.4 Hz, 1H), 3.75 (d, J = 11.2 Hz, 1H), 3.64 (dd, J = 11.2, 2.3 Hz, 1H), 3.49 (td, J = 11.7, 2.3 Hz, 1H), 3.27 (s, 3H), 3.11 (td, J = 12.6, 3.0 Hz, 1H), 2.17-1.98 (m, 4H), 1.82-1.71 (m, 2H), 1.70-1.60 (m, 2H), 1.17 (d, J = 6.6 Hz, 3H).

[0224] Example 16: Synthesis of compounds 16-A and 16-B [ka]

[0225] Compound 16-2 (85 mg) was synthesized in the same manner as described in Example 1, using compound O1 instead of dimethylsulfoximine in Step 1. Compound 16-2 was fractionated by chiral HPLC (mobile phase: n-hexane:ethanol = 3:2; flow rate: 40 mL / min; column temperature: 25°C; chromatography column: CHIRALART Cellulose-SB) to sequentially obtain compound 16-A (30 mg) and compound 16-B (28 mg), respectively. Compound 16-A:R t = 13.04 min. MS (ESI, [M+H] + ) m / z: 480.24. 1H NMR (500 MHz, DMSO-d6)δ 12.73 (s, 1H), 7.91 (s, 1H), 7.77 (s, 1H), 6.75 (s, 1H), 6.22 (s, 1H), 4.31 (d, J = 5.0 Hz, 1H), 4.04-3.85 (m, 2H), 3.68 (m, 3H), 3.49 (dd, J = 23.4, 2.7 Hz, 1H), 3.31 (s, 3H), 3.11 (m, 1H), 2.34 (t, J = 13.1 Hz, 2H), 2.21 (s, 2H), 2.13-1.68 (m, 4H), 1.17 (d, J = 6.6 Hz, 3H). Compound 16-B:R t = 18.03 min. MS (ESI, [M+H) + m / z: 480.24. 1 H-NMR (500 MHz, DMSO-d6): δ 12.73 (s, 1H), 7.90 (s, 1H), 7.81 (s, 1H), 6.79 (s, 1H), 6.24 (s, 1H), 4.30 (d, J = 4.7 Hz, 1H), 4.03-3.86 (m, 2H), 3.78-3.60 (m, 3H), 3.49 (m, 1H), 3.32-3.30 (m, 3H), 3.19-3.06 (m, 1H), 2.34 (t, J = 14.9 Hz, 2H), 2.21 (dd, J = 10.8, 4.7 Hz, 2H), 2.08-1.77 (m, 4H), 1.17 (d, J = 6.6 Hz, 3H).

[0226] Example 17: Synthesis of Compound 17

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[0227] ステップ1:Synthesis of compound 17-1 Compound A1 (170 mg), compound P1 (75 mg), tris(dibenzylideneacetone)dipalladium (25.4 mg), 4,5-bisdiphenylphosphin-9,9-dimethylxanthene (32.1 mg), cesium carbonate (362 mg), and 1,4-dioxane (6 mL) were mixed and reacted at 80°C for 1 hour under a nitrogen atmosphere. The reaction mixture was filtered, the filtrate was concentrated, and the crude product was separated and purified by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 17-1 (200 mg). MS (ESI, [M+H] + ) m / z: 548.31.

[0228] Step 2: Synthesis of Compound 17 Compound 17-1 (200 mg) was dissolved in tetrahydrofuran (2 mL), and tetrabutylammonium fluoride (1 g, 1.912 mL) was added to the reaction mixture. The mixture was reacted under a nitrogen atmosphere at 80°C for 16 hours. The reaction mixture was concentrated, and the crude product was separated and purified by column chromatography (dichloromethane:methanol = 13:1) to obtain compound 17 (50 mg). MS (ESI, [M+H] + ) m / z: 418.33. 1 H NMR (500 MHz, DMSO-d6)δ 12.72 (s, 1H), 7.94 (s, 1H), 7.80 (s, 1H), 6.79 (s, 1H), 6.26 (d, J = 10.6 Hz, 1H), 4.30 (d, J = 26.9 Hz, 1H), 3.93 (dd, J = 29.2, 11.9 Hz, 2H), 3.75 (d, J = 11.1 Hz, 1H), 3.65 (d, J = 10.9 Hz, 1H), 3.49 (t, J = 11.7 Hz, 1H), 3.21 (d, J = 4.4 Hz, 3H), 3.12 (t, J = 12.4 Hz, 1H), 1.50 (s, 9H), 1.23-1.05 (m, 3H).

[0229] Example 18: Synthesis of Compound 18 [ka]

[0230] Step 1: Synthesis of Compound 18-1 Compound A1-4 (3 g) was dissolved in tetrahydrofuran (30 mL), and a tetrahydrofuran solution of hydrazine (1 M, 11.15 mL) was added. The mixture was reacted at 60°C with stirring for 1 hour. The reaction mixture was concentrated, and the resulting crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain compound 18-1 (0.95 g). MS: (ESI, [MH] - ) m / z: 261.83 1 H NMR (500 MHz, DMSO-d6) δ 14.05 (s, 1H), 8.03 - 7.99 (m, 1H), 7.53 (s, 1H).

[0231] Step 2: Synthesis of Compound 18-2 Compound 18-1 (900 mg) is dissolved in dimethyl sulfoxide (10 mL), and (R)-3-methylmorpholine (1384 mg, 13.69 mmol) is added to the mixture. o The mixture was heated to 17°C and reacted for 16 hours. The residue was dissolved in ethyl acetate (20 mL), washed sequentially with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 18-2 (0.72 g). MS: (ESI, [M+H] + m / z: 344.90 1H NMR (500 MHz, DMSO-d6) δ 13.14 (s, 1H), 7.60 (s, 1H), 7.16 (s, 1H), 4.44 - 4.35 (m, 1H), 3.96 - 3.91 (m, 2H), 3.71 (d, J = 11.5 Hz, 1H), 3.62 (dd, J = 11.4, 3.1 Hz, 1H), 3.49 - 3.43 (m, 1H), 3.13 (td, J = 12.8, 3.8 Hz, 1H), 1.16 (d, J = 6.7 Hz, 3H).

[0232] Step 3: Synthesis of Compound 18-3 Compound 18-2 (700 mg) was dissolved in dioxane (10 mL), and dimethyl sulfoximine (227 mg), tris(dibenzylideneacetone)dipalladium (186 mg), 4,5-bisdiphenylphosphin-9,9-dimethylxanthene (235 mg), and cesium carbonate (1988 mg) were added. Under nitrogen protection, the reaction mixture was heated to 110°C using a microwave (400 W) and reacted for 1 hour. After suction filtration and concentration of the filtrate, the crude was separated and purified by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 18-3 (0.34 g). MS: (ESI, [M+H] + m / z: 310.02

[0233] Step 4: Synthesis of Compound 18 Mix compound 18-3 (330 mg), N-methylpyrrolidone (9 mL), 3-bromo-5-(trifluoromethyl)-1H-pyrazole (459 mg), cesium carbonate (1043 mg), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (303 mg), and cuprous iodide (305 mg), and 120 oThe mixture was placed in an oil bath (C) and heated for 16 hours. After suction filtration and concentration of the filtrate, the crude compound was separated and purified by column chromatography (dichloromethane:methanol = 10:1) to obtain 0.24 g of the crude compound of the target compound, which was then purified by HPLC (mobile phase: 0.1% glacial acetic acid aqueous solution:acetonitrile = 65:35; flow rate: 40 mL / min; column temperature: 25 o Using a chromatography column (YMC-Triart Prep C18-S), compound 18 (0.022 g) was obtained. 1 H NMR (500 MHz, CDCl3) δ 8.05 (s, 1H), 6.81 (s, 1H), 6.31 (s, 1H), 4.32 (d, J = 8.2 Hz, 1H), 4.07 (dd, J = 11.4, 3.8 Hz, 1H), 3.93 - 3.74 (m, 3H), 3.64 (td, J = 11.9, 3.2 Hz, 1H), 3.41 - 3.24 (m, 7H), 1.33 (d, J = 6.7 Hz, 3H). HRMS: (ESI, [M+H] + ) m / z: 444.1426.

[0234] Example 19: Synthesis of compounds 19-A and 19-B [ka]

[0235] Step 1: Synthesis of Compound 19-1 Compound 13-5 (550 mg), diisopropylethylamine (260 mg), and dichloromethane (20 mL) were mixed, and 2-(trimethylsilyl)ethoxymethyl chloride (268 mg) was added dropwise. The mixture was reacted at room temperature for 1 hour. Dichloromethane (20 mL) and saturated sodium bicarbonate (20 mL) were added to the reaction mixture, the organic phase was separated and concentrated, and the resulting crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 19-1 (503 mg). MS (ESI, [M+H] +) m / z: 555.07. 1 H NMR (500 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.31 (s, 1H), 6.41 (s, 1H), 5.45 (q, J = 11.3 Hz, 2H), 4.38 (dd, J = 6.5, 2.1 Hz, 1H), 3.99 (d, J = 11.7 Hz, 1H), 3.92 (dd, J = 11.4, 3.5 Hz, 1H), 3.71 (d, J = 11.4 Hz, 1H), 3.57 (dd, J = 11.5, 2.9 Hz, 1H), 3.42 (td, J = 11.9, 3.0 Hz, 1H), 3.21-3.07 (m, 3H), 2.24 (s, 3H), 1.16 (d, J = 6.7 Hz, 3H), 0.57 (t, J = 8.2 Hz, 2H), -0.24 (s, 9H).

[0236] Step 2: Synthesis of Compound 19-2 Compound 19-1 (400 mg), compound J1 (129 mg), tris(dibenzylideneacetone)dipalladium (66.1 mg), 4,5-bisdiphenylphosphin-9,9-dimethylxanthene (83 mg), cesium carbonate (588 mg), and 1,4-dioxane (20 mL) were mixed and reacted at 80°C for 1 hour under a nitrogen atmosphere. The reaction mixture was filtered, the filtrate was concentrated, and the crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 19-2 (310 mg). MS (ESI, [M+H] + ) m / z: 546.21. 1H NMR (500 MHz, DMSO-d6) δ 8.01 (d, J = 3.7 Hz, 1H), 6.36 (s, 1H), 6.20 (s, 1H), 5.54-5.44 (m, 2H), 4.25-4.15 (m, 1H), 3.96-3.80 (m, 2H), 3.72 (d, J = 11.4 Hz, 1H), 3.63-3.56 (m, 1H), 3.48-3.40 (m, 1H), 3.38 (d, J = 5.5 Hz, 3H), 3.27-3.17 (m, 2H), 3.10-2.94 (m, 2H), 2.23 (s, 3H), 1.37-1.26 (m, 1H), 1.24-1.18 (m, 1H), 1.17-1.08 (m, 5H), 0.65-0.57 (m, 2H), -0.20 (s, 9H).

[0237] Step 3: Synthesis of Compound 19-A and Compound 19-B Compound 19-2 (300 mg) was dissolved in dichloromethane (4 mL), cooled to 0°C, and triethylsilane (1.41 g) and trifluoroacetic acid (12 mL) were added. The mixture was reacted at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane and adjusted to pH 8 with saturated sodium bicarbonate solution. The organic phase was sequentially washed with water and saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the crude product was separated and purified by column chromatography (dichloromethane:methanol = 9:1) to obtain compound 19 (201 mg). Compound 19 was fractionated by chiral HPLC (mobile phase: n-hexane:ethanol = 70:30; flow rate: 40 mL / min; column temperature: 25 o (C; Chromatography column: CHIRALART Cellulose-SB 30×250), and compounds 19-A (52 mg) and 19-B (57 mg) were obtained sequentially. Compound 19-A:R t = 13.5 min. HRMS: (ESI, [M+H] + m / z: 416.1865. 1H NMR (500 MHz, DMSO-d6) δ 12.40 (s, 1H), 7.88 (s, 1H), 6.51 (s, 1H), 6.18 (s, 1H), 4.38-4.19 (m, 1H), 3.96 (d, J = 9.5 Hz, 1H), 3.90 (d, J = 12.7 Hz, 1H), 3.75 (d, J = 11.2 Hz, 1H), 3.64 (d, J = 10.9 Hz, 1H), 3.49 (t, J = 10.6 Hz, 1H), 3.37 (s, 3H), 3.11 (t, J = 11.2 Hz, 1H), 3.04-2.95 (m, 1H), 2.29 (s, 3H), 1.32-1.27 (m, 1H), 1.22-1.11 (m, 6H). Compound 19-B:R t = 18.0 min. HRMS: (ESI, [M+H] + m / z: 416.1865. 1 H NMR (500 MHz, DMSO-d6) δ 12.39 (s, 1H), 7.87 (s, 1H), 6.51 (s, 1H), 6.18 (s, 1H), 4.23 (d, J = 4.9 Hz, 1H), 3.95 (dd, J = 16.5, 8.3 Hz, 2H), 3.74 (d, J = 11.3 Hz, 1H), 3.64 (dd, J = 11.3, 2.8 Hz, 1H), 3.48 (td, J = 11.8, 3.0 Hz, 1H), 3.38 (s, 3H), 3.10 (td, J = 12.8, 3.5 Hz, 1H), 3.00-2.93 (m, 1H), 2.29 (s, 3H), 1.36-1.28 (m, 1H), 1.23-1.07 (m, 6H).

[0238] Example 20: Synthesis of Compound 20

change

[0239] Step 1: Synthesis of Compound 20-1 Compound A1-3 (6 g) was dissolved in tetrahydrofuran (60 mL), cooled to -78°C, and a 2M lithium diisopropylamide tetrahydrofuran / n-hexane solution (3 g, 14.00 mL) was added dropwise, and the reaction was allowed to proceed at -78°C for 1 hour. Acetaldehyde (1.32 g) was added to the reaction mixture, and the reaction was continued at -78°C for 30 minutes. Formic acid (2.29 g) and ethyl acetate (100 mL) were then added, and the reaction mixture was raised to room temperature. The organic phase was sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and the crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 20-1 (5 g).

[0240] Step 2: Synthesis of Compound 20-2 Compound 20-1 (5 g), manganese dioxide (15.25 g), and toluene (80 mL) were mixed and reacted at 60°C for 5 hours. The reaction mixture was filtered and washed, the mother liquor was collected and concentrated to obtain compound 20-2 (4 g). MS: (ESI, [M+H] + ) m / z: 284.12.

[0241] Step 3: Synthesis of Compound 20-3 Compound A1-2 (500 mg), compound 20-2 (500 mg), and ethanol (30 mL) were mixed and reacted at room temperature for 1 hour. The reaction solution was concentrated, the residue was dissolved in ethyl acetate, washed sequentially with saturated sodium bicarbonate, water, and saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 20-3 (400 mg). MS: (ESI, [M+H] + ) m / z: 363.91. 1 H NMR (500 MHz, DMSO-d6)δ 11.94 (s, 1H), 9.50 (s, 1H), 7.81 (s, 1H), 7.47 (s, 1H), 5.85 (s, 1H), 2.11 (s, 3H).

[0242] Step 4: Synthesis of Compound 20-4 Compound 20-3 (400 mg) and N-methylpyrrolidone (8 mL) were mixed and heated to 200°C in a microwave, and reacted for 20 minutes. Water was added to the reaction mixture to precipitate the solid, which was then filtered, washed, and dried to obtain compound 20-4 (320 mg). MS (ESI, [M+H] + ) m / z: 343.85. 1 H NMR (500 MHz, DMSO -d6) δ 13.03 (s, 1H), 7.90 (s, 1H), 7.65 (s, 1H), 6.62 (s, 1H), 2.69 (s, 3H).

[0243] Step 5: Synthesis of Compound 20-5 Compound 20-4 (320 mg), (R)-3-methylmorpholine (250 mg), and dimethyl sulfoxide (5 mL) were mixed and heated to 120°C, where they were reacted for 1 hour. Water was added to the reaction mixture to precipitate the solid, which was then filtered, washed, and dried to obtain compound 20-5 (260 mg). MS (ESI, [M+H] + ) m / z: 425.13.

[0244] Step 6: Synthesis of Compound 20-6 Compound 20-5 (260 mg), diisopropylethylamine (250 mg), and dichloromethane (5 mL) were mixed, and 2-(trimethylsilyl)ethoxymethyl chloride (211 mg) was added dropwise. The mixture was reacted at room temperature for 30 minutes. Dichloromethane (20 mL) and saturated sodium bicarbonate (20 mL) were added to the reaction mixture, the organic phase was separated and concentrated, and the resulting crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 20-6 (180 mg). MS (ESI, [M+H] + ) m / z: 555.30.

[0245] Step 7: Synthesis of Compound 20-7 Compound 20-6 (180 mg), dimethyl sulfoximine (59.52 mg), tris(dibenzylideneacetone)dipalladium (13.04 mg), 4,5-bisdiphenylphosphin-9,9-dimethylxanthene (16.48 mg), cesium carbonate (186 mg), and 1,4-dioxane (3 mL) were mixed and reacted at 80°C for 1 hour under a nitrogen atmosphere. The reaction mixture was filtered, the filtrate was concentrated, and the crude product was separated and purified by column chromatography (dichloromethane:methanol = 14:1) to obtain compound 20-7 (140 mg). MS (ESI, [M+H] + ) m / z: 520.27.

[0246] Step 8: Synthesis of Compound 20 Compound 20-7 (140 mg) was dissolved in dichloromethane (2 mL), cooled to 0°C, and triethylsilane (379 mg) and trifluoroacetic acid (15.9 g) were added. The mixture was reacted at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane and adjusted to pH 8 with saturated sodium bicarbonate solution. The organic phase was sequentially washed with water and saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the crude product was separated and purified by column chromatography (dichloromethane:methanol = 9:1) to obtain compound 20 (80 mg). MS (ESI, [M+H] + ) m / z: 390.27. 1H NMR (500 MHz, DMSO-d6)δ 12.63 (s, 1H), 7.76 (s, 1H), 6.75 (s, 1H), 6.11 (s, 1H), 4.30 (s, 1H), 3.95 (dd, J = 11.1, 2.8 Hz, 1H), 3.88 (d, J = 12.4 Hz, 1H), 3.74 (d, J = 11.3 Hz, 1H), 3.64 (dd, J = 11.3, 2.5 Hz, 1H), 3.49 (td, J = 11.8, 2.7 Hz, 1H), 3.40 (s, 6H), 3.32 (s, 3H), 3.11 (td, J = 12.4, 3.0 Hz, 1H), 1.16 (d, J = 6.6 Hz, 3H).

[0247] Example 21: Synthesis of Compound 21 [ka]

[0248] Step 1: Synthesis of Compound 21-1 Compound A1-3 (2 g) and tetrahydrofuran (20 mL) were mixed and cooled to -78°C. Under a nitrogen atmosphere, a tetrahydrofuran solution of lithium diisopropylamide (2 M, 6.21 mL) was added dropwise, and the mixture was reacted at -78°C for 1 hour. 3-methylbutyraldehyde (1.430 g) was added to the reaction mixture, and stirring was continued at -78°C for 1 hour. After that, the reaction mixture was raised to room temperature. Saturated ammonium chloride aqueous solution was added, and the organic phase was sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 19:1) to obtain compound 21-1 (2.0 g). 1 H NMR (500 MHz, CDCl3) δ 7.32 (d, J = 3.1 Hz, 1H), 5.08 - 5.04 (m, 1H), 2.19 - 2.16 (m, 1H), 1.96 - 1.76 (m, 2H), 1.56 - 1.50 (m, 1H), 1.03 - 1.00 (m, 6H).

[0249] Step 2: Synthesis of Compound 21-2 Mix compound 21-1 (2 g), manganese dioxide (5.32 g), and toluene (20 mL), and 90 o The mixture was heated to 1°C and reacted for 16 hours. TLC monitoring showed that some of the raw materials remained. After suction filtration and concentration of the filtrate, manganese dioxide (10.63 g) was added, and 90°C was added. o The mixture was heated to 1C and reacted for 2 hours. After filtration by Celite suction and concentration of the filtrate, compound 21-2 (1.6 g) was obtained. 1 H NMR (500 MHz, CDCl3) δ 7.39 (d, J = 2.8 Hz, 1H), 2.75 (dd, J = 6.7, 1.7 Hz, 2H), 2.34 -2.26 (m, 1H), 1.03 (d, J = 6.6 Hz, 6H).

[0250] Step 3: Synthesis of Compound 21-3 Compound 21-2 (1.5 g), 5-hydrazino-1H-pyrazole hydrochloride (3.10 g), and ethanol (20 mL) were mixed and heated to 80°C, and reacted overnight with stirring. After concentrating and removing the solvent, N-methylpyrrolidone (20 mL) and 5-hydrazino-1H-pyrazole hydrochloride (3.10 g) were added sequentially, and the mixture was heated to 130°C and reacted for 2 hours with stirring. After cooling to room temperature, water (50 mL) was added to precipitate the solid, and the mixture was filtered and dried to obtain compound 21-3 (1.5 g). MS: (ESI, [M+H] + ) m / z: 385.99. 1 H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 2.4 Hz, 1H), 7.37 (d, J = 1.5 Hz, 1H), 6.89 (d, J = 2.4 Hz, 1H), 3.04 (d, J = 7.2 Hz, 2H), 2.33 - 2.25 (m, 1H), 1.06 (d, J = 6.7 Hz, 6H).

[0251] Step 4: Synthesis of Compound 21-4 Mix compound 21-3 (1 g), (R)-3-methylmorpholine (1.313 g), and dimethyl sulfoxide (10 ml), and 120 o The mixture was heated to 1C and reacted for 1 hour. After cooling to room temperature, it was added dropwise to water (50 mL), filtered by suction, and dried to obtain compound 21-4 (1.5 g). MS: (ESI, [M+H] + ) m / z: 467.07. 1 H NMR (500 MHz, CDCl3d) δ 7.62 (d, J = 2.2 Hz, 1H), 7.05 (s, 1H), 6.87-6.82 (m, 1H), 4.36 - 4.34 (m, 1H), 4.06 (dd, J = 11.5, 3.8 Hz, 1H), 3.96 (dd, J = 13.0, 3.0 Hz, 1H), 3.84 (d, J = 11.3 Hz, 1H), 3.77 (dd, J = 11.5, 3.2 Hz, 1H), 3.62 (td, J = 11.8, 3.1 Hz, 1H), 3.34 (td, J = 12.7, 3.9 Hz, 1H), 2.92 (d, J = 7.2 Hz, 2H), 2.29 - 2.23 (m, 1H), 1.34 (d, J = 6.8 Hz, 3H), 1.03 (dd, J = 6.6, 1.3 Hz, 6H).

[0252] Step 5: Synthesis of Compound 21-5 Compound 21-4 (1.2 g), diisopropylethylamine (0.672 mL), and dichloromethane (20 mL) were mixed, and 2-(trimethylsilyl)ethoxymethyl chloride (0.515 g) was added. The mixture was reacted overnight at room temperature with stirring. The residue was dissolved in ethyl acetate (50 mL), and the organic phase was sequentially washed with saturated sodium bicarbonate aqueous solution and water to separate the organic phase. The mixture was concentrated, and the resulting crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain compound 21-5 (0.57 g). MS: (ESI, [M+H] + ) m / z: 597.16. 1 H NMR (500 MHz, CDCl3) δ 7.63 (d, J = 1.9 Hz, 1H), 7.02 (s, 1H), 6.54 (d, J = 1.9 Hz, 1H), 5.80 - 5.63 (m, 2H), 4.39 - 4.20 (m, 1H), 4.00 (dd, J = 11.5, 3.8 Hz, 1H), 3.92 (dd, J = 13.2, 2.9 Hz, 1H), 3.78 (d, J = 11.4 Hz, 1H), 3.70 (dd, J = 11.4, 3.2 Hz, 1H), 3.55 (td, J = 11.8, 3.1 Hz, 1H), 3.45 - 3.33 (m, 2H), 3.23 (td, J = 12.7, 3.9 Hz, 1H), 2.89 (dd, J = 7.2, 3.5 Hz, 2H), 2.27 - 2.22 (m, 1H), 1.28 (d, J = 6.7 Hz, 3H), 1.04 (dd, J = 6.6, 1.8 Hz, 6H), 0.79 - 0.70 (m, 2H), -0.16 (s, 9H).

[0253] Step 6: Synthesis of Compound 21-6 Compound 21-5 (0.16 g), dimethyl sulfoximine (0.027 g), tris(dibenzylideneacetone)dipalladium (0.012 g), 4,5-bisdiphenylphosphin-9,9-dimethylxanthene (0.016 g), cesium carbonate (0.175 g), and dioxane (5 mL) were mixed and heated to 80°C under nitrogen protection, and reacted for 1 hour. After suction filtration and concentration of the filtrate, the resulting crude compound was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 21-6 (0.17 g). MS: (ESI, [M+H] + ) m / z: 562.26 1H NMR (500 MHz, CDCl3) δ 7.62 (d, J = 1.9 Hz, 1H), 6.54 (d, J = 1.9 Hz, 1H), 6.24 (s, 1H), 5.74 (q, J = 11.0 Hz, 2H), 4.32 - 4.29 (m, 1H), 3.98 (dd, J = 11.3, 3.7 Hz, 1H), 3.91 (dd, J = 13.2, 2.9 Hz, 1H), 3.77 (d, J = 11.3 Hz, 1H), 3.71 (dd, J = 11.4, 3.1 Hz, 1H), 3.56 (td, J = 11.8, 3.1Hz, 1H), 3.44 - 3.36 (m, 2H), 3.27 (d, J = 1.4 Hz, 6H), 3.20 (td, J = 12.7, 3.8 Hz, 1H), 2.80 (dd, J = 7.1, 3.3 Hz, 2H), 2.18 (hept, J = 6.8 Hz, 1H), 1.25 (d, J = 6.5 Hz, 3H), 0.98 (dd, J = 6.6, 1.5 Hz, 6H), 0.78 - 0.70 (m, 2H), -0.15 (s, 9H).

[0254] Step 7: Synthesis of Compound 21 Compound 21-6 was dissolved in dichloromethane (10 ml), triethylsilane (207 mg) and trifluoroacetic acid (2.115 ml) were added, and the mixture was reacted at room temperature for half an hour. The pH was adjusted to 8 with saturated sodium bicarbonate solution, and the organic phase was sequentially washed with saturated sodium bicarbonate aqueous solution and saturated saline solution, and dried over anhydrous sodium sulfate. The mixture was filtered by suction, concentrated, and the resulting crude product was separated and purified by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 21 (0.067 g). HRMS: (ESI, [M+H] + m / z: 432.2175. 1H NMR (500 MHz, Chloroform-d) δ 7.58 (d, J = 2.1 Hz, 1H), 6.72 (d, J = 2.1 Hz, 1H), 6.27 (s, 1H), 4.36 - 4.34 (m, 1H), 4.05 (dd, J = 11.3, 3.7 Hz, 1H), 3.92 (dd, J = 13.0, 3.0 Hz, 1H), 3.88 - 3.73 (m, 2H), 3.64 (td, J = 11.8, 3.1 Hz, 1H), 3.35 - 3.28 (m, 7H), 2.82 (d, J = 7.1 Hz, 2H), 2.22 - 2.17 (m, 1H), 1.31 (d, J = 6.7 Hz, 3H), 0.97 (d, J = 6.6 Hz, 6H).

[0255] Example 22: Synthesis of Compound 22 [ka]

[0256] Step 1: Synthesis of Compound 22-1 Compound A1-3 (6 g) and tetrahydrofuran (60 mL) were mixed and cooled to -78°C. Under a nitrogen atmosphere, lithium diisopropylamide (2 M, 18.6 mL) was added dropwise, and the mixture was reacted at -78°C for 1 hour. Cyclopropylformaldehyde (3.5 g) was added to the reaction mixture. After stirring continued at -78°C for 1 hour, the reaction mixture was raised to room temperature. Saturated ammonium chloride aqueous solution was added, and the organic phase was sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 22-1 (6 g). 1H NMR (500 MHz, CDCl3) δ 7.33 (d, J = 3.1 Hz, 1H), 4.36 - 4.23 (m, 1H), 2.39 (dd, J = 6.7, 2.5 Hz, 1H), 1.59 - 1.54 (m, 1H), 0.80 - 0.64 (m, 1H), 0.62 - 0.43 (m, 3H).

[0257] Step 2: Synthesis of Compound 22-2 Mix compound 22-1 (6 g), manganese dioxide (33.5 g), and toluene (60 mL), and 90 o The mixture was heated to 17°C and reacted for 3 hours. After suction filtration and concentration of the filtrate, compound 22-2 (5.8 g) was obtained. 1 H NMR (500 MHz, CDCl3) δ 7.40 (d, J = 2.8 Hz, 1H), 2.39 - 2.15 (m, 1H), 1.45 - 1.38 (m, 2H), 1.22 - 1.08 (m, 2H).

[0258] Step 3: Synthesis of Compound 22-3 Compound 22-2 (5.7 g) and tetrahydrofuran (60 mL) were mixed, and a tetrahydrofuran solution of hydrazine (1 M, 0.743 mL) was added. After reacting for 1 hour, a tetrahydrofuran solution of hydrazine (1 M, 0.338 mL) was added, and the mixture was reacted overnight at room temperature. After concentrating the reaction mixture, it was separated and purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain compound 22-3 (2.4 g). MS: (ESI, [M+H] + ) m / z: 303.82. 1 H NMR (500 MHz, DMSO-d6) δ 13.48 (s, 1H), 7.51 (s, 1H), 2.61-2.55 (m, 1H), 1.03-0.98 (m, 4H).

[0259] Step 4: Synthesis of Compound 22-4 Mix compound 22-3 (2.4 g), (R)-3-methylmorpholine (4.00 g), and dimethyl sulfoxide (50 mL), and 120 o The reaction was carried out by heating to 14C. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with water and saturated brine respectively, and dried over anhydrous sodium sulfate. After suction filtration and concentration of the filtrate, compound 22-4 (2.9 g) was obtained. MS: (ESI, [M+H] + ) m / z: 385.01. 1 H NMR (500 MHz, CDCl3) δ 10.10 (brs, 1H), 6.99 (s, 1H), 4.40 - 4.26 (m, 1H), 4.03 (dd, J = 11.5, 3.9 Hz, 1H), 3.90 (dd, J = 13.2, 3.0 Hz, 1H), 3.82 - 3.74 (m, 2H), 3.61 (td, J = 11.9, 3.1 Hz, 1H), 3.30 (td, J = 12.7, 3.9 Hz, 1H), 2.53 - 2.44 (m, 1H), 1.29 (d, J = 6.8 Hz, 3H), 1.05 - 1.03 (m, 2H), 1.03 - 1.00 (m, 2H).

[0260] Step 5: Synthesis of Compound 22-5 Compound 22-4 (2.9 g) and N,N-dimethylformamide (50 mL) were mixed and, under ice cooling, 60% sodium hydride (0.362 g) was added and the mixture was reacted for half an hour. Then, 2-(trimethylsilyl)ethoxymethyl chloride (2.008 mL) was added dropwise and the mixture was reacted at room temperature for 1 hour. Saturated ammonium chloride aqueous solution was added and the mixture was stirred for 5 minutes. Extraction was performed with ethyl acetate, and the organic phases were washed with water and saturated brine, respectively. The mixture was dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated. The resulting crude material was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 22-5 (3.2 g). MS: (ESI, [M+H] + ) m / z: 515.14. 1H NMR (500 MHz, CDCl3) δ 6.97 (s, 1H), 5.56 (s, 2H), 4.35 (dd, J = 6.9, 2.9 Hz, 1H), 4.07 - 3.97 (m, 2H), 3.86 - 3.71 (m, 2H), 3.71 - 3.49 (m, 3H), 3.26 (td, J = 12.7, 3.8 Hz, 1H), 2.49 - 2.46 (m, 1H), 1.28 (d, J = 6.8 Hz, 3H), 1.07 - 1.05 (m, 2H), 1.01 - 0.99 (m, 2H), 0.93 - 0.89 (m, 2H), -0.06 (s, 9H).

[0261] Step 6: Synthesis of Compound 22-6 Compound 22-5 (0.259 g), tris(dibenzylideneacetone)dipalladium (0.116 g), 4,5-bisdiphenylphosphin-9,9-dimethylxanthene (0.146 g), cesium carbonate (1.647 g), and dioxane (20 mL) were mixed and heated to 80°C under a nitrogen atmosphere and reacted for 2 hours. After natural cooling to room temperature, the mixture was filtered by suction and the filtrate was concentrated. The resulting crude compound was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 22-6 (1.2 g). MS: (ESI, [M+H] + ) m / z: 480.29. 1H NMR (500 MHz, CDCl3) δ 6.22 (s, 1H), 5.55 (s, 2H), 4.44 - 4.25 (m, 1H), 3.98 (td, J = 14.0, 12.9, 3.3 Hz, 2H), 3.77 (t, J = 2.5 Hz, 2H), 3.60 (tdd, J = 9.5, 4.8, 3.0 Hz, 3H), 3.26 (s, 7H), 2.43 (tt, J = 8.3, 5.1 Hz, 1H), 1.25 (d, J = 6.7 Hz, 3H), 1.05 (dt, J = 5.9, 2.9 Hz, 2H), 1.02 - 0.82 (m, 4H), -0.07 (s, 9H).

[0262] Step 7: Synthesis of Compound 22-7 Compound 22-6 (1.2 g) was dissolved in dichloromethane (60 mL), triethylsilane (4.00 mL) and trifluoroacetic acid (29.7 mL) were added, and the mixture was reacted at room temperature for half an hour. The reaction mixture was diluted with dichloromethane and adjusted to pH 8 with saturated sodium bicarbonate solution. The organic phase was sequentially washed with water and saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the crude product was separated and purified by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 22-7 (0.82 g). 1 H NMR (500 MHz, CDCl3) δ 9.91 (brs, 1H), 6.23 (s, 1H), 4.33 - 4.29 (m, 1H), 4.00 (dd, J = 11.4, 3.7 Hz, 1H), 3.87 (dd, J = 13.1, 2.9 Hz, 1H), 3.78 (d, J = 2.1 Hz, 2H), 3.62 (td, J = 11.8, 3.1 Hz, 1H), 3.29 - 3.24 (m, 7H), 2.48 - 2.43 (m, 1H), 1.26 (d, J = 6.7 Hz, 3H), 1.08-0.97 (m, 2H), 0.92 - 0.89 (m, 2H).

[0263] Step 8: Synthesis of Compound 22-8 Compound 22-7 (400 mg), 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (742 mg), cesium carbonate (1119 mg), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (326 mg), cuprous iodide (327 mg), and N-methylpyrrolidone (20 mL) were mixed and heated to 140°C under a nitrogen atmosphere using a microwave (400 W) and reacted for 1 hour. After cooling to room temperature, the mixture was diluted with aqueous ammonia (10 mL) and ethyl acetate, washed with water and saturated aqueous sodium chloride solution respectively, and dried over anhydrous sodium sulfate. After suction filtration and concentration of the filtrate, the resulting crude compound was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:4) to obtain compound 22-8 (0.442 g). MS: (ESI, [M+H] + ) m / z: 546.27. 1 H NMR (500 MHz, CDCl3) δ 7.58 (d, J = 2.4 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 6.27 (s, 1H), 5.46 (s, 2H), 4.36 - 4.33 (m, 1H), 4.03 (dd, J = 11.4, 3.7 Hz, 1H), 3.97 (dd, J = 13.2, 2.9 Hz, 1H), 3.87-3.76 (m, 2H), 3.69 - 3.54 (m, 3H), 3.32 - 3.26 (m, 7H), 2.52 - 2.47 (m, 1H), 1.29 (d, J = 6.8 Hz, 3H), 1.20 (dd, J = 7.6, 5.2 Hz, 2H), 0.95 - 0.88 (m, 4H), -0.02 (s, 9H).

[0264] Step 9: Synthesis of Compound 22 Compound 22-8 (0.2 g) was dissolved in dichloromethane (10 mL), and triethylsilane (0.585 mL) and trifluoroacetic acid (4.36 mL) were added. The mixture was reacted at room temperature with stirring for half an hour. The reaction solution was diluted with dichloromethane and adjusted to pH 8 with saturated sodium bicarbonate solution. The organic phase was sequentially washed with water and saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the crude product was separated and purified by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 22 (0.037 g). HRMS: (ESI, [M+H] + ) m / z: 416.1866. 1 H NMR (500 MHz, CDCl3) δ 7.56 (d, J = 2.1 Hz, 1H), 6.69 (s, 1H), 6.28 (s, 1H), 4.37 - 4.32 (m, 1H), 4.05 (dd, J = 11.4, 3.7 Hz, 1H), 3.91 (dd, J = 13.0, 2.9 Hz, 1H), 3.88 - 3.71 (m, 2H), 3.64 (td, J = 11.8, 3.1 Hz, 1H), 3.34 - 3.29 (m, 7H), 2.51 - 2.47 (m, 1H), 1.30 (d, J = 6.7 Hz, 3H), 1.16 - 1.14 (m, 2H), 0.95 - 0.93 (m, 2H).

[0265] Example 23: Synthesis of Compound 23 [ka]

[0266] Step 1: Synthesis of Compound 23-1 Compound A1-4 (2.5 g) was dissolved in tetrahydrofuran (30 mL), and trifluoromethyltrimethylsilane (3.75 g) was added dropwise under nitrogen protection, and the mixture was reacted at room temperature for 10 minutes. Tetrabutylammonium fluoride (0.1 mL) was added, and the mixture was reacted at room temperature for 30 minutes. Then, aqueous hydrochloric acid (6N, 1.1 mL) was added, and the mixture was stirred at room temperature for 5 hours. The mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the resulting crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 23-1 (1.9 g).

[0267] Step 2: Synthesis of Compound 23-2 Compound 23-1 (1.9 g), manganese dioxide (4 g), and toluene (30 mL) were mixed and reacted at 70°C for 5 hours. The reaction solution was filtered and washed, the mother liquor was collected and concentrated to obtain compound 23-2 (1.3 g). MS: (ESI, [M+H] + ) m / z: 338.42.

[0268] Step 3: Synthesis of Compound 23-3 Compound A1-2 (3 g), compound 23-2 (1.1 g), and ethanol (15 mL) were mixed and reacted at room temperature for 1 hour. The reaction solution was concentrated, the residue was dissolved in ethyl acetate, washed sequentially with saturated sodium bicarbonate, water, and saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 23-3 (550 mg). MS: (ESI, [M+H] + ) m / z: 418.03. 1 H NMR (500 MHz, DMSO-d6)δ 12.25 (s, 1H), 10.76 (s, 1H), 8.00 (s, 1H), 7.60 (d, J = 12.3 Hz, 1H), 5.99 (d, J = 15.8 Hz, 1H).

[0269] Step 4: Synthesis of Compound 23-4 Compound 23-3 (500 mg) and N-methylpyrrolidone (5 mL) were mixed and heated to 200°C in a microwave oven, and reacted for 20 minutes. Water was added to the reaction mixture to precipitate the solid, which was then filtered, washed, and dried to obtain compound 23-4 (200 mg). MS (ESI, [M+H]+) m / z: 398.00. 1 H NMR (500 MHz, DMSO -d6) δ 13.32 (s, 1H), 8.01 (d, J = 8.4 Hz, 2H), 6.74 (s, 1H).

[0270] Step 5: Synthesis of Compound 23-5 Compound 23-4 (170 mg), (R)-3-methylmorpholine (100 mg), and dimethyl sulfoxide (3 mL) were mixed and heated to 120°C, where they were reacted for 1 hour. Water was added to the reaction mixture to precipitate the solid, which was then filtered, washed, and dried to obtain compound 23-5 (150 mg). MS (ESI, [M+H] + ) m / z: 479.10. 1 H NMR (500 MHz, DMSO -d6) δ 13.15 (s, 1H), 7.92 (s, 1H), 7.55 (s, 1H), 6.80 (s, 1H), 4.47 (d, J = 5.3 Hz, 1H), 4.06 (d, J = 12.4 Hz, 1H), 3.95 (dd, J = 11.4, 3.2 Hz, 1H), 3.74 (d, J = 11.5 Hz, 1H), 3.62 (dd, J = 11.5, 2.8 Hz, 1H), 3.47 (td, J = 11.9, 2.8 Hz, 1H), 3.19 (td, J = 12.8, 3.6 Hz, 1H), 1.20 (d, J = 6.6 Hz, 3H).

[0271] Step 6: Synthesis of Compound 23-6 Compound 23-5 (150 mg), diisopropylethylamine (105 mg), and dichloromethane (10 mL) were mixed, and 2-(trimethylsilyl)ethoxymethyl chloride (89 mg) was added dropwise. The mixture was reacted at room temperature for 30 minutes. Dichloromethane (30 mL) and saturated sodium bicarbonate (30 mL) were added to the reaction mixture, the organic phase was separated and concentrated, and the resulting crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 23-6 (110 mg). MS (ESI, [M+H]+) m / z: 609.30.

[0272] Step 7: Synthesis of Compound 23-7 Compound 23-6 (110 mg), dimethyl sulfoximine (33.7 mg), tris(dibenzylideneacetone)dipalladium (8.28 mg), 4,5-bisdiphenylphosphin-9,9-dimethylxanthene (10.46 mg), cesium carbonate (118 mg), and 1,4-dioxane (5 mL) were mixed and reacted at 80°C for 1 hour under a nitrogen atmosphere. The reaction mixture was filtered, the filtrate was concentrated, and the crude product was separated and purified by column chromatography (dichloromethane:methanol = 15:1) to obtain compound 23-7 (90 mg). MS (ESI, [M+H] + ) m / z: 574.17.

[0273] Step 8: Synthesis of Compound 23 Compound 23-7 (90 mg) was dissolved in dichloromethane (4 mL), cooled to 0°C, and triethylsilane (182 mg) and trifluoroacetic acid (2.8 g) were added. The mixture was reacted at room temperature for 1 hour. The reaction solution was diluted with dichloromethane and adjusted to pH 8 with saturated sodium bicarbonate solution. The organic phase was sequentially washed with water and saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the crude product was separated and purified by column chromatography (dichloromethane:methanol = 9:1) to obtain compound 23 (40 mg). MS (ESI, [M+H] + ) m / z: 444.16. 1H NMR (500 MHz, DMSO-d6)δ 12.97 (s, 1H), 7.88 (s, 1H), 6.81 (s, 1H), 6.28 (s, 1H), 4.32 (d, J = 5.0 Hz, 1H), 4.03-3.88 (m, 2H), 3.75 (d, J = 11.3 Hz, 1H), 3.64 (dd, J = 11.3, 2.6 Hz, 1H), 3.48 (td, J = 11.7, 2.6 Hz, 1H), 3.39 (s, 6H), 3.14 (td, J = 12.7, 3.6 Hz, 1H), 1.19 (d, J = 6.7 Hz, 3H).

[0274] Example 24: Synthesis of Compound 24 [ka]

[0275] Step 1: Synthesis of Compound 24-1 Compound A1-3 (1.3 g) and tetrahydrofuran (30 mL) were mixed and cooled to -78°C. A tetrahydrofuran / n-hexane solution of lithium diisopropylamide (2 M, 3.5 mL) was added dropwise, and the mixture was reacted at -78°C for 1 hour. Compound A1-2 (1 g) was added to the reaction mixture, and the reaction was continued at -78°C for 30 minutes. Next, formic acid (0.5 g) and ethyl acetate (100 mL) were added, and the reaction mixture was raised to room temperature. The organic phase was sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and the crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 24-1 (1.3 g). 1 H NMR (500 MHz, DMSO-d6)δ 7.76 (s, 1H), 5.88 (d, J = 4.6 Hz, 1H), 4.95 (dt, J = 9.3, 4.7 Hz, 1H), 2.49-2.37 (m, 1H), 2.37-2.23 (m, 1H), 2.05 (m, 1H), 1.85 (m, 1H).

[0276] Step 2: Synthesis of Compound 24-2 Compound 11-1 (1.3 g), manganese dioxide (4 g), and toluene (30 mL) were mixed and reacted at 70°C for 5 hours. The reaction mixture was filtered and washed, the mother liquor was collected and concentrated to obtain compound 24-2 (1 g). 1 H NMR (500 MHz, DMSO-d6)δ 7.93 (d, J = 2.1 Hz, 1H), 3.21 (t, J = 7.0 Hz, 2H), 2.79-2.59 (m, 2H).

[0277] Step 3: Synthesis of Compound 24-3 Compound A1-2 (1 g), compound 24-2 (1 g), and ethanol (20 mL) were mixed and reacted at room temperature for 1 hour. The reaction solution was concentrated, the residue was dissolved in ethyl acetate, washed sequentially with saturated sodium bicarbonate, water, and saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 24-3 (600 mg). MS: (ESI, [M+H] + ) m / z: 446.31.

[0278] Step 4: Synthesis of Compound 24-4 Compound 24-3 (600 mg) and N-methylpyrrolidone (5 mL) were mixed and heated to 200°C in a microwave and reacted for 20 minutes. Water was added to the reaction mixture to precipitate the solid, which was then filtered, washed, and dried to obtain compound 24-4 (250 mg). MS (ESI, [M+H] + ) m / z: 426.01.

[0279] Step 5: Synthesis of Compound 24-5 Compound 24-4 (250 mg), (R)-3-methylmorpholine (200 mg), and dimethyl sulfoxide (3 mL) were mixed and heated to 120°C, where they were reacted for 1 hour. Water was added to the reaction mixture to precipitate the solid, which was then filtered, washed, and dried to obtain compound 24-5 (170 mg). MS (ESI, [M+H] + ) m / z: 507.04. 1 H NMR (500 MHz, DMSO -d6) δ 13.09 (s, 1H), 7.92 (s, 1H), 7.70 (s, 1H), 6.64 (s, 1H), 3.50 -3.41 (m, 2H), 3.31 (t, J = 7.1 Hz, 4H), 2.95-2.79 (m, 2H), 2.18 (t, J = 8.1 Hz, 3H), 1.98-1.84 (m, 3H).

[0280] Step 6: Synthesis of Compound 24 Compound 24-5 (100 mg), dimethyl sulfoximine (37 mg), tris(dibenzylideneacetone)dipalladium (9 mg), 4,5-bisdiphenylphosphin-9,9-dimethylxanthene (11 mg), cesium carbonate (193 mg), and 1,4-dioxane (5 mL) were mixed and reacted at 80°C for 1 hour under a nitrogen atmosphere. The reaction mixture was filtered, the filtrate was concentrated, and the crude product was separated and purified by column chromatography (dichloromethane:methanol = 15:1) to obtain compound 24 (50 mg). MS (ESI, [M+H] + ) m / z: 472.21. 1 H NMR (500 MHz, DMSO-d6)δ 12.68 (s, 1H), 7.78 (s, 1H), 6.76 (s, 1H), 6.13 (s, 1H), 4.30 (d, J = 5.4 Hz, 1H), 3.96 (dd, J = 11.1, 2.6 Hz, 1H), 3.88 (d, J = 12.6 Hz, 1H), 3.75 (d, J = 11.3 Hz, 1H), 3.64 (dd, J = 11.3, 2.5 Hz, 1H), 3.53-3.45 (m, 1H), 3.41 (s, 6H), 3.21-3.05 (m, 3H), 2.73 (dq, J = 22.3, 11.3 Hz, 2H), 1.17 (d, J = 6.6 Hz, 3H).

[0281] Example 25: Synthesis of Compound 25 [ka]

[0282] Step 1: Synthesis of Compound 25-1 Compound A1-3 (10 g) and tetrahydrofuran (100 mL) were mixed and cooled to -78°C. A tetrahydrofuran / n-hexane solution of lithium diisopropylamide (2 M, 29 mL) was added dropwise, and the mixture was reacted at -78°C for 1 hour. Pivaraldehyde (7.15 g) was added to the reaction mixture, and the reaction was continued at -78°C for 30 minutes. Formic acid (3.82 g) and ethyl acetate (100 mL) were then added, and the reaction mixture was raised to room temperature. The organic phase was sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 25-1 (9.7 g).

[0283] Step 2: Synthesis of Compound 25-2 Compound 25-1 (9.5 g) and toluene (180 mL) were mixed and the mixture was heated to 70°C and reacted overnight. The reaction solution was filtered and concentrated to obtain compound 25-2 (9.3 g).

[0284] Step 3: Synthesis of Compound 25-3 Compound 25-2 (9 g) and tetrahydrofuran (90 mL) were mixed, cooled to 0°C, and a 1 M, 30 mL solution of hydrazine in tetrahydrofuran was added dropwise. The mixture was allowed to react overnight at room temperature. The reaction mixture was concentrated, and the crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 25-3 (2.9 g). MS (ESI, [MH] - ) m / z: 317.83. 1 H NMR (500 MHz, DMSO-d6) δ 13.59 (s, 1H), 7.65 (s, 1H), 1.61 (s, 9H).

[0285] Step 4: Synthesis of Compound 25-4 Compound 25-3 (2.8 g), (R)-3-methylmorpholine (4.44 g), and dimethyl sulfoxide (15 mL) were mixed and heated to 120°C, and the mixture was allowed to react overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the organic phase was sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 25-4 (3.2 g). MS (ESI, [M+H] + ) m / z: 401.10. 1 H NMR (500 MHz, DMSO-d6) δ 12.68 (s, 1H), 7.28 (s, 1H), 4.43-4.31 (m, 1H), 3.97-3.84 (m, 2H), 3.71 (d, J = 11.3 Hz, 1H), 3.62 (dd, J = 11.4, 2.8 Hz, 1H), 3.46 (td, J = 11.8, 2.9 Hz, 1H), 3.11 (td, J = 12.7, 3.7 Hz, 1H), 1.56 (s, 9H), 1.15 (d, J = 6.7 Hz, 3H).

[0286] Step 5: Synthesis of Compound 25-5 Compound 25-4 (3 g) and N,N-dimethylformamide (15 mL) were mixed and cooled to 0°C. 60% sodium hydride (360 mg) was added in portions, and the mixture was reacted at 0°C for 0.5 hours. 2-(trimethylsilyl)ethoxymethyl chloride (1.87 g) was added to the reaction mixture and the mixture was reacted at 0°C for 0.5 hours. Ethyl acetate (150 mL) and saturated ammonium chloride (50 mL) were added to the reaction mixture to separate the organic phase. The organic phase was sequentially washed with water and saturated brine, concentrated, and the resulting crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 25-5 (3.64 g). MS (ESI, [M+H] + ) m / z: 531.12. 1H NMR (500 MHz, DMSO-d6) δ 7.34 (s, 1H), 5.50 (s, 2H), 4.47-4.38 (m, 1H), 4.01-3.90 (m, 2H), 3.72 (d, J = 11.3 Hz, 1H), 3.62-3.55 (m, 3H), 3.45 (td, J = 11.8, 2.9 Hz, 1H), 3.12 (td, J = 12.8, 3.7 Hz, 1H), 1.57 (s, 9H), 1.16 (d, J = 6.7 Hz, 3H), 0.83-0.75 (m, 2H), -0.12 (s, 9H).

[0287] Step 6: Synthesis of Compounds 25-6 Compound 25-5 (1.5 g), dimethyl sulfoximine (290 mg), tris(dibenzylideneacetone)dipalladium (129 mg), 4,5-bisdiphenylphosphin-9,9-dimethylxanthene (164 mg), cesium carbonate (1.84 g), and 1,4-dioxane (20 mL) were mixed and reacted at 80°C for 1 hour under a nitrogen atmosphere. The reaction mixture was filtered, the filtrate was concentrated, and the crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 25-6 (1.02 g). MS (ESI, [M+H] + ) m / z: 496.30. 1H NMR (500 MHz, DMSO-d6) δ 6.13 (s, 1H), 5.44 (s, 2H), 4.33-4.24 (m, 1H), 3.94 (dd, J = 11.2, 3.3 Hz, 1H), 3.89-3.83 (m, 1H), 3.73 (d, J = 11.2 Hz, 1H), 3.62 (dd, J = 11.4, 2.7 Hz, 1H), 3.60-3.54 (m, 2H), 3.47 (td, J = 11.8, 3.0 Hz, 1H), 3.38 (s, 6H), 3.07 (td, J = 12.7, 3.7 Hz, 1H), 1.43 (s, 9H), 1.14 (d, J = 6.7 Hz, 3H), 0.87-0.75 (m, 2H), -0.10 (s, 9H).

[0288] Step 7: Synthesis of Compound 25-7 Compound 25-6 (1 g) was dissolved in dichloromethane (10 mL), cooled to 0°C, and triethylsilane (2.93 g) and trifluoroacetic acid (30 mL) were added. The mixture was reacted at room temperature for 1 hour. The reaction solution was diluted with dichloromethane and adjusted to pH 8 with saturated sodium bicarbonate solution. The organic phase was sequentially washed with water and saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:4) to obtain compound 25-7 (636 mg). MS (ESI, [M+H] + ) m / z: 366.19. 1H NMR (500 MHz, DMSO-d6) δ 12.08 (s, 1H), 6.09 (s, 1H), 4.27-4.18 (m, 1H), 3.93 (dd, J = 11.2, 3.3 Hz, 1H), 3.80-3.68 (m, 2H), 3.63 (dd, J = 11.3, 2.8 Hz, 1H), 3.47 (td, J = 11.8, 3.0 Hz, 1H), 3.36 (s, 6H), 3.06 (td, J = 12.6, 3.7 Hz, 1H), 1.42 (s, 9H), 1.13 (d, J = 6.7Hz, 3H).

[0289] Step 8: Synthesis of Compound 25-8 Compound 25-7 (400 mg), 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (532 mg), cuprous iodide (313 mg), (1R,2R)-cyclohexane-1,2-diamine (375 mg), cesium carbonate (1.07 g), and N-methylpyrrolidone (10 mL) were mixed and heated to 140°C by microwave and reacted for 1 hour. Ethyl acetate (100 mL) was added to the reaction mixture, and the organic phase was sequentially washed with 1 M aqueous ammonia solution, water, and saturated brine. The mixture was dried over anhydrous sodium sulfate, and the filtrate was concentrated. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 25-8 (88 mg). MS (ESI, [M+H] + ) m / z: 562.30. 1H NMR (500 MHz, DMSO-d6) δ 7.94 (d, J = 2.2 Hz, 1H), 6.86 (d, J = 2.2 Hz, 1H), 6.19 (s, 1H), 5.41 (s, 2H), 4.31-4.21 (m, 1H), 3.95 (dd, J = 11.2, 3.0 Hz, 1H), 3.84 (d, J = 12.0 Hz, 1H), 3.75 (d, J = 11.2 Hz, 1H), 3.64 (dd, J = 11.2, 2.5 Hz, 1H), 3.61-3.55 (m, 2H), 3.49 (td, J = 11.7, 2.6 Hz, 1H), 3.41 (s, 6H), 3.11 (td, J = 12.6, 3.6 Hz, 1H), 1.47 (s, 9H), 1.16 (d, J = 6.7 Hz, 3H), 0.88-0.84 (m, 2H), -0.03 (s, 9H).

[0290] Step 9: Synthesis of Compound 25 Compound 25-8 (80 mg) was dissolved in dichloromethane (1 mL), cooled to 0°C, and triethylsilane (331 mg) and trifluoroacetic acid (3 mL) were added. The mixture was reacted at room temperature for 1 hour. The reaction solution was diluted with dichloromethane and adjusted to pH 8 with saturated sodium bicarbonate solution. The organic phase was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the crude product was separated and purified by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 25 (48 mg). HRMS: (ESI, [M+H] + ) m / z: 432.2180. 1H NMR (500 MHz, DMSO-d6) δ 12.63 (s, 1H), 7.75 (s, 1H), 6.72 (s, 1H), 6.18 (s, 1H), 4.30-4.22 (m, 1H), 3.95 (dd, J = 11.2, 3.3 Hz, 1H), 3.84 (d, J = 12.0 Hz, 1H), 3.75 (d, J = 11.2 Hz, 1H), 3.64 (dd, J = 11.3, 2.8 Hz, 1H), 3.48 (td, J = 11.8, 3.0 Hz, 1H), 3.41 (s, 6H), 3.10 (td, J = 12.6, 3.7 Hz, 1H), 1.48 (s, 9H), 1.16 (d, J = 6.7 Hz, 3H).

[0291] Example 26: Synthesis of Compound 26 [ka]

[0292] Step 1: Synthesis of Compound 26-1 Compound A1-4 (5.3 g) and tetrahydrofuran (100 mL) were mixed, cooled to 0°C, and 85% hydrazine hydrate solution (817 mg) was added dropwise. The mixture was reacted overnight at room temperature. The reaction mixture was concentrated, and the crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 26-1 (1.8 g). MS (ESI, [MH] - ) m / z: 261.83. 1 H NMR (500 MHz, DMSO-d6) δ 14.05 (s, 1H), 8.03-7.99 (m, 1H), 7.53 (s, 1H).

[0293] Step 2: Synthesis of Compound 26-2 Compound 26-1 (1.8 g) and N,N-dimethylformamide (30 mL) were mixed and cooled to 0°C. N-bromosuccinimide (1.34 g) was added in portions, and the reaction mixture was heated to room temperature and stirred overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the organic phase was sequentially washed with water and saturated brine. The mixture was concentrated, and the resulting crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 26-2 (1.72 g). 1 H NMR (500 MHz, DMSO-d6) δ 14.35 (s, 1H), 7.67 (s, 1H).

[0294] Step 3: Synthesis of Compound 26-3 Compound 26-2 (1.7 g), (R)-3-methylmorpholine (2.51 g), and dimethyl sulfoxide (10 mL) were mixed and heated to 120°C, where they were reacted for 2 hours. Ethyl acetate (100 mL) was added to the reaction mixture, and the organic phase was sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and the crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 26-3 (1.75 g). MS (ESI, [M+H] + ) m / z: 422.94. 1 H NMR (500 MHz, DMSO-d6) δ 13.37 (s, 1H), 7.29 (s, 1H), 4.48-4.35 (m, 1H), 3.99-3.87 (m, 2H), 3.71 (d, J = 11.4 Hz, 1H), 3.61 (dd, J = 11.4, 2.9 Hz, 1H), 3.46 (td, J = 11.7, 2.9 Hz, 1H), 3.15 (td, J = 12.8, 3.7 Hz, 1H), 1.17 (d, J = 6.7 Hz, 3H).

[0295] Step 4: Synthesis of Compound 26-4 Compound 26-3 (1.7 g) and N,N-dimethylformamide (20 mL) were mixed and cooled to 0°C. 60% sodium hydride (193 mg) was added in portions, and the mixture was reacted at 0°C for 0.5 hours. 2-(trimethylsilyl)ethoxymethyl chloride (1.0 g) was added to the reaction mixture, and the mixture was reacted at 0°C for 0.5 hours. Ethyl acetate (100 mL) and saturated ammonium chloride (50 mL) were added to the reaction mixture to separate the organic phase. The organic phase was sequentially washed with water and saturated brine, concentrated, and the resulting crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 26-4 (1.85 g). MS (ESI, [M+H] + ) m / z: 552.90. 1 H NMR (500 MHz, DMSO-d6) δ 7.34 (s, 1H), 5.52 (s, 2H), 4.53-4.43 (m, 1H), 4.06 (d, J = 12.4 Hz, 1H), 3.94 (dd, J = 11.4, 3.3 Hz, 1H), 3.73 (d, J = 11.4 Hz, 1H), 3.63-3.52 (m, 3H), 3.45 (td, J = 11.6, 2.6 Hz, 1H), 3.16 (td, J = 13.0, 3.7 Hz, 1H), 1.18 (d, J = 6.7 Hz, 3H), 0.86-0.78 (m, 2H), -0.10 (s, 9H).

[0296] Step 5: Synthesis of Compound 26-5 Compound 26-4 (1.8 g), dimethyl sulfoximine (333 mg), tris(dibenzylideneacetone)dipalladium (298 mg), 4,5-bisdiphenylphosphin-9,9-dimethylxanthene (376 mg), cesium carbonate (2.12 g), and 1,4-dioxane (20 mL) were mixed and reacted at 80°C for 1 hour under a nitrogen atmosphere. The reaction mixture was filtered, the filtrate was concentrated, and the crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 26-5 (1.42 g). MS (ESI, [M+H] + ) m / z: 518.13. 1 H NMR (500 MHz, DMSO-d6) δ 6.10 (s, 1H), 5.46 (s, 2H), 4.36-4.28 (m, 1H), 3.97-3.89 (m, 2H), 3.73 (d, J = 11.3 Hz, 1H), 3.61 (dd, J = 11.5, 2.8 Hz, 1H), 3.56 (dq, J = 9.7, 3.0 Hz, 2H), 3.46 (td, J = 11.8, 2.9 Hz, 1H), 3.39 (s, 6H), 3.10 (td, J = 12.8, 3.7 Hz, 1H), 1.15 (d, J = 6.7 Hz, 3H), 0.88-0.78 (m, 2H), -0.09 (s, 9H).

[0297] Step 6: Synthesis of Compound 26-6 Compound 26-5 (500 mg), cyclopropylacetylene (637 mg), cuprous iodide (55 mg), bis(triphenylphosphine)dichloride palladium (203 mg), triethylamine (293 mg), cesium carbonate (2.12 g), and acetonitrile (10 mL) were mixed and reacted overnight at 85°C under a nitrogen atmosphere. The reaction mixture was filtered, the filtrate was concentrated, and the crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 26-6 (298 mg). MS (ESI, [M+H] + ) m / z: 504.30. 1H NMR (500 MHz, DMSO-d6) δ 6.07 (s, 1H), 5.45 (s, 2H), 4.36-4.26 (m, 1H), 3.98-3.86 (m, 2H), 3.73 (d, J = 11.2 Hz, 1H), 3.61 (dd, J = 11.3, 2.7 Hz, 1H), 3.54 (dq, J = 9.8, 3.0 Hz, 2H), 3.49-3.42 (m, 1H), 3.38 (s, 6H), 3.09 (td, J = 12.8, 3.7 Hz, 1H), 1.57 (tt, J = 8.3, 5.0 Hz, 1H), 1.14 (d, J = 6.6 Hz, 3H), 0.92-0.86 (m, 2H), 0.86-0.79 (m, 2H), 0.79-0.74 (m, 2H), -0.10 (s, 9H).

[0298] Step 7: Synthesis of Compound 26-7 Compound 26-6 (290 mg) was dissolved in dichloromethane (5 mL), cooled to 0°C, and triethylsilane (1.46 g) and trifluoroacetic acid (15 mL) were added. The mixture was reacted at room temperature for 1 hour. The reaction solution was diluted with dichloromethane and adjusted to pH 8 with saturated sodium bicarbonate solution. The organic phase was sequentially washed with water and saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 26-7 (191 mg). MS (ESI, [M+H] + ) m / z: 374.20. 1H NMR (500 MHz, DMSO-d6) δ 12.66 (s, 1H), 6.04 (s, 1H), 4.25 (d, J = 4.7 Hz, 1H), 3.92 (dd, J = 11.2, 3.2 Hz, 1H), 3.80 (d, J = 11.2 Hz, 1H), 3.71 (d, J = 11.3 Hz, 1H), 3.62 (dd, J = 11.3, 2.7 Hz, 1H), 3.46 (td, J = 11.7, 2.9 Hz, 1H), 3.36 (s, 6H), 3.08 (td, J = 12.7, 3.8 Hz, 1H), 1.56 (tt, J = 8.3, 5.0 Hz, 1H), 1.13 (d, J = 6.6 Hz, 3H), 0.90-0.84 (m, 2H), 0.78-0.72 (m, 2H).

[0299] Step 8: Synthesis of Compound 26-8 Compound 26-7 (150 mg), 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (260 mg), cuprous iodide (115 mg), (1R,2R)-cyclohexane-1,2-diamine (138 mg), cesium carbonate (393 mg), and N-methylpyrrolidone (5 mL) were mixed and heated to 140°C by microwave and reacted for 0.5 hours. Ethyl acetate (100 mL) was added to the reaction mixture, and the organic phase was sequentially washed with 1 M aqueous ammonia solution, water, and saturated brine. The mixture was dried over anhydrous sodium sulfate, and the filtrate was concentrated. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 26-8 (113 mg). MS (ESI, [M+H] + ) m / z: 570.40. 1H NMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 2.3 Hz, 1H), 6.89 (d, J = 2.3 Hz, 1H), 6.12 (s, 1H), 5.40 (s, 2H), 4.35-4.24 (m, 1H), 3.98-3.86 (m, 2H), 3.74 (d, J = 11.3 Hz, 1H), 3.64 (dd, J = 11.3, 2.6 Hz, 1H), 3.58 (t, J = 8.0 Hz, 2H), 3.48 (td, J = 11.8, 2.8 Hz, 1H), 3.41 (s, 6H), 3.12 (td, J = 12.7, 3.7 Hz, 1H), 1.61 (tt, J = 8.3, 5.0 Hz, 1H), 1.17 (d, J = 6.7 Hz, 3H), 0.92 (td, J = 6.6, 3.9 Hz, 2H), 0.85 (t, J = 8.0 Hz, 2H), 0.82-0.78 (m, 2H), -0.04 (s, 9H).

[0300] Step 9: Synthesis of Compound 26 Compound 26-8 (100 mg) was dissolved in dichloromethane (1 mL), cooled to 0°C, and triethylsilane (408 mg) and trifluoroacetic acid (3 mL) were added. The mixture was reacted at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (30 mL) and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The organic phase was sequentially washed with water and saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the crude product was separated and purified by column chromatography (dichloromethane:methanol = 19:1) to obtain compound 26 (48 mg). HRMS: (ESI, [M+H] + ) m / z: 440.1872. 1H NMR (500 MHz, DMSO-d6) δ 12.78 (s, 1H), 7.80 (s, 1H), 6.77 (s, 1H), 6.12 (s, 1H), 4.35-4.26 (m, 1H), 3.95 (dd, J = 11.2, 3.1 Hz, 1H), 3.90 (d, J = 12.5 Hz, 1H), 3.74 (d, J = 11.3 Hz, 1H), 3.63 (dd, J = 11.3, 2.7 Hz, 1H), 3.48 (td, J = 11.7, 2.8 Hz, 1H), 3.41 (s, 6H), 3.12 (td, J = 12.7, 3.5 Hz, 1H), 1.64-1.58 (m, 1H), 1.17 (d, J = 6.7 Hz, 3H), 0.94-0.89 (m, 2H), 0.83-0.78 (m, 2H).

[0301] Example 27: Synthesis of Compound 27 [ka]

[0302] Step 1: Synthesis of Compound 27-1 Compound A1-4 (2 g), compound Q1 (5.19 g), and ethanol (30 mL) were mixed and reacted at room temperature for 1 hour. The reaction solution was concentrated, the residue was dissolved in ethyl acetate, washed sequentially with saturated sodium bicarbonate, water, and saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 27-1 (2.6 g). MS: (ESI, [M+H] + ) m / z: 390.24. 1 HNMR (500 MHz, DMSO-d6)δ 11.73 (s, 1H), 10.75 (s, 1H), 7.90 (s, 1H), 7.80 (s, 1H), 5.65 (d, J = 9.0 Hz, 1H), 1.83 (dq, J = 8.5, 5.1 Hz, 1H), 1.01-0.85 (m, 2H), 0.74-0.61 (m, 2H).

[0303] Step 2: Synthesis of Compound 27-2 Compound 27-1 (2.6 g) and N-methylpyrrolidone (20 mL) were mixed and heated to 200°C in a microwave oven, and the mixture was reacted for 20 minutes. Water was added to the reaction solution to precipitate the solid, which was then filtered, washed, and dried to obtain compound 27-2 (1.6 g). MS (ESI, [M+H] + ) m / z: 370.14. 1 HNMR (500 MHz, DMSO-d6)δ 12.82 (s, 1H), 8.24 (s, 1H), 7.67 (s, 1H), 6.34 (s, 1H), 2.01 (dt, J = 8.4, 4.6 Hz, 1H), 1.06-0.96 (m, 2H), 0.86-0.70 (m, 2H).

[0304] Step 3: Synthesis of Compound 27-3 Compound 27-2 (500 mg), (R)-3-methylmorpholine (274 mg), and dimethyl sulfoxide (5 mL) were mixed and heated to 120°C, where they were reacted for 1 hour. Water was added to the reaction mixture to precipitate the solid, which was then filtered, washed, and dried to obtain compound 27-3 (260 mg). MS (ESI, [M+H] + ) m / z: 451.28. 1HNMR (500 MHz, DMSO-d6)δ 12.59 (s, 1H), 7.80 (s, 1H), 7.26 (s, 1H), 6.40 (s, 1H), 4.43 (d, J = 5.0 Hz, 1H), 4.03 (d, J = 12.9 Hz, 1H), 3.95 (dd, J = 11.3, 3.0 Hz, 1H), 3.74 (d, J = 11.4 Hz, 1H), 3.63 (dd, J = 11.4, 2.7 Hz, 1H), 3.48 (td, J = 11.8, 2.7 Hz, 1H), 3.16 (td, J = 12.9, 3.4 Hz, 1H), 2.03-1.91 (m, 1H), 1.19 (d, J = 6.6 Hz, 3H), 0.98 (d, J = 6.5 Hz, 2H), 0.76 (d, J = 3.3 Hz, 2H).

[0305] Step 4: Synthesis of Compound 27 Compound 27-3 (260 mg), dimethyl sulfoximine (81 mg), tris(dibenzylideneacetone)dipalladium (26 mg), 4,5-bisdiphenylphosphin-9,9-dimethylxanthene (33 mg), cesium carbonate (376 mg), and 1,4-dioxane (7 mL) were mixed and reacted at 80°C for 1 hour under a nitrogen atmosphere. The reaction mixture was filtered, the filtrate was concentrated, and the crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 27 (80 mg). HRMS: (ESI, [M+H] + ) m / z: 416.1896. 1HNMR (500 MHz, DMSO-d6) δ 12.45 (s, 1H), 7.86 (s, 1H), 6.42 (s, 1H), 6.16 (s, 1H), 4.30 (d, J = 5.3 Hz, 1H), 3.99-3.86 (m, 2H), 3.75 (d, J = 11.3 Hz, 1H), 3.64 (dd, J = 11.3, 2.8 Hz, 1H), 3.49 (td, J = 11.8, 2.9 Hz, 1H), 3.41 (s, 6H), 3.12 (td, J = 12.7, 3.5 Hz, 1H), 2.00-1.90 (m, 1H), 1.17 (d, J = 6.7 Hz, 3H), 0.96 (d, J = 5.8 Hz, 2H), 0.74 (d, J = 3.4 Hz, 2H).

[0306] Example 28: Synthesis of Compound 28 [ka]

[0307] Step 1: Synthesis of Compound 28-1 Compound 26-5 (0.5 g), (N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxamide (63 mg), copper acetylacetonate (50 mg), lithium hydroxide (69 mg), dimethyl sulfoxide (10 mL), and water (3 mL) were mixed and heated to 140°C under a nitrogen atmosphere using a microwave, and reacted for 0.5 hours. Ethyl acetate was added to the reaction mixture, and the organic phase was sequentially washed with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, and the filtrate was concentrated. The crude compound was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 28-1 (400 mg). MS (ESI, [M+H] + ) m / z: 456.30.

[0308] Step 2: Synthesis of Compound 28-2 Compound 28-1 (0.4 g), potassium hydroxide (1 g), acetonitrile (10 mL), and water (10 mL) were mixed and cooled to -20°C. Under a nitrogen atmosphere, diethyl bromofluoromethylphosphonate (0.7 g) was added in portions, and the reaction mixture was stirred at -20°C for 30 minutes. Ethyl acetate was added to the reaction mixture, and the organic phase was sequentially washed with water and saturated brine. The mixture was concentrated, and the resulting crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 28-2 (330 mg). MS (ESI, [M+H] + ) m / z: 506.26.

[0309] Step 3: Synthesis of Compound 28-3 Compound 28-2 (330 mg) was dissolved in dichloromethane (5 mL), cooled to 0°C, and triethylsilane (0.8 g) and trifluoroacetic acid (9 mL) were added. The mixture was reacted at room temperature for 1 hour. The reaction solution was diluted with dichloromethane and adjusted to pH 8 with saturated sodium bicarbonate solution. The organic phase was sequentially washed with water and saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 28-3 (220 mg). MS (ESI, [M+H] + ) m / z: 376.05.

[0310] Step 4: Synthesis of Compound 28-4 Compound 28-3 (220 mg), 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (385 mg), cuprous iodide (165 mg), (1R,2R)-cyclohexane-1,2-diamine (198 mg), cesium carbonate (572 mg), and N-methylpyrrolidone (11 mL) were mixed and heated to 140°C by microwave and reacted for 0.5 hours. Ethyl acetate was added to the reaction mixture, and the organic phase was sequentially washed with 1 M aqueous ammonia solution, water, and saturated brine. The mixture was dried over anhydrous sodium sulfate, and the filtrate was concentrated. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 28-4 (200 mg). MS (ESI, [M+H] + ) m / z: 572.27.

[0311] Step 5: Synthesis of Compound 28 Compound 28-4 (200 mg) was dissolved in dichloromethane (3 mL), cooled to 0°C, and triethylsilane (405 mg) and trifluoroacetic acid (5 mL) were added. The mixture was reacted at room temperature for 1 hour. The reaction solution was diluted with dichloromethane (40 mL) and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The organic phase was sequentially washed with water and saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the crude product was separated and purified by column chromatography (dichloromethane:methanol = 18:1) to obtain compound 28 (120 mg). HRMS: (ESI, [M+H] + m / z: 442.1469. 1 HNMR (500 MHz, DMSO-d6) δ 12.74 (s, 1H), 7.80 (s, 1H), 7.49 (m, 1H), 6.75 (s, 1H), 6.15 (s, 1H), 4.39-4.27 (m, 1H), 4.01-3.87 (m, 2H), 3.75 (d, J = 11.3 Hz, 1H), 3.64 (dd, J = 11.4, 2.8 Hz, 1H), 3.49 (dd, J = 11.8, 2.9 Hz, 1H), 3.44 (s, 6H), 3.14 (td, J = 12.7, 3.7 Hz, 1H), 1.18 (d, J = 6.7 Hz, 3H).

[0312] Test Example 1: In vitro selection of ATR kinase inhibitory activity 50 ng / μL of ATR mother liquor was diluted with kinase buffer (50 mM HEPES, 10 mM MgCl2, 2 mM DTT, 1 mM EGTA, 0.01% Tween 20), and 6 μL / well of 0.0835 ng / μL of 1.67× working solution (final concentration 0.05 ng / μL) was added. Using a nanoliter pipette, various compounds dissolved in DMSO were added to the wells at a total of 7 concentrations with a 4x gradient, so that the final concentrations of the compounds ranged from 1000 nM to 0.24 nM, and the positive result ranged from 100 nM to 0.024 nM. At the same time, blank control wells (enzyme-free) and negative control wells (enzyme-containing, with DMSO solvent) were set up. After reacting the enzyme with the compound or solvent for 30 minutes, a 1:1 mixture of 50 μM 5× ATP (final concentration 10 μM) and 0.5 μM 5× substrate (final concentration 0.1 μM, U Light-poly GT), prepared in kinase buffer, was added to each well at a rate of 4 μL / well. After sealing the plate with a sealing membrane, it was incubated at room temperature for 2 hours. Next, 5 μL of 40 mM 4× EDTA (final concentration 10 mM) was added to each well, and it was incubated at room temperature for 5 minutes. Finally, 5 μL of 8 nM 4× detection reagent (final concentration 2 nM, Eμ-anti-phospho-tyrosine antibody) was added to each well, and it was incubated at room temperature for 1 hour. Plate reading was performed using a PE instrument (excitation: 320 or 340 nm, emission: 665 nm), and IC was obtained by 4-parameter fitting. 50 The following was calculated. The results are shown in Table 1, where A is IC. 50 Represents <50nM

[0313] [Table 1]

[0314] Test Example 2: Measurement of CHK1 phosphorylation inhibitory activity in TMD-8 cells TMD-8 cells in a good proliferative state were collected, gathered in a centrifuge tube, and the cell density was set to 1 × 10⁻⁶. 7The compound was adjusted to cells / mL, inoculated into a 384-well plate (4 μL / well), and added to two wells using a nanoliter pipette to achieve a final concentration of 1000 nM to 0.24 nM, while simultaneously setting up a control. After culturing in a cell incubator for 0.5 hours, 10 mM HU (4 μL / well) was added, and the cells were incubated at room temperature for 2 hours. Detection was performed using the p-CHK1 (Ser345) assay kit (manufacturer: perkinelmer) and the AlphaLISA program of the Envision plate reader. Four parameters were analyzed, and dose-response curves were fitted. IC50 was obtained. 50 The calculation revealed that the compound in the example had an inhibitory activity on CHK1 phosphorylation in TMD-8 cells. 50 It was shown to be <50 nM.

[0315] Test Example 3: Measurement of TMD-8 cell proliferation inhibitory activity TMD-8 cells in a good proliferative state were collected, returned to a centrifuge tube, and the cell density was set to 4 × 10⁶. 4 The compound was adjusted to 1 / mL and inoculated into a 96-well plate (100 μL / well). The cells were incubated overnight in a cell incubator. Using a nanoliter pipette, the compound was added to two wells to achieve a final concentration of 10,000 nM to 4.57 nM, while simultaneously setting up a control. After 72 hours of incubation in the cell incubator, detection reagent CCK-8 (manufacturer: Dojin Chemical, 10 μL / well) was added. After incubation in the cell incubator for 4 hours, the absorbance at 450 nM was measured using an Envision plate reader. Four parameters were analyzed, and the dose-response curve was fitted for IC50. 50 Calculate the result, which is shown in Table 2, where A is IC. 50 This indicates a value of ≤200 nM.

[0316] [Table 2]

[0317] Test Example 4: Measurement of liver microsome stability in vitro The final incubation system (200 μL) contained 20 μL of liver microsomes (protein concentration: 5 mg / mL), 20 μL of NADPH + MgCl2, 2 μL of substrate, and 158 μL of PBS buffer. However, the proportion of organic solvent was 1%. Two sets of 0.2 mL each were prepared for each species. A homogeneous mixture of substrate and enzyme was prepared in each tube, totaling 180 μL. After pre-incubating with NADPH for 5 minutes each, 20 μL of NADPH + MgCl2 was added and mixed. 50 μL was then withdrawn at 0, 15, and 60 minutes, and the reaction was stopped with ice acetonitrile containing an internal standard.

[0318] 50 μL of the incubated sample was aspirated, 300 μL of acetonitrile containing an internal standard was added to allow precipitation, and the mixture was vortex-shaked for 5 minutes, followed by centrifugation for 10 minutes (13000 rpm, 20°C). 80 μL of the supernatant was aspirated into a 96-well plate, diluted with 80 μL of ultrapure water, homogeneously mixed, and 1 μL of the sample was injected for LC-MS / MS analysis. The test results are shown in Table 3.

[0319] [Table 3]

[0320] Test Example 5: Pharmacokinetic Evaluation of Compounds in Mice ICR mice weighing 18-22g were allowed to acclimate for 3-5 days, then randomly divided into four groups of 9 mice each. The test compound was administered orally (IG) at a dose of 10 mg / kg and intravenously (IV) at a dose of 1 mg / kg to each group.

[0321] The test animals (ICR mice) were fasted for 12 hours before administration, fed 4 hours after administration, and given free access to water before, during, and after the experiment.

[0322] After forced oral administration, approximately 0.1 mL of orbital blood was collected at 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 24 hours, respectively. After intravenous administration, approximately 0.1 mL of orbital blood was collected at 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 24 hours, respectively. Blood was collected from 3 mice at 3 to 4 time points, and blood was collected from 3 mice at each time point. Whole blood was collected in EDTA-K2-containing centrifuge tubes and stored at 4°C. Plasma was centrifuged for 1 hour under conditions of 4°C and 4000 rp × 10 minutes. After collecting the total volume of plasma, it was immediately stored at -20°C until measurement.

[0323] 30 μL of the test plasma sample and calibration curve sample were aspirated, 300 μL of acetonitrile solution containing an internal standard (diazepam 20 ng / mL) was added, and the mixture was shaken for 5 minutes to ensure homogeneity. The mixture was then centrifuged at 13,000 rpm for 10 minutes, 80 μL of the supernatant was taken, diluted with 80 μL of ultrapure water, and mixed homogeneously. 2 μL was aspirated and used for liquid chromatography-mass spectrometry to calculate pharmacokinetic parameters. The test results are shown in Table 4.

[0324] [Table 4]

Claims

1. A compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (In the formula, 【Chemistry 2】 It is a double bond, and X is CR ａ Y is selected from N, Ra is hydrogen, hydroxyl, cyano, halogen, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Selected from alkylamino, C3-6 cycloalkyl, 3-6 membered monocyclic heterocycloalkyl, or C3-6 cycloalkyl-C2-4 alkynyl, provided that the C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkylamino, C3-6 cycloalkyl, 3-6 membered monocyclic heterocycloalkyl, and C3-6 cycloalkyl-C2-4 alkynyl may optionally be substituted with one or more halogen, hydroxyl, or cyano substituents. R 1 and R ２ are each independently selected from C1-6 alkyl, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 6 aryl or 5- to 6-membered heteroaryl, provided that said C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 6 aryl and 5- to 6-membered heteroaryl are optionally substituted with one or more R ｃ , which may be substituted with Or, R １ , R ２ These, together with the sulfur atoms to which they are bonded, form a 3-10 membered heterocycloalkyl group, and the 3-10 membered heterocycloalkyl group can optionally have one or more R ｄ It may also be replaced with Each R ｃ and R ｄ These are, independently, halogen, hydroxyl, amino, or C １－６ Selected from alkyl groups, R ３ This is any one or more R ｅ Selected from five-membered heteroaryls containing nitrogen as a heteroatom, which may be substituted with R ｅ is hydroxy, amino, halogen, C １－６ Alkyl, Halogen C １－３ Alkyl, C ３－６ Selected from cycloalkyl or 3-6 member heterocycloalkyl groups.

2. R ａ is hydrogen, halogen, C １－６ Alkyl, C １－６ Selected from alkoxy, C3-6 cycloalkyl, or C3-6 cycloalkyl-C2-4 alkynyl, provided that the C １－６ Alkyl, C １－６ The alkoxy, C3-6 cycloalkyl, and C3-6 cycloalkyl-C2-4 alkynyl may be optionally substituted with one or more halogens. Or, R ａ is hydrogen, hydroxyl, halogen or C １－６ Selected from alkyl, provided that C １－６ The alkyl group may be optionally substituted with one or more halogens. Or, R ａ is hydrogen, hydroxyl, halogen or C １－３ Selected from alkyl, provided that C １－３ The alkyl group may be optionally substituted with one or more halogens. Or, R ａ is hydrogen, halogen, C １－４ Alkyl, C １－４ Alkoxy, C ３－６ Cycloalkyl or C ３－６ Cycloalkyl-C ２－４ Selected from alkynyl, provided that C １－４ Alkyl, C １－４ Alkoxy, C ３－６ Cycloalkyl and C ３－６ Cycloalkyl-C ２－４ Alkynyl may be substituted with one or more halogens as desired. Or, R ａ is selected from hydrogen, bromo, methyl, n-propyl, isobutyl, tert-butyl, methoxy, cyclopropyl, or cyclopropylethynyl, wherein the methyl, n-propyl, isobutyl, tert-butyl, methoxy, cyclopropyl, and cyclopropylethynyl may be optionally substituted with one or more halogens. Or, R ａ This is selected from hydrogen, bromo, methyl, trifluoromethyl, 3,3,3-trifluoropropyl, isobutyl, tert-butyl, difluoromethoxy, cyclopropyl, or cyclopropylethynyl. Or, R ａ The compound according to claim 1, wherein is selected from hydrogen or bromo.

3. R1 and R ２ Each of them is independent of C １－４ Alkyl, C ３－６ Selected from cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl, provided that the C ３－６ Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl may be any one or more R ｃ It may also be replaced with Or, R １ and R ２ Each of these is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, thienyl, pyridyl, pyrimidinyl, or furyl, wherein cyclopropyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, thienyl, pyridyl, pyrimidinyl, or furyl may be any one or more R ｃ It may also be replaced with Or, R １ and R ２ Each of them is independent of C １－３ Alkyl, C ３－４ Selected from cycloalkyl, phenyl, or 5-6 member heteroaryl, provided that the C ３－４ Cycloalkyl, phenyl, or 5-6 member heteroaryl may be any one or more R ｃ It may also be replaced with Or, R １ and R ２ Each of these is independently selected from methyl, ethyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl, wherein cyclopropyl, cyclopentyl, cyclohexyl, phenyl, and pyridyl may be any one or more R ｃ It may also be replaced with Alternatively, R1 and R2 may each be independently methyl, ethyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, or 【Transformation 3】 Selected from, Or, R １ and R ２ The compound according to claim 1, wherein each is independently selected from methyl, ethyl, cyclopropyl, phenyl, or pyridyl.

4. Structural unit 【Chemistry 4】 Selected from, Alternatively, structural unit 【Transformation 5】 A compound according to claim 1, selected from the following.

5. Each R ｃ and R ｄ These are, independently, halogen, hydroxyl, amino, or C １－３ Selected from alkyl groups, Alternatively, each R ｃ and R ｄ Each of these is independently selected from fluoro, chloro, bromo, hydroxy, amino, methyl, ethyl, n-propyl, or isopropyl. Alternatively, each R ｃ and R ｄ These are, independently, halogen or C １－３ Selected from alkyl groups, Or, R ｃ is selected from halogen, hydroxyl, or amino, Or, R ｃ It is selected from fluoro, chloro, or bromo, Or, R ｃ It was selected from Bromo, Or, R ｄ is halogen, hydroxy, amino or C １－３ Selected from alkyl groups, Or, R ｄ C １－３ Selected from alkyl groups, Or, R ｄ It is selected from methyl, ethyl, n-propyl, or isopropyl. Or, R ｄ The compound according to claim 1, wherein is selected from methyl.

6. R １ , R ２ These, together with the sulfur atoms to which they are bonded, form a 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, or 10-membered heterocycloalkyl, and the heterocycloalkyl is optionally one or more R ｄ It may also be replaced with Or, R １ , R ２ These, together with the sulfur atoms to which they are bonded, form a 4-6 member monoheterocycloalkyl or a 7-10 member spiroheterocycloalkyl, and the monoheterocycloalkyl or spiroheterocycloalkyl can optionally have one or more R ｄ It may also be replaced with Alternatively, R １ , R ２ , together with the sulfur atom to which they are bonded, form a 4-membered, 5-membered or 6-membered monoheterocycloalkyl, or a 7-membered or 9-membered spiroheterocycloalkyl, and said monoheterocycloalkyl or spiroheterocycloalkyl is optionally substituted with one, two or three R ｄ , Or, R １ , R ２ Along with the sulfur atoms to which they are bonded, 【Transformation 6】 Forming, Or, R １ , R ２ Along with the sulfur atoms to which they are bonded, 【Transformation 7】 Forming, Alternatively, R １ , R ２ , together with the sulfur atom to which they are bonded, 【Transformation 8】 The compound according to claim 1, which forms a compound.

7. R3 is any one or more R ｅ Selected from pyrazolyl which may be substituted with, Or, R ３ R is arbitrarily one ｅ Selected from pyrazolyl which may be substituted with, Or, R ３ teeth, 【Chemistry 9】 Selected from, Or, R ３ teeth, 【Chemistry 10】 Selected from, Or, R ３ teeth, 【Chemistry 11】 Selected from, Or, R ３ teeth, 【Chemistry 12】 A compound according to claim 1, selected from the following.

8. R ｅ is hydroxy, amino, halogen, C １－３ Alkyl, Halogen C １－３ Alkyl, C ３－６ Selected from cycloalkyl or 3-6 member heterocycloalkyl, Or, R ｅ C １－３ Alkyl, Halogen C １－３ Alkyl or C ３－６ Selected from cycloalkyl groups, Or, R ｅ The compound according to claim 1, wherein is selected from methyl, trifluoromethyl, or cyclopropyl.

9. A compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is selected from the compounds of formula (II), 【Chemistry 13】 During the ceremony, R １ , R2 and R ｅ This is as defined in any one of claims 1, 3 to 6, or 8, n is selected from 0, 1, or 2, and is a compound of formula (I) according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

10. A compound selected from the compound of formula (I-a), the compound of formula (I-b), the compound of formula (II-a), or the compound of formula (II-b), their stereoisomers, or their pharmaceutically acceptable salts. 【Chemistry 14】 During the ceremony, X, Y, R １ , R ２ , R 3 and R ｅ This is as defined in any one of claims 2 to 8, n is selected from 0, 1, or 2, and is a compound of formula (I) according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

11. The following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof. 【Chemistry 15-1】 【Chemistry 15-2】

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

13. Use of a compound according to any one of claims 1 to 11, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, in the manufacture of a medicament for treating diseases and / or disorders related to or mediated by ATR, wherein the diseases and / or disorders related to or mediated by ATR are optionally selected from hyperproliferative diseases.

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