Spirocyclic MTA-cooperative PRMT5 inhibitors

Abstract

This invention relates to compounds used as MTA-cooperative inhibitors of the protein arginine N-methyltransferase 5 (PRMT5). More specifically, this invention relates to MTA-cooperative PRMT5 inhibitors comprising pharmaceutical compositions containing the compounds, and methods of using them.

Description

Detailed description of the invention

[0001] [Field of Invention] This invention relates to compounds used as MTA-cooperative inhibitors of the protein arginine N-methyltransferase 5 (PRMT5). More specifically, this invention relates to MTA-cooperative PRMT5 inhibitors comprising pharmaceutical compositions containing the compounds, and methods of using them.

[0002] [background] The protein arginine methyltransferase PRMT5 is essential for maintaining cellular homeostasis by regulating gene transcription, ribosome biosynthesis, mRNA splicing, protein translation, DNA damage response, and immune function (Musiani, D et al., Proteomics profiling of arginine methylation defines PRMT5 substrate specificity. Sci. Signaling 2019, 12 (575), eaat8388). PRMT5 is a type II arginine methyltransferase that symmetrically dimethylates histone and non-histone proteins. PRMT5 catalyzes the methyl transfer (ω-monomethylation) of the guanidino functional group of a protein L-arginine residue from S-adenosyl-L-methionine (SAM) to the ω nitrogen, and the methyl transfer of the second methyl group to the other ω nitrogen, yielding symmetric dimethylarginine (sDMA) (Gary, JD, and Clarke, S. Prog. Nucleic Acid Res. Mol. Biol 1998, RNA and protein interactions modulated by protein arginine methylation. 61, 65-131).

[0003] Because PRMT5 is involved in multiple functions, complete inactivation of PRMT5 is lethal in most cell lines. Therefore, PRMT5 is considered an essential gene for cell survival (McDonald, ER et al., Project DRIVE: A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncovered by Large-Scale, Deep RNAi Screening. Cell 2017, 170(3), 577-592). PRMT5 is an attractive drug target in the field of oncology. Several potent selective inhibitors targeting the catalytic pocket of PRMT5 have been developed. However, given the essential role of PRMT5 in normal tissue homeostasis, simply inhibiting PRMT5 may be toxic and result in a limited therapeutic range.

[0004] Methylthioadenosine (MTA) is an endogenous competitor of SAM and partially inhibits PRMT5 without inhibiting other PRMT family members. Studies have shown that MTA-mediated inhibition of PRMT5 reduces methylation activity and sensitizes cells to PRMT5 inhibitors. MTA is a substrate of methylthioadenosine phosphorylase (MTAP) and can be converted to 5-methylthioribose 1-phosphate (MTR-1-P) by MTAP. Therefore, MTA does not accumulate in wild-type cells to reduce PRMT5 activity. Conversely, cells with homozygous deletion of MTAP have reduced PRMT5 activity by accumulating MTA in the cells (Kryukov, GV et al., MTAP deletion confers enhanced dependency on the arginine methyltransferase PRMT5 in human cancer cells. Science 2016, 351(6278), 1214-1218). Therefore, inhibition of PRMT5-MTA cooperation selectively inhibits PRMT5 activity in cells with homozygous deletion of MTAP.

[0005] Homozygous deletion of MTAP is relatively common in cancer, occurring in approximately 15% of cases. Higher incidences were observed in gliablastoma, bladder cancer, non-small cell lung cancer, and pancreatic cancer. This loss is attributed to its proximity to the P16 / CDKN2A tumor suppressor locus. Homozygous deletion of p16 / CDKN2a is generally associated with co-deletions of adjacent genes such as MTAP (Mavrakis, KJ et al., Disordered methionine metabolism in MTAP / CDKN2A-deleted cancers leads to dependence on PRMT5. Science 2016, 351(6278), 1208-1213).

[0006] The inventors have found that MTA-mediated inhibition of PRMT5 activity in MTAP-deficient cancers yields therapeutic benefits for a wide range of cancers. Therefore, there is a need to develop novel MTA-mediated PRMT5 inhibitors capable of inhibiting PRMT5 activity in MTAP-deficient cells.

[0007] [Overview of the prefecture] The compounds of the present invention offer this therapeutic benefit as MTA-cooperative inhibitors of PRMT5 for negatively regulating the activity of MTA-binding PRMT5 in cells, particularly MTAP-deficient cells, or for treating various forms of MTAP-related cancers.

[0008] One aspect of the present invention provides a compound of formula (I) or any of the pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled thereof: [ka] (In the formula, ring A, ring B, Y, L, R 1 , R 2 , R 3 , R A , R B m, n, p, and q are defined as follows: Ring A is selected from 5- to 11-membered monocyclic or fused bicyclic aryl, and 5- to 11-membered monocyclic or fused bicyclic heteroaryl, Ring B is selected from 6-membered monocyclic heteroaryl, 8- to 11-membered fused bicyclic heteroaryl, 8- to 11-membered fused bicyclic heterocyclyl, 10- to 15-membered fused tricyclic heteroaryl and 10- to 15-membered fused tricyclic heterocyclyl, Y is O or S, L is #-C(=O)-NH-$, wherein # is [Chemical formula] attached to, and $ is attached to Ring B, R1 is C1-C5 alkyl or C1-C5 alkoxy optionally substituted with 1 to 3 groups selected from the following: deuterium, halogen, oxo, -CN, -OH, -NH2, C1-C6 alkyl optionally substituted with 1 to 3 R z , C1-C6 alkoxy optionally substituted with 1 to 3 R z , C1-C6 haloalkyl optionally substituted with 1 to 3 R z , C1-C6 haloalkoxy optionally substituted with 1 to 3 R z , C3-C6 cycloalkyl optionally substituted with 1 to 3 R z , -NH(C1-C6 alkyl) optionally substituted with 1 to 3 R z , -N(C1-C6 alkyl)(C1-C6 alkyl) optionally substituted with 1 to 3 R z , C3-C6 cycloalkyl optionally substituted with 1 to 3 R z , 5- to 15-membered monocyclic, fused bicyclic or fused tricyclic heterocyclic group optionally substituted with 1 to 3 R z , 5- to 15-membered monocyclic, fused bicyclic or fused tricyclic aryl optionally substituted with 1 to 3 R z , or 5- to 15-membered monocyclic, fused bicyclic or fused tricyclic heteroaryl, R2 and R3 are independently hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 alkoxy. R1, the nitrogen atom to which R1 is connected, the carbon atoms to which R2 and R3 are connected, and one atom of ring A form a ring group, and the ring group and ring A are connected in a manner that they share the one atom, forming a spiro ring structure. R A This includes deuterium, halogen, hydroxyl, oxo, cyano, nitro, amine, C1-C6 alkyl, cyanoC1-C6 alkyl, C1-C6 alkoxy, -C1-C6 alkyl-C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), C3-C6 cycloalkyl, C1-C6 haloalkyl, -O-(C1-C6 haloalkyl), -NH-(C1-C6 haloalkyl), -N(C1-C6 haloalkyl)(C1-C6 haloalkyl), pentafluorosulfur (-SF5), C1-C6 haloalkoxy or halocycloalkyl, -S(O)2-(C1-C6 alkyl), -S(=O)(C1-C6 alkyl)NR z -S(=O)(=NR z )(C1-C6 alkyl), -P(=O)(C1-C6 alkyl)2, 1-3 R z 4-8 member heterocyclines that are optionally replaced, and 1-3 R z 5-8 member heteroaryls, 1-3 R, which are optionally substituted. z 6-10 member aryls and 1-3 R are optionally substituted. z It is a C3-C6 cycloalkyl that is optionally substituted, or Two R atoms connected to the same carbon atom A It forms an oxo group, or Two R atoms connected to the same carbon atom A They form a C3-C8 cycloalkyl group together with the carbon atoms they are connected to. R Bis deuterium, halogen, hydroxyl, oxo, thioketone, cyano, nitro, amine, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -(C1-C6 alkyl)-OH, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy or C3-C8 halocycloalkyl, or Two R atoms connected to the same carbon atom B They either form a C3-C8 cycloalkyl or 6-7 membered heterocycline together with the carbon atoms they are connected to, or Two Rs connected to different carbon atoms B They are connected to form a 6-7 member ring. R z These are independently selected from deuterium, halogen, C1-C6 alkyl, -CN, -OH, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)(C1-C6 alkyl), (C1-C6 alkyl)C(O)NH-, (C1-C6 alkyl)C(O)-, phenyl, pentafluorosulfur, 5-6 membered heteroaryl or 4-6 membered heterocyclyl, or Two R atoms connected to the same carbon atom z It forms an oxo group, or Two R atoms connected to the same carbon atom z They form a C3-C8 cycloalkyl group together with the carbon atoms to which they are connected. m is either 1 or 2. n is either 0 or 1. p is 0, 1, 2, 3, or 4. (q is 0, 1, 2, 3, 4, or 5).

[0009] One aspect of the present invention provides a compound of formula (IC-1) or any of the pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled thereof: [ka] (In the formula, ring A, ring B, Y, L, R2, R3, R A , R B m, n, p, and q are defined as follows: Ring A is selected from 8-11 member fused bicyclic aryls and 8-11 member fused bicyclic heteroaryls. m is either 1 or 2. Ring B is selected from a 6-membered monocyclic heteroaryl, an 8-11-membered condensed bicyclic heteroaryl, an 8-11-membered condensed bicyclic heterocyclyl, a 10-15-membered condensed tricyclic heteroaryl, and a 10-15-membered condensed tricyclic heterocyclyl. Y is either O or S, L is #-C(=O)-NH-$, and in the formula, # is [ka] $ is connected to ring B, n is either 0 or 1. Each R2 and each R3 is independently hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 alkoxy. R A This includes deuterium, halogen, hydroxyl, oxo, cyano, nitro, amine, C1-C6 alkyl, cyanoC1-C6 alkyl, C1-C6 alkoxy, -C1-C6 alkyl-C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), C3-C6 cycloalkyl, C1-C6 haloalkyl, -O-(C1-C6 haloalkyl), -NH-(C1-C6 haloalkyl), -N(C1-C6 haloalkyl)(C1-C6 haloalkyl), pentafluorosulfur, C1-C6 haloalkoxy or C3-C6 halocycloalkyl, -S(O)2-(C1-C6 alkyl), -S(=O)(=NR z )(C1-C6 alkyl), -P(=O)(C1-C6 alkyl)2, 1-3 R z A 4- to 8-membered heterocyclic group is optionally substituted, along with 1 to 3 R groups. z A 5-8 member heteroaryl group is optionally substituted, and 1-3 R z6-10 membered aryl groups, 1-3 R groups, which are optionally substituted. z It is a C3-C6 cycloalkyl group that is optionally substituted, or Two R atoms bonded to the same carbon atom A It forms an oxo group, or Two R atoms connected to the same carbon atom A The carbon atoms to which they are connected form a C3-C8 cycloalkyl group. R B is deuterium, halogen, hydroxyl, oxo, thioketone, cyano, nitro, amine, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -(C1-C6 alkyl)-OH, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy or C3-C8 halocycloalkyl, or Two R atoms connected to the same carbon atom B The carbon atoms to which they are connected form a C3-C8 cycloalkyl group or a 6-7 membered heterocycline, or Two Rs connected to different carbon atoms B They are connected to form a 6-7 member ring. R z These are independently selected from deuterium, halogen, C1-C6 alkyl, -CN, -OH, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), (C1-C6 alkyl)C(O)NH-, (C1-C6 alkyl)C(O)-, phenyl, pentafluorosulfur, 5-6 membered heteroaryl or 4-6 membered heterocyclic groups, or Two R atoms connected to the same carbon atom z It forms an oxo group, or Two R atoms connected to the same carbon atom z The carbon atoms to which they are connected form a C3-C8 cycloalkyl group. p is 0, 1, 2, 3, or 4. (q is 0, 1, 2, 3, 4, or 5).

[0010] One aspect of the present invention provides a compound of formula (IC-2) or any of the pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled thereof: [ka] (In the formula, ring A, ring D, Y, Z3, Z4, Z5, Z6, R2, R3, R A , R B m, p, and q are defined as follows: Z3 and Z6 are N or CR e Therefore, Z4 and Z5 are N, NH, NR e or CR e And at least one of Z4 and Z5 is N or NH, [ka] It is either a single bond or a double bond, and the position of the double bond changes when Z4 or Z5 is N or NH. R e These are hydrogen, deuterium, halogen, hydroxyl, cyano, -NH2, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)(C1-C6 alkyl), Ring D is either a 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered aryl, or 5-6 membered heteroaryl condensed into a 10-membered ring, or is absent. m is either 1 or 2. Ring A is defined as described above, Y, R2, R3, R A , R B (P and q are defined as described above).

[0011] One aspect of the present invention provides a compound of formula (IC-3) or any of the pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled thereof: [ka] (In the formula, ring A, W4, W5, W6, Y, L, R2, R3, R A , R B m, p, and q are defined as follows: -W4-W5-W6- is (1)-CR f =N-NR f -, (2)-NR f -N=CR f -, (3)-CR f R g -O-CR f R g (4)-SN=NR f -, (5)-CR f =NS-, (6)-CR f R g -CR f R g -NR f -, and (7) non-existence, R f and R g These are independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or two R atoms connected to the same carbon atom. f and R g It forms an oxo group, or two R groups connected to the same carbon atom. f and R g These and the carbon atoms to which they are connected form a C3-C8 cycloalkyl group, or R f and R B These are connected to form a 6-7 member ring, m is either 1 or 2. Ring A is defined as described above, Y, L, R2, R3, R A , R B (P and q are defined as described above).

[0012] Another aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), formula (IC-1), formula (IC-2), or formula (IC-3) or any pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemic compound, prodrug, solvate, hydrate, or isotope-labeled thereof, and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition of the present invention is used as an MTA-cooperative PRMT5 inhibitor.

[0013] Another aspect of the present invention provides the use of a compound of formula (I), formula (IC-1), formula (IC-2), or formula (IC-3) or any pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemic compound, prodrug, solvate, hydrate, or isotope-labeled thereof in the manufacture of a drug or pharmaceutical for an MTA cooperative PRMT5 inhibitor.

[0014] Another aspect of the present invention provides a method for treating cancer, comprising administering a therapeutically effective amount of a compound of formula (I), formula (IC-1), formula (IC-2), or formula (IC-3), or any pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemic compound, prodrug, solvate, hydrate, or isotope-labeled thereof, to a subject in need of cancer treatment, such that cancer growth in the subject is inhibited. Another aspect of the present invention provides a compound of formula (I), formula (IC-1), formula (IC-2), or formula (IC-3), or any pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemic compound, prodrug, solvate, hydrate, or isotope-labeled thereof, for use in the treatment of cancer. Compounds of formula (I), formula (IC-1), formula (IC-2), or formula (IC-3), their pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or any of the aforementioned isotope-labeled compounds may be used alone or in combination with other therapeutic agents and / or treatment methods.

[0015] Another aspect of the present invention provides a method for preparing a compound of formula (I), formula (IC-1), formula (IC-2), or formula (IC-3), or any pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemic compound, prodrug, solvate, hydrate, or isotope-labeled thereof.

[0016] [Embodiment] The present invention can be easily understood by referring to the following detailed descriptions of various embodiments, examples, and tables of the invention in conjunction with their respective descriptions. Unless otherwise defined, all terms used herein (including technical and scientific terms) have the same meaning as generally understood by those skilled in the art to which the invention belongs. Terms such as those defined in commonly used dictionaries should be interpreted in accordance with their meaning in the context of the relevant art, and it should be understood that they should not be interpreted in an ideal or overly formal sense unless explicitly defined herein. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments and is not intended to limit them.

[0017] definition The definitions set forth in this section are intended to clarify the terms used throughout this application. The term "as used herein" means the entire application.

[0018] It should be noted that, as used herein, the singular forms "a," "an," and "the" include plural concepts unless specifically indicated by the context. Therefore, unless otherwise required by the context, singular forms shall include plural forms, and plural terms shall include singular forms.

[0019] Generally, in this specification, a range is expressed as a range from one specific value "about" to and / or another specific value "about". Where such a range is expressed, the embodiment includes a range from one specific value to and / or the other specific value. Similarly, where a value is expressed as an approximation by the use of the word "about", it will be understood that a specific value constitutes another embodiment. It will also be understood that each endpoint of the range is important, whether in relation to the other endpoint or independently thereof. Where used herein, the term "about" refers to ±20%, preferably ±10%, and more preferably ±5%.

[0020] As used herein, the phrase "optionally substituted" means that the substitution is optional. In events where substitution is desirable, such substitution means that any number of hydrogens on a given atom are replaced by an element of choice from the group shown, but not exceeding the normal valence of the given atom, and the substitution results in a stable compound. For example, if the substituent is keto (i.e., =O), two hydrogens on the atom are replaced. Examples of substituents for the "substituted" group can be found in the exemplary compounds and embodiments disclosed herein, and examples include, but are not limited to, halogens, cyano, alkyl, alkoxy, haloalkyl, alkylamino, aminoalkyl, dialkylamino, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, alkylaminoalkoxy, alkylaminoalkyl, and alkylaminoalkyl.

[0021] As used herein, the term "halogen" includes fluorine, chlorine, bromine, and iodine. When used as a prefix to a group, "halo" means that one or more hydrogen atoms on the group are replaced by one or more halogens.

[0022] As used in this invention, the term "alkyl" refers to a monovalent, saturated, linear, or branched saturated hydrocarbon group containing 1 to 12 carbon atoms. Preferably, the alkyl is a C1-C8 alkyl group. More preferably, the alkyl is a C1-C6 alkyl group. The alkyl may be substituted with or without one or more substituents. Examples of C1-C6 alkyl groups, but not limited to, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl (including all isomers), and hexyl (including all isomers), heptyl (including all isomers), octyl (including all isomers), etc.

[0023] Unless otherwise specified, the term "cycloalkyl" as used herein refers to a monovalent saturated hydrocarbon group having a cyclic structure comprising monocyclic, bicyclic, tricyclic, and higher-order polycyclic alkyl groups (and, in the case of polycyclic, condensed and bridging bicyclic and spirocyclic parts) having 3 to 12 carbon atoms in each cyclic part. Preferably, a cycloalkyl has 3 to 8 carbon atoms. More preferably, a cycloalkyl has 3 to 6 carbon atoms. If a cycloalkyl contains more than one ring, the ring may be condensed or uncondensed, and may contain a bicyclic group. A condensed ring generally refers to at least two rings sharing two atoms. Examples of such cycloalkyl groups include monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, and 2-methylcyclooctyl, or bicyclic, polycyclic, or bridging ring structures such as adamantyl.

[0024] Unless otherwise specified, the term "heterocyclyl" refers to a compound with one or more ring heteroatoms, such as one, two, three, or four, including: -O-, -S(O)x- (where x is 0, 1, or 2), -N=, and -N(R). y)-(wherein R is hydrogen, alkyl, hydroxyl, alkoxy, acyl, or alkylsulfonyl), means a monovalent, saturated or partially unsaturated monocyclic group of 3 to 9 ring atoms or a monovalent, saturated or partially unsaturated condensed bicyclic group of 5 to 12 ring atoms, independently selected from (wherein R is hydrogen, alkyl, hydroxyl, alkoxy, acyl, or alkylsulfonyl), with the remaining ring atoms being carbon. One or two ring carbon atoms may be replaced by -C(O)-, -C(S)-, or -C(=NH)- groups. Condensed bicyclic groups include bridging ring systems. Unless otherwise specified, the valence of a group may be on any atom of any ring in the group, as permitted by the valence rules. In detail, R y It is absent when the valence position is on the nitrogen atom. More specifically, the term “heterocyclyl” includes, but is not limited to, piperidinyl, pyrimidinyl, morpholinyl, piperazinyl, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, 4-piperidinol, 2-oxopiperazinyl, tetrahydropyranil, 2-oxopiperidinyl, thiomorpholinyl, perhydroazepinyl, pyrazolidinyl, dihydroimidazolyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazolidinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, tetrahydrofuranil and tetrahydropyranil, and their derivatives, or N-oxides or their protected derivatives.

[0025] As used herein, the term "ring" refers to "cycloalkyl," "aryl," "heteroaryl," and "heterocyclyl" compounds that do not exist in radical form.

[0026] Unless otherwise specified, the term "aryl" means a monovalent 6-14 member monocyclic or bicyclic ring, such as an 8-11 member monocyclic or bicyclic ring, in which at least one of the rings in the bicyclic ring is a carbon aromatic ring. Representative examples, but not limited to, include phenyl, biphenyl, naphthyl, and indenyl. In an aryl group containing a bicyclic ring, any non-aromatic ring contained therein may be a cycloalkyl or heterocyclic group as described above, insofar as the total number of ring atoms satisfies the definition of aryl as used herein. In one embodiment of the aryl group, the fused bicyclic ring comprises a cycloalkyl group and an aryl group, or the fused bicyclic ring comprises a heterocyclic ring and an aryl group, and one or two ring carbon atoms of the cycloalkyl or heterocyclic ring may be replaced by -C(O)-, -C(S)-, or -C(=NH)- groups, and the heteroalkyl groups are: -O-, -S(O)x- (where x is 0, 1, or 2), -N=, -N(R y )-(wherein, R y The group comprises one or two ring heteroatoms independently selected from hydrogen, alkyl, hydroxyl, alkoxy, acyl, or alkylsulfonyl, with the remaining ring atom being carbon. Condensed bicyclic groups include bridging ring systems. Unless otherwise specified, the valence may be located on any atom of any ring of the aryl group, insofar as the valence rules allow.

[0027] Unless otherwise specified, "heteroaryls" are: -O-, -S(O)n- (where n is 0, 1, or 2), -N-, -N(R x )-(R xis a monovalent monocyclic, fused bicyclic, or fused tricyclic group comprising 5 to 14 ring atoms, comprising one or more ring heteroatom moieties independently selected from (where is hydrogen, alkyl, hydroxyl, alkoxy, acyl, or alkylsulfonyl), with the remaining ring atoms being carbon, wherein at least one of the fused rings containing the bicyclic or tricyclic group is an aromatic ring containing a ring heteroatom. In a heteroaryl containing a bicyclic or tricyclic group, any non-aromatic ring contained therein may be a cycloalkyl or heterocyclic group as described above, insofar as the total number of ring atoms satisfies the definition of a heteroaryl as used herein. In one embodiment of the heteroaryl, the fused bicyclic ring comprises a cycloalkyl group and a heteroaryl group, or the fused bicyclic ring comprises a heterocyclic group and a heteroaryl group, where one or two ring carbon atoms of the cycloalkyl group or heterocyclic group may be replaced by -C(O)-, -C(S)-, or -C(=NH)- groups, and the heteroalkyl group is one of the following: -O-, -S(O)x- (where x is 0, 1, or 2), -N=, -N(R y )-(wherein, R yThe group comprises one or two ring heteroatoms independently selected from hydrogen, alkyl, hydroxyl, alkoxy, acyl, or alkylsulfonyl, with the remaining ring atom being carbon. Condensed bicyclic groups include bridging ring systems. Unless otherwise specified, the valence may be located on any atom of any ring of the heteroaryl group, insofar as the valence rules allow. In particular, if the valence is located on nitrogen, Rx is absent.More specifically, the term heteroaryl does not limit itself to benzocyclopentanil, 2,3-dihydrobenzofuranil, 2,3-dihydroflof[3,2-b]pyridine, 2,3-dihydroflof[3,2-c]pyridine, 6,7-dihydro-5H-cyclopenta[b]pyridine, chromanil, isochromanil, 3,4-dihydro-2H-pyrano[2,3-b]pyridine, 5,8-dihydro-6H-pyrano[3,4-b]pyridine, 1,3,4,5-tetrahydrobenzo[c]oxazepine, indanil, phthalyl, and indolinil. , 1,2,4-Triazolyl, 1,3,5-Triazolyl, Phthalimidyl, Pyridyl, Pyrrolyl, Imidazolyl, Thienyl, Furanyl, Indolyl, 2,3-Dihydro-1H-Indolyl (including, for example, 2,3-Dihydro-1H-Indole-2-yl or 2,3-Dihydro-1H-Indole-5-yl, etc.), Isoindolyl, Indolinyl, Isoindolinyl, Benzimidazolyl, Benzodioxol-4-yl, Benzofuranyl, Synnolinyl, Indolidinyl, Naphthyridine-3-yl, Phthalazine-3-yl, Phthalazi 4-yl, pyridinyl, prinyl, quinazolinyl, quinoxaline, tetrazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridadinyl, diazinyl, oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl (e.g., including tetrahydroisoquinoline-4-yl or tetrahydroisoquinoline-6-yl), pyrrolo[3,2-c]pyridinyl (e.g., pyrrolo[3,2-c]pyridinyl-2-yl or pyrrolo[3,2-c]pyridinyl-7-yl), Examples include benzopyranyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl, benzothienyl, tetrahydrophlopyridyl, pyridotetrahydrofuryl, tetrahydropyranopyridyl, pyridotetrahydropyranyl, tetrahydropyranofyridyl or chromanil, pyridineoxazolyl, oxazolopyridyl, pyridopyrrolyl, pyrrolopyridyl, diazolophenyl, benzodiazolyl, benzoxazolyl, oxazolophenyl, and their derivatives, or N-oxides or their protected derivatives.

[0028] As used herein, “pharmaceutically acceptable salt” refers to a derivative of a disclosed compound that is modified by producing a pharmaceutically acceptable acid or base salt of the parent compound. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Examples of pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, furic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, phenylglycolic acid, methanesulfonic acid, mucinic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, p-aminobenzenesulfonic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Non-limiting examples of salts of the compounds of the present invention include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethanesulfonate, phosphate, hydrogen phosphate, acetate, adipine, alginate, aspartate, benzoate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, glycerol phosphate, hemisulfate, enantate, caproate, formate, succinate, malonate, fumarate, maleate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, trimethylacetic acid, propionate, trichloroacetate, trifluoroacetate, glutamate, bicarbonate, undecanoate, lactate, citrate, tartrate, and gluconate (glucose sugar). Examples include salt, benzenesulfonate, and p-toluenesulfonate.

[0029] As used herein, the term “geometric isomers” includes, but is not limited to, cis and trans; E and Z isomers; c, t, and r isomers; internal and external; R, S, and meso; boat, chair, twist, envelope, and half-chair; and combinations thereof.

[0030] As used herein, the term “enantiomer” refers to a pair of stereoisomers that are mirror images of each other and cannot be superimposed. A 1:1 mixture of a pair of enantiomers is a racemic mixture. The term “enantiomer” is used, where appropriate, to refer to a racemic mixture. A “diastereomer” is a stereoisomer having at least two atoms that are asymmetric but not mirror images of each other. Absolute stereochemistry can be assigned according to the Cahn-Ingold-Prelog-RS system. If a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be denoted by R or S. A compound that has been optically resolved can be represented as (+) or (-) depending on the direction in which it rotates plane-polarized light at the wavelength of the sodium D line (dextrorotatory or levorotatory). Certain compounds described herein may contain one or more asymmetric centers or axes and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- from the point of absolute stereochemistry. The present invention means that it includes all possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or can be optically resolved using prior art. If the compound contains a double bond, the substituent may be in an E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans- configuration.

[0031] As used herein, “prodrug” is intended to include any covalent carrier that, upon administration to a subject, releases the active parent drug according to formula (I) through in vivo physiological actions such as hydrolysis and metabolism. The suitability and techniques involved in the preparation and use of prodrugs are well known to those skilled in the art. Prodrugs of compounds of formula (I) (parent compounds) can be prepared by modifying functional groups present in the compound such that the modified portion is cleaved by a predetermined treatment or in vivo to form the parent compound. “Prodrugs” include compounds of formula (I) in which a hydroxyl, amino, or sulfhydryl group is bonded to any group that, upon administration to a subject, is cleaved to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, derivatives and metabolites of compounds of formula (I) containing a biohydrolyzable moiety, such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. In certain embodiments, the prodrug of a compound of formula (I) having a carboxyl functional group is a lower alkyl (e.g., C1-C6) ester of a carboxylic acid. The carboxylic acid ester is conveniently formed by esterifying one of the carboxylic acid moieties present in the molecule.

[0032] The present invention also includes all pharmaceutically acceptable isotope-labeled compounds that are identical to those of the present invention, except that one or more atoms are replaced by atoms having the same atomic number but different atomic masses or mass numbers from those that are naturally dominant. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, hydrogen isotopes (e.g., deuterium (D, 2H), tritium (T, 3H)), carbon isotopes (e.g., 11C, 13C, and 14C), chlorine isotopes (e.g., 36Cl), fluorine isotopes (e.g., 18F), iodine isotopes (e.g., 123I and 125I), nitrogen isotopes (e.g., 13N and 15N), oxygen isotopes (e.g., 15O, 17O, and 18O), phosphorus isotopes (e.g., 32P), and sulfur isotopes (e.g., 35S). Certain isotope-labeled compounds of the present invention (e.g., those incorporating radioisotopes) can be used in drug and / or substrate tissue distribution studies (e.g., assays). For this purpose, the radioisotopes tritium (i.e., 3H) and carbon-14 (i.e., 14C) are particularly useful because they are easy to incorporate and detect. Substitution with positron-emitting isotopes such as 11C, 18F, 15O, and 13N can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. The isotope-labeled compounds of the present invention can be prepared by methods similar to those described in the attached scheme and / or examples and preparations, by using a suitable isotope-labeling reagent instead of a previously employed unlabeled reagent. Examples of pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be substituted with an isotope, such as D2O, acetone-d6, or DMSO-d6.

[0033] As used herein, the term “solvate” means a compound or a pharmaceutically acceptable salt thereof that further contains a stoichiometric or non-stoichiometric amount of solvent, which is bound by non-covalent intermolecular forces. If the solvent is water, the solvate may be appropriately called a “hydrate,” such as a hemihydrate, monohydrate, sesquihydrate, dihydrate, or trihydrate.

[0034] compound The present invention provides any of the compounds of formula (I) or pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled thereof: [ka] (In the formula, the base is defined as described above.) The present invention provides a compound of formula (IC-1) or any of the pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled thereof: [ka] (In the formula, the base is defined as described above.)

[0035] In one embodiment, in formula (I) or formula (IC-1), ring B is selected from 8-11 member condensed bicyclic heteroaryls and 10-15 member condensed tricyclic heteroaryls.

[0036] In one embodiment, in formula (I) or formula (IC-1), ring B is selected from 8-11 member condensed bicyclic heteroaryls and 8-11 member condensed bicyclic heterocyclines, preferably 8-11 member condensed bicyclic heteroaryls.

[0037] In one embodiment, in formula (I) or formula (IC-1), ring B is selected from 10-15 member condensed tricyclic heteroaryls and 10-15 member condensed tricyclic heterocyclines, preferably 10-15 member condensed tricyclic heteroaryls.

[0038] In the embodiments described above, n is 0 in formula (I) or formula (IC-1).

[0039] In the foregoing embodiment, in formula (I) or formula (IC-1), n is 1, preferably ring B is a 9 to 10-membered fused bicyclic heteroaryl, more preferably ring B is a 9-membered fused bicyclic heteroaryl.

[0040] In the foregoing embodiment, in formula (I) or formula (IC-1), n is 1, preferably ring B is a 10 to 15-membered fused tricyclic heteroaryl, more preferably ring B is a 12 to 13-membered fused tricyclic heteroaryl.

[0041] In the foregoing embodiment, in formula (I) or formula (IC-1), m is 1.

[0042] In the foregoing embodiment, in formula (I) or formula (IC-1), m is 0.

[0043] In the foregoing embodiment, in formula (I) or formula (IC-1), ring B is a 10 to 15-membered fused tricyclic heteroaryl, preferably ring B is a 12 to 13-membered fused tricyclic heteroaryl.

[0044] In the foregoing embodiment, in formula (I) or formula (IC-1), ring B is

Chemical Structure

[0045] In the foregoing embodiment, in formula (I) or formula (IC-1), ring B is

Chemical Structure

[0046] In the foregoing embodiment, in formula (I) or formula (IC-1), ring B is [[Chem.]] selected from the group consisting of, wherein the wavy line represents a point of attachment.

[0047] In the foregoing embodiment, in formula (I) or formula (IC-1), ring B is [[Chem.]] selected from JPEG2026530351000014.jpg125149.

[0048] In one embodiment, the present invention provides a compound of formula (IC-2), or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemate, prodrug, solvate, hydrate or any isotopically labeled form of the foregoing:[[-END]] [[Chem.]] (wherein the groups are as defined above).

[0049] In one embodiment, in formula (IC-2), one of Z3 and Z6 is N and the other is CR e , Z4 is N, NH or NR e , and Z5 is CR e .

[0050] In one embodiment, in formula (IC-2), Z3 and Z6 are each independently CR e , Z4 is N, NH or NR e , and Z5 is CR e . In one embodiment, in formula (IC-2), the moiety formed by ring D fused to a 10-membered ring is [[Chem.]] selected from the group consisting of, R B and p are as defined in the foregoing embodiment.

[0051] In one embodiment, ring D is absent in formula (IC-2).

[0052] In one embodiment, in formula (IC-2), the portion formed by the ring D fused with the 10-membered ring is [ka] Selected from JPEG2026530351000018.jpg65149.

[0053] In one embodiment, the present invention provides a compound of formula (IC-3) or any of the pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled thereof: [ka] (wherein the formula, the base is as defined in the embodiment described above).

[0054] In one embodiment, in formula (IC-3), the portion formed by -W4-W5-W6- condensed with pyridine is [ka] Selected from.

[0055] In the embodiments described above, in formula (I), formula (IC-1), formula (IC-2), or formula (IC-3), ring A is [ka] Selected from, In the formula, * indicates a connection point of the helical ring. R A And q are as defined in the embodiments described above.

[0056] In the embodiments described above, in formula (I), formula (IC-1), formula (IC-2), or formula (IC-3), (1) R1, the nitrogen atom to which R1 is connected, the carbon atoms to which R2 and R3 are connected, and one atom of ring A form a cyclic group, and this cyclic group and ring A are connected in a manner that they share an atom to form a spirocyclic structure, or (2) the carbon atoms to which R2 and R3 are connected, the adjacent nitrogen atom, the adjacent methylene group, and one atom of ring A form a cyclic group, and this cyclic group and ring A are connected in a manner that they share an atom to form a spirocyclic structure, and the spirocyclic structure is [ka] Select from JPEG2026530351000023.jpg191149, JPEG2026530351000024.jpg205149, JPEG2026530351000025.jpg193149, and JPEG2026530351000026.jpg183149.

[0057] In one embodiment, the compound of formula (I) is the compound of formula (IC-1), (IC-2), or (IC-3). In one embodiment, the compound of formula (I) is the compound of formula (IC-1). In one embodiment, the compound of formula (IC-1) is the compound of formula (IC-2). In one embodiment, the compound of formula (IC-1) is the compound of formula (IC-3) or any of the pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled versions thereof.

[0058] In another preferred embodiment, the present invention is [ka] JPEG2026530351000028.jpg225149JPEG2026530351000029.jpg225149JPEG2026 530351000030.jpg225149JPEG2026530351000031.jpg155149JPEG202653035100 0032.jpg225149JPEG2026530351000033.jpg225149JPEG2026530351000034.jpg 225149JPEG2026530351000035.jpg225149JPEG2026530351000036.jpg225149JP The present invention provides a compound selected from EG2026530351000037.jpg225149JPEG2026530351000038.jpg225149JPEG2026530351000039.jpg223149JPEG2026530351000040.jpg216149JPEG2026530351000041.jpg183149JPEG2026530351000042.jpg58149 or any of the aforementioned pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled compounds thereof.

[0059] Pharmaceutical compositions, uses, and methods The compounds or derivatives of the present invention (including any of the pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled versions thereof) can be administered therapeutically as chemical substances in their raw form, but it may be more beneficial to administer the compounds in the form of pharmaceutical compositions or formulations. Accordingly, the present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I), formula (IC-1), formula (IC-2), or formula (IC-3) or any of the pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled versions thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0060] Pharmaceutical compositions can be administered in a variety of dosage forms, including, but not limited to, solid, liquid, oral, parenteral, intranasal, suppository, lozenge, sugar-coated, oral, controlled-release, pulse-release, immediate-release, intravenous solution, suspension, or combinations thereof. Compounds can be administered via oral or parenteral routes, including, for example, intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, respiratory (aerosol), rectal, vaginal, and topical (including oral and sublingual) administration.

[0061] In one embodiment of the present invention, the compound or derivative of formula (I) is administered orally. When administered orally, the compound can generally be provided in a unit dosage form suitable for ingestion by the subject, such as tablets, pills, sugar-coated tablets, lozenges, capsules, powders, granules, aqueous solutions, suspensions, liquids, gels, syrups, and slurries. The dosage form can be a tablet or a controlled-release dosage form formulated as a tablet. Tablets for oral use may contain the active ingredient mixed with one or more pharmaceutically acceptable excipients.

[0062] "Excipients" generally refer to substances, often inert, that are added to a pharmacological composition or used as a vehicle to further assist in the administration of a compound. Examples of excipients include, but are not limited to, inert diluents, disintegrants, binders, lubricants, sweeteners, flavorings, colorants, preservatives, effervescent mixtures, and adsorbents. If necessary, tablets may be coated with materials that delay their absorption in the gastrointestinal tract. The composition may also be further formulated into chewable tablets.

[0063] The pharmaceutical compositions of the present invention for oral use can be obtained by mixing the compound of formula (I) with a solid excipient, grinding them, and then processing the mixture to produce tablets or capsules after adding, if necessary, appropriate additional (active) compounds. Suitable solid excipients include, but are not limited to, those previously mentioned, sugars including lactose, sucrose, mannitol, or sorbitol; starches derived from corn, wheat, rice, potato, or other plants; celluloses such as methylcellulose, hydroxypropyl methylcellulose, or sodium carboxymethylcellulose; gums including gum arabic and tragacanth gum; and proteins such as gelatin and collagen, comprising carbohydrate or protein fillers.

[0064] Examples of orally administered capsules include, but are not limited to, rigid gelatin capsules containing one or more active ingredients mixed with one or more solid diluents, and soft gelatin capsules containing one or more active ingredients mixed with water or oil (such as peanut oil, mineral oil, or olive oil). A suitable sugar coating may be applied to the tablet core. The concentrated sugar solution may optionally further include gum arabic, talc, polyvinylpyrrolidone, carbopol gel, poly(ethylene glycol) and / or titanium dioxide, lacquer solution, and a suitable organic solvent or solvent mixture. Pigments or colorants may be introduced into the tablet or sugar-coated core to identify or characterize differences (combinations) in the dosage of one or more active compounds.

[0065] The pharmaceutical composition may optionally further include a suitable solid or gel phase support. Examples of such supports include, but are not limited to, calcium carbonate, calcium phosphate, various types of sugars, starch, cellulose derivatives, gelatin, and polymers such as poly(ethylene glycol).

[0066] The compounds and pharmaceutical compositions of the present invention contain an active ingredient administered in a therapeutically effective dose to achieve the intended purpose. The term "therapeutic dose" refers to the amount of any of the compounds of formula (I), its pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled compounds thereof, either alone or in combination with ionizing radiation or anticancer agents, that, when administered to a subject in a single or multiple dose, produces the desired effect in the subject under treatment. The toxicity and therapeutic efficacy of such compounds are, for example, IC 50 The value can be determined by standard pharmacological methods using cell cultures or experimental animals. Where used herein, "IC" refers to the IC50. 50 " is the concentration of a drug that can produce 50% of the maximum inhibitory response.

[0067] The actual dose of the compound or derivative of formula (I) to be administered is determined by a physician under relevant circumstances, including the condition to be treated, the size and type of neoplasm or tumor, possible routes of administration, the specific compound of the present invention to be administered, the timing of administration of the Hedgehog route modulator for other treatments, the type, species, age, weight, sex and medical status of the subject, the renal and hepatic function of the subject, and the severity of the subject's symptoms. To achieve optimal precision in obtaining drug concentrations within the therapeutic range, a scheme based on the kinetics of drug availability to the target site is required. This scheme includes drug distribution, balance, and elimination. In some cases, dosage levels below the lowest end of the aforementioned range may exceed the sufficient amount, while in other cases, higher dosages may be employed.

[0068] The “substances” to be treated by the method of the present invention mean humans or non-human animals such as primates, mammals, and vertebrates.

[0069] "In vivo" means within a living subject, such as an animal or a human. In this context, drugs may be used therapeutically in vivo to slow or eliminate the proliferation of abnormally replicating cells. Drugs may also be used in vivo as prophylactic agents to prevent the manifestation of abnormal cell proliferation or associated symptoms.

[0070] "In vitro" means non-living subjects. Examples of in vitro cell populations include cell cultures and biological samples such as liquid or tissue samples from humans or animals. Such samples can be obtained by methods well known in the art. Exemplary biological liquid samples include blood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samples include tumors and their biopsies. Against this backdrop, the compounds of the present invention can be used in a variety of applications, both therapeutic and experimental.

[0071] "Cancer" refers to a cell proliferation disorder, and while not limited to these, it includes: cardiac cancers such as sarcomas (e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas, and teratomas; bronchial cancers (e.g., squamous cell carcinoma, anaplastic small cell carcinoma, anaplastic large cell carcinoma, and adenocarcinoma), and alveolar carcinomas (e.g., bronchoalveolar carcinoma). Lung cancers such as carcinoma, bronchial adenoma, sarcoma, lymphoma, chondrolytic hamartoma, and mesothelioma; esophageal cancers (e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma), gastric cancers (e.g., lymphoma and leiomyosarcoma), pancreatic cancers (e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid and vasoactive intestinal peptide tumors), small intestine cancers (e.g., adenocarcinoma, lymphoma, carcinoid, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma), and colorectal cancers (e.g., adenocarcinoma, ductal adenoma, chorioadenoma, Gastrointestinal cancers such as malocclusion and leiomyoma; kidney cancers (e.g., adenocarcinoma, Wilms' tumor [nephroblastoma], lymphoma, and leukemia), bladder and urethral cancers (e.g., squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma), prostate cancers (e.g., adenocarcinoma and sarcoma), testicular cancers (e.g., spermatocyte carcinoma, teratoma, embryonal tumor, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, and lipoma); liver cancers such as hepatocellular carcinoma (e.g., hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocyte adenoma and hemangioma; osteosarcoma (osteogenic Bone cancers such as sarcoma (e.g., osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (e.g., reticular sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (e.g., osteochondral exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; skull cancers (e.g., osteoma, hemangioma, granuloma, xanthomas, and osteitis malformations), meningocarcinomatosis (e.g., meningioma, meningiosarcoma, and polygliosis), brain tumors (e.g., astrocytoma, medulloblastoma, glioma, ependymoma, blastoma (pineal tumor), glioblastoma, oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors), spinal neurofibroma, meningioma, glioma, and sarcoma;Uterine cancer (e.g., endometrial cancer), cervical cancer (e.g., cervical cancer and precancerous cervical dysplasia), ovarian cancer (e.g., serous cystadenocarcinoma, mucinous cystadenocarcinoma, and carcinomas of unknown categories), theca granulosa cell tumor, Sertoli-Leydig cell tumor. Gynecological cancers such as tumors, undifferentiated germ cell tumors, and malignant teratomas, vulvar cancers (e.g., squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, and melanoma), vaginal cancers (e.g., clear cell carcinoma, squamous cell carcinoma, staphylosarcoma (e.g., fetal rhabdomyosarcoma), and fallopian tube cancer); hematological cancers such as myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myeloproliferative disorders, multiple myeloma, and myelodysplasia), Hodgkin's disease, and non-Hodgkin lymphoma (malignant lymphoma); skin cancers such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, and psoriasis; adrenal adenocarcinomas such as neuroblastoma; or breast cancer.

[0072] The present invention also relates to the use of any of the compounds of formula (I) or any pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled thereof for the manufacture of pharmaceuticals for modulating the hedgehog pathway.

[0073] Furthermore, the present invention relates to a method for treating cancer in subjects requiring treatment of cancer, comprising administering a compound of formula (I) or any of the aforementioned pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled compounds thereof.

[0074] The present invention also relates to any of the compounds of formula (I) or pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled versions thereof for use in the treatment of cancer.

[0075] The compound or derivative of formula (I) can be administered alone or in combination with other known cancer treatments.

[0076] The term "in combination with" means that the compound or derivative of formula (I) may be administered before, after, or concurrently with any one or more other antitumor therapies, or before, after, or concurrently with any combination of other antitumor therapies. Thus, the compound or derivative of formula (I) and a second anticancer agent may be administered as a single composition, simultaneously as two separate compositions, or sequentially as two separate compositions. Similarly, the compound or derivative of formula (I) and chemotherapy or ionizing radiation therapy may be administered simultaneously, separately, or sequentially. Those skilled in the art will understand that the amount of the compound of formula (I) administered in combination with an anticancer therapy is preferably sufficient to enhance the effect of the anticancer therapy or to induce apoptosis or cell death when used in combination with an anticancer therapy that maintains anti-angiogenic activity.

[0077] The term "second anticancer agent," as used herein, refers, unless otherwise specified, to an agent that can inhibit or prevent the growth of a neoplasm or tumor, or that can inhibit the maturation and proliferation of malignant (cancer) cells. Examples of second anticancer agents suitable for use in combination with compounds of formula (I) include, but are not limited to, trastuzumab, ramucirumab, bismodegib, sonidecib, bevacizumab, everolimus, tamoxifen, toremifene, fulvestrant, anastrozole, exemestane, lapatinib, letrozole, pertuzumab, and ad-trastuzumab emtansine. emtansine), palbociclib, cetuximab, panitumumab, div-aflibercept, regorafenib, imatinib mesylate, lanreotide acetate, sunitinib, regorafenib, denosumab, alitretinoin, sorafenib, pazopanib, temsirolimus, everolimus, tretinoin, dasatinib, nilotinib, bosutinib, li Targeted cancer drugs such as tuximab, alemtuzumab, ofatumumab, obinutuzumab, ibrutinib, idelalisib, blinatumomab, sorafenib, crizotinib, erlotinib, gefitinib, afatinib dimaleate, ceritinib, ramucirumab, nivolumab, pembrolizumab, osimertinib, and necitumumab; busulfan, chloramine Alkylating agents such as mubucil, cyclophosphamide, ifosfamide, melphalan, nitrogen mustard, streptozocin, thiotepa, uracil nitrogen mustard, triethylenemelamine, temozolomide, and 2-chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU); antibiotics or plant alkaloids such as actinomycin-D, bleomycin, cryptophycin, daunorubicin, doxorubicin, idarubicin, irinotecan, L-asparaginase, mitomycin-C, mitramycin, navelbine, paclitaxel, docetaxel, topotecan, vinblastine, vincristine, teniposide (VM-26), and etoposide (VP-16);5α-reductase inhibitors, aminoglutethimide, anastrozole, bicalutamide, chlorotrianicene, diethylstilbestrol (DES), dromostanolone, estramustine, ethinylestradiol, flutamide, fluoxymesterone, goserelin, hydroxyprogesterone, letrozole, leuprolide, medroxyprogesterone acetate, megestrol acetate, methylprednisolone, methyltestosterone, mitotane, nilutamide, prednisolone, aldoxifen (SERM-3), tamoxifen, testolactone, testosterone, triamcinolone, and hormones or steroids such as zoladex; all-trans retinoic acid, carmustine (BCNU), carboplatin (CBDCA), lomustine (CCNU), cis-diaminedichloroplatin (cisplatin), dacarbazine, gliadel, hexamethylmelamine, hydro Synthetic substances such as xyurea, levamisole, mitoxantrone, o,p'-dichlorodiphenyldichloroethane (o,p'-DDD) (also known as lysodrene or mitotane), oxaliplatin, porfimer sodium, procarbazine, and imatinib mesylate (Gleevec®); chlorodeoxyadenosine, cytosine arabinoside, 2'-deoxycoformycin, fludarabine phosphate, 5-fluoro Examples include antimetabolites such as racil (5-FU), 5-fluoro-2'-deoxyuridine (5-FUdR), gemcitabine, camptothecin, 6-mercaptopurine, methotrexate, and thioguanine; as well as biological agents such as alpha-interferon, BCG (Bacillus calmette-Guérin), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2, and Herceptin.

[0078] Unless otherwise indicated, as used herein, the term “to treat” means to reverse, alleviate, slow the progression of, or prevent the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. Unless otherwise indicated, as used herein, the term “treatment” means the act or action of “to treat” as defined above.

[0079] Compound synthesis The present invention also relates to processes for the preparation of any of the compounds of formula (I) or pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled thereof. The compounds of the present invention can be prepared by those skilled in the art using conventional organic synthesis methods and commercially available materials.

[0080] In one embodiment, the present invention relates to a method for preparing compounds of formula (I), formula (IC-1), formula (IC-2), formula (IC-3), or any pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled versions thereof. Examples of the preparation method include, but are not limited to, the procedures of the method shown in the examples described herein.

[0081] It should be understood that the examples used herein are for illustrative purposes only and are not intended to limit the scope of the invention. Those skilled in the art may modify the processes or steps of the following examples to obtain the desired product.

[0082] [Examples] Example 1 Synthesis of compound 084 [ka] To a solution of intermediate 84-10 (134 mg, 0.55 mmol) in acetonitrile (1.5 mL), 1-methylimidazole (109 mg, 1.32 mmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (93 mg, 0.33 mmol) were added, and the reaction solution was stirred at room temperature for 2 hours. Then, intermediate 84-11 (50 mg, 0.22 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with acetonitrile (5 mL) and filtered. The filtrate cake was washed with acetonitrile (1 mL), and the filtrate was concentrated. The crude product was purified by preparative HPLC (Waters-SunFire-C18-10μm-19*250mm, mobile phase: 0.1%NH3HCO3 / H2O B:CH3CN, 9 min) to obtain compound 084 (10.19 mg, 0.02 mmol, yield 10.26%) as a white solid. MS m / z (ESI): 452.2 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 8.72 (d, J = 1.6 Hz, 1H), 8.10 (s, 1H), 7.89-7.73 (m, 2H), 7.65-7.53 (m, 2H), 7.50 (s, 1H), 5.94 (s, 2H), 4.52 (s, 3H), 4.45 (s, 4H), 3.01 (s, 2H), 2.51 (t, J = 7.2 Hz, 2H)

[0083] Synthesis of intermediate 084-10 [ka] Step 1 To a solution of compound 84-1 (10.0 g, 49.96 mmol) in THF (100 mL), lithium diisopropylamide (25 mL, 50.0 mmol, 2.0 M) was added at -10°C. The reaction solution was stirred at -10°C for 20 minutes, and then diethoxyphosphorylformonitrile (8.96 g, 54.96 mmol) was added. After stirring at -10°C for 10 minutes, the reaction was quenched with H2O (300 mL) and extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine (300 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain intermediate 84-2 as a yellow solid.

[0084] Step 2 A solution of intermediate 84-2 (16.7 g, 48.09 mmol) in boron trifluoride-diethyl etherate complex (30 mL) was stirred at room temperature for 30 minutes. The reaction solution was quenched with saturated aqueous NH4Cl solution (100 mL) and extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain intermediate 84-3 (8.32 g, 39.78 mmol, yield 82.71%) as a yellow solid.

[0085] Step 3 A mixture of intermediate 84-3 (8.3 g, 39.68 mmol) and 10% Pd / C (800 mg) in THF (50 mL) was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction mixture was filtered, and the cake was washed with THF (10 mL). The filtrate was concentrated to obtain intermediate 84-4 (5.2 g, 24.62 mmol, yield 62.05%) as a red solid. The crude product was used directly in the next step.

[0086] Step 4 To a solution of intermediate 84-4 (1.5 g, 7.10 mmol) in THF (15 mL), lithium diisopropylamide (7.81 mL, 15.62 mmol, 2.0 M) was added dropwise under a nitrogen atmosphere at -78°C. The reaction solution was stirred at -78°C for 30 minutes, and then methyl cyanoformate (1.21 g, 14.21 mmol) was added. After stirring at -78°C for 3 hours, the reaction solution was quenched with saturated aqueous NH4Cl solution (30 mL) and extracted with ethyl acetate (30 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain intermediate 84-5 (800 mg, 2.82 mmol, yield 39.77%) as a red oil.

[0087] Step 5 To a solution of intermediate 84-5 (800 mg, 2.82 mmol) in THF (10 mL), LiAlH4 (214 mg, 5.65 mmol) was added at -40°C. The reaction solution was stirred at -40°C for 1.5 hours, then quenched with sodium sulfate and filtered. The cake was washed with ethyl acetate (10 mL). The filtrate was concentrated to obtain intermediate 84-6 (190 mg, 0.77 mmol, yield 27.43%) as a colorless oil. The crude product was used directly in the next step.

[0088] Step 6 A solution of intermediate 84-6 (190 mg, 0.77 mmol), Boc2O (338 mg, 1.55 mmol), and TEA (314 mg, 3.10 mmol) in CH2Cl2 (1 mL) was stirred at room temperature for 3 hours. The reaction solution was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain intermediate 84-7 (180 mg, 0.52 mmol, yield 67.28%) as a white solid.

[0089] Step 7 To a solution of intermediate 84-7 (160 mg, 0.46 mmol) in CH2Cl2 (2.0 mL), TsCl (177 mg, 0.93 mmol), TEA (70 mg, 0.69 mmol), and DMAP (5.7 mg, 0.05 mmol) were added at room temperature. The reaction solution was stirred at room temperature for 10 hours, then quenched with H2O (10 mL), and extracted with ethyl acetate (5 mL). The combined organic layer was washed with brine (10 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain intermediate 84-8 (200 mg, 0.40 mmol, yield 86.42%) as a yellow oil. The crude product was used directly in the next step.

[0090] Step 8 A solution of intermediate 84-8 (500 mg, 1.00 mmol) and NaH (90 mg, 1.50 mmol) in DMF (5 mL) was stirred at room temperature for 18 hours. The reaction solution was quenched with H2O (1 mL) at 0°C and concentrated. The crude product was purified by silica gel layer chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain intermediate 84-9 (300 mg, 0.92 mmol, yield 91.56%) as a white solid.

[0091] Step 9 A mixture of intermediate 84-9 (40 mg, 0.12 mmol) and trifluoroacetic acid (0.1 mL, 1.34 mmol) in dichloromethane (1 mL) was stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain intermediate 84-10 (8 mg, 0.12 mmol, 100% yield) as brown oil, and the crude product was used directly in the next step.

[0092] Synthesis of intermediates 84-11 [ka] Step 1 Under a nitrogen atmosphere, intermediates 84-12 (5 g, 21.73 mmol), bis(pinacolate)diborone (16.56 g, 65.2 mmol), potassium acetate (6.40 g, 65.2 mmol), and Pd(dppf)Cl2·CH2Cl2 (3.18 g, 4.35 mmol) in dimethyl sulfoxide (150 mL) were heated to 100 °C and stirred for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. Water (500 mL) was added to the filtrate and extracted with ethyl acetate (300 mL). The organic layers were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain intermediate 84-13 (5.9 g, 21.29 mmol, yield 97.96%) as a yellow solid.

[0093] Step 2 Under a nitrogen atmosphere, intermediates 84-13 (700 mg, 2.53 mmol), 84-14 (563.81 mg, 3.03 mmol), X-Phos Pd G3 (213.8 mg, 0.25 mmol), X-Phos (240.83 mg, 0.51 mmol), and potassium phosphate (1.072 g, 5.05 mmol) were heated to 100°C in dioxane (5 mL) and stirred for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. Water (20 mL) was added to the filtrate and extracted with ethyl acetate (30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain intermediate 84-15 (630 mg, 2.46 mmol, yield 97.33%) as a white solid.

[0094] Step 3 Intermediate 84-15 (90 mg, 0.35 mmol) and lithium hydroxide (133 mg, 3.51 mmol) were dissolved in a mixed solution of methanol (3 mL) and water (0.6 mL), heated to 60°C, and stirred for 16 hours. After the reaction was complete, the reaction solution was adjusted to pH=3 with 1.0 N hydrochloric acid aqueous solution to precipitate the solid. After filtration, the filtration cake was washed with water (3 mL). The solid was dried under reduced pressure to obtain intermediate 84-11 (54 mg, 0.22 mmol, yield 63.47%) as a white solid.

[0095] Example 2 Synthesis of compound 112 [ka] Step 1 In an ice bath, monoethyl oxalyl chloride (180 mg, 1.32 mmol) was added to a solution of intermediate 84-10 (250 mg, 1.10 mmol) and TEA (0.46 mL, 3.30 mmol) in dichloromethane (3 mL). The reaction solution was stirred at room temperature for 0.5 hours, quenched with water (10 mL), and then extracted with ethyl acetate (3 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Crude intermediate 112-1 (250 mg, 0.76 mmol, yield 69.43%) was obtained as yellow oil. The crude product was used directly in the next step.

[0096] Step 2 A solution of intermediate 112-1 (200 mg, 0.61 mmol) in THF (1 mL) and ammonia-methanol (1 mL, 7 M) was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain intermediate 112-2 (160 mg, 0.54 mmol, yield 87.79%) as a yellow solid.

[0097] Step 3 A mixture of intermediates 112-2 (131 mg, 0.44 mmol), 76-3 (100 mg, 0.44 mmol), copper powder (5.6 mg, 0.09 mmol), cuprous iodide (126 mg, 0.66 mmol), cesium carbonate (430 mg, 1.32 mmol), and N,N'-dimethylethylenediamine (116 mg, 1.32 mmol) in 1,4-dioxane (2 mL) was stirred at 100 °C for 10 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature and filtered. The filtrate was diluted with water (5 mL) and extracted with ethyl acetate (2 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by preparative HPLC (column: Waters-Xbridge-C18-10μm-19*250mm, mobile phase: A: 10mM NH4HCO3 / H2O B: ACN, 40%A~50%B: Ret 9.0 min) to obtain compound 112 as a white solid (19.28 mg, 0.04 mmol, yield 9.85%). MS m / z (ESI): 445.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 7.88 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.60 (s, 1H), 6.21 (s, 2H), 4.74-4.64 (m, 2H), 4.26 (s, 3H), 4.25-4.15 (m, 2H), 2.96 (t, J = 7.2 Hz, 2H), 2.46 (t, J = 7.2 Hz, 2H).

[0098] Synthesis of intermediate 76-3 [ka] Step 1 Compound 39-5 (4.0 g, 7.44 mmol) was added to a TFA (30 mL) solution and stirred overnight at 90°C. After the reaction was complete, the reaction solution was cooled to room temperature and then concentrated. The crude product was purified by preparative HPLC (Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: 0.1% FA / H2O B:CH3CN) to obtain intermediate 76-1 (1.4 g, 6.57 mmol, yield 88.3%) as a white solid.

[0099] Step 2 Intermediate 76-1 (1.0 g, 4.69 mmol) was added to a solution of (dimethylamino) dimethoxymethane (30 mL) under a nitrogen atmosphere and stirred overnight at 120 °C. After the reaction was complete, the reaction solution was cooled to room temperature and then concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain intermediate 76-2 (750 mg, 2.38 mmol, 50.71%) as a white solid.

[0100] Step 3 To a methanol / water (20 mL 1:1) solution of intermediate 76-2 (1.0 g, 3.54 mmol), sodium hydroxide (0.57 g, 14.18 mmol) was added and the mixture was stirred overnight at 120 °C. After the reaction was complete, the reaction solution was cooled to room temperature and then concentrated. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain intermediate 76-3 (500 mg, 1.86 mmol, yield 52.56%) as a white solid.

[0101] Example 3 Synthesis of compound 122 [ka] At room temperature, intermediate 122-9 (30 mg, 0.13 mmol) was added to acetonitrile (2 mL), followed by intermediate 84-11 (61 mg, 0.26 mmol), N-methylimidazole (31 mg, 0.39 mmol), and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (53 mg, 0.59 mmol). The resulting mixture was stirred for 2 hours and then filtered. The filtered cake was washed with water (5 mL), dried, and further purified by preparative HPLC (Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: A: 10 mM NH4HCO3; B: ACN, gradient: 40-50%, retention time: 8.5 min) to obtain compound 122 (6.30 mg, 0.01 mmol, yield 10.80%) as a white solid.

[0102] Synthesis of compound 122-9 [ka] Step 1 To a solution of intermediate 122-1 (100 g, 476 mmol) in THF (1000 mL), lithium diisopropylamide (25 mL, 50.0 mmol, 2.0 M) was added at -10°C. The reaction solution was stirred under a nitrogen atmosphere at -10°C for 20 minutes, and then diethoxyphosphorylformonitrile (85 g, 524 mmol) was added. After stirring at -10°C for 30 minutes, the reaction was quenched with ice water (1000 mL) and extracted with ethyl acetate (800 mL). The combined organic layers were washed with brine (1000 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain intermediate 122-2 (130.0 g, 364.15 mmol, yield 76.47%) as brown oil.

[0103] Step 2 Intermediate 122-2 (130 g, 364 mmol) was added to boron trifluoride-diethyl etherate solution (900 mL) at 0°C, and the solution was stirred at room temperature for 16 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution (800 mL) and extracted with ethyl acetate (800 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (800 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain intermediate 122-3 (63.5 g, 289.99 mmol, yield 80.38%) as a pale yellow solid.

[0104] Step 3 Intermediate 122-3 (63.5 g, 289.99 mmol) was added to ethanol (700 mL) at 0°C, followed by the addition of sodium borohydride (65.77 g, 1.74 mol), and the mixture was stirred at 80°C for half an hour. After the reaction was complete, the reaction solution was quenched with ice water (700 mL) and extracted with ethyl acetate (600 mL). The combined organic layers were washed with brine (800 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain intermediate 122-4 (54.0 g, 244 mmol, yield 84.4%) as brown oil.

[0105] Step 4 To a solution of intermediate 122-4 (54 g, 244 mmol) in THF (600 mL), lithium diisopropylamide (269 mL, 2.0 M, 538 mmol) was added at -78 °C, and the solution was stirred under a nitrogen atmosphere for 30 minutes. Then, ethyl cyanoformate (48.4 g, 489 mmol) was added, and the mixture was stirred for 3 hours. The reaction was quenched with saturated ammonium chloride solution (600 mL) and extracted with ethyl acetate (500 mL). The combined organic layers were washed with brine (800 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain intermediate 122-5 (42.0 g, 143.34 mmol, yield 56.66%) as brown oil.

[0106] Step 5 To a solution of intermediate 122-5 (42.0 g, 143 mmol) in THF (450 mL), lithium aluminum hydride (115 mL, 2.5 M, 287 mmol) was added at -40°C, and the solution was stirred for 1.5 hours. The reaction was quenched with water (300 mL), and the resulting mixture was stirred at 0°C for 30 minutes. Then, di-tert-butyl dicarbonate (62.5 g, 287 mmol) was added to the reaction solution at room temperature, and the mixture was stirred for 16 hours, followed by filtration. The filtrate was extracted with ethyl acetate (500 mL). The combined organic layers were washed with brine (800 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain intermediate 122-6 (15.0 g, 51.19 mmol, yield 29.53%) as a pale yellow solid.

[0107] Step 6 Intermediate 122-6 (15.0 g, 51.19 mmol) was added to THF (150 mL), and then TEA (8.5 g, 102 mmol), DMAP (6.2 g, 61.4 mmol), and TsCl (12.8 g, 81.9 mmol) were added sequentially at room temperature. The solution was stirred for 16 hours, then quenched with water (150 mL), followed by extraction with dichloromethane (150 mL). The combined organic layer was washed with brine (300 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain intermediate 122-7 (14.0 g, 27.50 mmol, yield 65.12%) as a white solid.

[0108] Step 7 To a solution of intermediate 122-7 (14.0 g, 27.50 mmol) in N,N-dimethylformamide (150 mL), sodium hydride (2.20 g, 55.00 mmol) was added at 0°C, and the solution was stirred for 2 hours. The reaction solution was quenched with ice water (250 mL) and extracted with ethyl acetate (150 mL). The organic layer was washed with brine (400 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain intermediate 122-8 (1.4 g, 4.15 mmol, yield 15.1%) as a white solid.

[0109] Step 8 Intermediate 122-8 (50 mg, 0.15 mmol) was mixed with dichloromethane (2 mL), followed by trifluoroacetic acid (0.2 mL). After stirring at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure, then diluted with water, adjusted to pH=8 with saturated sodium bicarbonate solution, and subsequently extracted with ethyl acetate (2 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain intermediate 122-9 (30 mg, 0.13 mmol, yield 85.71%) as a yellow solid.

[0110] Example 4 Synthesis of compound 123 [ka] Step 1 To a solution of intermediate 123-1a (500 mg, 2.32 mmol) and intermediate 123-1 (486 mg, 2.32 mmol) in tetrahydrofuran (8 mL), lithium bis(trimethylsilyl)amide (1.0 N in THF, 2.56 mL, 2.56 mmol) was added under a nitrogen atmosphere and cooled to -5°C. The reaction solution was stirred for 1 hour, then heated to room temperature and stirred for 1 hour. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain yellow oil. Intermediate 123-2 (300 mg, 0.74 mmol, yield 31.94%).

[0111] Step 2 To a methanol (5 mL) solution of intermediate 123-2 (300 mg, 0.74 mmol), wet 10% Pd / C (50 mg, 0.05 mmol) was added under a nitrogen atmosphere. The atmosphere was then replaced with a hydrogen atmosphere, and the mixture was stirred for 16 hours. After filtration, the filtrate was washed with methanol (2 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain intermediate 123-3 (120 mg, 0.35 mmol, yield 47.25%) as a yellow solid.

[0112] Step 3 To a solution of intermediate 123-3 (110 mg, 0.32 mmol) in dichloromethane (1 mL), trifluoroacetic acid (0.5 mL) was added at room temperature, and the solution was stirred for 3 hours. The reaction solution was then concentrated under reduced pressure. The resulting residue was added to saturated sodium bicarbonate aqueous solution (5 mL), stirred, and then extracted with dichloromethane (5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the yellow solid intermediate 123-4 (50 mg, 0.21 mmol, yield 64.24%).

[0113] Step 4 To a solution of intermediate 84-11 (90 mg, 0.37 mmol) in acetonitrile (1.5 mL), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (78 mg, 0.28 mmol) and N-methylimidazole (92 mg, 1.11 mmol) were added at room temperature under a nitrogen atmosphere. The solution was stirred for 30 minutes, followed by the addition of intermediate 123-4 (45 mg, 0.19 mmol), and the reaction solution was stirred for 16 hours. The mixture was diluted with acetonitrile (5 mL) and then filtered. After filtration, the filter cake was washed with acetonitrile (2 mL) and concentrated under reduced pressure. The obtained residue was purified by HPLC (waters-xbridge-C18-10μm-19*250mm, mobile phase: 0.1%NH4HCO3 / H2O B:CH3CN, gradient: 55%B~85%B, retention time 8.5 min) to obtain compound 123 (1.43 mg, 0.003 mmol, yield 1.65%) as a white solid. MS m / z (ESI): 467.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.26 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.89 (dd, J = 2.0, 8.8 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.28 (s, 2H), 7.07 (s, 1H), 4.87-4.57 (m, 2H), 4.42 (s, 3H), 4.41-4.22 (m, 2H).

[0114] Example 5 Synthesis of compound 131 [ka] Step 1 To a solution of intermediate 122-8 (150 mg, 0.44 mmol) in dioxane / water = 1:1 (10 mL), potassium ferrocyanide (749 mg, 1.77 mmol), Xphos G3 (75 mg, 0.09 mmol), and potassium acetate (87 mg, 0.89 mmol) were added under a nitrogen atmosphere at 100 °C, and the solution was stirred for 16 hours. The reaction solution was filtered, quenched with ice water (10 mL), and extracted three times with ethyl acetate (10 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain intermediate 131-1 (100 mg, 0.35 mmol, yield 79.30%) as a colorless oil.

[0115] Step 2 To a solution of intermediate 131-1 (100 mg, 0.35 mmol) in dichloromethane (5 mL), dioxane hydrogen chloride (3 mL) was added at room temperature, and the solution was stirred for 2 hours. The reaction solution was then concentrated under reduced pressure to obtain intermediate 131-2 (60 mg, 0.33 mmol, yield 98.61%), a white solid.

[0116] Step 3 To a solution of Intermediate 131-2 (30 mg, 0.16 mmol) in acetonitrile (1 mL), Intermediate 84-11 (98 mg, 0.41 mmol), N-methylimidazole (33 mg, 0.41 mmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (68 mg, 0.24 mmol) were added at room temperature, and the solution was stirred for 16 hours. The reaction solution was quenched with water (2 mL) and extracted with ethyl acetate (2 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the obtained residue was purified by preparative TLC (dichloromethane / methanol = 20 / 1), then by HPLC (column: Welch ultimate XB-NH2 250*50*10μm, mobile phase: [heptane-EtOH (0.1% NH3·H2O)]; B% 10%-10%, 10 min) to give Compound 131 (4.71 mg, 10 μmol, yield 7.08%) as a white solid. MS m / z (ESI): 409.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 2.0 Hz, 1H), 8.28 (s, 1H), 7.84 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.76-7.68 (m, 2H), 7.60 (d, J = 8.6 Hz, 1H), 7.24 (s, 2H), 4.64 (s, 2H), 4.44 (s, 3H), 4.24 (d, J = 28.0 Hz, 2H), 3.00-2.90 (m, 2H), 2.44 (t, J = 7.2 Hz, 2H).

[0117] Example 6 Synthesis of Compound 133

Chemical Structure

[0118] Step 2 To a solution of Intermediate 133-2 (80 mg, 0.20 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.2 mL) at room temperature, and the solution was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, then diluted with water, and adjusted to pH=8 with saturated sodium bicarbonate solution. After extraction with ethyl acetate (2 mL), the combined organic layers were washed with brine (6 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give Intermediate 133-3 (50 mg, 0.17 mmol, yield 84.75%) as a yellow solid.

[0119] Step 3 To a solution of intermediate 133-3 (50 mg, 0.17 mmol) in acetonitrile (2 mL), intermediate 84-11 (82.59 mg, 0.34 mmol), N-methylimidazole (41.98 mg, 0.51 mmol), and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (71.67 mg, 0.26 mmol) were added at room temperature, and the solution was stirred for 2 hours. The reaction solution was filtered, the filter cake was washed with water (2 mL), dried, and passed through a preparative HPLC (Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: A: 10 mM NH4HCO3; B: ACN, gradient: 40-50%, retention time: 8.5 min) to obtain compound 133 (21.03 mg, 0.04 mmol, yield 23.86%) as a white solid. MS m / z (ESI): 518.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.55 (d, J = 2.0 Hz, 1H), 8.47 (s, 1H), 8.27 (s, 1H), 7.97-7.80 (m, 1H), 7.71-7.55 (m, 4H), 7.29 (s, 2H), 4.71 (s, 2H), 4.43 (s, 3H), 4.34-4.14 (m, 2H), 2.97-2.86 (m, 2H), 2.44 (t, J = 7.2 Hz, 2H).

[0120] Example 7 Synthesis of compound 134 [ka] Step 1 Under a nitrogen atmosphere, intermediate 123-2 (3.3 g, 8.16 mmol) was added to methanol (50 mL) and cooled to 0°C. Lithium borohydride (267 mg, 12.24 mmol) was added in batches. The mixture was slowly heated to room temperature, the reaction solution was stirred for 20 minutes, then heated to 50°C in an oil bath and stirred for 16 hours. The reaction solution was then concentrated under reduced pressure, the resulting residue was washed with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain intermediate 134-1 (2 g, 5.31 mmol, yield 65.12%) as a yellow solid.

[0121] Step 2 To a methanol (25 mL) solution of intermediate 134-1 (1.9, 5.05 mmol), Pd / C (10% activated carbon mixture, 100 mg, 0.09 mmol) was added under a nitrogen atmosphere, and the atmosphere was then replaced with hydrogen three times. The mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. After the reaction was complete, the reaction solution was filtered, the solid was washed with methanol (2 mL), and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to obtain intermediate 134-2 (1.3 g, 3.75 mmol, yield 74.34%) as a white solid.

[0122] Step 3 Under a nitrogen atmosphere at -5°C, intermediate 134-2 (500 mg, 1.44 mmol) and cuprous iodide (550 mg, 2.89 mmol) were added to acetonitrile (8 mL), followed by the addition of isoamyl nitrite (203 mg, 1.73 mmol) to the solution, and the solution was stirred for 20 minutes. The temperature was raised to 80°C, and the solution was stirred for a further 16 hours. Once the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filtrate was washed with dichloromethane (2 mL), and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1), followed by HPLC (mobile phase: A: 10 mM NH4HCO3; B: ACN, gradient: 40-50%, retention time: 8 min) to obtain intermediate 134-3 (100 mg, 0.30 mmol, yield 21.03%) as a white solid.

[0123] Step 4 To a solution of intermediate 134-3 (100 mg, 0.30 mmol) in dichloromethane (0.5 mL), trifluoroacetic acid (0.5 mL, 6.71 mmol) was added at room temperature, and the solution was stirred for 3 hours. The reaction solution was diluted with dichloromethane (10 mL), and then concentrated under reduced pressure at 40°C to obtain intermediate 134-4 (70 mg, 0.31 mmol, 100% yield). The crude product was used directly in the next step.

[0124] Step 5 To a solution of intermediate 84-11 (148 mg, 0.61 mmol) in acetonitrile (2.5 mL), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (128 mg, 0.46 mmol) and N-methylimidazole (151 mg, 1.83 mmol) were added at room temperature, and the solution was stirred for 30 minutes. Then, intermediate 134-4 (70 mg, 0.31 mmol) was added, and the reaction solution was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with dimethyl sulfoxide (3 mL) and filtered. The filtered cake was washed twice with dimethyl sulfoxide (1 mL). The filtrate was purified by preparative HPLC (mobile phase: A: 10 mM NH4HCO3; B: ACN, gradient: 40-50%, retention time: 8.5 min) to obtain compound 134 (50.37 mg, 0.11 mmol, yield 36.37%) as a white solid. MS m / z (ESI): 454.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 2.0 Hz, 1H), 8.27 (d, J = 1.2 Hz, 1H), 7.87 (dd, J = 4.0, 8.4 Hz, 2H), 7.60 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.26 (s, 2H), 7.17 (d, J = 1.6 Hz, 1H), 4.90 (s, 2H), 4.74 (s, 2H), 4.43 (s, 1H), 4.42 (s, 3H), 4.32 (s, 1H).

[0125] Example 8 Synthesis of compound 135 [ka] Step 1 To a 10 mL (150 mg, 0.44 mmol) solution of intermediate 122-8 in a dioxane / water = 1:1 ratio, potassium ferrocyanide (749 mg, 1.77 mmol), Xphos G3 (75 mg, 0.09 mmol), and potassium acetate (87 mg, 0.89 mmol) were added under a nitrogen atmosphere at 100 °C, and the solution was stirred for 16 hours. The reaction solution was filtered, quenched with ice water (10 mL), and extracted three times with ethyl acetate (10 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain intermediate 135-1 (100 mg, 0.35 mmol, yield 79.30%) as a colorless oil.

[0126] Step 2 Intermediate 135-1 (100 mg, 0.35 mmol) was dissolved in dichloromethane (5 mL) and dioxane hydrogen chloride (3 mL) was added at room temperature. The solution was then stirred for 2 hours. The reaction solution was then concentrated under reduced pressure to obtain the white solid intermediate 135-2 (60 mg, 0.33 mmol, yield 98.61%).

[0127] Step 3 To a solution of intermediate 135-2 (25 mg, 0.14 mmol) in acetonitrile (1 mL), intermediate 135-3 (125.55 mg, 0.34 mmol), N-methylimidazole (27.85 mg, 0.34 mmol), and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (57.11 mg, 0.20 mmol) were added at room temperature, and the solution was stirred for 16 hours. The reaction solution was quenched with water (2 mL) and extracted with ethyl acetate (2 mL). The combined organic layers were washed with brine (4 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the resulting residue was purified by preparative TLC (dichloromethane / methanol = 20 / 1) to obtain intermediate 135-4 (16 mg, 0.02 mmol, yield 18.09%) as a white solid.

[0128] Step 4 To a solution of Intermediate 135-4 (16 mg, 0.03 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at 80° C., and the solution was stirred for 16 hours. The reaction solution was cooled to room temperature and concentrated. The crude product was purified by preparative HPLC (waters-xbridge-C18-10μm-19*250mm, mobile phase: 0.1% NH4HCO3 / H2O B: CH3CN, gradient: 55% B-85% B, retention time 6.8 min) to give compound 135 (1.0 mg, 2.49 μmol, yield 8.12%) as a white solid. MS m / z (ESI): 402.2 [M+H + ; 1 H NMR (400 MHz, methanol-d4) δ 7.96 (s, 1H), 7.80 (s, 1H), 7.72 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.60 (s, 1H), 4.83-4.76 (m, 2H), 4.36 (s, 3H), 4.28 (t, J = 10.4 Hz, 2H), 3.00 (t, J = 7.2 Hz, 2H), 2.52 (t, J = 7.2 Hz, 2H).

[0129] Synthesis of Intermediate 135-3

Chemical Formula

[0130] Step 2 A mixture of compound 135-5 (1.0 g, 2.14 mmol), diphenylamine (1.16 g, 6.42 mmol), X-PHOS (0.41 g, 0.86 mmol), XPhos Pd G3 (0.36 g, 0.43 mmol), and Cs2CO3 (1.39 g, 4.28 mmol) was dissolved in 1,4-dioxane (20 mL), degassed and purged three times with nitrogen, stirred at 110 °C for 2 hours, concentrated under reduced pressure, and purified by flash column chromatography (SiO2, PE:siRNA=3:1 elution) to obtain compound 135-6 (700 mg, 1.03 mmol, yield 48.35%) as a white solid.

[0131] Step 3 To a solution of compound 135-6 (1.0 g, 1.76 mmol) in MeOH (10 mL), NaOAc (0.36 g, 4.40 mmol) and NH2OH.HCl (0.24 g, 3.52 mmol) were added. The mixture was stirred overnight at room temperature, diluted with water (50 mL), and extracted with siRNA (50 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 135-7 (1.0 g) as a white solid, which can be used directly in the next step.

[0132] Step 4 To a solution of compound 135-7 (120 mg, 0.30 mmol) in DMF (5 mL), ethyl 2-chloro-2-oxoacetate (41 mg, 0.30 mmol) and DIEA (77 mg, 0.59 mmol) were added, and the solution was stirred at room temperature for 2 hours. The reaction solution was quenched with water (20 mL) and extracted with  (10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (eluting with SiO2, PE: = 3:1) to obtain compound 135-8 (100 mg, 0.16 mmol, yield 53.10%) as a yellow solid.

[0133] Step 5 To a solution of compound 135-8 (100 mg, 0.20 mmol) in MeOH (8 mL) and H2O (1 mL), NaOH (31.7 mg, 0.79 mmol) was added. The mixture was stirred overnight at room temperature. The reaction solution was concentrated and freeze-dried to obtain crude compound 135-3 (100 mg) as a white solid, which was used directly in subsequent steps without further purification.

[0134] Example 9 Synthesis of compound 136 [ka] To a solution of intermediate 136-1 (30 mg, 0.13 mmol) in N,N-dimethylformamide (2 mL), intermediate 84-10 (29.4 mg, 0.13 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (43.6 mg, 0.16 mmol), and N-methylimidazole (27.7 mg, 0.34 mmol) were added, and the mixture was stirred at room temperature for 17 hours. The mixture was extracted with ethyl acetate (30 mL) and washed three times with water (10 mL). The combined organic layers were dried over saturated sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by preparative HPLC (Waters-Xbridge-C18-10μm-19*250mm, mobile phase: A: 10mM NH4HCO3; B: ACN, gradient: 40-60%, retention time: 9.0 min) to obtain compound 136 (7.98 mg, 0.02 mmol, yield 13.96%) as a white solid. MS m / z (ESI): 441.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.10 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 5.2 Hz, 2H), 7.13 (s, 2H), 5.41 (t, J = 3.6 Hz, 2H), 5.04 (d, J = 3.6 Hz, 2H), 4.88-4.73 (m, 2H), 4.31-4.17 (m, 2H), 2.97 (t, J = 7.2 Hz, 2H), 2.46 (t, J = 7.2 Hz, 2H).

[0135] Synthesis of intermediate 136-1 [ka] Step 1 To a solution of intermediate 136-2 (3 g, 25.18 mmol) in tetrahydrofuran (24 mL), 4,4,5,5-tetramethyl-1,3,2-dioxaborane (4.83 g, 37.77 mmol) was slowly added under a nitrogen atmosphere, and the internal temperature was maintained below approximately 50°C. The reaction mixture was stirred at 50°C for 1 hour and then cooled to 25°C. To the cooled reaction solution, a THF solution (12 mL) of bis(pinacolate)diborone (6.39 g, 25.18 mmol), 4,4'-di-tert-butyl-2,2'-dipyridine (0.41 g, 1.51 mmol), and (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (0.49 g, 0.76 mmol) was added. The resulting solution was heated to 65°C and reacted for 3 hours, then cooled to 40°C, quenched with isopropanol (3 mL), and stirred at the same temperature for 20 minutes. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 2) to obtain intermediate 136-3 (4.5 g, 18.36 mmol, yield 72.91%) as a white solid.

[0136] Step 2 To a solution of intermediate 136-3 (2 g, 8.16 mmol) in tetrahydrofuran (24 mL), dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II) (0.31 g, 0.41 mmol) and intermediate 136-4 (2.16 g, 8.16 mmol) were added, and the mixture was reacted at 65°C for 2 hours under a nitrogen atmosphere. The reaction mixture was filtered, the filter cake was washed with tetrahydrofuran and methanol, and then dried under vacuum to obtain a pale yellow crude intermediate 136-5 (650 mg, 2.72 mmol, yield 33.28%).

[0137] Step 3 Sodium hydroxide (1.2 mL, 12.0 mmol, 10 mol / L) was added to a solution of intermediate 136-5 (600 mg, 2.83 mol) in water (12 mL). The resulting solution was stirred at 80°C for 16 hours. The mixture was washed with water, and the reaction solution was heated to 55°C. HCl (37 wt%, 1.2 mL) was added, and the temperature was maintained below approximately 60°C. The resulting slurry was allowed to stand at 55°C for approximately 0.5 hours, cooled to 20°C, and then allowed to stand for a further 1.0 hour. The resulting slurry was filtered, and the filtered cake was washed twice with water (15 mL) and twice with isopropyl alcohol (15 mL). The product cake was then concentrated under reduced pressure to obtain the white solid intermediate 136-1 (350 mg, 1.51 mmol, yield 53.54%).

[0138] Example 10 Synthesis of compound 137 [ka] Step 1 To a solution of intermediate 137-1 (1.0 g, 5.08 mmol) in dioxane (10 mL), bis(pinacolate)diborone (2.58 g, 10.15 mmol), potassium acetate (1.49 g, 15.23 mmol), and Pd(dppf)Cl2 (0.37 g, 0.51 mmol) were added. The reaction solution was stirred at 80°C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography (methanol / dichloromethane = 0-30%) to obtain intermediate 137-2 (1.10 g, 4.51 mmol, yield 88.79%) as a grayish-white solid.

[0139] Step 2 To a solution of intermediate 137-5 (300 mg, 1.13 mmol) in dioxane (10 mL) and water (2 mL), intermediate 137-2 (414.07 mg, 1.70 mmol), potassium phosphate (720 mg, 3.39 mmol), and XPhos Pd G3 (191.45 mmol, 0.23 mmol) were added at room temperature. The solution was then stirred under nitrogen at 90°C for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain crude intermediate 137-3, which was used directly in the subsequent steps without further purification.

[0140] Step 3 To a solution of intermediate 137-3 (230 mg, 1.09 mmol) in H2O (10 mL), NaOH (435 mg, 10.9 mmol) was added at room temperature. The mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. After the reaction was complete, the pH was adjusted to 6.0 using formic acid solution. A brown precipitate was obtained by acidification of the aqueous solution, which was collected by filtration. The collected precipitate was washed with water (10 mL) and then with ethyl acetate (10 mL), dried under vacuum, and the mixture was concentrated under reduced pressure to obtain crude intermediate 137-4, which was used directly in the subsequent steps without further purification.

[0141] Step 4 To a solution of intermediate 137-4 (101 mg, 0.44 mmol) in DMF (3 mL), N-methylimidazole (0.05 mL, 0.66 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (123 mg, 0.44 mmol), and intermediate 84-10 (50 mg, 0.22 mmol) were added. The mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: A: 10 mM NH4HCO3; B: ACN, gradient: 10%~10%, retention time: 10 min) to obtain compound 137 as a grayish-white solid. MS m / z (ESI): 440.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.85-7.80 (m, 2H), 7.79 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.60 (s, 1H), 7.59-7.54 (m, 1H), 6.79 (s, 2H), 5.37 (t, J = 3.6 Hz, 2H), 5.01 (t, J = 3.6 Hz, 2H), 4.55 (s, 2H), 4.31-4.16 (m, 2H), 2.95 (s, 2H), 2.43 (t, J = 7.2 Hz, 2H).

[0142] Example 11 Synthesis of compound 139 [ka] Step 1 To a solution of intermediate 122-8 (250 mg, 0.75 mmol) in 4-dioxane (10 mL) and water (2.5 mL), intermediate 139-1 (194.35 mg, 0.75 mmol), potassium carbonate (307.13 mg, 2.25 mmol), and Pd(PPh3)4 (85.73 mg, 0.08 mmol) were added. The mixture was stirred at 80°C for 3 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, diluted with water (10 mL), and extracted three times with ethyl acetate (10 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain intermediate 139-2 (200 mg, 0.51 mmol, yield 68.72%) as a white solid.

[0143] Step 2 To a solution of intermediate 139-2 (200 mg, 0.51 mmol) in dichloromethane (5 mL), trifluoroacetic acid (0.5 mL) was added. The reaction solution was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, diluted with water, and adjusted to pH=8 with saturated sodium bicarbonate solution. It was then extracted three times with ethyl acetate (5 mL). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain intermediate 139-3 (130 mg, 0.44 mmol, yield 87.25%) as a yellow solid. The crude product was used directly in subsequent steps.

[0144] Step 3 Under ice bath conditions, monoethyl oxalyl chloride (90.51 mg, 0.66 mmol) was added to a solution of intermediate 139-3 (130 mg, 0.44 mmol) and triethylamine (89.62 mg, 0.88 mmol) in dichloromethane (4 mL). The reaction solution was stirred at room temperature for 0.5 hours, then quenched with water (5 mL), and extracted three times with ethyl acetate (5 mL). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain intermediate 139-4 (130 mg, 0.33 mmol, yield 74.71%) as a yellow solid.

[0145] Step 4 Intermediate 139-4 (130 mg, 0.33 mmol) was stirred in an ammonia-methanol (1 mL, 7 M) solution at 70°C for 3 hours. The reaction solution was concentrated under reduced pressure. Crude intermediate 139-5 (120 mg, 0.36 mmol, 99.40% yield) was obtained as a yellow solid and used directly in the subsequent steps.

[0146] Step 5 A mixture of intermediates 139-5 (120 mg, 0.36 mmol), 76-3 (89.74 mg, 0.43 mmol), copper powder (25.12 mg, 0.43 mmol), cuprous iodide (125.46 mg, 0.72 mmol), cesium carbonate (321.95 mg, 1.08 mmol), and N,N'-dimethylethylenediamine (58.07 mg, 0.72 mmol) in 1,4-dioxane (2 mL) was stirred at 95°C for 16 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, diluted with water (6 mL), and extracted three times with ethyl acetate (5 mL). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by column chromatography (dichloromethane / methanol = 10 / 1), followed by preparative HPLC (Waters-Xbridge-C18-10μm-19*250mm, mobile phase: A: 10mM NH4HCO3; B: ACN (gradient: 40-50%, retention time: 8.5 min) to obtain compound 139 (34.58 mg, 0.07 mmol, yield 20.58%) as a white solid. MS m / z (ESI): 511.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.98 (s, 1H), 8.47 (s, 1H), 7.89 (s, 1H), 7.81-7.55 (m, 4H), 6.25 (s, 2H), 4.68 (q, J = 10.4 Hz, 2H), 4.27 (s, 3H), 4.25-4.13 (m, 2H), 2.92 (t, J = 7.2 Hz, 2H), 2.44 (t, J = 6.8 Hz, 2H).

[0147] Example 12 Synthesis of compound 140 [ka] Step 1 To a solution of intermediate 134-4 (101 mg, 0.44 mmol) in acetonitrile (2.5 mL), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (184 mg, 0.65 mmol) and N-methylimidazole (83 mg, 2.62 mmol) were added, and the solution was stirred at room temperature for 30 minutes, followed by the addition of intermediate 136-1 (100 mg, 0.31 mmol). The reaction solution was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with dimethyl sulfoxide (3 mL) and filtered. The solid was washed twice with dimethyl sulfoxide (1 mL). The filtrate was purified by preparative HPLC (mobile phase: A: 10 mM NH4HCO3; B: ACN, gradient: 40-50%, retention time: 8.5 min) to obtain compound 140 (64.5 mg, 0.15 mmol, yield 33.42%) as a white solid. MS m / z (ESI): 443.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 0.8 Hz, 1H), 8.10 (d, J = 0.8 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H),7.30 (dd, J = 1.6, 8.0 Hz, 1H), 7.23-7.09 (m, 3H), 5.41 (t, J = 3.6 Hz, 2H), 5.05 (t, J = 3.6 Hz, 2H), 4.97 (d, J= 10.4 Hz, 1H), 4.89 (d, J = 10.4 Hz, 3H), 4.40 (d, J = 10.4 Hz, 1H), 4.29 (d, J = 10.4 Hz, 1H).

[0148] Example 13 Synthesis of compound 146 [ka] Step 1 To a solution of intermediate 137-4 (148 mg, 0.61 mmol) in acetonitrile (2.5 mL), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (184 mg, 0.65 mmol) and N-methylimidazole (83 mg, 2.62 mmol) were added, and the solution was stirred at room temperature for 30 minutes, followed by the addition of intermediate 134-4 (100 mg, 0.31 mmol). The reaction solution was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with dimethyl sulfoxide (3 mL) and filtered. The solid was washed twice with dimethyl sulfoxide (1 mL). The filtrate was purified by preparative HPLC (mobile phase: A: 10 mM NH4HCO3; B: ACN, gradient: 40-50%, retention time: 8.5 min) to obtain compound 146 (32.23 mg, 0.07 mmol, yield 16.74%) as a white solid. MS m / z (ESI): 442.1[M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.91-7.77 (m, 3H), 7.57 (d, J = 9.6 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.16 (s, 1H), 6.80 (s, 2H), 5.37 (s, 2H), 5.01 (s, 2H), 4.87 (s, 2H), 4.66 (s, 2H), 4.43-4.22 (m, 2H).

[0149] Example 14 Synthesis of compound 149 [ka] Step 1 To a solution of intermediate 149-1 (50 mg, 0.22 mmol) in acetonitrile (2 mL), intermediate 84-10 (243 mg, 0.88 mmol), N-methylimidazole (126 mg, 1.54 mmol), and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (92 mg, 0.33 mmol) were added at room temperature, and the solution was stirred for 10 hours. After the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted three times with ethyl acetate (5 mL). The organic layers were combined, washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the resulting residue was purified by preparative HPLC (Waters-Xbridge-C18-10μm-19*250mm, mobile phase: A: 10mM NH4HCO3; B: ACN, gradient: 5-61%, retention time: 9.5 min) to obtain compound 149 (26.72 mg, 0.05 mmol, yield 24.99%). MS m / z (ESI): 486.0, 488.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 2H), 7.79 (d, J = 8.0 Hz, 1H), 7.66 ( d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.59 (s, 1H), 7.32 (s, 2H), 4.42 (s, 3H), 4.30 (d, J = 10.0 Hz, 1H), 4.21 (d, J = 10.0 Hz, 1H), 4.15 (d, J = 8.8 Hz, 1H), 4.07 (d, J = 8.8 Hz, 1H), 3.01-2.87 (m, 2H), 2.49-2.35 (m, 2H).

[0150] Example 15 Synthesis of compound 155 [ka] Step 1 Intermediate 122-8 (200 mg, 0.59 mmol), bis(pinacolate)diborone (180 mg, 0.71 mmol), potassium acetate (116 mg, 1.18 mmol), and Pd(dppf)Cl2 (43 mg, 0.06 mmol) in a dimethyl sulfoxide solution (3 mL) were stirred at 80°C for 16 hours under a nitrogen atmosphere. The reaction solution was diluted with water (5 mL) and extracted three times with ethyl acetate (5 mL). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain intermediate 155-1 (200 mg, 0.52 mmol, yield 51.95%) as a yellow oil.

[0151] Step 2 To a solution of intermediate 155-1 (200 mg, 0.52 mmol) in tetrahydrofuran (4 mL) and water (1 mL), sodium carbonate (275 mg, 2.60 mmol) and 30% hydrogen peroxide solution (1 mL) were added. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was quenched with saturated sodium thiosulfate solution (5 mL) and extracted three times with ethyl acetate (5 mL). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain intermediate 155-2 (100 mg, 0.36 mmol, yield 70.42%) as a white solid.

[0152] Step 3 To a solution of intermediate 155-2 (100 mg, 0.36 mmol) in N,N-dimethylformamide (3 mL), potassium carbonate (150 mg, 1.08 mmol) and methyl iodide (103 mg, 0.72 mmol) were added. The reaction solution was stirred at room temperature for 16 hours. The reaction solution was quenched with water (5 mL) and extracted three times with ethyl acetate (5 mL). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain intermediate 155-3 (60 mg, 0.21 mmol, yield 57.14%) as a yellow solid.

[0153] Step 4 To a solution of intermediate 155-3 (60 mg, 0.21 mmol) in dichloromethane (2 mL), trifluoroacetic acid (0.2 mL) was added. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with water, and adjusted to pH=8 with saturated sodium bicarbonate solution. It was then extracted three times with ethyl acetate (2 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain crude intermediate 155-4 (35 mg, 0.19 mmol, yield 89.74%) as a yellow solid. The crude product was used directly in subsequent steps.

[0154] Step 5 To a solution of intermediate 155-4 (30 mg, 0.19 mmol) in acetonitrile (2 mL), intermediate 88-11 (77 mg, 0.38 mmol), N-methylimidazole (39 mg, 0.57 mmol), and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (67 mg, 0.29 mmol) were added sequentially at room temperature. The reaction solution was stirred at room temperature for 2 hours. The mixture was filtered, the solid was washed twice with water (5 mL), dried, and then passed through a preparative HPLC (Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: A: 10 mM NH4HCO3; B: ACN, gradient: 5-61%, retention time: 9.5 min) to obtain compound 155 (4.13 mg, 0.01 mmol, yield 6.30%) as a white solid. MS m / z (ESI): 414.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 2.0 Hz, 1H), 8.26 (s, 1H), 7.86 (dd, J = 8.8, 2.0 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.23 (s, 2H), 6.88-6.77 (m, 2H), 4.57 (d, J = 14.0 Hz, 2H), 4.42 (s, 3H), 4.20 (d, J = 29.2 Hz, 2H), 3.73 (s, 3H), 2.85 (t, J = 7.2 Hz, 2H), 2.39 (t, J = 7.2 Hz, 2H).

[0155] Example 16 Synthesis of compound 160 [ka] Step 1 To a solution of intermediate 135-2 (40 mg, 0.22 mmol) in acetonitrile (2 mL), intermediate 137-4 (100 mg, 0.44 mmol), N-methylimidazole (53 mg, 0.66 mmol), and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (91 mg, 0.33 mmol) were added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with water (4 mL), and extracted three times with ethyl acetate (5 mL). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by preparative HPLC (Waters-Xbridge-C18-10μm-19*250mm, mobile phase: A: 10mM NH4HCO3; B: ACN, gradient: 5-61%, retention time: 9.5 min) to obtain compound 160 (2.37 mg, 6.00 μmol, yield 2.80%) as a white solid. MS m / z (ESI): 397.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.83-7.68 (m,5H), 7.56 (m, 1H), 6.77 (s, 2H), 5.37 (t, J = 3.6 Hz,2H), 5.01 (t, J = 3.6 Hz, 2H), 4.54 (s, 2H), 4.32-4.05 (m, 2H), 3.00-2.87 (m, 2H), 2.42 (t, J = 7.2 Hz, 2H).

[0156] Example 17 Synthesis of compound 163 [ka] Step 1 To a solution of intermediate 163-1 (20 g, 105.26 mmol) in dibromomethane (150 mL), potassium hydrogen phosphate (55 g, 315.8 mmol) and palladium acetate (2.4 g, 10.52 mmol) were added under a nitrogen atmosphere at room temperature. The reaction solution was stirred at 130 °C for 5 days. The reaction solution was filtered, and the filtrate was concentrated. The crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 10 / 1) to obtain intermediate 163-2 (6.5 g, 32.13 mmol, yield 24.46%).

[0157] Step 2 To a solution of intermediate 163-2 (13 g, 64.32 mmol) in dichloromethane (130 mL), diisobutylaluminum hydride (70 mL, 1 N, 70 mmol) was added under a nitrogen atmosphere at -78°C and the mixture was stirred at -78°C for 2 hours. Water (250 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (150 mL). The organic layers were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 3 / 1) to obtain intermediate 163-3 (8 g, 39.19 mmol, yield 60.93%).

[0158] Step 3 To a solution of intermediate 163-3 (6 g, 29.39 mmol) in dichloromethane (60 mL), boron trifluoride ether (6.26 g, 44.09 mmol) and trimethylsilyl cyanide (8.75 g, 88.17 mmol) were added at -20°C, and the solution was stirred at -20°C for 30 minutes. Water (100 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The combined organic phases were concentrated under reduced pressure, and the crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 10 / 1) to obtain intermediate 163-4 (5.5 g, 25.80 mmol, yield 87.79%).

[0159] Step 4 To a solution of intermediate 163-4 (5.5 g, 25.80 mmol) and 3-bromopropene (9.36 g, 77.41 mmol) in N,N-dimethylformamide (50 mL), sodium hydride (2.06 g, 51.60 mmol) was added at room temperature, and the solution was stirred for 2 hours. Saturated aqueous ammonium chloride (200 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (50 mL). The organic layers were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The combined organic layers were concentrated under reduced pressure, and the crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 10 / 1) to obtain intermediate 163-5 (5.3 g, 20.93 mmol, yield 81.12%).

[0160] Step 5 A mixture of intermediate 163-5 (50 mg, 0.22 mmol), ruthenium trichloride (0.21 g, 0.79 mmol), acetonitrile (10 mL), tetrahydrofuran (10 mL), and water (10 mL) was mixed with sodium periodate (8.45 g, 39.49 mmol) in a batch manner at room temperature. The reaction solution was stirred at room temperature for 2 hours and then dried over anhydrous sodium sulfate. The dried product was concentrated under reduced pressure, and the crude product was purified by preparative TLC (dichloromethane / acetonitrile = 10 / 1) to obtain intermediate 163-6 (1.1 g, 4.06 mmol, yield 51.35%).

[0161] Step 6 To a methanol (10 mL) solution of intermediate 163-6 (1 g, 3.69 mmol), Raney nickel (100 mg) was added at room temperature under a nitrogen atmosphere. The reaction solution was stirred at room temperature for 2 hours and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by C18 column chromatography (acetonitrile / water (0.1% FA) = 20 / 1) to obtain intermediate 163-7 (300 mg, 1.09 mmol, yield 29.56%).

[0162] Step 7 A solution of intermediate 163-7 (300 mg, 1.09 mmol), N,N'-dicyclohexylcarbodiimide (292 mg, 0.79 mmol), and 4-dimethylaminopyridine (173 mg, 1.42 mmol) in dichloromethane (10 mL) was stirred at room temperature for 10 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 1 / 10) to obtain intermediate 163-8 (100 mg, 0.39 mmol, yield 35.67%).

[0163] Step 8 To a solution of intermediate 163-8 (40 mg, 0.16 mmol) in tetrahydrofuran (3 mL), boranedimethyl sulfide (0.03 mL, 10.0 M, 0.3 mmol) was added at room temperature. The reaction solution was refluxed for 2 hours and then cooled to room temperature. Methanol was added to the reaction solution until no more bubbles were generated. The resulting solution was concentrated under reduced pressure, and the crude product was purified by C18 column chromatography (acetonitrile / water (0.1% NH4HCO3) = 20 / 1) to obtain intermediate 163-9 (12 mg, 0.05 mmol, yield 31.72%).

[0164] Step 9 To a solution of intermediates 163-9 (12 mg, 0.05 mmol) and 84-11 (12 mg, 0.05 mmol) in N,N-dimethylformamide (2 mL), N-methylimidazole (32 mg, 0.40 mmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (21 mg, 0.07 mmol) were added at room temperature, and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: A: 10 mM NH4HCO3; B: ACN, gradient: 5-55%, retention time: 9.1 min) to obtain compound 163 (4.24 mg, 0.01 mmol, yield 18.11%). MS m / z (ESI): 468.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 14.0 Hz, 1H), 8.53-8.39 (m, 1H), 8.03-7.89 (m, 1H), 7.85-7.65 (m, 4H), 5.19-4.96 (m, 2H), 4.49 (d, J = 19.2 Hz, 3H), 4.06-3.67 (m, 4H), 2.42 (d, J = 10.4 Hz, 1H), 2.28-2.16 (m, 1H).

[0165] Example 18 Synthesis of compound 165 [ka] Step 1 To a solution of intermediates 149-1 (181 mg, 0.65 mmol) and 134-4 (50 mg, 0.22 mmol) in N,N-dimethylformamide (2 mL), N-methylimidazole (71 mg, 0.87 mmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (91 mg, 0.33 mmol) were added at room temperature, and the solution was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: A: 10 mM NH4HCO3; B: ACN, gradient: 5-60%, retention time: 8.5 min) to obtain compound 165 (30.66 mg, 0.06 mmol, yield 28.81%). MS m / z (ESI): 488.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.27 (s, 1H), 7.82 (d, J = 76 Hz, 1H), 7.61 (s, 1H), 7.37 (d, 1H), 7.32 (s, 2H), 7.15 (d, J = 1.6 Hz, 1H), 4.92 (d, J = 10.0 Hz, 1H), 4.82 (d, J = 10.0 Hz, 1H), 4.46-4.39 (m, 4H), 4.33-4.25 (m, 2H), 4.18 (d, J = 9.2 Hz, 1H).

[0166] Example 19 Synthesis of compound 162 [ka] Step 1 To a solution of intermediate 162-1 (6.0 g, 35.47 mmol) in chloroform (60 mL), N-bromosuccinimide (6.31 g, 35.47 mmol) was added under a nitrogen atmosphere at 0°C, and the solution was stirred at room temperature for 6 hours. The reaction mixture was quenched with saturated sodium bicarbonate (60 mL) and then extracted three times with dichloromethane (100 mL). The combined organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to obtain a grayish-white intermediate 162-2 (7.8 g, 31.45 mmol, yield 88.65%).

[0167] Step 2 To a solution of intermediate 162-2 (2.0 g, 8.06 mmol) in 1,4-dioxane (20 mL), bis(pinacolate)diborone (4.09 g, 16.13 mmol), potassium acetate (2.37 g, 24.19 mmol), and bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.18 g, 1.61 mmol) were added at room temperature. The reaction solution was stirred at 80 °C for 16 hours and then concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain intermediate 162-3 (2.2 g, 7.45 mmol, yield 92.46%) as a white solid.

[0168] Step 3 To a solution of intermediate 137-5 (500.0 mg, 1.88 mmol) in 1,4-dioxane (10 mL) and water (2 mL), intermediate 162-3 (832 mg, 2.82 mmol), tripotassium phosphate (1.2 g, 5.64 mmol), and methanesulfonate (2-dicyclohexylphosphin-2',6'-di-i-propoxy-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (318 mg, 0.376 mmol) were added at room temperature. The reaction solution was stirred at 90°C for 16 hours and then concentrated under reduced pressure. The crude product was purified by C18 reversed-phase column chromatography (water (0.1% NH3·H2O) / MeCN=3 / 2) to obtain intermediate 162-4 (150 mg, 0.57 mmol, yield 30.40%) as a yellow solid.

[0169] Step 4 To a solution of intermediate 162-4 (100 mg, 0.38 mmol) in methanol (5 mL) and water (5 mL), lithium hydroxide (80.0 mg, 1.91 mmol) was added at room temperature, and the solution was stirred for 17 hours. The reaction mixture was concentrated under reduced pressure to obtain intermediate 162-5 (90 mg, 0.36 mmol, yield 95.09%) as a yellow solid. The crude product was used directly in the next step.

[0170] Step 5 To a solution of intermediates 162-5 (54 mg, 0.22 mmol) and 84-10 (50 mg, 0.22 mmol) in N,N-dimethylformamide (5 mL), hexafluorophosphate azabenzotriazole tetramethyluronium (124 mg, 0.33 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.65 mmol) were added at room temperature. The reaction solution was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The crude product was purified by preparative HPLC column (Waters-CORTECS-C18-2.7μm-4.6*30mm, mobile phase: 0.1% (NH4HCO3, B:CH3CN, gradient: 36%~76%, retention time: 8 min) to obtain compound 162 (4.73 mg, 0.01 mmol, yield 4.68%) as a white solid. MS m / z (ESI): 458.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.79-7.70 (m, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.59 (s, 1H), 7.29 (d, J = 12.4 Hz, 1H), 6.88 (s, 2H), 5.40-5.31 (m, 2H), 5.04-4.96 (m, 2H), 4.28-4.21 (m, 2H), 4.21-4.13 (m, 2H), 2.98-2.91 (m, 2H), 2.45-2.39 (m, 2H).

[0171] Example 20 Synthesis of compound 164 [ka] Step 1 To a solution of intermediates 162-5 (54 mg, 0.22 mmol) and 134-4 (50 mg, 0.22 mmol) in N,N-dimethylformamide (5 mL), hexafluorophosphate azabenzotriazole tetramethyluronium (125 mg, 0.33 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.65 mmol) were added at room temperature. The reaction solution was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The crude product was purified by preparative HPLC (Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: A: 0.1% FA / H2O, B: ACN, gradient: 21%~51%, retention time: 8 min) to obtain compound 164 (4.82 mg, 0.01 mmol, yield 4.81%) as a white solid. MS m / z (ESI): 460.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.83-7.75 (m, 2H), 7.39-7.31 (m, 2H), 7.15 (s, 1H), 5.36 (s, 2H), 5.01 (s, 2H), 4.93-4.79 (m, 2H), 4.42-4.34 (m, 2H), 4.33-4.22 (m, 2H).

[0172] Example 21 Synthesis of compound 166 [ka] Step 1 To a solution of intermediate 162-3 (1.0 g, 3.39 mmol) in dioxane (10 mL) and water (1 mL), intermediate 166-1 (0.63 g, 3.39 mmol), tetrakis(triphenylphosphine)palladium (0.39 g, 0.34 mmol), and sodium carbonate (0.72 g, 6.78 mmol) were added at room temperature. The reaction solution was stirred at 100 °C under a nitrogen atmosphere for 10 hours, and then cooled to room temperature. The resulting precipitate was filtered, and the filter cake was washed with water (30 mL). After drying, intermediate 166-2 (300 mg, 1.09 mmol, yield 32.28%) was obtained.

[0173] Step 2 A solution of intermediate 166-2 (300 mg, 1.09 mmol) and lithium hydroxide (137 mg, 3.28 mmol) in methanol (5 mL) and water (1 mL) was stirred at 50°C for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. 1 M dilute hydrochloric acid was added to adjust the pH to 3. The mixture was filtered, and the filter cake was dried to obtain intermediate 166-3 (200 mg, 0.77 mmol, yield 70.26%).

[0174] Step 3 To a solution of intermediates 166-3 (136 mg, 0.52 mmol) and 134-4 (40 mg, 0.17 mmol) in N,N-dimethylformamide (2 mL), N-methylimidazole (57 mg, 0.70 mmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (73 mg, 0.26 mmol) were added at room temperature, and the solution was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: A: 10 mM NH4HCO3; B: ACN, gradient: 5-70%, retention time: 8.1 min) to obtain compound 166 (26.56 mg, 0.06 mmol, yield 32.28%). MS m / z (ESI): 472.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 7.6 Hz, 1H), 8.26 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.41-7.25 (m, 4H), 7.15 (s, 1H), 4.95-4.80 (m, 2H), 4.47-4.38 (m, 5H), 4.37-4.27 (m, 2H).

[0175] Example 22 Synthesis of compound 167 [ka] Step 1 To a solution of intermediate 167-1 (2.5 g, 7.22 mmol) and copper iodide (2.75 g, 14.44 mmol) in acetonitrile (30 mL), isoamyl nitrite (14.4 g, 12.27 mmol) was added dropwise at 0°C. After the addition was complete, the reaction solution was heated to 80°C and stirred for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 3) to obtain intermediate 167-2 (0.9 g, 1.97 mmol, yield 27.27%) as a pale yellow solid.

[0176] Step 2 A mixture of intermediate 167-2 (900 mg, 1.97 mmol), bis(diphenylphosphino)ferrocene]dichloropalladium(II) (144 mg, 0.2 mmol), N,N-dimethylformamide (5 mL), and methanol (2 mL) was heated to 100°C under a carbon monoxide atmosphere and stirred for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 3) to obtain intermediate 167-3 (350 mg, 0.98 mmol, yield 49.7%) as a pale yellow solid.

[0177] Step 3 To a solution of intermediate 167-3 (150 mg, 0.42 mmol) in dichloromethane (1 mL), trifluoroacetic acid (1 mL) was added, and the solution was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain crude intermediate 167-4 (110 mg, 0.42 mmol, 100% yield) as a yellow solid. The crude product was used directly in the subsequent steps.

[0178] Step 4 Intermediate 84-11 (66 mg, 0.27 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (115 mg, 0.41 mmol), and N-methylimidazole were mixed in acetonitrile (3 mL) and stirred at room temperature under a nitrogen atmosphere for 30 minutes, followed by the addition of intermediate 167-4 (70 mg, 0.27 mmol). The reaction solution was then stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with dimethyl sulfoxide (5 mL) and filtered. The filtrate was purified by preparative HPLC (waters-xbridge-C18-10μm-19*250mm, mobile phase: 0.1%FA / H2O B:CH3CN, gradient: 55%B~85%B, retention time 8.5 min) to obtain compound 167 (38.56 mg, 0.08 mmol, yield 29.43%) as a white solid. MS m / z (ESI): 482.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 2.0 Hz, 1H), 8.27 (s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 8.20-8.16 (m, 2H), 7.89 (dd, J = 2.0, 8.8 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.28 (s, 2H), 4.83 (s, 2H), 4.77-4.64 (m, 2H), 4.42 (s, 3H), 4.38-4.26 (m, 2H).

[0179] Example 23 Synthesis of compound 901 [ka] Step 1 Under a nitrogen atmosphere, a methanol (10 mL) solution of intermediate 167-3 (1.3 g, 3.64 mmol) was cooled to 0°C, and lithium borohydride (3.17 g, 14.55 mmol) was carefully and slowly added thereto. The reaction solution was then heated to room temperature and stirred for 2 hours. After the reaction was complete, saturated aqueous ammonium chloride (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL), and dried over anhydrous sodium sulfate. The combined organic phase was filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 3) to obtain intermediate 901-1 (1 g, 2.77 mmol, yield 76%) as a pale yellow solid.

[0180] Step 2 Under a nitrogen atmosphere, concentrated sulfuric acid (217 mg, 2.21 mmol) was added dropwise to a toluene solution (5 mL) of intermediate 901-1 (200 mg, 0.55 mmol). After the addition was complete, the mixture was heated to 110°C and stirred for 16 hours. The reaction solution was then cooled to room temperature and concentrated under reduced pressure to obtain crude intermediate 901-2 (134 mg, 0.55 mmol, 100% yield) as a yellow solid. The crude product was used directly in the next step.

[0181] Step 3 Under a nitrogen atmosphere, a solution of intermediate 84-11 (80 mg, 0.33 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (138 mg, 0.49 mmol), and N-methylimidazole (162 mg, 1.97 mmol) in acetonitrile (2 mL) was stirred at room temperature for 30 minutes, and then intermediate 901-2 (80 mg, 0.33 mmol) was added to the reaction solution. The mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with dimethyl sulfoxide (5 mL) and filtered. The filtrate was purified by preparative HPLC (waters-xbridge-C18-10μm-19*250mm, mobile phase: 0.1%NH4HCO3 / H2O B:CH3CN, gradient: 55%B~85%B, Ret 9.5 min) to obtain compound 901 (24.68 mg, 0.06 mmol, yield 17.22%) as a white solid. MS m / z (ESI): 467.9 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 2.0 Hz, 1H), 8.26 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.89 (dd, J = 2.0, 8.8 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.50 (s, 1H), 7.23 (s, 2H), 4.82 (s, 2H), 4.57 (d, J = 36.8 Hz, 2H), 4.42 (s, 3H), 4.18 (s, 2H), 4.10 (s, 2H).

[0182] Example 24 Synthesis of compound 178 [ka] Step 1 Under a nitrogen atmosphere, a solution of intermediate 136-1 (76 mg, 0.33 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (138 mg, 0.49 mmol), and N-methylimidazole (162 mg, 1.97 mmol) in acetonitrile (2 mL) was stirred at room temperature for 30 minutes, and then intermediate 901-2 (80 mg, 0.33 mmol) was added to the reaction solution. The mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with dimethyl sulfoxide (5 mL) and filtered. The filtrate was purified by preparative HPLC (waters-xbridge-C18-10μm-19*250mm, mobile phase: 0.1%NH4HCO3 / H2O B:CH3CN, gradient: 55%B~85%B, Ret 9.5 min) to obtain compound 178 (14.18 mg, 0.03 mmol, yield 9.41%) as a white solid. MS m / z (ESI): 457.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.10 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.67 (dd, J = 2.0, 8.4 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.13 (s, 2H), 5.45 - 5.36 (m, 2H), 5.10 - 5.01 (m, 2H), 4.82 (s, 2H), 4.80 - 4.69 (m, 2H), 4.22 - 4.12 (m, 2H), 4.10 (s, 2H).

[0183] Example 25 Synthesis of compound 1036 [ka] Step 1 Under a nitrogen atmosphere, sodium hydride (21.03 mg, 0.88 mmol) was added at 0°C to a solution of intermediate 123-3 (200 mg, 0.58 mmol) in dimethylacetamide (4 mL), and the mixture was stirred for 0.5 hours. Methyl iodide (55 μL, 0.88 mmol) was added dropwise to the reaction solution, and the mixture was stirred for a further 0.5 hours at 0°C, then the temperature was raised to room temperature and the mixture was stirred for a further 1 hour. After the reaction was complete, water (10 mL) was added to the reaction solution and extracted with ethyl acetate (10 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain intermediate 1036-1 (160 mg, 0.45 mmol, 76.85%) as yellow oil.

[0184] Step 2 To a solution of intermediate 1036-1 (160 mg, 0.45 mmol) in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the solution was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. Sodium bicarbonate aqueous solution (5 mL) was added, and the resulting solution was extracted with dichloromethane (5 mL). The combined organic layers were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude intermediate 1036-2 (110 mg, 0.43 mmol, 95.61%) as a yellow solid. The crude product was used directly in the subsequent steps.

[0185] Step 3 Under a nitrogen atmosphere, a solution of intermediate 84-11 (100 mg, 0.39 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (219.01 mg, 0.78 mmol), and N-methylimidazole (0.19 mL, 2.34 mmol) in acetonitrile (1.5 mL) was stirred at room temperature for 30 minutes. Then, intermediate 1036-2 (113.45 mg, 0.47 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was diluted with DMSO (5 mL) and filtered. The filtered cake was washed with DMSO (2 mL), and the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC (waters-xbridge-C18-10μm-19*250mm, mobile phase: 0.1%NH4HCO3 / H2O B:CH3CN, gradient: 55%B~85%B, Ret 8.5 min) to obtain compound 1036 (35 mg, 0.07 mmol, 18.67%) as a white solid. MS m / z (ESI): 481.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 2.0 Hz, 1H), 8.27 (s, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.90 (dd, J = 2.0, 8.8 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.39 (s, 1H), 7.26 (s, 2H), 4.82 - 4.66 (m, 2H), 4.42 (s, 3H), 4.41 - 4.28 (m, 2H), 3.21 (s, 3H).

[0186] Example 26 Synthesis of compound 1040 [ka] Step 1 Under a nitrogen atmosphere, sodium hydride (32 mg, 1.31 mmol) was added at 0°C to a solution of intermediate 123-3 (300 mg, 0.88 mmol) in dimethylacetamide (4 mL), and the mixture was stirred at 0°C for 0.5 hours. 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.19 mL, 1.31 mmol) was added dropwise to the reaction solution, and the resulting solution was stirred at 0°C for 0.5 hours, then the temperature was raised to room temperature and stirred for a further 1 hour. After the reaction was complete, water (10 mL) was added to the reaction solution and extracted with ethyl acetate (10 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain intermediate 1040-1 (270 mg, 0.64 mmol, 72.60%) as a yellow solid.

[0187] Step 2 To a solution of intermediate 1040-1 (270 mg, 0.64 mmol) in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added at room temperature, and the solution was stirred for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution (5 mL) was added to the crude product and stirred, and the mixture was extracted with dichloromethane (5 mL). The combined organic layers were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude intermediate 1040-2 (170 mg, 0.52 mmol, 89.00%) as a yellow solid. The crude product was used directly in the next step.

[0188] Step 3 Under a nitrogen atmosphere, the solutions of intermediate 84-11 (90 mg, 0.31 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (173.96 mg, 0.62 mmol), and N-methylimidazole (0.15 mL, 1.86 mmol) in acetonitrile (5 mL) were stirred at room temperature for 30 minutes. Then, intermediate 1040-2 (100 mg, 0.47 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. Once the reaction was complete, the reaction solution was diluted with DMSO (5 mL) and filtered. The filtered cake was washed with DMSO (2 mL), and the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC (waters-xbridge-C18-10μm-19*250mm, mobile phase: 0.1%NH4HCO3 / H2O B:CH3CN, gradient: 55%B~85%B, Ret 8.5 min) to obtain compound 1040 (16 mg, 0.03 mmol, 9.46%) as a white solid. MS m / z (ESI): 549.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 2.0 Hz, 1H), 8.27 (s, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.90 (dd, J = 2.0, 8.8 Hz, 1H), 7.67 - 7.56 (m, 3H), 7.26 (s, 2H), 4.93 - 4.62 (m, 4H), 4.42 (s, 3H), 4.40 - 4.31 (m, 2H).

[0189] Example 27 Synthesis of compound 902 [ka] Step 1 To a solution of intermediate 902-1 (1.00 g, 4.10 mmol) in tetrahydrofuran (10 mL), n-butyllithium (2 mL, 5.0 mmol, 2.5 M n-hexane solution) was added dropwise under a nitrogen atmosphere at -78°C. The reaction solution was stirred at -78°C for 2 hours. The atmosphere was then replaced with carbon dioxide three times, followed by stirring at room temperature for a further 2 hours. Sodium sulfate decahydrate was added to the reaction solution, and it was filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane / methanol = 8 / 1) to obtain intermediate 902-2 (1.00 g, 4.78 mmol, yield 116.69%).

[0190] Step 2 A solution of intermediate 902-2 (500 mg, 2.39 mmol) in thionyl chloride (3 mL) was heated under reflux for 3 hours. The reaction solution was cooled and then distilled under pressure. The resulting concentrated solution was slowly added dropwise to methanol (3 mL) and stirred at room temperature for 10 minutes. Water (10 mL) was added to the reaction solution and extracted with ethyl acetate (5 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 4) to obtain compound 902-3 (290 mg, 1.30 mmol, yield 74.19%).

[0191] Step 3 To a solution of intermediate 902-3 (290 mg, 1.30 mmol) and intermediate 123-1a (280 mg, 1.30 mmol) in tetrahydrofuran (5 mL), potassium bis(trimethylsilyl)amide (1.43 mL, 1.43 mmol, 1 N) was added dropwise under a nitrogen atmosphere in an ice bath. The reaction solution was stirred in an ice bath for 1 hour, then at room temperature for 1 hour, followed by the addition of water (10 mL). The solution was extracted with ethyl acetate (5 mL), and the organic layers were combined. The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 3) to obtain intermediate 902-4 (60 mg, 0.14 mmol, yield 11.03%).

[0192] Step 4 Under ice bath conditions, a methanol (2 mL) solution of intermediate 902-4 (60 mg, 0.14 mmol) was slowly added with lithium borohydride (12 mg, 0.56 mmol), and the solution was stirred at room temperature for 30 minutes. Sodium sulfate decahydrate was added to the reaction solution, and it was filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain intermediate 902-5 (40 mg, 0.11 mmol, yield 76.97%).

[0193] Step 5 To a solution of intermediate 902-5 (40 mg, 0.11 mmol) in toluene (2 mL), concentrated sulfuric acid (43 mg, 0.44 mmol) was added, and the solution was refluxed for 10 hours. The reaction solution was concentrated under reduced pressure to obtain crude intermediate 902-6, which was used directly in the next step.

[0194] Step 6 To acetonitrile (2 mL) solutions of intermediates 902-5 (20 mg, 0.08 mmol) and 84-11 (40 mg, 0.08 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (34 mg, 0.12 mmol) and N-methylimidazole (67 mg, 0.82 mmol) were added at room temperature, and the solution was stirred for 2 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by HPLC (Waters-Xbridge-C18-10μm-19*250mm, mobile phase: A: 10mM NH4HCO3; B: ACN, gradient: 10-95%, retention time: 10 min) to obtain compound 902 (6.73 mg, 0.01 mmol, yield 17.54%). MS m / z (ESI): 468.9 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.55 (d, J = 2.0 Hz, 1H), 8.27 (s, 1H), 7.91 (dd, J =2.0, 8.8 Hz, 1H), 7.71 (s, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.30 (s, 2H), 4.92 - 4.70 (m, 3H), 4.55 - 4.44 (m, 1H), 4.43 (s, 3H), 4.37 - 4.28 (m, 1H), 4.23 - 4.13 (m, 1H), 4.11 (s, 2H).

[0195] Example 28 Synthesis of compound 1039 [ka] Step 1 A solution of intermediate 123-3 (500 mg, 1.46 mmol), cyclopropylboronic acid (1000 mg, 11.64 mmol), sodium carbonate (310 mg, 2.92 mmol), and copper acetate (530 mg, 2.92 mmol) in dichloroethane (40 mL) was stirred at 70°C for 2 hours. The reaction solution was concentrated, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain intermediate 1039-1 (190 mg, 0.50 mmol, 34.02%) as a white solid.

[0196] Step 2 A solution of intermediate 1039-1 (130 mg, 0.34 mmol) in dichloromethane (3 mL) and trifluoroacetic acid (0.5 mL) was stirred at 25°C for 2 hours. The reaction solution was concentrated, quenched with saturated sodium bicarbonate aqueous solution (10 mL), and extracted with ethyl acetate (10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to obtain crude intermediate 1039-2 (100 mg, 0.35 mmol, 104.20%) as a brown solid, which was used directly in the next step.

[0197] Step 3 Intermediate 84-11 (100 mg, 0.41 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (170 mg, 0.61 mmol), and N-methylimidazole (0.10 mL, 1.20 mmol) were mixed in acetonitrile (10 mL) and stirred at 25°C for 30 minutes. Then, intermediate 1039-2 (113 mg, 0.40 mmol) was added, and the reaction solution was stirred at 25°C for 2 hours. The reaction solution was concentrated and diluted with dimethyl sulfoxide (3 mL). The crude product was purified by preparative HPLC (Waters-Xbridge-C18-10μm-19*250mm; mobile phase: A: 10mM ammonium bicarbonate / water B: acetonitrile; flow rate: 25) to obtain compound 1039 (10.67 mg, 0.02 mmol, 5.26%) as a white solid. MS m / z (ESI): 507.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 2.0 Hz, 1H), 8.27 (s, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.88 (dd, J =2.0, 8.8 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.31 (s, 1H), 7.26 (s, 2H), 4.83 - 4.71 (m, 1H), 4.68 - 4.54 (m, 1H), 4.42 (s, 3H), 4.39 - 4.33 (m, 1H), 4.31 - 4.22 (m, 1H), 2.76 - 2.70 (m, 1H), 1.08 - 0.97 (m, 2H), 0.89 - 0.79 (m, 2H).

[0198] Example 29 Synthesis of compound 1038 [ka] Step 1 Intermediate 123-3 (200 mg, 0.58 mmol) and sodium hydride (60 mg, 1.50 mmol, 60% w%) were dissolved in N,N-dimethylformamide (10 mL), to which 2-bromopropane (0.2 mL, 2.13 mmol) was added, and the solution was stirred at 50°C for 2 hours. The reaction solution was quenched with water (10 mL) and extracted with ethyl acetate (10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to obtain crude intermediate 1038-1 (250 mg, 0.65 mmol, 111.31%) as a white solid, which was used directly in the subsequent steps.

[0199] Step 2 A solution of intermediate 1038-1 (250 mg, 0.65 mmol) in trifluoroacetic acid (1 mL) and dichloromethane (5 mL) was stirred at 25°C for 2 hours. The reaction solution was quenched with saturated sodium bicarbonate aqueous solution (30 mL), extracted with ethyl acetate (20 mL), and the combined organic layer was dried over anhydrous sodium sulfate and concentrated to obtain crude intermediate 1038-2 (240 mg, 0.84 mmol, 129.81%) as a brown solid, which was used directly in the subsequent steps.

[0200] Step 3 Intermediate 84-11 (100 mg, 0.41 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (175 mg, 0.62 mmol), and N-methylimidazole (0.10 mL, 1.24 mmol) were mixed in acetonitrile (10 mL) and stirred at 25°C for 30 minutes. Then, intermediate 1038-2 (110 mg, 0.39 mmol) was added, and the reaction solution was stirred at 25°C for 2 hours. The reaction solution was concentrated, and the crude product was purified by preparative HPLC (Waters-Xbridge-C18-10 μm-19*250 mm; mobile phase: A: 10 mM ammonium bicarbonate / water B: acetonitrile; flow rate: 25) to obtain compound 1038 (14.95 mg, 0.03 mmol, 6.73%) as a white solid. MS m / z (ESI): 509.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 2.0 Hz, 1H), 8.27 (s, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.89 (dd, J = 2.0, 8.8 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.26 (s, 2H), 4.85 - 4.76 (m, 1H), 4.70 - 4.62 (m, 1H), 4.62 - 4.50 (m, 1H), 4.42 (s, 3H), 4.42 - 4.35 (m, 1H), 4.33 - 4.23 (m, 1H), 1.42 (d, J = 6.8 Hz, 6H).

[0201] Example 30 Synthesis of compound 189 [ka] Step 1 Under a nitrogen atmosphere, liquid bromine (1.10 mL, 21.45 mmol) was slowly added dropwise at 0°C to a methanol (40 mL) solution of intermediate 189-1 (4.7 g, 21.45 mmol), and the solution was stirred at 0°C for 1 hour. After the reaction was complete, water (30 mL) was added to the reactants, and then the mixture was extracted with ethyl acetate (30 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain intermediate 189-2 (2.8 g, 9.39 mmol, 43.80%) as a yellow solid.

[0202] Step 2 Under a nitrogen atmosphere, bis(pinacolate)diborone (638.98 mg, 2.52 mmol), potassium acetate (411.58 mg, 4.19 mmol), and Pd(dppf)Cl2 (136.21 mg, 0.17 mmol) were added to a solution of intermediate 189-2 (500 mg, 1.68 mmol) in 1,4-dioxane (5 mL). The reaction solution was stirred at 80°C for 2 hours. After the reaction was complete, the reaction solution was filtered and concentrated under reduced pressure to obtain crude intermediate 189-3 (400 mg, 1.16 mmol, 69.09%) as a yellow solid, which was used directly in the subsequent steps.

[0203] Step 3 Under a nitrogen atmosphere, intermediate 136-4 (553 mg, 1.60 mmol), tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.01 mmol), and potassium carbonate (51 mg, 0.37 mmol) were added to a solution of intermediate 189-3 (300 mg, 1.23 mmol) in 1,4-dioxane (8 mL) and water (0.8 mL), and the solution was stirred at 80°C for 18 hours. After the reaction was complete, water (30 mL) was added to the reaction solution, and then it was extracted with ethyl acetate (30 mL). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain intermediate 189-4 (350 mg, 1.12 mmol, 90.85%) as a yellow solid.

[0204] Step 4 To a methanol (2 mL) solution of intermediate 189-4 (200 mg, 0.64 mmol), tetrahydrofuran (2 mL) and water (2 mL) were added, along with lithium hydroxide (54 mg, 1.28 mmol). The reaction solution was heated at 75°C and stirred for 3 hours. After the reaction was complete, the pH of the reaction solution was adjusted to approximately 6 with 1 M dilute hydrochloric acid. The reaction solution was concentrated under reduced pressure and then freeze-dried to obtain intermediate 189-5 (237 mg, 0.64 mmol, 99.26%) as a yellow solid, which was used directly in the subsequent steps.

[0205] Step 5 Under a nitrogen atmosphere, a solution of intermediate 189-5 (100 mg, 0.27 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (150 mg, 0.54 mmol), and N-methylimidazole (0.13 mL, 1.61 mmol) in acetonitrile (5 mL) was stirred at room temperature for 30 minutes. Then, intermediate 134-4 (74 mg, 0.32 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. Once the reaction was complete, the reaction solution was diluted with DMSO (5 mL) and filtered. The filtered cake was washed with DMSO (2 mL). The filtrate was concentrated under reduced pressure, and the crude product was purified by HPLC (waters-xbridge-C18-10μm-19*250mm, mobile phase: 0.1%NH4HCO3 / H2O B:CH3CN, gradient: 55%B~85%B, Ret 8.5 min) to obtain compound 189 (27.22 mg, 0.05 mmol, 19.92%) as a white solid.

[0206] Example 31 Synthesis of compound 1102 [ka] Step 1 In an ice bath, monoethyl chlorooxoacetate (180 mg, 1.32 mmol) was added to a solution of intermediate 134-4 (250 mg, 1.10 mmol) and triethylamine (0.46 mL, 3.30 mmol) in dichloromethane (3 mL). The reaction solution was stirred at room temperature for 0.5 hours, then quenched with water (10 mL), and extracted with ethyl acetate (3 mL). The combined organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain crude intermediate 1102-1 (250 mg, 0.76 mmol, yield 69.43%) as a yellow oil. The crude product was used directly in the next step without further purification.

[0207] Step 2 A solution of intermediate 1102-1 (200 mg, 0.61 mmol) in tetrahydrofuran (1 mL) and ammonia-methanol (1 mL, 7 M) was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain intermediate 1102-2 (160 mg, 0.54 mmol, yield 87.79%) as a yellow solid.

[0208] Step 3 To a solution of intermediate 1102-2 (100 mg, 0.37 mmol) in 1,4-dioxane (2 mL), intermediate 1102-3 (111 mg, 0.37 mmol), copper powder (5 mg, 0.07 mmol), cuprous iodide (105 mg, 0.55 mmol), and cesium carbonate (360 mg, 1.11 mmol) were added at room temperature under a nitrogen atmosphere, and the reaction solution was stirred at 100 °C for 10 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL). The combined organic layer was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the resulting residue was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 3) to obtain black liquid intermediate 1102-4 (0.1 g, 0.20 mmol, yield 55.29%).

[0209] Step 4 At room temperature, a solution of intermediate 1102-4 (100 mg, 0.20 mmol) in trifluoroacetic acid (2 mL) was stirred at 80°C for 5 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC (Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: A: 10 mM NH4HCO3; B: ACN, gradient: 5-21%, retention time: 9 min) to obtain compound 1102 (13.23 mg, 0.03 mmol, yield 14.94%) as a white solid. MS m / z (ESI): 435.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.81 (s, 1H), 7.35 - 7.28 (m, 1H), 7.14 (d, J = 1.6 Hz, 1H), 5.96 (s, 2H), 4.90 - 4.85 (m, 4H), 4.84 - 4.81 (m, 2H), 4.81 - 4.70 (m, 2H), 4.36 - 4.18 (m, 2H).

[0210] Example 32 Synthesis of compound 1090 [ka] Step 1 To a solution of intermediate 1090-1 (10 g, 38.46 mmol) in water (40 mL) and dioxane (200 mL), potassium vinyltrifluoroborate (15 g, 111.98 mmol), Pd(dppf)Cl2 (1.57 g, 1.92 mmol), and potassium carbonate (16 g, 115.77 mmol) were added, and the mixture was stirred at 100°C for 18 hours. After the reaction was complete, water (50 mL) was added, and the aqueous layer was extracted with ethyl acetate (200 mL). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:100~1:10) to obtain intermediate 1090-2 (7.6 g, 36.68 mmol, 95.39%) as a white solid.

[0211] Step 2 To a solution of intermediate 1090-2 (8.5 g, 41.03 mmol) in water (150 mL) and tetrahydrofuran (300 mL), potassium osmite dihydrate (0.76 g, 2.05 mmol) and sodium periodate (35.10 g, 164.10 mmol) were added, and the mixture was stirred at 25°C for 1 hour. After the reaction was complete, water (200 mL) was added, and the aqueous layer was extracted with ethyl acetate (400 mL). The combined organic layers were washed with aqueous brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:100~1:10) to obtain intermediate 1090-3 (5.8 g, 27.73 mmol, 67.59%) as a white solid.

[0212] Step 3 To a solution of intermediate 1090-3 (5.8 g, 27.73 mmol) in dichloromethane (100 mL), DAST (15 mL, 138.65 mmol) was added at -78 °C. The reaction solution was slowly heated from -78 °C to room temperature and then stirred for 2 hours. After the reaction was complete, water (50 mL) was added, and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:100~1:10) to obtain the white solid intermediate 1090-4 (6 g, 1.51 mmol, 5.46%).

[0213] Step 4 To a solution of intermediate 1090-4 (6.1 g, 26.39 mmol) in ethanol (70 mL) and water (35 mL), iron powder (7.37 g, 131.95 mmol) and ammonium chloride (7.06 g, 131.95 mmol) were added, and the reaction solution was stirred at 80°C for 2 hours. After the reaction was complete, the reaction mixture was filtered through Celite while still hot, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure, the mixture was diluted with water (50 mL), and extracted with ethyl acetate (100 mL). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude intermediate 1090-5, which was used directly in the subsequent steps.

[0214] Step 5 To a solution of intermediate 1090-5 (4.8 g, 23.86 mmol) in acetonitrile (100 mL), N-bromosuccinimide (4.25 g, 23.86 mmol) was added, and the reaction solution was stirred at 20°C for 1 hour under a nitrogen atmosphere. After the reaction was complete, water (30 mL) was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate (60 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:100~1:5) to obtain intermediate 1090-6 (5.8 g, 20.71 mmol, 86.79%) as a white solid.

[0215] Step 6 To a solution of intermediate 1090-6 (500 mg, 1.79 mmol) in dioxane (15 mL), bis(pinacolate)diborone (545 mg, 2.15 mmol), potassium acetate (525 mg, 5.35 mmol), and Pd(dppf)Cl2 (145 mg, 0.18 mmol) were added. The mixture was stirred at 100°C for 1.5 hours. After the reaction was complete, the reaction mixture was filtered through Celite while still hot, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain crude intermediate 1090-7, which was used directly in the next step.

[0216] Step 7 To a solution of intermediates 136-4 (250 mg, 1.03 mmol) and 1090-7 (336 mg, 1.03 mmol) in water (1 mL) and dioxane (10 mL), tetrakis(triphenylphosphine)palladium(0) (115 mg, 0.10 mmol) and potassium carbonate (426 mg, 3.08 mmol) were added, and the reaction solution was stirred at 80°C for 18 hours. After the reaction was complete, the reaction mixture was filtered through Celite while still hot and washed with methanol / dichloromethane. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol = 100:1 to 10:1) to obtain intermediate 1090-8 (600 mg, 1.02 mmol, 99.16%) as a black solid.

[0217] Step 8 To a solution of intermediate 1090-8 (400 mg, 0.68 mmol) in tetrahydrofuran (2 mL), water (2 mL), and methanol (2 mL), lithium hydroxide (90 mg, 3.76 mmol) was added, and the mixture was stirred at 75°C for 3 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 3 with 2 M dilute hydrochloric acid. The aqueous layer was extracted with ethyl acetate (20 mL), and then the aqueous layer was freeze-dried to obtain crude intermediate 1090-9, which was used as is in the next step.

[0218] Step 9 To a solution of intermediate 1090-9 (200 mg, 0.23 mmol) in dimethyl sulfoxide (1 mL), intermediate 134-4 (74 mg, 0.32 mmol), 1-methylimidazole (0.14 mL, 1.71 mmol), and TCFH (90 mg, 0.32 mmol) were added, and the mixture was stirred at 25°C for 1 hour. After the reaction was complete, the reaction solution was filtered and purified by preparative HPLC (SunFire-C18-10 μm-19*250 mm, flow rate: 25 mL / min, mobile phase: A: 0.1% FA / H2O B: ACN) to obtain compound 1090 (46.3 mg, 0.09 mmol, 43.56%) as a white solid. MS m / z (ESI): 492.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J = 7.2 Hz, 2H), 7.75 (s, 1H), 7.54 - 7.21 (m, 2H), 7.15 (d, J = 1.6 Hz, 1H), 6.91 (s, 2H), 5.37 (t, J = 3.2 Hz, 2H), 5.02 (t, J = 3.2 Hz, 2H), 4.94 - 4.79 (m, 2H), 4.50 - 4.22 (m, 4H).

[0219] Example 33 Synthesis of compound 194 [ka] Step 1 At room temperature, intermediate 194-2 (213 mg, 0.81 mmol), tripotassium phosphate (312 mg, 1.47 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (70 mg, 0.07 mmol), and XPhos Pd G3 (70 mg, 0.15 mmol) were added to a solution of intermediate 194-1 (137 mg, 0.74 mmol) in dioxane (3 mL) and water (0.3 mL), and the reaction solution was stirred at 100 °C for 16 hours. After the reaction was complete, the reaction solution was filtered. Water (20 mL) was added to the filtrate and extracted with ethyl acetate (10 mL). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The crude product was washed with dichloromethane (10 mL) to obtain intermediate 194-3 (80 mg, 0.31 mmol, yield 42.39%).

[0220] Step 2 At room temperature, lithium hydroxide (27 mg, 1.15 mmol) was added to a solution of intermediate 194-3 (60 mg, 0.23 mmol) in methanol (3 mL) and water (1 mL), and the reaction solution was stirred at 50°C under a nitrogen atmosphere for 16 hours. The reaction solution was then cooled to room temperature and concentrated under reduced pressure. The pH was adjusted to 5 by adding 1 M dilute hydrochloric acid, the solid was recovered and dried to obtain intermediate 194-4 (40 mg, 0.17 mmol, yield 70.52%).

[0221] Step 3 At room temperature, N,N-diisopropylethylamine (90 mg, 0.74 mmol) and hexafluorophosphate azabenzotriazole tetramethyluronium (122 mg, 0.32 mmol) were added to a solution of intermediate 194-4 (60 mg, 0.25 mmol) and intermediate 134-4 (57 mg, 0.25 mmol) in N,N-dimethylformamide (3 mL), and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: A: 10 mM NH4HCO3; B: ACN, gradient: 5-70%, retention time: 8.1 min) to obtain compound 194 (6.6 mg, 0.01 mmol, yield 5.88%). MS m / z (ESI): 454.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.39 (d, J = 2.0 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.77 - 7.71 (m, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.37 - 7.31 (m, 1H), 7.16 (t, J = 1.2 Hz, 1H), 6.96 (s, 2H), 4.89 (s, 2H), 4.83 - 4.62 (m, 2H), 4.46 - 4.24 (m, 5H).

[0222] Example 34 Synthesis of compound 195 [ka] Step 1 Under a nitrogen atmosphere, a solution of intermediate 137-4 (95 mg, 0.41 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (173 mg, 0.62 mmol), and N-methylimidazole (203 mg, 2.47 mmol) in acetonitrile (2 mL) was stirred at room temperature for 30 minutes. Then, intermediate 901-2 (100 mg, 0.41 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with dimethyl sulfoxide (5 mL) and filtered. The filtrate was purified by preparative HPLC (waters-xbridge-C18-10μm-19*250mm, mobile phase: 0.1%NH4HCO3 / H2O B:CH3CN, gradient: 55%B~85%B, Ret 9.5 min) to obtain compound 195 (14.18 mg, 0.06 mmol, yield 14.94%) as a white solid. MS m / z (ESI): 456.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.99 (d, J = 8.4 Hz, 1H), 7.88 - 7.79 (m, 2H), 7.73 - 7.66 (m, 1H), 7.61 - 7.53 (m, 1H), 7.49 (s, 1H), 6.78 (s, 2H), 5.37 (t, J = 3.6 Hz, 2H), 5.01 (t, J = 3.6 Hz, 2H), 4.81 (s, 2H), 4.63 - 4.37 (m, 2H), 4.28 - 4.00 (m, 4H).

[0223] Example 35 Synthesis of compound 196 [ka] Step 1 Under a nitrogen atmosphere, a solution of intermediate 1036-2 (100 mg, 0.30 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (183 mg, 0.65 mmol), and N-methylimidazole (178 mg, 2.17 mmol) in acetonitrile (1.5 mL) was stirred at room temperature for 30 minutes. Then, intermediate 137-4 (100 mg, 0.41 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was diluted with dimethyl sulfoxide (5 mL) and filtered. The filtered cake was washed with dimethyl sulfoxide (2 mL), the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (waters-xbridge-C18-10 μm-19*250 mm, mobile phase: 0.1% NH4HCO3 / H2O B:CH3CN, gradient: 55%B~85%B, Ret 8.5 min) to obtain compound 196 (21.85 mg, 0.05 mmol, yield 15.34%) as a white solid. MS m / z (ESI): 469.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 7.6 Hz, 2H), 7.59 (d, J = 9.2 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.38 (s, 1H), 6.81 (s, 2H), 5.38 (s, 2H), 5.02 (s, 2H), 4.78 - 4.20 (m, 4H), 3.20 (s, 3H).

[0224] Example 36 Synthesis of compound 1100 [ka] Step 1 To a solution of intermediate 77-2 (58 mg, 0.10 mmol) in dioxane (2 mL), intermediate 1102-2 (30 mg, 0.10 mmol), cesium carbonate (66 mg, 0.20 mmol), N,N'-dimethylethylenediamine (13 mg, 0.15 mmol), cuprous iodide (29 mg, 0.15 mmol), and copper powder (8 mg, 0.12 mmol) were added at room temperature. The reaction solution was stirred at 100 °C for 16 hours under a nitrogen atmosphere, and then concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane / methanol = 18 / 1) to obtain intermediate 1100-1 (10.00 mg, 12.61 μmol, yield 12.47%) as a yellow solid.

[0225] Example 37 Synthesis of compound 1045 [ka] Step 1 To a solution of compound 1045-1 (1.0 g, 3.92 mmol) and imidazole (590 mg, 8.63 mmol) in dichloromethane (10 mL), tert-butyldimethylsilyl chloride (710 mg, 4.71 mmol) was added at 0°C. The mixture was slowly raised to room temperature and stirred for 16 hours. After the reaction was complete, the reaction solution was diluted with water (50 mL) and extracted with dichloromethane (30 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 50) to obtain intermediate 1045-2 (1.4 g, 3.79 mmol, yield 96.68%) as a colorless oil.

[0226] Step 2 Under a nitrogen atmosphere, a solution of intermediate 1045-2 (1.0 g, 2.71 mmol) in tetrahydrofuran (15 mL) was mixed with n-butyllithium solution (1.62 mL, 4.06 mmol) at -78°C and stirred for 0.5 hours. Then, intermediate 1045-3 (0.70 g, 4.06 mmol) in tetrahydrofuran (7 mL) was added to the reaction solution, and the mixture was stirred at room temperature under a nitrogen atmosphere for 6 hours. After the reaction was complete, the reaction solution was quenched with water (50 mL) and extracted with ethyl acetate (50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 4) to obtain intermediate 1045-4 (330 mg, 0.71 mmol, yield 26.40%) as a colorless oil.

[0227] Step 3 To a solution of intermediate 1045-4 (330 mg, 0.71 mmol) in tetrahydrofuran (15 mL), hydrochloric acid (7.15 mL, 7.15 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 4) to obtain a colorless oily intermediate 1045-5 (200 mg, 0.58 mmol, yield 80.54%).

[0228] Step 4 To a solution of intermediate 1045-5 (150 mg, 0.43 mmol) in tetrahydrofuran (6 mL), triethylamine (87.4 mg, 0.86 mmol) and methanesulfonyl chloride (34.63 mg, 0.3 mmol) were added, and the reaction solution was stirred at 70°C for 3 hours. After the reaction was complete, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (20 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 4) to obtain intermediate 1045-6 (76 mg, 0.23 mmol, yield 53.44%) as a colorless oil.

[0229] Step 5 To a solution of intermediate 1045-6 (76 mg, 0.23 mmol) in dichloromethane (4 mL), trifluoroacetic acid (2 mL) was added, and the reaction solution was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain crude intermediate 1045-7 (50 mg), which was used directly in the subsequent steps.

[0230] Step 6 To a solution of intermediates 1045-7 (50 mg, 0.23 mmol) and 84-11 (50 mg, 0.23 mmol) in N,N-dimethylformamide (2 mL), N-methylimidazole (151 mg, 1.83 mmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (128 mg, 0.46 mmol) were added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, the resulting residue was dissolved in dimethyl sulfoxide (3 mL), and filtered. The filtrate was purified by preparative HPLC (mobile phase: A: 0.1% FA; B: ACN, gradient: 16-56%, retention time: 9.2 min) to obtain compound 1045 (31.4 mg, 0.07 mmol, yield 31.74%) as a white solid. MS m / z (ESI): 453.9 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 2.0 Hz, 1H), 8.27 (s, 1H), 7.93 - 7.86 (m, 2H), 7.79 (d, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.29 (s, 2H), 5.17 (s, 2H), 4.80 - 4.45 (m, 4H), 4.43 (s, 3H).

[0231] Example 38 Synthesis of compound 1093 [ka] Step 1 Intermediate 1093-1 (8.6 mL, 111.70 mmol) was added to a tetrahydrofuran (100 mL) solution of sodium hydride (2.23 g, 55.85 mmol, 60%) under a nitrogen atmosphere at room temperature. Then, crotononitrile (11 mL, 134.45 mmol) was slowly added dropwise to the reaction solution at 65°C. The reaction was continued at 65°C for 2 hours with stirring. After the reaction was complete, the reactants were cooled, quenched with aqueous sodium hydroxide (50 mL, 2 M), extracted with methyl tert-butyl ether (50 mL), the aqueous phase was acidified to approximately pH 1 with concentrated hydrochloric acid, and then further extracted with dichloromethane (50 mL). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain intermediate 1093-2 (3.4 g, 27.17 mmol, 24.33%) as a colorless oil.

[0232] Step 2 Intermediate 1093-2 (3.5 g, 27.97 mmol) and diisopropylethylamine (9.27 mL, 55.94 mmol) were dissolved in dichloromethane (10 mL), to which trifluoromethanesulfonic anhydride (6.50 mL, 39.16 mmol) was added dropwise at -78°C. The reaction solution was stirred at -78°C for 2 hours. After the reaction was complete, the reactants were quenched with saturated sodium bicarbonate aqueous solution (50 mL) and extracted with dichloromethane (50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude intermediate 1093-3 (7.0 g, 27.22 mmol, crude) as a black solid, which was used directly in the subsequent steps.

[0233] Step 3 A solution of intermediates 1093-3 (200 mg, 0.78 mmol), 194-2 (646.54 mg, 2.33 mmol), tetrakis(triphenylphosphine)palladium(0) (89.9 mg, 0.08 mmol), and potassium carbonate (322.4 mg, 2.33 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was stirred at 90°C for 18 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain intermediate 1093-4 (200 mg, 0.39 mmol, 49.79%) as a yellow solid.

[0234] Step 4 A solution of intermediate 1093-4 (180 mg, 0.70 mmol) and lithium hydroxide (69 mg, 2.86 mmol) in water (5 mL), tetrahydrofuran (5 mL), and ethanol (5 mL) was stirred at 75°C for 3 hours. After the reaction was complete, the reaction solution was quenched with hydrochloric acid (2.8 mL, 1 M), filtered, and the filtered cake was dried under vacuum to obtain intermediate 1093-5 (80 mg, 0.33 mmol, 47.00%) as a yellow solid.

[0235] Step 5 Intermediate 134-4 (120 mg, 0.52 mmol) was added at room temperature to a solution of intermediate 1093-5 (70 mg, 0.29 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (120 mg, 0.43 mmol), and N-methylimidazole (0.11 mL, 1.43 mmol) in acetonitrile (7 mL), and the solution was stirred for 1 hour. After the reaction was complete, the reaction solution was concentrated and diluted with dimethyl sulfoxide (3 mL). The crude product was purified by HPLC (Waters-Xbridge-C18-10 μm-19*250 mm; mobile phase: A: 10 mM ammonium bicarbonate / water B: acetonitrile; flow rate: 25;) to obtain compound 1093 (16.98 mg, 0.04 mmol, 12.46%) as a white solid. MS m / z (ESI): 455.9 [M+H] + ; 1 H NMR (400 MHz, DMSO-6) d δ 7.88 - 7.79 (m, 3H), 7.60 - 7.53 (m, 1H), 7.38 - 7.31 (m, 1H), 7.16 (d, J = 1.6 Hz, 1H), 6.70 (s, 2H), 5.47 - 5.25 (m, 3H), 4.88 (s, 2H), 4.66 (br s, 2H), 4.35 - 4.27 (m, 2H), 1.41 (d, J = 6.0 Hz, 3H)

[0236] Example 39 Synthesis of compound 202 [ka] Step 1 Intermediate 137-4 (50 mg, 0.18 mmol) was added at room temperature to a solution of intermediate 1038-2 (50 mg, 0.22 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (75 mg, 0.27 mmol), and N-methylimidazole (0.04 mL, 0.53 mmol) in acetonitrile (5 mL), and the mixture was stirred for 2 hours. After the reaction was complete, the reaction solution was concentrated and diluted with dimethyl sulfoxide (3 mL). The crude product was purified by preparative HPLC (Waters-Xbridge-C18-10 μm-19*250 mm; mobile phase: A: 10 mM ammonium bicarbonate / water B: acetonitrile; flow rate: 25) to obtain compound 202 (13.02 mg, 0.03 mmol, 14.91%) as a white solid. MS m / z (ESI): 497.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d6) δ 7.97 (d, J = 7.6 Hz, 1H), 7.89 - 7.81 (m, 2H), 7.59 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 1.6 Hz, 1H), 6.80 (s, 2H), 5.38 (t, J = 3.6 Hz, 2H), 5.02 (t, J = 3.6 Hz, 2H), 4.73 - 4.69 (m, 1H), 4.61 - 4.47 (m, 2H), 4.36 - 4.23 (m, 2H), 1.42 (d, J = 6.8 Hz, 6H).

[0237] Example 40 Synthesis of compound 203 [ka] Step 1 To a solution of intermediate 203-1 (180 mg, 0.39 mmol) in dioxane (2 mL), potassium ferrocyanide (145 mg, 0.39 mmol), potassium acetate (95 mg, 0.97 mmol), tBuXPhos (32 mg, 0.08 mmol), and tBuXPhos-Pd-G3 (46 mg, 0.06 mmol) were added, and the solution was stirred at 100°C for 18 hours. After the reaction was complete, the reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol = 100:1 to 10:1) to obtain intermediate 203-2 (100 mg, 0.37 mmol, 95.83%) as a white solid.

[0238] Step 2 To a solution of intermediate 203-2 (80 mg, 0.30 mmol) in tetrahydrofuran (2 mL), water (2 mL), and methanol (2 mL), lithium hydroxide (45 mg, 1.88 mmol) was added, and the reaction solution was stirred at 75°C for 3 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 3 with dilute hydrochloric acid (2 M). The aqueous layer was extracted with ethyl acetate (20 mL), and then the aqueous layer was freeze-dried to obtain crude intermediate 203-3, which was used directly in the subsequent steps.

[0239] Step 3 To a solution of intermediate 203-3 (90 mg, 0.09 mmol) in dimethyl sulfoxide (1 mL), intermediate 134-4 (30 mg, 0.13 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (37.10 mg, 0.13 mmol), and N-methylimidazole (43 mg, 0.53 mmol) were added, and the reaction solution was stirred at 25°C for 1 hour. After the reaction was complete, the crude product was purified by preparative HPLC (SunFire-C18-10 μm-19*250 mm, flow rate: 25 mL / min, mobile phase: A: 0.1% FA / H2O B: ACN) to obtain compound 203 (5.38 mg, 0.01 mmol, 11.91%) as a pale yellow solid. MS m / z (ESI): 467.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), δ 7.94 - 7.79 (m, 2H), 7.43 - 7.33 (m, 1H), 7.20 - 7.07 (m, 3H), 5.44 - 5.35 (m, 2H), 5.03 (t, J = 3.6 Hz, 2H), δ 4.94 - 4.80 (m, 2H), 4.51 (s, 2H), 4.36 (dd, J = 10.4, 49.2 Hz, 2H).

[0240] Example 41 Synthesis of compound 204 [ka] Step 1 At room temperature, intermediate 204-2 (380 mg, 2.04 mmol), tetrakis(triphenylphosphine)palladium(0) (236 mg, 0.2 mmol), and potassium carbonate (0.56 g, 4.08 mmol) were added to a solution of intermediate 204-1 (500 mg, 2.04 mmol) in dioxane (5 mL) and water (0.5 mL). The reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 10 hours. The reaction solution was then cooled to room temperature, and the solid precipitated. The mixture was filtered, the filter cake was washed with water (10 mL), and dried to obtain intermediate 204-3 (200 mg, 0.89 mmol, yield 43.72%).

[0241] Step 2 A solution of intermediate 204-3 (200 mg, 0.89 mmol) and sodium hydroxide (143 mg, 3.57 mmol) in 2 mL of water was stirred at 85°C for 10 hours. After the reaction solution was cooled to room temperature, dilute hydrochloric acid (1 M) was added to adjust the pH to 3, and the solid was precipitated. The mixture was filtered, and the filtered cake was dried to obtain crude intermediate 204-4 (150 mg, 0.62 mmol, yield 69.14%), which was used as is in the subsequent steps.

[0242] Step 3 At room temperature, chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (172 mg, 0.61 mmol) and N-methylimidazole (236 mg, 2.87 mmol) were added to acetonitrile (2 mL) solutions of intermediate 204-4 (100 mg, 0.41 mmol) and intermediate 134-4 (94 mg, 0.41 mmol). The reaction solution was stirred at room temperature for 2 hours, then quenched with water (10 mL), and extracted with ethyl acetate (5 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (Waters-Xbridge-C18-10μm-19*250mm, mobile phase: A: 10mM FA; B: ACN, gradient: 10-60%, retention time: 10 min) to obtain compound 204 (2.36 mg, 0.01 mmol, yield 1.26%). MS m / z (ESI): 454.9 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.72 (s, 1H), 8.37 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.57 (s, 2H), 7.31 (d, J = 7.6 Hz, 1H), 7.16 (s, 1H), 4.99 (d, J = 10.4 Hz, 1H), 4.94 - 4.86 (m, 3H), 4.46 (s, 3H), 4.42 (d, J = 10.0 Hz, 1H), 4.32 (d, J = 10.0 Hz, 1H).

[0243] Example 42 Synthesis of compound 205 [ka] At room temperature, compound 144-4 (84 mg, 0.33 mmol), copper powder (4.0 mg, 0.06 mmol), cuprous iodide (90 mg, 0.06 mmol), and cesium carbonate (311 mg, 0.96 mmol) were added to a solution of compound 1102-2 (100 mg, 0.33 mmol) in 1,4-dioxane (2 mL). The atmosphere was purged three times with nitrogen and stirred at 100°C for 10 hours. The reaction solution was added with water (10 mL) and extracted with ethyl acetate (5 mL). The recovered organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters-Xbridge-C18-10μm-19*250mm, mobile phase: A: 10mM NH4HCO3; B: ACN, gradient: 5-85%, retention time: 7 min) to obtain compound 205 (18.27 mg, 0.04 mmol, yield 11.61%). MS m / z (ESI): 472.9 [M+H] + ; 1 H NMR (400 MHz, DMSO-6) δd 10.52 (s, 1H), 7.96 (s, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.71 (s, 1H), 7.33 (d, J = 1.6, 8.4 Hz, 1H), 7.22 (t, J = 3.2 Hz, 1H), 7.15 (d, J = 1.6 Hz, 1H), 4.89 (s, 2H), 4.86 - 4.75 (m, 2H), 4.49 - 4.42 (m, 2H), 4.39 - 4.22 (m, 2H), 3.46 - 3.38 (m, 2H), 2.22 - 2.15 (m, 2H).

[0244] Example 43 Synthesis of compound 1088 [ka] Step 1 At 0°C and under a nitrogen atmosphere, a solution of potassium-tert-butyl oxide in tetrahydrofuran (112 mL, 112 mmol, 1.0 M) was added to a solution of propionitrile (7.9 mL, 112 mmol) in DMSO (80 mL). The mixture was stirred for 15 minutes, followed by the addition of compound 1088-1 (10.0 g, 55.8 mmol), and then heated at 50°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (400 mL), and washed with ethyl acetate (800 mL). The pH of the aqueous layer was adjusted to approximately 6.5 using a 1.5 M HCl solution. The solid obtained by filtration was washed with water (1000 mL), then with acetone (1000 mL), and dried under vacuum. The obtained solid was stirred in MTBE (1000 mL) for 12 hours, filtered, and dried under vacuum to obtain compound 1088-2 (4.6 g, 22.8 mmol, yield 40.8%) as a brown solid.

[0245] Step 2 Under a nitrogen atmosphere, a solution of compound 134-4 (50 mg, 0.25 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (104 mg, 0.37 mmol), and N-methylimidazole (99.65 μL, 1.25 mmol) in acetonitrile (3 mL) was stirred at room temperature for 30 minutes, and then compound 1088-2 (57 mg, 0.25 mmol) was added. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was diluted with DMSO (5 mL), filtered, and the solid was washed with DMSO (2 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (waters-xbridge-C18-10μm-19*250mm, mobile phase: 0.1%NH4HCO3 / H2O B:CH3CN, gradient: 55%B~85%B, Ret 8.5 min) to obtain compound 1088 (16 mg, 0.03 mmol, 15.64%, 5.64%) as a white solid. MS m / z (ESI): 413.9 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.00 (d, J = 2.0 Hz, 1H), 7.89 - 7.80 (m, 2H), 7.75 (dd, J = 2.0, 8.8 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 1.6 Hz, 1H), 6.58 (s, 2H), 4.88 (s, 2H), 4.67 (s, 2H), 4.32 (d, J = 44.3 Hz, 2H), 2.22 (s, 3H).

[0246] Example 44 Synthesis of compound 208 [ka] A 1,4-dioxane (1.5 mL) solution of compound 95-4 (80 mg, 0.35 mmol), compound 1102-2 (104 mg, 0.35 mmol), copper powder (26 mg, 0.42 mmol), cuprous iodide (99 mg, 0.52 mmol), cesium carbonate (227 mg, 0.70 mmol), and (R,R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (99 mg, 0.70 mmol) was purged three times with nitrogen, heated to 95°C in a sealed tube, and stirred for 16 hours. After the reaction solution cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (mobile phase: A: 10 mM NH4HCO3; B: ACN, gradient: 40-50%, retention time: 8.5 min) to obtain compound 208 (1.87 mg, 0.004 mmol, yield 1.2%) as a white solid. MS m / z (ESI): 450.0 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.20 (s, 1H), 7.94 - 7.88 (m, 2H), 7.33 (d, J = 8.0 Hz, 1H), 7.19 (s, 2H), 7.15 (d, J = 1.6 Hz, 1H), 4.89 (s, 2H), 4.87 - 4.74 (m, 2H), 4.41 - 4.18 (m, 2H).

[0247] Example 45 Synthesis of compound 209 [ka] Step 1 Compound 204-1 (200 mg, 0.82 mmol), compound 1093-3 (630 mg, 2.45 mmol), potassium carbonate (340 mg, 2.46 mmol), and tetrakistriphenylphosphine palladium (94 mg, 0.08 mmol) were dissolved in a mixed solution of water (1 mL) and 1,4-dioxane (10 mL). The mixture was stirred under a nitrogen atmosphere at 90°C for 18 hours. After the reaction was complete, the reaction solution was filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 209-1 (200 mg, 0.44 mmol, yield 54.17%) as a yellow solid.

[0248] Step 2 A solution of compound 209-1 (300 mg, 1.33 mmol) and sodium hydroxide (320 mg, 8.00 mmol) in 10 mL of water was stirred at 85°C for 18 hours. After the reaction was complete, the reaction solution was filtered. The aqueous phase was acidified to pH=4 with hydrochloric acid (1 M) and filtered again. The filtered cake was washed with water (10 mL) and dried under vacuum to obtain compound 209-2 (84 mg, 0.34 mmol, yield 25.83%) as a yellow solid.

[0249] Step 3 A solution of compound 209-2 (100 mg, 0.41 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (172 mg, 0.61 mmol), and N-methylimidazole (0.10 mL, 1.22 mmol) in dimethylformamide (3 mL) was stirred at 25°C for 10 minutes, compound 134-4 (200 mg, 0.87 mmol) was added, and the mixture was stirred for 2 hours. After the reaction was complete, the reaction solution was filtered. The crude product was purified by preparative HPLC (Waters-Xbridge-C18-10 μm-19*250 mm; mobile phase: A: 10 mM formic acid / water B: acetonitrile; flow rate: 25) to obtain compound 209 (1.56 mg, 0.00 mmol, 0.80%) as a white solid. MS m / z (ESI): 457.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.13 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.33 - 7.22 (m, 3H), 7.16 (s, 1H), 5.52 - 5.32 (m, 3H), 5.00 - 4.80 (m, 4H), 4.41 (d, J = 10.4 Hz, 1H), 4.30 (d, J = 10.4 Hz, 1H), 1.43 (d, J = 6.0 Hz, 3H).

[0250] Example 46 Synthesis of compound 210 [ka] Step 1 Compound 194-2 (2500 mg, 2.71 mmol), XPhos Pd G3 (195 mg, 0.23 mmol), XPhos (165 mg, 0.35 mmol), and potassium phosphate (1480 mg, 6.97 mmol) were added to a solution of compound 210-1 (400 mg, 2.33 mmol) in water (2 mL) and dioxane (20 mL). The mixture was stirred at 100°C for 18 hours. After the reaction was complete, the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 10:1) to obtain compound 210-2 (900 mg, 1.86 mmol, 79.88%) as a black solid.

[0251] Step 2 To a solution of compound 210-2 (800 mg, 1.65 mmol) in tetrahydrofuran (4 mL), water (45 mL), and methanol (4 mL), lithium hydroxide (400 mg, 9.53 mmol) was added. The mixture was stirred at 75°C for 3 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 3 with dilute hydrochloric acid (2 M). The aqueous layer was washed with ethyl acetate (20 mL) and then freeze-dried to obtain the crude product compound 210-3, which was used directly in the subsequent steps.

[0252] Step 3 Compound 210 (2.1 mg, 0.00 mmol, yield 1.09%) was obtained as a white solid by HPLC (SunFire-C18-10μm-19*250mm, flow rate: 25 mL / min, mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN). Compound 210 (2.1 mg, 0.00 mmol, yield 1.09%) was added to a solution of compound 210-3 (500 mg, 0.44 mmol) in dimethyl sulfoxide (2 mL). + ; 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 2.0 Hz, 1H), 8.32 (s, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.81 (dd, J = 2.0, 8.8 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.22 (s, 2H), 7.17 (s, 1H), 4.88 (s, 2H), 4.77 - 4.70 (m, 2H), 4.41 - 4.31 (m, 2H).

[0253] Example 47 Synthesis of compound 211 [ka] Step 1 To a solution of compound 211-1 (25.0 g, 99.42 mmol) in methanol (250 mL) and water (25 mL), ammonium chloride (53.2 g, 994.19 mmol) and iron powder (27.3 g, 55.84 mmol) were added. The mixture was purged three times with nitrogen and stirred at 80°C for 5 hours. The reaction solution was filtered. Water (200 mL) was added to the filtrate and extracted with ethyl acetate (150 mL). The recovered organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 211-2 (20.1 g, 90.75 mmol, yield 91.28%) as a white solid.

[0254] Step 2 At room temperature, potassium acetate (8.4 g, 85.79 mmol) and acetic anhydride (13.1 g, 128.68 mmol) were added to a chloroform (250 mL) solution of compound 211-2 (19.0 g, 85.79 mmol) under stirring. The reaction solution was purged three times with nitrogen and then stirred at 65°C for 2 hours. The reaction solution was cooled to 0°C, and isoamyl nitrite (10.05 g, 85.79 mmol) and 1,4,7,10,13,16-hexaoxacyclooctadecane (2.72 g, 10.29 mmol) were added, and then stirred at 65°C for 18 hours. The reaction solution was cooled to room temperature, its pH was adjusted to 7 with a saturated aqueous solution of sodium bicarbonate, and it was extracted with dichloromethane (150 mL). The recovered organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain a yellow solid compound, which was washed with (petroleum ether / dichloromethane = 15 / 1, 200 mL) to obtain compound 211-3 (14.0 g, 60.22 mmol, yield 70.20%) as a white solid.

[0255] Step 3 At room temperature, sodium iodide (193 mg, 1.29 mmol) and potassium carbonate (445 mg, 3.23 mmol) were added to a solution of compound 211-3 (300 mg, 1.29 mmol) and compound 211-4 (434 mg, 1.94 mmol) in N,N-dimethylformamide (7 mL). The mixture was stirred at 80°C for 3 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL). The recovered organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 211-5 (150 mg, 0.40 mmol, yield 30.94%) as a white solid.

[0256] Step 4 At room temperature, a solution of hydrogen chloride and 1,4-dioxane (4.0 M, 5 mL) was added to compound 211-5 (150 mg, 0.40 mmol). The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, diluted with water, and adjusted to pH=8 with saturated sodium bicarbonate solution. It was then extracted with ethyl acetate (5 mL). The recovered organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain compound 211-6 (130 mg, 0.47 mmol) as a yellow solid, which was used directly in the subsequent steps.

[0257] Step 5 At room temperature, potassium carbonate (195 mg, 1.41 mmol) was added to compound 211-6 (130 mg, 0.47 mmol) in dimethyl sulfoxide (5 mL). The reaction solution was purged three times with nitrogen and then stirred at 120 °C for 16 hours. Water (20 mL) was added to the reaction solution and extracted with ethyl acetate (10 mL). The recovered organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 211-7 (60 mg, 0.25 mmol, yield 53.19%) as a white solid.

[0258] Step 6 At room temperature, a mixture of compound 211-7 (60 mg, 0.25 mmol), compound 1102-2 (90 mg, 0.30 mmol), copper powder (19 mg, 0.30 mmol), cuprous iodide (95 mg, 0.50 mmol), cesium carbonate (245 mg, 0.75 mmol), and N,N'-dimethylethylenediamine (44 mg, 0.50 mmol) in 1,4-dioxane (3 mL) was stirred at 90°C for 16 hours under a nitrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was purified by preparative HPLC (Waters-Xbridge-C18-10μm-19*250mm, mobile phase: A: 10mM NH4HCO3; B: ACN, gradient: 40-50%, retention time: 8.5 min) to obtain compound 211 (1.79 mg, 0.004 mmol, yield 1.55%) as a white solid. MS m / z (ESI): 459.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.41 (s, 1H), 7.92 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.35 - 7.28 (m, 2H), 7.15 (s, 1H), 4.89 (d, J = 7.2 Hz, 2H), 4.86 - 4.77 (m, 2H), 4.41 - 4.34 (m, 3H), 4.26 (d, J = 10.8 Hz, 1H), 3.72 (s, 2H).

[0259] Example 48 Synthesis of compound 919 [ka] Step 1 At -78°C and under a nitrogen atmosphere, KMHDMS (342 mL) was added dropwise to a solution of compound 919-1 (25 g, 114 mmol) and compound 123-1a (36.5 g, 1.71 mol) in THF (500 mL). The mixture was reacted at -78°C for 1 hour, then heated to room temperature and reacted for 2 hours. The reaction product was quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The recovered organic layer was washed with brine (1000 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the crude product, which was further purified by reverse-phase column chromatography (acetonitrile / water (trifluoroacetic acid 0.1%) = 35%) to obtain compound 919-2 (1.1 g, 2.65 mmol, yield 2.33%) as a yellow solid.

[0260] Step 2 Under 0°C and a nitrogen atmosphere, sodium borohydride (261 mg, 7.95 mmol) was added to a solution of compound 919-2 (110 mg, 2.65 mmol) and CaCl2 (552 mg, 10.6 mmol) in THF (10 mL) and EtOH (5 mL). The mixture was stirred at 0°C for 0.5 hours, then heated to room temperature for 2 hours. The reaction product was quenched with water and extracted with ethyl acetate (50 mL). The recovered organic layer was washed with brine (70 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain compound 919-3 (495 mg, 1.28 mmol, yield 48.03%) as a white solid.

[0261] Step 3 Under a nitrogen atmosphere, 10% Pd / C (50 mg) was added to a methanol (5 mL) solution of compound 919-3 (495 mg, 1.28 mmol). The mixture was stirred at room temperature for 2 hours. The reaction solution was filtered and concentrated to obtain compound 919-4 (440 mg, 1.25 mmol, yield 97.46%) as a white oil.

[0262] Step 4 To a solution of compound 919-4 (440 mg, 1.25 mmol) and CuI (481 mg, 2.50 mmol) in MeCN (20 mL), isoamyl nitrite (177 mg, 1.51 mmol) was added dropwise. The mixture was reacted at room temperature for 0.5 hours, then heated to 80 °C for 16 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The recovered organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 919-5 (230 mg, 0.68 mmol, yield 53.68%) as a colorless oil.

[0263] Step 5 A solution of compound 919-5 (495 mg, 1.28 mmol) in dichloromethane (5 mL) was mixed with a solution of HCl and 1,4-dioxane (3 mL). The mixture was stirred at room temperature for 2 hours and then concentrated to obtain compound 919-6 (150 mg, 0.63 mmol, yield 92.50%) as a white solid.

[0264] Step 6 To a solution of compound 919-6 (70 mg, 0.29 mmol) and compound 84-11 (84 mg, 0.35 mmol) in DMF (2 mL), TCFH (121 mg, 0.43 mmol) and N-methylimidazole (59 mg, 0.72 mmol) were added. The mixture was reacted at room temperature for 16 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (30 mL). The recovered organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by preparative TLC (dichloromethane / methanol = 10 / 1), followed by preparative HPLC (column: Welch ultimate XB-NH2 250*50*10 μm, mobile phase: [heptane-EtOH (0.1%NH3H:O)]; B% 10%~10%, 10 min) to obtain compound 919 (27.28 mg, 0.06 mmol, yield 20.37%). MS m / z (ESI): 464.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.53 - 8.51 (m, 1H), 8.26 (s, 1H), 7.95 - 7.90 (m, 1H), 7.85 (s, 1H), 7.62 - 7.59 (m, 1H), 7.57 - 7.53 (m, 1H), 7.32 - 7.31 (m, 1H), 7.24 (s, 2H), 4.92 (s, 2H), 4.75 (brs, 2H), 4.42 (s, 4H), 4.36 - 4.28 (m, 1H), 3.21 (s, 3H).

[0265] Example 49 Synthesis of compound 213 [ka] Step 1 To a solution of compound 213-1 (48 mg, 0.15 mmol) and triethylamine (0.06 mL, 0.44 mmol) in dimethylformamide (2 mL), iodomethane (0.05 mL, 0.73 mmol) was added. The reaction solution was stirred at 50°C for 3 hours. After the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 6:1) to obtain compound 5 (60 mg, 0.15 mmol, yield 100.70%) as a white solid.

[0266] Step 2 A solution of compound 213-2 (60 mg, 0.18 mmol) in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) was stirred at 25°C for 2 hours. TLC (dichloromethane:methanol = 20:1) was used to determine if the reaction was complete and if new spots appeared on the plate. The reaction solution was then concentrated to obtain the crude product, compound 213-3 (60 mg, 0.17 mmol, yield 96.10%), as a red solid.

[0267] Step 3 A solution of compound 84-11 (40 mg, 0.17 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (70 mg, 0.25 mmol), and N-methylimidazole (0.05 mL, 0.66 mmol) in dimethyl sulfoxide (1 mL) was stirred at 25°C for 10 minutes, and then compound 213-3 (40.00 mg, 0.17 mmol) was added. The mixture was stirred at 25°C for 2 hours. After the reaction was complete, the reaction solution was filtered and purified by HPLC (Waters-Xbridge-C18-10 μm-19*250 mm; mobile phase: A: 10 mM ammonium bicarbonate / water B: acetonitrile; flow rate: 25) to obtain compound 213 (10.68 mg, 0.02 mmol, yield 13.86%) as a white solid. MS m / z (ESI): = 467.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 2.0 Hz, 1H), 8.27 (s, 1H), 7.88 (dd, J = 8.4, 2.0 Hz, 1H), 7.64 - 7.56 (m, 2H), 7.24 (s, 2H), 7.03 (d, J = 7.6 Hz, 1H), 6.80 (s, 1H), 4.66 (s, 2H), 4.43 (s, 3H), 4.27 (d, J = 29.2 Hz, 2H), 3.71 (s, 2H), 2.81 (s, 3H).

[0268] Example 50 Synthesis of compound 1041 [ka] Step 1 At 0°C, a solution of lithium aluminum tetrahydride in tetrahydrofuran (2.5N, 0.91mL, 2.28 mmol) was added dropwise to a solution of compound 123-3 (780 mg, 2.28 mmol) in tetrahydrofuran (50 mL). The reaction solution was stirred at 0°C for 2 hours. After the reaction was complete, the reaction solution was quenched with sodium sulfate decahydrate and filtered. The organic layer was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 213-1 (140 mg, 0.43 mmol, yield 18.71%) as a white solid.

[0269] Step 2 A solution of compound 213-1 (120 mg, 0.37 mmol) in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) was stirred at 25°C for 2 hours. TLC (dichloromethane:methanol = 20:1) was used to determine if the reaction was complete and if new spots appeared on the plate. The reaction solution was then concentrated to obtain the crude product, compound 1041-1 (80 mg, 0.35 mmol, yield 95.91%), as a red solid.

[0270] Step 3 A solution of compound 84-11 (100 mg, 0.41 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (170 mg, 0.61 mmol), and N-methylimidazole (0.16 mL, 2.06 mmol) in dimethyl sulfoxide (1 mL) was stirred at 25°C for 30 minutes, and then compound 1041-1 (100 mg, 0.44 mmol) was added. The mixture was stirred at 25°C for 2 hours. After the reaction was complete, the reaction solution was concentrated and dissolved in dimethyl sulfoxide (3 mL). The crude product was purified by HPLC (Waters-Xbridge-C18-10μm-19*250mm; mobile phase: A: 10mM ammonium bicarbonate / water B: acetonitrile; flow rate: 25) to obtain compound 1041 (34.1 mg, 0.07 mmol, yield 18.12%) as a white solid. MS m / z (ESI): = 453.1 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 2.0 Hz, 1H), 8.27 (s, 1H), 7.87 (dd, J = 8.6, 2.0 Hz, 1H), 7.64 - 7.57 (m, 2H), 7.23 (s, 2H), 6.96 (d, J = 7.6 Hz, 1H), 6.74 (d, J = 1.6 Hz, 1H), 6.11 (s, 1H), 4.64 (s, 2H), 4.43 (s, 3H), 4.26 (s, 2H), 3.82 (d, J = 1.7 Hz, 2H).

[0271] Example 51 Synthesis of compound 215 [ka] Step 1 To a solution of compound 215-1 (2 g, 7.49 mmol) and compound 215-1a (1.81 g, 11.23 mmol) in 1,4-dioxane (40 mL) and water (10 mL), cesium carbonate (4.88 g, 14.98 mmol) and Pd(dppf)Cl2 (0.55 g, 0.75 mmol) were added. The mixture was reacted at 100°C under a nitrogen atmosphere for 3 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The recovered organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 215-2 (1.1 g, 4.97 mmol, yield 66.41%) as a yellow solid.

[0272] Step 2 At -78°C and under a nitrogen atmosphere, KMHDMS (7.2 mL) was added dropwise to a solution of compound 215-2 (1 g, 2.4 mmol) and compound 123-1a (1.03 g, 4.8 mmol) in THF (50 mL). The mixture was reacted at -78°C for 1 hour, then heated to room temperature for 2 hours. The reaction product was quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The recovered organic layer was washed with brine (1000 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (SiO2, PE / EA = 3 / 1) to obtain the crude product, which was then purified by liquid column chromatography (MeCN / H2O (TFA 0.1%) = 35%) to obtain compound 215-3 (143 mg, 0.36 mmol, yield 15.0%) as a yellow solid.

[0273] Step 3 Under 0°C and a nitrogen atmosphere, sodium borohydride (242.55 mg, 6.41 mmol) was added in batches to a solution of compound 215-3 (890 mg, 2.14 mmol) and CaCl2 (948.75 mg, 8.55 mmol) in THF (10 mL) and EtOH (5 mL). The mixture was stirred at 0°C for 0.5 hours, then heated to room temperature for 2 hours. The reaction product was quenched with water and extracted with ethyl acetate (50 mL). The recovered organic layer was washed with brine (70 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by column chromatography (PE / EA = 1 / 4) to obtain compound 215-4 (440 mg, 1.13 mmol, yield 53.0%) as a white solid.

[0274] Step 4 Under a nitrogen atmosphere, Pd / C (50 mg) was added to a methanol (5 mL) solution of compound 215-4 (440 mg, 1.13 mmol). The mixture was stirred at room temperature for 2 hours. The reaction solution was filtered and concentrated to obtain compound 215-5 (348 mg, 0.97 mmol, yield 86.0%) as a white oil.

[0275] Step 5 To a solution of compound 215-5 (348 mg, 0.97 mmol) and CuI (361 mg, 1.9 mmol) in MeCN (20 mL), isoamyl nitrite (133 mg, 1.14 mmol) was added dropwise. The mixture was reacted at room temperature for 0.5 hours, then heated at 80 °C for 16 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The recovered organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (SiO2, PE / EA = 1 / 1) to obtain compound 215-6 (110 mg, 0.32 mmol, yield 33.97%) as a colorless oil.

[0276] Step 6 A solution of compound 215-6 (110 mg, 0.32 mmol) in dichloromethane (5 mL) was mixed with a solution of 1,4-dioxane in HCl (3 mL). The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain compound 215-7 (70 mg, 0.29 mmol, yield 90.62%) as a white solid.

[0277] Step 7 To a solution of compound 215-7 (70 mg, 0.29 mmol) and compound 84-11 (84 mg, 0.29 mmol) in DMF (2 mL), TCFH (121 mg, 0.43 mmol) and N-methylimidazole (59 mg, 0.72 mmol) were added. The mixture was reacted at room temperature for 16 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (30 mL). The recovered organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by preparative TLC (dichloromethane / methanol = 10 / 1), followed by preparative HPLC (column: Welch ultimate XB-NH2 250*50*10 μm, mobile phase: [heptane-EtOH (0.1%NH3H:O)]; B% 10%~10%, 10 min) to obtain compound 215 (6.5 mg, 0.01 mmol, yield 4.81%). MS m / z (ESI): 466.0 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 2.0 Hz, 1H), 8.26 (s, 1H), 8.12 (s, 1H), 7.88 - 7.82 (m, 2H), 7.62 - 7.56 (m, 2H), 7.25 - 7.17 (m, 3H), 7.02 (d, J = 1.4 Hz, 1H), 4.80 (s, 2H), 4.70 (d, J = 15.3 Hz, 2H), 4.42 (s, 3H), 4.33 (d, J = 33.1 Hz, 2H), 3.84 (s, 3H).

[0278] Example 52 Synthesis of compound 216 [ka] Step 1 Under a nitrogen atmosphere at -78°C, potassium bis(trimethylsilyl)amide (1.0 M, 165 mL, 165 mmol) was added dropwise to a solution of compound 216-1 (20.0 g, 109.76 mmol) and compound 216-2 (19.4 g, 110 mmol) in tetrahydrofuran (100 mL). After the addition was complete, the mixture was stirred at -78°C for 2 hours. After the reaction was complete, the reaction solution was quenched with saturated ammonium chloride (100 mL), diluted with water (200 mL), and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 4) to obtain compound 216-3 (3.22 g, 9.49 mmol, yield 8.65%) as yellow oil.

[0279] Step 2 Under a nitrogen atmosphere at -78°C, a solution of compound 216-3 (3.22 g, 9.49 mmol) in toluene (20 mL) was mixed with diisobutylaluminum hydride (1.0 M, 28 mL, 28 mmol). The mixture was stirred at -78°C for 2 hours. After the reaction was complete, the reaction solution was quenched with methanol (20 mL) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 10) to obtain compound 216-4 (1.5 g, 4.38 mmol, yield 46.18%) as a yellow solid.

[0280] Step 3 At 0°C, sodium borohydride (0.25 g, 6.57 mmol) was added to a methanol (20 mL) solution of compound 216-4 (1.5 g, 4.38 mmol). The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was quenched with saturated ammonium chloride (50 mL) and extracted with ethyl acetate (30 mL). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 4) to obtain compound 216-5 (150 mg, 0.44 mmol, yield 9.94%) as yellow oil.

[0281] Step 4 To a solution of compound 216-5 (150 mg, 0.44 mmol) in methanol (1.5 mL), tetrahydrofuran (1.5 mL), and water (1.5 mL), ammonium chloride (235 mg, 4.4 mmol) and iron powder (123 mg, 2.2 mmol) were added. The mixture was stirred at 80°C for 1 hour. After the reaction was complete, the reaction solution was filtered. The filtrate was diluted with water (30 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 10) to obtain compound 216-6 (140 mg, 0.23 mmol, yield 100%) as a white solid.

[0282] Step 5 At 0°C, cuprous iodide (170 mg, 0.89 mmol) and isoamyl nitrite (62 mg, 0.53 mmol) were added to a solution of compound 216-6 (140 mg, 0.23 mmol) in acetonitrile (5 mL). The reaction solution was stirred at 0°C for 1 hour, and then heated to 80°C for 2 hours. After the reaction was complete, the reaction solution was filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) to obtain compound 216-7 (17 mg, 0.06 mmol, yield 12.84%) as a pale yellow oil.

[0283] Step 6 To a solution of compound 216-7 (17 mg, 0.06 mmol) in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain crude compound 216-8 (10 mg, crude), which was used directly in the subsequent steps without further purification.

[0284] Step 7 To a solution of compound 216-8 (10 mg, 0.05 mmol) and compound 84-11 (13 mg, 0.06 mmol) in N,N-dimethylformamide (1 mL), N-methylimidazole (25 mg, 0.3 mmol) and chloro-N,N,N',N'-tetramethylformamidine hexafluorophosphate (21 mg, 0.08 mmol) were added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was filtered. The filtrate was purified by preparative HPLC (mobile phase: A: 0.1% FA; B: ACN, gradient: 16-56%, retention time: 9.2 min) to obtain compound 216 (13.53 mg, 0.03 mmol, yield 63.31%) as a white solid. MS m / z (ESI): 422.0 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 2.0 Hz, 1H), 8.28 (s, 1H), 8.14 (s, 0.6H), 7.93 - 7.74 (m, 2H), 7.60 (d, J = 8.8 Hz, 1H), 7.40 - 7.20 (m, 2H), 7.01 - 6.97 (m, 1H), 4.86 (s, 2H), 4.70 (brs, 2H), 4.42 (s, 3H), 4.38 - 4.30 (m, 2H).

[0285] Example 53 Synthesis of compound 217 [ka] Step 1 A solution of intermediate 217-1 (50 mg, 0.19 mmol) dissolved in N,N-dimethylformamide ("DMF") (1.5 mL), N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate ("HATU") (110 mg, 0.29 mmol), and N,N-diisopropylethylamine (0.16 mL, 0.94 mmol) was stirred at 25°C for 10 minutes. Then, intermediate 1038-2 (100 mg, 0.35 mmol) was added to the solution, and stirring was continued at 25°C for 2 hours. After the reaction was complete, the reaction solution was filtered. The crude product was separated by high-pressure liquid chromatography-mass spectrometry (Waters-Xbridge-C18-10μm-19*250mm; mobile phase: A: 10mM ammonium bicarbonate / water B: acetonitrile; flow rate: 25) to obtain compound 217 (35.35 mg, 0.07 mmol, 34.78%) as a white solid. MS m / z (ESI): = 530.9 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J = 7.6 Hz, 1H), 7.72 (s, 1H), 7.62 (s, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.41 (s, 1H), 6.90 (s, 2H), 5.36 (q, J = 3.2 Hz, 2H), 5.00 (t, J = 3.6 Hz, 2H), 4.54 (p, J = 6.8 Hz, 1H), 4.36 - 4.23 (m, 2H), 4.22 - 4.10 (m, 2H), 1.41 (d, J = 6.8 Hz, 6H).

[0286] Synthesis of intermediate 217-1 [ka] Step 1 To a solution of intermediate 217-2 (3.00 g, 11.34 mmol) in 1,4-dioxane (60 mL), bis(pinacolate)diborone (3.46 g, 13.61 mmol), potassium acetate (3.34 g, 34.03 mmol), and Pd(dppf)Cl2 (0.5 g, 0.68 mmol) were added. The mixture was stirred at 100°C for 2 hours. After the reaction was complete, the reaction solution was filtered through Celite and washed with ethyl acetate. The solvent was removed under reduced pressure to obtain crude intermediate 217-3, which was used directly in the subsequent steps.

[0287] Step 2 To a solution of intermediate 217-4 (1 g, 4.11 mmol) in 1,4-dioxane (60 mL) and water (4 mL), intermediate 217-3 (1.92 g, 6.11 mmol), tetrakis(triphenylphosphine)palladium (0.48 g, 0.41 mmol), and potassium carbonate (1.71 g, 12.34 mmol) were added. The mixed solution was stirred and reacted at 80°C for 18 hours. After the reaction was complete, the reaction solution was filtered through Celite and washed with methanol and dichloromethane. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 10:1) to obtain intermediate 203-1 (1.1 g, 3.95 mmol, yield 95.98%) as a black solid.

[0288] Step 3 Lithium hydroxide (350 mg, 15.87 mmol) was added to a mixed solution of intermediate 203-1 (550 mg, 1.97 mmol) in tetrahydrofuran (5 mL), water (5 mL), and methanol (5 mL). The mixture was stirred at 75°C for 3 hours. After the reaction was complete, the reaction solution was adjusted to pH=3 with dilute hydrochloric acid (2 M). The aqueous layer was washed with ethyl acetate (20 mL) and freeze-dried to obtain crude intermediate 217-1, which was used directly in the subsequent synthesis procedure.

[0289] Example 54 Synthesis of compound 218 [ka] To a solution of intermediates 1045-7 (30 mg, 0.13 mmol) and 137-4 (30 mg, 0.13 mmol) in N,N-dimethylformamide (2 mL), HATU (74 mg, 0.2 mmol) and DIPEA (34 mg, 0.26 mmol) were added. The reaction solution was stirred at room temperature for 1 hour, and after the reaction was completed, it was concentrated under reduced pressure. The residue was dissolved in dimethyl sulfoxide (3 mL) and filtered. The filtrate was purified by preparative HPLC (mobile phase: A: 0.1% NH4HCO3; B: ACN, gradient: 16-56%, retention time: 9.2 min) to obtain compound 218 (6.58 mg, 0.01 mmol, yield 11.44%) as a white solid. MS m / z (ESI): 442.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.96 - 7.81 (m, 3H), 7.81 - 7.73 (m, 2H), 7.59 - 7.54 (m, 1H), 6.78 (s, 2H), 5.42 - 5.34 (m, 2H), 5.15 (s, 2H), 5.08 - 4.97 (m, 2H), 4.82 - 4.31 (m, 4H).

[0290] Example 55 Synthesis of compound 219 [ka] To a solution of intermediates 162-5 (30 mg, 0.13 mmol) and 134-4 (28 mg, 0.13 mmol) in N,N-dimethylformamide (2 mL), HATU (74 mg, 0.2 mmol) and DIPEA (34 mg, 0.26 mmol) were added. The reaction solution was stirred at room temperature for 1 hour, and after the reaction was completed, it was concentrated under reduced pressure. The crude product was dissolved in dimethyl sulfoxide (3 mL) and filtered. The filtrate was purified by preparative HPLC (mobile phase: A: 0.1% NH4HCO3; B: ACN, gradient: 16-56%, retention time: 9.1 min) to obtain compound 219 (18.19 mg, 0.04 mmol, yield 30.48%) as a white solid. MS m / z (ESI): 460.0 [M+H] + ; 1H NMR (400 MHz, CD3OD) δ 7.84 - 7.80 (m, 1H), 7.78 - 7.71 (m, 2H), 7.63 (s, 1H), 7.36 - 7.31 (m, 1H), 5.45 - 5.41 (m, 2H), 5.24 - 5.16 (m, 2H), 5.12 - 5.08 (m, 2H), 4.54 (s, 1H), 4.52 - 4.49 (m, 2H), 4.45 (s, 1H).

[0291] Example 56 Synthesis of compound 220 [ka] At room temperature, N-methylimidazole (82 mg, 1.01 mmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (113 mg, 0.40 mmol) were added to dimethyl sulfoxide (2 mL) solutions of intermediates 162-5 (50 mg, 0.20 mmol) and 901-2 (63 mg, 0.26 mmol). The reaction solution was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The crude product was purified by preparative HPLC (Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: A: 10 mM NH4HCO3; B: ACN, gradient: 5-70%, retention time: 8.1 min) to obtain compound 220 (12 mg, 0.03 mmol, yield 12.58%). MS m / z (ESI): 473.9 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.94 - 7.92 (m, 1H), 7.88 - 7.83 (m, 1H), 7.73 - 7.70 (m, 1H), 7.50 - 7.49 (m, 1H), 7.40 - 7.37 (m, 1H), 5.39 - 5.38 (m, 2H), 5.02 - 5.01 (m, 2H), 4.80 - 4.79 (m, 2H), 4.21 - 4.05 (m, 6H).

[0292] Example 57 Synthesis of compound 221 [ka] A solution of intermediate 162-5 (50 mg, 0.20 mmol), HATU (120 mg, 0.32 mmol), and N,N-diisopropylethylamine (0.18 mL, 1.01 mmol) in N,N-dimethylformamide (1 mL) was stirred at 25°C for 10 minutes. Intermediate 1038-2 (100 mg, 0.35 mmol) was added, and stirring was continued at 25°C for 2 hours. After the reaction was complete, the reaction solution was filtered. The filtrate was purified by HPLC-MS (Waters-Xbridge-C18-10 μm-19*250 mm; mobile phase: A: 10 mM formic acid / water B: acetonitrile; flow rate: 25) to obtain compound 221 (10 mg, 0.02 mmol, 9.58%) as a white solid. MS m / z (ESI): 515.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.41 (s, 1H), 7.31 (d, J = 12.4 Hz, 1H), 6.94 (s, 2H), 5.37 (d, J = 4.2 Hz, 2H), 5.00 (s, 2H), 4.60 - 4.45 (m, 1H), 4.39 - 4.22 (m, 4H), 1.41 (d, J = 6.8 Hz, 6H).

[0293] Example 58 Synthesis of compound 222 [ka] Step 1 Lithium hydroxide (4 g, 95.33 mmol) was added to a solution of intermediate 222-1 (8.50 g, 28.70 mmol) in water (30 mL), methanol (30 mL), and tetrahydrofuran (30 mL). The mixture was stirred at 75°C for 18 hours. After the reaction was complete, the reaction solution was adjusted to pH=3 with dilute hydrochloric acid (2 M), and a solid formed in the solution. The solution was filtered. The filtered cake was washed with 100 mL of water and dried under vacuum to obtain crude intermediate 222-2, which was used as is in the subsequent steps.

[0294] Step 2 A solution of intermediate 222-2 (8 g, 29.84 mmol) and CDI (9.68 g, 59.69 mmol) in N,N-dimethylformamide (100 mL) was stirred at 65°C for 2 hours. After the reaction solution was cooled to room temperature, it was added to aqueous ammonia (1500 mL, 33% purity) at 0°C. The mixture was stirred at room temperature for 18 hours. After the reaction was complete, the reaction solution was concentrated under vacuum and filtered. The filtered cake was washed with water (200 mL) and dried under vacuum to obtain intermediate 222-3.

[0295] Step 3 To a solution of intermediate 222-3 (8 g, 29.95 mmol) in N,N-dimethylformamide (100 mL), cyanuric chloride (3.3 g, 17.90 mmol) was added. The mixture was stirred at 65°C for 18 hours. After the reaction was complete, water (50 mL) was added. The solution was adjusted to pH=9 with saturated sodium bicarbonate solution and then filtered. The filtered cake was washed with water (200 mL) and dried under vacuum to obtain intermediate 222-4.

[0296] Step 4 A solution of intermediate 222-4 (7.5 g, 30.11 mmol) in phosphorus oxychloride (70 mL) was stirred at 100°C for 18 hours. After the reaction was complete, the reaction solution was concentrated under vacuum and then added with water (100 mL). The solution was adjusted to pH=9 with saturated sodium bicarbonate solution and then extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate:petroleum ether = 1 / 100 to 1 / 10) to obtain intermediate 222-5 (7.5 g, 28.04 mmol, 93.11%) as a white solid.

[0297] Step 5 Intermediate 222-5 (6.5 g, 24.30 mmol) in ethanol (65 mL) was mixed with hydrazine hydrate (52 mL). The mixture was stirred at 80°C for 0.5 hours. After the reaction was complete, the reaction solution was filtered to obtain intermediate 222-6 (5.00 g, 19.00 mmol, 78.21%) as a white solid.

[0298] Step 6 To a solution of intermediate 222-6 (50 mg, 0.19 mmol) in dimethyl sulfoxide (2 mL), intermediate 134-4 (65 mg, 0.28 mmol), triethylamine (80 μL, 0.58 mmol), and Pd(dppf)Cl2 dichloromethane complex (16 mg, 0.02 mmol) were added. The mixture was stirred at 100 °C for 18 hours, and after the reaction was completed, it was filtered. The crude product was purified by preparative HPLC (Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: A: 10 mM NH4HCO3; B: ACN, gradient: 5-70%, retention time: 8.1 min) to obtain compound 222 (10.9 mg, 0.02 mmol, 11.82%) as a yellow solid. MS m / z (ESI) = 439.9 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H), 9.16 (s, 1H), 8.62 (d, J = 1.9 Hz, 1H), 8.16 (s, 1H), 8.06 (d, J = 8.7 Hz, 1H), 7.99 (dd, J = 8.8, 1.9 Hz, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.40 - 7.33 (m, 1H), 7.17 (d, J = 1.6 Hz, 1H), 5.94 (s, 2H), 4.89 (d, J = 4.0 Hz, 2H), 4.75 (d, J = 17.4 Hz, 2H), 4.49 - 4.27 (m, 2H).

[0299] Example 59 Synthesis of compound 223 [ka] Step 1 Intermediate 223-1 (2 g, 5.77 mmol) and cuprous bromide (1.7 g, 11.85 mmol) were dissolved in acetonitrile (20 mL), to which tert-butyl nitrite (1.1 mL, 9.17 mmol) was added. The reaction solution was stirred at 80 °C for 4 hours, diluted with water (100 mL) and ammonia (2 mL), and extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and then concentrated. The crude product was purified by silica gel column chromatography (tetrahydrofuran:petroleum ether = 0-10%) to obtain intermediate 223-2 (1.28 g, 2.03 mmol, yield 35.11%, purity 65%) as a pale yellow colloid.

[0300] Step 2 Dess-Martin periodinane (1.1 g, 2.59 mmol) was added to a solution of intermediate 223-2 (1 g, 2.44 mmol) in dichloromethane (10 mL). The reaction solution was stirred at 25°C for 12 hours. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to obtain intermediate 223-3 (1.59 g, 2.45 mmol, 100.66%) as a pale yellow solid, which was used directly in the next step.

[0301] Step 3 Sodium hydride (0.43 g, 10.80 mmol, 60% purity) was added to a solution of methyltriphenylphosphonium bromide (4 g, 11.20 mmol) in tetrahydrofuran (15 mL). The reaction solution was stirred at 20°C for 30 minutes, after which intermediate 223-3 (1.59 g, 2.45 mmol) was added. The reaction solution was stirred at 60°C for 6 hours, quenched with saturated ammonium chloride solution (50 mL), and extracted with ethyl acetate (30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and then concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-5%) to obtain intermediate 223-4 (500 mg, 1.23 mmol, 50.16%) as a pale yellow oil.

[0302] Step 4 Under a nitrogen atmosphere, palladium acetate (28 mg, 0.12 mmol) was added to a solution of intermediate 223-4 (500 mg, 1.23 mmol), potassium acetate (365 mg, 3.72 mmol), and tetrabutylammonium bromide (480 mg, 1.49 mmol) in N,N-dimethylformamide (6 mL). The reaction solution was stirred at 100 °C for 8 hours, diluted with water (50 mL), and extracted with ethyl acetate (30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and then concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-5%) to obtain intermediate 223-5 (200 mg, 0.31 mmol, 24.97%) as a pale yellow oil.

[0303] Step 5 To a solution of intermediate 223-5 (50 mg, 0.15 mmol) in dichloromethane (0.5 mL), trifluoroacetic acid (120 μL, 1.57 mmol) was added. The reaction solution was stirred at 20°C for 2 hours, and then concentrated to obtain intermediate 223-6 (34.61 mg, 0.15 mmol, 99.99%) as a pale yellow oil.

[0304] Step 6 A mixed solution of intermediates 223-6 (34.61 mg, 0.15 mmol), 223-7 (60 mg, 0.18 mmol), and triethylamine (65 μL, 0.47 mmol) in tetrahydrofuran (1 mL) was stirred at 20°C for 2 hours and then concentrated. The crude product was purified by preparative HPLC (C18, 0.05% ammonium bicarbonate solution / acetonitrile) to obtain intermediate 223 (2.8 mg, 0.01 mmol, 4.05%) as a white solid. MS m / z (ESI): 450.1 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.56 (d, J = 2.0 Hz, 1H), 8.26 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.91 (dd, J = 2.0, 8.8 Hz, 1H), 7.71 (s, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.23 (s, 2H), 7.02 (d, J = 5.2 Hz, 1H), 6.91 (d, J = 5.6 Hz, 1H), 5.04 - 4.63 (m, 2H), 4.61 - 4.24 (m, 5H).

[0305] Synthesis of intermediate 223-7 [ka] To a solution of intermediate 84-11 (500 mg, 2.06 mmol) and triethylamine (350 μL, 2.52 mmol) in N,N-dimethylformamide (5 mL), isobutyl chloroformate (270 μL, 2.08 mmol) was added. The reaction solution was stirred at 20°C for 2 hours, diluted with water (50 mL) and ethyl acetate (50 mL), and the solid was removed by filtration. The filtrate was extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and then concentrated to obtain intermediate 223-7 (200 mg, 0.58 mmol, 28.30%) as a light brown solid. MS m / z (ESI): 343.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 2.4 Hz, 1H), 8.30 (s, 1H), 8.04 (dd, J = 8.8, 2.0 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.58 (s, 2H), 4.44 (s, 3H), 4.15 (d, J = 6.8 Hz, 2H), 2.02 (d, J = 6.8 Hz, 2H), 0.96 (d, J = 6.4 Hz, 6H).

[0306] Example 60 Synthesis of compound 224 [ka] At room temperature, intermediate 901-2 (41 mg, 0.17 mmol), N,N-diisopropylethylamine (44 mg, 0.34 mmol), and HATU (65 mg, 0.17 mmol) were added to a solution of intermediate 217-1 (30 mg, 0.11 mmol) in N,N-dimethylformamide (1 mL). The reaction solution was stirred at room temperature for 3 hours and then filtered. Water (3 mL) was added to the filtrate, and then extracted with ethyl acetate (1 mL). The organic layer was washed with brine (3 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC (Waters-Xbridge-C18-10μm-19*250mm, mobile phase: A: 10mM NH4HCO3; B: ACN, gradient: 10-65%, retention time: 14 min) to obtain compound 224 (9.73 mg, 0.02 mmol, yield 17.52%). MS m / z (ESI): 489.9,491.9 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.68 (s, 1H), 7.61 (s, 1H), 7.49 (s, 1H), 6.88 (s, 2H), 5.34 (t, J = 3.6 Hz, 2H), 4.99 (t, J = 3.6 Hz, 2H), 4.84 - 4.74 (m, 2H), 4.20 - 4.10 (m, 2H), 4.09 - 4.01 (m, 3H), 3.97 - 3.89 (m, 1H).

[0307] Example 61 Synthesis of compound 225 [ka] At room temperature, intermediate 1045-7 (39 mg, 0.17 mmol), N,N-diisopropylethylamine (44 mg, 0.34 mmol), and HATU (65 mg, 0.17 mmol) were added to a solution of intermediate 217-1 (30 mg, 0.11 mmol) in N,N-dimethylformamide (1 mL). The reaction solution was stirred at room temperature for 3 hours and then filtered. Water (3 mL) was added to the filtrate, and then extracted with ethyl acetate (1 mL). The organic layer was washed with brine (3 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC (Welch-Xtimate-C18-5μm-21.2*150mm, mobile phase: A: 10mM NH4HCO3; B: ACN, gradient: 10-65%, retention time: 11.4 min) to obtain compound 205 (28.25 mg, 0.06 mmol, yield 52.38%). MS m / z (ESI): 475.9 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 1.2 Hz, 2H), 7.74 (s, 1H), 7.71 (s, 1H), 7.60 (s, 1H), 6.88 (s, 2H), 5.39 - 5.28 (m, 2H), 5.19 - 5.08 (m, 2H), 4.99 (t, J = 3.6 Hz, 2H), 4.43 - 4.34 (m, 2H), 4.32 - 4.17 (m, 2H).

[0308] Example 62 Synthesis of compound 228 [ka] Step 1 Intermediate 228-1 (0.16 mL, 1.75 mmol) was added to a solution of intermediate 123-3 (300 mg, 0.88 mmol) and sodium hydride (100 mg, 2.50 mmol) in N,N-dimethylformamide (10 mL). The mixture was stirred at 50°C for 18 hours. After the reaction was complete, the reaction solution was added with water (30 mL) and then extracted with ethyl acetate (20 mL). The organic layer was washed with brine (50 mL) and then concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain intermediate 228-2 (350 mg, 0.87 mmol, 99.74%) as a white solid.

[0309] Step 2 A solution of intermediate 228-2 (350 mg, 0.87 mmol) in dichloromethane (5 mL) and trifluoroacetic acid (2 mL) was stirred at 25°C for 2 hours. After the reaction was complete, the reaction solution was concentrated to obtain crude intermediate 228-3 (340 mg, 0.82 mmol, 93.88%) as a red oil, which was used directly in the subsequent steps.

[0310] Step 3 Intermediate 137-4 (50 mg, 0.22 mmol), HATU (130 mg, 0.34 mmol), and a solution of N,N-diisopropylethylamine (0.19 mL, 1.09 mmol) in N,N-dimethylformamide (1 mL) were stirred at 25°C for 30 minutes. Intermediate 228-3 (70 mg, 0.23 mmol) was added, and stirring was continued at 25°C for 2 hours. After the reaction was complete, the reaction solution was filtered. The filtrate was purified by HPLC (Waters-Xbridge-C18-10 μm-19*250 mm; mobile phase: A: 10 mM ammonium bicarbonate / water B: acetonitrile; flow rate: 25) to obtain compound 228 (8.52 mg, 0.02 mmol, 7.57%) as a white solid. MS m / z (ESI): 513.0 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J = 7.6 Hz, 1H), 7.86 - 7.79 (m, 2H), 7.57 (dd, J = 0.8, 8.4 Hz, 1H), 7.51 - 7.45 (m, 1H), 7.43 (s, 1H), 6.78 (s, 2H), 5.36 (t, J = 3.6 Hz, 2H), 4.99 (t, J = 3.6 Hz, 2H), 4.72 (s, 1H), 4.55 (s, 1H), 4.33 - 4.28 (m, 2H), 3.90 (t, J = 5.6 Hz, 2H), 3.53 (t, J = 5.6 Hz, 2H), 3.20 (s, 3H).

[0311] Example 63 Synthesis of compound 229 [ka] Step 1 Intermediate 229-1 (0.65 mL, 4.38 mmol) was added to a solution of intermediate 123-3 (500 mg, 1.46 mmol) and sodium hydride (120 mg, 3.00 mmol) in N,N-dimethylformamide (10 mL). The reaction solution was stirred at 50°C for 18 hours. After the reaction was complete, water (30 mL) was added to the reaction solution and extracted with ethyl acetate (10 mL). The combined organic layers were dried over anhydrous sodium sulfate and then concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain intermediate 229-2 (489 mg, 1.04 mmol, 71.16%) as a colorless oil.

[0312] Step 2 A solution of intermediate 229-2 (200 mg, 0.43 mmol) in dichloromethane (5 mL) and trifluoroacetic acid (2.5 mL) was stirred at 25°C for 2 hours. After the reaction was complete, the reaction solution was concentrated to obtain crude intermediate 229-3 (110 mg, 0.38 mmol, 52.46%) as a yellow solid, which was used directly in the subsequent steps.

[0313] Step 3 A solution of intermediate 229-3 (40 mg, 0.17 mmol), HATU (100 mg, 0.26 mmol), and diisopropylethylamine (0.15 mL, 0.87 mmol) in N,N-dimethylformamide (1 mL) was stirred at 25°C for 10 minutes. Intermediate 137-4 (40 mg, 0.14 mmol) was added to the reaction solution, and stirring was continued at 25°C for 2 hours. After the reaction was complete, the reaction solution was filtered. The filtrate was purified by HPLC (Waters-Xbridge-C18-10 μm-19*250 mm; mobile phase: A: 10 mM formic acid / water B: acetonitrile; flow rate: 25) to obtain compound 229 (2.24 mg, 0.00 mmol, 2.49%) as a white solid. MS m / z (ESI): 499.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J = 7.6 Hz, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.86 - 7.84 (m, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.44 (s, 1H), 6.81 (s, 2H), 5.40 - 5.36 (m, 2H), 5.04 - 4.99 (m, 2H), 4.84 (t, J = 6.0 Hz, 1H), 4.77 - 4.71 (m, 1H), 4.61 - 4.54 (m, 1H), 4.39 - 4.24 (m, 2H), 3.83 - 3.77 (m, 2H), 3.64 - 3.58 (m, 2H).

[0314] Example 64 Synthesis of compound 230 [ka] Step 1 A solution of intermediate 229-3 (40 mg, 0.17 mmol), HATU (100 mg, 0.26 mmol), and diisopropylethylamine (0.14 mL, 0.80 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at 25°C for 10 minutes. Intermediate 84-11 (40 mg, 0.14 mmol) was added, and the reaction solution was further stirred at 25°C for 2 hours. After the reaction was complete, the reaction solution was filtered. The filtrate was purified by HPLC (Waters-Xbridge-C18-10 μm-19*250 mm; mobile phase: A: 10 mM ammonium bicarbonate / water B: acetonitrile; flow rate: 25) to obtain compound 230 (3.88 mg, 0.01 mmol, 4.73%) as a white solid. MS m / z (ESI): 511.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 2.0 Hz, 1H), 8.27(s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.90 (dd, J = 2.0, 8.8 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.45 (s, 1H), 7.26 (s, 2H), 4.85 (t, J = 6.0 Hz, 1H), 4.83 - 4.78 (m, 1H), 4.71 - 4.62 (m, 1H), 4.43 (s, 3H), 4.40 - 4.37 (m, 1H), 4.35 - 4.29 (m, 1H), 3.85 - 3.78 (m, 2H), 3.66 - 3.58 (m, 2H).

[0315] Example 65 Synthesis of compound 1042 [ka] Step 1 Under 0°C and a nitrogen atmosphere, DIAD (78 μL, 0.40 mmol) was added to a solution of triphenylphosphine (103 mg, 0.39 mmol) in tetrahydrofuran (1.5 mL), and then intermediate 1042-1 (150 mg, 0.28 mmol) and a solution of thioacetic acid (28 μL, 0.39 mmol) in tetrahydrofuran (1.5 mL) were added dropwise to the reaction solution. The mixture was stirred at 0°C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate and petroleum ether = 0-10%) to obtain intermediate 1042-2 (90 mg, 0.17 mmol, 62.63%) as a pale yellow oil.

[0316] Step 2 At 25°C under a nitrogen atmosphere, a solution of intermediate 1042-2 (99 mg, 0.19 mmol) in methanol (20 mL) was mixed with amine ethanol solution (1.0 mL, 2.0 mol / L). The mixture was stirred at 25°C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate and petroleum ether = 0-10%) to obtain intermediate 1042-3 (932 mg, 0.07 mmol, 38.58%) as a pale yellow oil.

[0317] Step 3 Under a nitrogen atmosphere at 25°C, trifluoroacetic acid (0.4 mL, 5.23 mmol) was added to a solution of intermediate 1042-3 (13 mg, 0.03 mmol) in dichloromethane (2.0 mL). The mixture was stirred at 25°C for 1 hour. After the reaction was complete, the reaction solution was concentrated to obtain crude intermediate 1042-4 (17 mg, 0.03 mmol, yield 98.98%) as a yellow oil, which was used directly in subsequent steps without further purification.

[0318] Step 4 Under a nitrogen atmosphere at 25°C, DIEA (11 mg, 0.09 mmol) was added to a DMSO (1.0 mL) solution of intermediates 84-11 (13 mg, 0.03 mmol) and HATU (33 mg, 0.09 mmol). The mixture was stirred at 25°C for half an hour. To the reaction solution, a DMSO (1.0 mL) solution of intermediate 1042-4 (17 mg, 0.03 mmol) was added, and stirring was continued at 25°C for 1.5 hours. After the reaction was complete, water (20 mL) was added to the reaction solution, and it was filtered. The filtered cake was purified by silica gel plate chromatography (CH2Cl2 / MeOH=15 / 1) to obtain compound 1042 (4.44 mg, 0.01 mmol, yield 16.04%) as a white solid. MS m / z (ESI): 470.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ: 8.53 (d, J = 2.0 Hz, 1H), 8.29 (s, 1H), 7.92 - 7.86 (m, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.56 - 7.49 (m, 1H), 7.46 - 7.19 (m, 2H), 4.78 - 4.57 (m, 2H), 4.43 (s, 3H), 4.41 - 4.16 (m, 2H), 3.82 (s, 2H).

[0319] Example 66 Synthesis of compound 232 [ka] Step 1 To a solution of intermediate 232-1 (10 g, 37.45 mmol) and intermediate 232-1a (13 g, 44.94 mmol) in 1,4-dioxane (160 mL) and water (40 mL), potassium carbonate (29.3 g, 74.9 mmol) and Pd(dppf)Cl2 (3.3 g, 3.74 mmol) were added. The mixture was stirred under nitrogen at 100 °C for 3 hours. After the reaction was complete, the reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (200 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 232-2 (8.0 g, 36.20 mmol, yield 96%) as a yellow solid.

[0320] Step 2 Under a nitrogen atmosphere at -78°C, LiHMDS (3.0 M, 13 mL, 40.32 mmol) was added dropwise to a solution of intermediate 232-2 (5.6 g, 13.44 mmol) and intermediate 123-1a (5.4 g, 13.44 mmol) in tetrahydrofuran (250 mL). The mixture was stirred at -78°C for 1 hour, then at room temperature for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 3) to obtain intermediate 232-3 (1.5 g, 3.6 mmol, yield 26.78%) as a yellow solid.

[0321] Step 3 Under 0°C and a nitrogen atmosphere, sodium borohydride (121 mg, 3.20 mmol) was added to a solution of intermediate 232-3 (450 mg, 1.0 mmol) and calcium chloride (474 ​​mg, 427 mmol) in tetrahydrofuran (10 mL) / ethanol (5 mL). The mixture was stirred at 0°C for 0.5 hours, then stirred at room temperature for 2 hours. The reaction product was quenched with water and extracted with ethyl acetate (50 mL). The combined organic layer was washed with brine (70 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 4) to obtain intermediate 232-4 (220 mg, 0.56 mmol, yield 53.0%) as a white solid.

[0322] Step 4 Under a nitrogen atmosphere, Pd / C (10%, 20 mg) was added to a methanol (5 mL) solution of intermediate 232-4 (90 mg, 0.23 mmol). The mixture was stirred at room temperature for 2 hours. The reaction solution was filtered and concentrated to obtain intermediate 232-5 (80 mg, 0.22 mmol, 95% yield) as a white oil.

[0323] Step 5 To a solution of intermediate 232-5 (50 mg, 0.14 mmol) and cuprous iodide (63 mg, 0.28 mmol) in acetonitrile (5 mL), isoamyl nitrite (24 mg, 0.03 mmol) was added dropwise. The mixture was stirred at room temperature for 0.5 hours, then heated to 80 °C and stirred for 16 hours. The reaction product was diluted with water (10 mL) and extracted with ethyl acetate (5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain intermediate 232-6 (30 mg, 0.09 mmol, yield 62%) as a colorless oil.

[0324] Step 6 To a solution of intermediate 232-6 (30 mg, 0.09 mmol) in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added. The mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure to obtain intermediate 232-7 (20 mg, 0.08 mmol, 92% yield) as a white solid.

[0325] Step 7 To a solution of intermediate 232-7 (20 mg, 0.08 mmol) and intermediate 5a (20 mg, 0.08 mmol) in DMF (2 mL), TCFH (35 mg, 0.12 mmol) and N-methylimidazole (17 mg, 0.2 mmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by preparative HPLC (column: Welch ultimate XB-NH2 250*50*10 μm, mobile phase: [heptane-EtOH (0.1% NH3H:O)]; B% 10%~10%, 10 min) to obtain compound 232 (9.8 mg, 0.02 mmol, yield 26%). MS m / z (ESI): 466.0 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 8.70 - 8.63 (m, 1H), 8.22 (s, 1H), 7.96 - 7.89 (m, 1H), 7.74 - 7.65 (m, 2H), 7.51 - 7.46 (m, 1H), 7.16 - 7.07 (m, 1H), 6.95 - 6.86 (m, 1H), 6.38 - 6.27 (m, 1H), 4.87 - 4.85 (m, 2H), 4.84 - 4.71 (m, 4H), 4.49 (s, 3H), 3.85 (s, 3H).

[0326] Example 67 Synthesis of compound 233 [ka] Step 1 At room temperature, intermediate 1102-2 (193 mg, 0.64 mmol), cesium carbonate (418 mg, 1.28 mmol), N,N'-dimethylethylenediamine (112 mg, 0.96 mmol), cuprous iodide (184 mg, 0.96 mmol), and copper powder (50 mg, 0.77 mmol) were added to a solution of intermediate 75-6 (300 mg, 0.64 mmol) in 1,4-dioxane (3 mL). The mixture was stirred at 95°C under a nitrogen atmosphere for 16 hours. The reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain intermediate 233-1 (100 mg, 0.15 mmol, yield 22.69%) as a white solid.

[0327] Step 2 Under room temperature and a nitrogen atmosphere, a solution of intermediate 233-1 (100 mg, 0.15 mmol) in trifluoroacetic acid (2 mL) was stirred for 16 hours. The reaction solution was concentrated and purified by preparative TLC (dichloromethane / methanol = 16 / 1), followed by preparative HPLC (column: Welch ultimate XB-NH2 250*50*10 μm, mobile phase: [heptane-EtOH (0.1% FA)]; B% 10%~10%, 10 min) to obtain compound 233 (24.5 mg, 0.05 mmol, yield 37.69%) as a white solid. MS m / z (ESI): 447.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.16 - 8.13 (m, 1H), 7.88 - 7.86 (m,1H), 7.44 (s, 1H), 7.34 - 7.32 (m, 1H), 7.15 (s, 1H), 6.94 (s, 2H), 4.89 - 4.88 (m, 2H), 4.82 - 4.71 (m, 2H), 4.39 - 4.25 (m, 2H), 3.97 (s, 3H).

[0328] Example 68 Synthesis of compound 234 [ka] Intermediate 166-3 (110 mg, 0.42 mmol), HATU (240 mg, 0.63 mmol), and a solution of N,N-diisopropylethylamine (0.37 mL, 2.11 mmol) in N,N-dimethyl sulfoxide (1 mL) were stirred at 25°C for 10 minutes. Intermediate 1038-2 (120.17 mg, 0.42 mmol) was added to this mixture. The reaction solution was stirred at 25°C for 2 hours. After the reaction was complete, the reaction solution was filtered and purified by HPLC-MS (Waters-Xbridge-C18-10 μm-19*250 mm; mobile phase: A: 10 mM formic acid / water B: acetonitrile; flow rate: 25) to obtain compound 234 (15.24 mg, 0.03 mmol, yield 6.47%) as a white solid. MS m / z (ESI): 527.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 7.6 Hz, 1H), 8.30 (s, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.43 (s, 1H), 7.36 (d, J = 12.4 Hz, 1H), 4.60 - 4.49 (m, 1H), 4.43 (s, 3H), 4.39 - 4.30 (m, 4H), 1.42 (d, J = 6.9 Hz, 6H).

[0329] Example 69 Synthesis of compound 237 [ka] To a solution of intermediate 166-3 (50 mg, 0.19 mmol) in N,N-dimethylformamide (5 mL), HATU (72.0 mg, 0.19 mmol) and N,N-diisopropylethylamine (73 mg, 0.57 mmol) were added. The mixture was stirred at room temperature for 0.5 hours. Intermediate 1045-7 (50 mg, 0.22 mmol) was added to the reaction solution, and the mixture was stirred further at room temperature for 2 hours. After the reaction was complete, the reaction solution was filtered. The filtrate was purified by preparative HPLC (column: Welch ultimate XB-NH2 250*50*10 μm, mobile phase: [heptane-EtOH (0.1% FA)]; B% 10%~10%, 10 min) to obtain compound 237 (27.51 mg, 0.06 mmol, yield 30.74%) as a white solid. MS m / z (ESI): 472.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 7.6 Hz, 1H), 8.26 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.37 (s, 2H), 7.31 (d, J = 12.4 Hz, 1H), 5.15 (d, J = 6.4 Hz, 2H), 4.50 - 4.34 (m, 7H).

[0330] Example 70 Synthesis of compound 238 [ka] Step 1 Under a nitrogen atmosphere, iodobenzene acetate (56 mg, 0.17 mmol) and ammonium carbamate (14 mg, 0.18 mmol) were added to a methanol (2.0 mL) solution of intermediate 1042-3 (18 mg, 0.05 mmol). The mixture was stirred at 25°C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane: dichloromethane and methanol = 0-7%) to obtain intermediate 238-1 (21 mg, 0.05 mmol, yield 96.33%) as a white solid.

[0331] Step 2 Under a nitrogen atmosphere at 25°C, trifluoroacetic acid (0.5 mL, 6.53 mmol) was added to a solution of intermediate 238-1 (21 mg, 0.06 mmol) in dichloromethane (2.5 mL). The mixture was stirred at 25°C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain crude intermediate 238-2 (27 mg, 0.05 mmol, yield 97.31%) as a yellow oil, which was used directly in the next step without further purification.

[0332] Step 3 Under a nitrogen atmosphere at 25°C, DIEA (10 mg, 0.08 mmol) was added to a DMSO (1.0 mL) solution of intermediates 84-11 (24 mg, 0.05 mmol) and HATU (32 mg, 0.08 mmol). The mixture was stirred at 25°C for half an hour, and then a DMSO (1.0 mL) solution of intermediate 238-2 (27 mg, 0.05 mmol) was added to the mixture. The mixture was stirred at 25°C for one and a half hours. After the reaction was complete, the reaction solution was introduced into water (20 mL) and filtered. The filtered cake was purified by silica gel column chromatography (dichloromethane: dichloromethane and methanol = 0-10%) to obtain intermediate 238 (19.68 mg, 0.04 mmol, yield 69.61%) as a pale yellow solid. MS m / z (ESI): 500.9 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ: 8.55 (d, J = 2.0 Hz, 1H), 8.34 (s, 1H), 8.23 ​​(d, J = 8.0 Hz, 1H), 8.11 - 8.06 (m, 1H), 8.02 (s, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 4.96 - 4.75 (m, 3H), 4.51 - 4.30 (m, 5H), 4.12 - 4.00 (m, 2H).

[0333] Example 71 Synthesis of compound 239 [ka] Step 1 Intermediate 239-1 (20 mg, 0.16 mmol), sodium nitrite (22 mg, 0.32 mmol), and sulfuric acid (20.00 μL, 0.32 mmol) were sequentially added to water (1 mL), and then cuprous bromide (46 mg, 0.32 mmol) was added. The mixture was stirred at 0°C for 2 hours. After the reaction was complete, water (5 mL) was added to the reaction solution. The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated and purified by silica gel plate chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain intermediate 239-2 (6 mg, 0.03 mmol, yield 19.9%) as a white solid.

[0334] Step 2 To a solution of intermediate 239-2 (60 mg, 0.32 mmol) in 1,4-dioxane (6 mL) and water (0.6 mL), XPhos Pd G3 (54 mg, 0.06 mmol), XPhos (60 mg, 0.13 mmol), potassium phosphate (200 mg, 0.094 mmol), and intermediate 194-2 (120 mg, 0.43 mmol) were added. The mixture was stirred at 100 °C for 2 hours. After the reaction was complete, water (5 mL) was added to the reaction solution. The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel thin-layer plate chromatography (petroleum ether:ethyl acetate = 1:1) to obtain intermediate 239-3 (55 mg, 0.21 mmol, yield 66.83%) as a yellow solid.

[0335] Step 3 Lithium hydroxide (4.16 mg, 0.17 mmol) was added to a solution of intermediate 239-3 (45 mg, 0.17 mmol) in water (2.25 mL), tetrahydrofuran (2.25 mL), and methanol (2.25 mL). The mixture was stirred at 75°C for 1 hour. After the reaction was complete, the reaction solution was adjusted to pH=3 with dilute hydrochloric acid aqueous solution (2 M) to form a solid as crude intermediate 239-4. The aqueous layer was extracted with ethyl acetate (20 mL) and then freeze-dried to obtain crude intermediate 239-4. The combined crude intermediate 239-4 was used as is in the subsequent steps.

[0336] Step 4 To a solution of intermediate 239-4 (10 mg, 0.04 mmol) in dimethyl sulfoxide (1 mL), intermediate 134-4 (15 mg, 0.07 mmol), TCFH (18 mg, 0.06 mmol), and 1-methylimidazole (20 μL, 0.25 mmol) were added. The mixture was stirred at 25°C for 1 hour. After the reaction was complete, the reaction solution was filtered and purified by preparative HPLC (column: Welch ultimate XB-NH2 250*50*10 μm, mobile phase: [heptane-EtOH (0.1% NH3H:O)]; B% 10%~10%, 10 min) to obtain compound 239 (0.4 mg, 0.00 mmol, yield 2.15%) as a white solid. MS m / z (ESI): 457.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.30 (d, J = 2.0 Hz, 1H), 7.96 - 7.78 (m, 2H), 7.74 - 7.60 (m, 3H), 7.34 (d, J = 7.9 Hz, 1H), 7.16 (s, 1H), 4.89 (s, 2H), 4.70 (brs, 2H), 4.39 - 4.30 (m, 2H).

[0337] Example 72 Synthesis of compound 1044 [ka] Step 1 Under 0°C and a nitrogen atmosphere, m-chloroperbenzoic acid (60 mg, 0.30 mmol) was added to a solution of intermediate 1042-4 (40 mg, 0.12 mmol) in dichloromethane (3.0 mL). The mixture was stirred at 0°C for 1 hour. After raising the temperature to 25°C, the reaction mixture was stirred for a further 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:dichloromethane and methanol = 0-5%) to obtain intermediate 1044-1 (28 mg, 0.07 mmol, yield 64.06%) as a pale yellow solid.

[0338] Step 2 Under a nitrogen atmosphere at 25°C, trifluoroacetic acid (0.3 mL, 3.92 mmol) was added to a solution of intermediate 1044-1 (28 mg, 0.07 mmol) in dichloromethane (3.0 mL). The mixture was stirred at 25°C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain intermediate 1044-2 (26 mg, 0.07 mmol, yield 99.85%) as a yellow oil, which was used directly in subsequent steps without further purification.

[0339] Step 3 At 25°C under a nitrogen atmosphere, N,N-diisopropylethylamine (14 mg, 0.11 mmol) was added to a solution of intermediates 84-11 (29 mg, 0.07 mmol) and HATU (42 mg, 0.11 mmol) in dimethyl sulfoxide (1.0 mL). The mixture was stirred at 25°C for 0.5 hours. A solution of intermediate 1044-2 (26 mg, 0.07 mmol) in dimethyl sulfoxide (1.0 mL) was added to the reaction solution, and the solution was stirred at 25°C for 1.5 hours. After the reaction was complete, the reaction solution was poured into water (20 mL) and filtered. The filtered cake was purified by preparative TLC (CH2Cl2 / MeOH=10 / 1) to obtain compound 1044 (7.8 mg, 0.02 mmol, yield 21.65%) as a white solid. MS m / z (ESI): 501.9 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ: 8.53 (d, J = 2.0 Hz, 1H), 8.34 (d, J = 8.0 Hz, 1H), 8.27 - 8.24 (m, 2H), 8.23 ​​- 8.19 (m, 1H), 7.87 (dd, J = 2.0, 8.5 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.25 (s, 2H), 4.92 - 4.73 (m, 2H), 4.57 - 4.35 (m, 2H), 4.41 (s, 3H), 4.23 (s, 2H).

[0340] Example 73 Synthesis of compound 242 [ka] Step 1 To a solution of intermediate 242-1 (2500 mg, 15.24 mmol) in tetrahydrofuran (50 mL), LDA (9.15 mL, 18.29 mmol) was added at -78°C. The mixture was stirred at -78°C for 30 minutes, and then a solution of ethyl cyanoformate (1.81 mL, 18.29 mmol) in tetrahydrofuran (10 mL) was added. The solution was stirred under a nitrogen atmosphere at -78°C for 1 hour. After the reaction was complete, the reaction solution was quenched with saturated aqueous ammonium chloride (50 mL). The resulting solution was extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain intermediate 242-2 (800 mg, 3.39 mmol, yield 22.23%) as a colorless liquid.

[0341] Step 2 To a solution of intermediate 242-2 (1200 mg, 5.08 mmol) in 1,4-dioxane (24 mL) and water (4.8 mL), intermediate 194-2 (1700 mg, 6.13 mmol), tetrakis(triphenylphosphine)palladium (450 mg, 0.39 mmol), and potassium carbonate (2107 mg, 15.25 mmol) were added. The mixture was stirred at 100°C for 18 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and then water (5 mL) and ethyl acetate (20 mL) were added to precipitate a large amount of solid. The solid was filtered and dried under reduced pressure to obtain crude intermediate 242-3 as a brown solid.

[0342] Step 3 A solution of intermediate 242-3 (1700 mg, 6.53 mmol) in phosphorus oxychloride (32 mL, 0.38 mmol) was stirred at 10°C for 18 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove most of the phosphorus oxychloride, and then slowly added to 200 mL of saturated sodium bicarbonate solution. The solution was extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 242-4 (1200 mg, 4.31 mmol, yield 65.92%), which was a red solid.

[0343] Step 4 To a solution of intermediate 242-4 (800 mg, 2.87 mmol) in acetonitrile (20 mL), (4-methoxyphenyl)methylamine (0.94 mL, 7.18 mmol) and potassium carbonate (1190 mg, 8.61 mmol) were added. The mixture was stirred at 80°C for 18 hours. After the reaction was complete, water (50 mL) was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain intermediate 242-5 (1000 mg, 1.85 mmol, yield 64.28%) as a yellow solid.

[0344] Step 5 Lithium hydroxide (115 mg, 2.74 mmol) was added to a solution of intermediate 242-5 (300 mg, 0.79 mmol) in methanol (3 mL), water (3 mL), and tetrahydrofuran (3 mL). The mixture was stirred at 75°C for 1 hour. After the reaction was complete, the reaction solution was adjusted to pH=6 with dilute hydrochloric acid aqueous solution (1 M). The solution was concentrated under reduced pressure and then freeze-dried to obtain crude intermediate 242-6, which was used directly in the subsequent steps.

[0345] Step 6 To a solution of intermediate 242-6 (280 mg, 0.77 mmol) in dimethyl sulfoxide (10 mL), intermediate 134-4 (260 mg, 1.13 mmol), TCFH (320 mg, 1.14 mmol), and 1-methylimidazole (380 μL, 4.77 mmol) were added. The mixture was stirred at 25°C for 1 hour. After the reaction was complete, water (20 mL) was added to the reaction solution. The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain intermediate 242-7 (60 mg, 0.10 mmol, yield 13.58%), which was a yellow liquid.

[0346] Step 7 A solution of intermediate 242-7 (60 mg, 0.10 mmol) in trifluoroacetic acid (1 mL, 13.07 mmol) was stirred for 18 hours at 80°C under a nitrogen atmosphere. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Welch ultimate XB-NH2 250*50*10 μm, mobile phase: [heptane-EtOH (0.1% NH3H:O)]; B% 10%~10%, 10 min) to obtain intermediate 242 (18.65 mg, 0.04 mmol, yield 36.35%) as a white solid. MS m / z (ESI): 457.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.69 (d, J = 2.0 Hz, 1H), 7.97 - 7.84 (m, 2H), 7.72 (d, J = 8.8 Hz, 1H), 7.40 - 7.32 (m, 1H), 7.16 (d, J = 1.6 Hz, 1H), 4.89 (s, 2H), 4.75 (d, J = 10.0 Hz, 2H), 4.48 - 4.27 (m, 2H).

[0347] Example 74 Synthesis of compound 243 [ka] Step 1 Under a nitrogen atmosphere at -20°C, nitric acid (3.3 mL, 78.4 mmol) was added dropwise to a solution of intermediate 243-1 (10.0 g, 49 mmol) in acetic anhydride (80 mL). After the addition was complete, the mixture was gradually heated to room temperature and stirred for 2 hours. After the reaction was complete, the reaction solution was quenched by adding it dropwise to ice water. The diluted reaction solution was extracted with ethyl acetate. The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) to obtain intermediate 243-2 (5.8 g, 23.29 mmol, yield 47%) as yellow oil.

[0348] Step 2 At 0°C, NaH (1.16 g, 46 mmol) was added to a solution of intermediate 243-2 (5.8 g, 23 mmol) in DMF (50 mL). The mixture was stirred at 0°C for 1 hour. 2-(trimethylsilyl)ethoxymethyl chloride (17.51 ​​g, 34.5 mmol) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 3 hours. The reaction solution was quenched with saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to obtain intermediate 243-3 (3.2 g, 8.4 mmol, yield 36%) as a yellow solid.

[0349] Step 3 To a solution of intermediate 243-3 (1.6 g, 4.2 mmol) in 1,4-dioxane (30 mL) and water (6 mL), intermediate 243-4 (2 g, 8.44 mmol), X-phos Pd G3 (0.36 g, 0.42 mmol), X-phos (0.40 g, 0.84 mmol), and potassium phosphate (2.7 g, 12.66 mmol) were added. The mixture was reacted under a nitrogen atmosphere at 95°C for 2 hours. After the reaction was complete, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) to obtain intermediate 243-5 (423 mg, 1.04 mmol, yield 24%) as a white solid.

[0350] Step 4 To a 10 mL methanol solution of intermediate 243-5 (450 mg, 1.11 mmol), Pd / C (10%, 45 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. After the reaction was complete, the reaction solution was filtered, washed three times with methanol, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate = 100%) to obtain intermediate 243-6 (43 mg, 0.11 mmol, yield 10%) as a red solid.

[0351] Step 5 Lithium hydroxide (111 mg, 0.27 mmol) was added to a methanol (5 mL) / water (0.5 mL) solution of intermediate 243-6 (100 mg, 0.27 mmol). The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain crude intermediate 243-7 (100 mg, 0.13 mmol) as a white solid.

[0352] Step 6 To a solution of intermediate 243-7 (100 mg, 0.27 mmol) in DMF (2 mL), intermediate 134-4 (63 mg, 0.27 mmol), TCFH (116 mg, 0.41 mmol), and N-methylimidazole (57 mg, 0.69 mmol) were added. The mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was purified by C18 silica gel column chromatography (70% acetonitrile in 1% NH4HCO3 in H2O) and lyophilized to obtain intermediate 243-8 (20 mg, 0.03 mmol, yield 12%) as a white solid.

[0353] Step 7 To a solution of intermediate 243-8 (50 mg, 0.09 mmol) in dichloromethane (4 mL), trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain the product. Ammonia in methanol (5 mL) solution was added to the product and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the crude product was concentrated under reduced pressure, a slurry was formed with methanol, and then a slurry was formed with acetonitrile to obtain compound 243 (21 mg, 0.056 mmol, yield 54%) as a white solid. MS m / z (ESI): 443.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 8.32 (s, 1H), 8.10 (s, 2H), 7.86 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.18 (d, J = 1.6 Hz, 1H), 6.72 (d, J = 2.4 Hz, 1H), 4.93 (d, J = 4.4 Hz, 2H), 4.79 (d, J = 13.6 Hz, 2H), 4.41 (s, 5H).

[0354] Synthesis of intermediate 243-4 [ka] To a solution of intermediate 243-9 (3.0 g, 28 mmol) and bis(pinacol boronic acid) (14.2 g, 56 mmol) in n-hexane (100 mL), methoxy(cyclooctadiene)iridium dimer (1.85 g, 2.8 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (1.5 g, 2.6 mmol) were added. The mixture was stirred at 50°C for 1 hour under a nitrogen atmosphere. After the reaction was complete, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 5) to obtain intermediate 243-4 (6.4 g, 27.46 mmol, yield 98%) as a white solid. MS m / z (ESI): 234.0 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 7.74 (s, 1H), 4.05 (d, J = 1.6 Hz, 3H), 1.34 (s, 6H), 1.24 (s, 6H).

[0355] Example 75 Synthesis of compound 245 [ka] Step 1 A solution of intermediate 213-1 (200 mg, 0.61 mmol), ethyl bromo (203.45 mg, 1.22 mmol), and potassium carbonate (252.54 mg, 1.83 mmol) in N,N-dimethylformamide (1 mL) was stirred at 50°C for 18 hours. After the reaction was complete, water (10 mL) was added to the reaction solution and extracted with ethyl acetate (10 mL). The combined organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 8 / 1 / 1) to obtain intermediate 245-1 (100 mg, 0.24 mmol, yield 39.61%) as a white solid.

[0356] Step 2 Sodium borohydride (40 mg, 1.06 mmol) was added to a solution of intermediate 245-1 (90 mg, 0.22 mmol) in ethanol (10 mL). The mixture was stirred at 25°C for 18 hours. After the reaction was complete, water (2 mL) was added to the reaction solution and extracted with ethyl acetate (2 mL). The organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / MeOH=30 / 1) to obtain intermediate 245-2 (80 mg, 0.21 mmol, yield 98.92%) as a white solid.

[0357] Step 3 A solution of intermediate 245-2 (90 mg, 0.24 mmol) in dichloromethane (1.5 mL) and trifluoroacetic acid (0.5 mL) was stirred at 25°C for 2 hours. After the reaction was complete, the reaction solution was concentrated to obtain crude intermediate 245-3 (70 mg, 0.18 mmol, yield 94.69%) as a brown solid, which was used directly in the subsequent steps.

[0358] Step 4 Intermediate 84-11 (75 mg, 0.31 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (110 mg, 0.39 mmol), and a solution of N-methylimidazole (0.07 mL, 0.84 mmol) in dimethyl sulfoxide (2 mL) were stirred at 25°C for 10 minutes. Intermediate 245-3 (76 mg, 0.28 mmol) was added to the reaction solution, and the mixture was then stirred at 25°C for 2 hours. After the reaction was complete, the reaction solution was filtered and purified by HPLC-MS (Waters-Xbridge-C18-10 μm-19*250 mm; mobile phase: A: 10 mM ammonium bicarbonate / water B: acetonitrile; flow rate: 25) to obtain compound 245 (5.44 mg, 0.01 mmol, yield 3.60%) as a white solid. MS m / z (ESI): 497.2 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 8.52 (d, J = 2.0 Hz, 1H), 8.26 (s, 1H), 7.86 (dd, J = 2.0, 8.5 Hz, 1H), 7.59 (t, J = 8.5 Hz, 2H), 7.23 (s, 2H), 6.95 (d, J = 7.5 Hz, 1H), 6.75 (d, J = 1.5 Hz, 1H), 4.73 (t, J = 5.5 Hz, 1H), 4.64 (s, 2H), 4.42 (s, 3H), 4.26 (d, J = 30.0 Hz, 2H), 3.86 (s, 2H), 3.61 (q, J = 5.5 Hz, 2H), 3.24 (d, J = 7.0 Hz, 2H).

[0359] Example 76 Synthesis of compound 247 [ka] Step 1 A solution of intermediate 213-1 (150 mg, 0.46 mmol), intermediate 247-0 (0.68 mL, 4.57 mmol), and cesium carbonate (1500 mg, 4.60 mmol) in N,N-dimethylformamide (10 mL) was stirred at 100 °C for 18 hours. After the reaction was complete, water (50 mL) was added to the reaction solution and extracted with ethyl acetate (50 mL). The organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain intermediate 247-1 (100 mg, 0.17 mmol, yield 37.18%) as a colorless oil.

[0360] Step 2 A solution of intermediate 247-1 (100 mg, 0.20 mmol) in trifluoroacetic acid (0.5 mL) and dichloromethane (1 mL) was stirred at 25°C for 2 hours. After the reaction was complete, the reaction solution was concentrated to obtain crude intermediate 247-2 as a yellow solid (50 mg, 0.20 mmol, yield 83.89%), which was used directly in the subsequent steps.

[0361] Step 3 Intermediate 84-11 (80 mg, 0.33 mmol), HATU (188 mg, 0.50 mmol), and a solution of N,N-diisopropylethylamine (0.29 mL, 1.65 mmol) in dimethyl sulfoxide (2 mL) were stirred at 25°C for 10 minutes. Intermediate 247-2 (104 mg, 0.33 mmol) was added to the reaction solution and stirred at 25°C for 2 hours. After the reaction was complete, the reaction solution was filtered and purified by preparative HPLC (Waters-Xbridge-C18-10 μm-19*250 mm; mobile phase: A: 10 mM ammonium bicarbonate / water B: acetonitrile; flow rate: 25) to obtain compound 247 (10 mg, 0.02 mmol, yield 5.61%) as a white solid. MS m / z (ESI): 541.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 2.0 Hz, 1H), 8.26 (s, 1H), 7.97 (s, 1H), 7.92 - 7.83 (m, 2H), 7.60 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.25 (s, 2H), 4.93 - 4.61 (m, 4H), 4.42 (brs, 6H), 4.34 - 4.15 (m, 4H), 3.70 - 3.62 (m, 2H).

[0362] Example 77 Synthesis of compound 251 [ka] Step 1 At room temperature, 3,4-dihydro-2H-pyran (8.2 g, 97.56 mmol) and trifluoroacetic acid (0.2 mL) were added to a solution of intermediate 251-1 (10 g, 48.78 mmol) in 1,2-dichloroethane (100 mL). The reaction solution was stirred at room temperature for 10 hours. After the reaction was complete, the reaction solution was diluted with water (300 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain intermediates 251-2a and 251-2b (8 g, 27.67 mmol, yield 56.72%) as colorless solids.

[0363] Step 2 At room temperature, intermediates 251-2a and 251-2b (1.4 g, 4.84 mmol) were dissolved in 1,4-dioxane (15 mL). Intermediate 194-2 (1.34 g, 4.84 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.23 g, 0.48 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.20 g, 0.24 mmol), and potassium phosphate (2.06 g, 9.68 mmol) were added sequentially under stirring. The mixture was purged three times with nitrogen and refluxed at 100°C for 10 hours. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filtrate was diluted with water (30 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain intermediates 251-3a and 251-3b (800 mg, 2.44 mmol, yield 50.47%) as white solids.

[0364] Step 3 At room temperature, p-toluenesulfonic acid (0.20 g, 1.16 mmol) was added to a solution of intermediates 251-3a and 251-3b (3.80 g, 11.61 mmol) in ethanol (40 mL) under stirring. The reaction solution was refluxed at 80°C for 3 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The concentrated solution was made into a slurry with acetonitrile (30 mL) to obtain intermediate 251-4 (2.00 g, 8.22 mmol, yield 70.83%) as a gray solid.

[0365] Step 4 At room temperature, N,N-diisopropylethylamine (1.59 g, 12.33 mmol) and N-methylmorpholine (0.10 g, 1.03 mmol) were sequentially added to a solution of intermediate 251-4 (0.50 mg, 2.06 mmol) in acetonitrile (6 mL) under stirring. The mixture was purged three times with nitrogen, and phosphorus oxychloride (1.23 g, 8.02 mmol) was added dropwise to the mixture under ice bath. The reaction solution was stirred at room temperature for 30 minutes, then heated to 60°C and stirred for 12 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 25 / 1) to obtain intermediate 251-5 (200 mg, 0.76 mmol, yield 37.18%) as a yellow solid.

[0366] Step 5 At room temperature, potassium carbonate (317 mg, 2.29 mmol), sodium iodide (344 mg, 2.29 mmol), and tert-butyl (2-bromoethyl) carbamate (257 mg, 1.15 mmol) were added to a solution of intermediate 251-5 (200 mg, 0.76 mmol) in DMF (2 mL) under stirring. The reaction solution was purged three times with nitrogen and stirred at 80°C for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filtrate was diluted with water (10 mL) and extracted with dichloromethane (5 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by C18 silica gel column chromatography (acetonitrile / water (0.1% FA) = 3 / 2) to obtain intermediates 251-6a (50 mg, 0.12 mmol, yield 16.16%) and 251-6b (150 mg, 0.37 mmol, yield 48.75%) as white solids.

[0367] Step 6 A solution of intermediate 251-6a (50 mg, 0.12 mmol) in 1,4-dioxane hydrogen chloride was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain intermediate 251-7 (35 mg, 0.11 mmol, yield 93.0%).

[0368] Step 7 A solution of intermediate 251-7 (35 mg, 0.11 mmol) and potassium carbonate (95 mg, 0.69 mmol) in DMSO (0.5 mL) was stirred at 120°C for 4 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was diluted with water (10 mL) and extracted with dichloromethane (5 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain intermediate 251-8 (10 mg, 0.04 mmol, yield 32.45%) as a white solid.

[0369] Step 8 At room temperature, intermediate 251-8 (10 mg, 0.04 mmol) and lithium hydroxide (6.26 mg, 0.15 mmol) were added to a mixed solution of methanol (0.5 mL) and water (0.1 mL). The reaction solution was stirred at 50°C for 10 hours, concentrated under reduced pressure, and dried to obtain intermediate 251-9 (9 mg, 0.04 mmol, yield 94.97%).

[0370] Step 9 At room temperature, N-methylimidazole (17 mg, 0.21 mmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (14 mg, 0.05 mmol) were added to a solution of intermediates 251-9 (9 mg, 0.04 mmol) and 134-4 (16 mg, 0.07 mmol) in N,N-dimethylformamide (1 mL). The mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The crude product was purified by preparative HPLC (Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: A: 10 mM NH4HCO3; B: ACN, gradient: 30-40%, retention time: 10.5 min) to obtain compound 251 (1.0 mg, yield 6.07%). MS m / z (ESI): 465.9 [M+H] + ; 1 H NMR (400 MHz, MeOD-d4)δ8.46-8.41 (m, 2H), 7.82-7.74 (m, 3H), 7.32-7.29 (m, 1H), 7.04 (s, 1H), 4.88 (s, 2H), 4.76 (s, 2H), 4.55-4.51 (m, 2H), 4.47 (s, 2H), 3.97 (t, J = 5.6 Hz, 2H).

[0371] Example 78 Synthesis of compound 253 [ka] At room temperature, intermediate 162-5 (220 mg, 0.89 mmol), N-methylimidazole (304 mg, 3.71 mmol), and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (416 mg, 1.48 mmol) were added to a solution of intermediate 1036-2 (190 mg, 0.74 mmol) in N,N-dimethylformamide (4 mL). The reaction solution was stirred at 50°C for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by C18 silica gel column chromatography HPLC (column: Welch ultimate XB-NH2 250*50*10 μm, mobile phase: [heptane-EtOH (0.1% HCOOH)]; B% 10%~10%, 10 min) to obtain compound 253 (30 mg, 0.06 mmol, yield 8.32%) as a grayish-white solid. MS m / z (ESI): 487.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 2H), 8.05 - 8.03 (m, 1H), 7.91 - 7.89 (m, 1H), 7.64 - 7.61 (m, 1H), 7.53 - 7.51 (m, 1H), 7.39 - 7.38 (m, 1H), 5.48 - 5.47 (m, 2H), 5.08 - 5.07 (m, 2H), 4.36 - 4.28 (m, 4H), 3.19 (s, 3H).

[0372] Example 79 Synthesis of compound 254 [ka] At room temperature, intermediate 162-5 (86 mg, 0.35 mmol), N-methylimidazole (53 mg, 0.65 mmol), and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (90 mg, 0.32 mmol) were added to a solution of intermediate 1040-2 (70 mg, 0.22 mmol) in N,N-dimethylformamide (4 mL). The reaction solution was stirred at 50°C for 5 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by C18 silica gel column chromatography-HPLC (column: Welch ultimate XB-NH2 250*50*10 μm, mobile phase: [heptane-EtOH (0.1% HCOOH)]; B% 10%~10%, 10 min) to obtain compound 254 (30 mg, 0.05 mmol, yield 25.06%) as a grayish-white solid. MS m / z (ESI): 555.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.97 - 7.96 (m, 1H), 7.80 - 7.78 (m, 1H), 7.63 - 7.57 (m, 2H), 7.32 - 7.29 (m, 1H), 6.93 (s, 2H), 6.93 (s, 2H), 5.36 (m, 2H), 5.00 - 4.99 (m, 2H), 4.76 - 4.69 (m, 2H), 4.41 - 4.31 (m, 4H).

[0373] Example 80 Synthesis of compound 257 [ka] Step 1 Under stirring at room temperature, N-methyl-4-piperidinol (252 mg, 2.19 mmol) was added to a solution of intermediate 123-3 (500 mg, 1.46 mmol) in toluene (6 mL), followed by the addition of (cyanomethylene)-tri-n-butylphosphoran (564 mg, 2.34 mmol). The reaction solution was purged three times with nitrogen and stirred at 100°C for 12 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 25 / 1) to obtain intermediate 257-1 (350 mg, 0.80 mmol, yield 54.52%) as a yellow oil.

[0374] Step 2 At room temperature, a solution of intermediate 257-1 (150 mg, 0.34 mmol) in 1,4-dioxane hydrogen chloride solution (2 mL) was stirred at room temperature for 1 hour, and then concentrated under reduced pressure to obtain intermediate 257-2 (100 mg, 0.29 mmol, yield 86.34%).

[0375] Step 3 At room temperature, N,N-diisopropylethylamine (156 mg, 1.21 mmol) and HATU (230 mg, 0.60 mmol) were added to a solution of intermediates 257-2 (100 mg, 0.40 mmol) and 162-5 (137 mg, 0.40 mmol) in N,N-dimethylformamide (2 mL). The reaction solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The crude product was purified by preparative HPLC (Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: A: 10 mM NH4HCO3; B: ACN, gradient: 26-56%, retention time: 11 min) to obtain compound 257 (13.66 mg, 0.02 mmol, yield 5.95%). MS m / z (ESI): 285.6 [1 / 2M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 7.94 - 7.87 (m, 1H), 7.81 - 7.75 (m, 1H), 7.53 - 7.47 (m, 1H), 7.43 (s, 1H), 7.34 - 7.27 (m, 1H), 6.92 (s, 2H), 5.41 - 5.30 (m, 2H), 5.03 - 4.91 (m, 2H), 4.38 - 4.23 (m, 4H), 4.17 - 4.07 (m, 1H), 2.95 - 2.84 (m, 2H), 2.38 - 2.31 (m, 2H), 2.23 (s, 3H), 2.14 - 2.04 (m, 2H), 1.66 - 1.56 (m, 2H).

[0376] Example 81 Synthesis of compound 258 [ka] Step 1 At room temperature, the mixture was stirred until intermediate 123-3 (400 mg, 1.17 mmol) dissolved in acetonitrile (5 mL). Under a nitrogen atmosphere, sodium hydride (36 mg, 1.17 mmol) was added to the solution. The reaction solution was stirred at room temperature for 10 hours, and then bromoacetonitrile (144 mg, 1.2 mmol) was added. The reaction solution was stirred at room temperature for 10 hours, water (10 mL) was added, and then the mixture was extracted with ethyl acetate (5 mL). The organic layer was washed with brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 2) to obtain intermediate 258-1 (250 mg, 0.66 mmol, yield 56.10%) as a colorless liquid.

[0377] Step 2 A solution of intermediate 258-1 (100 mg, 0.26 mmol) in dichloromethane (1 mL) was prepared at room temperature. Then, trifluoroacetic acid (0.25 mL) was added dropwise to the solution and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain intermediate 258-2 (80 mg, 0.28 mmol, yield 108.44%) as a colorless liquid.

[0378] Step 3 At room temperature, N-methylimidazole (82 mg, 1.42 mmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (280 mg, 0.43 mmol) were added dropwise to a solution of intermediate 258-2 (80 mg, 0.28 mmol) and compound 162-5 (113 mg, 0.46 mmol) in N,N-dimethylformamide (1 mL). The reaction solution was stirred at room temperature for 1 hour. The organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by HPLC (Waters-Xbridge-C18-10μm-19*250mm, mobile phase: A: 10mM NH4HCO3; B: ACN, gradient: 5-95%, retention time: 8.3 min) to obtain compound 258 (28.45 mg, 0.06 mmol, yield 19.56%). MS m / z (ESI): 512.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 7.59 Hz, 1H), 8.26 (s, 1H), 7.87 (d, J = 8.00 Hz, 1H), 7.80 (d, J = 7.91 Hz, 1H), 7.75 (s, 1H), 7.36 (s, 2H), 7.31 (d, J = 12.54 Hz, 1H), 5.15 (d, J = 6.18 Hz, 2H), 4.47 - 4.39 (m, 7H).

[0379] Example 82 Synthesis of compound 259 [ka] At room temperature, compound 166-3 (230 mg, 0.89 mmol), N-methylimidazole (202 mg, 2.46 mmol), and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (276 mg, 0.98 mmol) were added to a solution of intermediate 213-3 (126 mg, 0.49 mmol) in N,N-dimethylformamide (4 mL). The reaction solution was stirred at 50°C for 5 hours, cooled to room temperature, and concentrated under reduced pressure. The crude product was purified by C18 silica gel column chromatography HPLC (column: Welch ultimate XB-NH2 250*50*10 μm, mobile phase: [heptane-EtOH (0.1% HCOOH)]; B% 10%~10%, 10 min) to obtain compound 259 (60 mg, 0.12 mmol, yield 24.48%) as a grayish-white solid.

[0380] Example 83 Synthesis of compound 260 [ka] Step 1 Under room temperature and a nitrogen atmosphere, cesium carbonate (1.3 g, 4.09 mmol) was added to solutions of intermediate 123-3 (700 mg, 2.04 mmol) and intermediate 260-1a (451 mg, 2.45 mmol) in N,N-dimethylformamide (5 mL). The reaction solution was stirred at 60°C for 16 hours, water (2 mL) was added, and the mixture was extracted with ethyl acetate (5 mL). The combined organic layers were washed with brine (2 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 4) to obtain intermediate 260-1 (400 mg, 1.00 mmol, yield 49.10%) as a white solid.

[0381] Step 2 At room temperature, zinc bromide (1.27 g, 5.62 mmol) was added to a solution of intermediate 260-1 (560 mg, 1.41 mmol) in dichloromethane (30 mL). The reaction solution was stirred under a nitrogen atmosphere at room temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by C18 silica gel column chromatography (acetonitrile / water (0.1% FA) = 1 / 3) to obtain intermediate 260-2 (110 mg, 0.34 mmol, yield 71.98%) as a white solid.

[0382] Step 3 At room temperature, intermediate 162-6 (53 mg, 0.21 mmol), N-methylimidazole (55 mg, 0.67 mmol), and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (75 mg, 0.27 mmol) were added to a solution of intermediate 260-2 (40 mg, 0.13 mmol) in N,N-dimethylformamide (4 mL). The reaction solution was stirred at 50°C for 3 hours, cooled to room temperature, and concentrated under reduced pressure. The crude product was purified by C18 silica gel column chromatography-HPLC (column: Welch ultimate XB-NH2 250*50*10 μm, mobile phase: [heptane-EtOH (0.1% HCOOH)]; B% 10%~10%, 10 min) to obtain compound 260 (25 mg, 0.05 mmol, yield 35.28%) as a grayish-white solid. MS m / z (ESI): 529.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.97 - 7.95 (m, 1H), 7.80 - 7.78 (m, 1H), 7.64 (s, 1H), 7.58 - 7.56 (m, 1H), 7.32 - 7.29 (m, 1H), 6.93 (s, 2H), 5.48 - 5.44 (m, 3H), 5.02 - 4.99 (m, 4H), 4.93 - 4.89 (m, 2H), 4.35 - 4.25 (m, 4H).

[0383] Example 84 Synthesis of compound 261 [ka] Step 1 At room temperature and under a nitrogen atmosphere, intermediate 261-1a (76 mg, 0.88 mmol) and cyanomethylenetri-n-butylphosphorane (317 mg, 1.31 mmol) were added to a solution of intermediate 123-3 (300 mg, 0.88 mmol) in toluene (3 mL). The reaction solution was stirred at 100 °C for 10 hours, water (10 mL) was added to the reaction solution, and it was extracted with ethyl acetate (5 mL). The organic layer was washed with brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 2) to obtain intermediate 261-1 (130 mg, 0.32 mmol, yield 36.05%) as a colorless liquid.

[0384] Step 2 At room temperature, trifluoroacetic acid (0.25 mL) was added dropwise to a solution of intermediate 261-1 (130 mg, 0.32 mmol) in dichloromethane (1 mL). The reaction solution was stirred at room temperature for 1 hour, and then concentrated under reduced pressure to obtain intermediate 261-2 (98.36 mg, 0.32 mmol, 100% yield) as a colorless liquid.

[0385] Step 3 At room temperature, N-methylimidazole (131 mg, 1.60 mmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (135 mg, 0.48 mmol) were added dropwise to a solution of intermediate 261-2 (98 mg, 0.32 mmol) and intermediate 162-5 (127 mg, 0.51 mmol) in N,N-dimethylformamide (1 mL). The reaction solution was stirred at room temperature for 1 hour. The organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by HPLC (Waters-Xbridge-C18-10μm-19*250mm, mobile phase: A: 10mM NH4HCO3; B: ACN, gradient: 10-95%, retention time: 9.3 min) to obtain compound 261 (12.48 mg, 0.02 mmol, yield 7.20%). MS m / z (ESI): 542.4 [M+H]+ ; 1 H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.92 (d, J = 7.77 Hz, 1H), 7.78 (d, J = 7.80 Hz, 1H), 7.53 (d, J = 7.93 Hz, 1H), 7.30 (d, J = 12.52 Hz, 1H), 6.92 (s, 2H), 5.40 - 5.30 (m, 2H), 5.03 - 4.96 (m, 2H), 4.89 - 4.80 (m, 1H), 4.34 - 4.23 (m, 4H), 3.67 - 3.54 (m, 4H), 2.35 (s, 3H).

[0386] Example 85 Synthesis of compound 272 [ka] Step 1 At 0°C under a nitrogen atmosphere, sodium hydride (60 mg, 1.52 mmol, purity 60%) was added to a solution of intermediate 123-3 (400 mg, 1.17 mmol) in tetrahydrofuran (5 mL). The reaction solution was stirred at 0°C for 30 minutes, and then deuterated iodomethane (220 mg, 1.52 mmol) was added. The reaction solution was stirred at 0°C for 3 hours, water (2 mL) was added, and the mixture was extracted with ethyl acetate (5 mL). The combined organic layers were washed with brine (2 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) to obtain intermediate 272-1 (80 mg, 0.22 mmol, yield 19.05%) as a white solid.

[0387] Step 2 Under room temperature and a nitrogen atmosphere, 1,4-dioxane hydrogen chloride (4N, 1.00 mL, 5.00 mmol) was added to a solution of intermediate 272-1 (20 mg, 0.06 mmol) in dichloromethane (1 mL). The reaction solution was stirred under a nitrogen atmosphere at room temperature for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by C18 silica gel column chromatography (acetonitrile / water (0.1% FA) = 2 / 3) to obtain intermediate 272-2 (10 mg, 0.04 mmol, yield 69.30%) as a white solid.

[0388] Step 3 At room temperature, intermediate 162-5 (96 mg, 0.39 mmol), N-methylimidazole (106 mg, 1.29 mmol), and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (145 mg, 0.52 mmol) were added to a solution of intermediate 272-2 (67 mg, 0.26 mmol) in N,N-dimethylformamide (4 mL). The reaction solution was stirred at 50°C for 3 hours, cooled to room temperature, and concentrated under reduced pressure. The crude product was purified by C18 silica gel column chromatography-HPLC (column: Welch ultimate XB-NH2 250*50*10 μm, mobile phase: [heptane-EtOH (0.1% HCOOH)]; B% 10%~10%, 10 min) to obtain compound 272 (20 mg, 0.04 mmol, yield 15.81%) as a grayish-white solid. MS m / z (ESI): 490.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.90 - 7.89 (m, 1H), 7.82 - 7.80 (m, 1H), 7.52 - 7.49 (m, 1H), 7.37 - 7.32 (m, 2H), 7.05 (s, 2H), 5.39 - 5.36 (m, 2H), 5.01 - 4.99 (m, 2H), 4.34 - 4.25 (m, 4H).

[0389] Example 86 Synthesis of compound 273 [ka] At room temperature, intermediate 217-1 (38 mg, 0.15 mmol), N-methylimidazole (31 mg, 0.38 mmol), and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (63 mg, 0.23 mmol) were added to a solution of intermediate 213-3 (40 mg, 0.15 mmol) in N,N-dimethylformamide (4 mL). The reaction solution was stirred for 3 hours and then concentrated under reduced pressure. The crude product was purified by C18 silica gel column chromatography HPLC (column: Welch ultimate XB-NH2 250*50*10 μm, mobile phase: [heptane-EtOH (0.1% HCOOH)]; B% 10%~10%, 10 min) to obtain compound 273 (13 mg, 0.03 mmol, yield 17%) as a grayish-white solid. MS m / z (ESI): 503.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.90 - 7.85 (m, 1H), 7.72 (s, 1H), 7.61 (s, 1H), 7.56 - 7.50 (m, 1H), 7.39 - 7.37 (m, 1H), 6.92 (s, 2H), 5.40 - 5.30 (m, 2H), 4.99 (s, 2H), 4.35 - 4.30 (m, 1H), 4.28 - 4.24 (m, 1H), 4.20 - 4.11 (m, 2H), 3.19 (s, 3H).

[0390] Example 87 Synthesis of compound 274 [ka] Step 1 A solution of intermediate 213-3 (400 mg, 1.17 mmol), cyclopropylboronic acid (1.6 g, 18.7 mmol), potassium carbonate (485 mg, 3.51 mmol), and copper acetate (933 mg, 4.67 mmol) in 1,2-dichloroethane (10 mL) was stirred at 70°C for 4 hours. After the reaction was complete, the reaction solution was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain intermediate 274-1 (360 mg, 0.94 mmol, yield 80.57%) as a white solid.

[0391] Step 2 At room temperature, 1,4-dioxane hydrogen chloride (4N, 1 mL, 4.00 mmol) was added to a solution of intermediate 274-1 (20 mg, 0.05 mmol) in dichloromethane (1 mL). The reaction solution was stirred under a nitrogen atmosphere at room temperature for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by C18 silica gel column chromatography (acetonitrile / water (0.1% FA) = 2 / 3) to obtain intermediate 274-2 (2 mg, 0.01 mmol, yield 13.55%) as a white solid.

[0392] Step 3 At room temperature, intermediate 162-5 (132 mg, 0.53 mmol), N-methylimidazole (145 mg, 1.77 mmol), and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (200 mg, 0.71 mmol) were added to a solution of intermediate 274-2 (100 mg, 0.35 mmol) in N,N-dimethylformamide (4 mL). The reaction solution was stirred at 50°C for 5 hours, cooled to room temperature, and concentrated under reduced pressure. The crude product was purified by C18 chromatography column HPLC (column: Welch ultimate XB-NH2 250*50*10 μm, mobile phase: [heptane-EtOH (0.1% HCOOH)]; B% 10%~10%, 10 min) to obtain compound 274 (30 mg, 0.06 mmol, yield 16.52%) as a grayish-white solid. MS m / z (ESI): 513.0 [M+H] + ; 11H NMR (400 MHz, DMSO-d 6) δ 7.90 - 7.88 (m, 1H), 7.84 - 7.82 (m, 1H), 7.53 - 7.51 (m, 1H), 7.38 - 7.35 (m, 1H), 7.29 -7.28 (m, 1H), 5.40 - 5.37 (m, 2H), 5.02 - 5.00 (m, 2H), 4.31 - 4.23 (m, 4H), 2.72 (m, 1H), 1.03 - 1.01 (m, 2H), 0.82 - 0.81 (m, 2H).

[0393] Example 88 Synthesis of compound 276 [ka] At room temperature, chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (165 mg, 0.59 mmol) and N-methylimidazole (145 mg, 1.77 mmol) were added to solutions of intermediate 257-2 (200 mg, 0.59 mmol) and intermediate 217-1 (156 mg, 0.59 mmol) in N,N-dimethylformamide (2 mL). The reaction solution was stirred at room temperature for 10 hours. Water (10 mL) was added to the reaction solution and extracted with ethyl acetate (5 mL). The organic layer was washed with brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC (Waters-Xbridge-C18-10μm-19*250mm, mobile phase: A: 10mM FA; B: ACN, gradient: 10-95%, retention time: 8.6 min) to obtain compound 276 (11.82 mg, 0.02 mmol, yield 3.42%). MS m / z (ESI): 586.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 7.6 Hz, 1H), 7.71 (s, 1H), 7.61 (s, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.43 (s, 1H), 6.90 (s, 2H), 5.40 - 5.30 (m, 2H), 4.99 (d, J = 3.6 Hz, 2H), 4.34 - 4.24 (m, 2H), 4.19 - 4.07 (m, 3H), 2.86 (d, J = 10.0 Hz, 2H), 2.38 - 2.30 (m, 2H), 2.21 (s, 3H), 2.04 (t, J = 11.6 Hz, 2H), 1.61 (d, J = 12.0 Hz, 2H).

[0394] Example 89 Synthesis of compound 279 [ka] Step 1 A solution of intermediate 123-3 (380 mg, 1.11 mmol), intermediate 279-1a (213 mg, 1.67 mmol), sodium carbonate (307 mg, 2.22 mmol), and copper acetate (443 mg, 2.22 mmol) in 1,2-dichloroethane (5 mL) was stirred at 40°C for 16 hours. After the reaction was complete, the reaction solution was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain intermediate 279-1 (300 mg, 0.71 mmol, yield 63.68%) as yellow oil.

[0395] Step 2 At room temperature, Pd / C (251 mg, 2.02 mmol, 60%) was added to a methanol (2 mL) solution of intermediate 279-1 (100 mg, 0.2 mmol), and the solution was stirred at room temperature for 12 hours. After the reaction was complete, the reaction solution was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain intermediate 279-2 (20 mg, 0.04 mmol, yield 19.9%) as a white solid.

[0396] Step 3 A solution of intermediate 279-2 (30 mg, 0.07 mmol) in trifluoroacetic acid (1 mL) / dichloromethane (1 mL) was stirred at 25°C for 5 hours. After the reaction was complete, the reaction solution was quenched with saturated sodium bicarbonate aqueous solution (3 mL) and extracted with ethyl acetate (2 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain crude intermediate 279-3 (10 mg, 0.03 mmol, yield 43.56%) as a brown solid.

[0397] Step 4 Intermediate 162-5 (22.8 mg, 0.09 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (34 mg, 0.12 mmol), and N-methylimidazole (25 mg, 0.31 mmol) were mixed in N,N-dimethylformamide (3 mL) and stirred at 25°C for 30 minutes, then intermediate 279-3 (20 mg, 0.06 mmol) was added. The reaction mixture was stirred at 25°C for 2 hours. After the reaction was complete, the reaction solution was concentrated, and then dimethyl sulfoxide (3 mL) was added. The crude product was purified by preparative HPLC (Waters-Xbridge-C18-10μm-19*250mm; mobile phase: A: 10mM ammonium bicarbonate / water B: acetonitrile; flow rate: 25) to obtain compound 279 (10 mg, 0.02 mmol, yield 29.32%) as a white solid. MS m / z (ESI): 557.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.92 - 7.90 (m, 1H), 7.80 - 7.78 (m, 1H), 7.51 - 7.50(m, 2H), 7.32 - 7.29 (m, 1H), 6.94 (s, 2H), 5.38 - 5.35 (m, 2H), 5.01 - 4.99 (m, 2H), 4.37 - 4.25 (m, 5H), 3.96 - 3.94 (m, 2H), 3.49 - 3.43 (m, 2H), 2.39 - 2.36 (m, 2H), 1.62 - 1.61 (m, 2H).

[0398] Example 90 Synthesis of compound 280 [ka] Step 1 A solution of intermediate 280-1 (20 mg, 0.04 mmol) in trifluoroacetic acid (1 mL) / dichloromethane (1 mL) was stirred at 25°C for 2 hours. After the reaction was complete, the reaction solution was quenched with saturated sodium bicarbonate aqueous solution (3 mL) and extracted with ethyl acetate (2 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain crude intermediate 280-2 (4 mg, 0.01 mmol, yield 26.18%) as a brown solid.

[0399] Step 2 Intermediate 162-5 (23 mg, 0.09 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (35 mg, 0.12 mmol), and N-methylimidazole (25 mg, 0.31 mmol) were mixed in N,N-dimethylformamide (5 mL) and stirred at 25°C for 30 minutes, then intermediate 280-2 (20 mg, 0.06 mmol) was added. The reaction solution was stirred at 25°C for 2 hours. After the reaction was complete, the reaction solution was concentrated and dissolved in dimethyl sulfoxide (3 mL). The crude product was purified by preparative HPLC (Waters-Xbridge-C18-10μm-19*250mm; mobile phase: A: 10mM ammonium bicarbonate / water B: acetonitrile; flow rate: 25) to obtain compound 280 (5 mg, 0.01 mmol, yield 14.62%) as a white solid. MS m / z (ESI): 555.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 7.96 - 7.94 (m, 1H), 7.80 - 7.78 (m, 1H), 7.55 - 7.53 (m, 1H), 7.32 - 7.29 (m, 1H), 7.14 - 7.13(m, 1H), 6.93 (s, 2H), 6.04 -6.02 (m, 1H), 5.37 - 5.36 (m, 2H), 5.01 - 4.99 (m, 2H), 4.37 - 4.27 (m, 6H), 3.88 - 3.85 (m, 2H), 2.34 (s, 2H).

[0400] Example 91 Synthesis of compound 283 [ka] A solution of intermediate 217-1 (12 mg, 0.05 mmol), N,N,N',N'-tetramethylureahexafluorophosphate (14 mg, 0.04 mmol), and N,N-diisopropylethylamine (6.0 mg, 0.05 mmol) in N,N-dimethylformamide (2 mL) was stirred at 25°C for 30 minutes, and then intermediate 283-1 (10 mg, 0.03 mmol) was added. The reaction solution was stirred at 25°C for 2 hours. After the reaction was complete, the reaction solution was concentrated and dissolved in dimethyl sulfoxide (3 mL). The crude product was purified by preparative HPLC (Waters-Xbridge-C18-10μm-19*250mm; mobile phase: A: 10mM ammonium bicarbonate / water B: acetonitrile; flow rate: 25) to obtain compound 283 (2 mg, 3.49 μmol, yield 11.39%) as a white solid. MS m / z (ESI): 573.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 7.89 - 7.88(m, 1H), 7.72 (s, 1H), 7.62 (s, 1H), 7.53 - 7.51 (m, 2H), 6.91 (s, 2H), 5.37 - 5.34 (m, 2H), 5.00 - 4.98 (m, 2H), 4.37 - 4.25 (m, 3H), 4.19 - 4.12 (m, 2H), 3.96 - 3.94 (m, 2H), 3.49 - 3.43 (m, 2H), 2.39 - 2.35 (m, 2H), 1.61 - 1.60 (m, 2H).

[0401] Example 92 Synthesis of compound 185 [ka] To a solution of intermediate 217-1 (158 mg, 0.30 mmol) in dimethyl sulfoxide (3 mL), intermediate 134-4 (130 mg, 0.57 mmol), 1-methylimidazole (190 μL, 2.39 mmol), and TCFH (167 mg, 0.60 mmol) were added. The mixture was stirred at 20°C for 2 hours. After the reaction was complete, the crude product was purified by preparative HPLC (SunFire-C18-10 μm-19*250 mm, flow rate: 25 mL / min, mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN) to obtain compound 185 (16.86 mg, 0.04 mmol, yield 11.87%) as a white solid. MS m / z (ESI): 476.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 7.78 (d, J = 7.6 Hz, 1H), 7.68 (s, 1H), 7.61 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 1.6 Hz, 1H), 6.89 (s, 2H), 5.34 (s, 2H), 5.00 (t, J = 3.2 Hz, 2H), 4.94 - 4.77 (m, 2H), 4.39 (d, J = 10.4 Hz, 1H), 4.31 - 4.19 (m, 2H), 4.14 (d, J = 9.2 Hz, 1H).

[0402] Example 93 Synthesis of compound 284 [ka] A solution of intermediate 217-1 (12 mg, 0.05 mmol), N,N,N',N'-tetramethylureahexafluorophosphate (14 mg, 0.04 mmol), and N,N-diisopropylethylamine (6.0 mg, 0.05 mmol) in N,N-dimethylformamide (2 mL) was stirred at 25°C for 30 minutes, and then intermediate 284-1 (10 mg, 0.03 mmol) was added to the solution. The reaction solution was stirred at 25°C for 2 hours. After the reaction was complete, the reaction solution was concentrated and dissolved in dimethyl sulfoxide (3 mL). The crude product was purified by preparative HPLC (Waters-Xbridge-C18-10μm-19*250mm; mobile phase: A: 10mM ammonium bicarbonate / water B: acetonitrile; flow rate: 25) to obtain compound 284 (2 mg, 3.52 μmol, yield 11.69%) as a white solid. MS m / z (ESI): 571.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 7.93 - 7.91 (m, 1H), 7.72 (s, 1H), 7.62 (s, 1H), 7.57 - 7.55 (m, 1H), 7.14 - 7.13 (m, 1H), 6.90 (s, 2H), 6.04 - 6.03(m, 1H), 5.36 - 5.35 (m, 2H), 5.00 - 4.98 (m, 2H), 4.38 - 4.15 (m, 6H), 3.87 - 3.85 (m, 2H), 2.34 (s, 2H).

[0403] Example 94 Synthesis of compound 287 [ka] Step 1 At 0°C, triethylamine (124 mg, 1.23 mmol) and ethyl oxalyl chloride (123 mg, 0.9 mmol) were added to a solution of intermediate 1036-2 (210 mg, 1.00 mmol) in dichloromethane (6 mL). The reaction solution was stirred at 0°C for 3 hours and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain intermediate 287-1 (200 mg, 0.56 mmol, yield 68%) as a yellow solid.

[0404] Step 2 A solution of intermediate 287-1 (200 mg, 0.9 mmol) in ammonia (5 mL, 7 M methanol) was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain intermediate 287-2 (170 mg, 0.52 mmol, 92% yield) as a yellow solid.

[0405] Step 3 To a solution of intermediate 76-3 (34 mg, 0.15 mmol) and compound 6 (50 mg, 0.15 mmol) in 1,4-dioxane (2 mL), copper powder (11 mg, 0.18 mmol), cuprous iodide (34 mg, 0.18 mmol), cesium carbonate (99 mg, 0.31 mmol), and N,N'-dimethylethylenediamine (20 mg, 0.23 mmol) were added. The reaction solution was stirred at 100°C under a nitrogen atmosphere for 10 hours. The reaction solution was quenched with water (20 mL) and then extracted with ethyl acetate (30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (Waters-Xbridge-C18-10μm-19*250mm, mobile phase: A: 10mM NH4HCO3; B: ACN, gradient: 5-61%, retention time: 9.5 min) to obtain a white compound 287 (6 mg, 0.01 mmol, yield 8.3%). MS m / z (ESI): 474.2 [M+H] + ; 1 H NMR (400 MHz, CH3OD) δ 7.97 (s, 1H), 7.91 - 7.86 (m, 1H), 7.81 (s, 1H), 7.51 - 7.48 (m, 1H), 7.30 - 7.27 (m, 1H), 5.00 - 4.96 (m, 1H), 4.92 - 4.88 (m, 1H), 4.50 - 4.45 (m, 1H), 4.40 - 4.36 (m, 1H), 4.34 (s, 3H), 3.28 (s, 3H).

[0406] Example 95 Synthesis of compound 288 [ka] Step 1 At room temperature, bistriphenylphosphine palladium dichloride (98 mg, 0.14 mmol) and triphenylphosphine (73 mg, 0.28 mmol) were added to a solution of intermediate 28...

Claims

1. The compound of formula (I) or any of the pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled forms thereof: 【Chemistry 1】 (In the formula, ring A, ring B, Y, L, R １ , R ２ , R ３ , R Ａ , R Ｂ m, n, p, and q are defined as follows: Ring A is selected from 5-11 member monocyclic or fused bicyclic aryl compounds, or 5-11 member monocyclic or fused bicyclic heteroaryl compounds. Ring B is selected from a 6-membered monocyclic heteroaryl, an 8-11-membered condensed bicyclic heteroaryl, an 8-11-membered condensed bicyclic heterocyclyl, a 10-15-membered condensed tricyclic heteroaryl, and a 10-15-membered condensed tricyclic heterocyclyl. Y is either O or S, L is #-C(=O)-NH-$, and in the formula, # is 【Chemistry 2】 It is connected to and $ is connected to ring B, R １ is selected from the group consisting of: deuterium, halogen, oxo, -CN, -OH, -NH ２ , C1-C ｚ alkyl optionally substituted with 1 to 3 R １ -C ６ alkoxy optionally substituted with 1 to 3 R ｚ C1-C １ -C ６ haloalkyl optionally substituted with 1 to 3 R ｚ C1-C １ -C ６ haloalkoxy optionally substituted with 1 to 3 R ｚ C1-C １ -C ６ cycloalkyl optionally substituted with 1 to 3 R ｚ -NH(C1-C ３ -C ６ alkyl) optionally substituted with 1 to 3 R ｚ -N(C1-C １ -C ６ alkyl)(C1-C ｚ alkyl) optionally substituted with 1 to 3 R １ -C ６ cycloalkyl optionally substituted with 1 to 3 R １ -C ６ 5- to 15-membered monocyclic, fused bicyclic or fused tricyclic heterocyclic group optionally substituted with 1 to 3 R ｚ 5- to 15-membered monocyclic, fused bicyclic or fused tricyclic aryl optionally substituted with 1 to 3 R ３ -C ６ or 5- to 15-membered monocyclic, fused bicyclic or fused tricyclic heteroaryl, and is C1-C ｚ alkyl or C1-C ｚ alkoxy optionally substituted with 1 to 3 groups selected from the above, １ -C ５ １ -C ５ ;​ R ２ and R ３ These are independently hydrogen, deuterium, halogen, and C １ -C ６ Alkyl or C １ -C ６ It is an alkoxy, R １ And, R １ The nitrogen atom to which it is connected, and R ２ and R ３ The carbon atom to which the ring is connected and one atom of ring A form a ring group, and the ring group and ring A are connected in a manner that they share the one atom to form a spiro ring structure. R Ａ is deuterium, halogen, hydroxyl, oxo, cyano, nitro, amino, C １ -C ６ alkyl, cyano C １ -C ６ alkyl, C １ -C ６ alkoxy, -C １ -C ６ alkyl-C １ -C ６ alkoxy, -NH(C １ -C ６ alkyl), -N(C １ -C ６ alkyl)(C １ -C ６ alkyl), C ３ -C ６ cycloalkyl, C １ -C ６ haloalkyl, -O-(C １ -C ６ haloalkyl), -NH-(C １ -C ６ haloalkyl), -N(C １ -C ６ haloalkyl)(C １ -C ６ haloalkyl), pentafluorosulfur (-SF ５ ), C １ -C ６ haloalkoxy or halocycloalkyl, -S(O) ２ -(C １ -C ６ alkyl), -S(=O)(C １ -C ６ alkyl)NR ｚ , -S(=O)(=NR ｚ )(C １ -C ６ alkyl), -P(=O)(C １ -C ６ alkyl) ２ , 4- to 8-membered heterocyclyl optionally substituted with 1 to 3 R ｚ , 5- to 8-membered heteroaryl optionally substituted with 1 to 3 R ｚ optionally substituted with 1 to 3 R ｚ 6- to 10-membered aryl optionally substituted with, 1 to 3 R ｚ C optionally substituted with ３ -C ６ cycloalkyl, or Two R atoms connected to the same carbon atom Ａ It forms an oxo group, or Two R atoms connected to the same carbon atom Ａ Together with the carbon atoms to which they are connected, C ３ -C ８ Forming a cycloalkyl group, R Ｂ These are deuterium, halogen, hydroxyl, oxo, thioketone, cyano, nitro, amine, and C. １ -C ６ Alkyl, C １ -C ６ Alkoxy, -NH(C) １ -C ６ Alkyl), -N(C １ -C ６ (Alkyl) (C １ -C ６ Alkyl), -(C １ -C ６ Alkyl)-OH, C ３ -C ８ Cycloalkyl, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy or C ３ -C ８ It is a halocycloalkyl, or Two R atoms connected to the same carbon atom Ｂ Together with the carbon atoms to which they are connected, C ３ -C ８ They form cycloalkyl or 6-7 membered heterocyclines, or Two R's connected to different carbon atoms Ｂ They are connected to form a 6-7 member ring. R ｚ These are independently deuterium, halogen, and C １ -C ６ Alkyl, -CN, -OH, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, C ３ -C ６ Cycloalkyl, -NH ２ ,-NH(C １ -C ６ Alkyl) or -N(C) １ -C ６ (Alkyl) (C １ -C ６ (Alkyl), (C １ -C ６ Alkyl)C(O)NH-, (C １ -C ６ Selected from alkyl)C(O)-, phenyl, pentafluorosulfur, 5-6 membered heteroaryl or 4-6 membered heterocyclyl, or Two R atoms connected to the same carbon atom ｚ It forms an oxo group, or Two R atoms connected to the same carbon atom ｚ Together with the carbon atoms to which they are connected, C ３ -C ８ Forms a cycloalkyl group, m is 1 or 2, n is either 0 or 1, p is 0, 1, 2, 3 or 4, q is 0, 1, 2, 3, 4, or 5).

2. Formula (IC-1): 【Transformation 3】 (In the formula, ring A, ring B, Y, L, R ２ , R ３ , R Ａ , R Ｂ m, n, p, and q are defined as follows: Ring A is selected from 8-11 member fused bicyclic aryls and 8-11 member fused bicyclic heteroaryls. m is either 1 or 2. Ring B is selected from a 6-membered monocyclic heteroaryl, an 8-11-membered condensed bicyclic heteroaryl, an 8-11-membered condensed bicyclic heterocyclyl, a 10-15-membered condensed tricyclic heteroaryl, and a 10-15-membered condensed tricyclic heterocyclyl. Y is either O or S, L is #-C(=O)-NH-$, and in the formula, # is 【Chemistry 4】 It is connected to and $ is connected to ring B, n is either 0 or 1, Each R ２ and each R ３ These are independently hydrogen, deuterium, halogen, and C １ -C ６ Alkyl or C １ -C ６ It is an alkoxy, R Ａ These are deuterium, halogen, hydroxyl, oxo, cyano, nitro, amine, C １ -C ６ Alkyl, cyano C １ -C ６ Alkyl, C １ -C ６ Alkoxy, -C １ -C ６ Alkyl-C １ -C ６ Alkoxy, -NH(C) １ -C ６ Alkyl), -N(C １ -C ６ (Alkyl) (C １ -C ６ Alkyl), C ３ -C ６ Cycloalkyl, C １ -C ６ Haloalkyl, -O-(C) １ -C ６ Haloalkyl), -NH-(C) １ -C ６ Haloalkyl), -N(C) １ -C ６ (Haloalkyl) (C １ -C ６ Haloalkyl), pentafluorosulfur, C １ -C ６ Haloalkoxy or C ３ -C ６ Halocycloalkyl, -S(O) ２ - (C １ -C ６ Alkyl), -S (=O) (=NR ｚ ) (C １ -C ６ Alkyl), -P (=O) (C １ -C ６ Alkyl) ２ , 1 to 3 R ｚ A 4- to 8-membered heterocyclic group, 1 to 3 R groups, are optionally substituted. ｚ A 5- to 8-membered heteroaryl group is optionally substituted, along with 1 to 3 R ｚ A 6-10 membered aryl group, 1-3 R groups, which are optionally substituted. ｚ C is replaced by an optional choice. ３ -C ６ It is a cycloalkyl group, or Two R's bonded to the same carbon atom Ａ It forms an oxo group, or Two R atoms connected to the same carbon atom Ａ and the carbon atoms to which they are connected are C ３ -C ８ Forming a cycloalkyl group, R Ｂ These are deuterium, halogen, hydroxyl, oxo, thioketone, cyano, nitro, amine, and C. １ -C ６ Alkyl, C １ -C ６ Alkoxy, -NH(C) １ -C ６ Alkyl), -N(C １ -C ６ (Alkyl) (C １ -C ６ Alkyl), -(C １ -C ６ Alkyl)-OH, C ３ -C ８ Cycloalkyl, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy or C ３ -C ８ It is a halocycloalkyl, or Two R atoms connected to the same carbon atom Ｂ and the carbon atoms to which they are connected are C ３ -C ８ They form a cycloalkyl group or a 6-7 membered heterocycline, or Two R's connected to different carbon atoms Ｂ They are connected to form a 6-7 member ring. R ｚ These are independently deuterium, halogen, and C １ -C ６ Alkyl, -CN, -OH, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, C ３ -C ６ Cycloalkyl, -NH ２ ,-NH(C １ -C ６ Alkyl), -N(C １ -C ６ (Alkyl) (C １ -C ６ (Alkyl), (C １ -C ６ Alkyl)C(O)NH-, (C １ -C ６ Selected from alkyl)C(O)-, phenyl, pentafluorosulfur, 5-6 membered heteroaryl or 4-6 membered heterocyclic groups, Two R atoms connected to the same carbon atom ｚ It forms an oxo group, or Two R atoms connected to the same carbon atom ｚ and the carbon atoms to which they are connected are C ３ -C ８ Forms a cycloalkyl group, p is 0, 1, 2, 3 or 4, (q is 0, 1, 2, 3, 4, or 5) A compound of formula (I) as described in claim 1, or any of the pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled thereof, having the aforementioned.

3. Formula (IC-2): 【Transformation 5】 (In the formula, ring A, ring D, Y, Z ３ Z ４ Z ５ Z ６ , R ２ , R ３ , R Ａ , R Ｂ m, p, and q are defined as follows: Z ３ and Z ６ is N or CR ｅ Z ４ and Z ５ N, NH, NR ｅ or CR ｅ Z ４ and Z ５ At least one of them is N or NH, 【Transformation 6】 It is a single bond or a double bond, and the position of the double bond is Z ４ or Z ５ It changes when it is N or NH, R ｅ is hydrogen, deuterium, halogen, hydroxyl, cyano, -NH ２ , C １ -C ６ Alkyl, C １ -C ６ Alkoxy, -NH(C) １ -C ６ Alkyl) or -N(C １ -C ６ (Alkyl) (C １ -C ６ It is alkyl, Ring D is either a 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered aryl, or 5-6 membered heteroaryl condensed into a 10-membered ring, or is absent. m is either 1 or 2. Ring A is defined as described in claim 1, Y, R ２ , R ３ , R Ａ , R Ｂ (where p and q are as defined in claim 1) A compound of formula (I) as described in claim 1, or any of the pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled thereof, having the aforementioned.

4. Formula (IC-3): 【Transformation 7】 (In the formula, rings A, W ４ , W ５ , W ６ Y, L, R ２ , R ３ , R Ａ , R Ｂ m, p, and q are defined as follows: -W ４ -W ５ -W ６ - is (1)-CR ｆ = N - NR ｆ -, (2)-NR ｆ -N = CR ｆ -, (3)-CR ｆ R ｇ -O-CR ｆ R ｇ , (4)-SN=NR ｆ -, (5)-CR ｆ =NS-, (6)-CR ｆ R ｇ -CR ｆ R ｇ -NR ｆ -, and (7) non-existence, R ｆ and R ｇ These are independently hydrogen, deuterium, halogen, and C １ -C ６ Alkyl, C １ -C ６ It is either a haloalkyl group or two R groups connected to the same carbon atom. ｆ and R ｇ It forms an oxo group, or two R groups connected to the same carbon atom. ｆ and R ｇ And together with the carbon atoms to which they are connected, C ３ -C ８ Forms a cycloalkyl group, or R ｆ and R Ｂ These are connected to form a 6-7 member ring, m is either 1 or 2. Ring A is as defined in claim 1, Y, L, R ２ , R ３ , R Ａ , R Ｂ (where p and q are as defined in claim 1) A compound of formula (I) as described in claim 1, or any of the pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled thereof, having the aforementioned.

5. Ring B is 【Transformation 8】 Selected from, in the formula, the dashed line represents a connection point, R Ｂ and p are as defined in claim 1, The compound of formula (I) described in claim 1, or any of the pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled thereof.

6. Ring B is 【Chemistry 9】 【change】 A compound of formula (I) as described in claim 1 or 2, or any of the pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled compounds thereof, selected from the above.

7. Z ３ and Z ６ One of them is N, and the other is CR ｅ Z ４ is N, NH or NR ｅ Z ５ CR ｅ The compound of formula (I) described in claim 3, or any of the pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled thereof.

8. Z ３ and Z ６ Each independently CR ｅ Z ４ is N, NH or NR ｅ Z ５ CR ｅ The compound of formula (I) described in claim 3, or any of the pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled thereof.

9. The portion formed by the ring D fused with the 10-membered ring is 【Chemistry 10】 Selected from, R Ｂ and p is as defined in claim 3, The compound of formula (I) described in claim 3, or any of the pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled thereof.

10. The compound of formula (I) described in claim 3, or any pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemic compound, prodrug, solvate, hydrate, or isotope-labeled thereof, wherein ring D is absent.

11. The portion formed by the ring D fused with the 10-membered ring is 【Chemistry 11】 【change】 A compound of formula (I) as described in claim 3, or any of the pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled compounds thereof, selected from the above.

12. -W condensed with pyridine ４ -W ５ -W ６ - The portion formed by 【Chemistry 12】 A compound of formula (I) as described in claim 4, or any of the pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled compounds thereof, selected from the above.

13. Ring A 【Chemistry 13】 Selected from, In the formula, * indicates the connection point of the helical ring. R Ａ and q is as defined in claim 1, A compound of formula (I) as described in any one of claims 1 to 12, or any of the pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled thereof.

14. (1) R １ And, R １ The nitrogen atom to which it is connected, and R ２ and R ３ The carbon atom to which the atom is connected and one atom of ring A form a cyclic group, and this cyclic group and ring A are connected in a manner that they share atoms so that they form a spirocyclic structure, or (2) R ２ and R ３ The carbon atom to which it is connected, the adjacent nitrogen atom, the adjacent methylene group, and one atom of ring A form a cyclic portion, and this cyclic portion and ring A are connected in a manner that they share one atom, forming a spirocyclic structure. The aforementioned spirocyclic structure, 【Chemistry 14】 【change】 【change】 【change】 【change】 Selected from, A compound of formula (I) as described in any one of claims 1 to 12, or any of the pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled thereof. 【Request Item 15】 【Chemistry 15】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 or any of the pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled forms thereof. A compound of formula (I) as described in claim 1, or any of the pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled compounds thereof, selected from the above.

16. A pharmaceutical composition comprising any one of the compounds described in claims 1 to 15, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemic compound, prodrug, solvate, hydrate, or isotope-labeled thereof, and one or more pharmaceutically acceptable carriers or excipients.

17. Use in the manufacture of a pharmaceutical for treating cancer, the use of a pharmaceutical composition comprising any one of the compounds described in claims 1 to 15, or any of the pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled thereof, or any of the compounds described in claim 16.

18. Use of a pharmaceutical composition comprising any one of the compounds described in claims 1 to 15, or any of the pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemic compounds, prodrugs, solvates, hydrates, or isotope-labeled compounds thereof, or the compound described in claim 16, in the production of an MTA cooperative PRMT5 inhibitor.

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