MTA-synergistic PRMT5 inhibitors

Abstract

The present invention relates to compounds that are MTA synergistic inhibitors of protein arginine N-methyltransferase 5 (PRMT5). In particular, the present invention relates to MTA-synergistic PRMT5 inhibitors, pharmaceutical compositions comprising such compounds, and methods of use thereof.

Description

Technical Field

[0001] This invention relates to compounds that act as MTA synergistic inhibitors of protein arginine N-methyltransferase 5 (PRMT5). In particular, this invention relates to PRMT5 inhibitors of MTA synergism, pharmaceutical compositions comprising said compounds, and methods of using said compounds. Background Technology

[0002] Protein arginine methyltransferase (PRMT5) plays a crucial role in maintaining normal 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 histones and non-histone proteins. PRMT5 catalyzes the transfer of one methyl group from S-adenosyl-L-methionine (SAM) to the ω-nitro group of the L-arginine residue in a protein (ω-monomethylation) and the transfer of a second methyl group to another ω-nitro group, producing symmetrical 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 to most cell lines. Therefore, PRMT5 is considered an essential gene for cell viability (McDonald, ER, et al., Project DRIVE: A Compendium of Cancer Dependency and Synthetic Lethal Reasoning Uncovered by Large-Scale, Deep RNAi Screening. Cell 2017, 170(3), 577-592). PRMT5 is an attractive drug target in oncology. Several effective and selective inhibitors targeting the catalytic pocket of PRMT5 have been developed. However, given the important role of PRMT5 in normal tissue homeostasis, simply inhibiting PRMT5 may cause toxicity and limit the scope of treatment.

[0004] Methionine adenosine (MTA) is an endogenous competitor of SAM, partially inhibiting PRMT5 but not other PRMT family members. Studies have shown that inhibiting PRMT5 with MTA reduces methylation activity and sensitizes cells to PRMT5 inhibitors. MTA is a receptor for methylthioadenosine phosphorylase (MTAP) and can be converted to 5-methylthioribose-1-phosphate (MTR-1-P) by MTAP. Therefore, in MTAP wild-type cells, MTA does not accumulate and reduce its effect on PRMT5 activity. Conversely, cells lacking MTAP homozygosity will lead to MTA accumulation in the cells, resulting in decreased PRMT5 activity (Kryukov, GV et al., MTAP deletion confers enhanced dependency on the argininemethyltransferase PRMT5 in human cancer cells. Science 2016, 351 (6278), 1214-1218). Therefore, MTA-synergistic inhibition of PRMT5 selectively suppresses PRMT5 activity in MTAP isozygous deletion cells.

[0005] MTAP homozygous deletion is relatively common in cancers, occurring in approximately 15% of cases. A higher incidence is seen in glioblastoma, bladder cancer, non-small cell lung cancer, and pancreatic cancer. This deletion is caused by its proximity to the p16 / CDKN2A tumor suppressor locus. Homozygous deletion of p16 / CDKN2a often involves the co-deletion of neighboring 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] In MTAP-deficient cancers, we have realized that by utilizing the MTA synergistic mechanism, selective inhibition of PRMT5 activity in cancer cells can reduce the impact on normal tissue cells, potentially providing therapeutic benefits for a variety of cancers. Therefore, there is a need to develop novel MTA-synergistic PRMT5 inhibitors that can suppress PRMT5 activity in MTAP-deficient cells. Summary of the Invention

[0007] The compounds of this invention are PRMT5 inhibitors with MTA synergism that can provide the therapeutic benefit by negatively regulating the activity of PRMT5 that binds to MTA in cells, particularly MTAP-deficient cells, or for the treatment of various MTAP-related cancers.

[0008] One aspect of the present invention is to provide a compound of formula (I) or a pharmaceutically acceptable salt thereof, a geometric isomer, an enantiomer, a diastereomer, a racemic mixture, a prodrug, a solvate, a hydrate, or any of the foregoing labeled with an isotope:

[0009] (I)

[0010] Among them, ring A, ring B, Y, L, R1, R2, R3, R A R B m, n, p, and q are defined as follows:

[0011] Ring A is selected from 5-11 member monocyclic or fused bicyclic aryl, or 5-11 member monocyclic or fused bicyclic heteroaryl;

[0012] Ring B is selected from 6-membered monocyclic heteroaryl, 8-11-membered fused bicyclic heteroaryl, 8-11-membered fused bicyclic heterocyclic group, 10-15-membered fused tricyclic heteroaryl, and 10-15-membered fused tricyclic heterocyclic group;

[0013] Y is either O or S;

[0014] L is #-C(=O)-NH- , where # and Connected, Connected to ring B;

[0015] R1 is a C1-C5 alkyl or C1-C5 alkoxy group; wherein the C1-C5 alkyl or C1-C5 alkoxy group is optionally substituted by 1-3 groups selected from the following: deuterium, halogen, oxo group, -CN, -OH, -NH2, optionally substituted by 1-3 R groups. z Substituted C1-C6 alkyl groups, optionally with 1-3 R groups z Substituted C1-C6 alkoxy groups, optionally with 1-3 R groups z Substituted C1-C6 haloalkyl groups, optionally with 1-3 R groups z Substituted C1-C6 haloalkoxy groups, optionally with 1-3 R groups z Substituted C3-C6 cycloalkyl groups, optionally with 1-3 R... z Substituted -NH (C1-C6 alkyl), optionally with 1-3 R z Substituted -N(C1-C6 alkyl)(C1-C6 alkyl), optionally with 1-3 R z Substituted C3-C6 cycloalkyl groups, optionally with 1-3 R... z The 5-15 nucleotide monocyclic, fused bicyclic, or fused tricyclic heterocyclic groups are optionally replaced by 1-3 R groups. z The substituted 5-15 member monocyclic or fused bicyclic or fused tricyclic aryl or 5-15 member monocyclic or fused bicyclic or fused tricyclic heteroaryl;

[0016] R2 and R3 are independently hydrogen, deuterium, halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0017] Wherein, the nitrogen atom connected to R1, the carbon atom connected to R2 and R3 and one atom of ring A form a cyclic group, and this cyclic group and ring A are connected in the form of sharing the one atom to form a spiro ring structure;

[0018] R AFor deuterium, halogen, hydroxyl, oxo, cyano, nitro, amino, -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), pentafluoride sulfo, C1-C6 haloalkoxy or halocycloalkyl, -S(O)2-(C1-C6 alkyl), -S(=O)(C1-C6 alkyl)NRz, -S(=O)(=NR z (C1-C6 alkyl), -P(=O)(C1-C6 alkyl)2, optionally with 1-3 R z The 4-8 membered heterocyclic group is replaced, optionally with 1-3 R groups. z Replaced 5-8 heteroaryl groups, optionally with 1-3 R groups z Replaces 6-10 aryl groups, optionally with 1-3 R groups z Substituted C3-C6 cycloalkyl, or

[0019] Two R atoms attached to the same carbon atom A Formation of oxygen groups, or

[0020] Two R atoms attached to the same carbon atom A Together with the carbon atoms they are attached to, they form C3-C8 cycloalkyl groups;

[0021] R B It can be deuterium, halogen, hydroxyl, oxo, thionyl, cyano, nitro, amino, 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

[0022] Two R atoms attached to the same carbon atom B Together with the carbon atoms they are attached to, they form C3-C8 cycloalkyl groups or 6-7 membered heterocyclic groups, or

[0023] Two R atoms attached to different carbon atoms B The connection forms a 6-7 element ring;

[0024] R zIndependently 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, pentafluoride sulfo, 5-6 membered heteroaryl or 4-6 membered heterocyclic group, or

[0025] Two R atoms attached to the same carbon atom z Formation of oxygen groups, or

[0026] Two R atoms attached to the same carbon atom z Together with the carbon atoms they are attached to, they form C3-C8 cycloalkyl groups;

[0027] m is 1 or 2;

[0028] n is 0 or 1;

[0029] p is 0, 1, 2, 3 or 4;

[0030] q can be 0, 1, 2, 3, 4 or 5.

[0031] One aspect of the present invention is to provide a compound of formula (IC-1) or a pharmaceutically acceptable salt thereof, a geometric isomer, an enantiomer, a diastereomer, a racemic mixture, a prodrug, a solvate, a hydrate, or any of the foregoing labeled with an isotope:

[0032] (IC-1)

[0033] Among them, rings A, B, Y, L, R2, R3, and R A R B m, n, p, and q are defined as follows:

[0034] Ring A is selected from 8-11 member fused bicyclic aryl and 8-11 member fused bicyclic heteroaryl;

[0035] m is 1 or 2;

[0036] Ring B is selected from 6-membered monocyclic heteroaryl, 8-11-membered fused bicyclic heteroaryl, 8-11-membered fused bicyclic heterocyclic group, 10-15-membered fused tricyclic heteroaryl and 10-15-membered fused tricyclic heterocyclic group;

[0037] Y is either O or S;

[0038] L is #-C(=O)-NH- , where # and Connected, and Connected to ring B;

[0039] n is 0 or 1;

[0040] Each R2 and each R3 is independently hydrogen, deuterium, halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0041] R A For deuterium, halogen, hydroxyl, oxo, thionyl, cyano, nitro, amino, 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), sulfopentafluoride, 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, optionally with 1-3 R z The 4-8 membered heterocyclic group is replaced, optionally with 1-3 R groups. z Replaced 5-8 heteroaryl groups, optionally with 1-3 R groups z Replaces 6-10 aryl groups, optionally with 1-3 R groups z Substituted C3-C6 cycloalkyl groups, or,

[0042] Two R atoms attached to the same carbon atom A Formation of an oxo group, or,

[0043] Two R atoms attached to the same carbon atom A Together with the carbon atoms they are attached to, they form C3-C8 cycloalkyl groups;

[0044] R B It can be deuterium, halogen, hydroxyl, oxo, cyano, nitro, amino, 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,

[0045] Two R atoms attached to the same carbon atom B Together with the carbon atoms they are attached to, they form C3-C8 cycloalkyl groups or 6-7 membered heterocyclic groups, or...

[0046] Two R atoms attached to different carbon atoms B The connection forms a 6-7 element ring;

[0047] R z 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, pentafluoride sulfo, 5-6 membered heteroaryl or 4-6 membered heterocyclic group, or

[0048] Two R atoms attached to the same carbon atom z Formation of oxygen groups, or

[0049] Two R atoms attached to the same carbon atom z Together with the carbon atoms they are attached to, they form C3-C8 cycloalkyl groups;

[0050] p is 0, 1, 2, 3, or 4; and

[0051] q can be 0, 1, 2, 3, 4 or 5.

[0052] One aspect of the present invention is to provide a compound of formula (IC-2), or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemate, prodrug, solvate, hydrate, or any of the foregoing labeled thereof:

[0053] (IC-2)

[0054] Among them, rings A, D, Y, Z3, Z4, Z5, Z6, R2, R3, and R A R B m, p, and q are defined as follows:

[0055] Z3 and Z6 are N or CR. e Z4 and Z5 are N, NH, and NR, respectively. e or CR e And at least one of Z4 and Z5 is N or NH; where It can be a single bond or a double bond, and the position of the double bond changes depending on whether Z4 and Z5 are N or NH;

[0056] R e It can be hydrogen, deuterium, halogen, hydroxyl, cyano, -NH2, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)(C1-C6 alkyl);

[0057] Ring D is a 5- to 6-membered cycloalkyl, 5- to 6-membered heterocyclic, 5- to 6-membered aryl, 5- to 6-membered heteroaryl group fused with a 10-membered ring, or is absent;

[0058] m is 1 or 2;

[0059] Ring A is as defined above;

[0060] Y, R2, R3, R A R B p and q are as defined above.

[0061] One aspect of the present invention is to provide a compound of formula (IC-3), or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemate, prodrug, solvate, hydrate, or any of the foregoing labeled thereof:

[0062] (IC-3)

[0063] Among them, rings A, W4, W5, W6, Y, L, R2, R3, and R A R B m, p, and q are defined as follows:

[0064] -W4-W5-W6- is any of the following: (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 - or (7) does not exist;

[0065] R f R g Independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or two R atoms attached to the same carbon atom. f and R g The formed oxo group, or two R groups attached to the same carbon atom f and R g C3-C8 cycloalkyl groups formed together with the carbon atoms they are attached to, or R f and R B The connection forms a 6-7 element ring;

[0066] m is 1 or 2;

[0067] Ring A is as defined above;

[0068] Y, L, R2, R3, R A R B p and q are as defined above.

[0069] Another aspect of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), (IC-1), (IC-2), or (IC-3) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemate, prodrug, solvate, hydrate, or isotopically labeled thereof, and one or more pharmaceutically acceptable carriers or excipients thereof. The pharmaceutical composition of the present invention is a PRMT5 inhibitor synergistic with MTA.

[0070] Another aspect of the present invention is to provide the use of a compound of formula (I), formula (IC-1), formula (IC-2) or formula (IC-3) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemate, prodrug, solvate, hydrate or isotopically labeled thereof for the manufacture of an MTA-synergistic PRMT5 inhibitor drug or pharmaceutical agent.

[0071] Another aspect of the present invention is to provide a method for treating cancer, comprising administering to an individual in need a therapeutically effective amount of a compound of formula (I), (IC-1), (IC-2), or (IC-3), or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemate, prodrug, solvate, hydrate, or isotopically labeled thereof, to inhibit cancer growth in said individual. The compound of formula (I), (IC-1), (IC-2), or (IC-3), or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemate, prodrug, solvate, hydrate, or isotopically labeled thereof, may be used alone or in combination with another therapeutic agent and / or therapy.

[0072] Another aspect of the present invention is to provide a method for preparing a compound of formula (I), formula (IC-1), formula (IC-2) or formula (IC-3) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemate, prodrug, solvate, hydrate or isotopically labeled thereof. Attached Figure Description

[0073] none Detailed Implementation

[0074] The invention can be more readily understood by referring to the detailed description of the various embodiments, examples, and tables with their related descriptions below. Unless otherwise defined, all terms used herein (including technical and scientific terms) have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Furthermore, it should be further understood that terms defined in common dictionaries should be interpreted as having the same meaning as in the relevant field, and that, unless explicitly stated herein, the terms should not be interpreted in an idealized or overly formal sense. It is also understood that the language used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0075] definition

[0076] The definitions presented in this section are intended to clarify the terminology used throughout this application. The term "in this document" refers to the entire application.

[0077] It must be noted that, unless otherwise expressly stated herein, the singular forms “a” and “as referred to” as used herein include the plural of the referred to. Therefore, unless otherwise required herein, singular terms shall include the plural and plural terms shall include the singular.

[0078] Typically, ranges herein are expressed as "about" a particular value and / or "about" another particular value. When such ranges are expressed, one embodiment includes a range from one particular value and / or to another particular value. Similarly, when a value is expressed as an approximate value using the term "about," it can be understood that said particular value constitutes another embodiment. It should be further understood that the endpoints in each range are important in terms of relevance and independence. As used herein, the term "about" means ±20%, preferably ±10%, and even more preferably ±5%.

[0079] As used herein, the term “optionally substituted” means that substitution is optional. In cases where substitution is desired, such substitution means that any number of hydrogen atoms on a specified atom are replaced by an option selected from the specified group, subject to the constraint that the substitution does not exceed the normal valence of the specified atom, and that the substitution produces a stable compound. For example, when the substituent is a ketone group (i.e., =O), two hydrogen atoms on the atom are replaced. Examples of substituents referred to as “substituted” are those present in the exemplary compounds and examples disclosed herein, and may include, but are not limited to, halogen, cyano, alkyl, alkoxy, haloalkyl, alkylamino, aminoalkyl, dialkylamino, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, alkylaminoalkoxy, alkylaminoalkyl, etc.

[0080] As used herein, the term "halogen" includes fluorine, chlorine, bromine, and iodine. The use of "halogen" as a group prefix indicates that one or more hydrogen atoms in the group have been replaced by one or more halogens.

[0081] As used herein, the term "alkyl" refers to a monovalent, saturated, straight-chain, or branched hydrocarbon group containing 1 to 12 carbon atoms. Preferably, the alkyl group is a C1-C8 alkyl group. More preferably, the alkyl group is a C1-C6 alkyl group. The alkyl group may be unsubstituted or substituted with one or more substituents. Examples of C1-C6 alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (including all isomers) and hexyl (including all isomers), heptyl (including all isomers), octyl (including all isomers), and the like.

[0082] Unless otherwise specified, the term "cycloalkyl" as used herein refers to a saturated monovalent hydrocarbon group having a cyclic configuration, including monocyclic, bicyclic, tricyclic, and more cyclic alkyl groups (and, when polycyclic, including fused and bridged bicyclic and spirocyclic moieties), wherein each cyclic moieties have 3 to 12 carbon atoms. Preferably, the cycloalkyl group has 3 to 8 carbon atoms. More preferably, the cycloalkyl group has 3 to 6 carbon atoms. When the cycloalkyl group contains more than one ring, the rings may be fused or non-fused and may include bicyclic groups. A fused ring generally refers to at least two rings sharing two atoms therebetween. Such cycloalkyl groups include, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, etc., or bicyclic, polycyclic, or bridged ring structures such as adamantyl and the like.

[0083] Unless otherwise specified, "heterocyclic group" means a saturated or partially unsaturated monocyclic group with 3 to 9 ring atoms or a saturated or partially unsaturated monocyclic fused bicyclic group with 5 to 12 ring atoms, wherein one or more, for example, one, two, three or four heteroatoms are independently selected from: -O-, -S(O). x - (x is 0, 1, or 2), -N=, -N(R) y )-(where R y It is a hydrogen, alkyl, hydroxyl, alkoxy, acyl, or alkylsulfonyl group, with the remaining ring atoms being carbon. One or two ring carbon atoms can be substituted by -C(O)-, -C(S)-, or -C(=NH)- groups. Fused bicyclic groups include bridged ring systems. Unless otherwise stated, the valence of the group can be located on any atom of any ring within the group, provided that the valence rules permit. Specifically, when the valence position is on a nitrogen atom, R yNo. More specifically, the term "heterocyclic group" includes, but is not limited to: piperidinyl, pyrimidinyl, morpholinyl, piperazine, acridineyl, pyrrolylyl, 2-oxopyrrolylyl, 2,5-dihydro-1H-pyrrolyl, 4-piperidinoneyl, 2-oxopyrazineyl, tetrahydropyranyl, 2-oxopyridineyl, thiomorpholinyl, perhydroazepinyl, pyrazolidineyl, dihydroimidazolyl, imidazolyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolinyl, isoxazolinyl, thiazolinyl, thiazolylyl, quininecycloyl, isothiazolinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolinyl, tetrahydrofuranyl and tetrahydropyranyl, and derivatives thereof, as well as N-oxides or protected derivatives thereof.

[0084] Unless otherwise specified, the term "aryl" means a monocyclic or bicyclic ring with 6 to 14 members, such as 8 to 11 members, wherein at least one of the rings in the bicyclic ring is a carboxylic aromatic ring. Representative examples include, but are not limited to, phenyl, biphenyl, naphthyl, indenyl, etc. In a bicyclic aryl group, any non-aromatic ring contained therein may be a cycloalkyl or heterocyclic group as described above, provided that the total number of ring atoms meets the definition of aryl here. In a specific form of aryl, a fused bicyclic ring comprising a cycloalkyl group and an aryl group, or a fused bicyclic ring comprising a heterocyclic group and an aryl group, wherein one or two ring carbon atoms of the cycloalkyl or heterocyclic group may be substituted with a -C(O)-, -C(S)-, or -C(=NH)- group, and wherein the heteroalkyl group comprises one or two ring heteroatoms independently selected from: -O-, -S(O). x - (x is 0, 1, or 2), -N=, -N(R) y )-(where R y It is a hydrogen, alkyl, hydroxyl, alkoxy, acyl, or alkylsulfonyl group, with the remaining ring atoms being carbon. Fused bicyclic groups include bridged ring systems. Unless otherwise specified, the valence atom can be located on any atom of any ring of the aryl group, provided that the valence rules permit it.

[0085] Unless otherwise specified, "heteroaryl" means a monovalent group of 5 to 14 ring atoms in a monocyclic, fused bicyclic, or fused tricyclic ring, containing one or more, for example, one, two, three, or four independently selected cyclic heteroatomic moieties: -O-, -S(O). n - (n is 0, 1, or 2), -N-, -N(R) x )-(R xIt is a fused ring containing at least one of a bicyclic or tricyclic group (hydrogen, alkyl, hydroxyl, alkoxy, acyl, or alkylsulfonyl), and the remaining ring atoms are carbon, and is an aromatic ring containing a cyclic heteroatom. In a heteroaryl containing a bicyclic or tricyclic group, any non-aromatic ring may be one of the aforementioned cycloalkyl or heterocyclic groups, provided that the total number of ring atoms meets the definition of a heteroaryl here. In a specific form of heteroaryl, it comprises a fused bicyclic ring of a cycloalkyl and a heteroaryl, or a fused bicyclic ring of a heterocyclic group and a heteroaryl, wherein one or two ring carbon atoms of the cycloalkyl or heterocyclic group may be substituted with a -C(O)-, -C(S)-, or -C(=NH)- group, and wherein the heteroalkyl group contains one or two cyclic heteroatoms independently selected from: -O-, -S(O). x - (x is 0, 1, or 2), -N=, -N(R) y )-(where R y It is a hydrogen, alkyl, hydroxyl, alkoxy, acyl, or alkylsulfonyl group, with the remaining ring atoms being carbon. Fused bicyclic groups include bridged ring systems. Unless otherwise specified, the valence atom can be located on any atom of any ring of the heteroaryl group, provided that the valence rules permit it. Specifically, when the valence atom is located on nitrogen, R xNo. More specifically, the term "heteroaryl" includes, but is not limited to: benzocyclopentyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrofurano[3,2-b]pyridine, 2,3-dihydrofurano[3,2-c]pyridine, 6,7-dihydro-5H-cyclopentano[b]pyridine, alkyl, isoalkyl, 3,4-dihydro-2H-pyrano[2,3-b]pyridine, 5,8-dihydro-6H-pyrano[3,4-b]pyridine, 1,3,4,5-tetrahydrobenzo[c]oxazapyridine, and heptanediol. Alkenyl, indane, phthalyl, indololinyl, 1,2,4-triazolyl, 1,3,5-triazolyl, phthalimide, pyridyl, pyrroleyl, imidazolyl, thiophene, furanyl, indolyl, 2,3-dihydro-1H-indolyl (including, for example, 2,3-dihydro-1H-indol-2-yl or 2,3-dihydro-1H-indol-5-yl), isoindolyl, dihydroindolyl, isoindololinyl, benzimidazolyl, benzodioxane-4-yl, benzofuranyl, cinnolinyl linyl), indoleazinyl, naphthid-3-yl, phthalazin-3-yl, phthalazin-4-yl, pyridinyl, purinyl, quinazolinyl, quinazolinyl, tetrazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, tadalyl, diazinyl, oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl (including, for example, tetrahydroisoquinolin-4-yl or tetrahydroisoquinolin-6-yl), pyrrolo[3,2-c]pyridinyl (including, for example, pyrrolo[3,2-c]pyridin-2-yl or pyrrolo[3,2-c]pyridinyl) [3,2-c]pyridin-7-yl, etc.), benzopyranyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl, benzothiophene, tetrahydrofuranopyridyl, pyridotetrahydrofuranyl, tetrahydropyranopyridyl, pyridotetrahydropyranyl, tetrahydropyranophenyl or benzotetrahydropyranyl, pyridoxazolyl, oxazolopyridyl, pyridoxyrrolyl, pyrrolopyridyl, diazolophenyl, benzodiazolyl, benzooxazolyl, oxazolophenyl, and derivatives thereof, or N-oxides or protected derivatives thereof.

[0086] The term "ring" as used in this article refers to "cycloalkyl", "aryl", "heteroaryl", and "heterocyclic" rings that do not exist in free radical form, including "cycloalkane ring", "aromatic ring", "heteroaromatic ring", and "heterocyclic ring".

[0087] As used herein, "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound in which the parent compound is modified by preparing its pharmaceutically acceptable acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to: mineral salts or organic acid salts of basic residues (such as amines); alkali metal salts or organic salts of acidic residues (such as carboxylic acids); etc. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts formed from the parent compound with, for example, 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, furoic acid, galacturonic acid, glucuronic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroxyethylsulfonic acid, lactic acid, maleic acid, malic acid, phenylethanolic acid, methanesulfonic acid, viscous acid, nitric acid, dihydroxynaphthic 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, hydrogen sulfate, 2-hydroxyethanesulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, butyrate, camphorate, camphor sulfonate, citrate, diglucuronate, glyceryl phosphate, hemisulfate, heptanate, hexanoate, formate, succinate, malonate, transbutenedioate, maleate, methanesulfonate, mesitylenesulfonate, naphthalenesulfonate, nicotinate, oxalate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, picrate, trimethylacetate, propionate, trichloroacetate, trifluoroacetate, glutamate, bicarbonate, undecanoate, lactate, citrate, tartrate, glucuronate, benzenesulfonate, and p-toluenesulfonate.

[0088] As used herein, the term “geometric isomer” includes, but is not limited to: cis and trans; E- and Z-; c-, t- and r-; internal and external; R-, S- and meso-racemic; boat-, chair-, torsional, enclosed and semi-chair-; and combinations thereof.

[0089] As used herein, the term "enantiomer" refers to a pair of stereoisomers that are non-overlapping mirror images of each other. 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 asymmetric but non-mirror images of each other. Absolute stereochemistry can be specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by R or S. A resolved compound can be represented as (+) or (-) according to the direction (dextrorotatory or levorotatory) that rotates the plane-polarized light at the wavelength of the sodium D line. Some compounds described herein may contain one or more asymmetric centers or axes, and may thus produce enantiomers, diastereomers, and other stereoisomers, which, for absolute stereochemistry, can be defined as (R)- or (S)-. This invention is intended to include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)- isomers can be prepared using chiral synthetic components or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent can be E or Z configuration. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent can have a cis or trans configuration.

[0090] As used herein, “prodrug” means any covalently bonded carrier that, upon administration of such prodrug to an individual, releases the active parent drug of formula (I) via physiological processes (such as hydrolysis, metabolism, etc.) in vivo. 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 in such a way that the variant cleaves into the parent compound in conventional operation or in vivo. “Prodrug” includes compounds of formula (I) in which a hydroxyl, amino, or thioglycolic group is bonded to any group that, upon administration of the prodrug to an individual, cleaves to form a free hydroxyl, free amino, or free thioglycolic group, respectively. Examples of prodrugs include, but are not limited to, derivatives and metabolites of compounds of formula (I) that include biohydrolyzable moieties, such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable acylureas, and biohydrolyzable phosphate ester analogs. In a particular embodiment, the prodrug of a compound of formula (I) having a carboxyl functional group is a low-carbon alkyl (e.g., C1-C6) ester of a carboxylic acid. The carboxylic acid ester is preferably formed by esterification of any carboxylic acid moiety present on the molecule.

[0091] This invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of this invention, except that one or more atoms therein are replaced by atoms having the same atomic number but a different atomic mass or mass number than the dominant atomic mass or mass number found in nature. Examples of isotopes suitable to be included in the compounds of this invention include (but are not limited to) isotopes of hydrogen (e.g., deuterium (D, 2H), tritium (T, 3H)); isotopes of carbon (e.g., 11C, 13C, and 14C); isotopes of chlorine (e.g., 36Cl); isotopes of fluorine (e.g., 18F); isotopes of iodine (e.g., 123I and 125I); isotopes of nitrogen (e.g., 13N and 15N); isotopes of oxygen (e.g., 15O, 17O, and 18O); isotopes of phosphorus (e.g., 32P); and isotopes of sulfur (e.g., 35S). Certain isotopically labeled compounds of the present invention (e.g., those incorporating radioactive isotopes) can be used in pharmaceutical and / or substrate tissue distribution studies (e.g., analysis). Radioactive isotopes tritium (i.e., 3H) and carbon-14 (i.e., 14C) are particularly suitable for such purposes due to their ease of incorporation and detection. Substitution with positron-emitting isotopes (e.g., 11C, 18F, 15O, and 13N) can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. Isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations, by using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be isotopically substituted, for example, D2O, acetone-d6, or DMSO-d6.

[0092] As used herein, the term "solvent" means, further including, stoichiometric or nonstoichiometric compounds of solvents bound by noncovalent intermolecular forces, or their pharmaceutically acceptable salts. If the solvent is water, the solvate may also be called a "hydrate," such as a hemihydrate, monohydrate, sesquihydrate, dihydrate, trihydrate, etc.

[0093] compound

[0094] This invention provides a compound of formula (I), or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemate, prodrug, solvate, hydrate, or any of the foregoing labeled thereof:

[0095] (I)

[0096] The definition of the functional group is as described above.

[0097] The present invention also provides a compound of formula (IC-1) or a pharmaceutically acceptable salt thereof, a geometric isomer, an enantiomer, a diastereomer, a racemic mixture, a prodrug, a solvate, a hydrate, or any of the foregoing labeled with an isotope:

[0098] (IC-1)

[0099] The functional groups are as defined above.

[0100] In one embodiment, in formula (I) or formula (IC-1), ring B is selected from 8-11 fused bicyclic heteroaryl and 10-15 fused tricyclic heteroaryl.

[0101] In one embodiment, in formula (I) or formula (IC-1), ring B is selected from 8-11 fused bicyclic heteroaryl and 8-11 fused bicyclic heterocyclic groups, preferably 8-11 fused bicyclic heteroaryl.

[0102] In one embodiment, in formula (I) or formula (IC-1), ring B is selected from 10-15 fused tricyclic heteroaryl and 10-15 fused tricyclic heterocyclic groups, preferably 10-15 fused tricyclic heteroaryl.

[0103] In the foregoing embodiments, in formula (I) or formula (IC-1), n ​​is 0.

[0104] In the foregoing embodiments, in formula (I) or formula (IC-1), where n is 1, preferably ring B is a 9-10 fused bicyclic heteroaryl group, and more preferably ring B is a 9 fused bicyclic heteroaryl group.

[0105] In the foregoing embodiments, in formula (I) or formula (IC-1), where n is 1, preferably ring B is a 10-15 fused tricyclic heteroaryl, and more preferably ring B is a 12-13 fused tricyclic heteroaryl.

[0106] In the foregoing embodiments, in formula (I) or formula (IC-1), m is 1.

[0107] In the foregoing embodiments, in formula (I) or formula (IC-1), m is 0.

[0108] In the foregoing embodiments, in formula (I) or formula (IC-1), ring B is a 10-15 fused tricyclic heteroaryl group, preferably a 12-13 fused tricyclic heteroaryl group.

[0109] In the foregoing embodiments, in formula (I) or formula (IC-1), ring B is selected from... , , or The wavy line indicates the connection point, and RB p is as defined in the foregoing embodiments.

[0110] In the foregoing embodiments, in formula (I) or formula (IC-1), ring B is selected from... , , , , , , , , , , or .

[0111] In the foregoing embodiments, in formula (I) or formula (IC-1), ring B is selected from... , , , , , , , , , , , , or The wavy line indicates the connection point.

[0112] In the foregoing embodiments, in formula (I) or formula (IC-1), ring B is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0113] In one embodiment, the present invention also provides a compound having formula (IC-2), or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemate, prodrug, solvate, hydrate, or any of the foregoing labeled thereof:

[0114] (IC-2);

[0115] The definition of the functional groups is as described above.

[0116] In one embodiment, in formula (IC-2), one of Z3 and Z6 is N and the other is CR. e And Z4 is N, NH or NR. e And Z5 is CR e .

[0117] In one embodiment, in equation (IC-2), Z3 and Z6 are each independently CR e And Z4 is N, NH or NR. e And Z5 is CR e .

[0118] In one embodiment, in formula (IC-2), the group formed by the fusion of ring D with the 10-membered ring is selected from... , , , , , , , , or ;

[0119] RB p is as defined in the foregoing embodiments.

[0120] In one embodiment, in formula (IC-2), ring D is absent.

[0121] In one embodiment, in formula (IC-2), the group formed by the fusion of ring D and the 10-membered ring is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0122] In one embodiment, the present invention also provides a compound of formula (IC-3) or a pharmaceutically acceptable salt thereof, a geometric isomer, an enantiomer, a diastereomer, a racemic mixture, a prodrug, a solvate, a hydrate, or any of the foregoing labeled with an isotope:

[0123] (IC-3);

[0124] The definition of the functional groups is as described above.

[0125] In one embodiment, in formula (IC-3), the ring formed by the fusion of -W4-W5-W6- with pyridine is selected from... , , , , , , , , , , , or .

[0126] In the foregoing embodiments, in formula (I), formula (IC-1), formula (IC-2), or formula (IC-3), ring A is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or ;

[0127] * indicates a screw-ring connection point;

[0128] R A q are as defined in the foregoing embodiments.

[0129] In the foregoing embodiments, in formula (I), formula (IC-1), formula (IC-2), or formula (IC-3), wherein (1) the nitrogen atom connected to R1, the carbon atom connected to R2 and R3, and one atom of ring A form a cyclic group, and this cyclic group is connected to ring A in a spirocyclic structure sharing the one atom, or (2) the carbon atom connected to R2 and R3, the adjacent nitrogen atom, the adjacent methylene group, and one atom of ring A form a cyclic group, and this cyclic group is connected to ring A in a spirocyclic structure sharing the one atom, wherein the spirocyclic structure is selected from... , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , or .

[0130] In one embodiment, the compound of formula (I) is a compound of formula (IC-1), formula (IC-2), or formula (IC-3). In one embodiment, the compound of formula (I) is a compound of formula (IC-1). In one embodiment, the compound of formula (IC-1) is a compound of formula (IC-2). In one embodiment, the compound of formula (IC-1) is a compound of formula (IC-3); or any of the aforementioned pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemates, prodrugs, solvates, hydrates, or isotopically labeled compounds.

[0131] In another preferred embodiment, the present invention provides a compound selected from the following:

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149] ; or any of the aforementioned pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemates, prodrugs, solvates, hydrates, or isotopically labeled forms thereof.

[0150] Pharmaceutical compositions, uses and methods

[0151] The compounds or derivatives of the present invention (e.g., pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemates, prodrugs, solvates, hydrates, or isotopically labeled thereof) can be administered therapeutically as pure chemicals, but administration of said compounds in the form of pharmaceutical compositions or formulations is more effective. Therefore, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), (IC-1), (IC-2), or (IC-3) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, prodrug, solvate, hydrate, or isotopically labeled thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0152] Pharmaceutical compositions can be administered in various dosage forms, including but not limited to: solid dosage forms, liquid dosage forms, oral dosage forms, parenteral dosage forms, intranasal dosage forms, suppositories, lozenges, sugar-coated lozenges, oral administration, controlled-release dosage forms, pulsatile-release dosage forms, immediate-release dosage forms, intravenous solutions, suspensions, or combinations thereof. The compounds can be administered via routes such as oral or non-gastrointestinal routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, respiratory (aerosol), rectal, vaginal, and local (including oral and sublingual) routes.

[0153] In one embodiment of the invention, the compound or derivative of formula (I) is administered orally. For oral administration, the provided compound is in a unit dosage form suitable for individual intake, such as tablets, pills, sugar-coated tablets, lozenges, capsules, powders, granules, aqueous solutions, suspensions, liquids, gels, syrups, slurries, etc. The dosage form may be a controlled-release dosage form formulated as a tablet or tablet. Dosage forms for oral use may include the active ingredient mixed with one or more pharmaceutically acceptable excipients.

[0154] "Excipients" generally refer to substances added to a pharmacological composition or used as a mediator to further facilitate the administration of the compound, and are typically inert substances. Examples of excipients include, but are not limited to: inert diluents, disintegrants, binders, lubricants, sweeteners, flavorings, colorants, preservatives, foaming mixtures, and adsorbents. If desired, tablets may be coated with materials to delay absorption in the gastrointestinal tract. Compositions may also be formulated into chewable tablets, for example, through further refining.

[0155] The present invention utilizes a pharmaceutical composition administered orally, obtained by mixing a compound or derivative of formula (I) with a solid excipient, grinding the mixture, and then adding suitable other (active) compounds (if desired) to obtain a tablet or pill. Suitable solid excipients, in addition to those previously mentioned, include carbohydrate or protein fillers, including but not limited to: sugars, including lactose, sucrose, mannitol, or sorbitol; starches from corn, wheat, rice, potatoes, or other plants; celluloses, such as methylcellulose, hydroxypropyl methylcellulose, or sodium carboxymethylcellulose; gums, including gum arabic and gum tragali; and proteins, such as gelatin and collagen.

[0156] Capsules for oral use include, but are not limited to: hard gelatin capsules containing the active ingredient mixed with a solid diluent, and soft gelatin capsules containing the active ingredient mixed with water or oil (such as peanut oil, mineral oil, or olive oil). The tablet core may be coated with a suitable sugar coating. The concentrated sugar solution may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopolgel, polyethylene glycol and / or titanium dioxide, lacquer, and suitable organic solvents or solvent mixtures. Pigments or colorants may be added to the tablet or sugar-coated tablet core to differentiate or characterize different dosages (combinations) of active compounds.

[0157] Pharmaceutical compositions may optionally further comprise suitable solid-phase or gel-phase carriers. Examples of such carriers include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starch, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

[0158] The compounds and pharmaceutical compositions of the present invention comprise administration of a therapeutically effective amount of an active ingredient to achieve a desired therapeutic effect. The term "therapeutically effective amount" refers to a compound of formula (I) or any of its pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, prodrugs, solvates, hydrates, or isotopically labeled forms thereof, administered alone or in combination with a radiation or anticancer drug, in a single or multiple dose manner, to provide the desired therapeutic effect to the individual receiving treatment. The toxicity and efficacy of the compound can be determined using standard pharmaceutical procedures in cell cultures or laboratory animals, for example, by determining IC50. 50 Value. As used in this article, "IC" 50 "This refers to the concentration of the drug at which it may produce a 50% maximum inhibitory response."

[0159] The actual dosage of the compound or derivative of formula (I) is determined by the physician based on relevant conditions, including the condition to be treated, the size and type of the tumor, the possible route of administration, the compound of the present invention actually administered, the timing of administration of the hedgehog signaling pathway modulator compared to other therapies, the individual's type, species, age, weight, sex, and medical condition, the individual's renal and hepatic function, and the severity of their condition. To achieve optimal drug concentration accuracy within the therapeutic range, a kinetic protocol based on drug delivery to the target site is required. This includes drug distribution, equilibrium, and elimination. In some cases, doses below the aforementioned lower limit may be overdose, while in others, larger doses may be appropriate.

[0160] The “individual” to be treated by the method of the present invention refers to a human or non-human animal, such as a primate, mammal, or vertebrate.

[0161] "In vivo" means within a living individual, such as an animal or human. In this article, the drug can be used in vivo for therapeutic purposes to slow or eliminate the proliferation of abnormally replicating cells. The drug can also be used in vivo as a preventative agent to prevent the proliferation of abnormal cells or the manifestation of related symptoms.

[0162] "In vitro" means outside of a living individual. Examples of in vitro cell populations include cell cultures and biological samples, such as fluid or tissue samples from humans or animals. Such samples can be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samples include tumors and their biopsies. In this invention, the compounds of this invention can be used in a variety of therapeutic and experimental applications.

[0163] "Cancer" refers to a proliferative cell disease state, including but not limited to: cardiac cancers such as sarcomas (e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma), myxomas, rhabdomyosarcomas, fibromas, lipomas, and teratomas; lung cancers such as bronchial cancers (e.g., squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, and adenocarcinoma), alveolar carcinomas (e.g., bronchiolar carcinoma), bronchial adenomas, sarcomas, lymphomas, chondromalacia, and mesotheliomas; gastrointestinal cancers such as 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, glucocorticoma, gastrinoma, carcinoid, and vasoactive intestinal peptide tumor), and small bowel cancers (e.g., adenocarcinoma, lymphoma, carcinoid, and Kaposi's sarcoma). sarcoma), leiomyomas, hemangiomas, lipomas, neurofibromas, and fibromas; colorectal cancers (e.g., adenocarcinoma, ductal adenoma, villous adenoma, hamartoma, and leiomyomas); urogenital cancers, such as kidney cancer (e.g., adenocarcinoma, Wilms' tumor). Tumors (e.g., nephroblastoma), lymphomas and leukemias; 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., seminoma, teratoma, embryonal carcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, and lipoma); liver cancers such as hepatocellular carcinoma (e.g., hepatocellular carcinoma), bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma; bone cancers such as osteosarcoma (e.g., osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma. Cancers of the nervous system, such as sarcoma, malignant lymphomas (e.g., reticulum cell sarcoma), multiple myeloma, malignant giant cell tumors, chordoma, osteochondroma (e.g., osteochondral exostosis), benign chondroma, chondroblastoma, chondromycinous fibroma, osteoid osteoma, and giant cell tumors; cancers of the skull, such as skull cancers (e.g., osteoma, hemangioma, granulomatous tumor, xanthoma, and osteitis malformation), meningeal cancers (e.g., meningioma, spinal sarcoma, and glioma), brain cancers (e.g., astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors), spinal neurofibroma, meningioma, glioma, and sarcoma;Gynecological cancers, such as uterine cancer (e.g., endometrial cancer), cervical cancer (e.g., cervical cancer and pretumoral cervical dysplasia), ovarian cancer (e.g., ovarian cancer [e.g., serous cystadenocarcinoma, mucinous cystadenocarcinoma, and cancer of unknown type], granulosa cell tumors, Sertoli-Leydig cell tumors, dysgerminomas, and malignant teratomas), vulvar cancer (e.g., squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma), vaginal cancer (e.g., clear cell carcinoma, squamous cell carcinoma, staphyloid sarcoma [e.g., embryonal rhabdomyosarcoma], and fallopian tube cancer); hematologic cancers, such as myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, and myelodylocytysis), Hodgkin's disease. Diseases such as: non-Hodgkin's lymphoma (malignant lymphoma); skin cancers such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus of dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; adrenal adenocarcinomas such as neuroblastoma; or breast cancer.

[0164] The present invention also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, a geometric isomer, an enantiomer, a diastereomer, a prodrug, a solvate, a hydrate or an isotopically labeled thereof, for the manufacture of a medicament for modulating the hedgehog pathway.

[0165] Furthermore, the present invention relates to a method for treating cancer in an individual in need, comprising administering to the individual a therapeutically effective amount of a compound of formula (I) or a medically acceptable salt, geometric isomer, enantiomer, diastereomer, prodrug, solvate, hydrate, or isotopically labeled thereof.

[0166] The present invention also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, prodrug, solvate, hydrate or isotopically labeled thereof for the treatment of cancer.

[0167] The compound or derivative of formula (I) may be administered as a single active agent or co-administered with other known cancer treatments.

[0168] The term "combined with" means that a compound or derivative of formula (I) may be administered before, after, or simultaneously with one or more other anticancer therapies, or in any combination with other anticancer agents before, after, or simultaneously with their administration. Therefore, a compound or derivative of formula (I) and a second anticancer agent may be administered as a single composition or as two separate compositions simultaneously or sequentially. Similarly, a compound or derivative of formula (I) and chemotherapy or radiotherapy may be administered simultaneously, individually, or sequentially. Those skilled in the art will understand that the amount of a compound of formula (I) administered concurrently with an anticancer therapy is sufficient to enhance the effect of the anticancer therapy, or sufficient to induce apoptosis or cell death together with the anticancer therapy to maintain anti-angiogenic effects.

[0169] Unless otherwise specified, the term "secondary anticancer agent" as used herein refers to an agent capable of inhibiting or preventing tumor growth or hindering the maturation and proliferation of malignant (cancer) cells. Secondary anticancer agents suitable for use in combination with compounds of formula (I) include, but are not limited to, targeted cancer drugs.Examples include trastuzumab, ramucirumab, bevacizumab, everolimus, tamoxifen, toremifene, fulvestrant, anastrozole, exemestane, lapatinib, letrozole, pertuzumab, and ado-trastuzumab (entazoline). mabemtansine, palbociclib, cetuximab, panitumumab, ziv-aflibercept, regorafenib, imatinib mesylate, lanreotide acetate, sunitinib, regorafenib, denosumab, alitretinoin Sorafenib, Pazopanib, Temsirolimus, Everolimus, Tretinoin, Dasatinib, Nilotinib, Bosutinib, Rituximab, Alemtuzumab, Ofatumumab, Obinutuxumab, Ibrutinib, Idexab sib), blinatumomab, soragenib, crizotinib, erlotinib, gefitinib, afatinib dimaleate, ceritinib, ramucirumab, nivolumab, pembrolizumab, osimertinib, and necitumumab; alkylating agents,Examples include busulfan, chlorambucil, cyclophosphamide, ifosfamide, melphalan, nitrogen mustard, streptozotocin, thiotepa, uracil mustard, triethylmelamine, temozolomide, and 2-chloroethyl-3-sarcosamide-1-nitrosourea (SarCNU); antibiotics or plant alkaloids, such as actinomycin-D, bleomycin, candidin, daunorubicin, doxorubicin, idarubicin, irinotecan, L-asparaginase, and mitomycin-C. Mitomycin-C, mitramycin, navelbine, paclitaxel, docetaxel, topotecan, vinblastine, vincristine, teniposide (VM-26), and etoposide (VP-16); hormones or steroids, such as 5α-reductase inhibitors, aminoglutethimide, and anastrozole. astrozole, bicalutamide, trichlorotriaryl, diethylstilbestrol (DES), dromostanolone, estramustine, ethinylestradiol, flutamide, fluoxymesterone, goserelin, hydroxyprogesterone, letrozole, leuprolide, medroxyprogesterone acetate Acetate), megestrol acetate, methylprednisolone, methyltestosterone, mitotane, nilutamide, prednisolone, azoxifene (SERM-3), tamoxifen, testolactone, testosterone, triamicnolone, and zoladex; synthetic preparations,Examples include all-trans retinoic acid, carmustine (BCNU), carboplatin (CBDCA), lomustine (CCNU), cis-diaminodichloroplatin (cisplatin), dacarbazine, gliadel, hexamethylmelamine, hydroxyurea, levamisole, mitoxantrone, o,p'-dichlorodiphenyldichloroethane (o,p'-DDD) (also known as lysodren or mitotane), oxaliplatin, porfimersodium, procarbazine, and imatinib mesylate (Gleevec). ® Anti-metabolites, such as deoxyadenosine, cytosine arabinoside, 2'-deoxycoformycin, fludarabine phosphate, 5-fluorouracil (5-FU), 5-fluoro-2'-deoxyuridine (5-FUdR), gemcitabine, camptothecin, 6-mercaptopurine, methotrexate, and thioguanine; and biological agents, such as interferon-alpha, Bacillus Calmette-Guerin (BCG), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2, and herceptin.

[0170] Unless otherwise specified, as used herein, the term "treating" means reversing, alleviating, suppressing, or preventing the development of one or more symptoms of the condition or illness to which the term applies. Unless otherwise specified, as used herein, the term "treatment" means the act of "treating" as defined above.

[0171] Compound Synthesis

[0172] This invention also relates to a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, prodrug, solvate, hydrate, or isotopically labeled form thereof. The compounds of this invention can be prepared by those skilled in the art using conventional organic synthesis methods and commercially available materials.

[0173] In one embodiment, the present invention relates to a method for preparing a compound of formula (I), formula (IC-1), formula (IC-2) or formula (IC-3) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, prodrug, solvate, hydrate or isotopically labeled thereof.

[0174] The following examples are for illustrative purposes only and are not intended to be limiting. Those skilled in the art can modify the processes or steps in the examples to obtain the desired product.

[0175] Example

[0176] Example 1:

[0177] Synthesis of Compound 084

[0178]

[0179] Step 1:

[0180] 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 N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (93 mg, 0.33 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours, after which intermediate 84-11 (50 mg, 0.22 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with acetonitrile (5 mL) and filtered. The filter cake was washed with acetonitrile (1 mL), and the filtrate was concentrated. The crude product was analyzed by preparative HPLC (Waters-SunFire-C18-10µm-19). Purification was performed at 250 mm, with a mobile phase of 0.1% NH3HCO3 / H2O B:CH3CN for 9 min, yielding a white solid compound 084 (10.19 mg, 0.02 mmol, yield 10.26%).

[0181] MS m / z (ESI): 452.2 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 8.72 (d, J= 1.6Hz, 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).

[0182] Synthesis of intermediate 084-10

[0183]

[0184] Step 1:

[0185] At -10 °C, lithium diisopropylamino (25 mL, 50.0 mmol, 2.0 M) was added to a THF (tetrahydrofuran) (100 mL) solution of compound 84-1 (10.0 g, 49.96 mmol). After stirring at -10 °C for 20 min, diethyl cyanophosphonate (8.96 g, 54.96 mmol) was added. The reaction mixture was stirred at -10 °C for 10 min, quenched with water (300 mL), and extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine (300 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a yellow solid intermediate 84-2 (16.7 g, 48.09 mmol, 96.26% yield).

[0186] Step 2:

[0187] A solution of intermediate 84-2 (16.7 g, 48.09 mmol) in boron trifluoride diethyl ether complex (30 mL) was stirred at room temperature for 30 min. The reaction mixture was quenched with saturated NH4Cl (ammonium chloride) aqueous solution (100 mL) and extracted with ethyl acetate (50 mL). The combined organic layers were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give intermediate 84-3 (8.32 g, 39.78 mmol, 82.71% yield) as a yellow solid.

[0188] Step 3:

[0189] The mixture of intermediate 84-3 (8.3 g, 39.68 mmol) and 10% Pd / C (palladium / carbon) (800 mg) in THF (tetrahydrofuran) (50 mL) was stirred for 2 hours at room temperature under a nitrogen atmosphere. The reaction mixture was filtered, and the filter cake was washed with THF (tetrahydrofuran) (10 mL). The filtrate was concentrated to give 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.

[0190] Step 4:

[0191] Diisopropylaminolithium (7.81 mL, 15.62 mmol, 2.0 M) was added dropwise to a THF (tetrahydrofuran) (15 mL) solution of intermediate 84-4 (1.5 g, 7.10 mmol) at -78 °C under nitrogen atmosphere. After stirring at -78 °C for 30 min, methyl cyanoformate (1.21 g, 14.21 mmol) was added. The reaction mixture was stirred at -78 °C for 3 hours, quenched with a saturated aqueous solution of NH4Cl (ammonium chloride) (30 mL), and extracted with ethyl acetate (30 mL). The combined organic layers were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a red oily intermediate 84-5 (800 mg, 2.82 mmol, yield 39.77%).

[0192] Step 5:

[0193] At -40°C, LiAlH4 (lithium aluminum hydride) (214 mg, 5.65 mmol) was added to a tetrahydrofuran (10 mL) solution of intermediate 84-5 (800 mg, 2.82 mmol). The reaction mixture was stirred at -40°C for 1.5 h, quenched with sodium sulfate, and filtered. The filter cake was washed with ethyl acetate (10 mL). The filtrate was concentrated to give a colorless oily intermediate 84-6 (190 mg, 0.77 mmol, yield 27.43%), and the crude product was used directly in the next step.

[0194] Step 6:

[0195] A mixture of intermediate 84-6 (190 mg, 0.77 mmol), Boc2O (di-tert-butyl dicarbonate) (338 mg, 1.55 mmol), and TEA (triethylamine) (314 mg, 3.10 mmol) in CH2Cl2 (dichloromethane) (1.0 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give intermediate 84-7 (180 mg, 0.52 mmol, 67.28% yield) as a white solid.

[0196] Step 7:

[0197] At room temperature, TsCl (p-toluenesulfonyl chloride) (177 mg, 0.93 mmol), TEA (triethylamine) (70 mg, 0.69 mmol), and DMAP (4-dimethylaminopyridine) (5.7 mg, 0.05 mmol) were added to a CH2Cl2 (dichloromethane) (2 mL) solution of intermediate 84-7 (160 mg, 0.46 mmol) at room temperature. The reaction mixture was stirred at room temperature for 10 hours, 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 to give a yellow oily intermediate 84-8 (200 mg, 0.40 mmol, yield 86.42%). The crude product was used directly in the next step.

[0198] Step 8:

[0199] A mixture of intermediate 84-8 (500 mg, 1.00 mmol) and NaH (sodium hydride) (90 mg, 1.50 mmol) in DMF (5 mL) was stirred at room temperature for 18 hours. The reaction mixture was quenched with water (1 mL) at 0 °C and then concentrated. The crude product was purified by silica gel plate chromatography (petroleum ether / ethyl acetate = 3 / 1) to give intermediate 84-9 (300 mg, 0.92 mmol, yield 91.56%) as a white solid.

[0200] Step 9:

[0201] The 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 mixture was concentrated to give a brown oily intermediate 84-10 (8 mg, 0.12 mmol, 100% yield), and the crude product was used directly in the next step.

[0202] Synthesis of intermediate 084-11

[0203]

[0204] Step 1:

[0205] Under nitrogen atmosphere, a solution of intermediate 84-12 (5 g, 21.73 mmol), pinacol diborate (16.56 g, 65.2 mmol), potassium acetate (6.40 g, 65.2 mmol), and Pd(dppf)Cl2 ([1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex) (3.18 g, 4.35 mmol) in dimethyl sulfoxide (150 mL) was heated to 100 °C and stirred for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate (300 mL) after adding water (500 mL). The organic layers were combined, washed with saturated 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 give a yellow solid intermediate 84-13 (5.9 g, 21.29 mmol, yield 97.96%).

[0206] Step 2:

[0207] Under a nitrogen atmosphere, a solution of 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) in dioxane (5 mL) was heated to 100 °C and stirred for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate (30 mL) after adding water (20 mL). The combined organic layers were washed with saturated 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 give a white solid intermediate 84-15 (630 mg, 2.46 mmol, 97.33% yield).

[0208] Step 3:

[0209] 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). The solution was heated to 60 °C and stirred for 16 hours. After the reaction was complete, the pH of the solution was adjusted to 3 with 1.0 N hydrochloric acid aqueous solution, and a solid precipitated. After filtration, the filter cake was washed with water (3 mL). The solid was dried under reduced pressure to give a white solid intermediate 84-11 (54 mg, 0.22 mmol, yield 63.47%).

[0210] Example 2:

[0211] Synthesis of Compound 112

[0212]

[0213] Step 1:

[0214] In an ice bath, oxaloyl chloride monoethyl ester (180 mg, 1.32 mmol) was added to a solution of intermediate 84-10 (250 mg, 1.10 mmol) and TEA (triethylamine) (0.46 mL, 3.30 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at room temperature for 0.5 h, quenched with water (10 mL), and extracted with ethyl acetate (3 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give a yellow oily crude intermediate 112-1 (250 mg, 0.76 mmol, yield 69.43%), which was used directly in the next step.

[0215] Step 2:

[0216] Intermediate 112-1 (200 mg, 0.61 mmol) was mixed with 1 mL of THF (tetrahydrofuran) and 1 mL of ammonia-methanol solution (7 M) and stirred at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give intermediate 112-2 (160 mg, 0.54 mmol, yield 87.79%) as a yellow solid.

[0217] Step 3:

[0218] 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 nitrogen. The reaction mixture 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 saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was analyzed by preparative HPLC (column: Waters-Xbridge-C18-10µm-19). Purification was performed at 250 mm, with mobile phases: A: 10 mM NH4HCO3 / H2O and B: CAN, 40% A-50% B: Ret (9.0 min) to give a white solid compound 112 (19.28 mg, 0.04 mmol, yield 9.85%).

[0219] MS m / z (ESI): 445.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) 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).

[0220] Synthesis of intermediate 76-3

[0221]

[0222] Step 1:

[0223] 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 concentrated. The crude product was analyzed by preparative HPLC (Waters-SunFire-C18-10µm-19). Purification was performed using a mobile phase of 250 mm (0.1% FA / H2O B:CH3CN) to give a white solid intermediate 76-1 (1.4 g, 6.57 mmol, yield 88.3%).

[0224] Step 2:

[0225] Under a nitrogen atmosphere, intermediate 76-1 (1.0 g, 4.69 mmol) was added to a solution of (dimethylamino)dimethoxymethane (30 mL) and stirred overnight at 120 °C. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give intermediate 76-2 (750 mg, 2.38 mmol, yield 50.71%) as a white solid.

[0226] Step 3:

[0227] Sodium hydroxide (0.57 g, 14.18 mmol) was added to a methanol / water (20 mL 1:1) solution of intermediate 76-2 (1.0 g, 3.54 mmol), and the mixture was stirred overnight at 120 °C. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give intermediate 76-3 (500 mg, 1.86 mmol, 52.56% yield) as a white solid.

[0228] Example 3:

[0229] Synthesis of Compound 122

[0230]

[0231] Step 1:

[0232] 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 N,N,N',N'-Tetramethylchloromethylammonium hexafluorophosphate (53 mg, 0.59 mmol). The mixture was stirred for 2 hours and then filtered. The filter cake was washed with water (5 mL), dried, and then analyzed by preparative HPLC (Waters-Xbridge-C18-10 µm-19). Purification was performed using a mobile phase of 10 mM NH4HCO3 (250 mm, A: 10 mM NH4HCO3; B: ACN, gradient: 40-50%, residence time: 8.5 min) to obtain a white solid compound 122 (6.30 mg, 0.01 mmol, yield 10.80%).

[0233] Synthesis of compound 122-9

[0234]

[0235] Step 1:

[0236] At -10 °C, lithium diisopropylamino (25 mL, 50.0 mmol, 2.0 M) was added to a tetrahydrofuran (1000 mL) solution of intermediate 122-1 (100 g, 476 mmol). The reaction solution was stirred at -10 °C under a nitrogen atmosphere for 20 min, followed by the addition of diethyl cyanophosphate (85 g, 524 mmol). After stirring for 30 min, the reaction solution was quenched with ice water (1000 mL) and then extracted with ethyl acetate (800 mL). The combined organic layers were washed with saturated brine (1000 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give a brown oily intermediate 122-2 (130.0 g, 364.15 mmol, yield 76.47%).

[0237] Step 2:

[0238] Intermediate 122-2 (130 g, 364 mmol) was added to boron trifluoride-diethyl ether solution (900 mL) at 0 °C and stirred at room temperature for 16 hours. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution (800 mL) and then 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 crude residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give intermediate 122-3 (63.5 g, 289.99 mmol, yield 80.38%) as a pale yellow solid.

[0239] Step 3:

[0240] Intermediate 122-3 (63.5 g, 289.99 mmol) was added to ethanol (700 mL) at 0 °C, followed by sodium borohydride (65.77 g, 1.74 mol), and then stirred at 80 °C for half an hour. After the reaction was complete, the reaction mixture was quenched with ice water (700 mL) and then extracted with ethyl acetate (600 mL). The combined organic layers were washed with saturated brine (800 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give brown oily intermediate 122-4 (54.0 g, 244 mmol, yield 84.4%).

[0241] Step 4:

[0242] Diisopropylaminolithium (269 mL, 2.0 M, 538 mmol) was added to a THF (tetrahydrofuran) solution of compound 122-4 (54 g, 244 mmol) (600 mL) at -78 °C, and the mixture was stirred for 30 min under a nitrogen atmosphere at -78 °C. Ethyl cyanoformate (48.4 g, 489 mmol) was then added, and the mixture was stirred for 3 h. The reaction mixture was quenched with a saturated ammonium chloride solution (600 mL) and extracted with ethyl acetate (500 mL). The combined organic layers were washed with saturated brine (800 mL) and dried over anhydrous sodium sulfate. After filtration and concentration of the filtrate, the crude residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give a brown oily intermediate 122-5 (42.0 g, 143.34 mmol, yield 56.66%).

[0243] Step 5:

[0244] At -40°C, lithium aluminum hydride (115 mL, 2.5 M, 287 mmol) was added to a 450 mL solution of intermediate 122-5 (42.0 g, 143 mmol) in THF (tetrahydrofuran), and the reaction mixture was stirred for 1.5 h. After quenching with water (300 mL), the mixture was stirred at 0°C for 30 min. At room temperature, di-tert-butyl dicarbonate (62.5 g, 287 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours before filtration. The filtrate was extracted with ethyl acetate (500 mL). The combined organic layers were washed with saturated brine (800 mL) and dried over anhydrous sodium sulfate. After filtration and concentration of the filtrate, the crude residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give a pale yellow solid intermediate 122-6 (15.0 g, 51.19 mmol, yield 29.53%).

[0245] Step 6:

[0246] At room temperature, intermediate 122-6 (15.0 g, 51.19 mmol) was added to 150 mL of THF, followed by the sequential addition of TEA (triethylamine) (8.5 g, 102 mmol), DMAP (4-dimethylaminopyridine) (6.2 g, 61.4 mmol), and TsCl (p-toluenesulfonyl chloride) (12.8 g, 81.9 mmol). The reaction mixture was stirred for 16 hours, quenched with water (150 mL), and extracted with dichloromethane (150 mL). The combined organic layers were washed with saturated brine (300 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the crude residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give intermediate 122-7 (14.0 g, 27.50 mmol, yield 65.12%) as a white solid.

[0247] Step 7:

[0248] At 0 °C, in compound 122-7 (14.0 g, 27.50 mmol) N,N Sodium hydride (2.20 g, 55.00 mmol) was added to a 150 mL solution of dimethylformamide, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with ice water (250 mL) and extracted with ethyl acetate (150 mL). The organic layer was washed with saturated brine (400 mL) and dried over anhydrous sodium sulfate. After filtration and concentration of the filtrate, the crude residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give a white solid intermediate 122-8 (1.4 g, 4.15 mmol, yield 15.1%).

[0249] Step 8:

[0250] Intermediate 122-8 (50 mg, 0.15 mmol) was added to dichloromethane (2 mL), followed by trifluoroacetic acid (0.2 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, diluted with water, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was then extracted with ethyl acetate (2 mL). The organic layer was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give intermediate 122-9 (30 mg, 0.13 mmol, yield 85.71%) as a yellow solid.

[0251] Example 4:

[0252] Synthesis of Compound 123

[0253]

[0254] Step 1:

[0255] Under a nitrogen atmosphere, intermediate 123-1a (500 mg, 2.32 mmol) and compound 123-1 (486 mg, 2.32 mmol) were added to a solution of tetrahydrofuran (8 mL) with lithium bis(trimethylsilyl)amino (1.0 mmol). N In a tetrahydrofuran solution (2.56 mL, 2.56 mmol), the solution was cooled to -5°C. The reaction solution was stirred for 1 hour, then heated to room temperature and stirred for another hour. After the reaction was complete, water (10 mL) was added to quench the reaction, and the mixture was 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 purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give a yellow oily intermediate 123-2 (300 mg, 0.74 mmol, yield 31.94%).

[0256] Step 2:

[0257] Under a nitrogen atmosphere, 10% wet Pd / C (palladium / carbon) (50 mg, 0.05 mmol) was added to a methanol (5 mL) solution of intermediate 123-2 (300 mg, 0.74 mmol), followed by purging with hydrogen and stirring for 16 hours. After filtration, the filter cake was washed with methanol (2 mL). The filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give intermediate 123-3 (120 mg, 0.35 mmol, yield 47.25%) as a yellow solid.

[0258] Step 3:

[0259] At room temperature, a solution of intermediate 123-3 (110 mg, 0.32 mmol) in dichloromethane (1 mL) was added to trifluoroacetic acid (0.5 mL). After stirring the reaction solution for 3 hours, the mixture was concentrated under reduced pressure. The crude product was extracted with dichloromethane (5 mL) after adding the residue to a saturated sodium bicarbonate aqueous solution (5 mL) and stirring. The organic layer was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a yellow solid intermediate 123-4 (50 mg, 0.21 mmol, yield 64.24%).

[0260] Step 4:

[0261] Under a nitrogen atmosphere and at room temperature, N2 was added to a 1.5 mL solution of intermediate 84-11 (90 mg, 0.37 mmol) in acetonitrile. ,N,N',N'-Tetramethylchloroformamidine hexafluorophosphate (78 mg, 0.28 mmol) and N- After adding methylimidazole (92 mg, 1.11 mmol), 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 filtered. The filter cake was washed with acetonitrile (2 mL) and concentrated under reduced pressure. The residue was analyzed by residue HPLC (Waters-Xbridge-C18-10um-19). Purification was performed using a mobile phase of 0.1% NH4HCO3 / H2O (B:CH3CN), with a gradient of 55% B - 85% B, and a residence time of 8.5 min, yielding a white solid compound 123 (1.43 mg, 0.003 mmol, yield 1.65%). MS m / z (ESI): 467.1 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) 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).

[0262] Example 5:

[0263] Synthesis of Compound 131

[0264]

[0265] Step 1:

[0266] Potassium ferrocyanide (749 mg, 1.77 mmol), Xphos G3 (75 mg, 0.09 mmol), and potassium acetate (87 mg, 0.89 mmol) were added to a 1:1 (10 mL) solution of intermediate 122-8 (150 mg, 0.44 mmol) in dioxane / water. The mixture was stirred at 100 °C under a nitrogen atmosphere 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 saturated brine (20 mL) and dried over anhydrous sodium sulfate. After filtration and concentration of the filtrate, the crude residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a colorless oily intermediate 131-1 (100 mg, 0.35 mmol, yield 79.30%).

[0267] Step 2:

[0268] A solution of dioxane hydrochloride (3 mL) was added to a solution of intermediate 131-1 (100 mg, 0.35 mmol) in dichloromethane (5 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give a white solid intermediate 131-2 (60 mg, 0.33 mmol, yield 98.61%).

[0269] Step 3:

[0270] Intermediate 84-11 (98 mg, 0.41 mmol) was added to a 1 mL solution of acetonitrile (1 mL) containing intermediate 131-2 (30 mg, 0.16 mmol). N 2-Methylimidazole (33 mg, 0.41 mmol), N,N,N',N' Tetramethylchloromethanesulfonyl hexafluorophosphate (68 mg, 0.24 mmol) was stirred at room temperature for 16 hours. The mixture was quenched with water (2 mL) and then extracted with ethyl acetate (2 mL). The combined organic layers were washed with saturated brine (5 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by preparative TLC (dichloromethane / methanol = 20 / 1) and then by HPLC (column: Welch ultimate XB-NH2250). 50 Purification was performed at 10 μm in a mobile phase of [Heptane-EtOH (0.1% NH3H:O)]; B% 10%-10%, for 10 min, yielding a white solid compound 131 (4.71 mg, 10 μmol, yield 7.08%). MS m / z (ESI): 409.2 [M+H] + ; 1HNMR (400 MHz, DMSO- d 6) 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).

[0271] Example 6:

[0272] Synthesis of Compound 133

[0273]

[0274] Step 1:

[0275] Intermediate 122-8 (100 mg, 0.30 mmol), intermediate 133-1 (77.74 mg, 0.30 mmol), potassium carbonate (122.85 mg, 0.90 mmol), and Pd(PPh3)4 (tetra(triphenylphosphine)palladium) (34.29 mg, 0.03 mmol) were mixed in a solution of 1,4-dioxane (4 mL) and water (1 mL) and stirred at 80 °C under a nitrogen atmosphere for 3 hours. The reaction solution was concentrated under reduced pressure, diluted with water (3 mL), and extracted with ethyl acetate (3 mL). The combined organic layers were washed with saturated brine (6 mL) and dried over anhydrous sodium sulfate. After filtration and concentration of the filtrate, the crude residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give intermediate 133-2 (80 mg, 0.20 mmol, yield 68.60%) as a white solid.

[0276] Step 2:

[0277] Trifluoroacetic acid (0.2 mL) was added to a solution of intermediate 133-2 (80 mg, 0.20 mmol) in dichloromethane (2 mL), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, diluted with water, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (2 mL), and the combined organic layers were washed with saturated brine (6 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give intermediate 133-3 (50 mg, 0.17 mmol, 84.75% yield) as a yellow solid.

[0278] Step 3:

[0279] At room temperature, intermediate 84-11 (82.59 mg, 0.34 mmol) was added to a 2 mL solution of acetonitrile containing intermediate 133-3 (50 mg, 0.17 mmol). N -Methylimidazole (41.98 mg, 0.51 mmol) and N,N,N',N' -Tetramethylchloromethylammonium hexafluorophosphate (71.67 mg, 0.26 mmol) was stirred at room temperature for 2 hours. The reaction solution was filtered, the filter cake was washed with water (2 mL), dried, and then analyzed by preparative HPLC (Waters-Xbridge-C18-10µm-19). Purification was performed using a mobile phase of 250 mg / mL (A: 10 mM NH₄HCO₃; B: ACN, gradient: 40-50%, residence time: 8.5 min) to give a white solid compound 133 (21.03 mg, 0.04 mmol, yield 23.86%). MS m / z (ESI): 518.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) 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).

[0280] Example 7:

[0281] Synthesis of Compound 134

[0282]

[0283] Step 1:

[0284] Under a nitrogen atmosphere, intermediate 123-2 (3.3 g, 8.16 mmol) was added to methanol (50 mL), cooled to 0 °C, and lithium borohydride (267 mg, 12.24 mmol) was added in portions. The mixture was slowly heated to room temperature and stirred for 20 minutes, then heated to 50 °C in an oil bath and stirred for 16 hours. The crude product was concentrated under reduced pressure, and the residue was washed with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL). The combined organic layers were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give intermediate 134-1 (2 g, 5.31 mmol, yield 65.12%) as a yellow solid.

[0285] Step 2:

[0286] Under a nitrogen atmosphere, Pd / C (palladium / carbon) (10% activated carbon mixture, 100 mg, 0.09 mmol) was added to a methanol solution (25 mL) of intermediate 134-1 (1.9 g, 5.05 mmol), followed by purging 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 give intermediate 134-2 (1.3 g, 3.75 mmol, 74.34% yield) as a white solid.

[0287] Step 3:

[0288] Intermediate 134-2 (500 mg, 1.44 mmol) and cuprous iodide (550 mg, 2.89 mmol) were added to acetonitrile (8 mL) at -5 °C under a nitrogen atmosphere, followed by the addition of isoamyl nitrite (203 mg, 1.73 mmol) and stirring for 20 minutes. The temperature was then raised to 80 °C and the solution was stirred for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane (2 mL). 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 purification (mobile phase: A: 10 mM NH4HCO3; B: ACN, gradient: 40-50%, retention time: 8 min) to obtain a white solid intermediate 134-3 (100 mg, 0.30 mmol, yield 21.03%).

[0289] Step 4:

[0290] At room temperature, trifluoroacetic acid (0.5 mL, 6.71 mmol) was added to a solution of intermediate 134-3 (100 mg, 0.30 mmol) in dichloromethane (0.5 mL), 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. Intermediate 134-4 (70 mg, 0.31 mmol, 100% yield) was obtained, and the crude product was used directly in the next step.

[0291] Step 5:

[0292] At room temperature, add to a 2.5 mL solution of intermediate 84-11 (148 mg, 0.61 mmol) in acetonitrile (2.5 mL) N,N, N',N' -Tetramethylchloroformamidine hexafluorophosphate (128 mg, 0.46 mmol). N- Methylimidazole (151 mg, 1.83 mmol) was added to the reaction solution and 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 filter 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%, residence time: 8.5 min) to give a white solid compound 134 (50.37 mg, 0.11 mmol, yield 36.37%). MS m / z (ESI): 454.1 [M+H] + ; 1H NMR (400 MHz, DMSO- d 6) 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).

[0293] Example 8:

[0294] Synthesis of Compound 135

[0295]

[0296] Step 1:

[0297] Potassium ferrocyanide (749.25 mg, 1.77 mmol), Xphos G3 (75.07 mg, 0.09 mmol), and potassium acetate (87.04 mg, 0.89 mmol) were added to a 1:1 (10 mL) solution of intermediate 122-8 (150 mg, 0.44 mmol) in dioxane / water. The reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 16 hours. The reaction mixture was filtered, quenched with ice water (10 mL), and extracted three times with ethyl acetate (6 mL). The combined organic layers were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. After filtration and concentration of the crude product, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a colorless oily intermediate 135-1 (100 mg, 0.35 mmol, 79.30%).

[0298] Step 2:

[0299] A solution of dioxane hydrochloride (3 mL) was added to a 5 mL solution of intermediate 135-1 (100 mg, 0.35 mmol) in dichloromethane. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure to give a white solid intermediate 135-2 (60 mg, 0.33 mmol, yield 98.61%).

[0300] Step 3:

[0301] Add intermediate 135-3 (125.55 mg, 0.34 mmol) to a 1 mL solution of intermediate 135-2 (25 mg, 0.14 mmol) in acetonitrile. N 2-Methylimidazole (27.85 mg, 0.34 mmol), N,N,N',N' -Tetramethylchloromantadin hexafluorophosphate (57.11 mg, 0.20 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (2 mL) and extracted with ethyl acetate (2 mL). The combined organic layers were washed with saturated brine (4 mL) and dried over anhydrous sodium sulfate. After filtration and concentration of the crude product, the residue was purified by preparative TLC (dichloromethane / methanol = 20 / 1) to give a colorless oily intermediate 135-4 (16 mg, 0.02 mmol, 18.09% yield).

[0302] Step 4:

[0303] Trifluoroacetic acid (1 mL) was added to a solution of intermediate 135-4 (16 mg, 0.03 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at 80 °C for 16 hours. After cooling to room temperature, the mixture was concentrated. The crude product was analyzed by preparative HPLC (Waters-Xbridge-C18-10µm-19). Purification was performed using a mobile phase of 0.1% NH4HCO3 / H2O (B:CH3CN), with a gradient of 55% B - 85% B, and a residence time of 6.8 min, yielding a white solid compound 135 (1.0 mg, 2.49 μmol, 8.12% yield). MS m / z (ESI): 402.2 [M+H] + ; 1 H NMR (400 MHz, Methanol- d 4) 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).

[0304] Synthesis of intermediate 135-3

[0305]

[0306] Step 1:

[0307] At 0 °C, NaH (0.53 g, 13.21 mmol, 60% purity) was added fractionally to a DMF (15 mL) solution of compound 76-3 (1.0 g, 4.40 mmol). After stirring the reaction solution at 0 °C for 30 min, 4-(chloromethyl)-1-methoxybenzene (2.07 g, 13.21 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction solution was quenched with water (50 mL) and then extracted with EtOAc (30 mL). The combined organic layers were washed with water (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography (SiO2, eluted with DCM:MeOH = 10:1) to give compound 135-5 (1.2 g, 2.57 mmol, 58.30% yield) as a white solid.

[0308] Step 2:

[0309] 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 dioxane (20 mL), degassed, purged with nitrogen three times, stirred at 110 °C for 2 hours, concentrated under reduced pressure, and purified by rapid column chromatography (SiO2, PE: EtOAc = 3:1 elution) to give compound 135-6 (700 mg, 1.03 mmol, 48.35% yield) as a white solid.

[0310] Step 3:

[0311] To a MeOH (10 mL) solution of compound 135-6 (1.0 g, 1.76 mmol), 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 EtOAc (50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 135-7 (1.0 g) as a white solid, which was used directly in the next step.

[0312] Step 4:

[0313] To a DMF (5 mL) solution of compound 135-7 (120 mg, 0.30 mmol), ethyl 2-chloro-2-oxoethyl acetate (41 mg, 0.30 mmol) and DIEA (77 mg, 0.59 mmol) were added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was quenched with water (20 mL) and extracted with EtOAc (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 rapid column chromatography (SiO2, eluted with PE:EtOAc = 3:1) to give compound 135-8 (100 mg, 0.16 mmol, yield 53.10%) as a yellow solid.

[0314] Step 5:

[0315] 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 lyophilized to give crude product compound 135-3 (100 mg), a white solid, which was used directly in subsequent steps without further purification.

[0316] Example 9:

[0317] Synthesis of Compound 136

[0318]

[0319] Step 1:

[0320] Intermediate 84-10 (29.4 mg, 0.13 mmol), N,N,N',N'-tetramethylchloroformamide hexafluorophosphate (43.6 mg, 0.16 mmol), and N-methylimidazole (27.7 mg, 0.34 mmol) were added to a solution of intermediate 136-1 (30 mg, 0.13 mmol) in N,N-dimethylformamide (2 mL). 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 crude product was analyzed by preparative HPLC (Waters-Xbridge-C18-10µm-19). Purification was performed using a mobile phase of 10 mM NH4HCO3 (A: 10 mM NH4HCO3; B: ACN, gradient: 40-60%, residence time: 9.0 min) to give compound 136 (7.98 mg, 0.02 mmol, yield 13.96%) as a white solid. MS m / z (ESI): 441.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ8.84 (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).

[0321] Synthesis of intermediate 136-1

[0322]

[0323] Step 1:

[0324] Under a nitrogen atmosphere and with the internal temperature maintained below approximately 50°C, 4,4,5,5-tetramethyl-1,3,2-dioxoborane (4.83 g, 37.77 mmol) was added to a 24 mL solution of intermediate 136-2 (3 g, 25.18 mmol) in tetrahydrofuran. The reaction mixture was stirred at 50°C for 1 hour and then cooled to 25°C. A 12 mL solution of tetrahydrofuran containing pinacol diboronate (6.39 g, 25.18 mmol), 4,4'-di-tert-butyl-2,2'-dipyridine (0.41 g, 1.51 mmol), and methoxy(cyclooctadiene)iridium dimer (0.49 g, 0.76 mmol) was added to the cooled solution. The reaction mixture 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 give a white solid intermediate 136-3 (4.5 g, 18.36 mmol, 72.91% yield).

[0325] Step 2:

[0326] [4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene)]palladium(II) dichloride (0.31 g, 0.41 mmol) and intermediate 136-4 (2.16 g, 8.16 mmol) were added to a tetrahydrofuran (24 mL) solution of intermediate 136-3 (2 g, 8.16 mmol), and the reaction was carried out under a nitrogen atmosphere at 65 °C for 2 h. The reaction mixture was filtered, and the filter cake was washed with tetrahydrofuran and methanol and dried under vacuum to give a pale yellow crude product, intermediate 136-5 (650 mg, 2.72 mmol, 33.28% yield).

[0327] Step 3:

[0328] Sodium hydroxide (1.2 mL, 12.0 mmol, 10 mol / L) was added to a 12 mL aqueous solution of intermediate 136-5 (600 mg, 2.83 mol). The resulting solution was stirred at 80 °C for 16 hours. After rinsing the mixture with water, the reaction solution was heated to 55 °C, and HCl (37 wt%, 1.2 mL) was added while maintaining the temperature below approximately 60 °C. The product slurry was allowed to stand at 55 °C for approximately 0.5 hours, cooled to 20 °C, and then allowed to stand for another 1.0 hour. The product slurry was filtered, and the filter cake was washed twice with water (15 mL) and twice with isopropanol (15 mL). The product cake was concentrated under reduced pressure to give a white solid intermediate 136-1 (350 mg, 1.51 mmol, yield 53.54%).

[0329] Example 10:

[0330] Synthesis of Compound 137

[0331]

[0332] Step 1:

[0333] At room temperature, bis-pinacolborate (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 to a 10 mL solution of intermediate 137-1 (1.0 g, 5.08 mmol) in dioxane. The reaction mixture 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 crude product was purified by column chromatography (methanol / dichloromethane = 0-30%) to give a milky white solid intermediate 137-2 (1.10 g, 4.51 mmol, yield 88.79%).

[0334] Step 2:

[0335] At room temperature, 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 to a solution of intermediate 137-5 (300 mg, 1.13 mmol) in dioxane (10 mL) and water (2 mL). The reaction mixture was stirred at 90 °C under a nitrogen atmosphere 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 subsequent steps without further purification.

[0336] Step 3:

[0337] At room temperature, NaOH (435 mg, 10.9 mmol) was added to a solution of intermediate 137-3 (230 mg, 1.09 mmol) in H₂O (10 mL). The mixture was stirred at 100 °C under nitrogen for 16 hours. After the reaction was complete, the pH of the solution was adjusted to 6.0 with formic acid. Acidification of the aqueous solution yielded a brown precipitate, 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 the crude product intermediate 137-4, which was used directly in subsequent steps without further purification.

[0338] Step 4:

[0339] At room temperature, N-methylimidazole (0.05 mL, 0.66 mmol), N,N,N',N'-tetramethylchloromethanemid hexafluorophosphate (123 mg, 0.44 mmol), and intermediate 84-10 (50 mg, 0.22 mmol) were added to a 3 mL DMF solution of intermediate 137-4 (101 mg, 0.44 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction mixture was concentrated under reduced pressure and analyzed by preparative HPLC (Waters-Xbridge-C18-10µm-19). Purification was performed using a mobile phase of 250 nm (A: 10 mMNH4HCO3; B: ACN, gradient: 10%-10%, retention time: 10 min) to obtain a milky white solid intermediate 137 (12.8 mg, 0.03 mmol, yield 13.14%). MS m / z (ESI): 440.2 [M+H) + ; 1 H NMR (400 MHz, DMSO- d 6)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 = 3.6Hz, 2H), 4.55 (s, 2H), 4.31–4.16 (m, 2H), 2.95 (s, 2H), 2.43 (t, J = 7.2 Hz, 2H).

[0340] Example 11:

[0341] Synthesis of Compound 139

[0342]

[0343] Step 1:

[0344] Intermediate 139-1 (194.35 mg, 0.75 mmol), potassium carbonate (307.13 mg, 2.25 mmol), and Pd(PPh3)4 (tetra(triphenylphosphine)palladium) (85.73 mg, 0.08 mmol) were added to a solution of intermediate 122-8 (250 mg, 0.75 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL). The mixture was stirred at 80 °C under a nitrogen atmosphere for 3 hours. 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 layers were 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 give a white solid intermediate 139-2 (200 mg, 0.51 mmol, yield 68.72%).

[0345] Step 2:

[0346] Trifluoroacetic acid (0.5 mL) was added to a solution of intermediate 139-2 (200 mg, 0.51 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, diluted with water, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was then extracted three times 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 to give intermediate 139-3 (130 mg, 0.44 mmol, 87.25% yield) as a yellow solid. The crude product was used directly in the next step.

[0347] Step 3:

[0348] Oxaloyl chloride monoethyl ester (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) under ice bath conditions. The reaction mixture was stirred at room temperature for 0.5 h, then quenched with water (5 mL) and extracted three times 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. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give intermediate 139-4 (130 mg, 0.33 mmol, 74.71% yield) as a yellow solid.

[0349] Step 4:

[0350] A solution of intermediate 139-4 (130 mg, 0.33 mmol) in ammonia-methanol (1 mL, 7 M) was stirred at 70 °C for 3 hours. The reaction solution was concentrated under reduced pressure. A yellow solid crude intermediate 139-5 (120 mg, 0.36 mmol, yield 99.40%) was obtained and used directly in the next step.

[0351] Step 5:

[0352] Intermediate 139-5 (120 mg, 0.36 mmol), compound 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' A mixture of dimethylethylenediamine (58.07 mg, 0.72 mmol) was stirred in a solution of 1,4-dioxane (2 mL) at 95 °C under a nitrogen atmosphere for 16 hours. 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 layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1) and then by preparative HPLC (Waters-Xbridge-C18-10µm-19). Purification was performed using a mobile phase of 10 mM NH4HCO3 (A: 10 mM NH4HCO3; B: ACN, gradient: 40-50%, residence time: 8.5 min) to give a white solid compound 139 (34.58 mg, 0.07 mmol, yield 20.58%). MS m / z (ESI): 511.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) 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 = 10.4Hz, 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).

[0353] Example 12:

[0354] Synthesis of Compound 140

[0355]

[0356] Step 1:

[0357] Add to an acetonitrile (2.5 mL) solution of intermediate 134-4 (101 mg, 0.44 mmol) N,N,N',N' -Tetramethylchloroformamidine hexafluorophosphate (184 mg, 0.65 mmol), N- Methylimidazole (83 mg, 2.62 mmol) was reacted with the solution at room temperature for 30 minutes, followed by the addition of intermediate 136-1 (100 mg, 0.31 mmol). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the solution was diluted with dimethyl sulfoxide (3 mL) and filtered. The solid was washed twice with dimethyl sulfoxide (1 mL), and the filtrate was purified by preparative HPLC (mobile phase: A: 10 mM NH4HCO3; B: ACN, gradient: 40-50%, residence time: 8.5 min) to give 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- d 6) 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 = 10.4Hz, 1H), 4.89 (d, J = 10.4 Hz, 3H), 4.40 (d, J = 10.4 Hz, 1H), 4.29 (d, J = 10.4Hz, 1H).

[0358] Example 13:

[0359] Synthesis of Compound 146

[0360]

[0361] Step 1:

[0362] Add to an acetonitrile (2.5 mL) solution of intermediate 137-4 (148 mg, 0.61 mmol) N,N,N',N' -Tetramethylchloroformamidine hexafluorophosphate (184 mg, 0.65 mmol), N- Methylimidazole (83 mg, 2.62 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Intermediate 134-4 (100 mg, 0.31 mmol) was then added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was diluted with dimethyl sulfoxide (3 mL) and filtered. The solid was washed twice with dimethyl sulfoxide (1 mL), and the filtrate was purified by preparative HPLC (mobile phase: A: 10 mM NH4HCO3; B: ACN, gradient: 40-50%, residence time: 8.5 min) to give a white solid compound 146 (32.23 mg, 0.07 mmol, yield 16.74%). MS m / z (ESI): 442.1 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) 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).

[0363] Example 14:

[0364] Synthesis of Compound 149

[0365]

[0366] Step 1:

[0367] Intermediate 84-10 (243 mg, 0.88 mmol), N-methylimidazole (126 mg, 1.54 mmol), and N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (92 mg, 0.33 mmol) were added to a 2 mL solution of intermediate 149-1 (50 mg, 0.22 mmol) in acetonitrile. The reaction mixture was stirred at room temperature for 10 hours. After the reaction was complete, water (10 mL) was added to the reaction mixture, and the mixture was 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. The mixture was concentrated under reduced pressure, and the crude product was analyzed by preparative HPLC (Waters-Xbridge-C18-10µm-19). Purification was performed using a mobile phase of 10 mM NH4HCO3 (A: 10 mM NH4HCO3; B: ACN, gradient: 5-61%, retention time: 9.5 min) to give compound 149 (26.72 mg, 0.05 mmol, yield 24.99%). MS m / z (ESI): 486.0, 488.0 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) 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).

[0368] Example 15:

[0369] Synthesis of Compound 155

[0370]

[0371] Step 1:

[0372] A solution of intermediate 122-8 (200 mg, 0.59 mmol), pinacol diboronate (180 mg, 0.71 mmol), potassium acetate (116 mg, 1.18 mmol), and Pd(dppf)Cl2 (43 mg, 0.06 mmol) in dimethyl sulfoxide (3 mL) was stirred at 80 °C under a nitrogen atmosphere for 16 hours. The reaction mixture was diluted with water (5 mL) and extracted three times with ethyl acetate (5 mL). The combined organic layers were 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 give a yellow oily intermediate 155-1 (200 mg, 0.52 mmol, yield 51.95%).

[0373] Step 2:

[0374] Sodium carbonate (275 mg, 2.60 mmol) and 30% hydrogen peroxide solution (1 mL) were added to a solution of intermediate 155-1 (200 mg, 0.52 mmol) in tetrahydrofuran (4 mL) and water (1 mL). The reaction mixture was stirred at room temperature for 2 hours. After quenching the reaction mixture with saturated sodium thiosulfate solution (5 mL), it was extracted three times 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. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give intermediate 155-2 (100 mg, 0.36 mmol, yield 70.42%) as a white solid.

[0375] Step 3:

[0376] Under ice bath conditions, intermediate 155-2 (100 mg, 0.36 mmol) was... N,N Potassium carbonate (150 mg, 1.08 mmol) and methyl iodide (103 mg, 0.72 mmol) were added to a solution of dimethylformamide (3 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (5 mL) and extracted three times 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. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give a yellow solid intermediate 155-3 (60 mg, 0.21 mmol, 57.14% yield).

[0377] Step 4:

[0378] Trifluoroacetic acid (0.2 mL) was added to a solution of intermediate 155-3 (60 mg, 0.21 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, diluted with water, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was then extracted three times with ethyl acetate (2 mL). The combined organic layers were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give a yellow solid crude intermediate 155-4 (35 mg, 0.19 mmol, yield 89.74%). The crude product was used directly in the next step.

[0379] Step 5:

[0380] At room temperature, intermediate 88-11 (77 mg, 0.38 mmol) was added sequentially to a 2 mL solution of intermediate 155-4 (30 mg, 0.19 mmol) in acetonitrile. N -Methylimidazole (39 mg, 0.57 mmol) and N,N,N',N' -Tetramethylchloromethylammonium hexafluorophosphate (67 mg, 0.29 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was filtered, the solid was washed twice with water (5 mL) and dried, and then subjected to preparative HPLC (Waters-Xbridge-C18-10µm-19). 250 mm, mobile phase: A: 10 mM NH4HCO3; B: ACN, gradient: 5-61%, residence time: 9.5 min), yielded a white solid compound 155 (4.13 mg, 0.01 mmol, yield 6.30%). MS m / z (ESI): 414.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) 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).

[0381] Example 16:

[0382] Synthesis of Compound 160

[0383]

[0384] Step 1:

[0385] Intermediate 137-4 (100 mg, 0.44 mmol) was added sequentially to a 2 mL solution of acetonitrile containing intermediate 135-2 (40 mg, 0.22 mmol). N -Methylimidazole (53 mg, 0.66 mmol) and N,N,N',N' -Tetramethylchloromethanesulfonyl hexafluorophosphate (91 mg, 0.33 mmol), 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 layers were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The crude product was analyzed by preparative HPLC (Waters-Xbridge-C18-10µm-19). Purification was performed using a mobile phase of 10 mM NH4HCO3 (A: 10 mM NH4HCO3; B: ACN, gradient: 5-61%, residence time: 9.5 min) to give a white solid compound 160 (2.37 mg, 6.00 μmol, yield 2.80%). MS m / z (ESI): 397.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) 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).

[0386] Example 17:

[0387] Synthesis of Compound 163

[0388]

[0389] Step 1:

[0390] Under a nitrogen atmosphere and at room temperature, dipotassium hydrogen phosphate (55 g, 315.8 mmol) and palladium acetate (2.4 g, 10.52 mmol) were added to a solution of intermediate 163-1 (20 g, 105.26 mmol) in dibromomethane (150 mL). The reaction mixture was stirred at 130 °C for 5 days. After filtration, the filtrate was concentrated. The crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 10 / 1) to give intermediate 163-2 (6.5 g, 32.13 mmol, yield 24.46%).

[0391] Step 2:

[0392] Diisobutylaluminum hydride (70 mL) was added to a solution of intermediate 163-2 (13 g, 64.32 mmol) in dichloromethane (130 mL) under a nitrogen atmosphere and at -78 °C. 1N 70 mmol), then stirred at -78°C for 2 hours. Add (250 mL) to the reaction mixture and extract three times with ethyl acetate (150 mL). Combine the organic layers, wash with saturated brine (500 mL), dry with anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 3 / 1) to give intermediate 163-3 (8 g, 39.19 mmol, yield 60.93%).

[0393] Step 3:

[0394] At -20°C, boron trifluoride diethyl ether (6.26 g, 44.09 mmol) and trimethylcyanosilane (8.75 g, 88.17 mmol) were added to a solution of intermediate 163-3 (6 g, 29.39 mmol) in dichloromethane (60 mL). The reaction solution was kept at -20°C. o Stir at C for 30 minutes. Add water (100 mL) to the reaction mixture, and extract three times with ethyl acetate (50 mL). Combine the organic layers, wash with saturated brine (100 mL), and dry with anhydrous sodium sulfate. Concentrate under reduced pressure, and purify the crude product by preparative TLC (petroleum ether / ethyl acetate = 10 / 1) to give intermediate 163-4 (5.5 g, 25.80 mmol, yield 87.79%).

[0395] Step 4:

[0396] At room temperature, sodium hydride (2.06 g, 51.60 mmol) was added 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), and the reaction mixture was stirred for 2 hours. A saturated aqueous solution of ammonium chloride (200 mL) was added to the reaction mixture, followed by extraction 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 crude product was concentrated under reduced pressure and purified by preparative TLC (petroleum ether / ethyl acetate = 10 / 1) to give intermediate 163-5 (5.3 g, 20.93 mmol, yield 81.12%).

[0397] Step 5:

[0398] Sodium periodate (8.45 g, 39.49 mmol) was added fractionally to 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) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the crude product was purified by preparative TLC (dichloromethane / acetonitrile = 10 / 1) to give intermediate 163-6 (1.1 g, 4.06 mmol, yield 51.35%).

[0399] Step 6:

[0400] Raney nickel (100 mg) was added to a methanol (10 mL) solution of intermediate 163-6 (1 g, 3.69 mmol) under a nitrogen atmosphere at room temperature. The reaction mixture 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 give intermediate 163-7 (300 mg, 1.09 mmol, yield 29.56%).

[0401] Step 7:

[0402] 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 give intermediate 163-8 (100 mg, 0.39 mmol, yield 35.67%).

[0403] Step 8:

[0404] At room temperature, borane dimethyl sulfide (0.03 mL, 10.0 M, 0.3 mmol) was added to a 3 mL solution of tetrahydrofuran (40 mg, 0.16 mmol). The reaction mixture was refluxed for 2 hours and then cooled to room temperature. Methanol was added to the reaction mixture until no more bubbles were generated. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by C18 column chromatography (acetonitrile / water (0.1% NH4HCO3) = 20 / 1) to give intermediate 163-9 (12 mg, 0.05 mmol, yield 31.72%).

[0405] Step 9:

[0406] At room temperature, intermediates 163-9 (12 mg, 0.05 mmol) and 84-11 (12 mg, 0.05 mmol) were added to a solution of N,N-dimethylformamide (2 mL) containing N-methylimidazole (32 mg, 0.40 mmol) and N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (21 mg, 0.07 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was analyzed by preparative HPLC (Waters-Xbridge-C18-10µm-19). Purification was performed using a mobile phase of 10 mM NH4HCO3 (A: 10 mM NH4HCO3; B: ACN, gradient: 5-55%, residence time: 9.1 min) to give compound 163 (4.24 mg, 0.01 mmol, yield 18.11%). MS m / z (ESI): 468.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 8.61 (d, J = 14.0Hz, 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).

[0407] Example 18:

[0408] Synthesis of Compound 165

[0409]

[0410] Step 1:

[0411] At room temperature, N-methylimidazole (71 mg, 0.87 mmol) and N,N,N',N'-tetramethylchloroformamide hexafluorophosphate (91 mg, 0.33 mmol) were added to a solution of intermediate 149-1 (181 mg, 0.65 mmol) and intermediate 134-4 (50 mg, 0.22 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was analyzed by preparative HPLC (Waters-Xbridge-C18-10µm-19). Purification was performed using a mobile phase of 10 mM NH4HCO3 (A: 10 mM NH4HCO3; B: ACN, gradient: 5-60%, residence time: 8.5 min) to give compound 165 (30.66 mg, 0.06 mmol, yield 28.81%). MS m / z (ESI): 488.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) 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).

[0412] Example 19:

[0413] Synthesis of Compound 162

[0414]

[0415] Step 1:

[0416] Under a nitrogen atmosphere and at 0 °C, N-bromosuccinimide (6.31 g, 35.47 mmol) was added to a chloroform (60 mL) solution of intermediate 162-1 (6.0 g, 35.47 mmol), and the solution was stirred at room temperature for 6 hours. The reaction mixture was quenched with saturated sodium bicarbonate (60 mL), then extracted three times with dichloromethane (100 mL). The combined organic layers were 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 give a milky white intermediate 162-2 (7.8 g, 31.45 mmol, yield 88.65%).

[0417] Step 2:

[0418] At room temperature, a solution of intermediate 162-2 (2.0 g, 8.06 mmol) in 1,4-dioxane (20 mL) was reacted with pinacol bis(borate) ester (4.09 g, 16.13 mmol), potassium acetate (2.37 g, 24.19 mmol), and palladium dichloride (1.18 g, 1.61 mmol) (1,1'-bis(diphenylphosphine)ferrocene)dichloride. The reaction mixture was stirred at 80 °C for 16 hours, then concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give intermediate 162-3 (2.2 g, 7.45 mmol, 92.46% yield) as a white solid.

[0419] Step 3:

[0420] At room temperature, intermediate 162-3 (832 mg, 2.82 mmol), tripotassium phosphate (1.2 g, 5.64 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (318 mg, 0.376 mmol) were added to a solution of intermediate 137-5 (500.0 mg, 1.88 mmol) in 10 mL of 1,4-dioxane and 2 mL of water. The reaction mixture was stirred at 90 °C for 16 hours and then concentrated under reduced pressure. The crude product was purified by C18 reverse-phase column chromatography (water (0.1% NH3·H2O) / MeCN = 3 / 2) to give intermediate 162-4 (150 mg, 0.57 mmol, yield 30.40%) as a yellow solid.

[0421] Step 4:

[0422] Lithium hydroxide (80.0 mg, 1.91 mmol) was added to a methanol (5 mL) and water (5 mL) solution of intermediate 162-4 (100 mg, 0.38 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure to give intermediate 162-5 (90 mg, 0.36 mmol, 95.09% yield) as a yellow solid. The crude product was used directly in the next step.

[0423] Step 5:

[0424] At room temperature, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (124 mg, 0.33 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.65 mmol) were added to a solution of intermediate 162-5 (54 mg, 0.22 mmol) and compound 84-10 (50 mg, 0.22 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at room temperature for 3 hours, and then concentrated under reduced pressure. The crude product was analyzed using a preparative HPLC column (Waters-CORTECS-C18-2.7µm-4.6). Purification was performed using a mobile phase of 0.1% (NH4HCO3, B:CH3CN, gradient: 36%-76%, residence time: 8 min) at 30 mm to give a white solid, compound 162 (4.73 mg, 0.01 mmol, yield 4.68%). MS m / z (ESI): 458.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-) d 6) 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).

[0425] Example 20:

[0426] Synthesis of Compound 164

[0427]

[0428] Step 1:

[0429] At room temperature, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (125 mg, 0.33 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.65 mmol) were added to a solution of intermediate 162-5 (54 mg, 0.22 mmol) and compound 134-4 (50 mg, 0.22 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at room temperature for 3 hours, and then concentrated under reduced pressure. The crude product was analyzed by preparative HPLC (Waters-SunFire-C18-10µm-19). Purification was performed using a mobile phase of 250 mm, A: 0.1% FA / H₂O, B: ACN, gradient: 21%-51%, residence time: 8 min, to give a white solid compound 164 (4.82 mg, 0.01 mmol, yield 4.81%). MS m / z (ESI): 460.0 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) 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).

[0430] Example 21:

[0431] Synthesis of Compound 166

[0432]

[0433] Step 1:

[0434] At room temperature, 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 to a solution of intermediate 162-3 (1.0 g, 3.39 mmol) in dioxane (10 mL) and water (1 mL). The reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 10 hours and then cooled to room temperature. The solid precipitated, 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.

[0435] Step 2:

[0436] At room temperature, a solution of intermediate 166-2 (300 mg, 1.09 mmol) in methanol (5 mL) and water (1 mL) containing lithium hydroxide (137 mg, 3.28 mmol) was stirred at 50 °C for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The pH was adjusted to 3 by adding 1 M dilute hydrochloric acid. The mixture was filtered, and the filter cake was dried to give intermediate 166-3 (200 mg, 0.77 mmol, yield 70.26%).

[0437] Step 3:

[0438] At room temperature, N-methylimidazole (57 mg, 0.70 mmol) and N,N,N',N'-tetramethylchloroformamide hexafluorophosphate (73 mg, 0.26 mmol) were added to a solution of intermediate 166-3 (136 mg, 0.52 mmol) and compound 134-4 (40 mg, 0.17 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was analyzed by preparative HPLC (Waters-Xbridge-C18-10µm-19). Purification was performed using a mobile phase of 10 mM NH4HCO3 (A: 10 mM NH4HCO3; B: ACN, gradient: 5-70%, residence time: 8.1 min) to give 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- d 6) δ 8.39 (d, J = 7.6Hz, 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).

[0439] Example 22:

[0440] Synthesis of Compound 167

[0441]

[0442] Step 1:

[0443] Amyl nitrite (14.4 g, 12.27 mmol) was added dropwise to an acetonitrile (30 mL) solution of intermediate 167-1 (2.5 g, 7.22 mmol) and cuprous iodide (2.75 g, 14.44 mmol) at 0 °C. After the addition was complete, the reaction mixture was heated to 80 °C and stirred for 2 hours. After the reaction was complete, it was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by rubber tube column chromatography (ethyl acetate / petroleum ether = 1 / 3) to give a pale yellow solid compound 167-2 (0.9 g, 1.97 mmol, yield 27.27%).

[0444] Step 2:

[0445] Under a carbon monoxide atmosphere, a solution of intermediate 167-2 (900 mg, 1.97 mmol), [bis(diphenylphosphine)ferrocene]palladium(II) dichloride (144 mg, 0.2 mmol) in N,N-dimethylformamide (5 mL) and methanol (2 mL) was heated to 100 °C 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 give intermediate 167-3 (350 mg, 0.98 mmol, yield 49.7%) as a pale yellow solid.

[0446] Step 3:

[0447] Trifluoroacetic acid (1 mL) was added to a solution of intermediate 167-3 (150 mg, 0.42 mmol) in dichloromethane (1 mL), and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a yellow solid crude product intermediate 167-4 (110 mg, 0.42 mmol, 100% yield), which was used directly in the next step.

[0448] Step 4:

[0449] Compound 84-11 (66 mg, 0.27 mmol) was subjected to a nitrogen atmosphere. N,N,N',N' -Tetramethylchloroformamidine hexafluorophosphate (115 mg, 0.41 mmol) N- A solution of methylimidazole (134 mg, 1.63 mmol) in acetonitrile (3 mL) was stirred at room temperature for 30 minutes, followed by the addition of intermediate 167-4 (70 mg, 0.27 mmol). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dimethyl sulfoxide (5 mL) and filtered. The filtrate was analyzed by preparative HPLC (Waters-Xbridge-C18-10um-19). Purification was performed using a mobile phase of 0.1% FA / H₂O (B:CH₃CN), with a gradient of 55% B - 85% B, and a residence time of 8.5 min, yielding a white solid, compound 167 (38.56 mg, 0.08 mmol, yield 29.43%). MS m / z (ESI): 482.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 8.53 (d, J = 2.0Hz, 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).

[0450] Example 23:

[0451] Synthesis of Compound 901

[0452]

[0453] Step 1:

[0454] 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. The reaction mixture was then heated to room temperature and stirred for 2 hours. After the reaction was complete, a saturated ammonium chloride aqueous solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 3) to give a pale yellow solid intermediate 901-1 (1 g, 2.77 mmol, 76% yield).

[0455] Step 2:

[0456] Under a nitrogen atmosphere, concentrated sulfuric acid (217 mg, 2.21 mmol) was added dropwise to a 5 mL solution of intermediate 901-1 (200 mg, 0.55 mmol) in toluene. After the addition was complete, the mixture was heated to 110 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure to obtain a crude yellow solid intermediate 901-2 (134 mg, 0.55 mmol, 100% yield). The crude product was used directly in the next step.

[0457] Step 3:

[0458] Under a nitrogen atmosphere, a solution of intermediate 84-11 (80 mg, 0.33 mmol), N,N,N',N'-tetramethylchloromethamphexane 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. Then, intermediate 901-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 analyzed by preparative HPLC (Waters-Xbridge-C18-10um-19). Purification was performed using a mobile phase of 0.1% NH4HCO3 / H2O (B:CH3CN), with a gradient of 55% B - 85% B, and a Ret 9.5 min, yielding a white solid compound 901 (24.68 mg, 0.06 mmol, yield 17.22%). MS m / z (ESI): 467.9 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) 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, 8.8Hz, 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).

[0459] Example 24:

[0460] Synthesis of Compound 178

[0461]

[0462] Step 1:

[0463] Under a nitrogen atmosphere, a solution of intermediate 136-1 (76 mg, 0.33 mmol), N,N,N',N'-tetramethylchloromethamphexane 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. Then, intermediate 901-2 (80 mg, 0.33 mmol) was added to the reaction mixture. 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 analyzed by preparative HPLC (Waters-Xbridge-C18-10um-19). Purification was performed using a mobile phase of 0.1% NH4HCO3 / H2O (B:CH3CN), with a gradient of 55% B - 85% B, and a Ret 9.5 min, yielding a white solid, compound 178 (14.18 mg, 0.03 mmol, yield 9.41%). MS m / z (ESI): 457.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) 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).

[0464] Example 25:

[0465] Synthesis of Compound 1036

[0466]

[0467] Step 1:

[0468] Under a nitrogen atmosphere and at 0°C, sodium hydride (21.03 mg, 0.88 mmol) was added 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. Iodomethane (55 μL, 0.88 mmol) was then added dropwise, and the mixture was stirred at 0°C for another 0.5 hours. The temperature was then raised to room temperature and stirred for another hour. After the reaction was complete, water (10 mL) was added to the reaction mixture, followed by extraction 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 give intermediate 1036-1 (160 mg, 0.45 mmol, 76.85%) as a yellow oil.

[0469] Step 2:

[0470] Trifluoroacetic acid (1 mL) was added to a 5 mL solution of intermediate 1036-1 (160 mg, 0.45 mmol) in dichloromethane, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The solution was extracted with 5 mL of sodium bicarbonate aqueous solution followed by 5 mL of dichloromethane. The combined organic layers were washed with 5 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a yellow solid crude product, intermediate 1036-2 (110 mg, 0.43 mmol, 95.61%), which was used directly in the next step.

[0471] Step 3:

[0472] Under a nitrogen atmosphere, a solution of intermediate 84-11 (100 mg, 0.39 mmol), N,N,N',N'-tetramethylchloromethamphexane 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 filter cake was washed with DMSO (2 mL), and the filtrate was concentrated under reduced pressure. The crude product was analyzed by HPLC (Waters-Xbridge-C18-10um-19). Purification was performed using a mobile phase of 0.1% NH4HCO3 / H2O (B:CH3CN), with a gradient of 55% B - 85% B, and a relapse time of 8.5 min. The result was a white solid, compound 1036 (35 mg, 0.07 mmol, 18.67%). MS m / z (ESI): 481.1 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) 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).

[0473] Example 26:

[0474] Synthesis of Compound 1040

[0475]

[0476] Step 1:

[0477] Under a nitrogen atmosphere at 0°C, sodium hydride (32 mg, 1.31 mmol) was added 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. After adding 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.19 mL, 1.31 mmol), the mixture was stirred at 0°C for another 0.5 hours, then heated to room temperature and stirred for another hour. After the reaction was complete, water (10 mL) was added to the reaction mixture, followed by extraction 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 give intermediate 1040-1 (270 mg, 0.64 mmol, 72.60%) as a yellow solid.

[0478] Step 2:

[0479] Trifluoroacetic acid (1 mL) was added to a solution of intermediate 1040-1 (270 mg, 0.64 mmol) in dichloromethane (5 mL), and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The crude product was added to a saturated aqueous solution of sodium bicarbonate (5 mL), stirred, and 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 give a yellow solid crude intermediate 1040-2 (170 mg, 0.52 mmol, 89.00%). The crude product was used directly in the next step.

[0480] Step 3:

[0481] Under a nitrogen atmosphere, a solution of intermediate 84-11 (90 mg, 0.31 mmol), N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (173.96 mg, 0.62 mmol), and N-methylimidazole (0.15 mL, 1.86 mmol) in acetonitrile (5 mL) was stirred at room temperature for 30 minutes. Then, intermediate 1040-2 (100 mg, 0.47 mmol) was added to the reaction mixture, 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 filter cake was washed with DMSO (2 mL), and the filtrate was concentrated under reduced pressure. The crude product was analyzed by HPLC (Waters-Xbridge-C18-10um-19). Purification was performed using a mobile phase of 0.1% NH4HCO3 / H2O (B:CH3CN), with a gradient of 55% B - 85% B, and a relapse time of 8.5 min. The result was a white solid, compound 1040 (16 mg, 0.03 mmol, 9.46%). MS m / z (ESI): 549.3 [M+H] + ; 1 H NMR (400MHz, DMSO- d 6) 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).

[0482] Example 27:

[0483] Synthesis of Compound 902

[0484]

[0485] Step 1:

[0486] 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 at -78 °C under a nitrogen atmosphere. The reaction mixture was stirred at -78 °C for 2 hours. The atmosphere was then replaced with carbon dioxide three times, and the mixture was stirred again at room temperature for 2 hours. Sodium sulfate decahydrate was added to the reaction mixture, followed by filtration. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane / methanol = 8 / 1) to give intermediate 902-2 (1.00 g, 4.78 mmol, yield 116.69%).

[0487] Step 2:

[0488] 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 mixture was then cooled and distilled under pressure. The concentrate was slowly added dropwise to methanol (3 mL) and stirred at room temperature for 10 minutes. Water (10 mL) was added to the reaction mixture, and the mixture was 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 give intermediate 902-3 (290 mg, 1.30 mmol, 74.19% yield).

[0489] Step 3:

[0490] Under a nitrogen atmosphere and in an ice bath, potassium bis(trimethylsilyl)amino (1.43 mL, 1.43 mmol, 1 N) was slowly added dropwise to a tetrahydrofuran (5 mL) solution of intermediate 902-3 (290 mg, 1.30 mmol) and intermediate 123-1a (280 mg, 1.30 mmol). The reaction mixture was stirred in an ice bath for 1 hour, and then stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL). 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 give intermediate 902-4 (60 mg, 0.14 mmol, yield 11.03%).

[0491] Step 4:

[0492] Lithium borohydride (12 mg, 0.56 mmol) was slowly added to a methanol (2 mL) solution of intermediate 902-4 (60 mg, 0.14 mmol) under ice bath conditions, and the mixture was stirred at room temperature for 30 minutes. Sodium sulfate decahydrate was added to the reaction solution and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1) to give intermediate 902-5 (40 mg, 0.11 mmol, yield 76.97%).

[0493] Step 5:

[0494] Concentrated sulfuric acid (43 mg, 0.44 mmol) was added dropwise to a 2 mL solution of intermediate 902-5 (40 mg, 0.11 mmol) in toluene, and the reaction mixture was heated under reflux for 10 hours. The reaction mixture was then concentrated under reduced pressure to obtain intermediate 902-6 (30 mg, 0.12 mmol), which was used directly in the next step.

[0495] Step 6:

[0496] At room temperature, N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (34 mg, 0.12 mmol) and N-methylimidazole (67 mg, 0.82 mmol) were added to a solution of intermediate 902-5 (20 mg, 0.08 mmol) and intermediate 84-11 (40 mg, 0.08 mmol) in acetonitrile (2 mL), and the reaction mixture was stirred for 2 hours. Water (10 mL) was added to the reaction mixture, 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 analyzed by HPLC (Waters-Xbridge-C18-10µm-19). Purification was performed using a mobile phase of 10 mM NH4HCO3 (A: 10 mM NH4HCO3; B: ACN, gradient: 10-95%, residence time: 10 min) to give compound 902 (6.73 mg, 0.01 mmol, yield 17.54%). MS m / z (ESI): 468.9 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 9.23 (s, 1H), 8.55 (d, J = 2.0Hz, 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).

[0497] Example 28:

[0498] Synthesis of Compound 1039

[0499]

[0500] Step 1:

[0501] 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. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give intermediate 1039-1 (190 mg, 0.50 mmol, 34.02%) as a white solid.

[0502] Step 2:

[0503] A mixed solution of dichloromethane (3 mL) and trifluoroacetic acid (0.5 mL) containing intermediate 1039-1 (130 mg, 0.34 mmol) was stirred at 25 °C for 2 hours. The reaction solution was concentrated and 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 give crude intermediate 1039-2 (100 mg, 0.35 mmol, 104.20%) as a brown solid.

[0504] Step 3:

[0505] A solution of acetonitrile (10 mL) containing intermediate 84-11 (100 mg, 0.41 mmol), N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (170 mg, 0.61 mmol), and N-methylimidazole (0.10 mL, 1.20 mmol) was stirred at 25 °C for 30 min. After adding intermediate 1039-2 (113 mg, 0.40 mmol), the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated and diluted with dimethyl sulfoxide (3 mL). The crude product was analyzed by preparative HPLC (Waters-Xbridge-C18-10µm-19). 250 mm; Mobile phase: A: 10 mM ammonium bicarbonate / water; B: acetonitrile; Flow rate: 25) Purification yielded 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 (400MHz, DMSO- d 6) 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).

[0506] Example 29:

[0507] Synthesis of Compound 1038

[0508]

[0509] Step 1:

[0510] 2-Bromopropane (0.2 mL, 2.13 mmol) was added to a solution of N,N-dimethylformamide (10 mL) containing intermediate 123-3 (200 mg, 0.58 mmol) and sodium hydride (60 mg, 1.50 mmol, 60% w%). The reaction mixture was stirred at 50 °C for 2 hours. The reaction mixture 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 give crude intermediate 1038-1 (250 mg, 0.65 mmol, 111.31%) as a white solid.

[0511] Step 2:

[0512] A mixed solution of trifluoroacetic acid (1 mL) and dichloromethane (5 mL) containing intermediate 1038-1 (250 mg, 0.65 mmol) 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 layers were 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 next step.

[0513] Step 3:

[0514] A solution of acetonitrile (10 mL) containing intermediate 84-11 (100 mg, 0.41 mmol), N,N,N',N'-tetramethylchloromethylammonium hexafluorophosphate (175 mg, 0.62 mmol), and N-methylimidazole (0.10 mL, 1.24 mmol) was stirred at 25 °C for 30 min. Then, intermediate 1038-2 (110 mg, 0.39 mmol) was added. The reaction was stirred at 25 °C for 2 h. The reaction solution was concentrated, and the crude product was analyzed by preparative HPLC (Waters-Xbridge-C18-10µm-19). 250 mm; Mobile phase: A: 10 mM ammonium bicarbonate / water; B: acetonitrile; Flow rate: 25) Purification yielded compound 1038 (14.95 mg, 0.03 mmol, 6.73%) as a white solid. MS m / z (ESI): 509.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 8.54 (d, J = 2.0Hz, 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).

[0515] Example 30:

[0516] Synthesis of Compound 189

[0517]

[0518] Step 1:

[0519] Under a nitrogen atmosphere, liquid bromine (1.10 mL, 21.45 mmol) was slowly added dropwise to a methanol (40 mL) solution of intermediate 189-1 (4.7 g, 21.45 mmol) at 0 °C. After the addition was complete, the mixture was stirred at 0 °C for 1 hour. After the reaction was complete, water (30 mL) was added, followed by extraction 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 give intermediate 189-2 (2.8 g, 9.39 mmol, 43.80%) as a yellow solid.

[0520] Step 2:

[0521] Under a nitrogen atmosphere, pinacol diboronate (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 5 mL solution of intermediate 189-2 (500 mg, 1.68 mmol) in 1,4-dioxane. The reaction mixture was stirred at 80 °C for 2 hours. After the reaction was complete, the mixture was filtered and concentrated under reduced pressure to obtain a yellow solid crude intermediate 189-3 (400 mg, 1.16 mmol, 69.09%), which was used directly in the next step.

[0522] Step 3:

[0523] 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). The mixture was stirred at 80 °C for 18 hours. After the reaction was complete, water (30 mL) was added to the reaction solution, 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 give intermediate 189-4 (350 mg, 1.12 mmol, 90.85%) as a yellow solid.

[0524] Step 4:

[0525] Lithium hydroxide (54 mg, 1.28 mmol) was added to a solution of intermediate 189-4 (200 mg, 0.64 mmol) in methanol (2 mL), tetrahydrofuran (2 mL), and water (2 mL). The reaction mixture was stirred at 75 °C for 3 hours. After the reaction was complete, the pH of the reaction mixture was adjusted to ~6 with 1M dilute hydrochloric acid. The reaction mixture was concentrated under reduced pressure and then lyophilized to obtain a yellow solid crude intermediate 189-5 (237 mg, 0.64 mmol, 99.26%), which was used directly in the next step.

[0526] Step 5:

[0527] Under a nitrogen atmosphere, an acetonitrile (5 mL) solution containing intermediate 189-5 (100 mg, 0.27 mmol), N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (150 mg, 0.54 mmol), and N-methylimidazole (0.13 mL, 1.61 mmol) 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. After the reaction was complete, the reaction solution was diluted with DMSO (5 mL) and filtered. The filter cake was washed with DMSO (2 mL). The filtrate was concentrated under reduced pressure, and the crude product was analyzed by HPLC (Waters-Xbridge-C18-10um-19). Purification was performed at 250 mm, with a mobile phase of 0.1% NH4HCO3 / H2O and a gradient of 55% B - 85% B, Ret 8.5 min, yielding a white solid compound 189 (27.22 mg, 0.05 mmol, 19.92%).

[0528] Example 31:

[0529] Synthesis of Compound 1102

[0530]

[0531] Step 1:

[0532] Oxaloyl chloride monoethyl ester (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) under ice bath conditions. The reaction mixture was stirred at room temperature for 0.5 h, then quenched with water (10 mL) and extracted with ethyl acetate (3 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a yellow oily crude intermediate 1102-1 (250 mg, 0.76 mmol, 69.43% yield). The crude product was used directly in the next step.

[0533] Step 2:

[0534] A solution of 1 mL tetrahydrofuran and 1 mL ammonia-methanol solution (7 M) containing intermediate 1102-1 (200 mg, 0.61 mmol) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1) to give intermediate 1102-2 (160 mg, 0.54 mmol, yield 87.79%) as a yellow solid.

[0535] Step 3:

[0536] Under a nitrogen atmosphere, intermediates 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 to a 2 mL solution of intermediate 1102-2 (100 mg, 0.37 mmol) in 1,4-dioxane. The reaction mixture was stirred at 100 °C for 10 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL). The combined organic layers were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 3) to give intermediate 1102-4 (0.1 g, 0.20 mmol, yield 55.29%), which was a black liquid.

[0537] Step 4:

[0538] At room temperature, a solution of 2 mL of trifluoroacetic acid containing intermediate 1102-4 (100 mg, 0.20 mmol) was stirred at 80 °C for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was analyzed by HPLC (Waters-Xbridge-C18-10µm-19). Purification was performed using a mobile phase of 10 mM NH4HCO3 (A: 10 mM NH4HCO3; B: ACN, gradient: 5-21%, retention time: 9 min) to obtain a white solid compound 1102 (13.23 mg, 0.03 mmol, yield 14.94%). MS m / z (ESI): 435.2 [M+H] + ; 1 H NMR (400MHz, DMSO- d 6) 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).

[0539] Example 32:

[0540] Synthesis of Compound 1090

[0541]

[0542] Step 1:

[0543] To a solution of intermediate 1090-1 (10 g, 38.46 mmol) in water (40 mL) and dioxane (200 mL), potassium ethylenetrifluoroborate (15 g, 111.98 mmol), Pd(dppf)Cl2 (1.57 g, 1.92 mmol), and potassium carbonate (16 g, 115.77 mmol) were added. 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 to 1:10) to give a white solid intermediate 1090-2 (7.6 g, 36.68 mmol, 95.39%).

[0544] Step 2:

[0545] To a solution of intermediate 1090-2 (8.5 g, 41.03 mmol) in water (150 mL) and tetrahydrofuran (300 mL), potassium osmium tetroxide dihydrate (0.76 g, 2.05 mmol) and sodium periodate (35.10 g, 164.10 mmol) were added. 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 saturated 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 to 1:10) to give intermediate 1090-3 (5.8 g, 27.73 mmol, 67.59%) as a white solid.

[0546] Step 3:

[0547] DAST (15 mL, 138.65 mmol) was added to a solution of intermediate 1090-3 (5.8 g, 27.73 mmol) in dichloromethane (100 mL) at -78 °C. The reaction mixture was slowly heated from -78 °C to room temperature and 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 to 1:10) to give intermediate 1090-4 (6 g, 1.51 mmol, 5.46%) as a white solid.

[0548] Step 4:

[0549] 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 mixture was stirred at 80 °C for 2 hours. After the reaction was complete, the reaction mixture was filtered hot through diatomaceous earth, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure, 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 give crude intermediate 1090-5, which was used directly in the next step.

[0550] Step 5:

[0551] N-bromosuccinimide (4.25 g, 23.86 mmol) was added to a solution of intermediate 1090-5 (4.8 g, 23.86 mmol) in acetonitrile (100 mL), and the reaction mixture 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 mixture, 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 to 1:5) to give intermediate 1090-6 (5.8 g, 20.71 mmol, 86.79%) as a white solid.

[0552] Step 6:

[0553] To a 15 mL solution of intermediate 1090-6 (500 mg, 1.79 mmol) in dioxane, bis-pinacolborate (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 hot through diatomaceous earth, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give crude intermediate 1090-7, which was used directly in the next step.

[0554] Step 7:

[0555] Intermediate 136-4 (250 mg, 1.03 mmol) and intermediate 1090-7 (336 mg, 1.03 mmol) were dissolved in water (1 mL) and dioxane (10 mL), and tetrakis(triphenylphosphine)palladium(0) (115 mg, 0.10 mmol) and potassium carbonate (426 mg, 3.08 mmol) were added. The reaction mixture was stirred at 80 °C for 18 hours. After the reaction was complete, the reaction mixture was filtered hot through diatomaceous earth 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 give a black solid intermediate 1090-8 (600 mg, 1.02 mmol, 99.16%).

[0556] Step 8:

[0557] Lithium hydroxide (90 mg, 3.76 mmol) was added to a solution of intermediate 1090-8 (400 mg, 0.68 mmol) in tetrahydrofuran (2 mL), water (2 mL), and methanol (2 mL). 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 2M dilute hydrochloric acid. The aqueous layer was extracted with ethyl acetate (20 mL) and then lyophilized to obtain crude intermediate 1090-9, which was used directly in the next step.

[0558] Step 9:

[0559] To a 1 mL solution of intermediate 1090-9 (200 mg, 0.23 mmol) in dimethyl sulfoxide, 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. The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction solution was filtered and analyzed by preparative HPLC (SunFire-C18-10µm-19). Purification was performed at a flow rate of 25 mL / min and a mobile phase of 0.1% FA / H₂O (A: 0.1% FA / H₂O, B: ACN) to give a white solid, compound 1090 (46.3 mg, 0.09 mmol, 43.56%). MS m / z (ESI): 492.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) 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).

[0560] Example 33:

[0561] Synthesis of Compound 194

[0562]

[0563] Step 1:

[0564] At room temperature, intermediate 194-2 (213 mg, 0.81 mmol), tripotassium phosphate (312 mg, 1.47 mmol), 2-dicyclohexylphosphine-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), dioxane (3 mL), and water (0.3 mL). The reaction mixture was stirred at 100 °C for 16 hours. After the reaction was complete, the reaction mixture was filtered. Water (20 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (10 mL). The combined organic layers were 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 give intermediate 194-3 (80 mg, 0.31 mmol, yield 42.39%).

[0565] Step 2:

[0566] At room temperature, lithium hydroxide (27 mg, 1.15 mmol) was added to a methanol (3 mL) and water (1 mL) solution of intermediate 194-3 (60 mg, 0.23 mmol). The reaction mixture was stirred at 50 °C under a nitrogen atmosphere for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the pH was adjusted to 5 with 1 M dilute hydrochloric acid. The solid was collected, dried, and used to obtain intermediate 194-4 (40 mg, 0.17 mmol, yield 70.52%).

[0567] Step 3:

[0568] At room temperature, N,N-diisopropylethylamine (90 mg, 0.74 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (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). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was analyzed by preparative HPLC (Waters-Xbridge-C18-10µm-19). Purification was performed using a mobile phase of 250 mm, A: 10 mM NH4HCO3; B: ACN, gradient: 5-70%, and residence time: 8.1 min, yielding 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).

[0569] Example 34:

[0570] Synthesis of Compound 195

[0571]

[0572] Step 1:

[0573] Under a nitrogen atmosphere, an acetonitrile (2 mL) solution containing intermediate 137-4 (95 mg, 0.41 mmol), N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (173 mg, 0.62 mmol), and N-methylimidazole (203 mg, 2.47 mmol) 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 analyzed by preparative HPLC (Waters-Xbridge-C18-10um-19). Purification was performed using a mobile phase of 0.1% NH4HCO3 / H2O (B:CH3CN), with a gradient of 55% B - 85% B, and a Ret 9.5 min, yielding a white solid, 195 (14.18 mg, 0.06 mmol, yield 14.94%). 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).

[0574] Example 35:

[0575] Synthesis of Compound 196

[0576]

[0577] Step 1:

[0578] Under a nitrogen atmosphere, an acetonitrile (1.5 mL) solution containing intermediate 1036-2 (100 mg, 0.30 mmol), N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (183 mg, 0.65 mmol), and N-methylimidazole (178 mg, 2.17 mmol) was stirred at room temperature for 30 minutes. Then, intermediate 137-4 (78 mg, 0.30 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 filter cake was washed with DMSO (2 mL), and the filtrate was concentrated under reduced pressure. The residue was analyzed by preparative HPLC (Waters-Xbridge-C18-10um-19). Purification was performed using a mobile phase of 0.1% NH4HCO3 / H2O (B:CH3CN), with a gradient of 55% B - 85% B, and a relapse time of 8.5 min. The result was a white solid, compound 196 (21.85 mg, 0.05 mmol, 15.34%). MS m / z (ESI): 469.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-) d 6) 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).

[0579] Example 36:

[0580] Synthesis of Compound 1100

[0581]

[0582] Step 1:

[0583] At room temperature, 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 to a 2 mL solution of intermediate 77-2 (58 mg, 0.10 mmol) in dioxane. The reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 16 hours, and then concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane / methanol = 18 / 1) to give intermediate 1100-1 (10.00 mg, 12.61 μmol, yield 12.47%) as a yellow solid.

[0584] Example 37:

[0585] Synthesis of Compound 1045

[0586]

[0587] Step 1:

[0588] At 0 °C, tert-butyldimethylchlorosilane (710 mg, 4.71 mmol) was added to a solution of intermediate 1045-1 (1.0 g, 3.92 mmol) and imidazole (590 mg, 8.63 mmol) in dichloromethane (10 mL). The mixture was slowly heated 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. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 50) to give a colorless oily intermediate 1045-2 (1.4 g, 3.79 mmol, 96.68% yield).

[0589] Step 2:

[0590] Under a nitrogen atmosphere and at -78°C, a solution of n-butyllithium (1.62 mL, 4.06 mmol) was added to a tetrahydrofuran (15 mL) solution of intermediate 1045-2 (1.0 g, 2.71 mmol), and the mixture was stirred for 0.5 h. A tetrahydrofuran (7 mL) solution of intermediate 1045-3 (0.70 g, 4.06 mmol) was then added to the same solution, and the mixture was stirred at room temperature and under a nitrogen atmosphere for 6 h. After the reaction was complete, the reaction mixture 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 give a colorless oily intermediate 1045-4 (330 mg, 0.71 mmol, yield 26.40%).

[0591] Step 3:

[0592] Hydrochloric acid (7.15 mL, 7.15 mmol) was added to a tetrahydrofuran (15 mL) solution of intermediate 1045-4 (330 mg, 0.71 mmol), 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 give a colorless oily intermediate 1045-5 (200 mg, 0.58 mmol, yield 80.54%).

[0593] Step 4:

[0594] Triethylamine (87.4 mg, 0.86 mmol) and methanesulfonyl chloride (34.63 mg, 0.3 mmol) were added to a tetrahydrofuran (6 mL) solution of intermediate 1045-5 (150 mg, 0.43 mmol). The reaction mixture was stirred at 70 °C for 3 hours. After the reaction was complete, the reaction mixture 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 give a colorless oily intermediate 1045-6 (76 mg, 0.23 mmol, 53.44% yield).

[0595] Step 5:

[0596] Trifluoroacetic acid (2 mL) was added to a 4 mL solution of intermediate 1045-6 (76 mg, 0.23 mmol) in dichloromethane, and the reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain crude intermediate 1045-7 (50 mg, crude), which was directly used in the next step of the reaction.

[0597] Step 6:

[0598] 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 N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (128 mg, 0.46 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure, and the 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 give compound 1045 (31.4 mg, 0.07 mmol, yield 31.74%) as a white solid. MS m / z (ESI): 453.9 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) 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).

[0599] Example 38:

[0600] Synthesis of Compound 1093

[0601]

[0602] Step 1:

[0603] Under a nitrogen atmosphere and at room temperature, intermediate 1093-1 (8.6 mL, 111.70 mmol) was added to a 100 mL solution of sodium hydride (2.23 g, 55.85 mmol, 60%) in tetrahydrofuran. Then, crotonitrile (11 mL, 134.45 mmol) was slowly added dropwise to the reaction mixture at 65 °C, and the reaction was continued with stirring at 65 °C for 2 hours. After the reaction was complete, the reaction mixture was cooled and quenched with an aqueous sodium hydroxide solution (50 mL, 2 M), extracted with methyl tert-butyl ether (50 mL), and the aqueous phase was acidified to pH ~1 with concentrated hydrochloric acid and then 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 give intermediate 1093-2 (3.4 g, 27.17 mmol, 24.33%) as a colorless oil.

[0604] Step 2:

[0605] At -78°C, trifluoromethanesulfonic anhydride (6.50 mL, 39.16 mmol) was slowly added dropwise to a solution of intermediate 1093-2 (3.5 g, 27.97 mmol) and diisopropylethylamine (9.27 mL, 55.94 mmol) in 10 mL of dichloromethane. The reaction solution was stirred at -78°C for 2 hours. After the reaction was complete, it was 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 next step.

[0606] Step 3:

[0607] A solution of 1,4-dioxane (10 mL) and water (1 mL) containing intermediates 1093-3 (200 mg, 0.78 mmol), 194-2 (646.54 mg, 2.33 mmol), tetrakis(triphenylphosphine)palladium (89.9 mg, 0.08 mmol), and potassium carbonate (322.4 mg, 2.33 mmol) 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 give intermediate 1093-4 (200 mg, 0.39 mmol, 49.79%) as a yellow solid.

[0608] Step 4:

[0609] A mixture of water (5 mL), tetrahydrofuran (5 mL), and ethanol (5 mL) containing intermediate 1093-4 (180 mg, 0.70 mmol) and lithium hydroxide (69 mg, 2.86 mmol) 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) and filtered. The filter cake was dried under vacuum to obtain intermediate 1093-5 (80 mg, 0.33 mmol, 47.00%) as a yellow solid.

[0610] Step 5:

[0611] Compound intermediate 134-4 (120 mg, 0.52 mmol) was added to an acetonitrile (7 mL) solution containing intermediate 1093-5 (70 mg, 0.29 mmol), N,N,N',N'-tetramethylchloromethanemidazone hexafluorophosphate (120 mg, 0.43 mmol), and N-methylimidazole (0.11 mL, 1.43 mmol). The reaction solution was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated and diluted with dimethyl sulfoxide (3 mL). The crude product was analyzed by preparative HPLC (Waters-Xbridge-C18-10µm-19). 250 mm; Mobile phase: A: 10 mM ammonium bicarbonate / water; B: acetonitrile; Flow rate: 25 m / s; Purification yielded 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 (brs, 2H), 4.35 – 4.27 (m, 2H), 1.41 (d, J = 6.0 Hz, 3H).

[0612] Example 39:

[0613] Synthesis of Compound 202

[0614]

[0615] Step 1:

[0616] Intermediate 137-4 (50 mg, 0.18 mmol) was added to an acetonitrile (5 mL) solution containing intermediate 1038-2 (50 mg, 0.22 mmol), N,N,N',N'-tetramethylchloromethanemid hexafluorophosphate (75 mg, 0.27 mmol), and N-methylimidazole (0.04 mL, 0.53 mmol). The reaction mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the mixture was concentrated and diluted with dimethyl sulfoxide (3 mL). The crude product was analyzed by preparative HPLC (Waters-Xbridge-C18-10µm-19). 250 mm; Mobile phase: A: 10 mM ammonium bicarbonate / water; B: acetonitrile; Flow rate: 25) Purification yielded 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- d 6) 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 = 3.6Hz, 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).

[0617] Example 40:

[0618] Synthesis of Compound 203

[0619]

[0620] Step 1:

[0621] Potassium ferrocyanide (145 mg, 0.39 mmol), potassium acetate (95 mg, 0.97 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (32 mg, 0.08 mmol), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (46 mg, 0.06 mmol) were added to a dioxane (2 mL) solution of intermediate 203-1 (180 mg, 0.39 mmol). The reaction mixture was stirred at 100 °C for 18 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and 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 give intermediate 203-2 (100 mg, 0.37 mmol, 95.83%) as a white solid.

[0622] Step 2:

[0623] Lithium hydroxide (45 mg, 1.88 mmol) was added to a mixed solution of intermediate 203-2 (80 mg, 0.30 mmol) in tetrahydrofuran (2 mL), water (2 mL), and methanol (2 mL). The reaction mixture was stirred at 75 °C for 3 hours. After the reaction was complete, the pH of the reaction mixture was adjusted to 3 with dilute hydrochloric acid (2 M). The aqueous layer was extracted with ethyl acetate (20 mL) and then lyophilized to obtain the crude product intermediate 203-3, which was used directly in the next step.

[0624] Step 3:

[0625] Intermediate 134-4 (30 mg, 0.13 mmol), N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (37.10 mg, 0.13 mmol), and N-methylimidazole (43 mg, 0.53 mmol) were added to a 1 mL solution of intermediate 203-3 (90 mg, 0.09 mmol) in dimethyl sulfoxide. The reaction mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the crude product was analyzed by preparative HPLC (SunFire-C18-10µm-19). Purification was performed at a flow rate of 25 mL / min and a mobile phase of 0.1% FA / H₂O (A: 0.1% FA / H₂O, B: ACN) to give compound 203 (5.38 mg, 0.01 mmol, 11.91%) as a pale yellow solid. MS m / z (ESI): 467.2 [M+H] + ; 1 H 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).

[0626] Example 41:

[0627] Synthesis of Compound 204

[0628]

[0629] Step 1:

[0630] At room temperature, intermediate 204-2 (380 mg, 2.04 mmol), tetrakis(triphenylphosphine)palladium (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 for 10 hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, a solid precipitated. The mixture was filtered, the filter cake was washed with water (10 mL), and dried to give intermediate 204-3 (200 mg, 0.89 mmol, yield 43.72%).

[0631] Step 2:

[0632] At room temperature, a 2 mL solution of water containing intermediate 204-3 (200 mg, 0.89 mmol) and sodium hydroxide (143 mg, 3.57 mmol) was dissolved in 85 mL of water. o Stir at C for 10 hours. Cool the reaction mixture to room temperature and adjust the pH to 3 with dilute hydrochloric acid (1M), resulting in solid formation. Filter the mixture and dry the filter cake to obtain crude intermediate 204-4 (150 mg, 0.62 mmol, 69.14% yield), which can be used directly in the next step.

[0633] Step 3:

[0634] At room temperature, N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (172 mg, 0.61 mmol) and N-methylimidazole (236 mg, 2.87 mmol) were added to a solution of intermediate 204-4 (100 mg, 0.41 mmol) and intermediate 134-4 (94 mg, 0.41 mmol) in acetonitrile (2 mL). The reaction mixture was stirred at room temperature for 2 hours, then extracted 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 analyzed by preparative HPLC (Waters-Xbridge-C18-10µm-19). Purification was performed using a mobile phase of 10 mM FA (A: 10 mM FA; B: ACN, gradient: 10-60%, residence time: 10 min) at 250 mm to give compound 204 (2.36 mg, 0.01 mmol, 1.26% yield). MS m / z (ESI): 454.9 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) 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).

[0635] Example 42:

[0636] Synthesis of Compound 205

[0637]

[0638] At room temperature, intermediate 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 1,4-dioxane (2 mL) solution of intermediate 1102-2 (100 mg, 0.33 mmol). After purging the system three times with nitrogen, the reaction mixture was stirred at 100 °C for 10 hours. Water (10 mL) was added to the reaction mixture, followed by extraction 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. The residue was analyzed by preparative HPLC (Waters-Xbridge-C18-10µm-19). Purification was performed using a mobile phase of 10 mM NH4HCO3 (A: 10 mM NH4HCO3; B: ACN, gradient: 5-85%, residence time: 7 min) to give compound 205 (18.27 mg, 0.04 mmol, 11.61% yield). MS m / z (ESI): 472.9 [M+H] + ; 1 ¹H NMR (400 MHz, DMSO-6) δ d 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 = 1.6Hz, 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).

[0639] Example 43:

[0640] Synthesis of Compound 1088

[0641]

[0642] Step 1:

[0643] Under a nitrogen atmosphere, a solution of potassium tert-butoxide 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). After stirring the reaction mixture for 15 min, intermediate 1088-1 (10.0 g, 55.8 mmol) was added, and the mixture was heated to 50 °C and stirred for 16 h. The reaction mixture was cooled to room temperature, diluted with water (400 mL), and extracted with ethyl acetate (800 mL). The pH of the aqueous layer was adjusted to approximately 6.5 using 1.5 M HCl solution. The resulting solid was filtered, washed with water (1000 mL), then washed with acetone (1000 mL), and dried under vacuum. The solid was stirred in MTBE (1000 mL) for 12 h, filtered, and dried under vacuum to give a brown solid intermediate 1088-2 (4.6 g, 22.8 mmol, 40.8% yield).

[0644] Step 2:

[0645] Under a nitrogen atmosphere, a solution of intermediate 134-4 (50 mg, 0.25 mmol), N,N,N',N'-tetramethylchloromethamphexane 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. Then, intermediate 1088-2 (57 mg, 0.25 mmol) was added to the reaction mixture. 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 solid was washed with DMSO (2 mL). The filtrate was concentrated under reduced pressure, and the crude product was analyzed by preparative HPLC (Waters-Xbridge-C18-10um-19). Purification was performed using a mobile phase of 0.1% NH4HCO3 / H2O (B:CH3CN), with a gradient of 55% B - 85% B, and a Ret 8.5 min step, yielding a white solid compound 1088 (16 mg, 0.03 mmol, 15.64%). MS m / z (ESI): 413.9 [M+H] + ; 1 H NMR (400 MHz, DMSO-) d 6) 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).

[0646] Example 44:

[0647] Synthesis of Compound 208

[0648]

[0649] The mixture of intermediate 95-4 (80 mg, 0.35 mmol), intermediate 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 (1R,2R)-N,N-dimethyl-1,2-diaminocyclohexane (99 mg, 0.70 mmol) in 1,4-dioxane (1.5 mL) was purged three times with nitrogen, then heated to 95°C and stirred for 16 hours in a sealed tube. After the reaction mixture 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 give compound 208 as a white solid (1.87 mg, 0.004 mmol, 1.2% yield). MS m / z (ESI): 450.0 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) 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).

[0650] Example 45:

[0651] Synthesis of Compound 209

[0652]

[0653] Step 1:

[0654] Intermediate 204-1 (200 mg, 0.82 mmol), intermediate 1093-3 (630 mg, 2.45 mmol), potassium carbonate (340 mg, 2.46 mmol), and tetraphenylphosphine palladium (94 mg, 0.08 mmol) were dissolved in a mixed solution of water (1 mL) and 1,4-dioxane (10 mL). The reaction mixture was stirred at 90 °C under a nitrogen atmosphere for 18 hours. After the reaction was complete, the reaction mixture was filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give intermediate 209-1 (200 mg, 0.44 mmol, 54.17%) as a yellow solid.

[0655] Step 2:

[0656] A 10 mL aqueous solution containing intermediate 209-1 (300 mg, 1.33 mmol) and sodium hydroxide (320 mg, 8.00 mmol) 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 filter cake was washed with 10 mL of water and dried under vacuum to give intermediate 209-2 (84 mg, 0.34 mmol, 25.83%) as a yellow solid.

[0657] Step 3:

[0658] A solution of dimethylformamide (3 mL) containing intermediate 209-2 (100 mg, 0.41 mmol), N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (172 mg, 0.61 mmol), and N-methylimidazole (0.10 mL, 1.22 mmol) was stirred at 25 °C for 10 minutes. Then, intermediate 134-4 (200 mg, 0.87 mmol) was added, and stirring continued for 2 hours. After the reaction was complete, the reaction solution was filtered. The crude product was analyzed by preparative HPLC (Waters-Xbridge-C18-10µm-19). 250 mm; Mobile phase: A: 10 mM formic acid / water; B: acetonitrile; Flow rate: 25 m / s; Purification yielded 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).

[0659] Example 46:

[0660] Synthesis of Compound 210

[0661]

[0662] Step 1:

[0663] To a solution of intermediate 210-1 (400 mg, 2.33 mmol) in water (2 mL) and dioxane (20 mL), intermediate 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. The reaction mixture was stirred at 100 °C for 18 hours. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, 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 give intermediate 210-2 (900 mg, 1.86 mmol, 79.88%) as a black solid.

[0664] Step 2:

[0665] Lithium hydroxide (400 mg, 9.53 mmol) was added to a solution of intermediate 210-2 (800 mg, 1.65 mmol) in tetrahydrofuran (4 mL), water (45 mL), and methanol (4 mL). 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 extracted with ethyl acetate (20 mL) and then lyophilized to obtain the crude product intermediate 210-3, which was used directly in the next step.

[0666] Step 3:

[0667] To a 2 mL solution of intermediate 210-3 (500 mg, 0.44 mmol) in dimethyl sulfoxide, intermediate 134-4 (150 mg, 0.65 mmol), TCFH (184 mg, 0.66 mmol), and 1-methylimidazole (210.00 μL, 2.63 mmol) were added. The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the mixture was filtered and analyzed by HPLC (SunFire-C18-10µm-19). Purification was performed at a flow rate of 25 mL / min and a mobile phase of 10 mM NH4HCO3 / H2O (A: 10 mM NH4HCO3 / H2O; B: ACN) to give a white solid, compound 210 (2.1 mg, 0.00 mmol, 1.09%). MS m / z (ESI): 440.2 [M+H] + ; 1 H NMR (400MHz, DMSO- d 6) 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).

[0668] Example 47:

[0669] Synthesis of Compound 211

[0670]

[0671] Step 1:

[0672] At room temperature, ammonium chloride (53.2 g, 994.19 mmol) and iron powder (27.3 g, 55.84 mmol) were added to a methanol (250 mL) and water (25 mL) solution of intermediate 211-1 (25.0 g, 99.42 mmol). The mixture was purged with nitrogen three times and stirred at 80 °C for 5 hours. The reaction mixture was filtered, and water (200 mL) was added to the filtrate. The filtrate was extracted with ethyl acetate (150 mL). The combined organic layers were washed with saturated 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 give intermediate 211-2 (20.1 g, 90.75 mmol, 91.28% yield) as a white solid.

[0673] Step 2:

[0674] 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 intermediate 211-2 (19.0 g, 85.79 mmol) with stirring. The reaction mixture was purged with nitrogen three times and stirred at 65 °C for 2 hours. The reaction mixture was cooled to 0 °C, and isoamyl nitrite (10.05 g, 85.79 mmol) and 1,4,7,10,13,16-hexaoxane (2.72 g, 10.29 mmol) were added. The mixture was stirred at 65 °C for 18 hours. The reaction mixture was cooled to room temperature, and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (150 mL). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a yellow solid compound, which was washed with (petroleum ether / dichloromethane = 15 / 1, 200 mL) to give a white solid intermediate 211-3 (14.0 g, 60.22 mmol, yield 70.20%).

[0675] Step 3:

[0676] At room temperature, sodium iodide (193 mg, 1.29 mmol) and potassium carbonate (445 mg, 3.23 mmol) were added to a solution of intermediates 211-3 (300 mg, 1.29 mmol) and 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 mixture was diluted with water (20 mL) and extracted with ethyl acetate (15 mL). The combined organic layers were washed with saturated 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 give intermediate 211-5 (150 mg, 0.40 mmol, yield 30.94%) as a white solid.

[0677] Step 4:

[0678] Intermediate 211-5 (150 mg, 0.40 mmol) was added to a solution of hydrogen chloride and 1,4-dioxane (4.0 M, 5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, diluted with water, and the pH was adjusted to 8 with saturated sodium bicarbonate solution, followed by extraction 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 to give intermediate 211-6 (130 mg, 0.47 mmol) as a yellow solid, which was used directly in the next step.

[0679] Step 5:

[0680] Potassium carbonate (195 mg, 1.41 mmol) was added to a 5 mL solution of intermediate 211-6 (130 mg, 0.47 mmol) in dimethyl sulfoxide. The reaction mixture was purged with nitrogen three times and stirred at 120 °C for 16 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 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 silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give intermediate 211-7 (60 mg, 0.25 mmol, 53.19% yield) as a white solid.

[0681] Step 6:

[0682] At room temperature, a mixture of intermediate 211-7 (60 mg, 0.25 mmol), intermediate 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 under a nitrogen atmosphere for 16 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was analyzed by preparative HPLC (Waters-Xbridge-C18-10µm-19). Purification was performed using a mobile phase of 250 mg / mL (A: 10 mM NH₄HCO₃; B: ACN, gradient: 40-50%, retention time: 8.5 min) to give compound 211 as a white solid (1.79 mg, 0.004 mmol, 1.55% yield). MS m / z (ESI): 459.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) 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).

[0683] Example 48:

[0684] Synthesis of Compound 919

[0685]

[0686] Step 1:

[0687] KMHDMS (342 mL) was added dropwise to a THF (500 mL) solution of intermediate 919-1 (25 g, 114 mmol) and intermediate 123-1a (36.5 g, 1.71 mol) under a nitrogen atmosphere at -78 °C. The reaction mixture was reacted at -78 °C for 1 hour, then heated to room temperature for 2 hours. The reaction was quenched with a saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the combined organic layers were washed with saturated brine (1000 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the crude product, which was then purified by reversed-phase column chromatography (acetonitrile / water (trifluoroacetic acid 0.1%) = 35%) to give a yellow solid intermediate 919-2 (1.1 g, 2.65 mmol, yield 2.33%).

[0688] Step 2:

[0689] Sodium borohydride (261 mg, 7.95 mmol) was added in portions to a solution of intermediate 919-2 (110 mg, 2.65 mmol) and CaCl2 (552 mg, 10.6 mmol) in THF (10 mL) / EtOH (5 mL) under a nitrogen atmosphere at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h, then heated to room temperature and stirred for 2 h. The reaction was quenched with water and extracted with ethyl acetate (50 mL). The combined organic layers were washed with saturated brine (70 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give intermediate 919-3 (495 mg, 1.28 mmol, yield 48.03%) as a white solid.

[0690] Step 3:

[0691] Under a hydrogen atmosphere, 10% Pd / C (50 mg) was added to a methanol (5 mL) solution of intermediate 919-3 (495 mg, 1.28 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and concentrated to give a white oily intermediate 919-4 (440 mg, 1.25 mmol, yield 97.46%).

[0692] Step 4:

[0693] Amyl nitrite (177 mg, 1.51 mmol) was added dropwise to a MeCN (20 mL) solution of intermediate 919-4 (440 mg, 1.25 mmol) and CuI (481 mg, 2.50 mmol). The reaction mixture was reacted at room temperature for 0.5 h, then heated to 80 °C for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a colorless oily intermediate 919-5 (230 mg, 0.68 mmol, yield 53.68%).

[0694] Step 5:

[0695] HCl and 1,4-dioxane (3 mL) were added to a solution of intermediate 919-5 (495 mg, 1.28 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give intermediate 919-6 (150 mg, 0.63 mmol, 92.50% yield) as a white solid.

[0696] Step 6:

[0697] TCFH (121 mg, 0.43 mmol) and N-methylimidazole (59 mg, 0.72 mmol) were added to a 2 mL solution of intermediates 919-6 (70 mg, 0.29 mmol) and 84-11 (84 mg, 0.35 mmol) in DMF. The reaction mixture was reacted at room temperature for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by preparative TLC (dichloromethane / methanol = 10 / 1) followed by preparative HPLC (column: Welch ultimate XB-NH2250). 50 Purification was performed at 10 μm in a mobile phase of [heptane-EtOH (0.1% NH3H:O)]; B% 10%-10%, for 10 min, yielding compound 919 (27.28 mg, 0.06 mmol, yield 20.37%). MS m / z (ESI): 464.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d6) δ8.53 – 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).

[0698] Example 49:

[0699] Synthesis of Compound 213

[0700]

[0701] Step 1:

[0702] To a solution of dimethylformamide (2 mL) containing intermediate 213-1 (48 mg, 0.15 mmol) and triethylamine (0.06 mL, 0.44 mmol), iodomethane (0.05 mL, 0.73 mmol) was added. The reaction mixture was stirred at 50 °C for 3 hours. After the reaction was complete, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with saturated 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 give compound 5 (60 mg, 0.15 mmol, yield 100.70%) as a white solid.

[0703] Step 2:

[0704] A solution of intermediate 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 a new spot appeared on the plate. The reaction solution was concentrated to give crude intermediate 213-3 (60 mg, 0.17 mmol, 96.10%) as a red solid.

[0705] Step 3:

[0706] A solution of dimethyl sulfoxide (1 mL) containing intermediate 84-11 (40 mg, 0.17 mmol), N,N,N',N'-tetramethylchloromethanemid hexafluorophosphate (70 mg, 0.25 mmol), and N-methylimidazole (0.05 mL, 0.66 mmol) was stirred at 25 °C for 10 minutes, followed by the addition of intermediate 213-3 (40.00 mg, 0.17 mmol). The reaction mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the reaction solution was filtered, and the crude product was analyzed by HPLC (Waters-Xbridge-C18-10µm-19). 250 mm; Mobile phase: A: 10 mM ammonium bicarbonate / water; B: acetonitrile; Flow rate: 25 m / s; Purification yielded compound 213 (10.68 mg, 0.02 mmol, 13.86%) as a white solid. MS m / z (ESI): = 467.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) 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).

[0707] Example 50:

[0708] Synthesis of Compound 1041

[0709]

[0710] Step 1:

[0711] At 0 °C, a tetrahydrofuran solution of lithium aluminum hydride (2.5 N, 0.91 mL, 2.28 mmol) was added dropwise to a 50 mL solution of tetrahydrofuran containing intermediate 123-3 (780 mg, 2.28 mmol). The reaction mixture was stirred at 0 °C for 2 hours. After the reaction was complete, the reaction mixture 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 give intermediate 213-1 (140 mg, 0.43 mmol, yield 18.71%) as a white solid.

[0712] Step 2:

[0713] A solution of intermediate 213-1 (120 mg, 0.37 mmol) in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) was stirred at 25 °C for 2 hours. The reaction was confirmed to be complete by TLC (dichloromethane:methanol = 20:1) with the presence of a new spot on the plate. The reaction solution was concentrated to give crude intermediate 1041-1 (80 mg, 0.35 mmol, yield 95.91%) as a red solid.

[0714] Step 3:

[0715] A solution of intermediate 84-11 (100 mg, 0.41 mmol), N,N,N',N'-tetramethylchloromethanemid 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, followed by the addition of intermediate 1041-1 (100 mg, 0.44 mmol). The reaction 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 analyzed by HPLC (Waters-Xbridge-C18-10µm-19). 250 mm; Mobile phase: A: 10 mM ammonium bicarbonate / water; B: acetonitrile; Flow rate: 25 m / s. Purification yielded compound 1041 (34.1 mg, 0.07 mmol, yield 18.12%) as a white solid. MS m / z (ESI): = 453.1 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) 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).

[0716] Example 51:

[0717] Synthesis of Compound 215

[0718]

[0719] Step 1:

[0720] To a solution of intermediate 215-1 (2 g, 7.49 mmol) and intermediate 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 reaction mixture was reacted at 100 °C under a nitrogen atmosphere for 3 h. The reaction solution was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give intermediate 215-2 (1.1 g, 4.97 mmol, yield 66.41%) as a yellow solid.

[0721] Step 2:

[0722] KMHDMS (7.2 mL) was added dropwise to a THF (50 mL) solution of intermediate 215-2 (1 g, 2.4 mmol) and intermediate 123-1a (1.03 g, 4.8 mmol) under a nitrogen atmosphere at -78 °C. The reaction mixture was reacted at -78 °C for 1 hour, then at room temperature for another 2 hours. The reaction was quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The combined organic layers were washed with saturated brine (1000 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by silica gel column chromatography (SiO2, PE / EA = 3 / 1) to obtain the crude product, which was then purified by liquid chromatography (MeCN / H2O (TFA 0.1%) = 35%) to give a yellow solid intermediate 215-3 (143 mg, 0.36 mmol, yield 15.0%).

[0723] Step 3:

[0724] Sodium borohydride (242.55 mg, 6.41 mmol) was added in portions to a THF (10 mL) / EtOH (5 mL) solution of intermediate 215-3 (890 mg, 2.14 mmol) and CaCl2 (948.75 mg, 8.55 mmol) under a nitrogen atmosphere at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 hours, then heated to room temperature and stirred for another 2 hours. The reaction was quenched with water and extracted with ethyl acetate (50 mL). The combined organic layers were washed with saturated brine (70 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by column chromatography (PE / EA = 1 / 4) to give intermediate 215-4 (440 mg, 1.13 mmol, 53.0% yield) as a white solid.

[0725] Step 4:

[0726] Under a hydrogen atmosphere, Pd / C (50 mg) was added to a methanol (5 mL) solution of intermediate 215-4 (440 mg, 1.13 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and concentrated to give a white oily intermediate 215-5 (348 mg, 0.97 mmol, yield 86.0%).

[0727] Step 5:

[0728] Amyl nitrite (133 mg, 1.14 mmol) was added dropwise to a MeCN (20 mL) solution of intermediate 215-5 (348 mg, 0.97 mmol) and CuI (361 mg, 1.9 mmol). The reaction mixture was reacted at room temperature for 0.5 h, then at 80 °C for 16 h. The reaction solution was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by silica gel column chromatography (SiO2, PE / EA = 1 / 1) to give a colorless oily intermediate 215-6 (110 mg, 0.32 mmol, yield 33.97%).

[0729] Step 6:

[0730] A solution of 1,4-dioxane (3 mg) in HCl was added to a 5 mL solution of intermediate 215-6 (110 mg, 0.32 mmol) in dichloromethane. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to give intermediate 215-7 (70 mg, 0.29 mmol, 90.62% yield) as a white solid.

[0731] Step 7:

[0732] TCFH (121 mg, 0.43 mmol) and N-methylimidazole (59 mg, 0.72 mmol) were added to a DMF (2 mL) solution of intermediates 215-7 (70 mg, 0.29 mmol) and 84-11 (84 mg, 0.29 mmol). The reaction mixture was reacted at room temperature for 16 minutes. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by preparative TLC (dichloromethane / methanol = 10 / 1) followed by preparative HPLC (column: Welch ultimate XB-NH2 250). 50 Purification was performed at 10 μm in a mobile phase of [heptane-EtOH (0.1% NH3H:O)]; B% 10%-10%, for 10 min, yielding compound 215 (6.5 mg, 0.01 mmol, yield 4.81%). MS m / z (ESI): 466.0 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ8.52 (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).

[0733] Example 52:

[0734] Synthesis of Compound 216

[0735]

[0736] Step 1:

[0737] Under a nitrogen atmosphere and at -78°C, potassium bis(trimethylsilyl)amino (1.0 M, 165 mL, 165 mmol) was added dropwise to a tetrahydrofuran (100 mL) solution of intermediate 216-1 (20.0 g, 109.76 mmol) and intermediate 216-2 (19.4 g, 110 mmol). 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 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 silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 4) to give a yellow oily intermediate 216-3 (3.22 g, 9.49 mmol, 8.65% yield).

[0738] Step 2:

[0739] Under a nitrogen atmosphere and at -78°C, a toluene solution (20 mL) of intermediate 216-3 (3.22 g, 9.49 mmol) was added to a solution of diisobutylaluminum hydride (1.0 M, 28 mL, 28 mmol). The reaction 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 give a yellow solid intermediate 216-4 (1.5 g, 4.38 mmol, yield 46.18%).

[0740] Step 3:

[0741] Sodium borohydride (0.25 g, 6.57 mmol) was added to a methanol (20 mL) solution of intermediate 216-4 (1.5 g, 4.38 mmol) at 0 °C, and the reaction 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 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 silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 4) to give a yellow oily intermediate 216-5 (150 mg, 0.44 mmol, yield 9.94%).

[0742] Step 4:

[0743] Ammonium chloride (235 mg, 4.4 mmol) and iron powder (123 mg, 2.2 mmol) were added to a solution of intermediate 216-5 (150 mg, 0.44 mmol) in methanol (1.5 mL), tetrahydrofuran (1.5 mL), and water (1.5 mL). The reaction mixture was stirred at 80 °C for 1 hour. After the reaction was complete, the reaction mixture was filtered. The filtrate was diluted with water (30 mL) and extracted with ethyl acetate (20 mL). The 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 silica gel column chromatography (methanol / dichloromethane = 1 / 10) to give intermediate 216-6 (140 mg, 0.23 mmol, 100% yield) as a white solid.

[0744] Step 5:

[0745] At 0°C, cuprous iodide (170 mg, 0.89 mmol) and amyl nitrite (62 mg, 0.53 mmol) were added to a 5 mL solution of intermediate 216-6 (140 mg, 0.23 mmol) in acetonitrile. The reaction mixture was stirred at 0°C for 1 hour, then heated to 80°C and stirred for another 2 hours. After the reaction was complete, the mixture was filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) to give a pale yellow oily intermediate 216-7 (17 mg, 0.06 mmol, yield 12.84%).

[0746] Step 6:

[0747] Add 1 mL of trifluoroacetic acid to a 3 mL solution of intermediate 216-7 (17 mg, 0.06 mmol) in dichloromethane. Stir the reaction mixture at room temperature for 30 minutes. After the reaction is complete, concentrate the reaction mixture under reduced pressure to obtain crude intermediate 216-8 (10 mg, crude), which can be used directly in the next step of the reaction without further purification.

[0748] Step 7:

[0749] To a solution of intermediates 216-8 (10 mg, 0.05 mmol) and 84-11 (13 mg, 0.06 mmol) in N,N-dimethylformamide (1 mL), N-methylimidazole (25 mg, 0.3 mmol) and N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (21 mg, 0.08 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture 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 give compound 216 (13.53 mg, 0.03 mmol, yield 63.31%) as a white solid. MS m / z (ESI): 422.0 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) 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).

[0750] Example 53:

[0751] Synthesis of Compound 217

[0752]

[0753] Step 1:

[0754] A solution of dimethylformamide ("DMF") (1.5 mL) containing intermediate 217-1 (50 mg, 0.19 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea 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 the mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the reaction solution was filtered. The crude product was separated by high-performance liquid chromatography-mass spectrometry (Waters-Xbridge-C18-10µm-19). 250 mm; Mobile phase: A: 10 mM ammonium bicarbonate / water; B: acetonitrile; Flow rate: 25 m / s; Compound 217 (35.35 mg, 0.07 mmol, 34.78%) was obtained as a white solid. MS m / z (ESI): = 530.9 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ7.89 (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).

[0755] Synthesis of intermediate 217-1

[0756]

[0757] Step 1:

[0758] To a dioxane (60 mL) solution of intermediate 217-2 (3.00 g, 11.34 mmol), bis-pinacolborate (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 hot through diatomaceous earth and washed with ethyl acetate. The solvent was removed under reduced pressure to obtain the crude intermediate 217-3, which was used directly in the next step.

[0759] Step 2:

[0760] Intermediate 217-3 (1.92 g, 6.117 mmol), tetraphenylphosphine palladium (0.48 g, 0.41 mmol), and potassium carbonate (1.71 g, 12.34 mmol) were added to a solution of intermediate 217-4 (1 g, 4.11 mmol) in dioxane (60 mL) and water (4 mL). The mixture was stirred at 80 °C for 18 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth while hot 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 give intermediate 203-1 (1.1 g, 3.95 mmol, yield 95.98%) as a black solid.

[0761] Step 3:

[0762] 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 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 lyophilized to give crude intermediate 217-1, which was used directly in subsequent synthetic steps.

[0763] Example 54:

[0764] Synthesis of Compound 218

[0765]

[0766] HATU (74 mg, 0.2 mmol) and DIPEA (34 mg, 0.26 mmol) were added 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). The reaction mixture was stirred at room temperature for 1 hour until the reaction was complete. The mixture was then 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 give 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- d 6) 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).

[0767] Example 55:

[0768] Synthesis of Compound 219

[0769]

[0770] HATU (74 mg, 0.2 mmol) and DIPEA (34 mg, 0.26 mmol) were added 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). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture 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 give compound 219 as a white solid (18.19 mg, 0.04 mmol, 30.48% yield). 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).

[0771] Example 56:

[0772] Synthesis of Compound 220

[0773]

[0774] At room temperature, N-methylimidazole (82 mg, 1.01 mmol) and N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (113 mg, 0.40 mmol) were added to a 2 mL solution of intermediate 162-5 (50 mg, 0.20 mmol) and compound intermediate 901-2 (63 mg, 0.26 mmol) in dimethyl sulfoxide. After stirring at room temperature for 16 hours, the reaction solution was concentrated under reduced pressure. The crude product was analyzed by preparative HPLC (Waters-Xbridge-C18-10µm-19). Purification was performed using a mobile phase of 250 mM NH4HCO3 (A: 10 mM NH4HCO3; B: ACN, gradient: 5-70%, retention time: 8.1 min) to give compound 220 (12 mg, 0.03 mmol, yield 12.58%). MS m / z (ESI): 473.9 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ7.94 - 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).

[0775] Example 57:

[0776] Synthesis of Compound 221

[0777]

[0778] A solution of dimethylformamide (1 mL) containing intermediate 162-5 (50 mg, 0.20 mmol), HATU (120 mg, 0.32 mmol), and diisopropylethylamine (0.18 mL, 1.01 mmol) was stirred at 25 °C for 10 minutes. Intermediate 1038-2 (100 mg, 0.35 mmol) was added, and the reaction mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the reaction mixture was filtered and analyzed by HPLC-MS (Waters-Xbridge-C18-10µm-19). 250 mm; Mobile phase: A: 10 mM formic acid / water; B: acetonitrile; Flow rate: 25 m / s; Purification yielded 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- d 6) 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).

[0779] Example 58:

[0780] Synthesis of Compound 222

[0781]

[0782] Step 1:

[0783] 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 reaction mixture was stirred at 75 °C for 18 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 3 with dilute hydrochloric acid (2 M), and a solid was formed in the reaction solution. The solution was filtered, the filter cake was washed with 100 mL of water, and dried under vacuum to give crude compound 222-2, which was used directly in the next step.

[0784] Step 2:

[0785] A solution of N,N-dimethylformamide (100 mL) containing intermediate 222-2 (8 g, 29.84 mmol) and CDI (9.68 g, 59.69 mmol) was prepared at 65 °C. o The mixture was stirred at C for 2 hours. After cooling the reaction solution to room temperature, it was added to 1500 mL of ammonia water (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 filter cake was washed with 200 mL of water and dried under vacuum to obtain intermediate 222-3.

[0786] Step 3:

[0787] Cyanuric chloride (3.3 g, 17.90 mmol) was added to a solution of intermediate 222-3 (8 g, 29.95 mmol) in N,N-dimethylformamide (100 mL). 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 filter cake was washed with water (200 mL) and dried under vacuum to obtain intermediate 222-4.

[0788] Step 4:

[0789] A solution of phosphorus oxychloride (70 mL) containing intermediate 222-4 (7.5 g, 30.11 mmol) was stirred at 100 °C for 18 hours. After the reaction was complete, the reaction mixture was concentrated under vacuum and then water (100 mL) was added. The pH was adjusted to 9 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (100 mL). The combined organic layers were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. Purification was performed by column chromatography (ethyl acetate: petroleum ether = 1 / 100 to 1 / 10) to give a white solid intermediate 222-5 (7.5 g, 28.04 mmol, 93.11%).

[0790] Step 5:

[0791] Hydrazine hydrate (52 mL) was added to an ethanol (65 mL) solution of intermediate 222-5 (6.5 g, 24.30 mmol). The mixture was stirred at 80 °C for 0.5 h. After the reaction was complete, the reaction solution was filtered to give a white solid intermediate 222-6 (5.00 g, 19.00 mmol, 78.21%).

[0792] Step 6:

[0793] Intermediate 134-4 (65 mg, 0.28 mmol), triethylamine (80 μL, 0.58 mmol), and a Pd(dppf)Cl2 dichloromethane complex (16 mg, 0.02 mmol) were added to a 2 mL solution of intermediate 222-6 (50 mg, 0.19 mmol) in dimethyl sulfoxide. The mixture was stirred at 100 °C for 18 hours. After the reaction was complete, the reaction solution was filtered. The crude product was analyzed by preparative HPLC (Waters-Xbridge-C18-10µm-19). Purification was performed using a mobile phase of 10 mM NH4HCO3 (A: 10 mM NH4HCO3; B: ACN, gradient: 5-70%, retention time: 8.1 min) to give compound 222 (10.9 mg, 0.02 mmol, 11.82%) as a yellow solid. MS m / z (ESI) = 439.9 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) 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).

[0794] Example 59:

[0795] Synthesis of Compound 223

[0796]

[0797] Step 1:

[0798] To a solution of compound 223-1 (2 g, 5.77 mmol) and cuprous bromide (1.7 g, 11.85 mmol) in acetonitrile (20 mL), tert-butyl nitrite (1.1 mL, 9.17 mmol) was added. The reaction mixture was stirred at 80 °C for 4 hours. The reaction mixture was diluted with water (100 mL) and ammonia (2 mL) and extracted with ethyl acetate (50 mL). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (tetrahydrofuran: petroleum ether = 0-10%) to give a pale yellow colloidal intermediate 223-2 (1.28 g, 2.03 mmol, 35.11%, 65% purity).

[0799] Step 2:

[0800] Add Dys-Martin oxidant (1.1 g, 2.59 mmol) to a solution of intermediate 223-2 (1 g, 2.44 mmol) in dichloromethane (10 mL). Stir the reaction mixture at 25 °C for 12 hours. Dilute the reaction mixture with water (30 mL) and extract with ethyl acetate (20 mL). Wash the combined organic layers with saturated brine (30 mL), dry to anhydrous sodium sulfate, and concentrate to give a pale yellow solid intermediate 223-3 (1.59 g, 2.45 mmol, 100.66%), which was used directly in the next step.

[0801] Step 3:

[0802] Sodium hydride (0.43 g, 10.80 mmol, 60% purity) was added to a tetrahydrofuran (15 mL) solution of methyltriphenylphosphine bromide (4 g, 11.20 mmol). After stirring at 20 °C for 30 min, intermediate 223-3 (1.59 g, 2.45 mmol) was added. The reaction mixture was stirred at 60 °C for 6 h, quenched with saturated ammonium chloride solution (50 mL), and extracted with ethyl acetate (30 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-5%) to give a pale yellow oily intermediate 223-4 (500 mg, 1.23 mmol, 50.16%).

[0803] Step 4:

[0804] 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 mixture 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 saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-5%) to give a pale yellow oily intermediate 223-5 (200 mg, 0.31 mmol, 24.97%).

[0805] Step 5:

[0806] Trifluoroacetic acid (120 μL, 1.57 mmol) was added to a solution of intermediate 223-5 (50 mg, 0.15 mmol) in dichloromethane (0.5 mL). The reaction mixture was stirred at 20 °C for 2 hours. After concentration, a pale yellow oily intermediate 223-6 (34.61 mg, 0.15 mmol, 99.99%) was obtained.

[0807] Step 6:

[0808] A mixture 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 give compound 223 (2.8 mg, 0.01 mmol, 4.05%) as a white solid. MS m / z (ESI): 450.1 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ8.56 (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).

[0809] Synthesis of intermediate 223-7

[0810]

[0811] Isobutyl chloroformate (270 μL, 2.08 mmol) was added 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). The reaction mixture 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 saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give a light brown solid intermediate 223-7 (200 mg, 0.58 mmol, 28.30%, MS m / z (ESI): 343.2 [M+H]). + ; 1 H NMR (400 MHz, DMSO- d 6) 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).

[0812] Example 60:

[0813] Synthesis of Compound 224

[0814]

[0815] At room temperature, intermediates 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 mixture was stirred at room temperature for 3 hours and then filtered. The filtrate was extracted with ethyl acetate (1 mL) after adding water (3 mL). The organic layer was washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was analyzed by HPLC (Waters-Xbridge-C18-10µm-19). Purification was performed using a mobile phase of 250 nm (A: 10 mM NH4HCO3; B: ACN, gradient: 10-65%, retention time: 14 min) to give 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- d 6) 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).

[0816] Example 61:

[0817] Synthesis of Compound 225

[0818]

[0819] At room temperature, intermediates 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 mixture was stirred at room temperature for 3 hours and then filtered. The filtrate was extracted with ethyl acetate (1 mL) after adding water (3 mL). The organic layer was washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was analyzed by HPLC (Welch-Xtimate-C18-5μm-21.2). Purification was performed using a mobile phase of 10 mM NH4HCO3 (A: 10 mM NH4HCO3; B: ACN, gradient: 10-65%, retention time: 11.4 min) to give 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- d 6) 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).

[0820] Example 62:

[0821] Synthesis of Compound 228

[0822]

[0823] Step 1:

[0824] 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 dimethylformamide (10 mL). The reaction mixture was stirred at 50 °C for 18 hours. After the reaction was complete, the reaction mixture was added with water (30 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated brine (50 mL) and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give intermediate 228-2 (350 mg, 0.87 mmol, 99.74%) as a white solid.

[0825] Step 2:

[0826] A solution of dichloromethane (5 mL) and trifluoroacetic acid (2 mL) containing intermediate 228-2 (350 mg, 0.87 mmol) 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 oily substance, which was directly used in the next step.

[0827] Step 3:

[0828] The intermediate 137-4 (50 mg, 0.22 mmol), HATU (130 mg, 0.34 mmol), and... N,N -Diisopropylethylamine (0.19 mL, 1.09 mmol) N,N A 1 mL solution of dimethylformamide was stirred at 25 °C for 30 minutes. Intermediate 228-3 (70 mg, 0.23 mmol) was added, and the reaction mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the solution was filtered. The filtrate was analyzed by HPLC (Waters-Xbridge-C18-10µm-19). 250 mm; Mobile phase: A: 10 mM ammonium bicarbonate / water; B: acetonitrile; Flow rate: 25 m / s; Purification yielded compound 228 (8.52 mg, 0.02 mmol, 7.57%) as a white solid. MS m / z (ESI): 513.0 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) 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).

[0829] Example 63:

[0830] Synthesis of Compound 229

[0831]

[0832] Step 1:

[0833] The solution contained intermediate 123-3 (500 mg, 1.46 mmol) and sodium hydride (120 mg, 3.00 mmol). N,N Intermediate 229-1 (0.65 mL, 4.38 mmol) was added to a 10 mL solution of dimethylformamide. The reaction mixture was stirred at 50 °C for 18 hours. After the reaction was complete, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give intermediate 229-2 (489 mg, 1.04 mmol, 71.16%) as a colorless oil.

[0834] Step 2:

[0835] A solution of dichloromethane (5 mL) and trifluoroacetic acid (2.5 mL) containing intermediate 229-2 (200 mg, 0.43 mmol) 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 directly used in the next step.

[0836] Step 3:

[0837] A solution of dimethylformamide (1 mL) containing intermediate 229-3 (40 mg, 0.17 mmol), HATU (100 mg, 0.26 mmol), and diisopropylethylamine (0.15 mL, 0.87 mmol) 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 analyzed by HPLC (Waters-Xbridge-C18-10µm-19). 250 mm; Mobile phase: A: 10 mM formic acid / water; B: acetonitrile; Flow rate: 25 m / s; Purification yielded 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- d 6) 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).

[0838] Example 64:

[0839] Synthesis of Compound 230

[0840]

[0841] Step 1:

[0842] A solution of dimethylformamide (0.5 mL) containing intermediate 229-3 (40 mg, 0.17 mmol), HATU (100 mg, 0.26 mmol), and diisopropylethylamine (0.14 mL, 0.80 mmol) was stirred at 25 °C for 10 minutes. Intermediate 84-11 (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 analyzed by HPLC (Waters-Xbridge-C18-10µm-19). 250 mm; Mobile phase: A: 10 mM ammonium bicarbonate / water; B: acetonitrile; Flow rate: 25 m / s; Purification yielded 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- d 6) 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).

[0843] Example 65:

[0844] Synthesis of Compound 1042

[0845]

[0846] Step 1:

[0847] Under a nitrogen atmosphere and at 0 °C, DIAD (78 μL, 0.40 mmol) was added to a tetrahydrofuran (1.5 mL) solution of triphenylphosphine (103 mg, 0.39 mmol). Then, a tetrahydrofuran (1.5 mL) solution of compound 1042-1 (150 mg, 0.28 mmol) and thioacetic acid (28 μL, 0.39 mmol) was added dropwise to the reaction mixture. The mixture was stirred at 0 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate and petroleum ether = 0-10%) to give intermediate 1042-2 (90 mg, 0.17 mmol, 62.63%) as a pale yellow oil.

[0848] Step 2:

[0849] At 25°C and under a nitrogen atmosphere, an ammonia-ethanol solution (1.0 mL, 2.0 mol / L) was added to a methanol (20 mL) solution of intermediate 1042-2 (99 mg, 0.19 mmol). 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 give intermediate 1042-3 (932 mg, 0.07 mmol, 38.58%) as a pale yellow oil.

[0850] Step 3:

[0851] 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) under a nitrogen atmosphere at 25 °C. The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated to give crude intermediate 1042-4 (17 mg, 0.03 mmol, 98.98%) as a yellow oil. The crude product was used directly for the next step without further purification.

[0852] Step 4:

[0853] DIEA (11 mg, 0.09 mmol) was added to a DMSO (1.0 mL) solution of intermediate 84-11 (13 mg, 0.03 mmol) and HATU (33 mg, 0.09 mmol) under a nitrogen atmosphere at 25 °C. The mixture was stirred at 25 °C for half an hour. A DMSO (1.0 mL) solution of intermediate 1042-4 (17 mg, 0.03 mmol) was added to the reaction mixture, and stirring was continued at 25 °C for 1.5 hours. After the reaction was complete, water (20 mL) was added to the reaction mixture, and the mixture was filtered. The filter cake was purified by silica gel plate chromatography (CH2Cl2 / MeOH = 15 / 1) to give compound 1042 (4.44 mg, 0.01 mmol, 16.04%) as a white solid. MS m / z (ESI): 470.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) 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).

[0854] Example 66:

[0855] Synthesis of Compound 232

[0856]

[0857] Step 1:

[0858] Potassium carbonate (29.3 g, 74.9 mmol) and Pd(dppf)Cl2 (3.3 g, 3.74 mmol) were added 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). The reaction mixture was stirred at 100 °C under nitrogen for 3 hours. After the reaction was complete, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL). The combined organic layers were washed with saturated 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 give intermediate 232-2 (8.0 g, 36.20 mmol, 96% yield) as a yellow solid.

[0859] Step 2:

[0860] LiHMDS (3.0 M, 13 mL, 40.32 mmol) was added dropwise to a tetrahydrofuran (250 mL) solution of intermediate 232-2 (5.6 g, 13.44 mmol) and intermediate 123-1a (5.4 g, 13.44 mmol) under a nitrogen atmosphere at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour, then heated to room temperature and stirred for another 2 hours. The reaction was quenched with a saturated aqueous solution of ammonium chloride (100 mL) and extracted with ethyl acetate (100 mL). The combined organic layers were washed with saturated 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 give intermediate 232-3 (1.5 g, 3.6 mmol, 26.78% yield) as a yellow solid.

[0861] Step 3:

[0862] Sodium borohydride (121 mg, 3.20 mmol) was added to a solution of intermediate 232-3 (450 mg, 1.0 mmol), calcium chloride (474 ​​mg, 427 mmol) in tetrahydrofuran (10 mL) and ethanol (5 mL) under a nitrogen atmosphere at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 hours, then heated to room temperature and stirred for another 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (50 mL). The combined organic layers were washed with saturated 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 give intermediate 232-4 (220 mg, 0.56 mmol, 53.0% yield) as a white solid.

[0863] Step 4:

[0864] 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 reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and concentrated to give a white oily intermediate 232-5 (80 mg, 0.22 mmol, 95% yield).

[0865] Step 5:

[0866] Amyl nitrite (24 mg, 0.03 mmol) was added dropwise to a solution of intermediate 232-5 (50 mg, 0.14 mmol) and cuprous iodide (63 mg, 0.28 mmol) in acetonitrile (5 mL). The reaction mixture was stirred at room temperature for 0.5 hours, then heated to 80 °C and stirred for another 16 hours. The reaction mixture was diluted 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 and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a colorless oily intermediate 232-6 (30 mg, 0.09 mmol, 62% yield).

[0867] Step 6:

[0868] Trifluoroacetic acid (3 mL) was added to a solution of intermediate 232-6 (30 mg, 0.09 mmol) in dichloromethane (5 mL). After stirring the reaction mixture at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure to give intermediate 232-7 (20 mg, 0.08 mmol, 92% yield), a white solid.

[0869] Step 7:

[0870] TCFH (35 mg, 0.12 mmol) and N-methylimidazole (17 mg, 0.2 mmol) were added to a DMF (2 mL) solution of intermediate 232-7 (20 mg, 0.08 mmol) and intermediate 5a (20 mg, 0.08 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and analyzed by preparative HPLC (column: Welchultimate XB-NH2250). 50 Purification was performed at 10 μm in a mobile phase of [heptane-EtOH (0.1% NH3H:O)]; B% 10%-10%, for 10 min, yielding compound 232 (9.8 mg, 0.02 mmol, 26% yield). 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).

[0871] Example 67:

[0872] Synthesis of Compound 233

[0873]

[0874] Step 1:

[0875] 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 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 give intermediate 233-1 (100 mg, 0.15 mmol, 22.69% yield) as a white solid.

[0876] Step 2:

[0877] A solution of 2 mL of trifluoroacetic acid containing intermediate 233-1 (100 mg, 0.15 mmol) was stirred for 16 hours at room temperature and under a nitrogen atmosphere. 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 Purification was performed at 10 μm, mobile phase: [heptane-EtOH (0.1% FA)]; B% 10%-10%, 10 min, to give a white solid compound 233 (24.5 mg, 0.05 mmol, yield 37.69%). MS m / z (ESI): 447.2 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) 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).

[0878] Example 68:

[0879] Synthesis of Compound 234

[0880]

[0881] A solution of dimethyl sulfoxide (1 mL) containing intermediate 166-3 (110 mg, 0.42 mmol), HATU (240 mg, 0.63 mmol), and diisopropylethylamine (0.37 mL, 2.11 mmol) was stirred at 25 °C for 10 minutes. Intermediate 1038-2 (120.17 mg, 0.42 mmol) was then added. The reaction mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the solution was filtered and analyzed by HPLC-MS (Waters-Xbridge-C18-10µm-19). 250 mm; Mobile phase: A: 10 mM formic acid / water; B: acetonitrile; Flow rate: 25 m / s; Purification yielded 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- d 6) 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).

[0882] Example 69:

[0883] Synthesis of Compound 237

[0884]

[0885] 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 reaction mixture was stirred at room temperature for 0.5 hours. Intermediate 1045-7 (50 mg, 0.22 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature for another 2 hours. After the reaction was complete, the reaction mixture was filtered, and the filtrate was analyzed by preparative HPLC (column: Welch ultimate XB-NH2 250). 50 Purification was performed at 10 μm, mobile phase: [heptane-EtOH (0.1% FA)]; B% 10%-10%, 10 min, to give a white solid compound 237 (27.51 mg, 0.06 mmol, yield 30.74%). MS m / z (ESI): 472.0 [M+H] + ; 1 HNMR (400 MHz, DMSO- d 6) δ 8.40 (d, J = 7.6 Hz, 1H), 8.26 (s, 1H), 7.87 (d, J = 8.0Hz, 1H), 7.80 (d, J= 8.0 Hz, 1H), 7.75 (s, 1H), 7.37 (s, 2H), 7.31 (d, J = 12.4Hz, 1H), 5.15 (d, J = 6.4 Hz, 2H), 4.50 – 4.34 (m, 7H).

[0886] Example 70:

[0887] Synthesis of Compound 238

[0888]

[0889] Step 1:

[0890] 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 give intermediate 238-1 (21 mg, 0.05 mmol, 96.33%) as a white solid.

[0891] Step 2:

[0892] Under a nitrogen atmosphere, trifluoroacetic acid (0.5 mL, 6.53 mmol) was added to a 2.5 mL solution of intermediate 238-1 (21 mg, 0.06 mmol) in dichloromethane. The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain crude intermediate 238-2 (27 mg, 0.05 mmol, 97.31%) as a yellow oil. The crude product was used directly in the next step without further purification.

[0893] Step 3:

[0894] Under a nitrogen atmosphere, DIEA (10 mg, 0.08 mmol) was added to a DMSO (1.0 mL) solution of intermediate 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, followed by the addition of a DMSO (1.0 mL) solution of intermediate 238-2 (27 mg, 0.05 mmol). The mixture was stirred at 25 °C for one and a half hours. After the reaction was complete, the reaction solution was poured into water (20 mL) and filtered. The filter cake was purified by silica gel column chromatography (dichloromethane:dichloromethane and methanol = 0-10%) to give compound 238 (19.68 mg, 0.04 mmol, 69.61%) as a pale yellow solid. MS m / z (ESI): 500.9 [M+H] + ; 1 H NMR (500 MHz, DMSO- d 6) 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).

[0895] Example 71:

[0896] Synthesis of Compound 239

[0897]

[0898] Step 1:

[0899] 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 added sequentially to water (1 mL), followed by cuprous bromide (46 mg, 0.32 mmol). The mixture was stirred at 0 °C for 2 hours. After the reaction was complete, water (5 mL) was added to the reaction mixture. The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed with saturated 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 give intermediate 239-2 (6 mg, 0.03 mmol, 19.9%) as a white solid.

[0900] Step 2:

[0901] To a solution of intermediate 239-2 (60 mg, 0.32 mmol) in 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 saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel thin-layer chromatography (petroleum ether: ethyl acetate = 1:1) to give intermediate 239-3 (55 mg, 0.21 mmol, 66.83%) as a yellow solid.

[0902] Step 3:

[0903] 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 pH of the reaction solution was adjusted to 3 with 2M dilute hydrochloric acid aqueous solution to form crude intermediate 239-4 solid. The aqueous layer was extracted with ethyl acetate (20 mL) and then lyophilized to obtain crude intermediate 239-4. The crude intermediate 239-4 was combined and used directly in the next step.

[0904] Step 4:

[0905] Intermediate 134-4 (15 mg, 0.07 mmol), TCFH (18 mg, 0.06 mmol), and 1-methylimidazole (20 μL, 0.25 mmol) were added to a 1 mL solution of intermediate 239-4 (10 mg, 0.04 mmol) in dimethyl sulfoxide. The reaction mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction solution was filtered and analyzed by preparative HPLC (column: Welch ultimateXB-NH2 250). 50 Purification was performed at 10 μm in a mobile phase of [heptane-EtOH (0.1% NH3H:O)]; B% 10%-10%, 10 min, yielding 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- d 6) 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).

[0906] Example 72:

[0907] Synthesis of Compound 1044

[0908]

[0909] Step 1:

[0910] Under a nitrogen atmosphere, m-chloroperoxybenzoic 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, then the temperature was raised to 25°C and stirred for another 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 give intermediate 1044-1 (28 mg, 0.07 mmol, yield 64.06%) as a pale yellow solid.

[0911] Step 2:

[0912] 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) under a nitrogen atmosphere at 25 °C. The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give intermediate 1044-2 (26 mg, 0.07 mmol, 99.85% yield) as a yellow oil. No further purification was required for use in the next step.

[0913] Step 3:

[0914] Under a nitrogen atmosphere, N,N-diisopropylethylamine (14 mg, 0.11 mmol) was added to a solution of intermediate 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 h. Then, a solution of intermediate 1044-2 (26 mg, 0.07 mmol) in dimethyl sulfoxide (1.0 mL) was added to the reaction mixture, and the mixture was stirred at 25 °C for another 1.5 h. After the reaction was complete, the reaction mixture was poured into water (20 mL) and filtered. The filter cake was purified by Pre-TLC (CH2Cl2 / MeOH = 10 / 1) to give 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- d 6) 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).

[0915] Example 73:

[0916] Synthesis of Compound 242

[0917]

[0918] Step 1:

[0919] LDA (9.15 mL, 18.29 mmol) was added to a tetrahydrofuran (50 mL) solution of intermediate 242-1 (2500 mg, 15.24 mmol) at -78 °C. After stirring the mixture at -78 °C for 30 min, a tetrahydrofuran (10 mL) solution of ethyl cyanoformate (1.81 mL, 18.29 mmol) was added. The reaction mixture was stirred at -78 °C for 1 h under nitrogen. After the reaction was complete, it was quenched with a saturated ammonium chloride aqueous solution (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 the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give intermediate 242-2 (800 mg, 3.39 mmol, yield 22.23%) as a colorless liquid.

[0920] Step 2:

[0921] 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 to a solution of intermediate 242-2 (1200 mg, 5.08 mmol) in dioxane (24 mL) and water (4.8 mL). The mixture was stirred at 100 °C for 18 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and water (5 mL) and ethyl acetate (20 mL) were added, resulting in the precipitation of a large amount of solid. The solid was filtered and dried under reduced pressure to obtain crude intermediate 242-3, which was a brown solid.

[0922] Step 3:

[0923] A solution of phosphorus oxychloride (32 mL, 0.38 mmol) containing intermediate 242-3 (1700 mg, 6.53 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 reaction solution was extracted with ethyl acetate (50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give intermediate 242-4 (1200 mg, 4.31 mmol, yield 65.92%) as a red solid.

[0924] Step 4:

[0925] 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 mixture, 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, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give intermediate 242-5 (1000 mg, 1.85 mmol, yield 64.28%) as a yellow solid.

[0926] Step 5:

[0927] 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 pH of the reaction solution was adjusted to 6 with diluted hydrochloric acid (1 M). The reaction solution was concentrated under reduced pressure and then lyophilized to obtain crude intermediate 242-6, which was directly used in the next step.

[0928] Step 6:

[0929] Intermediate 134-4 (260 mg, 1.13 mmol), TCFH (320 mg, 1.14 mmol), and 1-methylimidazole (380 μL, 4.77 mmol) were added to a 10 mL solution of intermediate 242-6 (280 mg, 0.77 mmol) in dimethyl sulfoxide. The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, water (20 mL) was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed with saturated 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 give intermediate 242-7 (60 mg, 0.10 mmol, yield 13.58%) as a yellow liquid.

[0930] Step 7:

[0931] A solution of trifluoroacetic acid (1 mL, 13.07 mmol) containing intermediate 242-7 (60 mg, 0.10 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 analyzed by preparative HPLC (column: Welch Ultimate XB-NH2250). 50 Purification was performed at 10 μm in a mobile phase of [heptane-EtOH (0.1% NH3H:O)]; B% 10%-10%, for 10 min, yielding compound 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- d 6) 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).

[0932] Example 74:

[0933] Synthesis of Compound 243

[0934]

[0935] Step 1:

[0936] Nitric acid (3.3 mL, 78.4 mmol) was added dropwise to an acetic anhydride (80 mL) solution of intermediate 243-1 (10.0 g, 49 mmol) at -20 °C under a nitrogen atmosphere. 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 dropwise in ice water. The diluted reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated 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 give a yellow oily intermediate 243-2 (5.8 g, 23.29 mmol, 47% yield).

[0937] Step 2:

[0938] NaH (1.16 g, 46 mmol) was added to a DMF (50 mL) solution of intermediate 243-2 (5.8 g, 23 mmol) at 0 °C. The reaction 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 mixture, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with a saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with saturated 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 give intermediate 243-3 (3.2 g, 8.4 mmol, 36% yield) as a yellow solid.

[0939] Step 3:

[0940] 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 to a solution of intermediate 243-3 (1.6 g, 4.2 mmol) in dioxane (30 mL) and water (6 mL). The reaction mixture was reacted at 95 °C for 2 h under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with saturated 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 give intermediate 243-5 (423 mg, 1.04 mmol, 24% yield) as a white solid.

[0941] Step 4:

[0942] Pd / C (10%, 45 mg) was added to a methanol (10 mL) solution of intermediate 243-5 (450 mg, 1.11 mmol). The reaction mixture was stirred at room temperature under hydrogen atmosphere for 2 hours. After the reaction was complete, the reaction mixture was filtered, washed three times with methanol, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate = 100%) to give intermediate 243-6 (43 mg, 0.11 mmol, 10% yield) as a red solid.

[0943] Step 5:

[0944] Lithium hydroxide (111 mg, 0.27 mmol) was added to a methanol (5 mL) and water (0.5 mL) solution of intermediate 243-6 (100 mg, 0.27 mmol). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give a white solid crude intermediate 243-7 (100 mg, 0.13 mmol).

[0945] Step 6:

[0946] Intermediate 134-4 (63 mg, 0.27 mmol), TCFH (116 mg, 0.41 mmol), and N-methylimidazole (57 mg, 0.69 mmol) were added to a DMF (2 mL) solution of intermediate 243-7 (100 mg, 0.27 mmol). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was purified by C18 silica gel column chromatography (70% acetonitrile in 1% NH4HCO3 in H2O), and lyophilized to give a white solid intermediate 243-8 (20 mg, 0.03 mmol, yield 12%).

[0947] Step 7:

[0948] Trifluoroacetic acid (2 mL) was added to a solution of intermediate 243-8 (50 mg, 0.09 mmol) in dichloromethane (4 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain a crude product. Ammonia-methanol (5 mL) was added to the crude 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, slurried in methanol, and then slurried in acetonitrile to give a white solid compound 243 (21 mg, 0.056 mmol, yield 54%). MS m / z (ESI): 443.0 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) 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 = 1.6Hz, 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).

[0949] Synthesis of intermediate 243-4

[0950]

[0951] To a solution of intermediate 243-9 (3.0 g, 28 mmol) and pinacol diborate (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'-dipyridine (1.5 g, 2.6 mmol) were added. The reaction mixture was stirred at 50 °C for 1 hour under a nitrogen atmosphere. After the reaction was complete, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with saturated 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 give intermediate 243-4 (6.4 g, 27.46 mmol, 98% yield) 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).

[0952] Example 75:

[0953] Synthesis of Compound 245

[0954]

[0955] Step 1:

[0956] A solution of dimethylformamide (1 mL) containing intermediate 213-1 (200 mg, 0.61 mmol), ethyl bromoacetate (203.45 mg, 1.22 mmol), and potassium carbonate (252.54 mg, 1.83 mmol) was stirred at 50 °C for 18 hours. After the reaction was complete, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL). The combined organic layers were concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 8 / 1 / 1) to give intermediate 245-1 (100 mg, 0.24 mmol, 39.61%) as a white solid.

[0957] Step 2:

[0958] Sodium borohydride (40 mg, 1.06 mmol) was added to an ethanol (10 mL) solution of intermediate 245-1 (90 mg, 0.22 mmol). The reaction mixture was stirred at 25 °C for 18 hours. After the reaction was complete, water (2 mL) was added to the reaction mixture, and the mixture was 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 give intermediate 245-2 (80 mg, 0.21 mmol, 98.92%) as a white solid.

[0959] Step 3:

[0960] A solution of dichloromethane (1.5 mL) and trifluoroacetic acid (0.5 mL) containing intermediate 245-2 (90 mg, 0.24 mmol) 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, 94.69%) as a brown solid. This was used directly in the next step.

[0961] Step 4:

[0962] A solution of intermediate 84-11 (75 mg, 0.31 mmol), N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (110 mg, 0.39 mmol), and N-methylimidazole (0.07 mL, 0.84 mmol) in dimethyl sulfoxide (2 mL) was stirred at 25 °C for 10 minutes. Intermediate 245-3 (76 mg, 0.28 mmol) was then added to the reaction solution, and the mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the reaction solution was filtered and analyzed by HPLC-MS (Waters-Xbridge-C18-10µm-19). 250 mm; Mobile phase: A: 10 mM ammonium bicarbonate / water; B: acetonitrile; Flow rate: 25 m / s; Purification yielded compound 245 (5.44 mg, 0.01 mmol, yield 3.60%) as a white solid. MS m / z (ESI): 497.2 [M+H] + ; 1 H NMR (500 MHz, DMSO- d 6) δ8.52 (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).

[0963] Example 76:

[0964] Synthesis of Compound 247

[0965]

[0966] Step 1:

[0967] A solution of dimethylformamide (10 mL) containing 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) was stirred at 100 °C for 18 hours. After the reaction was complete, water (50 mL) was added to the reaction solution, and the mixture was 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 give intermediate 247-1 (100 mg, 0.17 mmol, yield 37.18%) as a colorless oil.

[0968] Step 2:

[0969] 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 (50 mg, 0.20 mmol, yield 83.89%) as a yellow solid, which was directly used in the next step.

[0970] Step 3:

[0971] A solution of dimethyl sulfoxide (2 mL) containing intermediate 84-11 (80 mg, 0.33 mmol), HATU (188 mg, 0.50 mmol), and diisopropylethylamine (0.29 mL, 1.65 mmol) was stirred at 25 °C for 10 minutes. Intermediate 247-2 (104 mg, 0.33 mmol) was then added to the reaction mixture, and the mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the reaction mixture was filtered and analyzed by preparative HPLC (Waters-Xbridge-C18-10µm-19). 250 mm; Mobile phase: A: 10 mM ammonium bicarbonate / water; B: acetonitrile; Flow rate: 25) Purification yielded 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- d 6) 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).

[0972] Example 77:

[0973] Synthesis of Compound 251

[0974]

[0975] Step 1:

[0976] 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 mixture was stirred at room temperature for 10 hours. After the reaction was complete, the mixture was diluted with water (300 mL), extracted with ethyl acetate (100 mL), the organic layer was washed with saturated 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 give intermediates 251-2a and 251-2b (8 g, 27.67 mmol, yield 56.72%) as colorless solids.

[0977] Step 2:

[0978] At room temperature, intermediate 194-2 (1.34 g, 4.84 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (0.23 g, 0.48 mmol), methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-tri-isopropyl-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 with stirring to a solution of 1,4-dioxane (15 mL) of intermediates 251-2a and 251-2b (1.4 g, 4.84 mmol). The mixture was purged with nitrogen three times and then refluxed at 100 °C for 10 hours. After the reaction was complete, the reaction solution was cooled to room temperature and then filtered. The filtrate was diluted with water (30 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with saturated 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 give intermediates 251-3a and 251-3b as white solids (800 mg, 2.44 mmol, yield 50.47%).

[0979] Step 3:

[0980] At room temperature, p-toluenesulfonic acid (0.20 g, 1.16 mmol) was added to a 40 mL ethanol solution of intermediates 251-3a and 251-3b (3.80 g, 11.61 mmol) with stirring. The reaction mixture was refluxed at 80 °C for 3 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated under reduced pressure. The concentrate was slurryed in acetonitrile (30 mL) to give intermediate 251-4 (2.00 g, 8.22 mmol, 70.83% yield), which was a gray solid.

[0981] Step 4:

[0982] At room temperature, N,N-diisopropylethylamine (1.59 g, 12.33 mmol) and N-methylmorpholine (0.10 g, 1.03 mmol) were added sequentially to a 6 mL acetonitrile solution of intermediate 251-4 (0.50 mg, 2.06 mmol) with stirring. After purging the mixture three times with nitrogen, phosphorus oxychloride (1.23 g, 8.02 mmol) was added dropwise under ice bath conditions. The reaction mixture was stirred at room temperature for 30 minutes, then heated to 60 °C and stirred for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 25 / 1) to give intermediate 251-5 (200 mg, 0.76 mmol, 37.18% yield) as a yellow solid.

[0983] Step 5:

[0984] 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 2 mL solution of intermediate 251-5 (200 mg, 0.76 mmol) in DMF with stirring. The reaction mixture was purged with nitrogen three times and stirred at 80 °C for 3 hours. After the reaction was complete, the reaction mixture 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 saturated 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 give a white solid intermediate 251-6a (50 mg, 0.12 mmol, 16.16% yield) and intermediate 251-6b (150 mg, 0.37 mmol, 48.75% yield).

[0985] Step 6:

[0986] At room temperature, a solution of dioxane hydrochloride containing intermediate 251-6a (50 mg, 0.12 mmol) was stirred for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give intermediate 251-7 (35 mg, 0.11 mmol, yield 93.0%).

[0987] Step 7:

[0988] A 0.5 mL solution of DMSO containing intermediate 251-7 (35 mg, 0.11 mmol) and potassium carbonate (95 mg, 0.69 mmol) was stirred at 120 °C for 4 hours. The reaction mixture was filtered after cooling to room temperature. The filtrate was diluted with 10 mL of water and extracted with 5 mL of dichloromethane. The organic layer was washed with 10 mL of saturated brine, 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 give intermediate 251-8 (10 mg, 0.04 mmol, 32.45% yield) as a white solid.

[0989] Step 8:

[0990] Intermediate 251-8 (10 mg, 0.04 mmol) and lithium hydroxide (6.26 mg, 0.15 mmol) were added to a methanol (0.5 mL) / water (0.1 mL) mixture at room temperature. The reaction mixture was stirred at 50 °C for 10 hours. After concentration under reduced pressure and drying, intermediate 251-9 (9 mg, 0.04 mmol, yield 94.97%) was obtained.

[0991] Step 9:

[0992] At room temperature, N-methylimidazole (17 mg, 0.21 mmol) and N,N,N',N'-tetramethylchloroformamide hexafluorophosphate (14 mg, 0.05 mmol) were added to a solution of intermediate 251-9 (9 mg, 0.04 mmol) and intermediate 134-4 (16 mg, 0.07 mmol) in N,N-dimethylformamide (1 mL). The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The crude product was analyzed by preparative HPLC (Waters-Xbridge-C18-10µm-19). Purification was performed using a mobile phase of 250 mg / z (A: 10 mM NH4HCO3; B: ACN, gradient: 30-40%, retention time: 10.5 min) to give 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).

[0993] Example 78:

[0994] Synthesis of Compound 253

[0995]

[0996] At room temperature, intermediate 162-5 (220 mg, 0.89 mmol), N-methylimidazole (304 mg, 3.71 mmol), and N,N,N',N'-tetramethylchloroformamide 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 mixture was stirred at 50 °C for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was subjected to HPLC analysis on a C18 silica gel column (column: Welch ultimate XB-NH2 250). 50 Purification was performed at 10 μm, mobile phase: [heptane-EtOH (0.1% HCOOH)]; B% 10%-10%, 10 min, to give a white solid compound 253 (30 mg, 0.06 mmol, yield 8.32%). MS m / z (ESI): 487.2 [M+H] + ; 1 H NMR (400MHz, DMSO- d 6) 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).

[0997] Example 79:

[0998] Synthesis of Compound 254

[0999]

[1000] At room temperature, intermediate 162-5 (86 mg, 0.35 mmol), N-methylimidazole (53 mg, 0.65 mmol), and N,N,N',N'-tetramethylchloroformamide 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 mixture was stirred at 50 °C for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was subjected to HPLC analysis on a C18 silica gel column (column: Welch Ultimate XB-NH2250). 50 Purification was performed at 10 μm, mobile phase: [heptane-EtOH (0.1% HCOOH)]; B% 10%-10%, 10 min, to give a white solid compound 254 (30 mg, 0.05 mmol, yield 25.06%). MS m / z (ESI): 555.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) 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).

[1001] Example 80:

[1002] Synthesis of Compound 257

[1003]

[1004] Step 1:

[1005] At room temperature, 1-methyl-4-piperidinol (252 mg, 2.19 mmol) and cyanomethylenetri-n-butylphosphine (564 mg, 2.34 mmol) were added to a 6 mL solution of intermediate 123-3 (500 mg, 1.46 mmol) in toluene under stirring. The reaction mixture was purged with nitrogen three times and stirred at 100 °C for 12 hours. After the reaction was complete, the mixture 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 give a yellow oily compound 257-1 (350 mg, 0.80 mmol, yield 54.52%).

[1006] Step 2:

[1007] At room temperature, a solution of dioxane hydrochloride (2 mL) containing intermediate 257-1 (150 mg, 0.34 mmol) was stirred for 1 hour and then concentrated under reduced pressure to give intermediate 257-2 (100 mg, 0.29 mmol, yield 86.34%).

[1008] Step 3:

[1009] At room temperature, N,N-diisopropylethylamine (156 mg, 1.21 mmol) and HATU (230 mg, 0.60 mmol) were added to a solution of intermediate 257-2 (100 mg, 0.40 mmol) and intermediate 162-5 (137 mg, 0.40 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The crude product was analyzed by preparative HPLC (Waters-Xbridge-C18-10µm-19). Purification was performed using a mobile phase of 10 mM NH4HCO3 (A: 10 mM NH4HCO3; B: ACN, gradient: 26-56%, retention time: 11 min) to give compound 257 (13.66 mg, 0.02 mmol, yield 5.95%). MS m / z (ESI): 285.6 [1 / 2 M + H2] + ; 1 H 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)

[1010] Example 81:

[1011] Synthesis of Compound 258

[1012]

[1013] Step 1:

[1014] Intermediate 123-3 (400 mg, 1.17 mmol) was added to acetonitrile (5 mL) at room temperature and stirred until dissolved. After purging the system three times with nitrogen, sodium hydride (36 mg, 1.17 mmol) was added. The reaction mixture was stirred at room temperature for 10 hours, and then bromoacetonitrile (144 mg, 1.2 mmol) was added. The reaction mixture was stirred at room temperature for 10 hours, and then water (10 mL) was added, followed by extraction with ethyl acetate (5 mL). The organic layer was washed with saturated 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 give colorless liquid intermediate 258-1 (250 mg, 0.66 mmol, yield 56.10%).

[1015] Step 2:

[1016] At room temperature, intermediate 258-1 (100 mg, 0.26 mmol) was added to a 100 mL single-necked flask, followed by the addition of dichloromethane (1 mL) and stirring until dissolved. Then, trifluoroacetic acid (0.25 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure to give a colorless liquid intermediate 258-2 (80 mg, 0.28 mmol, yield 108.44%).

[1017] Step 3:

[1018] At room temperature, N-methylimidazole (82 mg, 1.42 mmol) and N,N,N',N'-tetramethylchloroformamide hexafluorophosphate (280 mg, 0.43 mmol) were added dropwise to a solution of intermediate 258-2 (80 mg, 0.28 mmol) and intermediate 162-5 (113 mg, 0.46 mmol) in N,N-dimethylformamide (1 mL). The reaction mixture was stirred at room temperature for 1 hour. The organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was analyzed by HPLC (Waters-Xbridge-C18-10µm-19). Purification was performed using a mobile phase of 250 mM NH4HCO3 (A: 10 mM NH4HCO3; B: ACN, gradient: 5-95%, retention time: 8.3 min) to give compound 258 (28.45 mg, 0.06 mmol, yield 19.56%). MS m / z (ESI): 512.2 [M+H] + ; 1 H NMR (400MHz, DMSO- d 6) 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 = 12.54Hz, 1H), 5.15 (d, J = 6.18 Hz, 2H), 4.47 – 4.39 (m, 7H).

[1019] Example 82:

[1020] Synthesis of Compound 259

[1021]

[1022] At room temperature, intermediate 166-3 (230 mg, 0.89 mmol), N-methylimidazole (202 mg, 2.46 mmol), and N,N,N',N'-tetramethylchloroformamide 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 mixture was stirred at 50 °C for 5 hours, cooled to room temperature, and concentrated under reduced pressure. The crude product was subjected to HPLC chromatography on a C18 silica gel column (column: Welch ultimate XB-NH2 250). 50 Purification was performed using a mobile phase of [heptane-EtOH (0.1% HCOOH)] (B% 10%-10%, 10 min) to give a milky white solid compound 259 (60 mg, 0.12 mmol, 24.48% yield).

[1023] Example 83:

[1024] Synthesis of Compound 260

[1025]

[1026] Step 1:

[1027] Cesium carbonate (1.3 g, 4.09 mmol) was added to a solution of intermediate 123-3 (700 mg, 2.04 mmol) and intermediate 260-1a (451 mg, 2.45 mmol) in N,N-dimethylformamide (5 mL) at room temperature and under a nitrogen atmosphere. The reaction mixture was stirred at 60 °C for 16 hours, then water (2 mL) was added, and the mixture was extracted with ethyl acetate (5 mL). The combined organic layers were washed with saturated 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 give intermediate 260-1 (400 mg, 1.00 mmol, 49.10% yield) as a white solid.

[1028] Step 2:

[1029] Zinc bromide (1.27 g, 5.62 mmol) was added to a 30 mL solution of intermediate 260-1 (560 mg, 1.41 mmol) in dichloromethane at room temperature. The reaction mixture was stirred for 16 hours at room temperature under a nitrogen atmosphere. After the reaction was complete, the mixture was concentrated under reduced pressure. The crude product was purified by C18 silica gel column chromatography (acetonitrile / water (0.1% FA) = 1 / 3) to give intermediate 260-2 (110 mg, 0.34 mmol, yield 71.98%) as a white solid.

[1030] Step 3:

[1031] At room temperature, intermediates 162-6 (53 mg, 0.21 mmol), N-methylimidazole (55 mg, 0.67 mmol), and N,N,N',N'-tetramethylchloroformamide 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 mixture was stirred at 50 °C for 3 hours, cooled to room temperature, and concentrated under reduced pressure. The crude product was analyzed by HPLC on a C18 silica gel column (column: Welch ultimate XB-NH2250). 50 Purification was performed at 10 μm, mobile phase: [heptane-EtOH (0.1% HC, yield OOH)]; B% 10%-10%, 10 min, yielding a milky white solid, 260 (25 mg, 0.05 mmol, 35.28%). MS m / z (ESI): 529.0 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) 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).

[1032] Example 84:

[1033] Synthesis of Compound 261

[1034]

[1035] Step 1:

[1036] Intermediate 261-1a (76 mg, 0.88 mmol) and cyanomethylenetri-n-butylphosphine (317 mg, 1.31 mmol) were added to a toluene (3 mL) solution of intermediate 123-3 (300 mg, 0.88 mmol) at room temperature and under a nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 10 hours, water (10 mL) was added, and the mixture was extracted with ethyl acetate (5 mL). The organic layer was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 2) to give a colorless liquid intermediate 261-1 (130 mg, 0.32 mmol, yield 36.05%).

[1037] Step 2:

[1038] At room temperature, 0.25 mL of trifluoroacetic acid was added dropwise to a 1 mL solution of intermediate 261-1 (130 mg, 0.32 mmol) in dichloromethane. The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give a colorless liquid intermediate 261-2 (98.36 mg, 0.32 mmol, 100% yield).

[1039] Step 3:

[1040] At room temperature, N-methylimidazole (131 mg, 1.60 mmol) and N,N,N',N'-tetramethylchloroformamide 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 mixture was stirred at room temperature for 1 hour. The organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was analyzed by HPLC (Waters-Xbridge-C18-10µm-19). Purification was performed using a mobile phase of 250 mm, A: 10 mM NH4HCO3; B: ACN, gradient: 10-95%, retention time: 9.3 min, yielding compound 261 (12.48 mg, 0.02 mmol, yield 7.20%). MS m / z (ESI): 542.4 [M+H] + ; 1 H NMR (400MHz, DMSO- d 6) 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).

[1041] Example 85:

[1042] Synthesis of Compound 272

[1043]

[1044] Step 1:

[1045] Sodium hydride (60 mg, 1.52 mmol, 60% purity) was added to a 5 mL solution of intermediate 123-3 (400 mg, 1.17 mmol) in tetrahydrofuran under a nitrogen atmosphere at 0 °C. After stirring the reaction mixture at 0 °C for 30 min, deuterated iodomethane (220 mg, 1.52 mmol) was added. The reaction mixture was stirred at 0 °C for 3 hours, then water (2 mL) was added, and the mixture was extracted with ethyl acetate (5 mL). The combined organic layers were washed with saturated 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 give intermediate 272-1 (80 mg, 0.22 mmol, 19.05% yield) as a white solid.

[1046] Step 2:

[1047] At room temperature, a solution of dioxane hydrochloride (4 N, 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 mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The crude product was purified by C18 silica gel column chromatography (acetonitrile / water (0.1% FA) = 2 / 3) to give a white solid intermediate 272-2 (10 mg, 0.04 mmol, 69.30% yield).

[1048] Step 3:

[1049] At room temperature, intermediates 162-5 (96 mg, 0.39 mmol), N-methylimidazole (106 mg, 1.29 mmol), and N,N,N',N'-tetramethylchloroformamide 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 mixture was stirred at 50 °C for 3 hours, cooled to room temperature, and concentrated under reduced pressure. The crude product was analyzed by HPLC on a C18 silica gel column (column: Welch ultimate XB-NH2250). 50 Purification was performed at 10 μm, mobile phase: [heptane-EtOH (0.1% HCOOH)]; B% 10%-10%, 10 min, to give a milky white solid compound 272 (20 mg, 0.04 mmol, yield 15.81%). MS m / z (ESI): 490.0 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) 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).

[1050] Example 86:

[1051] Synthesis of Compound 273

[1052]

[1053] At room temperature, intermediate 217-1 (38 mg, 0.15 mmol), N-methylimidazole (31 mg, 0.38 mmol), and N,N,N',N'-tetramethylchloroformamide 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 mixture was stirred at room temperature for 3 hours, then concentrated under reduced pressure. The crude product was analyzed by HPLC on a C18 silica gel column (column: Welch Ultimate XB-NH2250). 50 Purification was performed at 10 μm, mobile phase: [heptane-EtOH (0.1% HCOOH)]; B% 10%-10%, 10 min, to give a milky white solid compound 273 (13 mg, 0.03 mmol, yield 17%). MS m / z (ESI): 503.0 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) 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).

[1054] Example 87:

[1055] Synthesis of Compound 274

[1056]

[1057] Step 1:

[1058] 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 give intermediate 274-1 (360 mg, 0.94 mmol, yield 80.57%) as a white solid.

[1059] Step 2:

[1060] At room temperature, a solution of dioxane hydrochloride (4 N, 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 mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The crude product was purified by C18 silica gel column chromatography (acetonitrile / water (0.1% FA) = 2 / 3) to give a white solid intermediate 274-2 (2 mg, 0.01 mmol, yield 13.55%).

[1061] Step 3:

[1062] At room temperature, intermediates 162-5 (132 mg, 0.53 mmol), N-methylimidazole (145 mg, 1.77 mmol), and N,N,N',N'-tetramethylchloroformamide 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 mixture was stirred at 50 °C for 5 hours, cooled to room temperature, and concentrated under reduced pressure. The crude product was analyzed by HPLC using a C18 silica gel column (column: Welch ultimate XB-NH2250). 50 Purification was performed at 10 μm, mobile phase: [heptane-EtOH (0.1% HCOOH)]; B% 10%-10%, 10 min, to give a milky white solid compound 274 (30 mg, 0.06 mmol, yield 16.52%). MS m / z (ESI): 513.0 [M+H] + ; 1 H NMR (400MHz, 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).

[1063] Example 88:

[1064] Synthesis of Compound 276

[1065]

[1066] At room temperature, N,N,N',N'-tetramethylchloroformamide hexafluorophosphate (165 mg, 0.59 mmol) and N-methylimidazole (145 mg, 1.77 mmol) were added to a solution 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 mixture was stirred at room temperature for 10 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL). The organic layer was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was analyzed by HPLC (Waters-Xbridge-C18-10µm-19). Purification was performed at 250 nm using a mobile phase of 10 mM FA (A: 10 mM FA; B: ACN, gradient: 10-95%, retention time: 8.6 min) to give compound 276 (11.82 mg, 0.02 mmol, yield 3.42%). MS m / z (ESI): 586.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 7.88 (d, J = 7.6Hz, 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).

[1067] Example 89:

[1068] Synthesis of Compound 279

[1069]

[1070] Step 1:

[1071] A solution of 1,2-dichloroethane (5 mL) containing 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) 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 give intermediate 279-1 (300 mg, 0.71 mmol, yield 63.68%) as a yellow oil.

[1072] Step 2:

[1073] At room temperature, a methanol (2 mL) solution of intermediate 279-1 (100...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemate, prodrug, solvate, hydrate, or any of the foregoing labeled thereof, (I) Among them, ring A, ring B, Y, L, R1, R2, R3, 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, 5-11 member monocyclic and fused bicyclic heteroaryl; Ring B is selected from 6-membered monocyclic heteroaryl, 8-11-membered fused bicyclic heteroaryl, 8-11-membered fused bicyclic heterocyclic group, 10-15-membered fused tricyclic heteroaryl and 10-15-membered fused tricyclic heterocyclic group; Y is either O or S; L is #-C(=O)-NH- , where # and Connected, Connected to ring B; R1 is a C1-C5 alkyl or C1-C5 alkoxy group; wherein the C1-C5 alkyl or C1-C5 alkoxy group is optionally substituted by 1 to 3 groups selected from the following: deuterium, halogen, oxo, -CN, -OH, -NH2, optionally substituted by 1 to 3 R groups. z Substituted C1-C6 alkyl groups, optionally with 1-3 R groups z Substituted C1-C6 alkoxy groups, optionally with 1-3 R groups z Substituted C1-C6 haloalkyl groups, optionally with 1-3 R groups z Substituted C1-C6 haloalkoxy groups, optionally with 1-3 R groups z Substituted C3-C6 cycloalkyl groups, optionally with 1-3 R... z Substituted -NH (C1-C6 alkyl), optionally with 1-3 R z Substituted -N(C1-C6 alkyl)(C1-C6 alkyl), optionally with 1-3 R z Substituted C3-C6 cycloalkyl groups, optionally with 1-3 R... z The 5-15 nucleotide monocyclic, fused bicyclic, or fused tricyclic heterocyclic groups are optionally replaced by 1-3 R groups. z The substituted 5-15 member monocyclic or fused bicyclic or fused tricyclic aryl groups, and 5-15 member monocyclic or fused bicyclic or fused tricyclic heteroaryl groups; R2 and R3 are independently hydrogen, deuterium, halogen, C1-C6 alkyl or C1-C6 alkoxy; In this ring, the nitrogen atom connected to R1, the carbon atom connected to R2 and R3, and one atom of ring A form a ring group, and this ring group is connected to ring A in the form of sharing the one atom to form a spiro ring structure. R A For deuterium, halogen, hydroxyl, oxo, cyano, nitro, amino, 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), pentafluoride sulfo, 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, optionally with 1-3 R z The 4-8 membered heterocyclic group is replaced, optionally with 1-3 R groups. z Replaced 5-8 heteroaryl groups, optionally with 1-3 R groups z Replaces 6-10 aryl groups, optionally with 1-3 R groups z Substituted C3-C6 cycloalkyl, or Two R atoms attached to the same carbon atom A Formation of oxygen groups, or Two R atoms attached to the same carbon atom A Together with the carbon atoms they are attached to, they form C3-C8 cycloalkyl groups; R B It can be deuterium, halogen, hydroxyl, oxo, thionyl, cyano, nitro, amino, 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 attached to the same carbon atom B Together with the carbon atoms they are attached to, they form C3-C8 cycloalkyl groups or 6-7 membered heterocyclic groups, or Two R atoms attached to different carbon atoms B The connection forms a 6-7 elemental ring; Rz is 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, pentafluoride sulfo, 5-6 membered heteroaryl or 4-6 membered heterocyclic group, or Two R atoms attached to the same carbon atom z Formation of oxygen groups, or Two R atoms attached to the same carbon atom z Together with the carbon atoms they are attached to, they form C3-C8 cycloalkyl groups; m is 1 or 2; n is 0 or 1; p is 0, 1, 2, 3 or 4; q can be 0, 1, 2, 3, 4 or 5.

2. A compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemate, prodrug, solvate, hydrate, or isotopically labeled thereof, wherein the compound has formula (IC-1): (IC-1) Among them, rings A, B, Y, L, R2, R3, and R A R B m, n, p, and q are defined as follows: Ring A is selected from 8-11 member fused bicyclic aryl and 8-11 member fused bicyclic heteroaryl; m is 1 or 2; Ring B is selected from 6-membered monocyclic heteroaryl, 8-11-membered fused bicyclic heteroaryl, 8-11-membered fused bicyclic heterocyclic group, 10-15-membered fused tricyclic heteroaryl and 10-15-membered fused tricyclic heterocyclic group; Y is either O or S; L is #-C(=O)-NH- , where # and Connected, and Connected to ring B; n is 0 or 1; Each R2 and each R3 is independently hydrogen, deuterium, halogen, C1-C6 alkyl or C1-C6 alkoxy; R A For deuterium, halogen, hydroxyl, oxo, thionyl, cyano, nitro, amino, 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), sulfopentafluoride, 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, optionally with 1-3 R z The 4-8 membered heterocyclic group is replaced, optionally with 1-3 R groups. z Replaced 5-8 heteroaryl groups, optionally with 1-3 R groups z Replaces 6-10 aryl groups, optionally with 1-3 R groups z Substituted C3-C6 cycloalkyl groups, or, Two R atoms attached to the same carbon atom A Formation of an oxo group, or, Two R atoms attached to the same carbon atom A Together with the carbon atoms they are attached to, they form C3-C8 cycloalkyl groups; R B It can be deuterium, halogen, hydroxyl, oxo, cyano, nitro, amino, 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 attached to the same carbon atom B Together with the carbon atoms they are attached to, they form C3-C8 cycloalkyl groups or 6-7 membered heterocyclic groups, or... Two R atoms attached to different carbon atoms B The connection forms a 6-7 elemental ring; R z 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, pentafluoride sulfo, 5-6 membered heteroaryl or 4-6 membered heterocyclic group, or Two R atoms attached to the same carbon atom z Formation of oxygen groups, or Two R atoms attached to the same carbon atom z Together with the carbon atoms they are attached to, they form C3-C8 cycloalkyl groups; p is 0, 1, 2, 3, or 4; and q can be 0, 1, 2, 3, 4 or 5.

3. A compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemate, prodrug, solvate, hydrate, or isotopically labeled thereof, wherein the compound has formula (IC-2): (IC-2) Among them, rings A, D, Y, Z3, Z4, Z5, Z6, R2, R3, and R A R B m, p, and q are defined as follows: Z3 and Z6 are N or CR. e Z4 and Z5 are N, NH, and NR, respectively. e or CR e And at least one of Z4 and Z5 is N or NH; where It can be a single bond or a double bond, and the position of the double bond changes depending on whether Z4 and Z5 are N or NH; R e It can be 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 a 5- to 6-membered cycloalkyl group fused with a 10-membered ring, a 5- to 6-membered heterocyclic group fused with a 10-membered ring, a 5- to 6-membered aryl group fused with a 10-membered ring, a 5- to 6-membered heteroaryl group fused with a 10-membered ring, or is absent. m is 1 or 2; Ring A as defined in claim 1; and Y, R2, R3, R A R B p, q as defined in claim 1.

4. A compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemate, prodrug, solvate, hydrate, or isotopically labeled thereof, wherein the compound has formula (IC-3): (IC-3) Among them, rings A, W4, W5, W6, Y, L, R2, R3, and R A R B m, p, and q are defined as follows: -W4-W5-W6- is any of the following: (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 - or (7) does not exist; R f R g Independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or two R atoms attached to the same carbon atom. f and R g The formed oxo group, or two R groups attached to the same carbon atom f and R g C3-C8 cycloalkyl groups formed together with the carbon atoms they are attached to, or R f and R B The connection forms a 6-7 elemental ring; m is 1 or 2; Ring A is as defined in claim 1; Y, L, R2, R3, R A R B p, q as defined in claim 1.

5. A compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemate, prodrug, solvate, hydrate, or isotopically labeled thereof, wherein ring B is selected from... , , , , , , , , , , and .

6. A compound of formula (I) as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof, a geometric isomer, an enantiomer, a diastereomer, a racemic mixture, a prodrug, a solvate, a hydrate, or any of the foregoing labeled with an isotope, wherein ring B is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

7. The compound of formula (I) as claimed in claim 3, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemate, prodrug, solvate, hydrate, or any of the foregoing labeled with an isotope, wherein one of Z3 and Z6 is N and the other is CR. e And Z4 is N, NH or NR. e And Z5 is CR e .

8. The compound of formula (I) as claimed in claim 3, or any of its pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemates, prodrugs, solvates, hydrates, or isotopically labeled forms thereof, wherein Z3 and Z6 are each independently CR e And Z4 is N, NH or NR. e And Z5 is CR e .

9. The compound of formula (I) as claimed in claim 3, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemate, prodrug, solvate, hydrate, or isotopically labeled thereof, wherein the group formed by the fusion of ring D and the 10-membered ring is selected from... , , , , , , , , and ; R B p is as defined in claim 3.

10. The compound of formula (I) as claimed in claim 3, or any of its pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemates, prodrugs, solvates, hydrates, or isotopically labeled forms thereof, wherein ring D is absent.

11. The compound of formula (I) as claimed in claim 3, or any of its pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemates, prodrugs, solvates, hydrates, or isotopically labeled forms thereof, wherein: The group formed by the fusion of ring D and a 10-membered ring is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

12. A compound of formula (I) as claimed in claim 4, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemate, prodrug, solvate, hydrate, or isotopically labeled thereof, wherein the ring formed by the fusion of -W4-W5-W6- with pyridine is selected from... , , , , , , , , , , , and .

13. A compound of formula (I) as claimed in any one of claims 1 to 12, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemate, prodrug, solvate, hydrate, or isotopically labeled thereof, wherein ring A is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,and ; in Indicates the screw-ring connection point; and R A q is as defined in claim 1.

14. A compound of formula (I) as claimed in any one of claims 1 to 12, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemate, prodrug, solvate, hydrate, or any of the foregoing labeled with an isotope, wherein: (1) A spiro ring structure is formed by R1, the nitrogen atom connected to R1, the carbon atoms connected to R2 and R3, and one atom of ring A, and this spiro ring structure is formed by connecting the spiro ring to ring A in the form of sharing the one atom. (2) The carbon atom connected to R2 and R3, the adjacent nitrogen atom, the adjacent methylene group, and one atom of ring A form a cyclic group, and this cyclic group is connected to ring A by sharing the one atom to form a spirocyclic structure, wherein the spirocyclic structure is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ... , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

15. A compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, a geometric isomer, an enantiomer, a diastereomer, a racemic mixture, a prodrug, a solvate, a hydrate, or an isotopically labeled thereof, selected from: Or, as described above, a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemate, prodrug, solvate, hydrate, or any of the aforementioned.

16. A pharmaceutical composition comprising a compound of formula (I) as described in any one of claims 1 to 15, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemate, prodrug, solvate, hydrate, or isotopically labeled thereof, and one or more pharmaceutically acceptable carriers or excipients.

17. Use of a compound of formula (I) as claimed in any one of claims 1 to 15, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemate, prodrug, solvate, hydrate, or isotopically labeled thereof, or the pharmaceutical composition as claimed in claim 16, for the manufacture of a pharmaceutical product for treating cancer.

18. Use of a compound of formula (I) as claimed in any one of claims 1 to 15, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemate, prodrug, solvate, hydrate, or isotopically labeled thereof, or the pharmaceutical composition as claimed in claim 16, for the manufacture of an MTA-synergistic PRMT5 inhibitor.

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