Fused pyridine ring-based Myt1 inhibitors

Abstract

The present invention provides a compound of formula (I): # imgabs0 wherein ring A, ring B, ring C, Y, RA, RB, RC, m, n, p and q are as disclosed in the specification. The present invention also provides a pharmaceutical composition comprising a compound of formula (I) as an inhibitor of SkMyt1 and methods of use thereof.

Description

Technical Field

[0001] The present invention relates to methods of using inhibitors of membrane-associated tyrosine and threonine-specific cdc2 inhibitory kinase (Myt1) (gene name PKMYT1), for example, for treating diseases or disorders, such as cancer, in particular, diseases or disorders that depend on Myt1 activity (e.g., cancers with CCNE1 amplification / overexpression or cancers with FBXW7 mutations). In particular, the present invention relates to Myt1 inhibitors based on fused pyridine rings, pharmaceutical compositions comprising the compounds, and methods of use thereof. Background Art

[0002] DNA is constantly exposed to insults from internal (e.g., stalled replication forks, reactive oxygen species) or external (ultraviolet light, ionizing radiation, chemicals) sources that can cause DNA damage. In response to these potential dangers, cells have evolved sophisticated mechanisms to counteract these harmful events to prevent them from compromising genome integrity and, thus, initiating genome-instability diseases such as cancer. These mechanisms are collectively referred to as the DNA damage response (DDR).

[0003] An integral part of the overall DDR is the activation of various checkpoint pathways that regulate specific DNA repair mechanisms at various stages of the cell cycle, including the G1, S, G2, and mitotic checkpoints. Due to p53 mutations, most cancer cells have lost the G1 checkpoint and, therefore, rely on the G2 checkpoint for necessary DNA damage correction before entering mitosis and dividing into two daughter cells.

[0004] PKMYT1 inhibits cell cycle progression and drives the progression of various tumors by suppressing the activity of cell cycle-related proteins such as cyclin A, CDK1, and CDK2.

[0005] Inhibitory phosphorylation of cdc2 is important for the timing of entry into mitosis. Phosphorylation of cdc2 at Tyr-15 and Thr-14 inhibits premature entry into mitosis during interphase (G1, S, and G2). At the G2-M transition, cdc2 is dephosphorylated at Tyr-15 and Thr-14, allowing mitosis to proceed.

[0006] Studies have shown that premature activation of cdc2 can lead to mitotic catastrophe and cell death. Myt1 is an important cell cycle regulator, particularly during the G2 / M phase. Inhibition of Myt1 is expected to lead to premature activation of cdc2, thereby killing rapidly proliferating cells. In addition, Myt1 inhibition is expected to reduce resistance to traditional chemotherapeutic drugs, as the mechanism by which cells avoid death involves arrest in the G2 phase of the cell cycle, as well as pre-mitotic repair or DNA damage. This arrest is prevented by blocking Myt1 inhibitory phosphorylation of cdc2, thereby forcing cells to enter mitosis prematurely. Myt1 provides an intervention point to inhibit the development of chemotherapeutic drug resistance by tumor cells through this mechanism. In summary, inhibition of Myt1 can have therapeutic benefits in itself in reducing tumor proliferation, and in addition, can be used in combination with conventional chemotherapy to overcome resistance.

[0007] Therefore, there is a need to develop effective Myt1 kinase inhibitors for the treatment of cancer, especially therapies that allow targeted cancer therapy. Summary of the invention

[0008] One aspect of the present invention is to provide a compound of formula (I), or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotope-labeled compound thereof:

[0009]

[0010] Among them, ring A, ring B, ring C, Y, R A , R B , R C , m, n, p and q are as defined in the specification.

[0011] Another aspect of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate or hydrate thereof and one or more pharmaceutically acceptable carriers or excipients thereof. The pharmaceutical composition of the present invention is used as a Myt1 inhibitor.

[0012] Another aspect of the present invention is to provide use of a compound of formula (I) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate or hydrate thereof in the manufacture of a medicament for use as a Myt1 inhibitor.

[0013] Another aspect of the present invention is to provide a method for treating cancer, which comprises administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate or hydrate thereof to inhibit the growth of cancer in the individual. The compound of formula (I) can be used alone or in combination with another therapeutic agent and / or therapy. DETAILED DESCRIPTION

[0014] The present invention can be more easily understood with reference to the detailed description of the various embodiments, examples and tables with their related descriptions of the present invention below. Unless otherwise defined, all terms used herein (including technical and scientific terms) have the same meanings as those generally understood by those skilled in the art to which the present invention belongs. In addition, it should be understood that those terms as defined in common dictionaries should be interpreted as being consistent with their meanings in the context of the relevant art, and, unless clearly defined herein, the terms will not be interpreted in an idealized or overly formal sense. It should also be understood that the terms used herein are only for the purpose of describing specific embodiments, and are not intended to be limiting.

[0015] definition

[0016] The definitions set forth in this section are intended to clarify the terms used throughout this application.The term "herein" means the entire application.

[0017] It must be noted that, as used herein, the singular forms "a", "an", and "the" include plural referents unless otherwise expressly provided herein. Thus, unless otherwise required herein, singular terms shall include pluralities and plural terms shall include the singular.

[0018] Typically, ranges herein are expressed as from "about" one particular value and / or to "about" another particular value. When such ranges are expressed, an embodiment includes a range from one particular value and / or to another particular value. Similarly, when values ​​are expressed as approximations using the word "about", it is understood that the particular value constitutes another embodiment. In addition, it is understood that the endpoints of each of the ranges are meaningful relative to and independent of the other endpoint. As used herein, the term "about" refers to ± 20%, preferably ± 10%, and even more preferably ± 5%.

[0019] As used herein, the term "optionally substituted" means that substitution is optional. Where substitution is desired, such substitution means that any number of hydrogens on the designated atom are replaced by an option from the designated group, provided that the normal valence of the designated atom is not exceeded and the substitution produces a stable compound. For example, when the substituent is keto (i.e., =O), then 2 hydrogens on the atom are replaced. Examples of substituents for "substituted" groups are those present in the exemplary compounds and embodiments disclosed herein, and may include, for example, halo, cyano, alkyl, alkoxy, haloalkyl, alkylamino, aminoalkyl, dialkylamino, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, alkylaminoalkoxy, alkylaminoalkyl, and the like.

[0020] As used herein, the term "halo" includes fluorine, chlorine, bromine and iodine. "Halo" used as a prefix of a group means that one or more hydrogens on the group are replaced by one or more halogens.

[0021] The term "alkyl" as used herein refers to a monovalent, saturated, straight 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 isomeric forms) and hexyl (including all isomeric forms), heptyl (including all isomeric forms), octyl (including all isomeric forms), etc.

[0022] The term "alkoxy" used alone or as a suffix or prefix refers to a group of the general formula -O-(alkyl), wherein alkyl is defined above. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.

[0023] As used herein, the term "alkenyl" refers to a non-cyclic monovalent straight or branched hydrocarbon group containing one, two or three carbon-carbon double bonds. Non-limiting examples of alkenyl include vinyl, prop-1-enyl, prop-2-enyl, 1-methylvinyl, but-1-enyl, but-2-enyl, but-3-enyl, 1-methylprop-1-enyl, 2-methylpropene-1-enyl and 1-methylpropene-2-enyl. Alkenyl can be optionally substituted as defined herein for alkyl.

[0024] "Amin" used as a prefix or suffix to a group means that one or more hydrogens on the group are replaced with one or more amine groups.

[0025] As used herein, the term "alkylamino" refers to a group having the formula -N(RN1)2 or -NHRN1, wherein RN1 is an alkyl group as defined herein. The alkyl portion of the alkylamino group may be optionally substituted as defined for an alkyl group. Each optional substituent on the substituted alkylamino group may itself be unsubstituted or, if valence permits, substituted with an unsubstituted substituent as defined herein for each corresponding group.

[0026] As used herein, the term "fused" refers to rings that share one covalent bond. A fused bicyclic compound refers to two rings that share two adjacent atoms. Examples of fused bicyclic rings include, for example, fused bicyclic aryl, heterocyclic or heteroaryl groups.

[0027] Unless otherwise specified, the term "cycloalkyl" as used herein refers to a saturated monovalent hydrocarbon group with a cyclic configuration, including monocyclic, bicyclic, tricyclic and high-order polycyclic alkyl groups (and when polycyclic, including fused and bridged bicyclic and spirocyclic moieties), wherein each cyclic moiety has 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 ring may be fused or non-fused and include a bicyclic group. 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, etc.

[0028] Unless the number of rings is otherwise specified, the term "aryl" means a monovalent 6-14 membered mono or bicyclic carbon ring, wherein the monocyclic ring is aromatic and at least one of the rings in the bicyclic ring is aromatic. Representative examples include, but are not limited to, phenyl, biphenyl, naphthyl, indenyl, etc.

[0029] Unless the number of rings is otherwise specified, "heteroaryl" means a monocyclic, fused bicyclic or fused tricyclic monovalent radical of 5 to 14 ring atoms containing one or more, for example one, two, three or four, ring heteroatoms independently selected from: -O-, -S(O) n -(n is 0, 1 or 2), -N-, -N(R x )-, and the remaining ring atoms are carbon, wherein the ring containing the monocyclic group is an aromatic ring and at least one of the fused rings containing the bicyclic or tricyclic group is an aromatic ring. One or two ring carbon atoms of any non-aromatic ring containing the bicyclic or tricyclic group may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. R xis hydrogen, alkyl, hydroxy, alkoxy, acyl or alkylsulfonyl. Fused bicyclic groups include bridged ring systems. Unless otherwise specified, the valence positions may be located on any atom of any ring of the heteroaryl group as permitted by the valence rules. Specifically, when the valence position is on nitrogen, R x More specifically, the term "heteroaryl" includes, but is not limited to, benzocyclopentyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrofuro[3,2-b]pyridine, 2,3-dihydrofuro[3,2-c]pyridine, 6,7-dihydro-5H-cyclopenta[b]pyridine, chromanyl, isochromanyl, 3,4-dihydro-2H-pyrano[2,3-b]pyridine, 5,8-dihydro-6H-pyrano[2,3-c]pyridine, 1,2-dihydro-1,2-dihydro-2,3 ... [3,4-b]pyridine, 1,3,4,5-tetrahydrobenzo[c]oxazepine, indanyl, phthalidyl, indolyl, 1,2,4-triazolyl, oxa-1,3,5-triazolyl, phthalimide, pyridyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro-1H-indolyl (including, for example, 2,3-dihydro-1H-indol-2-yl or 2,3-dihydro-1H-indolyl), -5-yl, etc.), isoindolyl, dihydroindolinyl, isoindolyl, benzimidazolyl, benzodioxol-4-yl, benzofuranyl, cinnolinyl, indolizinyl, naphthyridin-3-yl, phthalazin-3-yl, phthalazin-4-yl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolyl, linyl, tetrahydroisoquinolinyl (including, for example, tetrahydroisoquinolin-4-yl or tetrahydroisoquinolin-6-yl, etc.), pyrrolo[3,2-c]pyridinyl (including, for example, pyrrolo[3,2-c]pyridin-2-yl or pyrrolo[3,2-c]pyridin-7-yl, etc.), benzopyranyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl, benzothiophenyl, and derivatives thereof, or N-oxides or protected derivatives thereof.

[0030] Unless the number of rings is otherwise specified, "heterocyclyl" means a saturated or partially unsaturated monovalent monocyclic radical of 3 to 9 ring atoms or a saturated or partially unsaturated monovalent fused bicyclic radical of 5 to 12 ring atoms, wherein one or more, for example one, two, three or four, ring heteroatoms are independently selected from the following: -O-, -S(O)- x -(x is 0, 1 or 2), -N=, -N(R y )-(where R yis hydrogen, alkyl, hydroxyl, alkoxy, acyl or alkylsulfonyl), and the remaining ring atoms are carbon. One or two ring carbon atoms may be replaced by -C(O)-, -C(S)- or -C(=NH)- groups. As used herein, the term "heterocyclyl" means a monocyclic, bicyclic, tricyclic or tetracyclic ring system with fused, bridged and / or spirocyclic 3-, 4-, 5-, 6-, 7- or 8-members, unless otherwise indicated, containing one, two, three or four heteroatoms independently selected from nitrogen, oxygen and sulfur. Fused bicyclic groups include bridged ring systems. Unless otherwise indicated, the valence of a group may be located on any atom of any ring within the group, as long as the valence rules allow. Specifically, when the valence position is located on the nitrogen atom, R y More specifically, the term "heterocyclyl" includes, but is not limited to, piperidinyl, pyrimidinyl, morpholinyl, piperazinyl, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, 4-piperidonyl, 2-oxopiperazinyl, tetrahydropyranyl, 2-oxopiperidinyl, thiomorpholinyl, thimorpholinyl, perhydroazepinyl, pyrazolidinyl, dihydroimidazolyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidine, isothiazolidinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolinyl, tetrahydrofuranyl and tetrahydropyranyl, and derivatives thereof, as well as N-oxides or protected derivatives thereof.

[0031] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of the disclosed compounds, wherein the parent compound is modified by preparing a pharmaceutically acceptable acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali metal or organic salts of acidic residues such as carboxylic acids; and the like. 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 nontoxic 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, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, p-aminobenzenesulfonic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Non-limiting examples of salts of the compounds of the invention include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethanesulfonate, phosphate, hydrogenphosphate, acetate, adipate, alginate, aspartate, benzoate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, malonate, fumarate, maleate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, glutamate, bicarbonate, undecanoate, lactate, citrate, tartrate, gluconate, benzenesulfonate, and p-toluenesulfonate.

[0032] As used herein, the term "geometric isomers" includes, but is not limited to: cis and trans; E- and Z-; c-, t-, and r-; endo and exo; R-, S-, and meso; boat, chair, twist, enclosed, and semi-chair; and combinations thereof.

[0033] 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 to refer to a racemic mixture when appropriate. "Diastereomers" are stereoisomers with at least two asymmetric atoms that are not mirror images of each other. Absolute stereochemistry can be specified according to the Cahn-Ingold-PrelogR-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by R or S. The split compound can be represented as (+) or (-) according to the direction (right-handed or left-handed) in which the plane polarization is rotated at the wavelength of the sodium D line. Certain compounds described herein may contain one or more asymmetric centers or axes, and enantiomers, diastereomers, and other stereoisomeric forms can therefore be produced, which can be defined as (R)- or (S)- in terms of absolute stereochemistry. The present invention is intended to include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)-isomers may be prepared using chiral synthetic components or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituents may have a cis or trans configuration.

[0034] As used herein, the term "tautomer" refers to compounds that may have different points of hydrogen attachment. An example is a ketone and its enol form, known as keto-enol tautomers. Individual tautomers as well as mixtures thereof are encompassed by the present invention.

[0035] As used herein, "prodrug" is intended to include any covalently bonded carrier that releases the active parent drug according to formula I via physiological effects (such as hydrolysis, metabolism, etc.) in vivo when such prodrugs are administered to an individual. The applicability and technology involved in preparing and using prodrugs are well known to those of ordinary skill in the art. Prodrugs of compounds (parent compounds) of formula (I) can be prepared by modifying the functional groups present in the compound in such a way that the variant is cleaved into the parent compound in conventional operations or in vivo. "Prodrugs" include compounds of formula (I) in which hydroxyl, amine or sulfhydryl groups are bonded to any group, and when the prodrug is administered to an individual, the group is cleaved to form free hydroxyl, free amine or free sulfhydryl groups, respectively. Examples of prodrugs include, but are not limited to, derivatives and metabolites of compounds of formula (I), which include biohydrolyzable moieties, such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. In a particular embodiment, the prodrug of a compound of formula (I) having a carboxyl functional group is a lower alkyl (eg C1-C6) ester of a carboxylic acid. The carboxylic acid ester is conveniently formed by esterifying any carboxylic acid moiety present on the molecule.

[0036] As used herein, the term "solvate" means a compound or a pharmaceutically acceptable salt thereof that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. If the solvent is water, the solvate may be conveniently referred to as a "hydrate", such as a hemihydrate, a monohydrate, a sesquihydrate, a dihydrate, a trihydrate, etc.

[0037] As used herein, the term "Myt1 inhibitor" refers to a compound that, upon contact with the enzyme Myt1 (whether in vitro, in cell culture or in an animal), reduces Myt1 activity such that the measured Myt1 IC50 is 10 mM or less (e.g., 5 mM or less or 1 mM or less).

[0038] For certain Myt1 inhibitors, the Myt1 IC50 may be 100 nM or less (e.g., 10 nM or less, or 3 nM or less) and may be as low as 100 pM or 10 pM. Preferably, the Myt1 IC50 is 1 nM to 1 mM (e.g., 1 nM to 750 nM, 1 nM to 500 nM, or 1 nM to 250 nM).

[0039] Even more preferably, the Myt1 IC50 is less than 20 nm (e.g., 1 nM to 20 nM)

[0040] As used herein, "treatment" refers to the medical management of a subject with the intent to ameliorate, improve, stabilize, prevent, or cure a disease or condition.

[0041] The term includes active treatment (treatment intended to improve the disease or condition); causal treatment (treatment directed at the cause of the disease or condition in question); palliative treatment (treatment intended to relieve the symptoms of the disease or condition in question); preventive treatment (treatment intended to reduce or partially or completely inhibit the development of the disease or condition in question); and supportive treatment (treatment used to supplement another treatment).

[0042] Compound

[0043] 1. The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotope-labeled compound thereof,

[0044]

[0045] in:

[0046] Ring A is a 5-7 membered monocyclic aryl, heterocyclic or heteroaryl group or an 8-11 membered fused bicyclic aryl, heterocyclic or heteroaryl group;

[0047] Ring B is a 5-6-membered monocyclic aromatic group, heterocyclic group or heteroaryl group;

[0048] Ring C is a 5-7 membered monocyclic aryl, heterocyclic or heteroaryl group or an 8-11 membered fused bicyclic aryl, heterocyclic or heteroaryl group;

[0049] R A is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, halogen, hydroxyl, oxo, cyano or amine;

[0050] R B is hydrogen, C1-C6 alkyl, halogen, hydroxyl, oxo, cyano or amine;

[0051] R C is LQ-R1, hydrogen, halogen, hydroxyl, oxo, cyano, amine, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), C3-C6 cycloalkyl, C1-C6 haloalkyl, -O-(C1-C6 haloalkyl), -NH-(C1-C6 haloalkyl), -N(C1-C6 haloalkyl)(C1-C6 haloalkyl), Pentafluorosulfur, C1-C6 haloalkoxy or halocycloalkyl, -NH-S(O)2-(C1-C6 alkyl), -NHP(=O)-(C1-C6 alkyl), -NHC(O)-(C1-C6 alkyl), -C(O)NH-(C1-C6 alkyl), -NHC(O)NH-(C1-C6 alkyl), -S(O)2-(C1-C6 alkyl), -P(=O)(C1-C6 alkyl)2;

[0052] L is a direct bond, O or NH;

[0053] Q is absent, a direct bond, or a C1-C6 alkyl group;

[0054] R1 is C1-C6 alkyl, C3-C6 cycloalkyl or a 4-7 membered heterocyclic group containing one or two heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl or heterocyclic group is optionally substituted by one or two substituents R2;

[0055] R2 is C1-C6 alkyl, halogen, hydroxy, oxo, cyano, amine, -(C=O)(C1-C6 alkyl) or -N(C1-C6 alkyl)(C1-C6 alkyl);

[0056] Y is O, CR3, CR3R4, N or NH;

[0057] R3 and R4 are independently hydrogen, C1-C6 alkyl, halogen, hydroxyl, oxo, cyano or amine, or R3 and R4 connected to the same carbon atom together with the carbon atom to which they are connected constitute a C3-C7 cycloalkyl, or R3 and R4 connected to different carbon atoms together with the carbon atom to which they are connected constitute a C3-C7 cycloalkyl;

[0058] m is 1, 2, 3 or 4;

[0059] n is 0 or 1;

[0060] p is 1, 2, or 3;

[0061] q is 1 or 2.

[0062] 2. In some embodiments, q is 1, Y is CR3R4; R3 and R4 are as defined in 1.

[0063] 3. In some embodiments, wherein q is 1 and Y is NH.

[0064] 4. In some embodiments, q is 2, Y is CR3 or N; R3 is as defined in 1.

[0065] 5. In some embodiments, q is 2, Y is CR3R4; R3 and R4 are as defined in claim 1.

[0066] 6. In some embodiments, Ring B is a 5-6 membered heteroaryl group containing at least one N atom.

[0067] 7. In some embodiments, wherein Ring B is thiazole or pyridine.

[0068] 8. In some embodiments, ring A is selected from phenyl, a 5-6 membered heteroaryl containing at least one N atom, or an 8-11 membered fused bicyclic heteroaryl containing at least two N atoms.

[0069] 9. In some embodiments, ring A is selected from phenyl, a 6-membered heteroaryl containing at least one N atom, or a 9-membered fused bicyclic heteroaryl containing at least two N atoms.

[0070] 10. In some embodiments, wherein ring A is selected from R A , m are as defined in 1.

[0071] 11. In some embodiments, wherein Ring A is selected from R A1 , R A2 , R A3 , R A4 , R A5 and R A6 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, halogen, hydroxy, oxo, cyano or amine.

[0072] 12. In some embodiments, wherein Ring A is R A1 and R A2 It is methyl.

[0073] 13. In some embodiments, wherein Ring A is R A1 , R A2 is methyl; R A3 It is a halogen.

[0074] 14. In some embodiments, wherein Ring A is R A5 It is methyl.

[0075] 15. In some embodiments, wherein ring A is selected from

[0076] 16. In some embodiments, ring C is a 5-7 membered monocyclic heteroaryl or an 8-11 membered fused bicyclic heteroaryl containing at least two N atoms.

[0077] 17. In some embodiments, Ring C is a 9-membered fused bicyclic heteroaryl containing at least two N atoms.

[0078] 18. In some embodiments, wherein ring C is selected from

[0079] R C , p is as defined in 1.

[0080] 19. In some embodiments, wherein R C is selected from -CH3, -CH2CH3, -CH2CF3,

[0081] 20. In some embodiments, the compound of formula (I) is selected from:

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088] Pharmaceutical compositions, uses and methods

[0089] The compounds of the invention can be administered therapeutically as pure chemicals, but it may be appropriate to administer the compounds as pharmaceutical compositions or formulations. Accordingly, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, prodrug or solvate thereof and one or more pharmaceutically acceptable carriers or excipients.

[0090] In some embodiments, the use of a compound of formula (I) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, prodrug or solvate thereof is for the manufacture of a medicament for treating cancer in an individual in need thereof.

[0091] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, prodrug or solvate thereof is co-administered to the subject with a second anticancer agent, surgical therapy, ionizing radiation, or a combination thereof.

[0092] The pharmaceutical composition can be administered in various dosage forms, including but not limited to: solid dosage forms or liquid dosage forms, oral dosage forms, parenteral dosage forms, intranasal dosage forms, suppositories, lozenges, dragees, oral, controlled release dosage forms, pulse release dosage forms, immediate release dosage forms, intravenous solutions, suspensions or combinations thereof. The compound can be administered, for example, by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, respiratory (aerosol), rectal, vaginal and topical (including oral and sublingual) administration.

[0093] In one embodiment of the invention, the compound of formula (I) is administered orally. For oral administration, the compound will generally be provided as a tablet, pill, dragee, lozenge or capsule in a unit dosage form suitable for ingestion by an individual; as a powder or granules; or as an aqueous solution, suspension, liquid, gel, syrup, slurry, etc. The dosage form may be a controlled release dosage form formulated as a tablet or tablet. Tablets for oral use may include an active ingredient mixed with one or more pharmaceutically acceptable excipients.

[0094] "Excipient" generally refers to a substance added to a pharmacological composition or used as a vehicle to further assist in administering a compound, usually an inert substance. Examples of excipients include, but are not limited to, inert diluents, disintegrating agents, adhesives, lubricants, sweeteners, flavoring agents, colorants, preservatives, foaming mixtures, and adsorbents. Suitable inert diluents include, but are not limited to, sodium carbonate and calcium carbonate, sodium phosphate and calcium phosphate, lactose, etc. Suitable disintegrating agents include, but are not limited to, starch (such as corn starch), cross-linked polyvinyl pyrrolidone, agar, alginic acid or its salt (such as sodium alginate), etc. Adhesives may include, but are not limited to, magnesium aluminum silicate, starch (such as corn, wheat or rice starch), gelatin, methylcellulose, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, etc. If present, lubricants are usually magnesium stearate and calcium stearate, stearic acid, talc, or hydrogenated vegetable oils. If necessary, tablets can be coated with materials such as monostearate glyceryl or distearate glyceryl to delay absorption in the gastrointestinal tract. The composition may also be formulated as a chewable tablet, for example, by using substances such as mannitol in the formulation.

[0095] Pharmaceutical compositions for oral use can be obtained by combining a compound of formula (I) with a solid excipient, optionally grinding the resulting mixture, and processing the mixture granules after adding suitable other compounds (if necessary) to obtain tablets or dragee cores. Suitable solid excipients include carbohydrate or protein fillers in addition to those previously mentioned, including but not limited to: sugars, including lactose, sucrose, mannitol or sorbitol; starch from corn, wheat, rice, potato or other plants; cellulose, such as methylcellulose, hydroxypropyl methylcellulose or sodium carboxymethylcellulose; and gums, including gum arabic and tragacanth; and proteins, such as gelatin and collagen.

[0096] Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent and soft gelatin capsules in which the active ingredient is mixed with water or oil (such as peanut oil, liquid paraffin or olive oil).

[0097] The dragee core has a suitable coating. For this purpose, concentrated sugar solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer liquids and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings to identify or characterize different combinations of active compound dosages.

[0098] The pharmaceutical composition may also contain a suitable solid or gel phase carrier. Examples of such carriers include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

[0099] Compounds and pharmaceutical compositions suitable for use in the present invention include those in which the active ingredient is administered in an effective amount to achieve its intended purpose. The term "therapeutically effective amount" refers to an amount of a compound of formula (I) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, prodrug or solvate thereof, alone or in combination with ionizing radiation or an anticancer agent, that provides the desired effect in the individual being treated when a single or multiple doses are administered to the individual. The toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, such as determining the IC 50 As used herein, “IC 50 ” refers to the concentration of the drug that may produce 50% of the maximum inhibitory reaction.

[0100] The actual amount of the compound of formula (I) administered will be determined by the physician under relevant conditions, including the condition to be treated, the size and type of neoplasia, the route of administration selected, the actual compound of the invention administered, the timing of administration of the hedgehog pathway modulator relative to other therapies, the type, species, age, weight, sex and medical condition of the individual, the renal and liver function of the individual, and the severity of the individual's symptoms. Achieving optimal precision in producing drug concentrations within the efficacy range requires a regimen based on the kinetics of the drug's availability to the target site. This involves consideration of the distribution, equilibrium, and elimination of the drug. In some cases, dosage levels below the lower limit of the aforementioned range may be more than adequate, while in other cases still larger doses may be employed.

[0101] A "subject" to be treated by the methods of the present invention means a human or non-human animal, such as a primate, a mammal, and a vertebrate.

[0102] "In vivo" means within a living individual, such as an animal or human. As used herein, an agent may be used therapeutically in vivo to delay or eliminate the proliferation of abnormal replicating cells. An agent may also be used in vivo as a prophylactic agent to prevent the manifestation of abnormal cell proliferation or symptoms associated therewith.

[0103] "In vitro" means outside 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 biopsies thereof. As used herein, the compounds of the invention can be used in a variety of therapeutic and experimental applications.

[0104] The present invention also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, prodrug or solvate thereof for the manufacture of a medicament for modulating the Hedgehog pathway.

[0105] Furthermore, the present invention relates to a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, prodrug or solvate thereof.

[0106] "Cancer" refers to a cell proliferative disorder including, but not limited to, cardiac cancers such as sarcomas (e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas, and teratomas; lung cancers such as bronchial cancers (e.g., squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, and adenocarcinomas), alveolar cancers (e.g., bronchiolar carcinomas), bronchial adenomas, sarcomas, lymphomas, chondroitinomas, and mesotheliomas; gastrointestinal cancers such as esophageal cancers (e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphomas), gastric cancers (e.g., lymphomas and leiomyosarcomas), pancreatic cancers (e.g., ductal adenocarcinomas, insulinomas, glucagonomas, gastrinomas, carcinoids, and vipoma); small intestinal cancers (e.g., adenocarcinomas, lymphomas, carcinoids, Kaposi's sarcomas, and ulcerative colitis); sarcoma), leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma); colorectal cancer (e.g., adenocarcinoma, ductal adenoma, villous adenoma, hamartoma, and leiomyoma); genitourinary tract cancers, such as kidney cancer (e.g., adenocarcinoma, Wilms tumor [Nephroblastoma], lymphoma, and leukemia); bladder and urethral cancer (e.g., squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma); prostate cancer (e.g., adenocarcinoma and sarcoma), testicular cancer (e.g., spermatoma, teratoma, embryonal tumor, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, and lipoma); liver cancer, such as hepatocellular carcinoma (e.g., hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma; bone cancer, such as osteogenic sarcoma (e.g., osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma (Ewing's sarcoma), malignant lymphoma (e.g., reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (e.g., osteochondroma exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; cancers of the nervous system, such as skull cancer (e.g., osteoma, hemangioma, granuloma, xanthomas, and osteitis malformation), meningeal cancer (e.g., meningioma, meningeal sarcoma, and gliosis), brain cancer (e.g., astrocytoma, medulloblastoma, glioma, ependymoma, blastoma (pinealoma), 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 preneoplastic cervical dysplasia), ovarian cancer (e.g., ovarian cancer [e.g., serous cystadenocarcinoma, mucinous cystadenocarcinoma, and unspecified carcinoma], granulosa cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, and malignant teratoma), vulvar cancer (e.g., squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma), vaginal cancer (e.g., clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma [e.g., embryonal rhabdomyosarcoma], and fallopian tube cancer); hematological cancers, such as hematological cancers (myeloid leukemias [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, and myelodysplasia), Hodgkin's disease ( disease), non-Hodgkin's lymphoma [malignant lymphoma]; skin cancers such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; adrenal gland cancers such as neuroblastoma; or breast cancer. ;

[0107] The compounds of formula (I) may be administered as the sole active pharmaceutical agent, or in combination with other known cancer treatments.

[0108] The term "and together" means that the compound of formula (I) can be administered shortly before, shortly after, at the same time, or any combination of shortly before, shortly after, or at the same time with one or more other anti-tumor therapies. Thus, the compound of formula (I) and the second anticancer agent can be administered as a single composition or as two separate compositions simultaneously or as two separate compositions sequentially. Similarly, the compound of formula (I) and chemotherapy or ionizing radiation therapy can be administered simultaneously, separately, or sequentially. It will be understood by those skilled in the art that the amount of the compound of formula (I) administered in conjunction with the anticancer therapy is preferably an amount sufficient to enhance the effect of the anticancer therapy or an amount sufficient to induce apoptosis or cell death together with the anticancer therapy to maintain the anti-angiogenic effect.

[0109] Unless otherwise specified, the term "second anticancer agent" as used herein refers to an agent capable of inhibiting or preventing tumor growth or detecting the maturation and proliferation of malignant (cancer) cells. Second anticancer agents suitable for use in combination with a compound of formula (I) include, but are not limited to, targeted cancer drugs,Such as trastuzumab, ramucirumab, bevacizumab, everolimus, tamoxifen, toremifene, fulvestrant, anastrozole, exemestane, lapatinib, letrozole, pertuzumab, ado-trastuzumab, mabemtansine, palbociclib, cetuximab, panitumumab, ziv-aflibercept, regorafenib, lmatinib mesylate, lanreotide acetate, sunitinib, regorafenib, denosumab, alitretinoin, Sorafenib, pazopanib, temsirolimus, everolimus, tretinoin, dasatinib, nilotinib, bosutinib, rituximab, alemtuzumab, ofatumumab, obinutuxumab, ibrutinib, idelali sib), blinatumomab, soragenib, crizotinib, erlotinib, gefitinib, afatinib dimaleate, ceritnib, ramucirumab, nivolumab, pembrolizumab, osimertinib, and necitumumab; alkylating agents,such as busulfan, chlorambucil, cyclophosphamide, ifosfamide, melphalan, nitrogen mustard, streptozotocin, thiotepa, uracil mustard, triethylene melamine, temozolomide, and 2-chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU); antibiotics or plant alkaloids such as actinomycin-D, bleomycin, scintinomycin, daunorubicin, doxorubicin, idarubicin, irinotecan, L-asparaginase, mitomycin-C, mitramycin, navelbine, paclitaxel, docetaxel, topotecan, vinblastine vinblastine, vincristine, teniposide (VM-26), and etoposide (VP-16); hormones or steroids, such as 5α-reductase inhibitors, aminoglutethimide, anastrozole, bicalutamide, chlorothiazolidine, diethylstilbestrol (DES), dromostanolone, estramustine, ethinyl estradiol, flutamide, fluoxymesterone, goserelin, hydroxyprogesterone, letrozole, leuprolide, medroxyprogesterone acetate, acetate, megestrol acetate, methylprednisolone, methyltestosterone, mitotane, nilutamide, prednisolone, arzoxifene (SERM-3), tamoxifen, testolactone, testosterone, triamicnolone, and zoladex; synthetic preparations,Such as all-trans retinoic acid, carmustine (BCNU), carboplatin (CBDCA), lomustine (CCNU), cis-diamminedichloroplatinum (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, antimetabolites, such as chlorodeoxyadenosine, cytosine arabinoside, 2'-deoxycoformycin, fludarabine phosphate, 5-fluorouracil (5-FU), 5-fluoro-2'-deoxyuridine (5-FUdR), gemcitabine, camptothecin, 6-mercaptopurine, methotrexate, 4-methylamphetamine (4-MTA) and thioguanine; and biologics, 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.

[0110] Unless otherwise specified, the term "treating" as used herein means reversing, alleviating, inhibiting the development of, or preventing the disorder or condition or one or more symptoms of the disorder or condition to which the term applies. Unless otherwise specified, the term "treatment" as used herein refers to the act of treating as "treating" is defined above.

[0111] As used herein, the following abbreviations refer to what follows the colon:

[0112] DCM: dichloromethane;

[0113] DMF: dimethylformamide;

[0114] DMSO: dimethyl sulfoxide;

[0115] ESI: electrospray ionization;

[0116] HPLC: high performance liquid chromatography;

[0117] LCMS / LC-MS: liquid chromatography mass spectrometry;

[0118] NMI: N-methylimidazole;

[0119] TCFH: N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate;

[0120] TFA: trifluoroacetic acid;

[0121] TLC: thin layer chromatography;

[0122] Y: yield.

[0123] Examples

[0124] Example 1:

[0125] Synthesis of Compound 0031

[0126]

[0127] Step 1: Synthesis of compound I31-8

[0128] At room temperature, ethyl bromide (1.74 mL, 23.29 mmol) was added to a mixed solution of compound I31-7 (3 g, 19.41 mmol), potassium iodide (0.32 g, 1.94 mmol), triethylamine (8.07 mL, 58.23 mmol) and DMF (20 mL), and the mixture was stirred at room temperature for 18 hours. The reaction was completed by LCMS monitoring. Water (20 mL) was added for dilution, ethyl acetate (60 mL*3) was extracted, the organic phases were combined, washed with saturated ammonium chloride solution (20 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by column chromatography (ethyl acetate / petroleum ether (1 / 100 to 1 / 4) eluted silica gel) to obtain compound I31-8 (0.45 g, 2.46 mmol, Y=12.71%) as a white solid.

[0129] LC-MS (ESI): m / z = 183.0 [M+H] +

[0130] Step 2: Synthesis of compound I31-9

[0131] Compound I31-8 (300 mg, 1.64 mmol) was dissolved in aqueous ammonia (8 mL), heated to 80°C and stirred for 2 hours. The reaction was completed by LCMS monitoring. The reaction solution was concentrated to dryness to obtain compound I31-9 (260 mg, 1.59 mmol, Y=96.99%) as a white solid.

[0132] LC-MS (ESI): m / z = 164.2 [M+H] +

[0133] Step 3: Synthesis of compound I31-2

[0134] Under ice bath, add N-bromosuccinimide (2.85 g, 15.99 mmol) to a mixed solution of compound I31-1 (4 g, 15.99 mmol), azobisisobutyronitrile (0.26 g, 1.60 mmol) and tetrachloromethane (40 mL), heat to 80 ° C and stir for 16 hours. LCMS monitors the completion of the reaction. Filter, rinse with dichloromethane (30 mL), and concentrate the filtrate to dryness to obtain compound I31-2 (5 g, 15.20 mmol, Y = 95.06%) as a yellow solid.

[0135] LC-MS(ESI): m / z=327.9 / 329.8[M+H] +

[0136] Step 4: Synthesis of compound I31-4

[0137] At room temperature, potassium carbonate (3.68 g, 26.59 mmol) was added to a mixed solution of compound I31-2 (3.5 g, 10.64 mmol), compound I31-3 (1.93 g, 12.77 mmol) and N,N-dimethylformamide (30 mL), and stirred at room temperature for 2 hours. The reaction was completed by LCMS monitoring. Water (30 mL) was added for dilution, ethyl acetate (80 mL*3) was used for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by column chromatography (ethyl acetate / petroleum ether (1 / 100 to 1 / 20) eluted on silica gel) to obtain compound I31-4 (2.9 g, 7.26 mmol, Y=68.24%) as a yellow solid.

[0138] LC-MS(ESI): m / z=399.1 / 401.1[M+H] +

[0139] Step 5: Synthesis of compound I31-5

[0140] At room temperature, compound I31-4 (2.8 g, 7.01 mmol) was dissolved in a mixed solution of tetrahydrofuran (14 mL) and water (14 mL), sodium hydroxide (0.84 g, 21.04 mmol) was added, and stirred at room temperature for 18 hours. LCMS monitored the reaction to be complete. Concentrate, add saturated ammonium chloride solution to adjust the pH to 6-7, extract with ethyl acetate (40 mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate. The residue was separated and purified by column chromatography (methanol / dichloromethane (1 / 100 to 1 / 10) eluted silica gel) to obtain compound I31-5 (1.8 g, 4.85 mmol, Y=69.14%) as a yellow solid.

[0141] LC-MS(ESI): m / z=370.8 / 372.8[M+H] +

[0142] Step 6: Synthesis of compound I31-6

[0143] At room temperature, [chloro(dimethylamino)methylene]dimethylammonium hexafluoro-λ5-phosphoramide (1.00 g, 3.56 mmol) and 1-methylimidazole (0.83 mL, 10.37 mmol) were added to a mixed solution of compound I31-5 (1.1 g, 2.96 mmol) and acetonitrile (10 mL), respectively, and stirred at room temperature for 18 hours. The reaction was completed by LCMS monitoring. Concentrate, dilute with water (10 mL), extract with ethyl acetate (30 mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate. The residue was separated and purified by column chromatography (ethyl acetate / petroleum ether (1 / 100 to 1 / 4) eluted silica gel) to obtain compound I31-6 (700 mg, 1.98 mmol, Y=66.88%) as a white solid.

[0144] LC-MS(ESI): m / z=351.0 / 353.0[M+H] +

[0145] 1H NMR (400MHz, DMSO) δ: 7.14 (d, J = 8.4Hz, 1H), 6.97 (d, J = 8.4Hz, 1H), 4.81 (d, J = 5.4Hz, 2H), 3.79 (s, 3H), 2.07 (s, 2H), 1.95 (s, 3H)

[0146] Step 7: Synthesis of Compound I31-10

[0147] At room temperature, tris(dibenzylideneacetone)palladium (51.85 mg, 0.06 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (65.52 mg, 0.11 mmol) were added to a mixed solution of compound I31-6 (200 mg, 0.57 mmol), cesium carbonate (461.20 mg, 1.42 mmol), 1-ethylpyrazolo[3,4-d]pyrimidine-4-amine (101.63 mg, 0.62 mmol) and dioxane (6 ml), respectively, and nitrogen was purged 3 times. The temperature was raised to 80 ° C and stirred for 2.5 hours under nitrogen protection. LCMS monitored the completion of the reaction. Dilute with water (5 mL), extract with ethyl acetate (20 mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate. The residue was separated and purified by column chromatography (ethyl acetate / petroleum ether (1 / 100 to 7 / 3) eluted on silica gel) to obtain compound I31-10 (200 mg, 0.46 mmol, Y=81.11%) as a yellow solid.

[0148] LC-MS (ESI): m / z = 436.2 [M+H] +

[0149] Step 8: Synthesis of Compound 0031

[0150] Boron tribromide (4.72 mL, 8.50 mmol, 17% in DCM) was added dropwise to a mixed solution of compound I31-10 (0.37 g, 0.85 mmol) and dichloromethane (5 mL) under ice bath cooling, and the temperature was raised to 40°C for 1 hour. The reaction was completed by LCMS monitoring. The mixture was quenched with methanol and concentrated to dryness. The crude product was prepared by high performance liquid chromatography (Waters-sunfire-10um-19*250mm (eluent = 5% to 40% (v / v) acetonitrile and water with 0.1% NH4HCO3)) to obtain compound 0031 (16 mg, 0.04 mmol, Y = 4.47%) as a white solid.

[0151] LC-MS (ESI): m / z = 422.1 [M+H] +

[0152] 1H NMR (400MHz, DMSO) δ: 13.19 (s, 1H), 9.32 (s, 1H), 8.77 (s, 1H), 8.55 (s, 1H), 6.95 (d, J = 8.2Hz, 1H), 6.78 (d, J=8.2Hz,1H),4.67(d,J=2.8Hz,3H),4.46(q,J=7.1Hz,3H),2.04(s,4H),1.95(s,4H),1.43(t,J=7.2Hz,4H)

[0153] Example 2:

[0154] Synthesis of Compound 0032

[0155]

[0156] Step 1: Synthesis of compound I32-2

[0157] At -78 ° C, boron tribromide (0.91 mL, 0.91 mmol) was added to a solution of compound I32-1 (220 mg, 0.460 mmol) in dichloromethane (4 mL) within 30 minutes, and then the reaction solution was stirred at 25 ° C for 3 hours. LCMS detected that the raw material had been consumed and the product was generated. The reaction solution was concentrated, the residue was quenched with saturated sodium bicarbonate aqueous solution (5 mL), and dichloromethane (15 mL*3) was added for extraction. The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting crude product was purified by silica gel column chromatography (eluent = dichloromethane: methanol = 0 to 10%) to obtain compound I32-2 (130 mg, 0.28 mmol) as a yellow solid.

[0158] LC-MS (ESI): m / z = 468.2 [M+H] +

[0159] Step 2: Synthesis of compound I32-3

[0160] Dess-martin oxidant (508 mg, 1.20 mmol) was added to a dichloromethane solution of compound I32-2 (280 mg, 0.60 mmol), and the reaction solution was stirred at 25 ° C for 3 hours. LCMS detected that the raw material had been consumed and the product was generated. The reaction solution was adjusted to pH 7 with saturated sodium bicarbonate aqueous solution, and dichloromethane (5 mL*3) was added for extraction. The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained crude product was purified by silica gel column chromatography (eluent = dichloromethane: methanol = 0 to 5%) to obtain compound I32-3 (200 mg, 0.36 mmol, Y = 59.70%) as a yellow solid.

[0161] LC-MS (ESI): m / z = 448.1 [M+H] +

[0162] Step 3: Synthesis of Compound 0032

[0163] Boron tribromide (1.34 mL, 1.34 mmol) was added to a solution of compound I32-3 (120 mg, 0.270 mmol) in dichloromethane (2 mL), and the reaction solution was stirred at 25 ° C for 3 hours. LCMS showed that the raw material had been consumed and the product was generated. The reaction solution was quenched with saturated sodium bicarbonate aqueous solution (10 mL), and dichloromethane (15 mL*3) was added for extraction. The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Purification was performed using prep-HPLC (Gilson_306_1741Waters-SunFire-C18-10μm-19*250mm (eluent = 10% to 60% (v / v) acetonitrile and water with 0.1% NH4HCO3) to give compound 0032 (13.86 mg, 0.03 mmol) as a light yellow solid.

[0164] LC-MS (ESI): m / z = 434.1 [M+H] +

[0165] 1 H NMR(400MHz, DMSO-d6)δ:13.22(s,1H),9.51(s,1H),8.77(s,1H),8.55(s,1H),7.44(d,J=7.2Hz,1H),7.03(d ,J=8.2Hz,1H),6.85(d,J=7.4Hz,2H),4.46(q,J=7.2Hz,2H),1.90(s,3H),1.81(s,3H),1.43(t,J=7.2Hz,3H)

[0166] Example 3:

[0167] Synthesis of Compound 0034

[0168]

[0169] Step 1: Synthesis of compound I34-2

[0170] Potassium tert-butoxide (29.22 g, 260.42 mmol) was added to a solution of compound I34-1 (10 g, 52.08 mmol, Bid) in MeOH (200 mL), and the resulting mixture was stirred at 80 ° C for 16 hours. The desired product was detected by LCMS. The reactant was added with water (400 mL), and the mixture was adjusted to pH = 3 with HCl (1 M), the mixture was filtered and the filter cake was washed with H2O (50 mL * 3), and the filtrate was concentrated to dryness under reduced pressure to give a crude product compound I34-2 (10 g, 49.85 mmol, Y = 95.70%) as a white solid. The solid was used directly in the next step without purification.

[0171] LC-MS (ESI): m / z = 188.0 [M+H] +

[0172] Step 2: Synthesis of compound I34-4

[0173] A mixture of compound I34-2 (1.5 g, 8.00 mmol), compound I34-3 (1.45 g, 9.60 mmol, Bid), TCFH (6.73 g, 23.99 mmol) and NMI (2.55 mL, 31.99 mmol) in acetonitrile (30 mL) was stirred at 25 ° C for 16 hours. LCMS detected the desired product. The mixture was concentrated to dryness under reduced pressure to give a crude product. The residue was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 15% (V / V)) to give compound I34-4 (1070 mg, 3.34 mmol, Y = 41.47%) as a yellow solid.

[0174] LC-MS (ESI): m / z = 321.2 [M+H] +

[0175] Step 3: Synthesis of compound I34-6

[0176] Compound I34-5 (0.85 mL, 5.00 mmol, Bid), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (79.84 mg, 0.11 mmol) and Cs2CO3 (3.26 g, 10.01 mmol) were added to a solution of compound I34-4 (1.07 g, 3.34 mmol) in dioxane (16 mL) and H2O (4 mL). The mixture was replaced with N2 three times and heated to 100°C under N2 protection and stirred for 4 hours. LCMS showed that the starting material was completely consumed and the desired product was formed. The mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with brine (20 mL*3), dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 20%) to obtain compound I34-6 (800 mg, 2.56 mmol, Y = 76.78%) as a yellow solid.

[0177] LC-MS (ESI): m / z = 313.2 [M+H] +

[0178] Step 4: Synthesis of Compound I34-7

[0179] Potassium tert-butoxide (0.10 mL, 0.79 mmol) was added to a solution of compound I34-6 (820 mg, 2.63 mmol) in DMF (15 mL), the mixture was replaced 3 times with N2, and the mixture was stirred at 120 ° C under N2 for 16 hours. A black solution was formed. HPLC showed that the starting material was completely consumed and the desired product was formed. The mixture was poured into water (15 mL) and extracted with ethyl acetate (50 mL * 3). The combined organic phase was washed with brine (10 mL * 3), dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure to give a crude product compound I34-7 (200 mg, 0.64 mmol, Y = 24.39%) as a yellow solid. The solid was directly used in the next step without purification.

[0180] LC-MS (ESI): m / z = 313.2 [M+H] +

[0181] Step 5: Synthesis of Compound I34-8

[0182] POCl3 (0.12 mL, 1.28 mmol) was added to a DMF (2 mL) solution of compound I34-7 (200 mg, 0.64 mmol) at 0 ° C, and the resulting mixture was stirred at 80 ° C for 2 hours. LCMS showed that the starting material was completely consumed and the desired product was formed, and the mixture was concentrated to dryness under reduced pressure to obtain a crude product. The residue was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 50%-50%) to obtain compound I34-8 (143 mg, 0.45 mmol, Y = 70%) as a brown oil.

[0183] LC-MS (ESI): m / z = 317.2 [M+H] +

[0184] Step 6: Synthesis of Compound I34-9

[0185] To compound I34-8 (175 mg, 0.55 mmol), compound I31-9 (108.17 mg, 0.66 mmol, Bid), tris(dibenzylideneacetone)palladium (50.59 mg, 0.06 mmol), K2CO3 (229.03 mg, 1.66 mmol) and Xantphos (63.93 mg, 0.11 mmol. A black solution was formed. LCMS showed that the starting material was completely consumed and the desired product was formed. The mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure to give a crude product. The residue was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 50%-50%) to give compound I34-9 (200 mg, 0.45 mmol, Y = 81.63%) as a yellow solid.

[0186] LC-MS (ESI): m / z = 444.4 [M + H] +

[0187] Step 7: Synthesis of Compound 0034

[0188] At 0 ℃, BBr was added to a DCM (3mL) solution of compound I34-9 (150mg, 0.34mmol) (1.69mL, 1.69mmol), and the resulting mixture was stirred at 25 ℃ for 1 hour. LCMS shows that the starting material is completely consumed and the desired product is formed. The reaction mixture is concentrated to dryness under reduced pressure to obtain a crude product, and the mixture is quenched with saturated NH / MeOH (5mL). The crude product is purified by preparative HPLC (eluent = 25% to 55% (v / v) CH CN and H O and 10mmol / L NH HCO) to obtain compound 0034 (88.22mg, 0.20mmol, Y = 60.13%) as a white solid.

[0189] LC-MS (ESI): m / z = 430.2 [M+H] +

[0190] 1H NMR(400MHz,DMSO-d6)δ:11.22(s,1H),9.29(s,1H),8.66–8.64(m,1H),8.61(s,1H),8.58–8.54(m,1H),8.30–8.26(m,1H),6.9 4(d,1H),6.73(d,J=8.2Hz,1H),4.45–4.39(m,2H),3.79–3.75(m,2H),3.29–3.26(m,2H),2.08(s,3H),2.00(s,3H),1.42(t,3H)

[0191] Example 4:

[0192] Synthesis of Compound 0035

[0193]

[0194] Step 1: Synthesis of compound I35-2

[0195] To a solution of compound I35-1 (4 g, 23.31 mmol, Bid) in MeOH (50 mL) was added thionyl chloride (8.46 mL, 116.56 mmol, Bid), and the resulting mixture was stirred at 60 ° C for 18 hours. TLC (petroleum ether: ethyl acetate = 20 / 1) showed the formation of new spots. The mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 100: 1 to 20: 1) to give compound I35-2 (2.5 g, 13.47 mmol, Y = 57.7%) as a white solid.

[0196] LC-MS (ESI): m / z = 186.0 [M+H] +

[0197] Step 2: Synthesis of compound I35-3

[0198] To a solution of compound I35-2 (1.97 g, 10.61 mmol) and azobisisobutyronitrile (0.17 g, 1.06 mmol) in CCl4 (25 mL) was added N-bromosuccinimide (2.08 g, 11.68 mmol), and the resulting mixture was stirred at 80 ° C for 18 hours to obtain a yellow solution. TLC (petroleum ether: ethyl acetate = 10: 1) showed that new spots were formed. The mixture was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was then purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 100: 1 to 10: 1) to obtain a crude compound I35-3 (2.0 g, 3.78 mmol, Y = 35.6%) as a yellow solid.

[0199] LC-MS(ESI): m / z=264.0 / 266.0[M+H] +

[0200] Step 3: Synthesis of compound I35-5

[0201] To a mixture of compound I35-3 (700 mg, 2.65 mmol) and compound I35-4 (480.21 mg, 3.18 mmol) in DMF (15 mL) was added potassium carbonate (914.37 mg, 6.62 mmol, Bid), and the resulting mixture was stirred at 80 ° C for 18 hours. LCMS detected the required mass. The mixture was poured into water (20 mL) and extracted with ethyl acetate (60 mL * 3). The combined organic phases were concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 100: 1 to 4: 1) to give compound I35-5 (0.35 g, 1.05 mmol, Y = 39.5%) as a yellow solid.

[0202] LC-MS (ESI): m / z = 335.0 [M+H] +

[0203] Step 4: Synthesis of compound I35-6

[0204] Compound I35-5 (300 mg, 0.90 mmol) and acetic acid (2 mL) were added to a 5 mL microwave tube, and the resulting mixture was stirred at 120 ° C by microwave for 2 hours, and then cooled to room temperature. TLC (petroleum ether / ethyl acetate = 5 / 1) showed the consumed starting material and the new spots detected. The reaction mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was then purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 50: 1 to 5: 1) to give compound I35-6 (160 mg, 0.53 mmol, Y = 58.9%) as a yellow solid.

[0205] LC-MS (ESI): m / z = 303.2 [M+H] +

[0206] Step 5: Synthesis of Compound I35-8

[0207] To a mixture of compound I35-6 (160 mg, 0.53 mmol), compound I35-7 (86.24 mg, 0.53 mmol), Xantphos (61.16 mg, 0.11 mmol) and cesium carbonate (516.56 mg, 1.59 mmol) in DMF (1 mL) was added tris(dibenzylideneacetone)palladium (48.39 mg, 0.05 mmol), the mixture was replaced 3 times with N2, and stirred for 18 hours at 80°C under N2 protection. A black solution was formed. LCMS showed that the starting material was completely consumed and the desired product was formed. The reaction mixture was poured into water (3 mL) and extracted with ethyl acetate (10 mL*3). The combined organic phase was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 20: 1 to 1: 1) to give compound I35-8 (100 mg, 0.22 mmol, Y = 41.8%) as a yellow solid.

[0208] LC-MS (ESI): m / z = 430.2 [M+H] +

[0209] Step 6: Synthesis of Compound 0035

[0210] At 0°C, BBr (0.11 mL, 1.16 mmol) was added to a DCM (4 mL) solution of compound I35-8 (100 mg, 0.23 mmol), then stirred for 3 hours at 25°C. The mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by preparation (eluent = 30% to 60% (v / v) CHCN and HO with 0.025% NHHCO) to give compound 0035 (38.19 mg, 0.09 mmol, Y = 39.5%) as a white solid.

[0211] LC-MS (ESI): m / z = 416.2 [M+H] +

[0212] 1H NMR(400MHz, DMSO-d6)δ:11.36(s,1H),9.36(s,1H),8.71(d,J=8.6Hz,1H),8.63(d,J=3.6Hz,2H),8.23(d,J=8.6Hz,1H),6.97(d,J =8.3Hz,1H),6.80(d,J=13.2Hz,1H),4.70(d,J=1.9Hz,2H),4.42(q,J=7.2Hz,2H),2.03(s,3H),1.94(s,3H),1.42(t,J=7.2Hz,3H)

[0213] Example 5:

[0214] Synthesis of Compound 0044

[0215]

[0216] Step 1: Synthesis of compound I44-2

[0217] To a solution of compound I44-1 (235 mg, 1.29 mmol, Bid), p-methoxybenzylamine (0.17 mL, 1.32 mmol), XantPhos (127.44 mg, 0.22 mmol) and cesium carbonate (1076.38 mg, 3.30 mmol) in DMF (5 mL) was added tris(dibenzylideneacetone)palladium (100.84 mg, 0.11 mmol). The product MS was obtained by LCMS detection. The mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure to give a crude product. The residue was purified by silica gel chromatography (eluent = DCM: MeOH = 5%-5%) to give compound I44-2 (360 mg, 1.28 mmol).

[0218] LC-MS (ESI): m / z = 283.3 [M+H] +

[0219] Step 2: Synthesis of compound I44-3

[0220] At 0 ° C, trifluoroacetic acid (1 mL, 13.42 mmol) was added to a solution of compound I44-2 (360 mg, 1.28 mmol) in dichloromethane (1 mL). The reaction was stirred at 60 ° C for 3 hours. The product MS was detected by LCMS, and the mixture was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by HPLC (eluent = 25% to 40% (v / v) acetonitrile and water with 0.01% TFA) to obtain compound I44-3 (220 mg, 1.22 mmol) as a white solid.

[0221] LC-MS (ESI): m / z = 163.2 [M+H] +

[0222] Step 3: Synthesis of compound I44-5

[0223] To a solution of 2-bromo-5-(3-methoxy-2,6-dimethylphenyl)-4,5-dihydro-6-pyrrolo[3,4-d]thiazol-6-one (200 mg, 0.57 mmol), compound I44-3 (101.02 mg, 0.62 mmol), XantPhos (65.52 mg, 0.11 mmol) and cesium carbonate (553.44 mg, 1.70 mmol) in DMF (6 mL) was added tris(dibenzylideneacetone)palladium (51.85 mg, 0.06 mmol), the mixture was purged with nitrogen 3 times, and stirred at 90 ° C for 2 hours under nitrogen protection. LCMS detected the desired mass MS. The mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure to obtain a crude product. The residue was purified by HPLC (eluent = 40% to 40% (v / v) acetonitrile and water with 0.01% TFA) to give compound I44-5 (40 mg, 0.09 mmol) as a yellow solid.

[0224] LC-MS (ESI): m / z = 435.3 [M+H] +

[0225] Step 4: Synthesis of Compound 0044

[0226] The solution of compound I44-5 (40mg, 0.09mmol) and boron tribromide (0.46mL, 0.46mmol) in DCM (1mL) was stirred at 25°C for 1 hour to obtain a yellow solution. LCMS detected the required mass MS. The mixture was concentrated to dryness under reduced pressure to obtain a crude product. The reaction mixture was quenched with a methanol solution of ammonia (1M). The crude product was prepared and purified by HPLC (eluent = 27% to 57% (v / v) acetonitrile and water with 10mmol NH4HCO3) to obtain compound 0044 (8.56mg, 0.02mmol) as a white solid.

[0227] LC-MS (ESI): m / z = 421.1 [M+H] +

[0228] 1H NMR(400MHz,DMSO-d6)δ:12.55(s,1H),9.32(s,1H),8.64(s,1H),8.24–8.06(m,1H),7.48–7.27(m,1H),7.00–6.89 (m,1H),6.82–6.73(m,1H),4.69–4.56(m,2H),4.52–4.39(m,2H),2.05(s,3H),1.95(s,3H),1.41(t,J=7.2Hz,3H).

[0229] Example 6:

[0230] Synthesis of Compound 0045

[0231]

[0232] Step 1: Synthesis of compound I45-2

[0233] Under nitrogen protection, sodium hydride (0.78 g, 19.54 mmol, 60% purity) was added to a DMF (20 mL) solution of compound I45-1 (2.00 g, 13.02 mmol, Bid) at 0 ° C, and then iodoethane (1.15 mL, 14.33 mmol) was added to react. The reaction was stirred at 25 ° C for 16 hours. LCMS showed that the required MS was formed. The mixture was poured into a saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (100 mL x2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 100: 0 to 95: 5) to obtain compound I45-2 (1.95 g, 10.74 mmol) as a colorless oil.

[0234] LC-MS (ESI): m / z = 182.1 [M+H] +

[0235] Step 2: Synthesis of compound I45-3

[0236] Compound I45-2 (600 mg, 3.30 mmol) was added to ammonium hydroxide (2 mL, 15.58 mmol, 30% purity) and 1,4-dioxane (2 mL). The reaction was stirred in a microwave tube at 110 ° C for 3 hours. LCMS showed the desired MS was formed. The mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by HPLC (Phenomenex Gemini 150 mm * 25 mm * 10 um column (eluent = 10% to 900% (v / v) acetonitrile and water with 0.01% TFA) to give compound I45-3 (450 mg, 2.77 mmol) as a white solid.

[0237] LC-MS (ESI): m / z = 163.1 [M+H] +

[0238] Step 3: Synthesis of compound I45-4

[0239] To a solution of 2-bromo-5-(3-methoxy-2,6-dimethylphenyl)-4,5-dihydro-6-pyrrolo[3,4-d]thiazol-6-one (150 mg, 0.42 mmol) and compound I45-3 (68.88 mg, 0.42 mmol) in DMF (1.5 mL) were added tris(dibenzylideneacetone)palladium (38.89 mg, 0.04 mmol), Xantphos (49.14 mg, 0.08 mmol) and cesium carbonate (138.36 mg, 0.42 mmol). The reaction was stirred at 80 ° C for 2.5 hours, and LCMS showed that the desired MS was obtained. The mixture was poured into water (5 mL) and extracted with ethyl acetate (20 mL * 3). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by HPLC (Phenomenex Gemini 150mm*25mm*10um column (eluent = 30% to 60% (v / v) acetonitrile and water with 0.025% TFA) to give compound I45-4 (50 mg, 0.11 mmol) as a white solid.

[0240] LC-MS (ESI): m / z = 435.2 [M+H] +

[0241] Step 4: Synthesis of Compound 0045

[0242] Under nitrogen protection at -40°C, boron tribromide (0.58mL, 0.58mmol, 1M) was added to a solution of compound I45-4 (50mg, 0.12mmol) in dichloromethane (2mL) and the reaction was stirred at 25°C for 1 hour. LCMS showed the formation of the desired MS. Methanol (2mL) was added to the reaction to quench and concentrate. The crude product was prepared and purified by HPLC (Phenomenex Gemini 150mm*25mm*10umcolume (eluent = 30% to 60% (v / v) acetonitrile and water with 0.025% NH4HCO3) to obtain compound 0045 (11mg, 0.03mmol) as a white solid.

[0243] LC-MS (ESI): m / z = 421.3 [M+H] +

[0244] 1 H NMR(400MHz, DMSO-d6)δ:12.57(s,1H),9.31(s,1H),8.61(s,1H),7.53(d,J=3.5Hz,1H),7.06(d,J=3.5Hz,1H),6.94(d,J=8 .2Hz,1H),6.77(d,J=8.2Hz,1H),4.63(d,J=3.0Hz,2H),4.33–4.25(m,2H),2.04(s,3H),1.95(s,3H),1.38(t,J=7.2Hz,3H).

[0245] Example 7:

[0246] Synthesis of Compound 0046

[0247]

[0248] Step 1: Synthesis of compound I46-1

[0249] To a solution of compound I31-7 (500 mg, 3.23 mmol, Bid), cyclopropylboranediol (555.77 mg, 6.47 mmol), 2-(pyridin-2-yl)pyridine (431.86 μL, 3.23 mol) and sodium carbonate (685.75 mg, 6.43 mmol) in dichloroethane (15 mL), anhydrous copper acetate (587.57 mg, 3.23 mmol) was added, and the resulting mixture was stirred at 60 ° C for 16 hours under an oxygen atmosphere. LCMS detected the required mass MS. The mixture was filtered and the filtrate was concentrated to dryness, then the residue was diluted with ethyl acetate (30 mL) and washed with 0.1 M HCl (20 mL), and the organic phase was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10:01 to 10:1) to obtain compound I46-1 (70 mg, 0.36 mmol, Y = 11.1%) as a colorless oil.

[0250] LC-MS (ESI): m / z = 195.0 [M+H] +

[0251] Step 2: Synthesis of compound I46-2

[0252] Compound I46-1 (70 mg, 0.36 mmol) was dissolved in aqueous ammonia (3 mL) and stirred at 80° C. for 2 hours. The desired mass MS was detected by LCMS. The reactant was concentrated to dryness under reduced pressure to obtain compound I46-2 (99.86 mg, 0.57 mmol, crude product) as a white solid.

[0253] LC-MS (ESI): m / z = 176.0 [M+H] +

[0254] Step 3: Synthesis of compound I46-3

[0255] To a solution of compound I31-8 (200 mg, 0.57 mmol), compound I46-2 (99.86 mg, 0.57 mmmol) and cesium carbonate (464.29 mg, 1.43 mmol) in DMF (6 mL), tris(dibenzylideneacetone)palladium (52.20 mg, 0.06 mmol) and Xantphos (32.98 mg, 0.06 mmol) were added, and the mixture was replaced with nitrogen 3 times and stirred at 80 ° C for 2 hours under nitrogen protection. LCMS detected the required mass MS. The mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL * 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by Prep-HPLC ((eluent = 0% to 65% (v / v) acetonitrile and water with 0.01% TFA) to give compound I46-3 (90 mg, 0.20 mmol, Y = 35.5%) as a white solid.

[0256] LC-MS (ESI): m / z = 448.2 [M+H] +

[0257] Step 4: Synthesis of Compound 0046

[0258] Under nitrogen protection, boron tribromide (0.56mL, 0.56mmol) was added to a solution of compound I46-3 (50mg, 0.11mmol) in dichloromethane (1mL), and the resulting mixture was stirred at 25°C for 2 hours to obtain a yellow solution. LCMS detected the required mass MS. The reaction was quenched with MeOH (10mL) and concentrated to dryness. The residue was then alkalized to pH=7-8 and spin-dried with a methanol solution of 7M NH to obtain a crude product. The crude product was prepared and purified by HPLC (Waters-Xbridge-C18-10μm-19*250mm (eluent=10% to 95% (v / v) acetonitrile and water with 0.1% NH4HCO3) to obtain compound 0046 (28.76mg, 0.09mmol, Y=41.3%) as a yellow solid.

[0259] LC-MS (ESI): m / z = 434.1 [M+H] +

[0260] 1H NMR(400MHz, DMSO-d6)δ:13.17(s,1H),9.32(s,1H),8.77(s,1H),8.49(s,1H),6.94(d,J=8.3Hz,1H),6.77(d,J=8 .2Hz,1H),4.73-4.58(m,2H),3.97-3.91(m,1H),2.04(s,3H),1.94(s,3H),1.24–1.17(m,2H),1.16–1.10(m,2H).

[0261] Example 8:

[0262] Synthesis of Compound 0047

[0263]

[0264] Step 1: Synthesis of compound I47-2

[0265] Compound I47-1 (2.00 g, 13.11 mmol, Bide) was dissolved in N,N-dimethylformamide (20 mL), sodium hydride (0.47 g, 19.66 mmol, 60% in oil, Energy Chemical) was added under nitrogen protection at 0°C, and after reacting at 0°C for 0.5 hours, iodoethane (1.26 mL, 15.73 mmol, Bide) was added dropwise to the reaction solution, and stirring was continued at 25°C for 3 hours. LCMS detected the target product, and the mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 10: 1-6: 1) to obtain compound I47-2 (1.65 g, 9.13 mmol) as a yellow oil.

[0266] LC-MS (ESI): m / z = 181.0 [M+H] +

[0267] Step 2: Synthesis of Compound I47-3

[0268] Compound I47-2 (500 mg, 2.77 mmol) and tert-butyl carbamate (0.43 mL, 4.15 mmol, Energy Chemical) were dissolved in toluene (15 mL), tris(dibenzylideneacetone)dipalladium (126.74 mg, 0.14 mmol, Energy Chemical), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (131.96 mg, 0.28 mmol, Energy Chemical) and cesium carbonate (1803.80 mg, 5.54 mmol) were added, and stirred at 90°C for 16 hours. The target product was detected by LCMS, and the mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 10: 1-1: 1, R f =0.26) to obtain compound I47-3 (630 mg, 2.41 mmol) as a yellow oil.

[0269] LC-MS (ESI): m / z = 262.5 [M+H] +

[0270] Step 3: Synthesis of Compound I47-4

[0271] Compound I47-3 (300 mg, 1.15 mmol) was added to hydrochloric acid / dioxane (10 mL, 40.00 mmol, Energy Chemical), and the reaction was stirred at 25 ° C for 2 hours. LCMS detected the target product, and the reaction solution was concentrated to obtain yellow oily compound I47-4 (200 mg, 0.91 mmol, crude)

[0272] LC-MS (ESI): m / z = 162.1 [M+H] +

[0273] Step 4: Preparation of Compound I47-5

[0274] Compound I47-4 (200 mg, 0.57 mmol) and 2-bromo-5-(3-methoxy-2,6-dimethylphenyl)-4,5-dihydro-6H-pyrrolo[3,4-d]thiazol-6-one (68.88 mg, 0.42 mmol) were dissolved in N,N-dimethylformamide (4 mL), tris(dibenzylideneacetone)dipalladium (51.85 mg, 0.06 mmol, Energy Chemical), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (65.52 mg, 0.11 mmol, Energy Chemical) and cesium carbonate (553.44 mg, 1.70 mmol) were added, and stirred at 90° C. for 3 hours. The target product was detected by LCMS, and the mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a crude product. The crude product was purified by Prep-HPLC (Phenomenex Gemini 150mm*25mm*10um column (eluent = 30% to 60% (v / v) acetonitrile and water with 0.025% TFA) to give compound I47-5 (51 mg, 0.12 mmol) as a white solid.

[0275] LC-MS (ESI): m / z = 434.2 [M+H] +

[0276] Step 5: Synthesis of Compound 0047

[0277] Compound I47-5 (50 mg, 0.12 mmol) was dissolved in dichloromethane (2 mL), and boron tribromide (0.69 mL, 0.69 mmol, Energy Chemical) was added under nitrogen protection at 0°C, and the reaction was carried out at 25°C for 2 hours. The target product was detected by LCMS, and methanol (2 mL) was added to the reaction solution and concentrated. The crude product was purified by Prep-HPLC (Phenomenex Gemini 150 mm*25 mm*10 um column (eluent = 30% to 60% (v / v) acetonitrile and water with 0.025% NH4HCO3) to obtain compound 0047 (14.48 mg, 0.03 mmol) as a white solid.

[0278] LC-MS (ESI): m / z = 420.3 [M+H] +

[0279] 1H NMR(400MHz,DMSO-d6)δ:11.07(s,1H),9.34(s,1H),8.25–8.09(m,2H),7.50(s,1H),6.97–6.91(m,1H) ,6.88–6.71(m,2H),4.74–4.56(m,2H),4.32–4.22(m,2H),2.04(s,3H),1.94(s,3H),1.43–1.33(m,3H).

[0280] Example 9:

[0281] Synthesis of Compound 0049

[0282]

[0283] Step 1: Synthesis of compound I49-2

[0284] To a mixture of compound I49-1 (5 g, 36.45 mmol, Bid) was added dichloromethane (100 mL), N-bromosuccinimide (6.49 g, 36.45 mmol), and the resulting mixture was stirred at 25 ° C for 3 hours. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0 to 9%) to obtain compound I49-2 (6.5 g, 26 mmol) as a yellow oil.

[0285] LC-MS(ESI): m / z=216.0 / 218.0[M+H] +

[0286] Step 2: Synthesis of compound I49-3

[0287] To a solution of compound I49-2 (6.46 g, 29.90 mmol) in acetonitrile (60 mL) was added N-chlorosuccinimide (3.99 g, 29.90 mmol, Bid), and the resulting mixture was stirred at 80 ° C for 3 hours. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0 to 15%) to give compound I49-3 (2.1 g, 8.38 mmol) as a yellow solid.

[0288] LC-MS(ESI): m / z=250.0 / 252.0[M+H] +

[0289] Step 3: Synthesis of compound I49-4

[0290] To a solution of compound I49-3 (2.1 g, 8.38 mmol) in methanol (10 mL) were added palladium (0) (0.2 g, 0.19 mmol, Anaiji) and acetic acid (0.02 mL, 0.35 mmol, and the resulting mixture was stirred under hydrogen at 25°C for 18 hours. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was filtered through celite and washed with methanol (10 mL*3), and the filtrate was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0 to 20%) to give compound I49-4 (200 mg, 1.17 mmol) as a yellow oil.

[0291] LC-MS (ESI): m / z = 172.0 [M+H] +

[0292] Step 4: Synthesis of Compound I49-6

[0293] N, N-dimethylformamide (5 mL) and potassium carbonate (393.80 mg, 2.85 mmol) were added to a mixed solution of compound I49-5 (500 mg, 1.14 mmol) and compound I49-4 (156.49 mg, 0.91 mmol), and the resulting mixture was stirred at 80 ° C for 4 hours. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was poured into water (15 mL) and extracted with ethyl acetate (20 mL * 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0 to 5%) to give compound I49-6 (150 mg, 0.36 mmol) as a white solid.

[0294] LC-MS(ESI): m / z=419.0 / 421.0[M+H] +

[0295] Step 5: Synthesis of Compound I49-7

[0296] Compound I49-6 (180 mg, 0.43 mmol) was added to a mixed solution of water and methanol (1: 1, 1.5 mL), and sodium hydroxide (51.46 mg, 1.29 mmol, Bide) was added, and the resulting mixture was stirred at 50 ° C for 1 hour. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was concentrated to dryness and the pH was adjusted to 7 with hydrochloric acid (1 M). The mixture was then filtered, and the filtered solid was washed with water (10 mL) and dried under reduced pressure to obtain compound I49-7 (150 mg, 0.38 mmol) as a white solid.

[0297] LC-MS(ESI): m / z=391.1 / 393.1[M+H] +

[0298] Step 6: Synthesis of Compound I49-8

[0299] Compound I49-7 (150 mg, 0.38 mmol) and [chloro(dimethylamino)methylene]dimethylhexafluorohexafluoro-λ5-phosphamide (214.92 mg, 0.77 mmol, Bide) were added to acetonitrile (1.5 mL), and 1-methylimidazole (0.12 mL, 1.53 mmol, Bide) was added, and the resulting mixture was stirred at 25 ° C for 18 hours. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0 to 15%) to obtain compound I49-8 (110 mg, 0.29 mmol) as a white solid.

[0300] LC-MS(ESI): m / z=373.0 / 375.0[M+H] +

[0301] Step 7: Synthesis of Compound I49-10

[0302] To a mixture of compound I49-8 (110 mg, 0.29 mmol), compound I49-9 (57.65 mg, 0.35 mmol), cesium carbonate (287.76 mg, 0.88 mmol, Bid) and [5-(diphenylphosphino)-9,9-dimethyl-9H-flavan-4-yl]diphenylphosphine (34.07 mg, 0.06 mmol, Bid) was added tris[(1E, 4E)-1,5-diphenylpenta-1,4-diene-3-one]bis[palladium (0)] (26.96 mg, 0.03 mmol, Bid), and the reaction solution was stirred at 90 ° C for 3 hours under nitrogen protection. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was poured into water (3 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0 to 50%) to obtain compound I49-10 (70 mg, 0.15 mmol) as a yellow solid.

[0303] LC-MS (ESI): m / z = 456.1 [M+H] +

[0304] Step 8: Synthesis of Compound 0049

[0305] Compound I49-10 (70mg, 0.15mmol) is added to dichloromethane (4mL), tribromoborane (0.77mL, 0.77mmol, Bid) is added, and the resulting mixture is stirred at 25°C for 2 hours to obtain a yellow solution. LCMS shows that the starting material is consumed and the desired product is formed. The reaction mixture is quenched with methanol (1mL), and concentrated to dryness under reduced pressure to obtain a crude product. The crude product is purified by preparative HPLC (Phenomenex Gemini 150mm*25mm*10umcolumn) (eluent=10% to 75% (v / v) acetonitrile and water, 0.025% ammonium bicarbonate) to obtain compound 0049 (22.49mg, 0.05mmol) as a white solid.

[0306] LC-MS (ESI): m / z = 442.1 [M+H] +

[0307] 1 H NMR(400MHz,DMSO-d6)δ:13.23(s,1H),10.17(s,1H),8.76(s,1H),8.54(s,1H),7.12(d,J=8.6Hz,1H) ,6.97(d,J=8.4Hz,1H),4.78-4.66(m,2H),4.46(q,J=7.2Hz,2H),2.12(s,3H),1.43(t,J=7.2Hz,3H).

[0308] Example 10:

[0309] Synthesis of Compound 0050

[0310]

[0311] Step 1: Synthesis of compound I50-3

[0312] At 0°C, compound I50-1 (1.85 mL, 14.58 mmol, Bid) was added to dichloromethane (10 mL), and N-chlorosuccinimide (2.04 g, 15.31 mmol, Bid) was added, and the reactants were stirred at 0°C for 1 hour. TLC showed that the starting material was consumed and a new spot was obtained. The mixture was poured into water (20 mL) and extracted with dichloromethane (30 mL*3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10: 1 to 3: 1) to obtain compound I50-3 (600 mg, 3.50 mmol, Y = 23.9%) as a yellow solid.

[0313] LC-MS (ESI): m / z = 172.1 [M+H] +

[0314] 1 H NMR (400MHz, DMSO-d6) δ: 7.03 (d, J = 8.8 Hz, 1H), 6.27 (d, J = 8.8 Hz, 1H), 4.97 (s, 2H), 3.71 (s, 3H), 1.98 (s, 3H).

[0315] Step 2: Synthesis of compound I50-4

[0316] Compound I50-3 (417.30 mg, 2.43 mmol) and compound I50-2 (800 mg, 2.43 mmol) were added to N, N-dimethylformamide (5 mL), potassium carbonate (840.10 mg, 6.08 mmol) was added, the temperature was raised to 80 ° C and stirred for 16 hours. LCMS showed that the raw material was completely consumed and the product was mainly generated. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10: 1 to 5: 1) to obtain compound I50-4 (407 mg, 0.97 mmol) as a white solid.

[0317] LC-MS(ESI): m / z=419.0 / 421.0[M+H] +

[0318] Step 3: Synthesis of compound I50-5

[0319] Compound I50-4 (400 mg, 0.95 mmol) was added to a mixed solution of tetrahydrofuran (5 mL) and water (5 mL), and sodium hydroxide (114.36 mg, 2.86 mmol) was added. The mixture was heated to 50°C and stirred for 1 hour. LCMS showed that the raw material was completely consumed and the product was mainly generated. The mixture was poured into water (5 mL), adjusted to pH = 4 with hydrochloric acid (1 M), and extracted with ethyl acetate (30 mL x 1). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain compound I50-5 (270 mg, 0.69 mmol) as a white solid.

[0320] LC-MS(ESI): m / z=390.8 / 392.8[M+H] +

[0321] Step 4: Synthesis of Compound I50-6

[0322] Compound I50-5 (260 mg, 0.66 mmol) was added to acetonitrile (3 mL), and TCFH (465.65 mg, 1.66 mmol, Anaiji) and methylimidazole (0.21 mL, 2.64 mmol, Anaiji) were added respectively, and the reactants were stirred at 25 ° C for 16 hours. LCMS showed that the raw materials were completely consumed, and the main product was the product. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x2). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10: 1 to 7: 1) to obtain compound I50-6 (200 mg, 0.54 mmol) as a white solid.

[0323] LC-MS(ESI): m / z=372.8 / 374.8[M+H] +

[0324] Step 5: Synthesis of Compound I50-8

[0325] Under nitrogen protection, compound I50-6 (200 mg, 0.57 mmol) and compound I50-7 (68.88 mg, 0.42 mol) were added to dioxane (2 mL), and tris(dibenzylideneacetone)dipalladium (36.76 mg, 0.04 mmol, Anaiji), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (46.46 mg, 0.08 mmol, Anaiji) and cesium carbonate (392.40 mg, 1.20 mmol) were added respectively, and the temperature was raised to 80 ° C and stirred for 2.5 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10 / 1-1 / 1) to obtain compound I50-8 (123 mg, 0.27 mmol) as a yellow oil.

[0326] LC-MS (ESI): m / z = 456.0 [M+H] +

[0327] Step 6: Synthesis of Compound 0050

[0328] Under nitrogen protection, compound I50-8 (123 mg, 0.27 mmol) was added to dichloromethane (2 mL), and then boron tribromide (1.35 mL, 1.35 mmol, 1 moL / L, Anaiji) was added and stirred at 0 ° C for 2 hours. 2 mL of methanol was added to the reactant to quench and concentrate to dryness. The crude product was purified by preparative high performance liquid chromatography (Agilent-porous body HPH-C18-2.7um-4.6*50mm (eluent = 20% to 80% (v / v) acetonitrile and water 0.025% ammonium bicarbonate) to give compound 0050 (57.72 mg, 0.14 mmol) as a white solid.

[0329] LC-MS (ESI): m / z = 442.2 [M+H] +

[0330] 1 H NMR(400MHz,DMSO-d6)δ:13.24(s,1H),9.91(s,1H),8.78(s,1H),8.54(s,1H),7.24(d,J=12Hz,1 H), 6.91 (d, J = 8Hz, 1H), 4.78–4.64 (m, 2H), 4.50–4.42 (m, 2H), 2.02 (s, 3H), 1.43 (t, J = 7.2Hz, 3H).

[0331] Example 11:

[0332] Synthesis of Compound 0051

[0333]

[0334] Step 1: Synthesis of compound I51-2

[0335] Under nitrogen protection, compound I51-1 (1.0 g, 4.91 mmol) and sodium tert-butoxide (0.48 g, 4.96 mmol, Bid) were added to isopropanol (15 mL), and allyl [1,3-bis (2,6-diisopropylphenyl) imidazole-2-ylidene] chloropalladium (II) (0.07 g, 0.12 mmol, Bid) was added, and the resulting mixture was stirred at 120 ° C for 1 hour to obtain a black solution. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was filtered and the filtered solid was washed with ethyl acetate (10 mL * 3), and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0 to 5%) to obtain compound I51-2 (740 mg, 4.37 mmol) as a yellow solid.

[0336] LC-MS (ESI): m / z = 170.2 [M+H]+

[0337] Step 2: Synthesis of compound I51-4

[0338] Compound I51-3 (1.94 g, 4.43 mmol) and compound I51-2 (0.60 g, 3.55 mmol) were added to DMF (15 mL), followed by potassium carbonate (1.53 g, 11.08 mmol, Bid), and the resulting mixture was stirred at 80 ° C for 2 hours. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was poured into water (30 mL) and extracted with ethyl acetate (75 mL * 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0 to 5%) to give compound I51-4 (1.0 g, 2.40 mmol) as a yellow solid.

[0339] LC-MS(ESI): m / z=417.0 / 419.0[M+H] +

[0340] Step 3: Synthesis of compound I51-5

[0341] Compound I51-4 (500 mg, 1.20 mmol) was added to a mixed solution of tetrahydrofuran (2.5 mL) and water (2.5 mL), and sodium hydroxide (143.78 mg, 3.59 mmol, Bid) was added. The resulting mixture was stirred at 25 ° C for 18 hours. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was adjusted to pH = 7 with hydrochloric acid (1 M), filtered, and the filter cake was washed with water (10 mL) and dried under reduced pressure to obtain compound I51-5 (320 mg, 0.82 mmol) as a white solid.

[0342] LC-MS(ESI): m / z=389.0 / 391.0[M+H] +

[0343] Step 4: Synthesis of Compound I51-6

[0344] Compound I51-5 (440 mg, 1.13 mmol) and [chloro(dimethylamino)methylene]dimethylhexafluoro-λ5-ammonium phosphide (634.34 mg, 2.26 mmol, Bid) were added to acetonitrile (10 mL), and 1-methylimidazole (0.36 mL, 4.52 mmol, Bid) was added, and the resulting mixture was stirred at 25 ° C for 18 hours. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was poured into water (15 mL) and extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0 to 5%) to give compound I51-6 (317 mg, 0.85 mmol) as a white solid.

[0345] LC-MS(ESI): m / z=371.1 / 373.1[M+H] +

[0346] Step 5: Synthesis of Compound I51-8

[0347] Compound I51-6 (100 mg, 0.27 mmol), compound I51-7 (48.35 mg, 0.30 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (31.17 mg, 0.05 mmol, Bide) and cesium carbonate (263.31 mg, 0.81 mmol, Bide) were added to N,N-dimethylformamide (1.5 mL), and tris(dibenzylideneacetone)dipalladium (24.67 mg, 0.03 mmol, Bide) was added, the mixture was degassed and purged with nitrogen three times, and the mixture was heated to 90 ° C and stirred for 2.5 hours under N2 protection. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was poured into water (5 mL) and extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0 to 50%) to give compound I51-8 (100 mg, 0.22 mmol) as a brown solid.

[0348] LC-MS (ESI): m / z = 454.0 [M+H] +

[0349] Step 6: Synthesis of Compound 0051

[0350] Compound I51-8 (110 mg, 0.24 mmol) was added to dichloromethane (4 mL), and then boron tribromide (1.21 mL, 1.21 mmol, 1 M, Bid) was added, and the resulting mixture was stirred at 25 ° C for 2 hours. LCMS showed that the starting material was consumed and the desired product was formed. Methanol was added to quench, and the mixture was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative chromatography (Phenomenex Gemini 150 mm * 25 mm * 10 um column (eluent = 10% to 75% (v / v) acetonitrile and water 0.025% ammonium bicarbonate) to obtain compound 0051 (58.44 mg, 0.13 mmol) as a white solid.

[0351] LC-MS (ESI): m / z = 440.2 [M+H] +

[0352] 1 H NMR(400MHz,DMSO-d6)δ:13.22(s,1H),9.83(s,1H),8.76(s,1H),8.55(s,1H),6.68(d,J=11 .1Hz, 1H), 4.69 (s, 2H), 4.46 (q, J = 7.2Hz, 2H), 1.93 (d, J = 11.1Hz, 6H), 1.43 (t, J = 7.2Hz, 3H).

[0353] Example 12:

[0354] Synthesis of Compound 0052

[0355]

[0356] Step 1: Synthesis of compound I52-3

[0357] Compound I52-2 (2 g, 4.56 mmol) and compound I52-1 (0.62 g, 3.65 mmol) were added to N, N-dimethylformamide (15 mL), followed by potassium carbonate (1.58 g, 11.40 mmol). The resulting mixture was stirred at 80 ° C for 2 hours to obtain a yellow solution. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL * 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The residue was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 3% to 30%) to obtain compound I52-3 (830 mg, 1.99 mmol) as a yellow solid.

[0358] LC-MS(ESI): m / z=417.0 / 419.0[M+H] +

[0359] Step 2: Synthesis of compound I52-4

[0360] Compound I52-3 (800 mg, 1.92 mmol) and sodium hydroxide (230.06 mg, 5.75 mmol) were added to tetrahydrofuran (4 mL) and water (4 mL), respectively, and the resulting mixture was stirred at 50° C. for 1 hour to obtain a yellow solution. The mixture was concentrated, the pH of the mixture was adjusted to 6-7 with citric acid, extracted with ethyl acetate (20 mL*3), and the combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain compound I52-4 (800 mg, 1.85 mmol) as a yellow oil.

[0361] LC-MS(ESI): m / z=389.1 / 391.1[M+H] +

[0362] Step 3: Synthesis of compound I52-5

[0363] Compound I52-4 (750 mg, 1.93 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (1081.26 mg, 3.85 mmol) were added to acetonitrile (5 mL), and methylimidazole (0.61 mL, 7.71 mmol) was added, and the resulting mixture was stirred at 25 ° C for 16 hours to obtain a yellow solution. The mixture was poured into water (15 mL) and extracted with ethyl acetate (25 mL*3). The combined organic phase was washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 20%-20%) to obtain compound I52-5 (610 mg, 1.64 mmol) as a yellow solid.

[0364] LC-MS(ESI): m / z=371.1 / 373.1[M+H] +

[0365] Step 4: Synthesis of Compound I52-7

[0366] Under nitrogen protection, compound I52-5 (200 mg, 0.54 mmol), compound I52-6 (96.71 mg, 0.59 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (62.35 mg, 0.11 mmol) and cesium carbonate (526.62 mg, 1.62 mmol) were added to N,N-dimethylformamide (3 mL), and tris(dibenzylideneacetone)dipalladium (49.34 mg, 0.05 mmol) was added. The reaction was stirred at 90 ° C for 2 hours to form a black solution. The mixture was poured into water (5 mL) and extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 50% to 50%) to obtain compound I52-7 (170 mg, 0.37 mmol) as a brown solid.

[0367] LC-MS (ESI): m / z = 454.3 [M+H] +

[0368] Step 5: Synthesis of Compound 0052

[0369] At 0 ° C, compound I52-7 (170 mg, 0.37 mmol) was added to a dichloromethane (2 mL) solution, and boron tribromide (0.18 mL, 1.87 mmol, 1 M, Anaiji) was added, and the resulting mixture was stirred at 25 ° C for 1 hour to obtain a yellow solution. The mixture was concentrated to dryness under reduced pressure to obtain a crude product, which was quenched with ammonia methanol (2 M, 2 mL). The mixture was purified by preparative HPLC (Waters-Xbridge-C18-10um 19*250mm (eluent = 20% to 50% (v / v) acetonitrile and water with 10m% ammonium bicarbonate) to obtain compound 0052 (27.20 mg, 0.06 mmol) as a white solid.

[0370] LC-MS (ESI): m / z = 440.3 [M + H] +

[0371] 1 H NMR(400MHz, DMSO-d6)δ:13.20(s,1H),9.42–9.37(m,1H),8.76(s,1H),8.55(s,1H),7.00(d,J=11 .4Hz,1H),4.73–4.63(m,2H),4.50–4.42(m,2H),2.06(s,3H),2.00(s,3H),1.43(t,J=7.2Hz,3H).

[0372] Example 13:

[0373] Synthesis of Compound 0053

[0374] Step 1: Synthesis of compound I53-3

[0375] Compound I53-1 (0.36 mL, 3.70 mmol, Bid), compound I53-2 (1.20 mL, 5.55 mmol, Bid) and potassium carbonate (767.04 mg, 5.55 mmol) were added to N, N-dimethylformamide (5 mL), and the resulting mixture was stirred at 25 ° C for 16 hours to obtain a yellow solution. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL * 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The residue was purified by silica gel chromatography (eluent = ethyl acetate) to obtain compound I53-3 (350 mg, 1.19 mmol, Y = 32.23%) as a yellow solid.

[0376] LC-MS (ESI): m / z = 294.3 [M+H] +

[0377] Step 2: Synthesis of compound I53-4

[0378] Under nitrogen protection, compound I31-8 (200 mg, 0.57 mmol), compound I53-3 (182.77 mg, 0.62 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (65.52 mg, 0.11 mmol) and cesium carbonate (553.44 mg, 1.70 mmol) were added to N,N-dimethylformamide (5 mL), and tris(dibenzylideneacetone)dipalladium (51.85 mg, 0.06 mmol) was added. Stir at 90 ° C for 2 hours to form a black solution. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The residue was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0% to 70%) to give compound I53-4 (240 mg, 0.42 mmol, Y = 74.92%) as a brown oil.

[0379] LC-MS (ESI): m / z = 566.4 [M+H] +

[0380] Step 3: Synthesis of compound I53-5

[0381] Compound I53-4 (200 mg, 0.35 mmol) was added to a tetrahydrofuran (1 mL) solution, and tetrabutylammonium fluoride (0.18 mL, 0.18 mmol, 1 M) was added. The resulting mixture was stirred at 25 ° C for 1 hour to obtain a yellow solution. The reaction mixture was quenched with saturated ammonium chloride (5 mL). It was extracted with ethyl acetate (10 mL * 3), and the combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain compound I53-5 (140 mg, 0.31 mmol, Y = 87.71%) as a yellow solid.

[0382] LC-MS (ESI): m / z = 452.3 [M+H] +

[0383] Step 4: Synthesis of Compound 0053

[0384] Compound I53-5 (140 mg, 0.31 mmol) was added to dichloromethane (2 mL), and boron tribromide (1.33 mmol, 1.33 mL, 1 M, Anaiji) was added, and the resulting mixture was stirred at 25 ° C for 1 hour to give a yellow solution. The mixture was concentrated to dryness under reduced pressure to give a crude product, and the reaction mixture was quenched with ammonia methanol (1 M). The crude product was purified by preparative HPLC ((eluent = 17% to 47% (v / v) acetonitrile and water with 0.1% FA) to give compound 0053 (67.11 mg, 0.15 mmol, Y = 57.72%) as a white solid.

[0385] LC-MS (ESI): m / z = 438.3 [M+H] +

[0386] 1 H NMR(400MHz, DMSO-d6)δ:13.14(s,1H),9.32(s,1H),8.72(s,1H),8.51(s,1H),6.94(d,J=8.3Hz,1H),6.78(d,J=8 .2Hz,1H),4.87(s,1H),4.70–4.60(m,2H),4.45(t,J=5.8Hz,2H),3.85(t,J=6.0Hz,2H),2.04(s,3H),1.95(s,3H).

[0387] Example 14:

[0388] Synthesis of Compound 0054

[0389]

[0390] Step 1: Synthesis of compound I54-2

[0391] Under an ice bath, thionyl chloride (2 mL) was added dropwise to a mixed solution of dichloromethane (3 mL) and compound I54-1 (0.34 mL, 3.37 mmol, Bid), and the reaction solution was stirred at 25 ° C for 18 hours. TLC showed that the starting material point disappeared, and spots with less polarity were observed to be generated. The reaction solution was concentrated to dryness to obtain compound I54-2 (450 mg, 3.12 mmol, crude product) as a white solid. It was used directly in the next step without further treatment.

[0392] Step 2: Synthesis of compound I54-3

[0393] Potassium carbonate (2061.80 mg, 14.92 mmol) was added to a mixed solution of compound I54-2 (450 mg, 3.12 mmol, crude product) and compound I53-1 (420 mg, 3.11 mmol, Bid) in N, N-dimethylformamide (10 mL), and the reaction solution was stirred at 60 ° C for 2 hours. The target molecular weight was detected by LCMS. The reaction solution was filtered, and the filter cake was washed with N, N-dimethylformamide (5 mL x2), and the organic phases were combined and purified by preparative HPLC ((eluent = 0% to 8% (v / v) CH3CN and H2O with 0.01% NH4HCO3) to obtain compound I54-3 (350 mg, 1.70 mmol, Y = 54.60%) as a white solid.

[0394] LC-MS (ESI): m / z = 207.1 [M+H] +

[0395] Step 3: Synthesis of compound I54-4

[0396] Compound I31-8 (120 mg, 0.34 mmol), a stirrer, compound I54-3 (259.25 mg, 1.26 mmol), cesium carbonate (276.72 mg, 0.85 mmol) and N, N-dimethylformamide (6 mL) were added to a 10 mL microwave tube, the resulting mixed solution was purged with nitrogen for 5 minutes, tris (dibenzylideneacetone) dipalladium (31.11 mg, 0.03 mmol) and 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (39.31 mg, 0.07 mmol) were added to the reaction solution, and then the resulting mixture was purged with nitrogen for 5 minutes, the reaction solution was microwaved at 90 ° C for 2.5 hours, and then cooled to room temperature. The target molecular weight was detected by LCMS. The reaction solution was then poured into water (20 mL) and extracted with ethyl acetate (30 mL*3), the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by preparative HPLC ((eluent = 0% to 45% (v / v) CH3CN and H2O with 0.01% NH4HCO3) to give compound I54-4 (150 mg, 0.31 mmol, Y = 92.0%) as a yellow solid.

[0397] LC-MS (ESI): m / z = 479.2 [M+H] +

[0398] Step 4: Synthesis of Compound 0054

[0399] At room temperature, a dichloromethane (15 mL) solution of compound I54-4 (150 mg, 0.31 mmol) was added dropwise with a dichloromethane solution of boron tribromide (3.13 mL, 1 M / L), and the reaction solution was stirred at 25 ° C for 18 hours. The target molecular weight was detected by LCMS. The reaction solution was quenched with methanol (5 ml). Then the reaction solution was alkalized to pH = 8-9 with 4 mL of ammonia methanol solution (7 M / L). The reaction solution was concentrated to dryness to obtain a crude compound. The crude product was purified by preparative HPLC (Phenomenex Gemini 150mm*25mm*10um column (eluent = 5% to 55% (v / v) CH3CN and H2O, 0.1% HCOOH) to obtain compound 0054 (2.75 mg, 0.01 mmol, Y = 1.85%) as a white solid.

[0400] LC-MS (ESI): m / z = 465.0 [M+H] +

[0401] 1H NMR(400MHz, DMSO-d6)δ:8.72(s,1H),8.49(s,1H),8.19(s,1H),6.94(d,J=8.4Hz,1H),6.77(d,J=8.2Hz,1H ),4.64(d,J=2.8Hz,2H),4.50(t,J=6.4Hz,2H),2.77(t,J=6.4Hz,2H),2.17(s,6H),2.04(s,3H),1.95(s,3H)

[0402] Example 15:

[0403] Synthesis of Compound 0055

[0404]

[0405] Step 1: Synthesis of compound I55-2

[0406] Boron tribromide (3.26 mL, 3.26 mmol, 1 moL / L) was added to a dichloromethane (2 mL) solution of compound I55-1 (230 mg, 0.65 mmol) under a nitrogen environment of -40 °C. The reaction solution was stirred at -40 °C for 2 hours. Methanol (2 mL) was added to the reaction solution to quench it, and then concentrated. The concentrated reaction solution was poured into water (20 mL) and extracted with dichloromethane (30 mL x2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain compound I55-2 (180 mg, 0.53 mmol) as a yellow solid.

[0407] LC-MS(ESI): m / z=338.9 / 340.9[M+H] +

[0408] Step 2: Synthesis of compound I55-4

[0409] At room temperature, 3-iodooxetane (0.76 mL, 8.88 mmol, Bid) and cesium carbonate (4.82 g, 14.80 mmol) were added to a solution of compound I55-3 (0.72 mL, 7.40 mmol, Bid) in N, N-dimethylformamide (20 mL), and the reaction solution was stirred at 80 ° C for 3.5 hours. The suspension was filtered through diatomaceous earth, and the filter residue was washed with ethyl acetate (20 mL * 3), and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (Phenomenex Gemini 150 mm * 25 mm * 10 um column (eluent = 30% to 60% (v / v) CH3CN and H2O with 0.025% NH4HCO3) to obtain compound I55-4 (150 mg, 0.78 mmol) as a white solid.

[0410] LC-MS (ESI): m / z = 192.0 [M+H] +

[0411] 1 H NMR (400MHz, DMSO-d6) δ: 8.23 ​​(s, 1H), 8.18 (s, 1H), 7.77 (d, J = 6.6Hz, 2H), 5.98–5.88 (m, 1H), 5.06-5.00 (m, 2H), 4.99–4.94 (m, 2H).

[0412] Step 3: Synthesis of Compound 0055

[0413] Under nitrogen, compound I55-4 (96.6 mg, 0.51 mmol), tris(dibenzylideneacetone)dipalladium (46.43 mg, 0.05 mmol, Bid), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (58.68 mg, 0.10 mmol, Bid) and cesium carbonate (495.63 mg, 1.52 mmol) were added to a solution of compound I55-2 (172 mg, 0.51 mmol) in N,N-dimethylformamide (5 mL) in sequence. The reaction solution was stirred at 90 ° C for 2.5 hours. The reaction solution was quenched with dilute hydrochloric acid (1M, 10 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (Waters-CORTECS-C18-2.7 μm-4.6*30 mm (A: 10 mM NH4HCO3 / H2O b: acetonitrile, b / A=5 to 95%)) to give Compound 0055 (8.55 mg, 0.02 mmol) as a yellow solid.

[0414] LC-MS (ESI): m / z = 450.2 [M+H] +

[0415] 1 H NMR (400MHz, DMSO-d6) δ: 13.28 (s, 1H), 9.32 (s, 1H), 8.76 (s, 1H), 8.65 (s, 1H), 6.94 (d, J = 8.1Hz, 1H), 6. 78(d,J=8.2Hz,1H),6.16–6.04(m,1H),5.12–4.96(m,4H),4.73–4.58(m,2H),2.04(s,3H),1.95(s,3H).

[0416] Example 16:

[0417] Synthesis of Compound 0056

[0418]

[0419] Step 1: Synthesis of compound I56-2

[0420] At 0°C, sodium hydride (62.49 mg, 60% purity, 1.56 mmol) was added to a mixture of compound I56-1 (200 mg, 1.04 mmol, Leyan) and N, N-2-methylformamide (2 mL), the mixture was replaced with nitrogen 3 times, stirred for 30 minutes, and then compound I31-2 (513.97 mg, 1.56 mmol) was added and stirred at 25°C for 1 hour. A black solution was formed. The reaction mixture was quenched with aqueous ammonium chloride solution (5 mL). And extracted with ethyl acetate (15 mL*3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0% to 5%) to obtain compound I56-2 (150 mg, 0.34 mmol, Y = 32.72%) as a yellow solid.

[0421] LC-MS(ESI): m / z=441.0 / 443.0[M+H] +

[0422] Step 2: Synthesis of compound I56-3

[0423] Sodium hydroxide (40.90 mg, 1.02 mmol) was added to a mixed solution of tetrahydrofuran (2 ml) and water (2 ml) of compound I56-2 (150 mg, 0.34 mmol), and the resulting mixture was stirred at 50 ° C for 4 hours to obtain a yellow solution. The reaction mixture was quenched with citric acid aqueous solution and extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound I56-3 (130 mg, 0.32 mmol, Y=92.57%) as a yellow solid.

[0424] LC-MS(ESI): m / z=413.0 / 415.0[M+H] +

[0425] Step 3: Synthesis of compound I56-4

[0426] N-methylimidazole (0.13 ml, 1.65 mmol) was added to a solution of compound I56-3 (170 mg, 0.41 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (231.50 mg, 0.83 mmol), and the resulting mixture was stirred at 25 ° C for 16 hours to obtain a yellow solution. The mixture was poured into water (15 mL) and extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0%-45%) to obtain compound I56-4 (150 mg, 0.38 mmol, Y = 92.27%) as a yellow solid.

[0427] LC-MS(ESI): m / z=395.0 / 397.0[M+H] +

[0428] Step 4: Synthesis of compound I56-5

[0429] To a solution of compound I56-4 (130 mg, 0.33 mmol), compound I31-9 (59.22 mg, 0.36 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (38.18 mg, 0.07 mmol) and cesium carbonate (322.46 mg, 0.99 mmol) in N,N-dimethylformamide (3 ml) was added tri(dibenzylideneacetone)dipalladium (30.21 mg, 0.03 mmol), the mixture was replaced with nitrogen 3 times, and stirred at 90° C. for 2 hours. A black solution was formed. The mixture was poured into water (5 mL) and extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0% - 50%) to obtain compound I56-5 (164 mg, 0.31 mmol, Y = 93.93%) as a brown solid.

[0430] LC-MS(ESI): m / z=476.2 / 478.2[M+H] +

[0431] Step 5: Synthesis of Compound 0056

[0432] Compound I56-5 (164 mg, 0.31 mmol) was stirred at 65 ° C for 16 hours in a mixed solution of hydrobromic acid acetic acid solution (1 mL, 33%, wt) to give a yellow solution. The mixture was concentrated under reduced pressure to give a crude product, which was quenched with ammonia methanol solution (1 M) and concentrated. The crude product was purified by preparative HPLC (eluent = 17% to 47% (v / v) acetonitrile and water with 0.1% ammonium bicarbonate) to give 0056 (3.36 mg, 0.01 mmol, Y = 2.04%) as a white solid.

[0433] LC-MS(ESI): m / z=462.0 / 464.0[M+H] +

[0434] 1 H NMR(400MHz, DMSO-d6)δ:13.28(s,1H),10.78(s,1H),8.76(s,1H),8.52(s,1H),7.43(d,J= 9.0Hz,1H),7.09(d,J=8.8Hz,1H),4.72(s,2H),4.46(q,J=7.2Hz,2H),1.43(t,J=7.2Hz,3H)

[0435] Example 17:

[0436] Synthesis of Compound 0057

[0437]

[0438] Step 1: Synthesis of compound I57-3

[0439] At room temperature, compound I57-2 (2.80 mL, 19.41 mmol, Bide) and cesium carbonate (8.43 g, 25.88 mmol) were added to a solution of compound I57-1 (2 g, 12.94 mmol, Bide) in N,N-dimethylformamide (20 mL). The reaction solution was stirred at 25 ° C for 2 hours. The reaction solution was poured into water (200 mL) and extracted with ethyl acetate (100 mL*3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (eluent = petroleum ether: ethyl acetate = 10: 1 to 8: 1) to obtain compound I57-3 (650 mg, 2.75 mmol) as a yellow oil.

[0440] LC-MS (ESI): m / z = 237.0 [M+H] +

[0441] 1 H NMR (400MHz, DMSO-d6) δ8.98 (s, 1H), 8.67 (s, 1H), 5.49 (q, J = 9.0Hz, 2H).

[0442] Step 2: Synthesis of compound I57-4

[0443] At room temperature, compound I57-3 (640 mg, 2.71 mmol) was mixed with aqueous ammonia (6 mL, 45.18 mmol, 29%, Bid) and stirred at 80°C for 2 hours. The reaction solution was lyophilized to obtain compound I57-4 (680 mg, 3.13 mmol) as a yellow solid, which was used directly in the next step without further purification.

[0444] LC-MS (ESI): m / z = 218.0 [M+H] +

[0445] Step 3: Synthesis of compound I57-6

[0446] Under nitrogen environment, compound I57-5 (68.88 mg, 0.42 mmol), tris(dibenzylideneacetone)dipalladium (51.85 mg, 0.06 mmol, Anaiji), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (65.52 mg, 0.11 mmol, Anaiji) and cesium carbonate (553.44 mg, 1.70 mmol) were added to a solution of compound I57-4 (200 mg, 0.57 mmol) in N,N-dimethylformamide (3 mL) in sequence. The reactants were stirred at 90 ° C for 2.5 hours. The reaction solution was poured into water (20 mL) and extracted with ethyl acetate (30 mL * 3), and the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent = petroleum ether:ethyl acetate = 3:1 to 0:1) to obtain compound I57-6 (230 mg, 0.47 mmol) as a yellow solid.

[0447] LC-MS (ESI): m / z = 490.0 [M+H] +

[0448] Step 4: Synthesis of Compound 0057

[0449] Under nitrogen environment, boron tribromide (2.30mL, 2.30mmol, 1mol / L, Anaiji) solution was added dropwise to a solution of compound I57-6 (225mg, 0.46mmol) in dichloromethane (2mL) at -40°C. After the addition was complete, the temperature was raised to 25°C and stirred for 2 hours. The reaction solution was quenched with methanol (2mL) and then concentrated to give a crude product. The crude product was purified by preparative high performance liquid chromatography (Agilent-Poroshell HPH-C18-2.7um-4.6*50mm (eluent = 20% to 80% (v / v) CH3CN and H2O, 0.025% NH4HCO3) to give compound 0057 (64.89mg, 0.14mmol) as a white solid.

[0450] LC-MS (ESI): m / z = 476.2 [M+H] +

[0451] 1 H NMR(400MHz,DMSO-d6)δ:13.32(s,1H),9.33(s,1H),8.84(s,1H),8.67(s,1H),6.95(d,J=8.3Hz,1 H), 6.78 (d, J = 8.2Hz, 1H), 5.39 (d, J = 9.0Hz, 2H), 4.68 (d, J = 2.8Hz, 2H), 2.04 (s, 3H), 1.95 (s, 3H).

[0452] Example 18:

[0453] Synthesis of Compound 0060

[0454]

[0455] Step 1: Synthesis of compound I31-10

[0456] Under nitrogen, cesium carbonate (461.20 mg, 1.42 mmol), tris(dibenzylideneacetone)dipalladium (51.85 mg, 0.06 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (65.52 mg, 0.11 mmol) were added to a mixed solution of ethylene glycol dimethyl ether (10 mL) of compound I31-8 (200 mg, 0.57 mmol) and compound I31-9 (93.01 mg, 0.57 mmol) in sequence, and the reaction solution was stirred at 100 ° C for 2 hours. The target molecular weight was detected by LCMS. The reaction solution was poured into water (20 mL) and extracted with ethyl acetate (30 mL*3), and the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent = petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain compound I31-10 (150 mg, 0.21 mmol, Y = 37.7%) as a yellow solid.

[0457] LC-MS (ESI): m / z = 436.1 [M+H] +

[0458] Step 2: Synthesis of compound I60-1

[0459] At -65 ° C, lithium bis(trimethylsilyl)amide (52.50 μL, 0.05 mmol) (1M hexane solution) was added dropwise to a solution of compound I31-10 (50 mg, 0.07 mmol) in tetrahydrofuran (1.5 mL), and stirred at -65 ° C for 20 minutes after the addition was complete. Then, a solution of N-(dioxophenyl-λ6-sulfenyl)-N-fluorobenzenesulfonamide (13.24 mg, 0.04 mmol) in tetrahydrofuran (0.5 mL) was added dropwise to the solution, and stirred at -65 ° C for another 30 minutes, warmed to 25 ° C, and stirred for another 30 minutes. The reaction solution was then quenched with a saturated ammonium chloride solution (3 mL), extracted with ethyl acetate (30 mL*3), and the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC ((eluent = 5% to 65% (v / v) CH3CN and H2O, containing 0.01% TFA) to give compound I60-1 (50 mg, 0.04 mmol, Y = 63.6%) as a yellow solid.

[0460] LC-MS (ESI): m / z = 472.0 [M+H] +

[0461] Step 3: Synthesis of Compound 0060

[0462] Boron tribromide (0.34 mL, 0.34 mmol) solution was added dropwise to a dichloromethane (2 mL) solution of compound I60-1 (50 mg, 0.04 mmol), and the resulting reaction solution was stirred at 25 ° C for 1 hour, and the reaction solution turned yellow. The target molecular weight was detected by LCMS. The reaction was quenched with methanol (5 mL), and the reaction solution was alkalized to pH = 8 to 9 with 7M ammonia methanol solution (6 mL), and then concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography (Phenomenex Gemini 150 mm * 25 mm * 10 um column (eluent = 5% to 60% (v / v) CH3CN and H2O, 0.01% NH4HCO3) to obtain compound 0060 (1.59 mg, Y = 8.2%) as a yellow solid.

[0463] LC-MS (ESI): m / z = 458.1 [M+H] +

[0464] 1H NMR(400MHz,DMSO-d6)δ:13.70(s,1H),9.54(s,1H),8.80(s,1H),8.52(s,1H),7.04(d,J=8.3Hz,1 H), 6.88 (d, J = 8.3Hz, 1H), 4.48 (q, J = 7.2Hz, 2H), 2.08 (s, 3H), 1.98 (s, 3H), 1.44 (t, J = 7.2Hz, 3H).

[0465] Example 19:

[0466] Synthesis of Compound 0064

[0467]

[0468] Step 1: Synthesis of compound I64-2

[0469] Under N2, 0 ° C, triethylamine (1.97 mL, 14.19 mmol) was added dropwise to an ethanol solution (20 mL) of compound I64-1 (2 g, 9.46 mmol, BIDE) and oxalic acid ethylenediamine (1.42 g, 9.46 mmol, BIDE), and the reaction mixture was warmed to 25 ° C and stirred for 18 hours. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was filtered and the solid was washed with ethyl acetate (20 mL * 3), and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 10% to 50%) to obtain compound I64-2 (1.26 g, 5.81 mmol) as a white solid.

[0470] LC-MS(ESI): m / z=217.0 / 219.0[M+H] +

[0471] Step 2: Synthesis of compound I64-3

[0472] THF (20 mL) and potassium carbonate (2005.67 mg, 14.51 mmol, BIDE) were added to a mixed solution of compound I64-2 (1.26 g, 5.81 mmol) and (4-methoxyphenyl)methylamine (758.42 μL, 5.81 mmol, BIDE), and the resulting mixture was stirred at 0°C for 4 hours. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 10% to 50%) to obtain a yellow oily compound I64-3 (1.57 g, 4.94 mmol, Y = 85.33%).

[0473] LC-MS (ESI): m / z = 318.1 [M+H] +

[0474] Step 3: Synthesis of compound I64-4

[0475] To an ethanol solution (15 mL) of compound I64-3 (1.57 g, 4.94 mmol) was added sodium thiomethanoate (0.69 g, 9.88 mmol, Bid), and the resulting mixture was stirred at 60 ° C for 18 hours to obtain a yellow solution. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 10% to 20%) to obtain a yellow oily compound I64-4 (1.16 g, 3.52 mmol).

[0476] LC-MS (ESI): m / z = 330.1 [M+H] +

[0477] Step 4: Synthesis of compound I64-5

[0478] At a temperature not exceeding 0°C, within 0.5h, 3-chlorobenzene-1-carboxylic acid (2.39mL, 7.75mmol) was added to a mixed solution of compound I64-4 (1.16g, 3.52mmol) and DCM (12mL) in batches, and the resulting mixture was stirred at 25°C for 2 hours. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was poured into DCM (20mL), washed with saturated brine (20mL), the organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 10% to 50%) to obtain compound I64-5 (830mg, 2.30mmol) as a yellow oil.

[0479] LC-MS (ESI): m / z = 362.0 [M+H] +

[0480] Step 5: Synthesis of compound I64-6

[0481] Cesium carbonate (1122.37 mg, 3.44 mmol) was added to a mixed solution of compound I64-5 (415 mg, 1.15 mmol) and cyclopropanol (0.67 mL, 11.48 mmol), and the resulting mixture was stirred at 50 ° C for 18 hours to obtain a yellow solution. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was filtered and the solid was washed with ethyl acetate (20 mL * 3), and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 10% to 50%) to obtain compound I64-6 (400 mg, 1.17 mmol) as a yellow solid.

[0482] LC-MS (ESI): m / z = 340.2 [M+H] +

[0483] Step 6: Synthesis of compound I64-7

[0484] A mixed solution of compound I64-6 (380 mg, 1.12 mmol) and 2,2,2-trifluoroacetic acid (5 mL) was stirred at 80 ° C for 18 hours. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was adjusted to pH = 7-8 with saturated NaHCO3 solution (20 mL) and extracted with ethyl acetate (20 mL * 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain compound I64-7 (210 mg, 0.96 mmol) as a yellow solid.

[0485] LC-MS (ESI): m / z = 220.2 [M+H] +

[0486] Step 7: Synthesis of Compound I64-9

[0487] To a mixture of compound I64-8 (200 mg, 0.57 mmol), compound I64-7 (124.14 mg, 0.57 mmol), cesium carbonate (553.44 mg, 1.70 mmol) and [5-(diphenylphosphino)-9,9-dimethyl-9H-pyridin-4-yl]diphenylphosphine (65.52 mg, 0.11 mmol) in dioxane (1 mL) was added tris[(1E, 4E)-1,5-diphenylpentaene-1,4-diene-3-one]bis[palladium (0)] (51.85 mg, 0.06 mmol), the mixture was degassed and purged with N2 3 times, and stirred at 90 ° C for 18 hours under N2 protection. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was filtered and the filter cake was washed with ethyl acetate (10 mL * 3), and the filtrate was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 10% to 50%) to give compound I64-9 (150 mg, 0.31 mmol) as a brown solid.

[0488] LC-MS (ESI): m / z = 492.2 [M+H] +

[0489] Step 8: Synthesis of Compound 0064

[0490] Boron tribromide (1.22 mL, 1.22 mmol, 1 M in DCM) was added dropwise to a mixed solution of compound I64-9 (120 mg, 0.24 mmol) and DCM (8 mL), and the reaction mixture was warmed to 25 ° C and stirred for 2 hours. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was quenched with MeOH (2 mL) and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by Prep-HPLC (Phenomenex Gemini 150 mm*25 mm*10 um column (eluent = 30% to 60% (v / v) CH3CN and H2O, 0.025% NH4HCO3) to obtain compound 0064 (34.81 mg, 0.07 mmol) as a white solid.

[0491] LC-MS (ESI): m / z = 478.2 [M+H] +

[0492] 1H NMR (400MHz, DMSO-d6) δ: 13.20 (s, 1H), 9.35 (s, 1H), 8.42 (s, 1H), 6.94 (d, J = 8.4Hz, 1H), 6.77 (d, J = 8.3Hz, 1H), 4.67 (d, J = 3.2Hz,2H),4.59-4.52(m,1H),4.30(q,J=7.2Hz,2H),2.03(s,3H),1.94(s,3H),1.38(t,J=7.2Hz,3H),0.92-0.81(m,4H).

[0493] Example 20:

[0494] Synthesis of Compound 0065

[0495]

[0496] Step 1: Synthesis of compound I65-2

[0497] Tris(dibenzylideneacetone)dipalladium (51.85 mg, 0.06 mmol) was added to a mixed solution of compound I31-8 (200 mg, 0.57 mmol), compound I65-1 (84.45 mg, 0.57 mmol, Bid), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (65.52 mg, 0.11 mmol) and cesium carbonate (553.44 mg, 1.70 mol) in N,N-dimethylformamide (4 ml), and the mixture was replaced with nitrogen three times and stirred at 90 ° C for 2 hours. The mixture was poured into water (5 mL) and extracted with ethyl acetate (15 mL * 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The residue was purified by silica gel chromatography (eluent = tetrahydrofuran: petroleum ether: = 0% to 50%) to give compound I65-2 (300 mg, 0.56 mmol, Y = 99.31%) as a yellow oil.

[0498] LC-MS (ESI): m / z = 422.3 [M+H] +

[0499] Step 2: Synthesis of Compound 0065

[0500] Boron tribromide (0.27ml, 2.85mmol, 1M) was added to a solution of compound I65-2 (240mg, 0.57mmol) in dichloromethane (1ml), and stirred for 2 hours at 60°C. A black solution was formed. The mixture was concentrated under reduced pressure to give a crude product, and the reaction mixture was quenched with ammonia methanol solution (1M). The crude product was purified by preparative HPLC (eluent = 17% to 47% (v / v) acetonitrile and water with 0.1% formic acid and ammonium bicarbonate secondary preparation) to give compound 0065 (13.86mg, 0.03mmol, Y = 5.97%) as a white solid.

[0501] LC-MS (ESI): m / z = 408.1 [M+H] +

[0502] 1H NMR(400MHz, DMSO-d6)δ:13.18(s,1H),9.33(s,1H),8.77(s,1H),8.53(s,1H),6.95(d,J=8.2 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 4.67 (d, J = 3.0 Hz, 2H), 4.03 (s, 3H), 2.04 (s, 3H), 1.95 (s, 3H).

[0503] Example 21:

[0504] Synthesis of Compound 0067

[0505]

[0506] Step 1: Synthesis of compound I67-3

[0507] Compound I67-1 (250 mg, 1.32 mmol) and compound I67-2 (522.30 mg, 1.98 mmol) were added to methanol (3 mL), and AcOH (100 μL, 1.75 mmol) was added. The reactants were stirred at 25 ° C for 0.5 hours, and then sodium cyanoborohydride (165.71 mg, 2.64 mmol, Anaiji) was added. The reaction was stirred at 25 ° C for 2.5 hours. LCMS showed that the desired MS was obtained. The mixture was poured into water (10 mL) and extracted with ethyl acetate (60 mL * 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 100: 1 to 95: 5) to obtain compound I67-3 (245 mg, 0.56 mmol, Y = 42.5%) as a yellow solid.

[0508] LC-MS(ESI): m / z=437.0 / 439.0[M+H] +

[0509] Step 2: Synthesis of compound I67-4

[0510] Compound I67-3 (245 mg, 0.64 mmol) was added to tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL), and NaOH (65.80 mg, 1.64 mmol) was added. Stirred at 50 ° C for 1 hour, and LCMS showed that the desired MS was obtained. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL). The combined aqueous phase was adjusted to pH = 2, extracted with ethyl acetate (30 mL*2), the organic phases were combined, washed with brine (20 mL), and concentrated under reduced pressure to give compound I67-4 (230 mg, 0.56 mmol, crude product) as a white solid.

[0511] LC-MS(ESI): m / z=409.0 / 411.0[M+H] +

[0512] Step 3: Synthesis of compound I67-5

[0513] Compound I67-4 (230 mg, 0.56 mmol) was added to acetonitrile (3 mL), and N, N, N', N'-tetramethylchloroformamidine hexafluorophosphate (393.83 mg, 1.40 mmol, Anaiji) and methylimidazole (179.03 μL, 2.25 mmol, Anaiji) were added. The reactants were stirred at 25 ° C for 16 hours. LCMS showed that the required MS was given. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x2). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: sodium sulfate = 10: 1 to 7: 3) to give compound I67-5 (101 mg, 0.26 mmol, Y = 45.9%) as a white solid.

[0514] LC-MS(ESI): m / z=391.0 / 393.0[M+H] +

[0515] Step 4: Synthesis of compound I67-6

[0516] Compound I67-5 (100 mg, 0.26 mmol) and compound I31-9 (50.00 mg, 0.31 mmol) were added to a solution of N, N-dimethylformamide (1 mL), and tris(dibenzyl-BASE acetone)dipalladium (23.38 mg, 0.03 mmol, Anaiji), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (29.55 mg, 0.05 mmol, Anaiji) and cesium carbonate (249.58 mg, 0.77 mmol) were added. The reactants were stirred at 90 ° C for 3 h under nitrogen protection. LCMS showed the desired MS. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL * 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether:THF = 10:1 to 1:1) to obtain compound I67-6 (102 mg, 0.22 mmol, Y = 84.9%) as a yellow solid.

[0517] LC-MS (ESI): m / z = 474.2 [M+H] +

[0518] Step 5: Synthesis of Compound 0067

[0519] Under nitrogen protection, at -40 ° C, compound I67-6 (101 mg, 0.22 mmol) was added to a solution of dichloromethane (2 mL), and boron tribromide (1.08 mL, 1.08 mmol, 1 mol / L, Anaiji) was added. The reaction was stirred at 25 ° C for 2 hours, and LCMS showed that the required Ms was given. 2 mL of MeOH was added to the reaction solution to quench and concentrate. The crude product was subjected to preparative high performance liquid chromatography (Agilent-hole shell HPH-C18-2.7um-4.6 * 50mm (eluent = 20% to 80% (v / v) acetonitrile and water, 0.025% ammonium bicarbonate) to give compound 0067 (18.07 mg, 0.04 mmol, 20.1%) as a white solid.

[0520] LC-MS (ESI): m / z = 460.2 [M+H] +

[0521] 1H NMR(400MHz, DMSO-d6)δ:13.16(s,1H),10.43(s,1H),8.76(s,1H),8.53(s,1H),6.90(d,J= 10.7Hz, 1H), 4.79–4.65 (m, 2H), 4.46 (q, J = 7.3Hz, 2H), 2.00 (s, 3H), 1.43 (t, J = 7.2Hz, 3H).

[0522] Example 22:

[0523] Synthesis of Compound 0068

[0524]

[0525] Step 1: Synthesis of compound I68-2

[0526] Potassium carbonate (1.58 g, 11.40 mmol) was added to a mixed solution of compound I68-1 (417.30 mg, 2.43 mmol), compound I31-2 (1.5 g, 4.56 mmol) and N,N-dimethylformamide (15 mL). The reaction solution was stirred at 80 ° C for 16 hours. The mixture was poured into (50 mL) of water and extracted with ethyl acetate (60 mL×3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10: 1 to 5: 1) to obtain compound I68-2 (1.67 g, 3.82 mmol, Y = 83.7%) as a white solid.

[0527] LC-MS(ESI): m / z=436.8 / 438.8[M+1] +

[0528] Step 2: Synthesis of compound I68-3

[0529] Water (10 mL) and sodium hydroxide (0.46 g, 11.45 mmol) were added to a solution of compound I68-2 (1.67 g, 3.82 mmol, 83.7%) in tetrahydrofuran (10 mL) respectively. The reactant was stirred at 50 ° C for 1 hour. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 1). The combined aqueous phase was adjusted to pH = 2 and extracted with ethyl acetate (30 mL × 2), and the combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude compound I68-3 (1.06 g, 2.59 mmol, Y = 67.8%) as a white solid.

[0530] LC-MS(ESI): m / z=409.1 / 411.1[M+H] +

[0531] Step 3: Synthesis of compound I68-4

[0532] To a solution of compound I68-3 (1.06 g, 2.59 mmol) in acetonitrile (10 mL) was added TCFH (1.82 g, 6.47 mmol) and NMI (825.11 μL, 10.35 mmol). The reactants were stirred at 25 ° C for 18 hours. The mixture was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10: 1 to 7: 3) to obtain compound I68-4 (800 mg, 2.04 mmol, Y = 75.4%,) as a white solid.

[0533] LC-MS(ESI): m / z=390.9 / 392.9[M+H] +

[0534] Step 4: Synthesis of compound I68-5

[0535] Compound I31-9 (68.88 mg, 0.42 mmol), DMF (2 mL), tris(dibenzylideneacetone)palladium (46.76 mg, 0.05 mmol, Anaiji), Xantphos (59.10 mg, 0.10 mmol, Anaiji) and cesium carbonate (499.16 mg, 1.53 mmol) were added to compound I68-4 (200 mg, 0.57 mmol). The reactants were stirred at 90 ° C for 3 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: THF = 10: 1 to 1: 1) to give compound I68-5 (120 mg, 0.18 mmol, Y = 35.2%) as a yellow oil.

[0536] LC-MS (ESI): m / z = 474.0 [M+H] +

[0537] Step 5: Synthesis of Compound 0068

[0538] Under nitrogen -40 ° C, BBr3 (0.75 mL, 0.75 mmol, 1 mmol / L, Anaiji) was added to a solution of compound I68-5 (100 mg, 0.15 mmol) and dichloromethane (2 mL). The reactant was stirred at 25 ° C for 2 hours. 2 mL of methanol was added to the reactant to quench and concentrated to dryness. The crude product was purified by preparative HPLC (Agilent HPH-C18-2.7um-4.6*50mmB (eluent = 20% to 80% (v / v) CH3CN and H2O, 0.025% NH4HCO3) to give 0068 (12.21 mg, 0.14 mmol, Y = 18.1%) as a white solid.

[0539] LC-MS (ESI): m / z = 460.1 [M+H] +

[0540] 1 H NMR(400MHz,DMSO-d6)δ:13.33(s,1H),10.05(s,1H),8.76(s,1H),8.53(s,1H),7.51–7.37(m ,1H),4.71(d,J=13.0Hz,2H),4.46(d,J=7.2Hz,2H),2.10–2.07(m,3H),1.43(t,J=7.2Hz,3H)

[0541] Example 23:

[0542] Synthesis of Compound 0072

[0543] Step 1: Synthesis of compound I72-2

[0544] Sodium hydride (0.39 g, 9.83 mmol, 60% oil solution) was added to a mixed solution of compound I72-1 (1.00 g, 6.55 mmol, Bid) and N, N-dimethylformamide (10 mL), and then iodoethane (0.53 mL, 6.62 mmol) was added to react at 0 ° C. under nitrogen. The reactant was stirred at 25 ° C. for 16 hours. The desired molecular weight was detected by LCMS. The reaction mixture was quenched with aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (20 mL * 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The residue was purified by silica gel chromatography (eluent = tetrahydrofuran: petroleum ether = 0% to 50%) to obtain compound I72-2 (1.16 g, 6.42 mmol, Y = 97.99%) as a white solid.

[0545] LC-MS (ESI): m / z = 181.1 [M+H] +

[0546] Step 2: Synthesis of compound I72-3

[0547] To a solution of compound I72-2 (470 mg, 2.60 mmol), p-methoxybenzylamine (0.41 mg, 3.12 mmol, Bid), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (301.12 mg, 0.52 mmol) and cesium carbonate (2543.35 mg, 7.81 mmol) in N,N-dimethylformamide (5 mL) was added tris(dibenzyl-BASE acetone)dipalladium (238.27 mg, 0.26 mmol), the mixture was replaced with nitrogen 3 times, and stirred at 85 ° C for 16 hours. A black solution was formed. The desired molecular weight was detected by LCMS. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The residue was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0% to 100%) to give compound I72-3 (220 mg, 0.78 mmol, Y = 30.05%) as a yellow oil.

[0548] LC-MS (ESI): m / z = 282.2 [M+H] +

[0549] Step 3: Synthesis of compound I72-4

[0550] Compound I72-3 (220 mg, 0.78 mmol) was added to trifluoroacetic acid (1 mL) and stirred at 60 ° C for 16 hours to form a black solution. The desired molecular weight was detected by LCMS. The mixture was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by Prep-HPLC ((eluent = 30% to 30% (v / v) acetonitrile and water with 0.1% ammonium bicarbonate) to obtain compound I72-4 (100 mg, 0.62 mmol, Y = 79.33%) as a yellow solid.

[0551] LC-MS (ESI): m / z = 162.1 [M+H] +

[0552] Step 4: Synthesis of compound I72-5

[0553] To a solution of compound I31-8 (197.81 mg, 0.56 mmol), compound I72-4 (143.57 mg, 0.25 mmol) and cesium carbonate (1212.65 mg, 3.72 mmol) in N,N-dimethylformamide (4 mL) was added tris(dibenzyl-BASE acetone)dipalladium (113.61 mg, 0.12 mmol), the mixture was replaced with nitrogen 3 times, and stirred at 90 ° C for 2 hours to form a black solution. The desired molecular weight was detected by LCMS. The mixture was poured into water (15 mL) and extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The residue was purified by silica gel chromatography (eluent = tetrahydrofuran: petroleum ether = 0% to 50%) to give compound I72-5 (250 mg, 0.58 mmol, Y = 46.48%) as a yellow oil.

[0554] LC-MS (ESI): m / z = 434.3 [M+H] +

[0555] Step 5: Synthesis of Compound 0072

[0556] At 0 ° C, boron tribromide (1.15 mL, 1.15 mmol) was added to a mixed solution of compound I72-5 (100 mg, 0.23 mmol) and dichloromethane (2 mL), and the mixture was stirred at 25 ° C for 16 hours to form a black solution. LCMS detected the required molecular weight. The mixture was concentrated to dryness under reduced pressure to obtain a crude product, which was quenched with ammonia methanol (1 M). The mixture was purified by Prep-HPLC ((eluent = 35% to 65% (v / v) acetonitrile and water with 0.1% ammonium bicarbonate) to obtain compound 0072 (4.43 mg, 0.01 mmol, Y = 4.58%) as a white solid.

[0557] LC-MS (ESI): m / z = 420.1 [M+H] +

[0558] 1H NMR(400MHz, DMSO-d6)δ:12.06(s,1H),9.29(s,1H),8.02(d,J=5.8Hz,1H),7.45(d,J=3.2Hz,1H),7.26(d,J=6.0Hz,1H),7.15(d,J=3.2Hz,1H ),6.94(d,J=8.2Hz,1H),6.77(d,J=8.2Hz,1H),4.59(d,J=3.2Hz,2H),4.24(d,J=7.2Hz,2H),2.04(s,3H),1.95(s,3H),1.36(t,J=7.2Hz,3H)

[0559] Example 24:

[0560] Synthesis of Compound 0074

[0561]

[0562] Step 1: Synthesis of compound I74-2

[0563] To a mixed solution of compound I74-1 (200 mg, 0.60 mmol), compound I45-2 (152.89 mg, 0.72 mmol), cesium carbonate (485.69 mg, 1.49 mmol) and DME (1.5 mL), tris(dibenzylideneacetone)palladium (54.60 mg, 0.06 mmol) and Xantphos (69.00 mg, 0.12 mmol) were added respectively, replaced with N2 3 times, and stirred at 100 ° C for 4 hours. The desired molecular weight was detected by LCMS. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The residue was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10: 1 to 2: 3) to give compound I74-2 (180 mg, 0.25 mmol, Y = 42.7%) as a yellow solid.

[0564] LC-MS (ESI): m / z = 481.1 [M+H] +

[0565] Step 2: Synthesis of compound I74-3

[0566] Boron tribromide (499.39 μL, 0.50 mmol) was added to a solution of compound I74-2 (100 mg, 0.17 mmol) in dichloromethane (1.5 mL) at -65 ° C, and the resulting mixture was stirred at -65 ° C for 1 hour. The desired molecular weight was detected by LCMS. The reaction mixture was quenched with MeOH (5 mL) and concentrated to dryness, and the residue was then alkalized with 3 mL NH3 (7M in MeOH) and concentrated to dryness to give a crude product. The crude product was purified by silica gel chromatography (DCM: MeOH = 100: 1 to 20: 1) to give compound I74-3 (80 mg, 0.15 mmol, Y = 89.6%) as a yellow solid.

[0567] LC-MS (ESI): m / z = 467.4 [M+H] +

[0568] Step 3: Synthesis of compound I74-4

[0569] Under ice-water cooling, Dess-Martin reagent (101.82 mg, 0.24 mmol) was added to a solution of compound I74-3 (80 mg, 0.12 mmol) in dichloromethane (4 mL), and the resulting mixture was stirred at 20 ° C for 18 hours to obtain a yellow solution. The desired molecular weight was detected by LCMS. The reaction mixture was adjusted to pH 7-8 with saturated sodium bicarbonate (10 mL) solution, extracted with dichloromethane (30 mL*3), and the combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by Prep-HPLC (eluent = 0% to 50% (v / v) CH3CN / H2O, 0.1% HCOOH) to obtain compound I74-4 (60 mg, 0.11 mmol, Y = 89.5%) as a white solid.

[0570] LC-MS (ESI): m / z = 447.2 [M+H] +

[0571] Step 4: Synthesis of Compound 0074

[0572] Under ice-water cooling, boron tribromide (0.45mL, 0.45mmol) was added to a solution of compound I74-4 (40mg, 0.09mmol) in dichloromethane (3mL), and the resulting mixture was stirred at 20°C for 2 hours to obtain a yellow solution. The desired molecular weight was detected by LCMS. The residue was quenched with methanol (5mL) and concentrated to dryness, and then the residue was alkalized to pH=8-9 with 6mL ammonia (7M in MeOH), and then the residue was concentrated to dryness to obtain a crude product. The crude product was purified by Prep-HPLC (Phenomenex Gemini 150mm*25mm*10um column (eluent=10% to 60% (v / v) CH3CN / H2O, 0.01NH4HCO3) to obtain compound 0074 (3.8mg, 0.01mmol, Y=12.9%) as a yellow solid.

[0573] LC-MS (ESI): m / z = 433.0 [M+H] +

[0574] 1 H NMR (400MHz, DMSO-d6) δ: 12.63 (s, 1H), 9.49 (s, 1H), 8.62 (s, 1H), 7.54 (d, J = 3.4Hz, 1H), 7.41 (d, J = 7.4Hz, 1H), 7.06 (d, J = 3.4Hz, 1H), 7. 02(d,J=8.4Hz,1H),6.84(d,J=8.4Hz,1H),6.80(d,J=7.2Hz,1H),4.29(q,J=7.4Hz,2H),1.89(s,3H),1.80(s,3H),1.38(t,J=7.2Hz,3H)

[0575] Example 25:

[0576] Synthesis of Compound 0075

[0577]

[0578] Step 1: Synthesis of compound I75-3

[0579] Under nitrogen, bis[5-(diphenylphosphino)cyclopentyl-1,3-dienyl]-λ2-iron(II)palladium chloride (2.19 g, 3.00 mmol, Bid) was added to a mixture of compound I75-1 (15 g, 60.00 mmol, Bid), compound I75-2 (10.15 mL, 71.99 mmol, Bid), cesium carbonate (39.10 g, 119.99 mmol, Bid), 1,4-dioxane (100 mL) and water (25 mL), and stirred at 85 ° C for 18 hours under N2. TLC showed that the starting material was completely consumed and new spots were generated. The mixture was filtered, the filter cake was washed with ethyl acetate (20 mL*3), and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 50: 1 to 10: 1) to obtain compound I75-3 (10 g, 54.01 mmol, Y = 90.02%) as a white solid.

[0580] 1 H NMR(400MHz, DMSO-d6)δ:7.80(d,J=8.0Hz,1H),7.44(d,J=12.0Hz,1H),3.92(s,3H),2.46(s,3H)

[0581] Step 2: Synthesis of compound I75-4

[0582] Iron powder (6.03 g, 108.02 mmol, Bid) was added to a mixture of compound I75-3 (5.0 g, 27.01 mmol), ammonium chloride (4.33 g, 81.02 mmol, Bid), ethanol (25 mL) and water (5 mL), and the mixture was stirred at 80 ° C for 2 hours. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was filtered and washed with ethyl acetate (20 mL * 3), and the filtrate was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 100: 1 to 5: 1) to give compound I75-4 (3.0 g, 19.33 mmol, Y = 71.59%) as a gray solid.

[0583] LC-MS (ESI): m / z = 156.0 [M+H] +

[0584] Step 3: Synthesis of compound I75-5

[0585] 1-Chloropyrrole-2,5-dione (0.36 g, 2.71 mmol) was added to a solution of compound I75-4 (0.3 g, 1.93 mmol) in acetonitrile (6 mL), and the reaction mixture was warmed to 90 ° C and stirred for 1.5 hours. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 100: 1 to 10: 1) to give compound I75-5 (50 mg, 0.26 mmol, Y = 13.64%) as a yellow oil.

[0586] LC-MS (ESI): m / z = 190.0 [M+H] +

[0587] Step 4: Synthesis of compound I75-6

[0588] A mixed solution of compound I75-5 (70 mg, 0.37 mmol), compound I67-2 (194.99 mg, 0.74 mmol) and acetic acid (2 mL) was stirred for 1 hour, and then sodium cyanoborate (46.40 mg, 0.74 mmol, Bid) was added. The reaction mixture was stirred for another hour. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 100: 1 to 5: 1) to obtain compound I75-6 (140 mg, 0.32 mmol, Y = 86.64%) as a yellow oil.

[0589] LC-MS(ESI): m / z=437.0 / 439.0[M+H] +

[0590] Step 5: Synthesis of compound I75-7

[0591] To a solution of compound I75-6 (140 mg, 0.32 mmol) in tetrahydrofuran (1 mL) was added sodium hydroxide (16.45 mg, 0.41 mmol) dissolved in water (1 mL), and the resulting mixture was stirred at 50 ° C for 2 hours to obtain a yellow solution. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was adjusted to pH = 3 with HCl (1 M) and extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain a crude compound I75-7 (150 mg, 0.37 mmol, crude product) as a yellow solid.

[0592] LC-MS(ESI): m / z=409.0 / 411.0[M+H]+

[0593] Step 6: Synthesis of Compound I75-8

[0594] 1-Methylimidazole (77.84 μL, 0.98 mmol) was added to a mixed solution of compound I75-7 (100 mg, 0.24 mmol), [chloro(dimethylamino)methylene]dimethylammonium hexafluoro-λ5-phosphide (171.23 mg, 0.61 mmol, Bid) and acetonitrile (3.0 mL), and the resulting mixture was stirred at 25 ° C for 18 hours. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was filtered, the filter cake was washed with ethyl acetate (20 mL * 3), and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 50: 1 to 5: 1) to obtain compound I75-8 (100 mg, 0.26 mmol, crude product) as a yellow solid.

[0595] LC-MS(ESI): m / z=390.8 / 392.8[M+H] +

[0596] Step 7: Synthesis of Compound I75-10

[0597] Under nitrogen, tris[(1E, 4E)-1,5-diphenylpenta-1,4-diene-3-one]bis[palladium(0)](25.72mg, 0.03mmol) was added to a 1,4-dioxane solution of compound I75-8(110mg, 0.28mmol), compound I31-9(50.42mg, 0.31mmol, Bid), cesium carbonate(274.54mg, 0.84mmol) and [5-(diphenylphosphino)-9,9-dimethyl-9H-xan-4-yl]diphenylphosphine(32.50mg, 0.06mmol), and stirred at 110°C for 18 hours under nitrogen. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was filtered, the filter cake was washed with ethyl acetate(20mL*3), and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10:1 to 1:1) to obtain compound I75-10 (110 mg, 0.23 mmol, Y = 82.64%) as a brown solid.

[0598] LC-MS (ESI): m / z = 474.2 [M+H] +

[0599] Step 8: Synthesis of Compound 0075

[0600] Compound I75-10 (70 mg, 0.15 mmol) was dissolved in hydrogen bromide (4 mL, 33%, AcOH), and the mixture was stirred at 90 ° C for 2.5 hours. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by preparative HPLC (Phenomenex Gemini 150 mm*25 mm*10 um column (eluent=30% to 60% (v / v) CH3CN and H2O, 0.01% NH4HCO3) to give compound 0075 (19.47 mg, 0.04 mmol, Y=28.66%) as a white solid.

[0601] LC-MS (ESI): m / z = 460.2 [M+H] +

[0602] 1 H NMR(400MHz,DMSO-d6)δ:13.00(s,1H),10.38(s,1H),8.74(s,1H),8.56(s,1H),7.22(d,J =11.4Hz,1H),4.77-4.59(m,2H),4.32(q,J=7.4Hz,2H),2.14(s,3H),1.46(t,J=7.3Hz,3H)

[0603] Example 26:

[0604] Synthesis of Compound 0076

[0605]

[0606] Step 1: Synthesis of compound I76-2

[0607] At 0°C, under nitrogen protection, a tetrahydrofuran (100mL) solution of compound I76-1 (25g, 89.56mmol, Bid) was added to a tetrahydrofuran (100mL) solution of lithium diisopropylamide (147.77mL, 295.54mmol, 2mol / L, Anaiji), and the reaction solution was stirred at 0°C for 0.5 hours. Diethyl pyrocarbonate (43.6g, 268.67mmol, Bid) was added at 0°C, and the reaction solution was warmed to 25°C and stirred for 16 hours. The reaction solution was poured into ammonium chloride (aq, 250mL) to quench, and extracted with ethyl acetate (500mL*3); the combined organic phases were washed with saturated brine (200mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10: 1 to 1: 1) to obtain compound I76-2 (6 g, 17.08 mmol, Y = 19.08%) as a yellow solid.

[0608] LC-MS(ESI): m / z=295.2 / 297.2[M+H] +

[0609] 1 H NMR (400MHz, DMSO-d6)δ:12.30(s,1H),4.33-4.16(m,2H),1.50(s,9H),1.28(t,J=7.1Hz,3H)

[0610] Step 2: Synthesis of compound I76-3

[0611] Compound I76-2 (6 g, 17.08 mmol) was added to water (30 mL), and then tetrahydrofuran (30 mL) and sodium hydroxide (2.05 g, 51.25 mmol) were added. The reaction was stirred at 50°C for 2 hours. Most of the THF was concentrated under reduced pressure in the reaction solution, and the residue was poured into water (20 mL) for reaction. The aqueous phase was adjusted to pH = 2 to 3 with hydrochloric acid (1 M), extracted with ethyl acetate (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain compound I76-3 (3.7 g, 11.45 mmol, Y = 67.0%) as a yellow solid.

[0612] LC-MS(ESI): m / z=266.8 / 268.8[M+H] +

[0613] Step 3: Synthesis of compound I76-4

[0614] Compound I76-3 (1.5 g, 4.64 mmol) was added to acetonitrile (15 mL), and then compound I76-3.1 (0.70 g, 4.64 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (3.26 g, 11.60 mmol, Anaiji) and methylimidazole (1.52 g, 18.57 mmol, Anaiji) were added. The reaction solution was stirred at 25 ° C for 16 hours. The system was directly concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10: 1 to 1: 1) to obtain compound I76-4 (1800 mg, 3.94 mmol, Y = 85.0%) as a yellow solid.

[0615] LC-MS(ESI): m / z=456.1 / 458.1[M+H] +

[0616] Step 4: Synthesis of compound I76-5

[0617] Compound I76-4 (700 mg, 1.53 mmol), cuprous iodide (23.2 mg, 0.15 mmol), bistriphenylphosphine palladium dichloride (53.83 mg, 0.08 mmol, Anaiji), ethynyltrimethylsilane (262 μL, 1.84 mmol, Anaiji) were added to triethylamine (7 mL), and the system was replaced with nitrogen three times and then heated to 85 ° C and stirred for 16 hours. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (30 mL * 3), and the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a brown solid crude compound I76-5 (700 mg, 1.74 mmol, crude product).

[0618] LC-MS (ESI): m / z = 402.2 [M+H] +

[0619] Step 5: Synthesis of Compound I76-6

[0620] Compound I76-5 (700 mg, 1.74 mmol) was added to N,N-dimethylformamide (7 mL), and sodium tert-butoxide (335 mg, 3.49 mmol, Anaiji) was added. The reactants were stirred at 100 ° C for 16 hours, and LCMS showed the desired MS. The mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL * 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10: 1 to 4: 1) to give compound I76-6 (415 mg, 1.03 mmol, Y = 59.7%) as a white solid.

[0621] LC-MS (ESI): m / z = 402.1 [M+H] +

[0622] 1 H NMR(400MHz, DMSO-d6)δ:12.19(s,1H),7.42(d,J=7.2Hz,1H),7.20(d,J=8.4Hz,1H),7.02( d,J=8.4Hz,1H),6.79(d,J=7.2Hz,1H),3.83(s,3H),1.91(s,3H),1.80(s,3H),1.53(s,9H)

[0623] Step 6: Synthesis of compound I76-7

[0624] Compound I76-6 (416 mg, 1.04 mmol) was added to a solution of hydrogen chloride / ethyl acetate (6 mL, 24.00 mmol, ethyl acetate solution 4 mol / L, Anergy), the system was heated to 70°C, and stirred at this temperature for 2 hours. The system was concentrated under reduced pressure to obtain compound I76-7 (280 mg, 0.93 mmol, Y=89.7%) as a yellow solid.

[0625] LC-MS (ESI): m / z = 302.3 [M+H] +

[0626] Step 7: Synthesis of Compound I76-9

[0627] Compound I76-7 (150 mg, 0.50 mmol) and compound I76-8 (89.91 mg, 0.50 mmol) were added to 1,4-dioxane (3 mL), and tris(dibenzylideneacetone)dipalladium (22.79 mg, 0.02 mmol, Anaiji), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (28.80 mg, 0.05 mmol, Anaiji) and cesium carbonate (486.52 mg, 1.49 mmol) were added. The system was replaced with nitrogen three times, and the temperature was raised to 100 ° C and stirred for 16 hours. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether:ethyl acetate = 10:1 to 7:3) to obtain compound I76-9 (50 mg, 0.11 mmol, Y = 19.8%) as a yellow solid.

[0628] LC-MS (ESI): m / z = 446.2 [M+H] +

[0629] Step 8: Synthesis of Compound 0076

[0630] Under nitrogen protection, compound I76-9 (50 mg, 0.11 mmol) was added to dichloromethane (2 mL), and boron tribromide (0.45 mL, 0.45 mmol, Anaiji) was slowly added dropwise at -40 ° C. After the addition, the reaction solution was warmed to 25 ° C and stirred for 2 hours. The reaction solution was added to methanol (1 mL) and concentrated under reduced pressure to obtain a crude product, which was purified by Prep-HPLC (Waters-Xbridge-C18-10 μm-19*250 mm, A: 10 mM ammonium bicarbonate / B: acetonitrile) to obtain a white solid 0076 (12.1 mg, 0.03 mmol, 31.5%).

[0631] LC-MS (ESI): m / z = 432.1 [M+H] +

[0632] 1 H NMR(400MHz,DMSO-d6)δ:12.13(br s,1H),9.54(br s,1H),8.03(d,J=5.8Hz,1H),7.46(d,J=3.2Hz,1H),7.37(d,J=7.2Hz,1H),7.28(d,J=5.8Hz,1H),7.16(d,J=3.0Hz,1H),7.02(d, J=8.2Hz,1H),6.84(d,J=8.2Hz,1H),6.75(d,J=7.2Hz,1H),4.24(q,J=7.2Hz,2H),1.90(s,3H),1.80(s,3H),1.36(t,J=7.2Hz,3H)

[0633] Example 27:

[0634] Synthesis of Compound 0077

[0635]

[0636] Step 1: Synthesis of compound I77-2

[0637] Under nitrogen protection, sodium hydride (1.17 g, purity 60%, 29.30 mmol) was added to N,N-dimethylformamide (30 mL) of compound I77-1 (3 g, 19.54 mmol, Bid) at 0°C, and then iodoethane (1.58 mL, 19.73 mmol, Bid) was added to the reaction solution. The reaction solution was stirred at 25°C for 16 hours. LCMS showed that the starting material was completely consumed and the target product was formed. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (40 mL*3), and the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0% to 21%) to obtain compound I77-2 (1 g, 5.51 mmol, Y = 28.19%) as a white solid.

[0638] LC-MS (ESI): m / z = 182.0 [M+H] +

[0639] Step 2: Synthesis of compound I77-4

[0640] Under nitrogen protection, compound I77-3 (300 mg, 0.89 mmol) was added to 1,4-dioxane (5 mL), followed by Xantphos (103.51 mg, 0.18 mmol), compound I77-2 (162.44 mg, 0.89 mmol), cesium carbonate (874.24 mg, 2.68 mmol) and tris(dibenzylideneacetone)palladium (81.90 mg, 0.09 mmol), the mixture was degassed and purged with nitrogen 3 times, and stirred at 100 ° C for 16 hours. LCMS showed that the raw material was consumed and the desired product was formed. The reaction mixture was filtered and washed with methanol (20 mL) and dichloromethane (20 mL), and the filtrate was concentrated to dryness under reducing conditions to give a crude product. The crude product was purified by silica gel chromatography (eluent = methanol: dichloromethane = 0% - 10%) to obtain compound I77-4 (370 mg, 0.77 mmol, Y = 86.08%) as a white solid.

[0641] LC-MS (ESI): m / z = 481.2 [M+H] +

[0642] Step 3: Synthesis of compound I77-5

[0643] Under nitrogen protection, boron tribromide (561.81 μL, 0.56 mmol, Bid) was added to a solution of compound I77-4 (180 mg, 0.37 mmol) in dichloromethane (3 mL), the temperature did not exceed -65 ° C, the mixture was stirred at -65 ° C for 1 hour, then warmed to 25 ° C and stirred for another 2 hours. A light yellow solution was formed. LCMS showed that the reactants reacted completely and formed the desired product. The reaction mixture was quenched with methanol (5 mL), adjusted to pH = 7 with ammonia methanol solution, and then the mixture was concentrated to dryness to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = methanol: dichloromethane = 0% to 6%) to obtain compound I77-5 (80 mg, 0.14 mmol, Y = 68.67%) as a yellow solid.

[0644] LC-MS (ESI): m / z = 467.2 [M+H] +

[0645] Step 4: Synthesis of compound I77-6

[0646] At 0°C, to a solution of compound I77-5 (120 mg, 0.26 mmol) in dichloromethane (1 mL) was added Dess-Martin (218.18 mg, 0.51 mmol, Bid), and the mixture was then warmed to 25°C and stirred for 24 hours. LCMS showed that the starting material reacted completely and formed the desired product. The reaction mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (eluent = methanol: dichloromethane = 0% to 4%) to give compound I77-6 (40 mg, 0.06 mmol, yield: 34.83%) as a yellow solid.

[0647] LC-MS (ESI): m / z = 447.2 [M+H] +

[0648] Step 5: Synthesis of Compound 0077

[0649] At 0°C, boron tribromide (450.00 μL, 0.45 mmol, Bid) was added to a solution of compound I77-6 (40 mg, 0.09 mmol) in dichloromethane (0.7 mL), and the mixture was warmed to 25°C and stirred for 1 hour. A yellow solution was formed. LCMS showed that the raw material reaction was complete and the desired product was formed. The reaction mixture was quenched with methanol (3 mL), and alkalized to pH = 9 to 10 with ammonia methanol solution, and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by preparative high performance liquid chromatography (Phenomenex Gemini 150 mm * 25 mm * 10 um column (eluent = water (containing 10 mM ammonium bicarbonate solution): acetonitrile = 30% to 60%) to give 0077 (2.38 mg, 0.01 mmol, Y = 6.14%) as a white solid.

[0650] LC-MS (ESI): m / z = 433.2 [M+H] +

[0651] 1 H NMR(400MHz, DMSO-d6)δ:12.59(s,1H),9.51(s,1H),8.64(s,1H),8.16(d,J=4.4Hz,1H),7.39(d,J=5.6Hz,2H), 7.01(d,J=7.6Hz,1H),6.90-6.74(m,2H),4.45(d,J=6.4Hz,2H),1.89(s,3H),1.80(s,3H),1.40(t,J=5.6Hz,3H)

[0652] Example 28:

[0653] Synthesis of Compound 0078

[0654]

[0655] Step 1: Synthesis of compound I78-2

[0656] To a solution of compound I78-1 (500 mg, 1.15 mmol) in dioxane (5 mL) was added hydrochloric acid (2.30 mL, 9.20 mmol), and the resulting mixture was stirred at 80 ° C for 4 hours. LCMS detected that it was mainly the product. The reactant was concentrated to dryness, and the pH was adjusted to 7-8 with aqueous sodium bicarbonate solution (10 mL), and extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain compound I78-2 (320 mg, 0.95 mmol, Y=83.10%) as a yellow solid.

[0657] LC-MS (ESI): m / z = 336.2 [M+H] +

[0658] Step 2: Synthesis of compound I78-4

[0659] Under nitrogen, tri(dibenzylideneacetone)dipalladium (87.36 mg, 0.10 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (110.41 mg, 0.19 mmol) were added to a solution of compound I78-2 (320 mg, 0.95 mmol) and compound I78-3 (222.81 mg, 1.14 mmol) in ethylene glycol dimethyl ether (12 mL), respectively, and stirred at 100 ° C for 4 hours under nitrogen. The desired molecular weight was detected by LCMS. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (eluent = 0% to 50% (v / v) acetonitrile / water, containing 0.01% formic acid) to give compound I78-4 (400 mg, 0.77 mmol, Y = 80.7%) as a white solid.

[0660] LC-MS (ESI): m / z = 494.0 [M+H] +

[0661] Step 3: Synthesis of compound I78-5

[0662] Boron tribromide (300.00 μL, 0.30 mmol) was added to a solution of compound I78-4 (100 mg, 0.20 mmol) in dichloromethane (2 mL) at -65 ° C, and the temperature was controlled to react for 1 hour, and then stirred at 25 ° C for another hour. The desired molecular weight was detected by LCMS, quenched with methanol (10 mL), adjusted to pH = 8-9 with ammonia (5 mL, MeOH solution 7M), concentrated to dryness, and the crude product was purified by silica gel chromatography (dichloromethane: methanol = 100: 1 to 10: 1) to obtain compound I78-5 (280 mg, 0.58 mmol, Y = 72.0%) as a yellow solid.

[0663] LC-MS (ESI): m / z = 480.2 [M+H] +

[0664] Step 4: Synthesis of compound I78-6

[0665] 1,1,1-triacetoxy-1,3-dihydro-1λ5-benzo[d][1,2]iodine-3-one (571.35mg, 1.35mmol) was added to a solution of compound I78-5 (340mg, 0.67mmol) in dichloromethane (10mL), and the resulting mixture was stirred at 25°C for 18 hours. The desired molecular weight was detected by LCMS. It was quenched with sodium bicarbonate solution (20mL) and extracted with dichloromethane (30mL*3). The combined organic phase was washed with brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by preparative HPLC (eluent = 5% to 45% (v / v) acetonitrile and water, containing 0.01% formic acid) to give compound I78-6 (180mg, 0.39mmol, Y = 58.4%) as a yellow solid.

[0666] LC-MS (ESI): m / z = 460.2 [M+H] +

[0667] Step 5: Synthesis of Compound 0078

[0668] Under ice bath, to dichloromethane (7mL) solution of compound I78-6 (130mg, 0.28mol) add boron tribromide (1.41mL, 1.41mmol), then stir 1 hour at 25 ℃.The molecular weight required is detected by LCMS.Quenched with MeOH (5mL) and concentrated to dryness, then residue is alkalized to pH=8-9 with 4mL ammonia (7M / L), concentrated to dryness, and crude product is obtained.The crude product is purified by preparative HPLC (Phenomenex Gemini 150mm*25mm*10um column (eluent=5% to 55% (v / v) acetonitrile and water, containing 0.1% formic acid) to obtain compound 0078 (10.41mg, 0.02mmol, Y=8.26%) of yellow solid.

[0669] LC-MS (ESI): m / z = 446.0 [M+H] +

[0670] 1 H NMR (400MHz, DMSO-d6) δ: 13.21 (s, 1H), 9.51 (s, 1H), 8.77 (s, 1H), 8.47 (s, 1H), 7.43 (d, J=7.3Hz, 1H), 7.02 (d, J= 8.4Hz,1H),6.88-6.80(m,2H),3.98-3.86(m,1H),1.89(s,3H),1.80(s,3H),1.23–1.18(m,2H),1.16–1.10(m,2H)

[0671] Example 29:

[0672] Synthesis of Compound 0079

[0673]

[0674] Step 1: Synthesis of compound I79-3

[0675] Under ice bath, oxalyl chloride (170.18 μL, 1.98 mmol) and N,N-dimethylformamide (12.86 μL, 0.17 mmol) were added to a solution of compound I79-2 (500 mg, 1.65 mmol) in dichloromethane (5 mL), and the mixture was stirred at 25 ° C for 1.5 hours and concentrated to obtain a crude acyl chloride. The crude acyl chloride was dissolved in dichloromethane (5 mL), and then compound I79-1 (340.57 mg, 1.98 mmol) and triethylamine (411.04 μL, 2.48 mmol) were added, and the reactants were stirred at 25 ° C for 2 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10: 1 to 1: 1) to obtain compound I79-3 (390 mg, 0.86 mmol, Y = 51.7%) as a white solid.

[0676] LC-MS (ESI): m / z = 456.2 [M+H] +

[0677] Step 2: Synthesis of compound I79-4

[0678] Hydrogen chloride (3 mL, 12.00 mmol, 4 mol / L hydrochloric acid dioxane solution, Anergy) was added to compound I79-3 (390 mg, 0.86 mmol). The mixture was stirred at 85 ° C for 4 hours. The reaction solution was concentrated to obtain compound I79-4 (300 mg, 0.84 mmol, crude product) as a yellow solid.

[0679] LC-MS (ESI): m / z = 356.2 [M+H] +

[0680] Step 3: Synthesis of compound I79-6

[0681] Under nitrogen, 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (29.27 mg, 0.05 mmol, Anaiji) and tris(dibenzylideneacetone)dipalladium (23.16 mg, 0.03 mmol) were added to a solution of compound I79-4 (180 mg, 0.51 mmol), compound I79-5 (106.67 mg, 0.59 mmol) and cesium carbonate (494.44 mg, 1.52 mmol) in dioxane (3 mL). The mixture was stirred at 100 ° C for 16 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10: 1 to 3: 7) to obtain compound I79-6 (160 mg, 0.30 mmol, Y = 5 8.9%) as a white solid.

[0682] LC-MS (ESI): m / z = 502.2 [M+H] +

[0683] Step 4: Synthesis of compound I79-7

[0684] Boron tribromide (956.19 μL, 0.96 mmol, 1 mol / L) was added dropwise to a solution of compound I79-6 (240 mg, 0.48 mmol) in dichloromethane (2 mL) at -65 °C and stirred at -60 °C for 2 hours. 3 mL of MeOH was added to the reactant to quench and concentrate to dryness. The crude product was purified by silica gel chromatography (eluent = petroleum ether: tetrahydrofuran = 10: 1 to 1: 1) to obtain compound I79-7 (130 mg, 0.27 mmol, Y = 55.7%) as a yellow solid.

[0685] LC-MS (ESI): m / z = 488.2 [M+H] +

[0686] Step 5: Synthesis of compound I79-8

[0687] 1,1,1-triacetoxy-1,3-dihydro-1λ5-benzo[d][1,2]iodineoxy-3-one (0.17mL, 0.53mmol, Anaiji) was added to a solution of compound I79-7 (130mg, 0.27mmol) in dichloromethane (3mL). The reactants were stirred at 25°C for 16 hours. The mixture was poured into sodium thiosulfate (10mL) and extracted with ethyl acetate (30mL*3). The combined organic phase was washed with saturated sodium bicarbonate solution (10mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: tetrahydrofuran = 10:1 to 1:1) to give compound I79-8 (70mg, 0.10mmol, Y = 39.1%) as a yellow oil.

[0688] LC-MS (ESI): m / z = 468.2 [M+H] +

[0689] Step 6: Synthesis of Compound 0079

[0690] Boron tribromide (0.53 mL, 0.53 mmol, 1 mol / L dichloromethane solution, Anaiji) was added to a solution of compound I79-8 (70 mg, 0.10 mmol) in dichloromethane (2 mL) at -40 ° C. The reactant was stirred at 25 ° C for 2 hours. 1 mL of methanol was added to the reactant to quench and concentrate. The crude product was purified by high performance liquid chromatography (Agilent-Poroshell HPH-C18-2.7um-4.6*50mm (eluent = 20% to 80% (v / v) acetonitrile / water, 0.025% ammonium bicarbonate) to give compound 0079 (6.17 mg, 0.01 mmol, Y = 12.78%) as a white solid.

[0691] LC-MS (ESI): m / z = 454.2 [M+H] +

[0692] 1 H NMR (400MHz, DMSO-d6) δ13.26(s,1H),10.09(s,1H),8.77(s,1H),8.53(s,1H),7.49(d,J=7.2Hz,1H),7.31(d,J=8 .8Hz,1H),6.97(d,J=8.8Hz,1H),6.86(d,J=7.4Hz,1H),4.46(q,J=7.2Hz,2H),1.87(s,3H),1.43(t,J=7.2Hz,3H)

[0693] Example 30:

[0694] Synthesis of Compound 0082

[0695]

[0696] Step 1: Synthesis of compound I82-2

[0697] To a solution of compound I31-8 (130.70 mg, 0.37 mmol), compound I82-1 (50 mg, 0.37 mmol, Bid), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (43.14 mg, 0.07 mmol) and cesium carbonate (364.34 mg, 1.12 mmol) in N,N-dimethylformamide (4 mL), tris(dibenzylideneacetone)dipalladium (34.13 mg, 0.04 mmol) was added, and the mixture was replaced with nitrogen three times and stirred at 90 ° C for 2 hours. The mixture was poured into water (15 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The residue was purified by silica gel chromatography (eluent = tetrahydrofuran: petroleum ether = 0% to 70%) to give compound I82-2 (115 mg, 0.28 mmol, 75.90%) as a yellow oil.

[0698] LC-MS (ESI): m / z = 407.2 [M+H] +

[0699] Step 2: Synthesis of Compound 0082

[0700] At 0°C, boron tribromide (2.20ml, 2.20mmol) was added to a solution of compound I82-2 (180mg, 0.44mmol) in dichloromethane (1ml), and stirred for 1 hour at 25°C. The mixture was concentrated to dryness under reduced pressure to give a crude product, and the reaction mixture was quenched with ammonia methanol solution (1M) and concentrated. The crude product was purified by preparative HPLC ((eluent = 18% to 48% (v / v) acetonitrile and water with 0.1% ammonium bicarbonate) to give compound 0082 (6.91mg, 0.02mmol, 3.98%) as a white solid.

[0701] LC-MS (ESI): m / z = 393.1 [M+H] +

[0702] 1H NMR(400MHz,DMSO-d6)δ:12.57(s,1H),9.05(s,1H),8.52(s,1H),8.25(s,1H),8.06–7.95(m,1H),7. 42–7.31(m,1H),6.94(d,J=8.2Hz,1H),6.79(d,J=8.2Hz,1H),4.62(s,2H),2.06(s,3H),1.98(s,3H)

[0703] Example 31:

[0704] Synthesis of Compound 0083

[0705]

[0706] Step 1: Synthesis of compound I83-3

[0707] Under nitrogen protection at -78°C, butyl lithium (2.83 mL, 7.07 mmol, 2.5 mol / L, Anaiji) was added to a solution of di(propyl-2-yl)amine (0.99 mL, 7.07 mmol, Bid) in tetrahydrofuran (10 mL). The reaction solution was stirred at -78°C for 0.5 hours, and then a solution of compound I83-1 (1 g, 6.10 mmol, Bid) in tetrahydrofuran (10 mL) was added. After 0.5 hours, compound I83-2 (0.72 mL, 7.32 mmol, Bid) was added, and the reaction solution was stirred at -78°C for 0.5 hours. At -60 ° C, saturated ammonium chloride solution (10 mL) was added to the reaction system, and extracted with ethyl acetate (10 mL*3); the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 100: 1 to 95: 5) to give compound I83-3 (1.12 g, 4.74 mmol, Y = 77.8%) as a white solid.

[0708] 1 H NMR(400MHz, DMSO-d6)δ:8.79(s,1H),4.37(q,J=7.1Hz,2H),1.39–1.29(m,3H)

[0709] Step 2: Synthesis of compound I83-4

[0710] Compound I83-3 (890 mg, 3.77 mmol) was added to a dioxane (8 mL) solution at room temperature, followed by phenylmethylamine (824.46 μL, 7.54 mmol), tris(dibenzylidene-BASE acetone)dipalladium (345.22 mg, 0.38 mmol, Anergy) and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (436.28 mg, 0.75 mmol, Anergy), cesium carbonate (3684.93 mg, 11.31 mmol). The system was replaced with nitrogen three times, and the reaction solution was heated to 100°C and stirred for 16 hours. The reaction solution was poured into water (20 mL) and extracted with ethyl acetate (30 mL*3); the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10: 1 to 5: 1) to give compound I83-4 (230 mg, 0.88 mmol, Y = 23.1%) as a yellow oil.

[0711] LC-MS (ESI): m / z = 263.0 [M+H] +

[0712] Step 3: Synthesis of compound I83-5

[0713] At 0°C, compound I83-4 (150 mg, 0.57 mmol) was added to concentrated sulfuric acid (2 mL), and the reaction solution was heated to 85°C and stirred for 1 hour. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL*3); the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10: 1 to 1: 1) to obtain compound I83-5 (70 mg, 0.41 mmol, Y = 71.1%) as a yellow oil.

[0714] LC-MS (ESI): m / z = 173.0 [M+H] +

[0715] Step 4: Synthesis of compound I83-6

[0716] At room temperature, compound I83-5 (140 mg, 0.81 mmol) was added to formamide (0.5 mL, 4.57 mmol), and the reaction system was stirred at 180° C. for 2 hours under microwave. After cooling, the reaction solution was directly purified by preparative HPLC (Phenomenex Gemini 150 mm*25 mm*10 um colume) (eluent = 10% to 60% (v / v) acetonitrile and water, containing 0.025% formic acid) to obtain compound I83-6 (120 mg, 0.78 mmol, Y=96.4%) as a yellow solid.

[0717] LC-MS (ESI): m / z = 154.0 [M+H] +

[0718] Step 5: Synthesis of compound I83-7

[0719] At room temperature, compound I83-6 (70 mg, 0.46 mmol) was added to phosphorus oxychloride (2 mL), and the reaction system was heated to 110 ° C and stirred for 2 h. The reactants were concentrated and poured into water (10 mL), extracted with ethyl acetate (10 mL * 3); the combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative TLC (eluent = petroleum ether: ethyl acetate = 5: 1) to obtain compound I83-7 (35 mg, 0.20 mmol, Y = 44.6%) as a yellow solid.

[0720] LC-MS (ESI): m / z = 172.0 [M+H] +

[0721] Step 6: Synthesis of Compound I83-8

[0722] Compound I83-7 (35 mg, 0.20 mmol) was added to aqueous ammonia (3 mL, 23.37 mmol, purity: 30%, Anergy), and the reaction system was heated to 80°C and stirred for 2 h. The reaction solution was concentrated to obtain compound I83-8 (20 mg, 0.13 mmol, Y=64.6%) as a yellow solid, which was directly used for the next step.

[0723] LC-MS (ESI): m / z = 153.0 [M+H] +

[0724] Step 7: Synthesis of Compound I83-9

[0725] Compound I83-8 (17.23 mg, 0.11 mmol) and compound I31-8 (40 mg, 0.11 mmol) were added to 1,4-dioxane (0.5 mL), and then tri(dibenzylideneacetone)dipalladium (10.37 mg, 0.01 mmol, Anergy), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (13.10 mg, 0.02 mmol, Anergy) and cesium carbonate (110.69 mg, 0.34 mmol) were added respectively; the reaction system was replaced with nitrogen three times, and then heated to 85°C and stirred for 2.5 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL*3); the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by preparative TLC (eluent = petroleum ether: ethyl acetate = 1:1) to give compound I83-9 (20 mg, 0.05 mmol, Y = 43.0%) as a yellow solid.

[0726] LC-MS (ESI): m / z = 425.1 [M+H] +

[0727] Step 8: Synthesis of Compound 0083

[0728] At 0°C under nitrogen protection, compound I83-9 (20 mg, 0.05 mmol) was added to dichloromethane (1 mL), and then boron tribromide (0.24 mL, 0.24 mmol, 1 mol / L, Anaiji) was added; the reactants were warmed to 25°C and stirred for 1 hour. 1 mL of methanol was added to the reaction system to quench the reaction, and the system was concentrated under reduced pressure to obtain a crude product, which was purified by Pre-HPLC (Waters-CORTECS-C18-2.7 μm-4.6*30 mm, A: 10 mM ammonium bicarbonate / water B: acetonitrile, 10-95) to obtain compound 0083 (1.01 mg, 0.009 mmol, Y=5.7%) as a yellow solid.

[0729] LC-MS (ESI): m / z = 411.2 [M+H] +

[0730] 1 H NMR(400MHz, DMSO-d6)δ:9.09–9.04(m,1H),8.94–8.88(m,1H),7.00–6.96(m,1H),6.79–6.74(m,1H),4.68–4.62(m,2H),2.12(s,3H),2.06(s,3H)

[0731] Example 32:

[0732] Synthesis of Compound 0084

[0733]

[0734] Step 1: Synthesis of compound I84-3

[0735] Compound I84-2 (1.00 g, 7.78 mmol, Bid) was added to a tetrahydrofuran (30 mL) solution of compound I84-1 (1.47 mL, 10.89 mmol, Bid), and the resulting mixture was stirred at 50 ° C for 18 hours to obtain a yellow solution. LCMS detection revealed the target molecular weight. The reaction solution was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent = petroleum ether: ethyl acetate = 10: 1 to 1: 1) to obtain compound I84-3 (2.05 g, 8.03 mmol, Crude) as a yellow solid.

[0736] LC-MS (ESI): m / z = 256.0 [M+H] +

[0737] Step 2: Synthesis of compound I84-4

[0738] A solution of compound I84-3 (500 mg, 1.96 mmol) in concentrated H2SO4 (3 mL) was stirred at 110 ° C for 4 hours to obtain a brown solution. The target molecular weight was found by LCMS detection. The reaction solution was poured into water (20 mL) and adjusted to pH = 7 with sodium hydroxide (1 M) aqueous solution. Then it was extracted with ethyl acetate (30 mL * 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product compound I84-4 (160 mg, 1.06 mmol, Y = 54.03%) as a white solid.

[0739] LC-MS (ESI): m / z = 152.0 [M+H] +

[0740] Step 3: Synthesis of compound I84-5

[0741] To a mixed solution of compound I84-4 (107.01 mg, 0.71 mmol) and compound I31-8 (250 mg, 0.71 mmol) in N,N-dimethylformamide (3 mL) were added 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (81.91 mg, 0.14 mmol, Bid), cesium carbonate (691.80 mg, 2.12 mmol, Bid) and tris(dibenzylideneacetone)dipalladium (64.81 mg, 0.07 mmol, Bid), the reaction solution was degassed and purged with nitrogen three times, and stirred at 80 ° C for 2.5 hours under nitrogen. LCMS detection found the target molecular weight. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent = petroleum ether:ethyl acetate = 50:1 to 1:1) to obtain compound I84-5 (120 mg, 0.28 mmol, Y = 40.03%) as a yellow solid.

[0742] LC-MS (ESI): m / z = 424.2 [M+H] +

[0743] Step 4: Synthesis of Compound 0084

[0744] At 0°C, a dichloromethane (2mL) solution of compound I84-5 (85 mg, 0.20 mmol) was added dropwise with a dichloromethane solution of boron tribromide (1.00 mL, 1 M). After the addition was complete, the reaction solution was stirred at 25°C for 1 hour to obtain a yellow solution. The target molecular weight was detected by LCMS. The reaction solution was quenched with MeOH (1 mL) and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (Phenomenex Gemini 150mm*25mm*10um colume) (eluent = 30% to 60% (v / v) CH3CN and H2O with 0.025% NH4HCO3) to obtain compound 0084 (7.66 mg, 0.02 mmol, Y = 9.32%) as a yellow solid.

[0745] LC-MS (ESI): m / z = 410.2 [M+H] +

[0746] 1H NMR (400MHz, DMSO-d6) δ: 13.40 (s, 1H), 9.35 (s, 1H), 8.92 (s, 1H), 8.39 (d, J = 5.2Hz, 1H), 8.05 (d, J = 5 .2Hz,1H),6.95(d,J=8.4Hz,1H),6.78(d,J=8.2Hz,1H),4.73-4.58(m,2H),2.04(s,3H),1.94(s,3H)

[0747] Example 33:

[0748] Synthesis of Compound 0088

[0749]

[0750] Step 1: Synthesis of compound I88-3

[0751] Acetonitrile (15 ml), compound I88-2 (1.57 g, 9.28 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (6.51 g, 23.21 mmol) and N-methylimidazole (2.96 ml, 37.13 mmol) were added to compound I88-1 (3 g, 9.28 mmol) respectively, and the mixture was stirred at 25° C. for 16 hours. The reactant was concentrated, and the crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0%-25%) to obtain compound I88-3 (2.58 g, 5.44 mmol, Y = 58.59%) as a yellow oil.

[0752] LC-MS(ESI): m / z=474.2 / 476.2[M+H] +

[0753] Step 2: Synthesis of compound I88-4

[0754] A mixed solution of compound I88-3 (2.58 g, 5.44 mmol), cuprous iodide (0.06 mL, 1.63 mmol), ethynyltrimethylsilane (1.94 mL, 13.60 mmol) and bistriphenylphosphine palladium dichloride (0.38 g, 0.54 mmol) in triethylamine (15 mL) was replaced with nitrogen three times and stirred at 80 ° C for 2 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0%-35%) to obtain compound I88-4 (1.68 g, 4.01 mmol, Y = 73.64%) as a yellow solid.

[0755] LC-MS (ESI): m / z = 420.2 [M+H] +

[0756] Step 3: Synthesis of compound I88-5

[0757] Sodium tert-butoxide (0.77 g, 8.01 mmol) was added to a solution of compound I88-4 (1.68 g, 4.01 mmol) in N,N-dimethylformamide (15 mL). The reactants were stirred at 100 ° C for 2 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product compound I88-5 (2 g, 3.81 mmol, Y = 95.24%) as a yellow solid.

[0758] LC-MS (ESI): m / z = 420.2 [M+H] +

[0759] Step 4: Synthesis of compound I88-6

[0760] Hydrogen chloride-ethyl acetate (20 mL, 4 mol / L) solution was added to compound I88-5 (2 g, 4.77 mmol). The reactant was stirred at 60 ° C for 2 hours. The reaction mixture was adjusted to pH = 7 with sodium bicarbonate aqueous solution and extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0% to 75%) to obtain compound I88-6 (600 mg, 1.88 mmol, Y = 39.41%) as a yellow solid.

[0761] LC-MS (ESI): m / z = 320.2 [M+H] +

[0762] Step 5: Synthesis of compound I88-8

[0763] To a mixed solution of compound I88-6 (150 mg, 0.47 mmol), compound I88-7 (78.26 mg, 0.47 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (54.36 mg, 0.09 mmol) and cesium carbonate (459.12 mg, 1.41 mmol) in N,N-dimethylformamide (3 ml), tri(dibenzylideneacetone)dipalladium (43.01 mg, 0.05 mmol) was added, and the mixture was replaced with nitrogen 3 times and stirred at 100 ° C in a microwave for 2 hours. The mixture was poured into water (5 mL) and extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = tetrahydrofuran: petroleum ether = 0% - 60%) to obtain compound I88-8 (50 mg, 0.11 mmol, Y = 23.68%) as a yellow oil.

[0764] LC-MS (ESI): m / z = 450.1 [M+H] +

[0765] Step 6: Synthesis of Compound 0088

[0766] Boron tribromide (0.44 ml, 0.44 mmol, 1 M) was added to a solution of compound I88-8 (50 mg, 0.11 mmol) and dichloromethane (2 mL), and the reaction solution was stirred at 20 ° C for 1 hour. The mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by preparative HPLC (eluent = 30% to 60% (v / v) acetonitrile and water, 0.025% ammonium bicarbonate) to give compound 0088 (7.36 mg, 0.02 mmol, Y = 15.19%) as a white solid.

[0767] LC-MS (ESI): m / z = 436.2 [M+H] +

[0768] 1 H NMR(400MHz, DMSO-d6)δ:12.13(s,1H),9.55(s,1H),8.24–8.00(m,1H),7.47–7.35(m,2H),7.31–7. 22(m,1H),7.20–7.13(m,1H),7.13–7.03(m,1H),6.85–6.73(m,1H),3.83(s,3H),2.05–1.84(m,6H)

[0769] Example 34:

[0770] Synthesis of Compound 0097

[0771]

[0772] Step 1: Synthesis of compound I97-3

[0773] Under nitrogen protection, compound I97-1 (100 mg, 0.31 mmol), compound I97-2 (60.63 mg, 0.31 mmol), Xantphos (36.24 mg, 0.06 mmol) and cesium carbonate (306.08 mg, 0.94 mmol) were added to N, N-dimethylformamide (2 mL), followed by the addition of tris(dibenzylideneacetone)dipalladium (28.67 mg, 0.03 mmol), the reaction solution was replaced with nitrogen three times, and then reacted at 90 ° C for 2 hours. A black solution was formed. The product was detected by LCMS. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL*3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (tetrahydrofuran:petroleum ether=0%-60%) to obtain compound I97-3 (80 mg, 0.17 mmol, Y=53.0%) as a yellow oil.

[0774] LC-MS (ESI): m / z = 477.2 [M+H] +

[0775] Step 2: Synthesis of Compound 0097

[0776] Compound I97-3 (60 mg, 0.13 mmol) was dissolved in dichloromethane (1 mL), boron tribromide (0.50 mL, 0.50 mmol) was added, and the mixture was stirred at 25 ° C for 1 hour. A black solution was formed. The product was detected by LCMS. The mixture was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography (Phenomenex Gemini 150 mm * 25 mm * 10 um column (eluent = acetonitrile: water containing 0.025% sodium bicarbonate = 30% to 60%) to obtain compound 0097 (9.45 mg, 0.02 mmol, Y = 16.0%) as a white solid.

[0777] LC-MS (ESI): m / z = 463.1 [M+H] +

[0778] 1H NMR(400MHz,DMSO-d6)δ:12.61(br s,1H),9.57(s,1H),8.71–8.60(m,1H),7.48–7.38(m,2H),7.13–6.99(m,2H),6.87–6. 77(m,1H),3.66–3.60(m,1H),1.95–1.89(m,3H),1.89–1.83(m,3H),1.12–1.01(m,4H)

[0779] Example 35:

[0780] Synthesis of Compound 0099

[0781]

[0782] Step 1: Synthesis of compound I99-3

[0783] Under nitrogen protection, tri(dibenzylideneacetone)dipalladium (28.67 mg, 0.03 mmol) was added to a solution of compound I99-1 (100 mg, 0.31 mmol), compound I99-2 (56.87 mg, 0.31 mmol), Xantphos (36.24 mg, 0.06 mmol) and cesium carbonate (306.08 mg, 0.94 mmol) in N,N-dimethylformamide (2 mL), the mixture was degassed and purged with nitrogen 3 times, and the reaction solution was stirred at 90 ° C for 2 hours. A black solution was formed. The product was detected by LCMS. The mixture was poured into water (5 mL) and extracted with ethyl acetate (15 mL*3). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = tetrahydrofuran: petroleum ether = 0% - 60%) to obtain compound I99-3 (80 mg, 0.17 mmol, Y = 55.00%) as a yellow oil.

[0784] LC-MS (ESI): m / z = 465.2 [M+H] +

[0785] Step 2: Synthesis of Compound 0099

[0786] Compound I99-3 (60 mg, 0.13 mmol) was dissolved in dichloromethane (1 mL), followed by the addition of boron tribromide (0.52 mL, 0.52 mmol). The reactants were stirred at 25 ° C for 1 hour. The product was detected by LCMS. The mixture was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography (Phenomenex Gemini 150mm*25mm*10um column (eluent = acetonitrile: containing 0.025% ammonium bicarbonate = 30% to 60%) to obtain compound 0099 (12.29 mg, 0.03 mmol, Y = 21.0%) as a white solid.

[0787] LC-MS (ESI): m / z = 451.1 [M+H] +

[0788] 1 H NMR(400MHz, DMSO-d6)δ:12.63(s,1H),9.56(s,1H),8.62(s,1H),7.54(d,J=3.6Hz,1H),7.42(d,J=7.2Hz,1H), 7.13–7.02(m,2H),6.81(d,J=7.2Hz,1H),4.29(q,J=7.1Hz,2H),1.91(s,3H),1.86(s,3H),1.39(t,J=7.2Hz,3H)

[0789] Example 36:

[0790] Synthesis of Compound 0102

[0791]

[0792] Step 1: Synthesis of compound I102-3

[0793] Compound I102-1 (0.9 g, 2.78 mmol) and compound I102-2 (0.64 g, 2.78 mmol) were added to acetonitrile (20 mL), and TCFH (1.95 g, 6.96 mmol, Anaiji) and NMI (888.06 μL, 11.14 mmol, Anaiji) were added. The reactants were stirred at 25 ° C for 16 hours. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10: 1 to 1: 1) to obtain compound I102-3 (1.4 g, 2.61 mmol, Y = 93.1%) as a yellow oil.

[0794] LC-MS(ESI): m / z=534.2 / 536.2[MH] +

[0795] Step 2: Synthesis of compound I102-4

[0796] Compound I102-3 (1.4 g, 2.61 mmol), compound 3.1 (0.82 mL, 3.91 mmol, Anaiji) were added to a mixed solution of dioxane (3 mL) and water (14 mL), and tricyclohexylphosphine (146.38 mg, 0.52 mmol, Anaiji), tris(dibenzylidene-BASE acetone)dipalladium (238.98 mg, 0.26 mmol, Anaiji) and potassium carbonate (901.67 mg, 6.52 mmol) were added. The reactants were stirred at 95 ° C for 18 hours under nitrogen protection. The reactants were then cooled to 25 ° C, and HCl (10 mL, 40.00 mmol, 6 moL / L, Anaiji) was added and stirred at 25 ° C for 3 hours. The reaction mixture was quenched with aqueous solution, washed with saturated sodium bicarbonate (50 mL) solution, extracted with ethyl acetate (30 mL*3), and the combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = dichloromethane: methanol = 100: 1 to 10: 1) to obtain compound I102-4 (330 mg, 1.11 mmol, Y = 42.5%) as a yellow solid.

[0797] 1 H NMR(400MHz,DMSO-d6)δ:13.26(s,1H),8.09(s,2H),7.68(s,1H),7.61–7.55(m,1H), 7.44(d,J=7.2Hz,1H),7.36(d,J=8.5Hz,1H),6.57(d,J=7.2Hz,1H),3.21–3.14(m,3H)

[0798] Step 3: Synthesis of Compound 0102

[0799] Compound I102-4 (100 mg, 0.34 mmol) and compound I102-4.1 (58.61 mg, 0.30 mmol) were added to dioxane (0.8 mL) and water (0.2 mL), and tris(dibenzyl-BASE acetone)dipalladium (30.80 mg, 0.03 mmol, Anaiji), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (38.92 mg, 0.07 mmol, Anaiji) and cesium carbonate (328.73 mg, 1.01 mmol) were added. The reactants were stirred at 100 ° C for 2.5 hours under nitrogen protection. The mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (Phenomenex Gemini 150mm*25mm*10u mcolume (Waters-Xbridge-C18-10μm-19*250mm, A: 10mM ammonium bicarbonate / water B: acetonitrile) to give compound 0102 (3.03mg, 0.01mmol, Y=2.6%) as a white solid.

[0800] LC-MS (ESI): m / z = 455.1 [M+H] +

[0801] 1 H NMR(400MHz,DMSO-d6)δ:13.29(s,1H),8.67–8.62(m,1H),7.76–7.71(m,1H),7.63–7.56(m,2H),7.44 –7.37(m,2H),7.04–6.97(m,1H),6.88–6.80(m,1H),3.66–3.60(m,1H),2.16(s,3H),1.09–1.04(m,4H)

[0802] Example 37:

[0803] Synthesis of Compound 0105

[0804] Step 1: Synthesis of compound I105-3

[0805] Compound I105-1 (89.91 mg, 0.50 mmol) and compound I105-2 (129.16 mg, 0.66 mmol) were added to 1,4-dioxane (3 mL), and then tri(dibenzylideneacetone)dipalladium (30.39 mg, 0.03 mmol, Anergy), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (38.40 mg, 0.07 mmol, Anergy) and cesium carbonate (648.70 mg, 1.99 mmol) were added. After nitrogen was replaced three times, the temperature was raised to 100 ° C and the reaction was stirred for 16 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10: 1 to 3: 7) to give compound I105-3 (160 mg, 0.35 mmol, Y = 52.70%) as a yellow solid.

[0806] LC-MS (ESI): m / z = 459.2 [M+H] +

[0807] Step 2: Synthesis of Compound 0105

[0808] Under nitrogen protection at -40°C, compound I105-3 (160 mg, 0.35 mmol) was added to dichloromethane (3 mL), and then boron tribromide (1.74 mL, 1.74 mmol, 1 mol / L, Anaiji) was added. After the addition, the reaction solution was warmed to 25°C and stirred for 2 hours. The temperature was controlled in an ice-water bath, and 1 mL of methanol was added to the reactant to quench. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by preparative high performance liquid chromatography (Waters-Xbridge-C18-10 μm-19*250 mm, A: 10 mM ammonium bicarbonate / water B: acetonitrile) to obtain compound 0105 (6.2 mg, 0.02 mmol, Y=6.5%) as a white solid.

[0809] LC-MS (ESI): m / z = 445.2 [M+H] +

[0810] 1H NMR(400MHz,DMSO-d6)δ:12.59(br s,1H),9.48(s,1H),8.63(s,1H),7.44-7.37(m,2H),7.05-6.98(m,2H),6.85(d,J=8.2Hz, 1H),6.79(d,J=7.2Hz,1H),3.67–3.59(m,1H),1.90(s,3H),1.81(s,3H),1.11–1.04(m,4H)

[0811] Example 38:

[0812] Synthesis of Compound 0106

[0813]

[0814] Step 1: Synthesis of compound I106-2

[0815] At 0°C, sodium hydride (0.24 g, 5.98 mmol, 60% purity) was added to a solution of compound I106-1 (1 g, 4.98 mmol, Bid) in acetonitrile (15 mL), and then iodoethane (0.60 ml, 7.48 mmol) was added while maintaining 0°C, and the reaction solution was heated to 50°C and stirred for 3 hours. The reaction system was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0% to 20%) to obtain compound I106-2 (230 mg, 1.01 mmol, Y = 20.18%) as a white solid.

[0816] LC-MS (ESI): m / z = 229.0 [M+H] +

[0817] Step 2: Synthesis of compound I106-3

[0818] To a solution of compound I106-2 (230 mg, 1.01 mmol) in dichloromethane (4 ml) was added meta-chloroperbenzoic acid (0.93 mL, 3.02 mmol) at room temperature, and the mixture was stirred at room temperature for 3 hours at 25° C. The reaction system was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0% to 100%) to obtain compound I106-3 (450 mg, 0.86 mmol, Y = 85.82%) as a white solid.

[0819] LC-MS (ESI): m / z = 261.0 [M+H] +

[0820] Step 3: Synthesis of Compound I106-5

[0821] At 0°C, cesium carbonate (374.94 mg, 1.15 mmol) was added to a mixed solution of compound I106-3 (100 mg, 0.38 mmol), zinc chloride (0.77 mL, 0.77 mmol) and compound I106-4 (0.09 mL, 1.15 mmol) in tetrahydrofuran (2 mL), and the reaction system was heated to 70°C and stirred for 4 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0% to 50%) to obtain compound I106-5 (22 mg, 0.08 mmol, Y = 20.63%) as a yellow solid.

[0822] LC-MS (ESI): m / z = 253.0 [M+H] +

[0823] Step 4: Synthesis of Compound 0106

[0824] Tri(dibenzylideneacetone)dipalladium (7.97 mg, 0.01 mmol) was added to a solution of compound I106-5 (22 mg, 0.09 mmol), compound I106-6 (25.02 mg, 0.09 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (10.08 mg, 0.02 mmol) and cesium carbonate (85.10 mg, 0.26 mmol) in N,N-dimethylformamide (1 mL), the mixture was replaced with nitrogen three times, the temperature was raised to 90°C and the reaction was stirred for 3 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL*3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by preparative HPLC (Phenomenex Gemini 150 mm*25 mm*10 um colume) (eluent = 28% to 58% (v / v) acetonitrile and water with 0.01% ammonium bicarbonate) to give compound 0106 (4.09 mg, 0.01 mmol, Y=9.33%) as a white solid.

[0825] LC-MS (ESI): m / z = 504.2 [M+H] +

[0826] 1H NMR(400MHz,DMSO-d6)δ:13.23(br s,1H),9.54(s,1H),8.51(s,1H),7.45(d,J=7.4Hz,1H),7.03(d,J=8.4Hz,1 H),6.86(d,J=7.8Hz,2H),5.13–5.00(m,1H),4.49–4.38(m,2H),4.20–4.13 (m,1H),3.97–3.92(m,1H),2.42–2.37(m,1H),2.32–2.25(m,1H),2.15–2.0 9(m,1H),2.03–1.97(m,1H),1.90(s,3H),1.81(s,3H),1.43(t,J=7.2Hz,3H)

[0827] Example 39:

[0828] Synthesis of compounds 0114 and 0134

[0829]

[0830] Step 1: Synthesis of compound 0106

[0831] Under nitrogen environment, compound I114-1 (200 mg, 1.98 mmol, Bid) and acetic anhydride (166.7 μL, 1.78 mmol) were added to pyridine (1 mL), and the resulting mixture was stirred at 25°C for 3 hours to obtain a yellow solution. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (eluent = dichloromethane: methanol = 100: 1 to 10: 1) to obtain compound I114-2 (190 mg, 1.33 mmol, Y = 67.11%) as a yellow oil.

[0832] 1 H NMR (400MHz, DMSO-d6) δ4.91–4.77(m,1H),3.58–3.48(m,2H),3.21–2.89(m,2H),2.56– 2.47(m,1H),2.01–1.94(m,3H),1.88–1.72(m,1H),1.72–1.57(m,1H),1.46–1.20(m,2H)

[0833] Step 2: Synthesis of compounds 0114 and 0134

[0834] Under nitrogen atmosphere, N,N-diisopropylethylamine (0.03 mL, 0.23 mmol) was added to a solution of compound I114-3 (50 mg, 0.09 mmol) and compound I114-2 (79.5 mg, 0.55 mmol) in dimethyl sulfoxide (1 mL), and the solution was heated to 100°C and stirred for 16 hours. The mixture was filtered, and the filter cake was washed with dimethyl sulfoxide (2 mL) to obtain a filtrate, which was subjected to preparative HPLC (Phenomenex Gemini 150 mm*25 mm*10 um colume (eluent = 37% to 47% (v / v) acetonitrile and water with 0.1% formic acid) to obtain compound 0114 (3.96 mg, 0.01 mmol, Y = 7.09%) as a white solid and compound 0134 (3.58 mg, 0.01 mmol, Y = 6.59%) as a white solid.

[0835] Compound 0114

[0836] LC-MS (ESI): m / z = 603.9 [M+H] +

[0837] 1 H NMR (400MHz, DMSO-d6) δ12.62(s,1H),9.58(s,1H),7.43(d,J=7.3Hz,1H),7.21–7.14(m, 1H),7.08(d,J=11.4Hz,1H),6.91(s,1H),6.81(d,J=7.2Hz,1H),5.20-5.11(m,1H),4.11 –3.86(m,1H),3.63–3.54(m,2H),3.51–3.44(m,2H),2.23–2.14(m,1H),1.98(d,J=21.7H z,3H),1.91(s,3H),1.85(s,3H),1.81–1.62(m,2H),1.61–1.43(m,1H),1.05–0.97(m,4H)

[0838] Compound 0134

[0839] LC-MS (ESI): m / z = 603.9 [M+H] +

[0840] 1H NMR(400MHz, DMSO-d6)δ12.60(s,1H),9.57(s,1H),7.41(d,J=7.4Hz,1H),7.20–7.14(m, 1H),7.08(d,J=11.4Hz,1H),6.88(s,1H),6.79(d,J=7.2Hz,1H),5.20–5.13(m,1H),4.10 –3.88(m,1H),3.63–3.54(m,2H),3.52–3.45(m,2H),2.24–2.14(m,1H),1.98(d,J=24.3H z,3H),1.91(s,3H),1.86(s,3H),1.82–1.64(m,2H),1.62–1.45(m,1H),1.05–0.98(m,4H)

[0841] Example 40:

[0842] Synthesis of Compound 0115

[0843]

[0844] Step 1: Synthesis of compound I115-3

[0845] To a mixed solution of compound I115-1 (1.0 g, 3.13 mmol), compound I115-2 (0.75 g, 3.13 mmol) and cesium carbonate (3.06 g, 9.39 mmol) in N,N-dimethylformamide were added [5-(diphenylphosphino)-9,9-dimethyl-9H-oxacyclo-4-yl]diphenylphosphine (0.36 g, 0.63 mmol) and tris(1,5-diphenylpenta-1,4-dien-3-one)palladium(0) (0.25 g, 0.31 mmol), the mixture was degassed and purged with nitrogen three times, and the temperature was raised to 100°C under a nitrogen environment and stirred for 18 hours. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL*3). The combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10:1 to 1:1) to give compound I115-3 (750 mg, 0.31 mmol) as a yellow solid.

[0846] LC-MS (ESI): m / z = 523.2 [M+H] +

[0847] Step 2: Synthesis of compound I115-4

[0848] Tribromoborane (5.02 ml, 5.02 mmol) was added to a solution of compound I115-3 (750 mg, 0.31 mmol) in dichloromethane (6 ml) at 0°C, and then the reaction solution was heated to 25°C and stirred for 1 hour. The reaction solution was poured into water (6 mL) and extracted with dichloromethane (10 mL*3); the combined organic phase was washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (eluent = dichloromethane: methanol = 80: 1 to 20: 1) to obtain compound I115-4 (500 mg, 0.98 mmol) as a yellow solid.

[0849] LC-MS (ESI): m / z = 509.2 [M+H] +

[0850] Step 3: Synthesis of compound I115-5

[0851] At 0°C, 3-chlorobenzene-1-carbon peroxyacid (414.66 mg, 2.40 mmol) was added to a solution of compound I115-4 (455 mg, 0.89 mmol) in dichloromethane (10 mL), and then the reaction solution was heated to 25°C and stirred for 18 hours. The reaction solution was poured into water (30 mL) and extracted with dichloromethane (30 mL*3); the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (eluent = dichloromethane: methanol = 80: 1 to 20: 1) to obtain compound I115-5 (320 mg, 0.59 mmol) as a yellow solid.

[0852] LC-MS (ESI): m / z = 541.2 [M+H] +

[0853] Step 4: Synthesis of Compound 0115

[0854] Potassium tert-butoxide (31.14 mg, 0.28 mmol) was added to a mixed solution of compound I115-5 (60 mg, 0.11 mmol) and 3-methylbutane-1,3-diol (69.36 mg, 0.67 mmol, Bid) in dimethyl sulfoxide (2 mL) at room temperature, and the mixture was stirred at 100° C. for 4 hours. The reaction solution was filtered, the filter cake was washed with dimethyl sulfoxide (4 mL), and the filtrates were combined and purified by preparative HPLC (Phenomenex Gemini 150 mm*25 mm*10 umcolume (eluent = 30% to 60% (v / v) CH3CN and H2O, 0.025% NH4HCO3) to obtain compound 0115 (8.22 mg, 0.01 mmol, Y = 13.12%) as a white solid.

[0855] LC-MS (ESI): m / z = 565.4 [M+H] +

[0856] 1 H NMR(400MHz,DMSO)δ12.55(br s,1H),9.59(br s,1H),7.42(d,J=7.2Hz,1H),7.15(d,J=3.6Hz,1H),7.08(d,J=11.2Hz,1H),6.89(d,J=3.2Hz,1H),6.80(d,J=7.2Hz,1H),4.58 (t,J=7.2Hz,2H),4.40(s,1H),3.53-3.47(m,1H),1.96-1.92(m,2H),1.91(s,3H),1.85(s,3H),1.21(s,6H),1.05-0.98(m,4H)

[0857] Example 41:

[0858] Synthesis of Compound 0116

[0859]

[0860] Step 1: Synthesis of compound I116-2

[0861] Cyclopropylboric acid (9.14 g, 106.38 mmol), copper acetate (9.66 g, 53.19 mmol), 2-(pyridin-2-yl)pyridine (8.31 g, 53.19 mmol) and sodium bicarbonate (8.94 g, 106.38 mmol) were added to a solution of compound I116-1 (10 g, 65.12 mmol) in 1,2-dichloroethane (30 mL), and the reaction system was heated to 80°C and stirred for 18 hours. The reaction system was filtered and the filter cake was washed with dichloromethane (50 mL*3), and the filtrates were combined and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 100: 1 to 5: 1) to obtain compound I116-2 (5.0 g, 21.92 mmol, Y = 41.2%) as a white solid.

[0862] LC-MS (ESI): m / z = 228.0 [M+H] +

[0863] Step 2: Synthesis of compound I116-3

[0864] Under ice-water bath, sodium thiomethoxide (0.86 g, 12.28 mmol) was added to a solution of compound I116-2 (2.8 g, 12.28 mmol) in N,N-dimethylformamide (40 mL), and the reaction system was stirred at 25°C for 2 hours. The reaction solution was poured into water (50 mL) and extracted 3 times with ethyl acetate (100 mL*3), and the organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 100: 1 to 10: 1) to obtain compound I116-3 (2 g, 8.34 mmol, Y = 67.9%) as a white solid.

[0865] LC-MS (ESI): m / z = 240.0 [M+H] +

[0866] Step 3: Synthesis of compound I116-4

[0867] Under nitrogen atmosphere, palladium chloride bis(triphenylphosphine) (0.26 g, 0.38 mmol) was added to a mixed solution of compound I116-3 (1 g, 3.75 mmol) and cyclopropylboronic acid (0.32 g, 3.75 mmol), potassium carbonate (1.30 g, 9.39 mmol) in 1,4-dioxane (10 mL) and water (2 mL), and the reaction system was heated to 100 ° C and stirred for 18 hours. The reaction solution was poured into water (20 mL) and extracted 3 times with ethyl acetate (50 mL*3), and the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC ((eluent = 5% to 65% (v / v) CH3CN / H2O, containing 0.1% HCOOH) to obtain compound I116-4 (300 mg, 1.04 mmol, Y = 27.7%) as a white solid.

[0868] LC-MS (ESI): m / z = 246.5 [M+H] +

[0869] Step 4: Synthesis of Compound I116-5

[0870] To a solution of compound I116-4 (200 mg, 0.82 mmol) in dichloromethane (5 mL) was added meta-chloroperbenzoic acid (281.34 mg, 1.63 mmol) at room temperature, and the resulting mixture was stirred at 25°C for 2 hours. The reaction solution was quenched with sodium thiosulfate solution (5 mL) and extracted 3 times with dichloromethane (20 mL×3); the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 100: 1-4: 1) to obtain compound I116-5 (80 mg, 0.27 mmol, Y = 33.6%) as a white solid.

[0871] LC-MS (ESI): m / z = 278.1 [M+H] +

[0872] Step 5: Synthesis of Compound I116-7

[0873] Potassium tert-butoxide (78.2 mg, 0.7 mmol) was added to a solution of compound I116-6 (70 mg, 0.23 mmol) and compound I116-5 (80 mg, 0.27 mmol) in dimethyl sulfoxide (3 mL), and the reaction system was heated to 100°C and stirred for 18 hours. The reaction solution was poured into water (20 mL) and extracted 3 times with ethyl acetate (30 mL*3), and the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10: 1 to 4: 1) to obtain compound I116-7 (50 mg, 0.08 mmol, Y = 34.10%) as a yellow solid.

[0874] LC-MS (ESI): m / z = 499.2 [M+H] +

[0875] Step 6: Synthesis of Compound 0116

[0876] Boron tribromide (0.3 mL, 0.3 mmol) was added to a solution of compound I116-7 (30 mg, 0.06 mmol) in dichloromethane (2 mL) at 0°C, and the reaction system was warmed to 25°C and stirred for 1 hour. The reaction solution was quenched with methanol (2 mL) under an ice-water bath, and then the pH was adjusted to 7-8 with NH3 (7 M in MeOH), and the mixed solution was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (Phenomenex Gemini 150 mm*25 mm*10 um colume) (eluent = 5% to 60% (v / v) acetonitrile / water, 0.01% NH4HCO3) to obtain compound 0116 (3.94 mg, 0.01 mmol, Y = 13.51%) as a white solid.

[0877] LC-MS (ESI): m / z = 485.6 [M+H] +

[0878] 1H NMR(400MHz,DMSO-d6)δ:12.47(br s,1H),9.50(s,1H),7.40(d,J=7.2Hz,1H),7.26(d,J=3.6Hz,1H),7.02(d,J=8.3Hz,1H),6.92(d,J=3.6Hz,1H),6.85(d,J=8.3Hz, 1H),6.79(d,J=7.2Hz,1H),3.63–3.55(m,1H),2.29–2.18(m,1H),1.90(s,3H),1.80(s,3H),1.33–1.26(m,2H),1.12–0.99(m,6H)

[0879] Example 42:

[0880] Synthesis of Compound 0120

[0881]

[0882] Step 1: Synthesis of compound I120-2

[0883] Under nitrogen environment, copper acetate (9.66 g, 53.19 mmol), 2-(pyridin-2-yl)pyridine (8.31 g, 53.19 mmol) and sodium bicarbonate (8.94 g, 106.38 mmol) were added to a solution of compound I120-1 (10 g, 65.12 mmol) and cyclopropylboranediol (9.14 g, 106.38 mmol) in 1,2-dichloroethane (150 mL). The reaction solution was stirred at 80 ° C for 18 hours. The reaction solution was filtered and the filter cake was washed with dichloromethane (50 mL × 3). The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 15-20%) to obtain compound I120-2 (5.04 g, 22.10 mmol, Y = 41.55%) as a white solid.

[0884] LC-MS(ESI): m / z=228.0 / 230.0[M+H] +

[0885] Step 2: Synthesis of compound I120-3

[0886] Ammonium hydroxide (40 mL, 25% aqueous solution, Anaiji) was added to a solution of compound I120-2 (1.00 g, 4.38 mmol) in tetrahydrofuran (10 mL) at room temperature, and the resulting reaction solution was stirred at 90°C for 18 hours. The reaction solution was poured into water (30 mL) and extracted with ethyl acetate (30 mL*3); the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 40 to 80%) to obtain compound I120-3 (510 mg, 2.44 mmol, Y = 55.75%) as a white solid.

[0887] LC-MS(ESI): m / z=209.0 / 211.0[M+H] +

[0888] Step 3: Synthesis of compound I120-4

[0889] To a solution of compound I120-3 (410 mg, 1.97 mmol) and cyclopropylboranediol (843.97 mg, 9.83 mmol) in 1,4-dioxane (8 mL) and water (2 mL) were added a solution of bis[5-(diphenylphosphino)cyclopenta-1,3-dienyl]-λ2-iron(II)palladium chloride (143.78 mg, 0.20 mmol) and Cs2CO3 (1920.72 mg, 5.90 mmol), the mixture was replaced with N2 three times, and the reaction system was stirred at 110°C under a nitrogen atmosphere for 18 hours. The reaction solution was poured into water (20 mL) and extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 50 to 100%) to give compound I120-4 (220 mg, 1.03 mmol, Y = 52.25%) as a white solid.

[0890] LC-MS (ESI): m / z = 215.2 [M+H] +

[0891] Step 4: Synthesis of compound I120-5

[0892] To a solution of compound I31-8 (250 mg, 0.71 mmol) and compound I120-4 (151.65 mg, 0.71 mmol) in 1,4-dioxane (3 mL) were added tris[dibenzylideneacetone]dipalladium(0) (64.81 mg, 0.07 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (81.91 mg, 0.14 mmol) and cesium carbonate (691.80 mg, 2.12 mmol), the mixture was replaced with nitrogen three times, the reaction solution was heated to 100°C and stirred for 18 hours. The reaction solution was poured into water (20 mL) and extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 10 to 50%) to give compound I120-5 (275 mg, 0.57 mmol, Y = 79.85%) as a brown solid.

[0893] LC-MS (ESI): m / z = 487.2 [M+H] +

[0894] Step 5: Synthesis of Compound 0120

[0895] Tribromoborane (2.04 mL, 2.04 mmol) was added to a solution of compound I120-5 (200 mg, 0.41 mmol) in dichloromethane (4 mL) at 0°C, and the mixture was stirred and reacted for 1 hour after the addition was returned to room temperature. 2 mL of methanol was added to the reaction solution at 0°C to quench the reaction, and the pH was adjusted to 8 with ammonia methanol solution; the reaction system was concentrated under reduced pressure to obtain a crude product, which was purified by preparative high performance liquid chromatography (Waters-Xbridge-C18-10 μm-19*250 mm colume (eluent = 36% to 66% (v / v) acetonitrile and water with 10 mM NH4HCO3) to obtain compound 0120 (86.28 mg, 0.18 mmol, Y = 59.23%) as a white solid.

[0896] LC-MS (ESI): m / z = 473.2 [M+H] +

[0897] 1H NMR(400MHz,DMSO-d6)δ:12.41(br s,1H),9.33(s,1H),7.26(d,J=3.6Hz,1H),6.94(d,J=8.2Hz,1H),6.91(d,J=3.6Hz,1H),6.78(d,J=8.2Hz,1H),4.63( d,J=3.4Hz,2H),3.63–3.56(m,1H),2.29-2.21(m,1H),2.04(s,3H),1.95(s,3H),1.36–1.28(m,2H),1.11–1.00(m,6H)

[0898] Example 43:

[0899] Synthesis of Compound 0127

[0900]

[0901] Step 1: Synthesis of compound I127-2

[0902] At 0°C, m-chloroperbenzoic acid (863 mg, 5.01 mmol) was added to a solution of compound I127-1 (480 mg, 2.00 mmol) in dichloromethane (8 mL), and the reaction solution was heated to 25°C and stirred for 3 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 10 to 50%) to obtain compound I127-2 (370 mg, 1.36 mmol, Y = 68.01%) as a white solid.

[0903] LC-MS (ESI): m / z = 272.0 [M+H] +

[0904] Step 2: Synthesis of compound I127-4

[0905] Under nitrogen environment, 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (58.38 mg, 0.10 mmol) and tris(dibenzylideneacetone)dipalladium (46.20 mg, 0.05 mmol) were added to a solution of compound I127-3 (150 mg, 0.50 mmol), compound I127-2 (109.66 mg, 0.40 mmol) and cesium carbonate (493.10 mg, 1.51 mmol) in N,N-dimethylformamide (6 mL), and stirred at 100 °C for 18 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL*3); the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product; the crude product was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether: = 5-50%) to give compound I127-4 (50 mg, 0.09 mmol, Y = 18.61%) as a yellow solid.

[0906] LC-MS (ESI): m / z = 533.2 [M+H] +

[0907] Step 3: Synthesis of Compound 0127

[0908] At 0°C, sodium bis(trimethylsilyl)amide (3760.00 μL, 3.76 mmol) was added to a solution of cyclopropanol (110.15 μL, 1.88 mmol, Bis(trimethylsilyl)amide) in tetrahydrofuran (2 mL), and the resulting mixture was stirred at 25°C for 1 hour; then a solution of compound I127-4 (40 mg, 0.08 mmol) in tetrahydrofuran was added to the above mixed solution, and the mixture was stirred at 75°C for 18 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (Phenomenex Gemini 150 mm*25 mm*10 um colume) (eluent = 30 to 60% (v / v) acetonitrile / water, 1% mol / L ammonium bicarbonate) to obtain compound 0127 (0.81 mg, 0.00 mmol, Y = 2.11%) as a white solid.

[0909] LC-MS (ESI): m / z = 511.2 [M+H] +

[0910] 1H NMR(400MHz,DMSO-d6)δ:13.27(br s,1H),7.72(s,1H),7.59(d,J=8.4Hz,2H),7.39(d,J=8.8Hz,1H),7.19(d,J=3.6Hz,1H),6.91(d,J=3.6Hz,1H), 6.84(d,J=7.4Hz,1H),4.50-4.44(m,1H),3.52-3.48(m,1H),2.15(s,3H),1.04-1.00(m,4H),0.85-0.82(m,4H).

[0911] Example 44:

[0912] Synthesis of Compound 0135

[0913]

[0914] Step 1: Synthesis of compound I135-2

[0915] Ammonia water (40 mL) was added to a solution of compound I135-1 (1.48 g, 6.49 mmol) in tetrahydrofuran (10 mL) at room temperature, and the reaction system was heated to 90°C and stirred for 18 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL*3); the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 5:1 to 3:2) to obtain compound I135-2 (1.44 g, 6.49 mmol, Y = 99.98%) as a white solid.

[0916] LC-MS (ESI): m / z = 209.0 [M+H] +

[0917] Step 2: Synthesis of compound I135-4

[0918] Under a nitrogen atmosphere, to a solution of compound I135-2 (740 mg, 3.55 mmol), compound I135-3 (1.52 g, 17.73 mmol) and cesium carbonate (3.47 g, 10.64 mmol) in 1,4-dioxane (12 mL) and purified water (3 mL) was added bis[5-(diphenylphosphino)cyclopentyl-1,3-dienyl]-λ2-iron(II)palladium chloride (259.51 mg, 0.35 mmol); the reactants were heated to 110°C and stirred for 18 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phases were washed with saturated brine (50 mL) and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 5:1 to 3:2) to obtain compound I135-4 (260 mg, 1.21 mmol, Y = 34.21%) as a white solid.

[0919] LC-MS (ESI): m / z = 215.2 [M+H] +

[0920] Step 3: Synthesis of compound I135-6

[0921] Under a nitrogen atmosphere, tri(dibenzylideneacetone)dipalladium (30.84 mg, 0.03 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (38.98 mg, 0.07 mmol) were added to a solution of compound I135-5 (150 mg, 0.34 mmol), compound I135-4 (79.4 mg, 0.37 mmol) and cesium carbonate (274.4 mg, 0.84 mmol) in N,N-dimethylformamide (6 mL), and the temperature was raised to 100°C and stirred for 2 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phases were washed with saturated brine (50 mL) and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10: 1 to 1: 2) to give compound I135-6 (150 mg, 0.26 mmol, Y = 76.95%) as a yellow solid.

[0922] LC-MS (ESI): m / z = 579.4 [M+H] +

[0923] Step 4: Synthesis of Compound 0135

[0924] Compound I135-6 (100 mg, 0.17 mmol) was dissolved in a hydrochloric acid dioxane solution (4 mL) and stirred at 25 ° C for 2 hours. The reaction was adjusted to pH = 7-8 with ammonia (7M in MeOH) and concentrated to dryness to give a crude product. The crude product was purified by preparative HPLC (Phenomenex Gemini 150mm*25mm*10um colume) (eluent = 5% to 60% (v / v) acetonitrile / water, 0.01% NH4HCO3) to give compound 0135 (30.5 mg, 0.06 mmol, Y = 35.7%) as a white solid.

[0925] LC-MS (ESI): m / z = 495.2 [M+H] +

[0926] 1 H NMR (400MHz, DMSO-d6) δ13.28(s,1H),12.52(s,1H),7.73(s,1H),7.63-7.56(m,2H),7.40(d,J=8.4Hz,1H),7.28(d,J=3.6Hz,1H),6. 93(d,J=3.6Hz,1H),6.84(d,J=7.2Hz,1H),3.66-3.53(m,1H),2.29-2.10(m,1H),2.16(s,3H),1.33-1.27(m,2H),1.11–0.99(m,6H).

[0927] Example 45:

[0928] Synthesis of Compound 0140

[0929]

[0930] Step 1: Synthesis of compound I140-2

[0931] At 0°C, sodium hydride (152.3 mg, 3.81 mmol, 60% purity) was added to a solution of compound I140-1 (500 mg, 2.54 mmol) in N,N-dimethylformamide (10 mL). The mixture was replaced with nitrogen three times and stirred at 0°C for 30 minutes under a nitrogen environment. Iodomethane (189.6 μL, 3.05 mmol) was added and the reaction system was stirred at 25°C for 17.5 hours. The mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL*3); the combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 5%-50%) to obtain compound I140-2 (630 mg, 2.54 mmol, Y = 93.5%) as a yellow solid.

[0932] LC-MS(ESI): m / z=211.0 / 213.0[M+H] +

[0933] Step 2: Synthesis of Compound 0140

[0934] To a solution of compound I140-2 (125.3 mg, 0.50 mmol) in N,N-dimethylformamide (2 mL) were added compound I140-3 (150 mg, 0.50 mmol), tris(dibenzylideneacetone)dipalladium(0) (46.20 mg, 0.05 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (58.40 mg, 0.10 mmol) and cesium carbonate (493.10 mg, 1.51 mmol), the mixture was replaced with nitrogen three times, and the reaction was stirred in a microwave at 100 °C under a nitrogen environment for 2 hours. The reaction solution was directly purified by preparative HPLC (Waters-Xbridge-C18-10 μm-19*250 mm (eluent = 37% to 67% (v / v) acetonitrile and water, 10 mM ammonium bicarbonate) to obtain compound 0140 (34.41 mg, 0.08 mmol, Y = 15.96%) as a white solid.

[0935] LC-MS (ESI): m / z = 428.2 [M+H] +

[0936] 1H NMR(400MHz, DMSO-d6)δ:13.27(s,1H),12.17(s,1H),8.06(d,J=5.8Hz,1H),7.75–7.70(m,1H),7.61–7.54(m,2H),7 .42–7.37(m,2H),7.25(dd,J=6.0,1.0Hz,1H),7.16(d,J=3.2Hz,1H),6.80(d,J=7.4Hz,1H),3.83(s,3H),2.16(s,3H)

[0937] Example 46:

[0938] Synthesis of Compound 0141

[0939]

[0940] Step 1: Synthesis of compound 0141

[0941] Compound I141-1 (200 mg, 0.67 mmol), compound I141-2 (121.50 mg, 0.67 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (77.84 mg, 0.67 mmol), cesium carbonate (657.47 mg, 2.02 mmol) and 1,4-dioxane (3 mL) were added to a 10 mL microwave tube, and tris(dibenzylideneacetone)dipalladium (61.59 mg, 0.07 mmol) was added to the resulting mixture under nitrogen, and then the resulting mixture was stirred at 120° C. for 2 hours, and then cooled to room temperature. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (eluent = methanol: dichloromethane = 0% to 10%) to obtain a crude product of 150 mg. The crude product was purified by preparative HPLC (Phenomenex Gemini 150mm*25mm*10um colume (eluent = 30% to 60% (v / v) acetonitrile and water with 0.025% ammonium bicarbonate) to give compound 0141 (47.63 mg, 0.11 mmol, Y=16.04%) as a white solid.

[0942] LC-MS (ESI): m / z = 442.2 [M+H] +

[0943] 1H NMR(400MHz,DMSO-d6)δ13.27(s,1H),12.16(s,1H),8.04(d,J=5.8Hz,1H),7 .75-7.70(m,1H),7.61-7.58(m,1H),7.56(d,J=7.3Hz,1H),7.46(d,J=3.4Hz, 1H),7.39(d,J=8.6Hz,1H),7.28(dd,J=5.9,0.9Hz,1H),7.20-7.16(m,1H),6. 80(d,J=7.2Hz,1H),4.25(q,J=7.2Hz,2H),2.16(s,3H),1.37(t,J=7.2Hz,3H)

[0944] Example 47:

[0945] Synthesis of Compound 0142

[0946]

[0947] Step 1: Synthesis of compound I142-2

[0948] Under ice bath, sodium hydride (1.04 g, 26.04 mmol, 60% purity) was added in batches to a solution of compound I142-1 (2 g, 13.02 mmol, Bid) in N,N-dimethylformamide (20 mL), and the resulting mixture was stirred at 25°C for 16 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (50 mL*3), and the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (eluent = petroleum ether: ethyl acetate = 10: 1 to 1: 1) to obtain a colorless and transparent oil compound I142-2 (2 g, 9.36 mmol, Y = 71.87%).

[0949] LC-MS (ESI): m / z = 181.1 [MH] -

[0950] Step 2: Synthesis of Compound 0142

[0951] Under a nitrogen atmosphere, tri(dibenzylideneacetone)dipalladium (6.41 mg, 0.01 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (8.10 mg, 0.01 mmol) were added to a solution of compound I142-3 (150 mg, 0.50 mmol), compound I142-2 (111.98 mg, 0.55 mmol) and potassium carbonate (174.30 mg, 1.26 mmol) in N,N-dimethylformamide (6 mL), and the mixture was replaced with nitrogen three times and stirred at 100°C for 2 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was purified by preparative HPLC (Phenomenex 150 mm*25 mm*10 um colume) (eluent = 5% to 60% (v / v) acetonitrile / water, 0.01% ammonium bicarbonate) to give compound 0142 (14.3 mg, 0.03 mmol, Y = 6.72%) as a white solid.

[0952] LC-MS (ESI): m / z = 443.6 [M+H] +

[0953] 1 H NMR(400MHz, DMSO-d6)δ:13.28(s,1H),8.63(s,1H),7.73(s,1H),7.63-7.57(m,2H),7.55(d,J=3.5Hz,1H),7.39(d ,J=8.6Hz,1H),7.07(d,J=3.5Hz,1H),6.85(d,J=7.2Hz,1H),4.35–4.24(m,2H),2.16(s,3H),1.39(t,J=7.2Hz,3H)

[0954] Example 48:

[0955] Synthesis of Compound 0143

[0956]

[0957] Step 1: Synthesis of compound 0143

[0958] Compound I143-1 (49.13 mg, 0.27 mmol) and compound I143-2 (100 mg, 0.34 mmol) were added to dioxane (3 mL), and tris(dibenzyl-BASE acetone)dipalladium (5.07 mg, 0.01 mmol, Anaiji), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (38.92 mg, 0.07 mmol, Anaiji) and cesium carbonate (328.73 mg, 1.01 mmol) were added. The reactants were stirred at 100° C. for 2.5 hours under nitrogen protection. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography (Waters-Xbridge-C18-10 μm-19*250 mm (A: 10 mM ammonium bicarbonate) / Water B: acetonitrile, Agilent-Poroshell HPH-C18-2.7um-4.6*50mm, 10-95) was purified to give compound 0143 (15.92mg, 0.05mmol, Y=13.4%) as a white solid.

[0959] LC-MS (ESI): m / z = 444.1 [M+H] +

[0960] 1 H NMR(400MHz, DMSO-d6)δ:13.29(s,1H),8.77(s,1H),8.54(s,1H),7.74(s,1H),7.68–7.54(m,2H),7. 40(d,J=8.6Hz,1H),6.89(d,J=7.2Hz,1H),4.46(q,J=7.1Hz,2H),2.16(s,3H),1.43(t,J=7.2Hz,3H)

[0961] Example 49:

[0962] Synthesis of Compound 0144

[0963]

[0964] Step 1: Synthesis of compound I144-2

[0965] To a solution of compound I144-1 (200 mg, 1.01 mmol, Bid) in N,N-dimethylformamide (3 mL) was added sodium hydride (60.60 mg, 1.51 mmol, 60% purity) under a nitrogen environment at 0 ° C, and then iodoethane (81.6 μL, 1.02 mmol) was added for reaction. The reactants were stirred at 25 ° C for 16 hours. The reaction mixture was quenched with aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (20 mL * 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The residue was purified by silica gel chromatography (eluent = ethyl acetate: petroleum ether = 0% to 14%) to give compound I144-2 (350 mg, 1.93 mmol, Y = 59.19%) as a white solid.

[0966] LC-MS(ESI): m / z=226.0 / 228.0[M+H] +

[0967] 1 H NMR (400MHz, DMSO-d6) δ8.22(d,J=1.0Hz,1H),8.17(d,J=6.0Hz,1H),7.82(dd,J=6.0,0.9Hz,1H),4.50(q,J=7.2Hz,2H),1.43(t,J=7.2Hz,3H)

[0968] Step 2: Synthesis of Compound 0144

[0969] Under nitrogen, tris(dibenzylideneacetone)dipalladium (20.25 mg, 0.02 mmol) was added to a solution of compound I144-3 (72.3 mg, 0.24 mmol), compound I144-2 (50 mg, 0.22 mmol), cesium carbonate (216.18 mg, 0.66 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (25.59 mg, 0.04 mmol) in 1,4-dioxane (1.5 mL), and the mixture was replaced with nitrogen three times and reacted at 90° C. for 40 minutes. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (eluent = methanol: dichloromethane = 0% to 10%) to obtain 50 mg of a crude product. The crude product was purified by preparative HPLC (Phenomenex Gemini 150mm*25mm*10um colume (eluent = 30% to 60% (v / v) acetonitrile and water with 0.025% ammonium bicarbonate) to give compound 0144 (25.63 mg, 0.06 mmol, Y = 26.19%) as a white solid.

[0970] LC-MS (ESI): m / z = 443.2 [M+H] +

[0971] 1 H NMR (400MHz, DMSO-d6) δ13.28(s,1H),12.69(s,1H),8.66(s,1H),8.18(d,J=6.2Hz,1H),7.73(s,1H),7.62–7. 57(m,2H),7.42–7.37(m,2H),6.84(d,J=7.2Hz,1H),4.46(d,J=7.2Hz,2H),2.16(s,3H),1.41(t,J=7.2Hz,3H)

[0972] Example 50:

[0973] Synthesis of Compound 0145

[0974]

[0975] Step 1: Synthesis of compound I145-2

[0976] At 0°C, sodium hydride (0.41 g, 10.15 mmol, 60% purity, Bid) was added to a solution of compound I145-1 (1 g, 5.08 mmol, Bid) in N,N-dimethylformamide (20 mL), stirred at 0°C for 10 minutes, and iodoethane (0.488 mL, 6.09 mmol, Bid) was added. The resulting mixture was stirred at 25°C for 18 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with saturated brine (20 mL×4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent = petroleum ether: ethyl acetate = 10:1 to 3:1) to obtain compound I145-2 (1 g, 4.44 mmol, Y = 79.6%) as a brown oil.

[0977] LC-MS(ESI): m / z=225.0 / 227.0[M+H] +

[0978] Step 2: Synthesis of Compound 0145

[0979] 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (58.38 mg, 0.10 mmol) and tris(dibenzylideneacetone)dipalladium (46.20 mg, 0.05 mmol) were added to a solution of compound I145-3 (150 mg, 0.50 mmol), compound I145-2 (114 mg, 0.50 mol) and cesium carbonate (493.10 mg, 1.51 mmol) in 1.4-dioxane (5 mL). The mixture was replaced with nitrogen three times, and the temperature was raised to 100° C. and stirred for 2.5 hours. The mixture was poured into water (5 mL), and extracted with ethyl acetate (10 mL*3); the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by preparative HPLC (Waters-SunFire-C18-10 μm-19*250 mm (eluent = 25% to 75% (v / v) acetonitrile and water, containing 0.1% formic acid) to give compound 0145 (40.13 mg, 0.09 mmol, Y = 18.02%) as a white solid.

[0980] LC-MS (ESI): m / z = 442.2 [M+H] +

[0981] 1 H NMR(400MHz,DMSO-d6)δ:13.30(s,1H),11.15(br s,1H),8.26-8.22(m,2H),7.74(s,1H),7.63-7.57(m,2H),7.52(d,J=3.6Hz,1H),7.39(d, J=8.6Hz,1H),6.92-6.85(m,2H),4.30(q,J=7.2Hz,2H),2.16(s,3H),1.39(t,J=7.2Hz,3H)

[0982] Example 51:

[0983] Other compounds were synthesized according to the similar operation procedures of Examples 1 to 50.

[0984] Biological examples:

[0985] Example A: PKMYT1 inhibitory activity test

[0986] 1. PKMYT1- Transient transfection of fusion vector DNA into HEK293 cells

[0987] Remove the medium from the cell flask by aspiration, trypsinize and dissociate the cells from the flask. Neutralize the trypsin with cell culture medium and centrifuge at 200 × g for 5 minutes to pellet the cells. Aspirate the medium and resuspend the cells in assay medium. Adjust the density to 2 × 10 5 cells / ml.

[0988] Prepare lipid:DNA complexes as follows:

[0989] a. Prepare 10 μg / ml DNA Opti-MEM solution:

[0990] (1) 1mL Opti-MEM (gibco, 11058021).

[0991] (2) 9.0 μg / ml transfection vector DNA (Promega, E4881),

[0992] (3) 1.0 μg / ml PMYT1- Fusion vector DNA (Promega, NV1871)

[0993] b. Mix thoroughly.

[0994] c. 30 μl HD transfection reagent (Promega, E2311) was added to the DNA solution to form lipid:DNA complex.

[0995] d. Invert and mix 5-10 times.

[0996] e. Incubate at room temperature for 20 minutes to allow complex formation.

[0997] In a sterile conical tube, mix 1 part lipid:DNA complex (e.g. 1 ml) with 20 parts 2 x 10 5 Mix with 100 cells / ml HEK293 cells (e.g. 20 ml). Mix gently by inverting 5 times.

[0998] Dispense 40 μL of [cells+lipid:DNA] complexes into 384-well assay plates and incubate for 20-30 h.

[0999] 2. Preparation of NanoBRET TM Tracer reagents are added to cells

[1000] Prepare 20X tracer: (final concentration 2 μM)

[1001] (1) Prepare 100X tracer (200 μM) in 100% DMSO: add 43 μL of 400 μM tracer to 43 μL of DMSO.

[1002] (2) Prepare 20X tracer: add 86 μL of 200 μM tracer to 344 μL of tracer dilution buffer.

[1003] Dispense 2 μL of 4X tracing reagent into each well of cells and mix at 1000 rpm for 1 minute.

[1004] 3. Add test compounds

[1005] 40 nL of compound solution was transferred per well in a 384 plate by Echo 655. The plate was incubated at 37°C, 5% CO2 for 2 hours.

[1006] 4. NanoBRET TM Assay

[1007] Prepare 3X substrate plus inhibitor solution in Opti-MEM. Mix gently by inverting in a conical tube 5-10 times. (Final inhibitor concentration is 20 μM). Add 20 μL of 3X complete substrate plus inhibitor solution to a 384-well plate. Incubate at room temperature for 2-3 minutes. Measure donor emission wavelength (450 nm) and acceptor emission wavelength (610 nm) using an EnVision Xcite Multilabel Reader.

[1008] 5. Data Analysis

[1009] %Inhibition=(Signalcompound-SignalAve_PC) / (SignalAve_NC-SignalAve_PC)*100

[1010] Example B: Anti-HCC1569 cell proliferation activity test

[1011] Cell culture

[1012] HCC1569 cells were cultured in T150 cell culture flasks in RPMI-1640, 10% FBS, 1% P / S medium in a 37°C, 5% CO2 incubator.

[1013] Experimental procedures

[1014] Day 0

[1015] Prepare compounds starting from 10000 nM and dilute 3-fold for a total of 10 concentrations. Add 5 μL of compound solution to a 384-well plate according to the plate layout. Inoculate 1.11x10 4 (6ml) / 5.55x10 3 (6 ml) cells. The cells were incubated at 37°C, 5% CO2 for 7 days.

[1016] Day 7

[1017] The test plate was removed from the incubator and equilibrated at room temperature for 30 minutes. 25 μL of cell titration (Promega) reagent was added to each well. The plate was centrifuged at 1000 rpm for 1 minute and then incubated at room temperature for 10 minutes to stabilize the luminescent signal. The luminescent signal was recorded by Envision.

[1018] Data analysis

[1019] Proliferation Inhibition%=100%-(Avg.compound-Avg.PC) / (Avg.NC-Avg.PC)x100%

[1020] Table 1: Cell viability data

[1021]

[1022]

[1023]

[1024] Although the present invention has been described and illustrated with reference to specific embodiments of the present invention, these descriptions and illustrations are not restrictive. It should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the present invention as defined by the appended claims. The illustrations may not necessarily be drawn to scale. Due to manufacturing processes and tolerances, there may be differences between the process reproduction in the present invention and the actual equipment. There may be other embodiments of the present invention that are not specifically described. This specification and drawings should be regarded as illustrative rather than restrictive. Modifications may be made to make specific situations, materials, material compositions, methods or processes suitable for the goals, spirit and scope of the present invention. All such modifications are intended to be within the scope of the appended claims. Although the methods disclosed herein have been described with reference to specific operations performed in a specific order, it should be understood that these operations may be combined, subdivided or reordered to form equivalent methods without departing from the teachings of the present invention. Accordingly, unless specifically indicated herein, the order and grouping of operations are not limitations of the present invention.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, racemate, prodrug, solvate, hydrate or isotope-labeled compound thereof, in: Ring A is a 5-7 membered monocyclic aryl, heterocyclic or heteroaryl group or an 8-11 membered fused bicyclic aryl, heterocyclic or heteroaryl group; Ring B is a 5-6-membered monocyclic aromatic group, heterocyclic group or heteroaryl group; Ring C is a 5-7 membered monocyclic aryl, heterocyclic or heteroaryl group or an 8-11 membered fused bicyclic aryl, heterocyclic or heteroaryl group; R A is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, halogen, hydroxyl, oxo, cyano or amine; R B is hydrogen, C1-C6 alkyl, halogen, hydroxyl, oxo, cyano or amine; R C is LQ-R1, hydrogen, halogen, hydroxyl, oxo, cyano, amine, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), C3-C6 cycloalkyl, C1-C6 haloalkyl, -O-(C1-C6 haloalkyl), -NH-(C1-C6 haloalkyl), -N(C1-C6 haloalkyl)(C1-C6 haloalkyl), Pentafluorosulfur, C1-C6 haloalkoxy or halocycloalkyl, -NH-S(O)2-(C1-C6 alkyl), -NHP(=O)-(C1-C6 alkyl), -NHC(O)-(C1-C6 alkyl), -C(O)NH-(C1-C6 alkyl), -NHC(O)NH-(C1-C6 alkyl), -S(O)2-(C1-C6 alkyl), -P(=O)(C1-C6 alkyl)2; L is a direct bond, O or NH; Q is absent, a direct bond, or a C1-C6 alkyl group; R1 is C1-C6 alkyl, C3-C6 cycloalkyl or a 4-7 membered heterocyclic group containing one or two heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl or heterocyclic group is optionally substituted by one or two substituents R2; R2 is C1-C6 alkyl, halogen, hydroxy, oxo, cyano, amine, -(C=O)(C1-C6 alkyl) or -N(C1-C6 alkyl)(C1-C6 alkyl); Y is O, CR3, CR3R4, N or NH; R3 and R4 are independently hydrogen, C1-C6 alkyl, halogen, hydroxyl, oxo, cyano or amine, or R3 and R4 connected to the same carbon atom together with the carbon atom to which they are connected constitute a C3-C7 cycloalkyl, or R3 and R4 connected to different carbon atoms together with the carbon atom to which they are connected constitute a C3-C7 cycloalkyl; m is 1, 2, 3 or 4; n is 0 or 1; p is 1, 2, or 3; q is 1 or 2.

2. The compound according to claim 1, wherein q is 1, Y is CR3R4; R3, R4 are as defined in claim 1.

3. The compound according to claim 1, wherein q is 1, and Y is NH.

4. The compound according to claim 1, wherein q is 2, Y is CR3 or N; R3 is as defined in claim 1.

5. The compound according to claim 1, wherein q is 2, Y is CR3R4; R3, R4 are as defined in claim 1.

6. The compound according to any one of claims 1 to 5, wherein Ring B is a 5-6 membered heteroaryl group containing at least one N atom.

7. The compound according to claim 6, wherein Ring B is thiazole or pyridine.

8. The compound according to any one of claims 1 to 7, wherein Ring A is selected from phenyl, a 5-6 membered heteroaryl group containing at least one N atom, or an 8-11 membered fused bicyclic heteroaryl group containing at least two N atoms.

9. The compound according to claim 8, wherein Ring A is selected from phenyl, a 6-membered heteroaryl group containing at least one N atom, or a 9-membered fused bicyclic heteroaryl group containing at least two N atoms.

10. The compound according to claim 9, wherein Ring A is selected from R A , m as defined in claim 1.

11. The compound according to claim 10, wherein Ring A is selected from R A1 , R A2 , R A3 , R A4 , R A5 and R A6 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, halogen, hydroxy, oxo, cyano or amine.

12. The compound according to claim 11, wherein Ring A is R A1 and R A2 It is methyl.

13. The compound according to claim 11, wherein Ring A is R A1 , R A2 is methyl; R A3 It is a halogen.

14. The compound according to claim 11, wherein Ring A is R A5 It is methyl.

15. The compound according to claim 11, wherein Ring A is selected from 16. The compound according to any one of claims 1 to 15, wherein Ring C is a 5-7 membered monocyclic heteroaryl group or an 8-11 membered condensed bicyclic heteroaryl group containing at least two N atoms.

17. The compound according to claim 16, wherein Ring C is a 9-membered fused bicyclic heteroaryl group containing at least two N atoms.

18. The compound according to claim 17, wherein Ring C is selected from R C , p as defined in claim 1.

19. The compound according to claim 18, wherein R C is selected from -CH3, -CH2CH3, -CH2CF3, 20. The compound according to claim 1, wherein The compound of formula (I) is selected from:

21. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, prodrug or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

22. Use of a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, prodrug or solvate thereof, for the manufacture of a medicament for treating cancer in an individual in need thereof.

23. The use according to claim 22, wherein the compound or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, tautomer, prodrug or solvate thereof is co-administered to the subject with a second anticancer agent, surgical therapy, ionizing radiation or a combination thereof.

24. The use according to claim 22, wherein the second anticancer agent is selected from: targeted cancer drugs such as trastuzumab, ramucirumab, bevacizumab, everolimus, tamoxifen, toremifene, fulvestrant, anastrozole, exemestane, lapatinib, letrozole, pertuzumab, adotrastuzumab emtansine, palbociclib, cetuximab, panitumumab, zulafalib, regorafenib, imatinib mesylate, lanreotide acetate, sunitinib, regorafenib, denosumab, alitretinoin, sorafenib, pazopanib, temsirolimus, everolimus, tretinoin, dasatinib, nilotinib, Bosutinib, rituximab, alemtuzumab, ofavumab, obinumab, ibrutinib, idexib, brinumab, soranib, crizotinib, erlotinib, gefitinib, afatinib dimaleate, ceritinib, ramucirumab, nivolumab, pembrolizumab, osimertinib, and lecithinib; alkylating agents, such as busulfan, chlorambucil, cyclophosphamide, ifosfamide, melphalan, mechlorethamine, streptozotocin, thiotepa, uracil mustard, triethylenemelamine, temozolomide, and 2-chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU); antibiotics or plant alkaloids, such as actinomycetes hormones or steroids, such as 5α-reductase inhibitors, aminoglutethimide, anastrozole, bicalutamide, chlortetracycline, diethylstilbestrol (DES), drostanolone, estramustine, ethinyl estradiol, flutamide, fluoxymesterone, goserelin, hydroxyprogesterone, letrozole, leuprolide, medroxyprogesterone acetate, acetylcholine, dapoxetine, tadalafil, oxadiazine, chlortetracycline, dapoxetine, chlortetracycline, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine megestrol acetate, methylprednisolone, methyltestosterone, mitotane, nilutamide, prednisolone, arzoxifene (SERM-3), tamoxifen, testolactone, testosterone, triamcinolone, and Zoladex; synthetic preparations such as all-trans retinoic acid, carmustine (BCNU), carboplatin (CBDCA), lomustine (CCNU), cis-diamminedichloroplatinum (cisplatin), dacarbazine, golidel, altretinoin, hydroxyurea, levamisole, mitoxantrone, o,p'-dichlorodiphenyldichloroethane (o,p'-DDD) (also known as mitotane), oxaliplatin, porfimer sodium, procarbazine, and imatinib mesylate antimetabolites, such as chlorodeoxyadenosine, cytosine arabinoside, 2'-deoxycoformycin, fludarabine phosphate, 5-fluorouracil (5-FU), 5-fluoro-2'-deoxyuridine (5-FUdR), gemcitabine, camptothecin, 6-mercaptopurine, methotrexate, 4-methylamphetamine (4-MTA), and thioguanine; and biologics, such as interferon alpha, bacillus Calmette-Guérin (BCG), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2, and Herceptin.

25. The use according to claim 22, wherein the cancer is a cardiac cancer, such as a sarcoma (e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma), a myxoma, a rhabdomyoma, a fibroma, a lipoma, and a teratoma; Lung cancer, such as bronchial cancer (e.g., squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, and adenocarcinoma), alveolar cancer (e.g., bronchiolar carcinoma), bronchial adenoma, sarcoma, lymphoma, chondroitinoma, and mesothelioma; Gastrointestinal cancer, such as esophageal cancer (e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma), gastric cancer (e.g., lymphoma and leiomyosarcoma), pancreatic cancer (e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid, and vipoma), small intestine cancer (e.g., adenocarcinoma, lymphoma, carcinoid, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma) , colorectal cancer (e.g., adenocarcinoma, ductal adenoma, villous adenoma, hamartoma, and leiomyoma); genitourinary tract cancers, such as kidney cancer (e.g., adenocarcinoma, Wilms' tumor [Nephroblastoma], lymphoma, and leukemia), bladder and urethral cancer (e.g., squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma), prostate cancer (e.g., adenocarcinoma and sarcoma), testicular cancer (e.g., spermatoma, teratoma, embryonal tumor, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, and lipoma); liver cancers, such as hepatocellular carcinoma (e.g., hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma; Bone cancers, such as osteogenic sarcomas (e.g., osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphomas (e.g., reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (e.g., osteochondroma exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; Nervous system cancers, such as skull cancers (e.g., osteoma, hemangioma, granuloma, xanthomas, and osteitis malformations), meningeal cancers (e.g., meningiomas, meningeal sarcomas, and glial hyperplasia), brain cancers (e.g., astrocytomas, medulloblastomas, gliomas, ependymomas, blastomas (pinealomas), glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, and congenital tumors), spinal neurofibromas, meningiomas, gliomas, and sarcomas; gynecological cancers, such as uterine cancer (e.g., endometrial cancer), cervical cancer (e.g., cervical cancer and preneoplastic cervical dysplasia), ovarian cancer (e.g., ovarian cancer [e.g., serous cystadenocarcinoma, mucinous cystadenocarcinoma, and carcinoma of unspecified type], granulosa cell tumor, Stoltrig-Redig cell tumor, dysgerminoma, and malignant teratoma), vulvar cancer (e.g., squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma), vaginal cancer (e.g., clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma [e.g., embryonal rhabdomyosarcoma], and fallopian tube cancer); hematological cancers, such as Blood cancer (myeloid leukemias [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, and myelodysplasia), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; skin cancers such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; adrenal gland cancers such as neuroblastoma; or breast cancer.

Images