5,6-dihydrothieno[3,4-h]quinazoline compounds

Abstract

Provided are a series of 5,6-dihydrothieno[3,4-h]quinazoline compounds represented by formula (P) and pharmaceutically acceptable salts thereof, and application of the compounds or the pharmaceutically acceptable salts thereof in preparation of solid tumor drugs, for example, solid tumor drugs related to selective PLK1 inhibitors.

Description

[0001] The present invention claims the following priority:

[0002] CN202110172946.6, application date: February 8, 2021;

[0003] CN202110655630.2, application date: June 11, 2021;

[0004] CN202110864387.5, application date: July 29, 2021;

[0005] CN202111137961.3, application date: September 27, 2021;

[0006] CN202111473661.2, application date: November 29, 2021. Technical Field

[0007] The present invention relates to a series of 5,6-dihydrothieno[3,4-h]quinazoline compounds, and in particular to compounds represented by formula (P) and pharmaceutically acceptable salts thereof. Background Art

[0008] Polo-like kinases (PLKs) are a highly conserved class of serine / threonine protein kinases. They all possess a highly homologous serine / threonine kinase domain at their N-termini and a characteristic polobox domain (PBD) at their C-termini that regulates PLK activity and subcellular localization. The PLK family comprises a large number of members, with four isoforms in humans: PLK1, PLK2, PLK3, and PLK4. They all play crucial roles in regulating various phases of the cell cycle. Of these four family members, PLK1 is currently the most thoroughly studied. Therefore, PLK1 is a highly sought-after target in tumor diagnosis and treatment.

[0009] Cardiff Oncology (formerly Trovagene), under license from Nerviano, is developing onvansertib (PCM-075; NMS-P937; nms-1286937; NMS-937), an oral PLK-1 inhibitor, as a fumarate salt. Onvansertib is a potential oral cancer treatment for indications including metastatic colorectal cancer (mCRC), solid tumors, acute myeloid leukemia (AML), and metastatic castration-resistant prostate cancer. Onvansertib is a novel, highly selective PLK1 inhibitor, a potent therapeutic target that is overexpressed in most cancers.

[0010] The PLK1 inhibitor Onvansertib is the first PLK1 inhibitor to enter clinical development. Early clinical study results show that 88% of patients with KRAS-mutant mCRC experience clinical benefit and demonstrate an acceptable safety profile. Compared with KRASG12C inhibitors, PLK1 inhibitors have a higher response rate in CRC patients and are effective across all KRAS mutation subtypes. CRC is the third most common malignancy after lung cancer and breast cancer, with a global market value of approximately $25 billion in 2018. Therefore, the search for highly active, selective, and metabolically stable small molecule PLK1 inhibitors is warranted for tumor treatment. Summary of the Invention

[0011] The present invention provides a compound represented by formula (P) or a pharmaceutically acceptable salt thereof

[0012]

[0013] in,

[0014] T1 is selected from CR1 and N;

[0015] T2 is selected from CH and N;

[0016] R1 is selected from H;

[0017] R2 is selected from H, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, S(=O)2C 1-3 Alkyl, C 2-3 Alkynyl, C 3-5 Cycloalkyl, -OC 3-5 Cycloalkyl and 5-membered heteroaryl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, S(=O)2C 1-3 Alkyl, C 2-3 Alkynyl, C 3-5 Cycloalkyl, -OC 3-5 Cycloalkyl and 5-membered heteroaryl are optionally substituted with 1, 2 or 3 Rb;

[0018] R3 is selected from C 1-4 Alkyl, piperazinyl and 7-9 membered heterocycloalkyl, the C 1-4 Alkyl, piperazinyl and 7-9 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R c replace;

[0019] R4 is selected from C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C1-3 The alkoxy group is optionally substituted with 1, 2 or 3 R d replace;

[0020] R5 is selected from H and OH;

[0021] Alternatively, R1 and R3 form a ring with the atoms to which they are connected, so that the structural fragment Selected from

[0022] Each R b Each independently selected from F, Cl, Br, I, OH and OCH3;

[0023] Each R c are independently selected from =O, C 1-3 Alkyl, C 1-4 Alkylamino and heterocyclic butyl, the C 1-3 Alkyl, C 1-4 Alkylamino and heterocyclobutyl are optionally substituted with 1, 2 or 3 R;

[0024] Each R d are independently selected from F, Cl, Br and I;

[0025] Each R is independently selected from F, Cl, Br, I and OH;

[0026] The heteroatom of the “heterocyclobutyl” and “7-9 membered heterocycloalkyl” is selected from N, O and S.

[0027] In some embodiments of the present invention, R2 is selected from H, CN, SCH3, SCH2CH3, SCH(CH3)2, S(=O)2CH3, OCH3, OCH2CH3, OCH(CH3)2, CH3, CH2CH3, CH(CH3)2, cyclopropyl, The SCH3, SCH2CH3, SCH(CH3)2, S(=O)2CH3, OCH3, OCH2CH3, OCH(CH3)2, CH3, CH2CH3, CH(CH3)2, cyclopropyl, Optional 1, 2 or 3 R b Substitution, other variables are as defined in the present invention.

[0028] In some embodiments of the present invention, R2 is selected from H, CN, SCH3, SCH2CH2OH, S(=O)2CH3, OCH2CH3, OCH2CH2OH, OCH2CH2OCH3, CH3, CH2CH2OH, CH2OCH3, cyclopropyl, Other variables are as defined in the present invention.

[0029] In some embodiments of the present invention, the Rc Selected from =O, CH3, CH2CH3, N(CH3)2 and The CH3, CH2CH3 and N(CH3)2 are optionally substituted with 1, 2 or 3 R, and the other variables are as defined herein.

[0030] In some embodiments of the present invention, the R c Selected from =O, CH3, CH2CH2OH, N(CH3)2 and Other variables are as defined in the present invention.

[0031] In some embodiments of the present invention, the R3 is selected from CH2CH2CH3, The CH2CH2CH3, Optional 1, 2 or 3 R c Substitution, other variables are as defined in the present invention.

[0032] In some embodiments of the present invention, the R3 is selected from The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R4 is selected from CH3, OCH3, OCHF2 and OCF3, and the other variables are as defined in the present invention.

[0033] The present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof

[0034]

[0035] in,

[0036] T1 is selected from CR1 and N;

[0037] T2 is selected from CH and N;

[0038] R1 is selected from H;

[0039] R2 is selected from H, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, S(=O)2C 1-3 Alkyl, C 2-3 Alkynyl, C 3-5 Cycloalkyl, -OC 3-5 Cycloalkyl and 5-membered heteroaryl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, S(=O)2C 1-3 Alkyl, C 2-3 Alkynyl, C 3-5 Cycloalkyl, -OC 3-5Cycloalkyl and 5-membered heteroaryl are optionally substituted with 1, 2 or 3 Rb;

[0040] R3 is selected from C 1-4 Alkyl, piperazinyl and 7-9 membered heterocycloalkyl, the C 1-4 Alkyl, piperazinyl and 7-9 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R c replace;

[0041] R4 is selected from C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted with 1, 2 or 3 R d replace;

[0042] Alternatively, R1 and R3 form a ring with the atoms to which they are connected, so that the structural fragment Selected from

[0043] Each R b Each independently selected from F, Cl, Br, I, OH and OCH3;

[0044] Each R c are independently selected from =O, C 1-3 Alkyl, C 1-4 Alkylamino and heterocyclic butyl, the C 1-3 Alkyl, C 1-4 Alkylamino and heterocyclobutyl are optionally substituted with 1, 2 or 3 R;

[0045] Each R d are independently selected from F, Cl, Br and I;

[0046] Each R is independently selected from F, Cl, Br, I and OH;

[0047] The heteroatom of the “heterocyclobutyl” and “7-9 membered heterocycloalkyl” is selected from N, O and S.

[0048] In some embodiments of the present invention, R2 is selected from H, CN, SCH3, SCH2CH3, SCH(CH3)2, S(=O)2CH3, OCH3, OCH2CH3, OCH(CH3)2, CH3, CH2CH3, CH(CH3)2, cyclopropyl, The SCH3, SCH2CH3, SCH(CH3)2, S(=O)2CH3, OCH3, OCH2CH3, OCH(CH3)2, CH3, CH2CH3, CH(CH3)2, cyclopropyl, Optional 1, 2 or 3 R b Substitution, other variables are as defined in the present invention.

[0049] In some embodiments of the present invention, R2 is selected from H, CN, SCH3, SCH2CH2OH, S(=O)2CH3, OCH2CH3, OCH2CH2OH, OCH2CH2OCH3, CH3, CH2CH2OH, CH2OCH3, cyclopropyl, Other variables are as defined in the present invention.

[0050] In some embodiments of the present invention, the R c Selected from CH3, CH2CH3, N(CH3)2 and The CH3, CH2CH3 and N(CH3)2 are optionally substituted with 1, 2 or 3 R, and the other variables are as defined herein.

[0051] In some embodiments of the present invention, the R c Selected from CH3, CH2CH2OH, N(CH3)2 and Other variables are as defined in the present invention.

[0052] In some embodiments of the present invention, the R3 is selected from CH2CH2CH3, The CH2CH2CH3, Optional 1, 2 or 3 R c Substitution, other variables are as defined in the present invention.

[0053] In some embodiments of the present invention, the R3 is selected from Other variables are as defined in the present invention.

[0054] In some embodiments of the present invention, R4 is selected from CH3, OCH3, OCHF2 and OCF3, and other variables are as defined in the present invention.

[0055] The present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof

[0056]

[0057] in,

[0058] T1 is selected from CR1 and N;

[0059] T2 is selected from CH and N;

[0060] R1 is selected from H;

[0061] R2 is selected from H, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio and C 3-5 Cycloalkyl, the C1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio and C 3-5 The cycloalkyl group is optionally substituted with 1, 2 or 3 R b replace;

[0062] R3 is selected from C 1-4 Alkyl, piperazinyl and 7-9 membered heterocycloalkyl, the C 1-4 Alkyl, piperazinyl and 7-9 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R c replace;

[0063] R4 is selected from C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted with 1, 2 or 3 R d replace;

[0064] Alternatively, R1 and R3 form a ring with the atoms to which they are connected, so that the structural fragment Selected from

[0065] Each R a Each independently selected from F, Cl, Br, I, CH3 and CF3;

[0066] Each R b Each independently selected from F, Cl, Br, I, OH and OCH3;

[0067] Each R c are independently selected from =O, C 1-3 Alkyl, C 1-4 Alkylamino and heterocyclic butyl, the C 1-3 Alkyl, C 1-4 Alkylamino and heterocyclobutyl are optionally substituted with 1, 2 or 3 R;

[0068] Each R d are independently selected from F, Cl, Br and I;

[0069] Each R is independently selected from F, Cl, Br, I and OH;

[0070] The heteroatom of the “heterocyclobutyl” and “7-9 membered heterocycloalkyl” is selected from N, O and S.

[0071] In some embodiments of the present invention, the R2 is selected from H, CN, SCH3, SCH2CH3, SCH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, CH3, CH2CH3, CH(CH3)2 and cyclopropyl, and the SCH3, SCH2CH3, SCH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, CH3, CH2CH3, CH(CH3)2 and cyclopropyl are optionally replaced by 1, 2 or 3 R b Substitution, other variables are as defined in the present invention.

[0072] In some embodiments of the present invention, R2 is selected from H, CN, SCH3, SCH2CH2OH, OCH2CH3, OCH2CH2OH, CH3, CH2CH2OH, CH2OCH3 and cyclopropyl, and other variables are as defined in the present invention.

[0073] In some embodiments of the present invention, the R c Selected from CH3, CH2CH3, N(CH3)2 and The CH3, CH2CH3 and N(CH3)2 are optionally substituted with 1, 2 or 3 R, and the other variables are as defined herein.

[0074] In some embodiments of the present invention, the R c Selected from CH3, CH2CH2OH, N(CH3)2 and Other variables are as defined in the present invention.

[0075] In some embodiments of the present invention, the R3 is selected from CH2CH2CH3, The CH2CH2CH3, Optional 1, 2 or 3 R c Substitution, other variables are as defined in the present invention.

[0076] In some embodiments of the present invention, the R3 is selected from Other variables are as defined in the present invention.

[0077] In some embodiments of the present invention, R4 is selected from CH3, OCH3, OCHF2 and OCF3, and other variables are as defined in the present invention.

[0078] The present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof

[0079]

[0080] in,

[0081] T1 is selected from CR1 and N;

[0082] T2 is selected from CH and N;

[0083] R1 is selected from H;

[0084] R2 is selected from C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 Alkylthio, the C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 The alkylthio group is optionally substituted with 1, 2 or 3 R b replace;

[0085] R3 is selected from C 1-4 Alkyl and piperazinyl, the C 1-4 The alkyl and piperazinyl groups are optionally substituted with 1, 2 or 3 R c replace;

[0086] R4 is selected from C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted with 1, 2 or 3 R d replace;

[0087] Alternatively, R1 and R3 together with the atoms to which they are attached form a pyrrolidinyl group, which is optionally replace;

[0088] Each R a Each independently selected from F, Cl, Br, I, CH3 and CF3;

[0089] Each R b are independently selected from F, Cl, Br, I and OH;

[0090] Each R c are independently selected from C 1-3 Alkyl, C 1-4 Alkylamino and heterocyclic butyl, the C 1-3 Alkyl, C 1-4 Alkylamino and heterocyclobutyl are optionally substituted with 1, 2 or 3 R;

[0091] Each R d are independently selected from F, Cl, Br and I;

[0092] Each R is independently selected from F, Cl, Br, I and OH;

[0093] The heteroatom of the heterocyclobutyl group is selected from N, O and S.

[0094] In some embodiments of the present invention, the R2 is selected from SCH3, SCH2CH3, SCH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, CH3, CH2CH3 and CH(CH3)2, and the SCH3, SCH2CH3, SCH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, CH3, CH2CH3 and CH(CH3)2 are optionally replaced by 1, 2 or 3 R b Substitution, other variables are as defined in the present invention.

[0095] In some embodiments of the present invention, R2 is selected from SCH3, SCH2CH2OH, OCH2CH3 and CH2CH2OH, and other variables are as defined in the present invention.

[0096] In some embodiments of the present invention, the R c Selected from CH3, CH2CH3, N(CH3)2 and The CH3, CH2CH3 and N(CH3)2 are optionally substituted with 1, 2 or 3 R, and the other variables are as defined herein.

[0097] In some embodiments of the present invention, the R c Selected from CH3, CH2CH2OH, N(CH3)2 and Other variables are as defined in the present invention.

[0098] In some embodiments of the present invention, the R3 is selected from CH2CH2CH3 and described Optional 1, 2 or 3 R c Substitution, other variables are as defined in the present invention.

[0099] In some embodiments of the present invention, the R3 is selected from Other variables are as defined in the present invention.

[0100] In some embodiments of the present invention, R4 is selected from CH3, OCH3 and OCF3, and other variables are as defined in the present invention.

[0101] In some embodiments of the present invention, the R1 and R3 form a pyrrolidine group with the atoms connected thereto, so that the structural fragment Selected from Other variables are as defined in the present invention.

[0102] In some embodiments of the present invention, the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

[0103]

[0104] wherein R2 and R3 are as defined in the present invention.

[0105] In some embodiments of the present invention, the compound or a pharmaceutically acceptable salt thereof is selected from

[0106]

[0107] Among them, R2 and R c As defined in the present invention.

[0108] In some embodiments of the present invention, R2 is selected from C 1-3 Alkoxy, C 1-3 Alkylthio and -OC 3-5 Cycloalkyl, the C 1-3 Alkoxy, C 1-3 Alkylthio and -OC 3-5 The cycloalkyl group is optionally substituted with 1, 2 or 3 R b Substitution, other variables are as defined in the present invention.

[0109] In some embodiments of the present invention, R2 is selected from SCH3, SCH2CH3, SCH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2 and The SCH3, SCH2CH3, SCH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2 and Optional 1, 2 or 3 R b Substitution, other variables are as defined in the present invention.

[0110] In some embodiments of the present invention, R2 is selected from SCH3, SCH2CH2OH, OCH2CH3, OCH2CH2OH, OCH2CH2OCH3 and Other variables are as defined in the present invention.

[0111] In some embodiments of the present invention, the R c Selected from CH3 and CH2CH2OH.

[0112] The present invention also provides a compound represented by formula (P-3) or a pharmaceutically acceptable salt thereof

[0113]

[0114] in,

[0115] R c As defined in the present invention;

[0116] L1 is selected from O and S;

[0117] R6 is selected from C1-3 Alkyl and C 3-5 Cycloalkyl.

[0118] In some embodiments of the present invention, R6 is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl and cyclobutyl.

[0119] Some other solutions of the present invention are obtained by any combination of the above variables.

[0120] The present invention also provides the following compounds or pharmaceutically acceptable salts thereof, wherein the compound is selected from

[0121]

[0122]

[0123]

[0124] The present invention also provides the use of the compound or a pharmaceutically acceptable salt thereof in preparing a drug for treating solid tumors.

[0125] The present invention also provides the use of the compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating solid tumors associated with a selective PLK1 inhibitor.

[0126] In some embodiments of the present invention, the solid tumor is colorectal cancer.

[0127] Related definitions

[0128] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0129] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0130] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine) and organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0131] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two.

[0132] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0133] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0134] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be any on the basis of chemical achievable.

[0135] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0136] When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0137] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0138] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the connection mode of the chemical bond is non-positional, and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds, becoming a group with a corresponding valence. When the group is a cyclic, spirocyclic or bridged ring structure, and the cyclic, spirocyclic or bridged ring structure is connected to other groups through non-positional chemical bonds, any one or more sites of the cyclic, spirocyclic or bridged ring can be connected to other groups through chemical bonds. The chemical bond connecting the site to the other group can be a straight solid line bond. Straight dotted key or wavy lines For example, the straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups; The wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least In these four connection methods, even if an H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group. Indicates that any linkable site on the group can be connected to other groups through one chemical bond, including at least These 8 connection methods.

[0139] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 , and C 12 , also includes any range from n to n+m, such as C 1-12 Including C 1-3 、C 1-6 、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C 6-12 , and C 9-12 Similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range from n to n+m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-7-membered ring, a 6-8-membered ring, and a 6-10-membered ring, etc.

[0140] Unless otherwise specified, the term "7-9 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 7 to 9 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spirocyclic, fused and bridged rings. In addition, with respect to the "7-9 membered heterocycloalkyl", a heteroatom may occupy the position at which the heterocycloalkyl is connected to the rest of the molecule. The 7-9 membered heterocycloalkyl includes 7-membered, 8-membered and 9-membered heterocycloalkyl. Examples of 7-9 membered heterocycloalkyl include, but are not limited to wait.

[0141] Unless otherwise specified, “C3-5 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms, which is a monocyclic system. 3-5 Cycloalkyl groups include C 3-4 and C 4-5 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-5 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.

[0142] Unless otherwise specified, the terms "5-membered heteroaromatic ring" and "5-membered heteroaryl" are used interchangeably in the present invention. The term "5-membered heteroaryl" refers to a monocyclic group with a conjugated π electron system consisting of 5 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). The 5-membered heteroaryl group may be attached to the rest of the molecule via a heteroatom or carbon atom. Examples of the 5-membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1, 2, 3-triazolyl, 2 H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.).

[0143] Unless otherwise specified, the term “C 1-4 "Alkylamino" means an alkyl group containing 1 to 4 carbon atoms which is attached to the rest of the molecule via an amino group. 1-4 Alkylamino groups include C 1-3 、C 1-2 、C 2-4 , C4, C3 and C2 alkylamino, etc. 1-4 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, and the like.

[0144] Unless otherwise specified, the term “C 1-3"Alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 、C 2-3 , C3 and C2 alkoxy, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0145] Unless otherwise specified, the term “C 1-3 "Alkylthio" refers to those alkyl groups containing 1 to 3 carbon atoms which are linked to the rest of the molecule via a sulfur atom. 1-3 Alkylthio includes C 1-3 、C 1-2 and C3 alkylthio, etc. 1-3 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like.

[0146] Unless otherwise specified, the term “C 1-4 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms. 1-4 Alkyl groups include C 1-2 、C 1-3 and C 2-3 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-4 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), and the like.

[0147] Unless otherwise specified, the term “C 1-3 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0148] Unless otherwise specified, “C 2-3 "Alkynyl" is used to represent a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. It may be monovalent, divalent or polyvalent. The C 2-3 Alkynyl groups include C3 and C2 alkynyl groups.2-3 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like.

[0149] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0150] The structures of the compounds of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compounds, the absolute configuration can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data on the cultured single crystal using a Bruker D8 venture diffractometer, using CuKα radiation as the light source and scanning mode: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0151] The solvent used in the present invention is commercially available. BRIEF DESCRIPTION OF THE DRAWINGS

[0152] Figure 1 In vivo pharmacodynamic study of human colon cancer HCT-116 cell subcutaneous xenograft tumor model (tumor volume graph);

[0153] Figure 2 . In vivo pharmacodynamic study of human colon cancer HCT-116 cell subcutaneous xenograft tumor model. Body weight changes.

[0154] Technical Effects

[0155] The compounds of the present invention have a strong and selective inhibitory effect on PLK1, exhibiting strong inhibitory activity against cell proliferation, demonstrating significant anti-tumor effects in in vivo efficacy studies, and are well tolerated by animals. The compounds of the present invention also exhibit excellent pharmacokinetic properties. DETAILED DESCRIPTION

[0156] The present invention is described in detail below by way of examples, but is not intended to limit the present invention in any way. While the present invention has been described in detail herein, and specific embodiments thereof have been disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0157] Example 1

[0158]

[0159] Step 1: Synthesis of compound 1-2

[0160] Compound 1-1 (500 mg, 1.85 mmol, 1 eq) was dissolved in tetrahydrofuran (5 mL), and tert-butoxybis(dimethylamino)methane (966.93 mg, 5.55 mol, 3 eq) was added at 20°C. After the addition, the temperature was raised to 90°C and the reaction was carried out for 12 hours. After the disappearance of the raw material by LCMS detection, the temperature was lowered to 20°C, and the solvent was removed by concentration under reduced pressure using an oil pump to obtain compound 1-2, which was directly used in the next reaction.

[0161] Characterization of compound 1-2:

[0162] 1 H NMR (400MHz, CDCl3) δ: 1.30 (t, J=7.04Hz, 3H), 2.51 (s, 3H), 2.78-2.82 (m, 2H), 3.05 (s, 6H), 3.07-3.11 (m, 2H), 4.25 (q, J=7.04Hz, 2H), 7.52 (s, 1H).

[0163] Step 2: Synthesis of Compounds 1-4

[0164] Compound 1-2 (180 mg, 553.09 μmol, 1 eq) and compound 1-3 (193.05 mg, 608.40 μmol, 1.1 eq) were dissolved in N, N-dimethylformamide (4 mL) in sequence, and the temperature was raised to 110 ° C. for reaction for 20 hours. After LCMS detection, the raw material 1-2 disappeared, and water (20 mL) was added to dilute the system, and the mixture was extracted with ethyl acetate (20 mL * 3). The liquids were separated, and the organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the filtrate was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated by thin layer chromatography (developing solvent: dichloromethane: methanol = 20: 1) to obtain compound 1-4.

[0165] Characterization of compounds 1-4:

[0166] LCMS: m / z (ESI) = 580.17 [M+H] + .

[0167] 1H NMR (400MHz, CDCl3) δ: 1.46-1.50 (m, 3H), 2.30 (s, 3H), 2.53 (s, 4H), 2.58-2.62 (m, 3H), 2.66-2.70 (m, 2H), 3.09-3 .32(m, 6H), 4.25-4.29(m, 2H), 6.35-6.45(m, 1H), 7.03-7.07(m, 1H), 7.24(s, 1H), 8.21(s, 1H), 8.32-8.36(m, 1H).

[0168] Step 3: Synthesis of compound 1

[0169] Compound 1-4 (90 mg, 155.26 μmol, 1 eq) was dissolved in tetrahydrofuran (1 mL), cooled to 0°C, and ammonium chloride (49.83 mg, 931.59 μmol, 6.0 eq) was added. A 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.55 mL, 10 eq) was added. After the addition, the temperature was raised to 25°C and the reaction was allowed to react at this temperature for 2 hours. The reaction was quenched by the addition of ethanol (2 mL), and the solvent was removed by concentration under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative HPLC (HPLC preparative method: Phenomenex preparative chromatograph; column: C18 80*40 mm*3 μm; mobile phase A: aqueous solution containing 0.05% ammonia, mobile phase B: acetonitrile; gradient: B%: 38%-68%, running time: 8 min) to obtain compound 1.

[0170] Characterization of Compound 1:

[0171] LCMS: m / z (ESI) = 551.15 [M+H] + .

[0172] 1 H NMR (400MHz, CDCl3) δ: 2.22 (s, 3H), 2.43-2.46 (m, 4H), 2.54 (s, 3H), 2.72-2.76 (m, 2H), 3.08-3.18 (m, 6H), 6.68-6.73(m, 1H), 7.15-7.21(m, 1H), 7.44(s, 2H), 7.48-7.54(m, 1H), 8.33(s, 1H), 8.48(s, 1H).

[0173] Example 2

[0174]

[0175]

[0176] Step 1: Synthesis of compound 2-2

[0177] Sodium tert-butoxide (127.13 mg, 1.32 mmol, 2 eq) was dissolved in tetrahydrofuran (1.6 mL). Ethanol (154 μL, 1.32 mmol, 1.9 eq) was added at 20°C. After stirring for 30 minutes, the system was cooled to 0°C and compound 2-1 (200 mg, 661.45 μmol, 1 eq) was added. The reaction was continued for 1 hour. After the reaction was completed, water (20 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (30 mL*3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4:1) to obtain compound 2-2.

[0178] Characterization of compound 2-2:

[0179] 1 H NMR (400MHz, CDCl3) δ: 1.38-1.42 (m, 3H), 1.62-1.67 (m, 3H), 2.02-2.14 (m, 2H), 2.49-2.60 (m, 2H), 3.20-3.27 (m, 2H), 4.34-4.38 (m, 4H).

[0180] Step 2: Synthesis of compound 2-3

[0181] Compound 2-2 (80 mg, 298.14 μmol, 1 eq) was dissolved in tetrahydrofuran (0.5 mL), and tert-butoxybis(dimethylamino)methane (156.4 mg, 894.10 μmol, 3 eq) was added. The temperature was raised to 90°C and the reaction was allowed to proceed for 12 hours. After the reaction, the temperature was lowered to 20°C and the solvent was removed by concentration under reduced pressure using an oil pump to obtain compound 2-3, which was used directly in the next reaction.

[0182] Characterization of compound 2-3:

[0183] 1 H NMR (400MHz, CDCl3) δ: 1.26-1.32 (m, 3H), 1.45-1.52 (m, 3H), 2.73-2.76 (m, 2H), 3.00-3.07 (m, 8H), 4.19-4.25 (m, 4H), 7.51 (s, 1H).

[0184] Step 3: Synthesis of Compound 2-4

[0185] Compound 2-3 (10 mg, 30.92 μmol, 1 eq) and compound 1-3 (8.33 mg, 26.26 μmol, 0.849 eq) were dissolved in N, N-dimethylformamide (0.5 mL) in sequence, and the temperature was raised to 110 ° C. for 12 hours. After the reaction, water (2 mL) was added to dilute the system, and the mixture was extracted with ethyl acetate (2 mL * 3). The organic phases were combined and washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by thin layer chromatography (developing solvent: dichloromethane ∶ Methanol = 20 ∶ 1), to obtain compound 2-4.

[0186] Characterization of compounds 2-4:

[0187] LCMS: m / z (ESI) = 578.20 [M+H] + .

[0188] 1 H NMR (400MHz, CDCl3) δ: 1.30-1.33 (m, 3H), 1.45-1.50 (m, 3H), 2.30 (s, 3H), 2.53 (s, 4H), 2.68-2.72 (m, 2H), 3.15-3 .25(m, 6H), 4.25-4.29(m, 4H), 4.36-4.43(m, 1H), 7.01-7.08(m, 1H), 7.24(s, 1H), 8.21(s, 1H), 8.30-8.37(m, 1H).

[0189] Step 4: Synthesis of compound 2

[0190] Compound 2-4 (80 mg, 138.50 μmol, 1 eq) was dissolved in tetrahydrofuran (0.5 mL), and ammonium chloride (45 mg, 831.00 μmol, 6 eq) was added. The system was cooled to 0°C, and a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.39 mL, 1.39 mmol, 10 eq) was slowly added dropwise. After the addition, the temperature was slowly raised to 20°C and the reaction was allowed to react at this temperature for 2 hours. Ethanol (3 mL) was added to quench the reaction, and the solvent was removed by concentration under reduced pressure to obtain a crude product. The crude product was separated and purified by high-performance liquid chromatography (high-performance liquid chromatography preparation method: Phenomenex preparative chromatograph; chromatographic column: C18 80*40 mm*3 μm; mobile phase A: aqueous solution containing 0.05% ammonia water, mobile phase B: acetonitrile; running gradient: B%: 36%-66%, running time 8 min.) to obtain compound 2.

[0191] Characterization of Compound 2:

[0192] LCMS: m / z (ESI) = 549.19 [M+H] + .

[0193] 1 H NMR (400MHz, CDCl3) δ: 1.27-1.37 (m, 3H), 2.22 (s, 3H), 2.34 (s, 3H), 2.68 (s, 2H), 3.04-3.20 (m, 7H), 4 .19-4.26(m, 2H), 6.67(s, 1H), 7.17(s, 1H), 7.35(s, 2H), 7.84(s, 1H), 8.16-8.24(m, 1H), 8.32(s, 1H).

[0194] Example 3

[0195]

[0196]

[0197] Step 1: Synthesis of compound 3-2

[0198] Compound 2-1 (450 mg, 1.49 mmol, 1 eq) was dissolved in ethanol (5 mL), and 2-mercaptoethanol (151.17 mg, 1.93 mmol, 134.97 μL, 1.3 eq) and triethylamine (301.19 mg, 2.98 mmol, 414.29 μL, 2 eq) were added. The mixture was stirred at 20°C for 2 hours. Water (10 mL) was added to dilute the reaction system, followed by extraction with ethyl acetate (10 mL x 3). The organic phases were separated, combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0 to 70:30) to obtain compound 3-2.

[0199] The characterization of compound 3-2 is as follows:

[0200] LCMS: m / z (ESI) = 301.0 [M+H] + .

[0201] 1 H NMR (400MHz, CDCl3) δ: 4.30-4.39 (m, 2H), 3.99-4.05 (m, 2H), 3.26-3.34 (m, 2H) ), 3.17-3.24(m, 2H), 2.53-2.61(m, 2H), 2.06-2.11(m, 2H), 1.34-1.42(m, 3H).

[0202] Step 2: Synthesis of compound 3-3

[0203] Compound 3-2 (260 mg, 865.53 μmol, 1 eq) was dissolved in tetrahydrofuran (5 mL), and tert-butoxybis(dimethylamino)methane (452.54 mg, 2.60 mmol, 536.18 μL, 3 eq) was added and stirred at 80°C for 16 hours. The reaction system was cooled to 20°C, and water (20 mL) was added to dilute the reaction system. Ethyl acetate (10 mL) was then added and stirred, and the mixture was filtered. The filter cake was slurried with ethanol (10 mL) for 0.5 hours, filtered, and the filter cake was concentrated under reduced pressure using an oil pump to remove the residual solvent to obtain compound 3-3.

[0204] Characterization of compound 3-3:

[0205] 1 H NMR (400MHz, CDCl3) δ: 7.65 (s, 1H), 4.28-4.37 (m, 2H), 3.88-3.98 (m, 2H), 3.21-3 .28(m, 2H), 3.15-3.20(m, 2H), 3.14(s, 6H), 2.82-2.91(m, 2H), 1.32-1.43(m, 3H).

[0206] Step 3: Synthesis of compound 3-4

[0207] Compound 3-3 (300 mg, 843.95 μmol, 1 eq) was dissolved in N,N-dimethylaminoformamide (5 mL), and compound 1-3 (267.79 mg, 843.95 μmol, 1 eq) was added. The mixture was stirred at 110°C for 16 hours. Saturated brine (15 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were separated, combined, 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 (gradient elution: dichloromethane / methanol = 100:0-90:10) to obtain compound 3-4.

[0208] Characterization of compound 3-4:

[0209] LCMS: m / z (ESI) = 610.20 [M+H] + .

[0210] 1H NMR (400MHz, CD3OD) δ: 8.29 (s, 1H), 7.88-7.93 (m, 1H), 7.15-7.22 (m, 1H), 6.66-6.76 (m, 1H), 4.29-4.36 (m, 2H), 3.79-3 .89 (m, 2H), 3.26-3.30 (m, 6H), 3.21-3.25 (m, 4H), 2.78-2.85 (m, 2H), 2.69 (s, 3H), 2.39-2.44 (m, 2H), 1.33-1.39 (m, 3H).

[0211] Step 4: Synthesis of Compound 3-5

[0212] Compound 3-4 (100 mg, 164.02 μmol, 1 eq) was dissolved in dichloromethane (2 mL), and triethylamine (24.90 mg, 246.03 μmol, 34.24 μL, 1.5 eq) and 4-dimethylaminopyridine (2.00 mg, 16.40 μmol, 0.1 eq) were added. Then, tert-butyldimethylsilyl chloride (29.67 mg, 196.82 μmol, 24.12 μL, 1.2 eq) was added, and the mixture was stirred at 20° C. for 20 hours. The reaction solution was concentrated to dryness under reduced pressure to obtain a crude product, which was purified by thin-layer chromatography (developing solvent: dichloromethane / methanol = 10:1) to obtain compound 3-5.

[0213] Characterization of compounds 3-5:

[0214] LCMS: m / z (ESI) = 724.30 [M+H] + .

[0215] 1 H NMR (400MHz, CD3OD) δ: 8.29 (s, 1H), 7.94-8.00 (m, 1H), 7.12-7.20 (m, 1H), 6.65-6.73 (m, 1H), 4.27-4.36 (m, 2H), 3.91-3.99 (m, 2H), 3. 25-3.29(m, 6H), 3.21-3.25(m, 2H), 2.78-2.87(m, 2H), 2.60-2.70(m, 4H), 2.37(s, 3H), 1.32-1.40(m, 3H), 0.84(s, 9H), -0.01(s, 6H).

[0216] Step 5: Synthesis of Compounds 3-6

[0217] Compound 3-5 (70 mg, 96.69 μmol, 1 eq) was dissolved in tetrahydrofuran (1 mL), and ammonium chloride (31.03 mg, 580.16 μmol, 6 eq) was added. The temperature was then lowered to 0°C, and a 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (966.93 μL, 10 eq) was added. The temperature was raised to 20°C and stirred for 4 hours. Water (5 mL) was added to the reaction system, followed by extraction with ethyl acetate (5 mL*3). The organic phases were separated, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain compound 3-6.

[0218] Characterization of compounds 3-6:

[0219] LCMS: m / z (ESI) = 695.20 [M+H] + .

[0220] 1 H NMR (400MHz, CD3OD) δ: 8.29 (s, 1H), 7.99-8.03 (m, 1H), 7.14-7.21 (m, 1H), 6.64-6.71 (m, 1H), 3.90-3.96 (m, 2H), 3. 24-3.29(m, 6H), 3.21-3.24(m, 2H), 2.79-2.86(m, 2H), 2.58-2.65(m, 4H), 2.37(s, 3H), 0.84(s, 9H), -0.02(s, 6H).

[0221] Step 6: Synthesis of compound 3

[0222] Compound 3-6 (60 mg, 86.34 μmol, 1 eq) was dissolved in tetrahydrofuran (0.5 mL), followed by the addition of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (172.69 μL, 2 eq). The resulting reaction mixture was stirred at 20°C for 2 hours. Water (10 mL) was added for washing, followed by extraction with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the crude product. The crude product was separated and purified by preparative HPLC (HPLC preparative method: Waters Xbridge BEH preparative chromatograph; column: C18 100 x 30 mm x 10 μm; mobile phase A: 10 mM aqueous ammonium bicarbonate (containing 0.05% ammonia), mobile phase B: acetonitrile; gradient: B%: 25%-55% over 8 min) to yield compound 3.

[0223] Characterization of compound 3:

[0224] LCMS: m / z (ESI) = 581.30 [M+H] + .

[0225] 1 H NMR (400MHz, DMSO-d6) δ: 8.43 (s, 1H), 8.32 (s, 1H), 7.40-7.48 (m, 3H), 7.13-7.20 (m, 1H), 6.68-6.75 (m, 1H), 5.02-5.0 9(m, 1H), 3.63-3.71(m, 2H), 3.12-3.17(m, 4H), 3.04-3.11(m, 4H), 2.71-2.76(m, 2H), 2.42-2.46(m, 4H), 2.07(s, 3H).

[0226] Example 4

[0227]

[0228] Step 1: Synthesis of compound 4-2

[0229] Compound 4-1 (10 g, 45.87 mmol, 1 eq) was dissolved in dichloromethane (300 mL), and N,N-diisopropylethylamine (8.90 g, 68.89 mmol, 12.00 mL, 1.50 eq) and chloromethyl methyl ether (4.47 g, 55.52 mmol, 4.22 mL, 1.21 eq) were added. The mixture was stirred at 20°C for 4 hours. The reaction mixture was concentrated to dryness under reduced pressure, and water (150 mL) and dichloromethane (150 mL) were added to the crude product. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure to dryness to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0-90:10) to obtain compound 4-2.

[0230] The characterization of compound 4-2 is as follows:

[0231] 1 H NMR (400MHz, CDCl3) δ: 3.53 (s, 3H), 5.29 (s, 2H), 7.20-7.28 (m, 1H), 7.61 (s, 1H), 7.92-7.99 (m, 1H).

[0232] Step 2: Synthesis of compound 4-3

[0233] Compound 4-2 (2 g, 7.63 mmol, 1 eq) was dissolved in toluene (12 mL) and dimethyl sulfoxide (4 mL), and then N-methylmorpholine (1.15 g, 11.45 mmol, 1.27 mL, 1.5 eq), cesium carbonate (7.46 g, 22.90 mmol, 3 eq), tris(dibenzylideneacetone)dipalladium (139.77 mg, 152.64 μmol, 0.02 eq), (S)-(-)-2,2-bis(di-p-tolylphosphine)-1,1-binaphthyl (207.22 mg, 305.28 μmol, 0.04 eq) were added in sequence. The mixture was protected by nitrogen and stirred at 90 ° C for 16 hours. The reaction solution was filtered through a diatomaceous earth-lined funnel, and the filter cake was rinsed with ethyl acetate (150 mL). The filtrate was concentrated to dryness under reduced pressure. Ethyl acetate (50 mL) and saturated brine (50 mL) were added to the crude product, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-98:2) to obtain compound 4-3.

[0234] The characterization of compound 4-3 is as follows:

[0235] LCMS: m / z (ESI) = 282.0 [M+H] + .

[0236] 1 H NMR (400MHz, CDCl3) δ: 2.37 (s, 3H), 2.55-2.61 (m, 4H), 3.14-3.24 (m, 4H), 3 .53(s, 3H), 5.20(s, 2H), 7.09(s, 1H), 7.22-7.26(m, 1H), 7.30-7.36(m, 1H).

[0237] Step 3: Synthesis of compound 4-4

[0238] Compound 4-3 (950 mg, 3.38 mmol, 1 eq) was dissolved in dichloromethane (10 mL), and methanol (8.4 mL) and 12 M concentrated hydrochloric acid (1.6 mL, 5.69 eq) were added. The mixture was stirred at 15°C for 16 hours. The temperature was raised to 35°C and stirred for 8 hours. The solvent was concentrated under reduced pressure to dryness to obtain the hydrochloride salt of compound 4-4.

[0239] The hydrochloride of compound 4-4 is characterized as follows:

[0240] LCMS: m / z (ESI) = 238.1 [M+H] + .

[0241] Step 4: Synthesis of compound 4-5

[0242] The hydrochloride of compound 4-4 (400 mg, 1.46 mmol, 1 eq) was dissolved in dichloromethane (8 mL) and cooled to 0°C in an ice bath. A mixed solution of potassium hydroxide (491.95 mg, 8.77 mmol, 6 eq) and water (2.4 mL) was added. (Bromodifluoromethyl)trimethylsilane (605.72 mg, 2.92 mmol, 2 eq) was added at 0°C, and the mixture was stirred at 20°C for 16 hours. Dichloromethane (5 mL) and water (5 mL) were added to the reaction solution for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure to dryness to obtain a crude product. The crude product was separated by thin-layer chromatography (developing solvent: dichloromethane / methanol = 10:1) to obtain compound 4-5.

[0243] The characterization of compound 4-5 is as follows:

[0244] 1 H NMR (400MHz, CDCl3) δ: 2.44-2.54 (m, 3H), 2.67-2.84 (m, 4H), 3.37 (s, 4H), 6.26-6.75 (m, 1H), 7.06-7.10 (m,, 1H), 7.26 (s, 1H), 7.30-7.40 (m, 1H).

[0245] Step 5: Synthesis of Compounds 4-6

[0246] Under a slight argon flow, 10% pure wet palladium on carbon (50 mg), methanol (5 mL), and compound 4-5 (30 mg, 104.43 μmol, 1 eq) were added sequentially. The reaction mixture was reacted at 15°C under hydrogen (15 psi) for 2 hours. The reaction mixture was directly filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain compound 4-6.

[0247] The characterization of compounds 4-6 is as follows:

[0248] 1 H NMR (400MHz, CD3OD) δ: 2.92 (s, 3H), 3.05-3.71 (m, 8H), 6.26-6.32 (m, 1H), 6.36-6.78 (m, 2H), 6.91-6.95 (m, 1H).

[0249] Step 6: Synthesis of Compounds 4-7

[0250] Compound 4-6 (18 mg, 69.96 μmol, 1 eq) was dissolved in 6 M aqueous hydrochloric acid (180.00 μL, 15.44 eq), followed by the addition of aminonitrile (61.92 mg, 1.40 mmol, 61.92 μL, 20 eq) and stirring at 60°C for 1 hour. Water (5 mL) and dichloromethane (5 mL) were added to the reaction solution, and the layers were separated. Solid sodium hydroxide was then added to the aqueous phase to adjust the pH to greater than 12, followed by extraction with ethyl acetate (5 mL*2). The layers were separated, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure to dryness to obtain compound 4-7.

[0251] The characterization of compounds 4-7 is as follows:

[0252] LCMS: m / z (ESI) = 300.1 [M+H] + .

[0253] Step 7: Synthesis of Compounds 4-8

[0254] Compound 1-2 (20 mg, 44.68 μmol, 2.4 eq) was dissolved in N,N-dimethylformamide (0.5 mL), followed by the addition of compound 4-7 (6.26 mg, 18.62 μmol, 1 eq). The reaction mixture was stirred at 110°C for 12 hours. Saturated brine (5 mL) and water (5 mL) were added to the reaction mixture, followed by extraction with ethyl acetate (5 mL x 6). The organic phases were separated and combined, washed with saturated brine (5 mL x 6), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative HPLC (HPLC preparative method: Phenomenex preparative chromatograph; column: C18 75 x 30 mm x 3 μm; mobile phase A: 0.1% aqueous ammonium bicarbonate solution, mobile phase B: acetonitrile; gradient: B%: 55%-85% over 12 min) to obtain compound 4-8.

[0255] The characterization of compounds 4-8 is as follows:

[0256] LCMS: m / z (ESI) = 562.2 [M+H] + .

[0257] 1H NMR (400MHz, CD3OD) δ: 1.20-1.28 (m, 3H), 2.36 (s, 3H), 2.58-2.65 (m, 7H), 2.80-2.86 (m, 2H), 3.19-3.26 (m, 4H ), 3.25-3.30(m, 2H), 4.30-4.36(m, 2H), 6.69-6.73(m, 2H), 7.04-7.13(m, 1H), 8.00-8.05(m, 1H), 8.28(s, 1H).

[0258] Step 8: Synthesis of compound 4

[0259] Compound 4-8 (2 mg, 3.56 μmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (1 mL). Ammonium chloride (38.09 mg, 712.17 μmol, 200 eq) and a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.42 mL, 400 eq) were added, and the mixture was stirred at 20°C for 3 hours. Methanol (5 mL) was added to the reaction mixture, and the solvent was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative HPLC (HPLC preparative method: Waters Xbridge BEH preparative chromatograph; column: C18 100*25 mm*5 μm; mobile phase A: 0.1% aqueous ammonium bicarbonate solution, mobile phase B: acetonitrile; gradient: B%: 20%-55% over 10 min) to obtain compound 4.

[0260] The characterization of compound 4 is as follows:

[0261] LCMS: m / z (ESI) = 533.2 [M+H] + .

[0262] 1 H NMR (400MHz, CD3OD) δ: 2.36 (s, 3H), 2.59-2.69 (m, 5H), 2.82-2.86 (m, 2H), 3.11-3.2 7 (m, 8H), 6.50-6.93 (m, 2H), 7.05-7.25 (m, 1H), 8.03 (d, J=2.86Hz, 1H), 8.29 (s, 1H).

[0263] Example 5

[0264]

[0265] Step 1: Synthesis of compound 5-2

[0266] Compound 5-1 (2 g, 8.26 mmol, 1 eq) was dissolved in toluene (20 mL), and N-methylpiperazine (827.81 mg, 8.26 mmol, 916.73 μL, 1.00 eq), sodium tert-butoxide (1.19 g, 12.40 mmol, 1.5 eq), tris(dibenzylideneacetone)dipalladium (378.41 mg, 413.23 μmol, 0.05 eq), and (R)-(+)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (257.31 mg, 413.23 μmol, 0.05 eq) were added. The mixture was stirred at 80°C under nitrogen for 16 hours. Water (5 mL) was added to quench the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were separated, combined, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-95:5) to obtain compound 5-2. The characterization of compound 5-2 is as follows:

[0267] LCMS: m / z (ESI) = 262.30 [M+H] + .

[0268] 1 H NMR (400MHz, CDCl3) δ: 8.07-8.14 (m, 1H), 7.32-7.39 (dd, J=9.2Hz, 1H), 6.57-6.67 (d , J=9.2Hz, 1H), 3.52-3.61 (t, J=5.2Hz, 4H), 2.46-2.58 (t, J=5.2Hz, 4H), 2.36 (s, 3H).

[0269] Step 2: Synthesis of compound 5-3

[0270] Under nitrogen at -78°C, compound 5-2 (500 mg, 1.91 mmol, 1 eq) was dissolved in tetrahydrofuran (5 mL). A 2M solution of lithium diisopropylamide in tetrahydrofuran (1.44 mL, 1.5 eq) was added. The resulting reaction solution was stirred at -78°C for 2 hours. Iodine (728.65 mg, 2.87 mmol, 1.5 eq) in anhydrous tetrahydrofuran (2 mL) was then added. The reaction solution was stirred at -78°C for 2 hours. The reaction system was then warmed to 80°C and stirred for 16 hours. Water (10 mL) was added to the reaction system to quench the reaction. The mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0 to 95:5) to obtain compound 5-3.

[0271] Characterization of compound 5-3:

[0272] LCMS: m / z (ESI) = 388.00 [M+H] + .

[0273] 1 H NMR (400 MHz, CDC13) δ: 7.99 - 8.06 (m, 1H), 7.09 (s, 1H), 3.55 - 3.67 (m, 4H), 2.48 - 2.65 (m, 4H), 2.40 (s, 3H).

[0274] Step 3: Synthesis of compound 5-4

[0275] Compound 1-2 (300 mg, 921.81 pmol, 1 eq) was dissolved in N,N- dimethylformamide (5 mL), guanidine carbonate (415.20 mg, 2.30 mmol, 2.5 eq) was added, stirred at 110 °C for 3 hours. Water (10 mL) was added to the reaction solution, stirred for 0.5 hours, filtered, the filter cake was rinsed with methanol (10 mL), and then the residual solvent was removed under reduced pressure with an oil pump to obtain compound 5-4.

[0276] Characterization of compound 5-4:

[0277] LCMS: m / z (ESI) = 321.90 [M+H] + .

[0278] 1 H NMR (400 MHz, DMSO-d6) δ: 8.13 (s, 1H), 6.31 - 6.39 (m, 2H), 4.22 - 4.31 (m, 2H), 3.14 - 3.21 (m, 2H), 2.65 - 2.72 (m, 2H), 2.61 (s, 3H), 1.25 - 1.33 (m, 3H).

[0279] Step 4: Synthesis of compound 5-5

[0280] Compound 5-4 (49.81 mg, 154.98 μmol, 1 eq) was dissolved in 1,4-dioxane (2 mL). Tris(dibenzylideneacetone)dipalladium (14.19 mg, 15.50 μmol, 0.1 eq), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (8.97 mg, 15.50 μmol, 0.1 eq), cesium carbonate (100.99 mg, 309.97 μmol, 2 eq), and compound 5-3 (60 mg, 154.98 μmol, 1 eq) were added under nitrogen and stirred at 100°C for 3 hours. The reaction mixture was quenched by the addition of water (10 mL), then extracted with ethyl acetate (10 mL*3). The organic phases were separated, combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-95:5) to give compound 5-5.

[0281] Characterization of compound 5-5:

[0282] LCMS: m / z (ESI) = 581.20 [M+H] + .

[0283] 1 H NMR (400MHz, CDCl3) δ: 1.40-1.46 (m, 3H), 2.38 (3H), 2.53-2.65 (m, 4H), 2.67 (s, 3H), 2.83-2.86 (m, 2H), 3. 23-3.37(m, 6H), 4.35-4.39(m, 2H), 6.50-6.55(m, 1H), 7.12-7.16(m, 1H), 8.24-8.30(m, 1H), 8.30(s, 1H).

[0284] Step 5: Synthesis of compound 5

[0285] Compound 5-5 (90 mg, 155.00 μmol, 1 eq) was dissolved in tetrahydrofuran (2 mL), and ammonium chloride (49.75 mg, 930.00 μmol, 6 eq) was added. Under nitrogen protection, a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (3.10 mL, 20 eq) was added at 0°C, and the mixture was stirred at 20°C for 3 hours. Water (10 mL) was added to the reaction system to quench the reaction, and then ethyl acetate (15 mL*3) was added for extraction. The liquids were separated, and the organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative HPLC (preparative HPLC method: Waters Xbridge BEH preparative chromatograph; chromatographic column: C18 100*30 mm*10 μm; mobile phase A: 10 mM aqueous ammonium bicarbonate solution (containing 0.05% ammonia water), mobile phase B: acetonitrile; running gradient: B%: 30%-60%, running time 8 min.) to obtain compound 5.

[0286] Characterization of compound 5:

[0287] LCMS: m / z (ESI) = 552.20 [M+H] + .

[0288] 1 H NMR (400MHz, DMSO-d6) δ: 8.77 (s, 1H), 8.48 (s, 1H), 8.02-8.06 (m, 1H), 7.70 (s, 1H), 7.47 (s, 2H), 3. 45-3.53(m, 4H), 3.10-3.19(m, 2H), 2.77-2.84(m, 2H), 2.61(s, 3H), 2.36-2.41(m, 4H), 2.20(s, 3H).

[0289] Example 6

[0290]

[0291]

[0292] Step 1: Synthesis of compound 6-2

[0293] Potassium carbonate (51.77 g, 374.58 mmol, 2 eq) was dissolved in dimethyl sulfoxide (200 mL), and then compound 6-1 (21 g, 187.29 mmol, 1 eq) was added, and stirred at 20°C for 10 minutes. Carbon disulfide (15.69 g, 206.02 mmol, 12.45 mL, 1.1 eq) was added, and stirred at 20°C for 10 minutes. Then, a mixed solution of ethyl bromoacetate (31.28 g, 187.29 mmol, 20.71 mL, 1 eq) and methyl iodide (26.58 g, 187.29 mmol, 11.66 mL, 1 eq) was added at 0°C, and the temperature was controlled at 15-20°C. After the addition was complete, the mixture was stirred at 20°C for 1 hour. Water (500 mL) and saturated brine (300 mL) were added to the reaction solution, extracted with ethyl acetate (500 mL*3), separated, the combined organic phases were washed with saturated brine (500 mL), separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0-90:10) to give the product, and then slurried with methyl tert-butyl ether (15 mL) for 1 hour, filtered, and the filter cake was collected to give compound 6-2.

[0294] The characterization of compound 6-2 is as follows:

[0295] LCMS: m / z (ESI) = 343.0 [M+H] + .

[0296] 1 H NMR (400MHz, CDCl3) δ: 1.28-1.34(m, 3H), 1.34-1.42(m, 3H), 1.92-2.16(m, 2H), 2.48-2.68(m, 2H), 3.18-3.26(m, 2H), 3.86(s, 2H), 4.18-4.44(m, 4H).

[0297] Step 2: Synthesis of compound 6-3

[0298] Under a slight argon flow, Raney nickel (5.20 g, 60.70 mmol, 4.00 eq) and ethanol (150 mL) were added, followed by compound 6-2 (5.2 g, 15.19 mmol, 1 eq). The reaction mixture was reacted at 30°C under hydrogen (50 psi) for 48 hours. The reaction mixture was passed through a funnel covered with diatomaceous earth, the filter cake was rinsed with ethanol (800 mL), and the filtrate was concentrated under reduced pressure to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0-90:10) to obtain the product. The product was dissolved in methyl tert-butyl ether (20 mL) and then petroleum ether (30 mL) was added. After beating for 1 hour, the mixture was filtered and the filter cake was collected to obtain compound 6-3.

[0299] The characterization of compound 6-3 is as follows:

[0300] 1 H NMR (400MHz, CDCl3) δ: 1.40-1.50 (m, 3H), 1.96-2.24 (m, 2H), 2.41-2.75 (m, 2H), 3.23-3.26 (m, 2H), 4.34-4.40 (m, 2H), 8.29 (s, 1H).

[0301] Step 3: Synthesis of compound 6-4

[0302] Compound 6-3 (1 g, 4.46 mmol, 1 eq) was dissolved in anhydrous ethanol (20 mL), and sodium borohydride (280 mg, 7.40 mmol, 1.66 eq) was added, and the mixture was stirred at 20°C for 2 hours. Water (10 mL) was added to the reaction solution, and the pH was adjusted to 6 with 1 M dilute hydrochloric acid aqueous solution. The mixture was concentrated under reduced pressure until the solvent no longer decreased. Water (10 mL) and saturated brine (10 mL) were added to the crude product, and the mixture was extracted with ethyl acetate (40 mL*2). The organic phases were separated, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure to dryness. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0-90:10) to give compound 6-4.

[0303] The characterization of compound 6-4 is as follows:

[0304] LCMS: m / z (ESI) = 209.1 [M-17] + .

[0305] 1H NMR (400MHz, CDCl3) δ: 1.34-1.40 (m, 3H), 1.54-1.83 (m, 3H), 1.92-2.12 (m, 2H), 3.03-3.09(m, 2H), 4.33-4.38(m, 2H), 4.74-4.87(m, 1H), 7.53(s, 1H).

[0306] Step 4: Synthesis of compound 6-5

[0307] Compound 6-4 (8 g, 35.35 mmol, 1 eq) was dissolved in dichloromethane (110 mL), and then acetyl chloride (11.10 g, 141.41 mmol, 10.09 mL, 4 eq) and 4-dimethylaminopyridine (431.90 mg, 3.54 mmol, 0.1 eq) and pyridine (13.98 g, 176.76 mmol, 14.27 mL, 5 eq) were added. The mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated under reduced pressure to 1 / 3 of the original volume, and then water (30 mL) was added. The organic phase was separated, and the organic phase was washed with water (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0-85:15) to obtain compound 6-5.

[0308] The characterization of compound 6-5 is as follows:

[0309] LCMS: m / z (ESI) = 209.0 [M-59] + .

[0310] 1 H NMR (400MHz, CDCl3) δ: 1.37-1.40 (m, 3H), 1.78-2.01 (m, 4H), 2.08 (s, 3H), 2.76-3.30 (m, 2H), 4.33-4.38 (m, 2H), 5.93-6.00 (m, 1H), 7.52 (s, 1H).

[0311] Step 5: Synthesis of compound 6-6

[0312] Compound 6-5 (3.1 g, 11.55 mmol, 1 eq) was dissolved in N,N-dimethylformamide (31 mL), and N-bromosuccinimide (6.37 g, 35.81 mmol, 3.1 eq) was added, and the mixture was stirred at 50°C for 16 hours. Ethyl acetate (50 mL) and saturated brine (50 mL) were added to the reaction solution, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate and filtered, and the solvent was concentrated under reduced pressure to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0-95:5) to obtain compound 6-6.

[0313] The characterization of compound 6-6 is as follows:

[0314] LCMS: m / z(ESI)=286.9, 288.9[M-59] + .

[0315] 1 H NMR (400MHz, CDCl3) δ: 1.31-1.40 (m, 3H), 1.71-1.89 (m, 3H), 2.09 (s, 3H), 2.19 (s, 1H), 2.64-2.79 (m, 1H), 3.29-3.49 (m, 1H), 4.32-4.39 (m, 2H), 5.86-6.20 (m, 1H).

[0316] Step 6: Synthesis of Compound 6-7

[0317] Compound 6-6 (3.7 g, 10.66 mmol, 1 eq) was dissolved in ethanol (37 mL), and potassium carbonate (1.47 g, 10.66 mmol, 1 eq) was added. The mixture was stirred at 40°C for 16 hours, then heated to 60°C and stirred for 4 hours. The reaction mixture was filtered, and the filter cake was rinsed with ethanol (500 mL). The filtrate was collected and the solvent was concentrated under reduced pressure to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0-90:10) to obtain compound 6-7.

[0318] The characterization of compound 6-7 is as follows:

[0319] LCMS: m / z(ESI)=286.9, 288.8[M-17] + .

[0320] 1 H NMR (400MHz, CDCl3) δ: 1.36-1.42 (m, 3H), 1.77-1.80 (m, 4H), 2.02-2.20 (m, 1H), 2.61-2.81 (m, 1

[0321] H), 3.24-3.44(m, 1H), 4.32-4.40(m, 2H), 4.88-4.93(m, 1H).

[0322] Step 7: Synthesis of Compounds 6-8

[0323] Compound 6-7 (1.76 g, 5.77 mmol, 1 eq) was dissolved in dichloromethane (30 mL), and pyridinium chlorochromate (3.73 g, 17.30 mmol, 3 eq) and sodium acetate (1.42 g, 17.30 mmol, 3 eq) were added, and stirred at 20°C for 2 hours. The reaction solution was filtered through a funnel covered with celite, rinsed with ethyl acetate (50 mL) and dichloromethane (50 mL), and the solvent was concentrated under reduced pressure to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0-80:20) to obtain compound 6-8.

[0324] The characterization of compounds 6-8 is as follows:

[0325] LCMS: m / z(ESI)=302.9, 304.9[M+H] + .

[0326] 1 H NMR (400MHz, CDCl3) δ: 1.38-1.42 (m, 3H), 2.10-2.15 (m, 2H), 2.59-2.65 (m, 2H), 3.27-3.30 (m, 2H), 4.35-4.40 (m, 2H).

[0327] Step 8: Synthesis of Compounds 6-10

[0328] Compound 6-8 (203 mg, 669.59 μmol, 1 eq), compound 6-9 (332.79 mg, 1.34 mmol, 2 eq), 2-dicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl (62.49 mg, 133.92 μmol, 0.2 eq), bis(acetonitrile)palladium(II) chloride (17.37 mg, 66.96 μmol, 0.1 eq), cesium carbonate (654.49 mg, 2.01 mmol, 3 eq) were added to the reaction flask, and then a mixed solution of water (1 mL) and tert-butanol (1 mL) was added and stirred at 100 ° C for 16 hours under nitrogen protection. Ethyl acetate (100 mL), saturated brine (50 mL) and water (50 mL) were added to the reaction solution, the liquid was separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure to dryness to obtain a crude product, which was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0-90:10) to obtain compound 6-10.

[0329] The characterization of compounds 6-10 is as follows:

[0330] LCMS: m / z (ESI) = 375.0 [M+Na] + .

[0331] 1 H NMR (400MHz, CDCl3) δ: 1.38-1.43 (m, 3H), 1.54-1.57 (m, 6H), 2.07-2.10 (m, 2H), 2.47-2 .62(m, 2H), 3.23-3.30(m, 2H), 3.59-3.62(m, 6H), 4.34-4.37(m, 2H), 4.66-4.70(m, 1H).

[0332] Step 9: Synthesis of Compounds 6-11

[0333] Compound 6-10 (283 mg, 802.96 μmol, 1 eq) was dissolved in ethanol (10 mL), and p-toluenesulfonic acid monohydrate (158.48 mg, 833.15 μmol, 1.04 eq) was added. The mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure to dryness to obtain a crude product, which was then purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0 to 80:20) to obtain compound 6-11.

[0334] The characterization of compounds 6-11 is as follows:

[0335] LCMS: m / z (ESI) = 268.9 [M+H] + .

[0336] 1 H NMR (400MHz, CDCl3) δ: 1.38-1.41 (m, 3H), 1.80 (s, 1H), 2.01-2.17 (m, 2H), 2.49-2.63 (m, 2H), 3.24-3.30 (m, 2H), 3.51-3.56 (m, 2H), 3.95-4.06 (m, 2H), 4.34-4.38 (m, 2H).

[0337] Step 10: Synthesis of Compounds 6-12

[0338] Compound 6-11 (50 mg, 186.34 μmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (7.5 mL), and then tert-butoxybis(dimethylamino)methane (162.38 mg, 931.70 μmol, 192.39 μL, 5 eq) was added and stirred at 80° C. for 12 hours. The solvent was concentrated to dryness under reduced pressure to obtain compound 6-12.

[0339] The characterization of compounds 6-12 is as follows:

[0340] LCMS: m / z (ESI) = 297.0 [M-26] + .

[0341] Step 11: Synthesis of Compounds 6-13

[0342] Compound 6-12 (60 mg, 185.53 μmol, 1 eq) was dissolved in N,N-dimethylformamide (1.2 mL), followed by the addition of compound 1-3 (58.87 mg, 185.53 μmol, 1 eq), and the mixture was stirred at 110°C for 12 hours. Ethyl acetate (10 mL), water (5 mL), and saturated brine (5 mL) were added to the reaction solution, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure to dryness. The crude product was then purified by silica gel column chromatography (gradient elution: dichloromethane: methanol = 100:0-90:10) to obtain compound 6-13.

[0343] The characterization of compound 6-13 is as follows:

[0344] LCMS: m / z (ESI) = 578.1 [M+H] + .

[0345] Step 12: Synthesis of compound 6

[0346] Compound 6-13 (8 mg, 13.85 μmol, 1 eq) was dissolved in tetrahydrofuran (0.8 mL) and nitrogen was added at 0°C. Ammonium chloride (30 mg, 560.84 μmol, 40.49 eq) and a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (567.85 μL, 41 eq) were then stirred at 20°C for 1 hour. The reaction mixture was quenched by methanol (5 mL) and the solvent was concentrated to dryness under reduced pressure. The crude product was then separated and purified by preparative HPLC (HPLC preparative method: Waters Xbridge BEH preparative chromatograph; column: Prep sunfire C18 100*30 mm*10 μm; mobile phase A: 10 mM aqueous ammonium bicarbonate solution, mobile phase B: acetonitrile; gradient: B%: 35%-50% over 8 min) to obtain compound 6. Compound 6 was characterized as follows:

[0347] LCMS: m / z (ESI) = 549.3 [M+H] + .

[0348] 1H NMR (400 MHz, DMSO-d6) δ: 2.18-2.26 (m, 3H), 2.29-2.38 (m, 4H), 2.40-2.46 (m, 4H), 2.68-2.81 (m, 4H), 3.02-3.17 (m, 4H), 4.55-4.70 (m, 1H), 6.66-6.87 (m, 1H), 7.11-7.27 (m, 2H), 7.32-7.51 (m, 2H), 8.27-8.37 (m, 1H), 8.62-8.74 (m, 1H).

[0349] Example 7

[0350]

[0351] Step 1: Synthesis of compound 7-2

[0352] Compound 7-1 (4 g, 15.62 mmol, 1 eq) was dissolved in tetrahydrofuran (40 mL), 2-dicyclohexylphospho-2-(N,N-dimethylamine)-diphenyl (491.90 mg, 1.25 mmol, 0.08 eq), tris(dibenzylideneacetone)dipalladium (1.14 g, 1.25 mmol, 0.08 eq) were added, and the resulting reaction solution was stirred at 80 °C under nitrogen protection for 3 hours. Water (60 mL) was added to quench the reaction, and dichloromethane (50 mL*3) was added to extract the product. The organic phase was combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (gradient elution: dichloromethane:methanol = 100:0-98:2) to obtain compound 7-2.

[0353] Compound 7-2 was characterized as follows:

[0354] LCMS: m / z (ESI) = 362.10 [M+H] + .

[0355] 1 1H NMR (400 MHz, CDCl3) δ: 7.00-7.06 (m, 1H), 6.26-6.35 (m, 2H), 3.78-3.86 (m, 2H), 3.53-3.58 (m, 4H), 3.02-3.14 (m, 4H), 1.49 (s, 9H).

[0356] Step 2: Synthesis of compound 7-3

[0357] Compound 7-2 (2 g, 5.53 mmol, 1 eq) was dissolved in dimethyl sulfoxide (60 mL), and sodium nitrite (1.53 g, 22.14 mmol, 4 eq) was added. 45% aqueous hydroiodic acid (3.78 g, 13.28 mmol, 2.22 mL, 2.4 eq) was then added dropwise at 20°C. The reaction temperature was then raised to 35°C and stirred for 16 hours. Water (60 mL) was added to the reaction system to dilute the reaction, followed by extraction with ethyl acetate (50 mL x 3). The organic phases were separated, combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0 to 80:20) to obtain compound 7-3.

[0358] Characterization of compound 7-3:

[0359] LCMS: m / z (ESI) = 473.00 [M+H] + .

[0360] 1 H NMR (400MHz, CDCl3) δ: 7.32-7.34 (m, 1H), 7.11-7.16 (m, 1H), 6.85-6.91 (m, 1H), 3.55-3.61 (m, 4H), 3.09-3.16 (m, 4H), 1.49 (s, 9H).

[0361] Step 3: Synthesis of compound 7-4

[0362] Compound 5-4 (180.36 mg, 561.16 μmol, 1 eq) was dissolved in 1,4-dioxane (8 mL). Tris(dibenzylideneacetone)dipalladium (51.39 mg, 56.12 μmol, 0.1 eq), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (32.47 mg, 56.12 μmol, 0.1 eq), and cesium carbonate (365.67 mg, 1.12 mmol, 2 eq) were added under nitrogen. The atmosphere was purged with nitrogen three times, and compound 7-3 (265 mg, 561.16 μmol, 1 eq) was added. The resulting reaction solution was stirred at 100°C for 5 hours. Water (20 mL) was added to the reaction system to quench the reaction, followed by extraction with ethyl acetate (20 mL*3). The organic phases were separated, combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0-80:20) to obtain compound 7-4.

[0363] Characterization of compound 7-4:

[0364] LCMS: m / z (ESI) = 666.20 [M+H]+ .

[0365] 1 H NMR (400MHz, CDCl3) δ: 8.31 (s, 1H), 8.27-8.30 (m, 1H), 7.09-7.19 (m, 1H), 6.48-6.56 (m, 1H), 5.28-5.35 (m, 1H), 4.32-4.42 (m, 2 H), 3.53-3.63 (m, 4H), 3.28-3.37 (m, 2H), 3.12-3.24 (m, 4H), 2.83 (t, J=7.2Hz, 2H), 2.66 (s, 3H), 1.49 (s, 9H), 1.38-1.43 (m, 3H).

[0366] Step 4: Synthesis of compound 7-5

[0367] Compound 7-4 (300 mg, 450.62 μmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (10 mL), and ammonium chloride (144.63 mg, 2.70 mmol, 6 eq) was added. Under nitrogen protection, the reaction temperature was lowered to 0°C, and a 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (9.01 mL, 20 eq) was added. The resulting reaction solution was stirred at 20°C for 3 hours. Water (15 mL) was added to the reaction system to quench the mixture, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phases were separated and combined, and the organic phases were concentrated to dryness under reduced pressure. The crude product was separated by thin-layer chromatography (developing solvent: dichloromethane / methanol = 10:1) to obtain compound 7-5.

[0368] Characterization of compound 7-5:

[0369] LCMS: m / z (ESI) = 637.20 [M+H] + .

[0370] 1 H NMR (400MHz, CDCl3) δ: 8.25-8.31 (m, 1H), 8.14-8.24 (m, 1H), 7.13-7.21 (m, 1H), 6.52-6.63 (m, 1H), 5.50-5.59 (m, 2H), 3.54-3.65 (m, 4H), 3.25-3.33 (m, 2H), 3.13-3.25 (m, 4H), 2.81-2.90 (m, 2H), 2.64 (s, 3H), 1.49 (s, 9H).

[0371] Step 5: Synthesis of compound 7

[0372] Compound 7-5 (100 mg, 157.06 μmol, 1 eq) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (3.85 g, 33.77 mmol, 2.50 mL, 214.99 eq) was added, and stirred at 20°C for 2 hours. The reaction system was directly concentrated to dryness under reduced pressure, and the crude product was separated and purified by preparative HPLC (HPLC preparative method: Waters Xbridge Prep OBD preparative chromatograph; chromatographic column: C18 150*40 mm*10 μm; mobile phase A: 10 mM aqueous ammonium bicarbonate solution (0.05% ammonia water), mobile phase B: acetonitrile; running gradient: B%: 20%-50%, running time 8 min.) to obtain compound 7.

[0373] Characterization of compound 7:

[0374] LCMS: m / z (ESI) = 537.10 [M+H] + .

[0375] 1 H NMR (400MHz, DMSO-d6) δ: 8.46 (s, 1H), 8.32 (s, 1H), 7.47-7.51 (m, 1H), 7.41-7.46 (m, 2H), 7.13-7.20 (m, 1H), 6.66-6.71 (m, 1H), 3.08-3.15 (m, 2H), 2.95-3.05 (m, 4H), 2.79-2.84 (m, 4H), 2.71-2.76 (m, 2H), 2.54 (s, 3H).

[0376] Example 8

[0377]

[0378] Step 1: Synthesis of compound 8-1

[0379] Compound 7 (80 mg, 149.09 μmol, 1 eq) was dissolved in a mixed solution of anhydrous tetrahydrofuran (5 mL) and dimethyl sulfoxide (2.5 mL). The pH was adjusted to 7-8 with triethylamine (15.09 mg, 149.09 μmol, 20.75 μL, 1 eq), and then adjusted to 5-6 with acetic acid (35.81 mg, 596.36 μmol, 34.11 μL, 4 eq). (tert-Butyldimethylsilyloxy)acetaldehyde (64.97 mg, 372.72 μmol, 71.01 μL, 2.5 eq) was added at 0°C and stirred for 0.5 hour. Sodium triacetoxyborohydride (69.52 mg, 328.00 μmol, 2.2 eq) was added at 0°C, and the resulting reaction solution was stirred at 20°C for 2 hours. Water (3 mL) was added to the reaction system, followed by extraction with ethyl acetate (5 mL*3). The organic phases were separated, combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin-layer chromatography (developing solvent: dichloromethane / methanol = 10:1) to obtain compound 8-1.

[0380] The characterization of compound 8-1 is as follows:

[0381] LCMS: m / z (ESI) = 695.20 [M+H] + .

[0382] 1 H NMR (400MHz, CDCl3) δ: 8.31 (s, 1H), 8.20-8.27 (m, 1H), 7.32-7.38 (m, 1H), 7.12-7.20 (m, 1H), 6.47-6.56 (m, 1H), 5.65-5.75 (m, 2H), 3 .86-4.01 (m, 2H), 3.37-3.44 (m, 2H), 3.21-3.35 (m, 4H), 2.81-2.99 (m, 6H), 2.66 (s, 3H), 1.24-1.29 (m, 2H), 0.90 (s, 9H), 0.09 (s, 6H).

[0383] Step 2: Synthesis of compound 8

[0384] Compound 8-1 (100 mg, 143.90 μmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (0.5 mL), and a 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (287.81 μL, 2 eq) was added. The mixture was stirred at 20°C for 16 hours. Water (20 mL) was added to the reaction mixture for washing, followed by extraction with ethyl acetate (25 mL x 3). The organic phases were separated and combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product, which was then separated and purified by preparative HPLC (HPLC preparative method: Waters XbridgePrep OBD preparative chromatograph; column: C18 150 x 40 mm x 10 μm; mobile phase A: 10 mM aqueous ammonium bicarbonate (containing 0.05% ammonia), mobile phase B: acetonitrile; gradient: B%: 20%-50%, 8 min) to afford compound 8.

[0385] Characterization of compound 8:

[0386] LCMS: m / z (ESI) = 581.20 [M+H] + .

[0387] 1 H NMR (400MHz, DMSO-d6) δ: 8.44-8.48 (m, 1H), 8.31 (s, 1H), 7.49-7.52 (m, 1H), 7.40-7.46 (m, 2H), 7.13-7.19 (m, 1H), 6.68-6.72 (m, 1 H), 4.39-4.45 (m, 1H), 3.49-3.56 (m, 2H), 3.29 (s, 3H), 3.09-3.17 (m, 6H), 2.71-2.77 (m, 2H), 2.52-2.60 (m, 4H), 2.40-2.46 (m, 2H).

[0388] Example 9

[0389]

[0390] Step 1: Synthesis of compound 9-2

[0391] To a reaction flask, compound 9-1 (2.4 g, 11.06 mmol, 1 eq), dichlorobis(triphenylphosphine)palladium(II) (194.06 mg, 276.47 μmol, 0.025 eq), and cuprous iodide (105.31 mg, 552.94 μmol, 0.05 eq) were added. Diethylamine (25 mL) and 1-dimethylamino-2-propyne (1.15 g, 13.82 mmol, 1.47 mL, 1.25 eq) were then added. The mixture was stirred at 60°C under nitrogen for 3 hours. After the reaction, the temperature was lowered to 20°C, and the reaction mixture was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether:ethyl acetate = 100:0 to 0:100) to obtain compound 9-2.

[0392] The characterization of compound 9-2 is as follows:

[0393] LCMS: m / z (ESI) = 220.0 [M+H] + .

[0394] 1 H NMR (400MHz, CDCl3) δ: 2.38 (s, 6H), 2.84 (s, 3H), 3.51 (s, 2H), 8.24-8.26 (m, 1H), 8.69-8.75 (m, 1H).

[0395] Step 2: Synthesis of compound 9-3

[0396] Under a gentle argon stream, Raney nickel (1.4 g, 16.34 mmol, 2.56 eq), ethanol (50 mL), and compound 9-2 (1.4 g, 6.39 mmol, 1 eq) were added. The reaction mixture was stirred at 25°C under hydrogen (15 psi) for 4 hours. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-95:5) to afford compound 9-3.

[0397] The characterization of compound 9-3 is as follows:

[0398] LCMS: m / z (ESI) = 194.1 [M+H] + .

[0399] Step 3: Synthesis of compound 9-4

[0400] Compound 9-3 was dissolved in 6M aqueous hydrochloric acid solution (517.36 μL, 6 eq), and then amino cyanide (174.00 mg, 4.14 mmol, 174.00 μL, 8 eq) was added, and stirred at 60°C for 1 hour. Water (5 mL) and dichloromethane (5 mL) were added to the reaction solution, and the aqueous phase was adjusted to a pH greater than 12 by adding sodium hydroxide solid, and then the solvent was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was separated and purified by high performance liquid preparative chromatography (high performance liquid preparative method: Waters Xbridge Prep OBD preparative chromatograph; column: C18 150*40mm*10μm; mobile phase A: 10 mM ammonium bicarbonate aqueous solution (containing 0.05% ammonia water), mobile phase B: acetonitrile; running gradient: B%: 1%-15%, running for 8 min.), to obtain compound 9-4.

[0401] Compound 9-4 was characterized as follows:

[0402] LCMS: m / z (ESI) = 236.3 [M+H] + .

[0403] 1 H NMR (400 MHz, DMSO-d6) d: 1.56-1.63 (m, 2H), 2.08 (s, 6H), 2.10-2.18 (m, 5H), 2.40-2.47 (m, 2H), 5.08 (s, 4H), 6.77 (s, 1H), 7.82 (s, 1H).

[0404] Step 4: Synthesis of compound 9-5

[0405] Compound 9-4 (40 mg, 169.98 μmol, 1 eq) was dissolved in N,N dimethylformamide (1 mL), and then compound 1-2 (76.09 mg, 169.98 μmol, 1 eq) was added, and stirred at 110°C for 12 hours. Ethyl acetate (10 mL), saturated brine (5 mL), and water (5 mL) were added to the reaction solution, and the organic phase was separated, combined, and dried with anhydrous sodium sulfate, and then the solvent was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was separated and purified by high performance liquid preparative chromatography (high performance liquid preparative method: Waters Xbridge BEH preparative chromatograph; column: C18 100*30mm*10μm; mobile phase A: 0.04% hydrochloric acid aqueous solution, mobile phase B: acetonitrile; running gradient: B%: 30%-50%, running for 8 min.), to obtain compound 9-5.

[0406] Compound 9-5 was characterized as follows:

[0407] LCMS: m / z (ESI) = 498.2 [M+H] +.

[0408] 1 H NMR (400MHz, DMSO-d6) δ: 1.09-1.23(m, 3H), 1.92-2.07(m, 2H), 2.33-2.36(m, 3H), 2.54-2.57(m, 3H), 2.59-2.67(m, 2H), 2.68-2.72(m, 6 H), 2.73-2.81(m, 2H), 2.95-3.02(m, 2H), 3.04-3.13(m, 2H), 4.02-4.17(m, 2H), 8.01-8.14(m, 1H), 8.24-8.36(m, 1H), 8.43-8.55(m, 1H).

[0409] Step 5: Synthesis of compound 9

[0410] Compound 9-5 (24 mg, 48.22 μmol, 1 eq) was dissolved in a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (964.49 μL, 20 eq). Ammonium chloride (25.80 mg, 482.24 μmol, 10 eq) was then added. Under nitrogen, the mixture was stirred at 20°C for 16 hours. Methanol (5 mL) was added to quench the mixture, and the solvent was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative HPLC (HPLC preparative method: Waters Xbridge BEH preparative chromatograph; column: C18 100*30 mm*10 μm; mobile phase A: 0.1% aqueous ammonium bicarbonate solution, mobile phase B: acetonitrile; gradient: B%: 15%-45% over 8 min) to obtain compound 9.

[0411] The characterization of compound 9 is as follows:

[0412] LCMS: m / z (ESI) = 469.1 [M+H] + .

[0413] 1 H NMR (400MHz, CDCl3) δ: 1.76-1.84 (m, 2H), 2.24 (s, 6H), 2.33-2.37 (m, 2H), 2.49 (s, 3H), 2.55 (s, 3H), 2.58-2.63 (m, 2H), 2.70-2.80 (m, 2H), 3.15-3.23 (m, 2H), 5.49 (s, 2H), 6.72 (s, 1H), 8.00 (s, 1H), 8.20 (s, 1H), 8.29 (s, 1H).

[0414] Example 10

[0415]

[0416] Step 1: Synthesis of compound 10

[0417] Compound 7 (10 mg, 18.64 μmol, 1 eq) was dissolved in dichloroethane (0.5 mL), and 3-oxetanone (1.48 mg, 20.50 μmol, 1.1 eq) was added, followed by tetraethoxytitanium (4.25 mg, 18.64 μmol, 3.86 μL, 1 eq). The resulting reaction solution was stirred at 20°C for 1 hour, followed by the addition of sodium triacetoxyborohydride (4.34 mg, 20.50 μmol, 1.1 eq) and stirring at 20°C for 12 hours. Water (5 mL) was added to the reaction system, and a large amount of white flocculent material precipitated. Ethyl acetate (5 mL*5) was then added for extraction. The organic phases were separated, combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative HPLC (HPLC preparation method: Waters Xbridge BEH preparative chromatograph; chromatographic column: Prep sunfire C18 100*30mm*10μm; mobile phase A: 0.1% ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; running gradient: B%: 35%-50%, running time 8min) to obtain compound 10.

[0418] Characterization of compound 10:

[0419] LCMS: m / z (ESI) = 593.20 [M+H] + .

[0420] 1 H NMR (400MHz, CD3OD) δ: 8.29 (s, 1H), 7.95-7.99 (m, 1H), 7.16-7.21 (m, 1H), 6.66-6.72 (m, 1H), 4.70-4.75 (m, 2H), 4.62-4.66 (m , 2H), 3.53-3.59(m, 1H), 3.27-3.30(m, 4H), 3.21(t, J=7.20Hz, 2H), 2.80-2.85(m, 2H), 2.60-2.65(m, 3H), 2.49-2.55(m, 4H).

[0421] Example 11

[0422]

[0423] Step 1: Synthesis of compound 11-2

[0424] Compound 11-1 (2 g, 10.30 mmol, 1 eq) and potassium carbonate (2.85 g, 20.60 mmol, 2 eq) were dissolved in tetrahydrofuran (20 mL). The reaction mixture was cooled to 0°C under nitrogen, and then bromoacetyl bromide (3.12 g, 15.45 mmol, 1.34 mL, 1.5 eq) was added and stirred at 0°C for 10 minutes. Then, a 40% aqueous solution of dimethylamine (3.48 g, 30.90 mmol, 3.91 mL, 3 eq) was added at 0°C and stirred at 0°C for 10 minutes. The reaction solution was slowly poured into ice water (200 mL) for quenching and extracted with ethyl acetate (100 mL*3). The organic phases were separated and combined, washed with saturated brine (100 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-95:5) to obtain compound 11-2.

[0425] The characterization of compound 11-2 is as follows:

[0426] 1 H NMR (400MHz, CDCl3) δ: 8.67 (s, 1H), 6.92 (s, 1H), 4.26 (t, J=8.60Hz, 2H), 3.92 (s, 3H), 3.16-3.32 (m, 4H), 2.41 (s, 6H).

[0427] Step 2: Synthesis of compound 11-3

[0428] Under a gentle argon stream, 10% wet palladium on carbon (1 g) was added, followed by anhydrous methanol (2 mL) and compound 11-2 (1 g, 3.58 mmol, 1 eq). The reaction mixture was stirred at 40°C under hydrogen (15 psi) for 12 hours. The reaction mixture was passed through a celite-lined funnel, and the filter cake was rinsed with methanol (50 mL x 2). The filtrate was collected and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate + 0.5% ammonia water = 100:0 to 0:100) to obtain compound 11-3.

[0429] Characterization of compound 11-3:

[0430] 1 H NMR (400MHz, DMSO-d6) δ: 7.55 (s, 1H), 6.70 (s, 1H), 4.63 (s, 2H), 3.95-4.1 9(m, 2H), 3.65-3.71(m, 3H), 3.13(s, 2H), 2.87-3.04(m, 2H), 2.25(s, 6H).

[0431] Step 3: Synthesis of compound 11-4

[0432] Compound 11-3 (200 mg, 802.22 μmol, 1 eq) was dissolved in 6 M aqueous hydrochloric acid solution (802.22 μL, 6 eq), and then aminonitrile (269.80 mg, 6.42 mmol, 269.80 μL, 8 eq) was added. The temperature was raised to 100°C and stirred for 2 hours. Then, aminonitrile (134.90 mg, 3.21 mmol, 134.90 μL, 4 eq) was added, and the reaction solution was stirred at 100°C for 12 hours. Water (10 mL) and dichloromethane (10 mL) were added to the reaction solution, extracted, and the aqueous phase was collected and separated. The aqueous phase was adjusted to pH 11 with saturated aqueous sodium hydroxide solution and then concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative HPLC chromatography (preparative HPLC method: Waters 2767 / QDa preparative chromatograph; chromatographic column: Waters Xbridge BEH C18 100*25mm*5μm; mobile phase A: 0.1% ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; running gradient: B%: 1%-25%, running time 10min) to obtain compound 11-4.

[0433] Characterization of compound 11-4:

[0434] 1 H NMR (400MHz, DMSO-d6) δ: 7.61 (s, 1H), 6.84 (s, 1H), 5.50 (s, 3H), 4.12 (t, J= 8.40Hz, 2H), 3.67 (s, 3H), 3.14 (s, 2H), 3.05 (t, J=8.40Hz, 2H), 2.25 (s, 6H).

[0435] Step 4: Synthesis of compound 11-5

[0436] Compound 1-2 (67.02 mg, 205.94 μmol, 1 eq) was dissolved in N,N-dimethylformamide (2 mL), and compound 11-4 (60 mg, 205.94 μmol, 1 eq) was added. The mixture was stirred at 110°C for 16 hours. The reaction solution was poured into water (30 mL) to quench the mixture, and then extracted with ethyl acetate (15 mL*3). The organic phases were separated and combined, washed with saturated brine (15 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography (developing solvent: dichloromethane / methanol = 10:1) to obtain compound 11-5.

[0437] Characterization of compound 11-5:

[0438] 1H NMR (400MHz, CDCl3) δ: 9.25 (s, 1H), 8.32 (s, 1H), 6.76 (s, 1H), 4.35 (q, J=7.20Hz, 2H), 4.18 (t, J=8.20Hz, 2H), 3.82-3.95 (m, 3H), 3.60 (s, 1H), 3 .25-3.36(m, 2H), 3.16-3.25(m, 2H), 3.09-3.16(m, 1H), 2.98-3.09(m, 1 H), 2.73-2.89 (m, 2H), 2.65 (s, 3H), 2.39 (s, 6H), 1.40 (t, J=7.20Hz, 3H).

[0439] Step 5: Synthesis of compound 11-6

[0440] Compound 11-5 (50 mg, 90.30 μmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (4 mL) and anhydrous ethanol (1 mL). Lithium hydroxide monohydrate (18.95 mg, 451.51 μmol, 5 eq) was dissolved in water (1 mL) and added to the reaction mixture. The mixture was stirred at 40°C for 5 hours. The reaction mixture was adjusted to pH 7 with 1 M dilute hydrochloric acid and freeze-dried to obtain compound 11-6.

[0441] Characterization of compound 11-6:

[0442] 1 H NMR (400MHz, DMSO-d6) δ: 10.35 (s, 1H), 8.82 (s, 1H), 8.54 (s, 1H), 8.34 (s, 1H), 7.07 (s, 1H), 4.45 (d, J=4.40Hz, 2H), 4.10 (t, J=8.20Hz, 2H), 3.80 (s, 3H), 3.17-3.24 (m, 4H), 2.88 (d, J=4.40Hz, 6H), 2.79 (t, J=7.00Hz, 2H), 2.56 (s, 3H).

[0443] Step 6: Synthesis of compound 11

[0444] Compound 11-6 (110 mg, 209.27 umol, 1 eq) was dissolved in N,N- dimethylformamide (2 mL), then N,N-diisopropyl ethylamine (81.14 mg, 627.80 umol, 109.35 uL, 3 eq), 2-(7-azobenzo triazole)-N,N,N,N-tetramethyl urea hexafluorophosphate (103.44 mg, 272.05 umol, 1.3 eq), ammonium bicarbonate (49.63 mg, 627.80 umol, 51.70 uL, 3 eq) were added successively, and stirred at 20 °C for 2 hours under nitrogen protection. The reaction solution was directly filtered, the filtrate was collected, and the filtrate was separated and purified by high performance liquid preparative chromatography (high performance liquid preparative method: Waters 2767 / QDa preparative chromatograph; column: Phenomenex C18 80*40mm*3um; mobile phase A: 0.1% ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; running gradient: B%: 30%-60%, running 8 min.). Compound 11 was obtained.

[0445] Characterization of compound 11:

[0446] LCMS: m / z (ESI) = 525.30 [M+H] + .

[0447] 1 H NMR (400 MHz, DMSO-d6) d: 8.67 (s, 1H), 8.29 (s, 1H), 7.84 (s, 1H), 7.42 (s, 2H), 6.96 (s, 1H), 4.16 (t, J = 8.20 Hz, 2H), 3.79 (s, 3H), 3.17 (s, 2H), 3.11 (t, J = 7.20 Hz, 4H), 2.70-2.77 (m, 2H), 2.53 (s, 3H), 2.26 (s, 6H).

[0448] Example 12

[0449]

[0450] Step 1: synthesis of compound 12-1

[0451] Compound 6-3 (200 mg, 891.76 umol, 1 eq) was dissolved in anhydrous tetrahydrofuran (4 mL), then tert-butoxy bis(dimethylamino)methane (466.25 mg, 2.68 mmol, 552.43 uL, 3 eq) was added, and stirred at 80 °C for 2 hours under nitrogen protection. The solvent was concentrated to dryness under reduced pressure to obtain compound 12-1.

[0452] Compound 12-1 was characterized as follows:

[0453] LCMS: m / z (ESI) = 253.2 [M-26] + .

[0454] Step 2: Synthesis of compound 12-2

[0455] Compound 12-1 (100 mg, 357.97 μmol, 1 eq) was dissolved in N,N-dimethylformamide (2 mL), followed by the addition of compound 1-3 (113.59 mg, 357.97 μmol, 1 eq), and the mixture was stirred at 110°C for 16 hours. Ethyl acetate (20 mL), water (10 mL), and saturated brine (10 mL) were added to the reaction mixture. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was concentrated under reduced pressure to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-98:2) to obtain compound 12-2.

[0456] The characterization of compound 12-2 is as follows:

[0457] LCMS: m / z (ESI) = 534.3 [M+H] + .

[0458] 1 H NMR (400MHz, CDCl3) δ: 1.42 (t, J=7.2Hz, 3H), 2.39 (s, 3H), 2.62 (s, 4H), 2.89 (t, J=7.2Hz, 2H), 3.26-3.43 (m, 6H), 4. 39(q, J=7.2Hz, 2H), 6.50-6.55(m, 1H), 7.15-7.20(m, 1H), 7.35(s, 1H), 8.25(s, 1H), 8.37(s, 1H), 8.40-8.46(m, 1H).

[0459] Step 3: Synthesis of compound 12

[0460] Compound 12-2 (135 mg, 253.02 μmol, 1 eq) was dissolved in a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (2 mL, 7.90 eq). Ammonium chloride (54.14 mg, 1.01 mmol, 4 eq) was then added and stirred at 20°C for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure, followed by methanol (2 mL) and continued concentration to dryness to afford the crude product. The crude product was separated and purified by preparative HPLC (HPLC preparative method: Waters 2767 / QDa preparative chromatograph; column: Phenomenex C18 80*40 mm*3 μm; mobile phase A: 0.1% aqueous ammonium bicarbonate solution, mobile phase B: acetonitrile; gradient: B%: 25%-55% over 8 min) to afford compound 12.

[0461] The characterization of compound 12 is as follows:

[0462] LCMS: m / z (ESI) = 505.1 [M+H] + .

[0463] 1 H NMR (400MHz, CDCl3) δ: 2.39 (s, 3H), 2.57-2.69 (m, 4H), 2.90 (t, J=7.15Hz, 2H), 3.26-3.38 (m, 6H), 5.65 (d, J=5.77Hz, 2H), 6 .55 (dd, J=9.03, 3.01Hz, 1H), 7.16 (dd, J=8.91, 1.51Hz, 1H), 7.36 (s, 1H), 8.18 (s, 1H), 8.37 (s, 1H), 8.41 (d, J=2.89Hz, 1H).

[0464] Example 13

[0465]

[0466] Step 1: Synthesis of compound 13-1

[0467] Compound 6-8 (300 mg, 989.54 μmol, 1 eq) was dissolved in N,N-dimethylformamide (4.5 mL), followed by the addition of cuprous cyanide (265.88 mg, 2.97 mmol, 648.49 μL, 3 eq) and potassium iodide (32.85 mg, 197.91 μmol, 0.2 eq). The mixture was stirred at 140°C under nitrogen for 0.5 h. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction solution, which was then filtered. The filtrate was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0 to 90:10) to obtain compound 13-1.

[0468] The characterization of compound 13-1 is as follows:

[0469] LCMS: m / z (ESI) = 250.2 [M+1] + .

[0470] 1 H NMR (400MHz, CDCl3) δ: 1.41 (t, J=7.2Hz, 3H), 2.15 (t, J=6.8Hz, 2H), 2.59-2.77 (m, 2H), 3.27 (t, J=6.8Hz, 2H), 4.41 (q, J=7.2Hz, 2H).

[0471] Step 2: Synthesis of compound 13-2

[0472] Compound 13-1 (145 mg, 581.66 μmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (6 mL), and tert-butoxybis(dimethylamino)methane (304.12 mg, 1.74 mmol, 360.33 μL, 3 eq) was added. The mixture was stirred at 80°C for 3 hours. The reaction mixture was directly concentrated to dryness under reduced pressure to obtain compound 13-2.

[0473] The characterization of compound 13-2 is as follows:

[0474] LCMS: m / z (ESI) = 305.2 [M+H] + .

[0475] Step 3: Synthesis of compound 13-3

[0476] Compound 13-2 (177 mg, 581.54 μmol, 1 eq) was dissolved in DMF (4.5 mL), followed by the addition of compound 1-3 (184.53 mg, 581.54 μmol, 1 eq), and the mixture was stirred at 110°C for 16 hours. Ethyl acetate (20 mL), water (10 mL), and saturated brine (10 mL) were added to the reaction solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was concentrated under reduced pressure to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-90:10) to obtain compound 13-3.

[0477] The characterization of compound 13-3 is as follows:

[0478] LCMS: m / z (ESI) = 559.3 [M+H] + .

[0479] 1 H NMR (400MHz, CDCl3) δ: 1.43 (t, J=7.2Hz, 3H), 2.38 (s, 3H), 2.62 (s, 4H), 2.89 (t, J=7.2Hz, 2H), 3.17-3.44 (m, 6H ), 4.42 (q, J=6.8Hz, 2H), 6.51-6.62 (m, 1H), 7.10-7.19 (m, 1H), 7.39 (s, 1H), 8.15 (d, J=2.8Hz, 1H), 8.46 (s, 1H).

[0480] Step 4: Synthesis of compound 13-4

[0481] Compound 13-3 (200 mg, 358.05 μmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (5 mL), and then lithium hydroxide monohydrate (45.07 mg, 1.07 mmol, 3 eq) and water (1 mL) were added. The mixture was stirred at 40° C. for 1 hour. The reaction solution was directly concentrated to dryness to obtain compound 13-4.

[0482] The characterization of compound 13-4 is as follows:

[0483] LCMS: m / z (ESI) = 531.1 [M+1] + .

[0484] Step 5: Synthesis of compound 13

[0485] Compound 13-4 (200 mg, 376.99 μmol, 1 eq) was dissolved in N,N-dimethylformamide (2 mL), followed by the addition of N,N-diisopropylethylamine (146.17 mg, 1.13 mmol, 196.99 μL, 3 eq), 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (215.01 mg, 565.48 μmol, 1.5 eq), and ammonium bicarbonate (89.41 mg, 1.13 mmol, 93.13 μL, 3 eq). The mixture was stirred at 20°C for 5 hours. Ethyl acetate (10 mL), water (5 mL), and saturated brine (5 mL) were added to the reaction solution, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate and filtered, and the solvent was concentrated under reduced pressure to dryness to obtain a crude product. The crude product was separated and purified by preparative HPLC (HPLC preparative method: Waters 2767 / QDa preparative chromatograph; chromatographic column: Phenomenex C18 75*30mm*3μm; mobile phase A: 0.1% ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; running gradient: B%: 25%-55%, running time 8 min.) to obtain compound 13.

[0486] The characterization of compound 13 is as follows:

[0487] LCMS: m / z (ESI) = 530.1 [M+1] + .

[0488] 1 H NMR (400MHz, CDCl3) δ: 2.35 (s, 3H), 2.52-2.70 (m, 4H), 2.85-2.92 (m, 2H), 3.12-3.43 (m, 6H), 5 .81(s, 2H), 6.49-6.61(m, 1H), 7.10-7.20(m, 1H), 7.46(s, 1H), 8.05-8.19(m, 1H).8.47(s, 1H).

[0489] Example 14

[0490]

[0491] Step 1: Synthesis of compound 14-2

[0492] Compound 14-1 (2 g, 7.81 mmol, 1.1 eq) was dissolved in 1,4-dioxane (30 mL), followed by the addition of 1-methyl-3-oxopiperazine (810.63 mg, 7.10 mmol, 1 eq). The atmosphere was purged with nitrogen three times, and cesium carbonate (4.63 g, 14.20 mmol, 2 eq) was added. N,N-dimethylethylenediamine (626.02 mg, 7.10 mmol, 775.73 μL, 1 eq) was then added under nitrogen again. Finally, cuprous iodide (676.26 mg, 3.55 mmol, 0.5 eq) was added under nitrogen, and the reaction was stirred at 120°C for 16 hours. Additional 1-methyl-3-oxopiperazine (810.63 mg, 7.10 mmol, 1 eq) and cuprous iodide (676.26 mg, 3.55 mmol, 0.5 eq) were added, and stirring was continued at 120°C for 24 hours. Water (50 mL) was added to the reaction system, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (70 mL x 3). The organic phases were separated, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-90:10) to obtain compound 14-2.

[0493] The characterization of compound 14-2 is as follows:

[0494] LCMS: m / z (ESI) = 290.0 [M+H] + .

[0495] 1 H NMR (400MHz, CDCl3) δ: 2.41 (s, 3H), 2.71-2.85 (m, 2H), 3.23-3.32 (m, 2H), 3.62-3.72 (t, J=5.20Hz, 2H), 3.9 4 (s, 2H), 6.58-6.66 (dd, J=8.8, 2.4Hz, 1H), 6.73-6.80 (d, J=2.4Hz, 1H), 7.10-7.15 (dd, J=8.8, 1.2Hz, 1H).

[0496] Step 2: Synthesis of compound 14-3

[0497] To compound 14-2 (300 mg, 1.04 mmol, 1 eq) was added 6M aqueous hydrochloric acid (1.20 mL, 6.94 eq), then amino cyanide (348.82 mg, 8.30 mmol, 348.82 μL, 8 eq), stirred at 60 °C for 16 hours. To the reaction system was added water (2 mL) to dilute, extracted with ethyl acetate (5 mL*2), and separated. The aqueous phase was adjusted to pH = 13 with 1M aqueous potassium hydroxide solution, then extracted with ethyl acetate (5 mL*3) again, separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 14-3.

[0498] Compound 14-3 was characterized as follows:

[0499] LCMS: m / z (ESI) = 332.0 [M+H] + .

[0500] 1 H NMR (400 MHz, DMSO-d6) δ: 2.26 (s, 3H), 2.65-2.73 (m, 2H), 3.08 (s, 2H), 3.60-3.67 (t, J = 5.20 Hz, 2H), 5.27-5.34 (m, 2H), 5.36-5.45 (m, 2H), 6.81-6.89 (m, 2H), 7.14-7.20 (m, 1H).

[0501] Step 3: Synthesis of compound 14-4

[0502] To compound 14-3 (196.47 mg, 603.70 μmol, 1 eq) in N,N-dimethylformamide (2 mL) was added compound 1-2 (200 mg, 603.70 μmol, 1 eq), stirred at 110 °C for 16 hours. To the reaction system was added water (5 mL) to wash, then extracted with ethyl acetate (5 mL*3), separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was separated by thin layer preparation plate (developing agent: dichloromethane / methanol = 10:1) to give compound 14-4.

[0503] Compound 14-4 was characterized as follows:

[0504] LCMS: m / z (ESI) = 594.1 [M+H] + .

[0505] 1H NMR (400MHz, DMSO-d6) δ: 1.26-1.33 (m, 3H), 2.28 (s, 3H), 2.59 (s, 3H), 2.60 -2.70 (m, 2H), 2.76-2.82 (m, 2H), 3.11 (s, 2H), 3.22 (t, J=7.2Hz, 2H), 3.63-3 .69 (t, J=5.2Hz, 2H), 4.18-4.28 (q, J=7.2Hz, 2H), 7.07-7.14 (d, J=8.4Hz, 1H ), 7.35-7.42 (d, J=8.4Hz, 1H), 8.12-8.20 (m, 1H), 8.39 (s, 1H), 8.82 (s, 1H).

[0506] Step 4: Synthesis of compound 14-5

[0507] Compound 14-4 (80 mg, 134.76 μmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (1.6 mL) solution, and anhydrous ethanol (0.4 mL) and water (0.4 mL) were added, followed by the addition of lithium hydroxide monohydrate (28.28 mg, 673.81 μmol, 5 eq). The mixture was purged with nitrogen three times. After the addition, the temperature was raised to 45 ° C and stirred for 5 hours. The pH of the reaction system was adjusted to 7 with 1M aqueous hydrochloric acid solution, and the organic solvent in the system was dried with a water pump. The remaining aqueous solution was then lyophilized to obtain a crude product. Methanol (5 mL) was added to the crude product, ultrasonicated for five minutes, filtered, and the filter cake was dried with a water pump to obtain compound 14-5.

[0508] The characterization of compound 14-5 is as follows:

[0509] LCMS: m / z (ESI) = 566.0 [M+H] + .

[0510] 1 H NMR (400MHz, DMSO-d6) δ: 2.55 (s, 3H), 2.67 (s, 3H), 2.75-2.80 (m, 4H), 3.14 (s, 2H), 3.20 (t, J=7.2 Hz, 2H), 3.77-3.85 (m, 2H), 7.08-7.15 (m, 1H), 7.40-7.48 (m, 1H), 8.05-8.13 (m, 1H), 8.37 (s, 1H).

[0511] Step 5: Synthesis of compound 14-6

[0512] Compound 14-5 (30 mg, 53.04 μmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (0.5 mL), oxalyl chloride (53.86 mg, 424.34 μmol, 37.14 μL, 8 eq) was added at 0 °C, nitrogen was replaced for three times, then N, N-dimethylformamide (387.71 μg, 5.30 μmol, 4.08e-1 μL, 0.1 eq) was added, and the reaction was stirred at 0 °C for 0.5 h. The reaction was poured into 25% ammonia water (5 mL) at 20 °C and stirred for 0.5 h. Ethyl acetate (15 mL*4) was added to the reaction system, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product crude. The crude product was separated and purified by high performance liquid preparative chromatography (high performance liquid preparative method: Waters Xbridge BEH preparative chromatograph; column: Phenomenex C18 100*30mm*10 μm; mobile phase A: 10 mM ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; running gradient B%: 20%-55%, 10 min) to obtain compound 14.

[0513] Compound 14 was characterized as follows:

[0514] LCMS: m / z (ESI) = 565.1 [M+H] + .

[0515] 1 H NMR (400 MHz, DMSO-d6) δ: 2.29 (s, 3H), 2.56 (s, 3H), 2.69-2.79 (m, 4H), 3.07-3.16 (m, 4H), 3.63-3.70 (t, J = 5.2 Hz, 2H), 7.06-7.12 (m, 1H), 7.36-7.42 (m, 1H), 7.42-7.49 (m, 2H), 8.19-8.24 (d, J = 2.4 Hz, 1H), 8.38 (s, 1H), 8.75 (s, 1H).

[0516] Example 15

[0517]

[0518] Step 1: Synthesis of compound 15-3

[0519] Compound 15-1 (1 g, 2.73 mmol, 1 eq), compound 15-2 (540.37 mg, 2.73 mmol, 1 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (157.70 mg, 272.55 μmol, 0.1 eq), tris(dibenzylideneacetone)dipalladium (249.58 mg, 272.55 μmol, 0.1 eq), and sodium tert-butoxide (785.80 mg, 8.18 mmol, 3 eq) were dissolved in anhydrous toluene (20 mL). The reaction mixture was stirred at 60°C under nitrogen for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0 to 90:10) to obtain compound 15-3.

[0520] The characterization of compound 15-3 is as follows:

[0521] LCMS: m / z(ESI)=381.0, 383.0[M-55] + .

[0522] 1 H NMR (400MHz, CDCl3) δ: 7.18-7.22 (m, 1H), 6.92 (d, J = 3.0Hz, 1H), 6.62-6.66 (m, 1H), 4.31 (d, J = 5.0Hz, 2H), 3.67-4.04 (m, 2H), 3.27 (d, J=10.4Hz, 2H), 2.68-2.72 (m, 1H), 1.48 (d, J=8.7Hz, 1H), 1.39 (s, 9H).

[0523] Step 2: Synthesis of compound 15-4

[0524] Compound 5-4 (240 mg, 746.69 μmol, 1 eq), compound 15-3 (391.79 mg, 896.03 μmol, 1.2 eq), palladium acetate (8.38 mg, 37.33 μmol, 0.05 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (21.60 mg, 37.33 μmol, 0.05 eq), and cesium carbonate (729.86 mg, 2.24 mmol, 3 eq) were dissolved in 1,4-dioxane (12 mL) and stirred at 110°C under a nitrogen atmosphere for 40 hours. Ethyl acetate (10 mL), water (5 mL), and saturated brine (5 mL) were added to the reaction solution, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, compound 15-4.

[0525] Characterization of compound 15-4:

[0526] LCMS: m / z (ESI) = 678.2 [M+H] + .

[0527] 1 H NMR (400MHz, CDCl3) δ: 8.30 (s, 1H), 7.92 (s, 1H), 7.30-7.41 (m, 1H), 7.15-7.19 (m, 1H), 6.32-6.44 (m, 1H), 4.19-4.46 (m, 4H), 3.71-4.14 (m, 2H), 3.21-3.47 (m, 4H), 2.83 (t, J=7.2Hz, 2H), 2.65 (s, 4H), 1.49 (d, J=8.4Hz, 1H), 1.36-1.43 (m, 12H).

[0528] Step 3: Synthesis of compound 15-5

[0529] Compound 15-4 (150 mg, 221.32 μmol, 1 eq) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (770.00 mg, 6.75 mmol, 0.5 mL, 30.51 eq) was added. The mixture was stirred at 20°C for 16 hours. The solvent was concentrated under reduced pressure to dryness. Water (10 mL) and ethyl acetate (10 mL) were added to the crude product, and the pH was adjusted to greater than 8 with saturated sodium bicarbonate aqueous solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was then concentrated under reduced pressure to dryness to obtain compound 15-5.

[0530] Characterization of compound 15-5:

[0531] LCMS: m / z (ESI) = 578.2 [M+H] + .

[0532] 1 H NMR (400MHz, CDCl3) δ: 8.31 (s, 1H), 7.93 (d, J=3.0Hz, 1H), 7.26 (s, 1H), 7.18-7.22 (m, 1H), 6.33-6.35 (m, 1H), 5.31 (s, 1H), 4.36-4.40 (m, 2H), 3.92 (d, J=5.8Hz, 2H), 3.51-3.73 (m, 4H), 3.33 (t, J=7.2Hz, 2H), 2.83 (t, J=7.2Hz, 3H), 2.64 (s, 3H), 1.60-1.65 (m, 1H), 1.40 (t, J=7.2Hz, 3H).

[0533] Step 4: Synthesis of compound 15-6

[0534] Compound 15-5 (120 mg, 207.74 μmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (6.5 mL), and 37% pure formaldehyde solution (238.46 mg, 2.94 mmol, 218.77 μL, 14.14 eq) was added, followed by acetic acid (229.45 mg, 830.97 μmol, 218.52 μL, 4 eq). The mixture was stirred at 25°C for 15 minutes, and then sodium acetate borohydride (176.12 mg, 830.97 μmol, 4 eq) was added. The mixture was stirred at 25°C under nitrogen for 45 minutes. Ethyl acetate (10 mL), water (5 mL), and saturated sodium bicarbonate aqueous solution (5 mL) were added to the reaction solution, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate and filtered to obtain a crude product. The crude product was purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-90:10) to give compound 15-6.

[0535] Characterization of compound 15-6:

[0536] LCMS: m / z (ESI) = 592.2 [M+H] + .

[0537] 1 H NMR (400MHz, CDCl3) δ: 8.32 (s, 1H), 8.03 (d, J=2.9Hz, 1H), 7.30 (s, 1H), 7.20-7.22 (m, 1H), 6.34-6.40 (m, 1H), 4.36-4.40 (m, 2H), 4.04 (d, J=4.1 Hz, 2H), 3.54-3.74 (m, 4H), 3.33 (t, J=7.2Hz, 2H), 2.84 (t, J=7.2Hz, 2H) , 2.64 (s, 3H), 2.34 (s, 3H), 1.76 (d, J = 9.2Hz, 1H), 1.40 (t, J = 7.2Hz, 3H).

[0538] Step 5: Synthesis of compound 15

[0539] Compound 15-6 (90 mg, 152.11 μmol, 1 eq) and ammonium chloride (48.82 mg, 912.68 μmol, 6 eq) were dissolved in a 1 M solution of lithium bis(trimethylsilyl)amide in n-hexane (1.52 mL, 10 eq) and stirred at 20°C for 2 hours under a nitrogen atmosphere. The reaction mixture was quenched by the addition of methanol (3 mL), and the solvent was concentrated to dryness under reduced pressure. The crude product was separated and purified by preparative HPLC (preparative HPLC method: Waters Xbridge BEH preparative chromatograph; column: Phenomenex C18 100*30 mm*10 μm; mobile phase A: 10 mM ammonium bicarbonate in water, mobile phase B: acetonitrile; gradient: acetonitrile %: 15%-85% over 8 min) to obtain compound 15.

[0540] Characterization of compound 15:

[0541] LCMS: m / z (ESI) = 563.2 [M+H] + .

[0542] 1H NMR (400MHz, CD3OD) δ: 8.30 (s, 1H), 7.63 (d, J=2.8Hz, 1H), 7.21 (d, J=9.0Hz, 1H), 6.50-6.55 (m, 1H), 3.60-3.80 (m, 4H), 3.44-3.57 (m, 2H), 3.23 (t, J=7.2Hz, 2H), 2.84 (t, J=7.2Hz, 2H), 2.50-2.72 (m, 4H), 2.19 (s, 3H), 1.70 (d, J=8.4Hz, 1H).

[0543] Example 16

[0544]

[0545] Step 1: Synthesis of compound 16-1

[0546] Compound 6-8 (400 mg, 1.32 mmol, 1 eq), cyclopropylboronic acid (147.33 mg, 1.72 mmol, 1.3 eq), potassium phosphate (1.01 g, 4.75 mmol, 3.6 eq), palladium acetate (29.62 mg, 131.94 μmol, 0.1 eq), and tricyclohexylphosphine (111.00 mg, 395.82 μmol, 128.32 μL, 0.3 eq) were added to a reaction flask. Anhydrous toluene (12 mL) and water (0.6 mL) were then added. After nitrogen evacuation three times, the mixture was stirred at 80°C for 16 hours. After completion of the reaction, the solvent was concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-90:10) to obtain compound 16-1.

[0547] The characterization of compound 16-1 is as follows:

[0548] LCMS: m / z (ESI) = 265.1 [M+H] + .

[0549] 1 H NMR (400MHz, CDCl3) δ: 4.30-4.38 (m, 2H), 3.41 (s, 1H), 3.21 (t, J=6.2Hz, 2H), 2.50-2.65 ( m, 2H), 2.05 (t, J=6.3Hz, 2H), 1.37 (t, J=7.2Hz, 3H), 1.25-1.32 (m, 2H), 0.77-0.91 (m, 2H).

[0550] Step 2: Synthesis of compound 16-2

[0551] Compound 16-1 (225 mg, 851.18 μmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (4.5 mL), followed by the addition of tert-butoxybis(dimethylamino)methane (445.04 mg, 2.55 mmol, 527.30 μL, 3 eq). The mixture was stirred at 80°C for 20 hours. After completion of the reaction, the solvent was concentrated to dryness under reduced pressure to obtain crude compound 16-2, which was used directly in the next step without purification.

[0552] Characterization of compound 16-2:

[0553] LCMS: m / z (ESI) = 293.1 [M-26] + .

[0554] Step 3: Synthesis of compound 16-3

[0555] Compound 16-2 (270 mg, 845.29 μmol, 1 eq) was dissolved in N,N-dimethylformamide (3.5 mL), followed by the addition of compound 1-3 (268.22 mg, 845.29 μmol, 1 eq), and the mixture was stirred at 110°C for 20 hours. After the reaction, ethyl acetate (50 mL) and water (50 mL) were added to the reaction mixture, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate and filtered, and the solvent was concentrated under reduced pressure to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-90:10) to obtain compound 16-3.

[0556] Characterization of compound 16-3:

[0557] LCMS: m / z (ESI) = 574.3 [M+H] + .

[0558] 1 H NMR (400MHz, CDCl3) δ: 8.35 (s, 1H), 8.09 (d, J=2.8Hz, 1H), 7.11-7.16 (m, 2H), 6.52-6.54 (m, 1H), 4.34 (d, J=7.2Hz, 2H), 3.55 (s, 1H) , 3.28-3.30 (m, 6H), 2.79-2.82 (m, 2H), 2.57-2.73 (m, 4H), 2.42 (s, 3H), 1.38 (t, J=7.2Hz, 3H), 1.17-1.25 (m, 2H), 0.82-0.90 (m, 2H).

[0559] Step 4: Synthesis of compound 16

[0560] Compound 16-3 (120 mg, 209.19 μmol, 1 eq) and ammonium chloride (67.14 mg, 1.26 mmol, 6 eq) were dissolved in a 1 M solution of lithium bis(trimethylsilyl)amide in n-hexane (2.09 mL, 10 eq) and stirred at 20°C for 1 hour under nitrogen. After the reaction, methanol (3 mL) was added to quench the reaction mixture, and the solvent was concentrated to dryness under reduced pressure. The crude product was separated and purified by preparative HPLC (HPLC preparative method: Waters Xbridge BEH preparative chromatograph; column: Phenomenex C18 100*30 mm*10 μm; mobile phase A: 10 mM ammonium bicarbonate in water, mobile phase B: acetonitrile; gradient B%: 15%-85% over 8 min) to obtain compound 16.

[0561] Characterization of compound 16:

[0562] LCMS: m / z (ESI) = 545.3 [M+H]+ .

[0563] 1H NMR (400MHz, CD3OD) δ: 8.32 (s, 1H), 7.60 (m, 1H), 7.19-7.23 (m, 1H), 6.76-6.72 (m, 1H), 3.39-3.48 (m, 1H), 3.25 (s, 4H), 3.17 (t, J=6.8Hz, 2H), 2.80 (t, J=6.8Hz, 2H), 2.67 (s, 4H), 2.40 (s, 3H), 1.04-1.10 (m, 2H), 0.75-0.79 (m, 2H).

[0564] Example 17

[0565]

[0566] Step 1: Synthesis of compound 17-2

[0567] Under nitrogen at -75°C, a solution of compound 17-1 (1.25 g, 8.65 mmol, 1 eq) in anhydrous tetrahydrofuran (5 mL) was added to a 0.1 M solution of 2,2,6,6-tetramethylpiperidinium lithium in tetrahydrofuran (172.94 mL, 2 eq). The mixture was stirred for 0.5 hours. Iodine (2.59 g, 10.20 mmol, 2.06 mL, 1.18 eq) was then added at -75°C and stirred for 3 hours. The reaction mixture was washed with saturated aqueous ammonium chloride (150 mL), separated, and extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Compound 17-2 was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0 to 95:5) to obtain compound 17-2.

[0568] The characterization of compound 17-2 is as follows:

[0569] LCMS: m / z (ESI) = 271.0 [M+H] + .

[0570] 1 H NMR (400MHz, DMSO-d6) δ: 4.05 (s, 3H), 8.44 (s, 1H).

[0571] Step 2: Synthesis of compound 17-3

[0572] To a solution of compound 17-2 (600 mg, 2.22 mmol, 1 eq) in dimethyl sulfoxide (12 mL) were added p-methoxybenzylamine (912.99 mg, 6.66 mmol, 861.31 μL, 3 eq) and potassium fluoride (386.66 mg, 6.66 mmol, 155.91 μL, 3 eq), and the mixture was stirred at 120°C for 3 hours. Water (10 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were separated, combined, and concentrated under reduced pressure. Purification by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0 to 60:40) afforded compound 17-3.

[0573] The characterization of compound 17-3 is as follows:

[0574] LCMS: m / z (ESI) = 279.9 [M+H] + .

[0575] 1 H NMR (400MHz, DMSO-d6) δ: 3.71 (s, 3H), 4.00 (s, 3H), 4.28-4.38 (d, J=6.4Hz2H), 6.45 (s, 1H), 6.85-6.92 (d, J=8.8Hz, 2H), 7.21-7.29 (d, J=8.8Hz, 2H), 7.50-7.58 (m, 1H).

[0576] Step 3: Synthesis of compound 17-4

[0577] Compound 17-3 (250 mg, 893.75 μmol, 1 eq) was dissolved in 1,4-dioxane (2 mL), and 2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl (208.53 mg, 446.87 μmol, 0.5 eq) and (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl) [2-(2-amino-1,1-biphenyl)] palladium (II) (373.75 mg, 446.87 μmol, 0.5 eq) were added. The atmosphere was replaced with nitrogen three times, and sodium tert-butoxide (171.78 mg, 1.79 mmol, 2 eq) and N-methylpiperazine (179.04 mg, 1.79 mmol, 198.27 μL, 2 eq) were added. The mixture was stirred at 110°C for 4 hours. Water (10 mL) was added to the reaction system for washing, followed by extraction with ethyl acetate (10 mL x 4). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The product was purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-90:10) to obtain compound 17-4.

[0578] The characterization of compound 17-4 is as follows:

[0579] LCMS: m / z (ESI) = 344.2 [M+H] + .

[0580] 1 H NMR (400MHz, CDCl3) δ: 2.36 (s, 3H), 2.49-2.63 (m, 4H), 3.47-3.50 (m, 4H), 3.82 (s, 3H), 4.08 (s, 3H) , 4.23-4.30 (d, J=5.2Hz, 2H), 5.93 (s, 1H), 6.89-6.93 (d, J=8.8Hz, 2H), 7.23-7.26 (d, J=8.8Hz, 2H).

[0581] Step 4: Synthesis of compound 17-5

[0582] Trifluoroacetic acid (6 mL) was added to compound 17-4 (190 mg, 553.25 μmol, 1 eq) and stirred at 50°C for 16 hours. The reaction system was directly concentrated under reduced pressure to obtain the crude product. Water (5 mL) was added to the system, followed by washing with dichloromethane (5 mL*3). The aqueous phase was adjusted to pH 14 with 1M sodium hydroxide aqueous solution and extracted with dichloromethane (20 mL*6). The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 17-5.

[0583] The characterization of compound 17-5 is as follows:

[0584] LCMS: m / z (ESI) = 224.0 [M+H] + .

[0585] 1 H NMR (400MHz, CD3OD) δ: 2.35 (s, 3H), 2.52-2.62 (m, 4H), 3.40-3.44 (m, 4H), 3.99 (s, 3H), 6.30 (s, 1H).

[0586] Step 5: Synthesis of compound 17-6

[0587] To a solution of compound 5-4 (200 mg, 622.24 μmol, 1 eq) in ethyleneglycol dimethyl ether (20 mL) was added cesium iodide (96.88 mg, 684.47 μmol, 59.43 μL, 1.1 eq), iodine (86.86 mg, 342.23 μmol, 68.94 μL, 0.55 eq), copper(I) iodide (37.92 mg, 199.12 μmol, 0.32 eq), isoamyl nitrite (116.63 mg, 995.59 μmol, 134.06 μL, 1.6 eq) successively. The mixture was stirred at 70 °C for 18 h. To the reaction mixture was added aqueous ammonia (10 mL) and washed, then washed with saturated aqueous sodium thiosulfate (20 mL). The organic phase was combined and dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude product. Purification by column chromatography on silica gel (gradient elution: dichloromethane / methanol = 100:0-90:10) gave compound 17-6.

[0588] Compound 17-6 was characterized as follows:

[0589] LCMS: m / z (ESI) = 432.9 [M+H] + .

[0590] Step 6: Synthesis of compound 17-7

[0591] Compound 17-5 (50 mg, 223.94 μmol, 1.5 eq) was dissolved in 1,4-dioxane (2 mL), and compound 17-6 (64.54 mg, 149.29 μmol, 1 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.46 mg, 5.97 μmol, 0.04 eq), cesium carbonate (145.93 mg, 447.88 μmol, 3 eq) were added. After being replaced with nitrogen for three times, palladium acetate (670.35 μg, 2.99 μmol, 0.02 eq) was added. After being replaced with nitrogen for three times, the mixture was stirred at 110 °C for 2 h. To the reaction mixture was added water (5 mL), and then extracted with ethyl acetate (10 mL*3). The organic phase was directly concentrated under reduced pressure to give the crude product. Purification by thin layer preparation plate (developing agent: dichloromethane / methanol = 10:1) gave compound 17-7.

[0592] Compound 17-7 was characterized as follows:

[0593] LCMS: m / z (ESI) = 528.1 [M+H] + .

[0594] 1H NMR (400MHz, DMSO-d6) δ: 1.29-1.32 (m, 3H), 2.31-2.35 (m, 4H), 2.41 (s, 3H), 2.65-2.69 (m, 4H), 2.71 (s, 3H), 2.8 2-2.87 (m, 2H), 3.24-3.27 (m, 2H), 4.02 (s, 3H), 4.27-4.31 (m, 2H), 8.04-8.13 (m, 1H), 8.18 (s, 1H), 8.56 (s, 1H).

[0595] Step 7: Synthesis of compound 17

[0596] To a solution of compound 17-7 (35 mg, 66.33 μmol, 1 eq) in anhydrous tetrahydrofuran (3.5 mL) was added ammonium chloride (21.29 mg, 397.98 μmol, 6 eq), followed by a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (663.30 μL, 10 eq), and the mixture was stirred at 20°C for 2 hours. Saturated aqueous ammonium chloride (10 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (10 mL*3). The organic phases were separated, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative HPLC (HPLC preparative method: Waters Xbridge BEH preparative chromatograph; chromatographic column: C18 100*30mm*10μm; mobile phase A: 10mM ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; running gradient B%: 10%-40%, 8min) to obtain compound 17.

[0597] The characterization of compound 17 is as follows:

[0598] LCMS: m / z (ESI) = 499.2 [M+H] + .

[0599] 1 H NMR (400MHz, DMSO-d6) δ: 2.22 (s, 3H), 2.41-2.45 (m, 4H), 2.66 (s, 3H), 2.78-2.85 (m, 2H), 3.10-3 .17 (m, 2H), 3.41-3.45 (m, 4H), 4.02 (s, 3H), 7.49 (s, 2H), 8.03 (s, 1H), 8.20 (s, 1H), 8.53 (s, 1H).

[0600] Example 18

[0601]

[0602] Step 1: Synthesis of compound 18-1

[0603] Under nitrogen at 0°C, 60% pure sodium hydride (132.29 mg, 3.31 mmol, 2 eq) was added to a solution of cyclopropanol (192.08 mg, 3.31 mmol, 2 eq) in anhydrous tetrahydrofuran (8 mL). The mixture was stirred at 0°C for 0.5 hour, and compound 2-1 (500 mg, 1.65 mmol, 1 eq) was added. The reaction was continued at 0°C for 1 hour. After the reaction, water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phase was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by thin-layer chromatography (developing solvent: petroleum ether / ethyl acetate = 100:0-60:40) to obtain compound 18-1.

[0604] The characterization of compound 18-1 is as follows:

[0605] LCMS: m / z (ESI) = 280.9 [M+H] + .

[0606] 1H NMR (400MHz, CDCl3) δ: 0.90-0.97 (m, 2H), 1.06-1.14 (m, 2H), 1.33-1.42 (t, J=7.2Hz, 3H), 1.96-2.06 (m, 2H) ), 2.44-2.53 (t, J=6.0Hz, 2H), 3.16-3.23 (t, J=7.2Hz, 2H), 4.05-4.12 (m, 1H), 4.28-4.39 (q, J=7.2Hz, 2H).

[0607] Step 2: Synthesis of compound 18-2

[0608] Compound 18-1 was dissolved in anhydrous toluene (10 mL), and tert-butoxybis(dimethylamino)methane (1.99 g, 11.41 mmol, 2.36 mL, 20 eq) was added. The mixture was stirred at 90°C for 2 hours. After the reaction, water (10 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 18-2.

[0609] The characterization of compound 18-2 is as follows:

[0610] LCMS: m / z (ESI) = 308.9 [M-26] + .

[0611] Step 3: Synthesis of compound 18-3

[0612] Compound 18-2 (150 mg, 447.20 μmol, 1 eq) was dissolved in N,N-dimethylformamide (2 mL), and compound 1-3 (141.90 mg, 447.20 μmol, 1 eq) was added. The mixture was stirred at 110°C for 4 hours. After the reaction, water (5 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (10 mL*3). The organic phases were separated, combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was then purified by column chromatography (gradient eluent: dichloromethane / methanol = 100:0-90:10) to obtain compound 18-3.

[0613] The characterization of compound 18-3 is as follows:

[0614] LCMS: m / z (ESI) = 590.1 [M+H] + .

[0615] 1 H NMR (400MHz, CDCl3) δ: 0.88-0.97 (m, 2H), 1.05-1.14 (m, 2H), 1.38-1.42 (t, J=7.2Hz, 3H), 2.41 (s, 3H), 2.57-2.71 (m, 4H), 2.78-2.88 (t, J=7.2Hz, 2 H), 3.26-3.36(m, 6H), 4.14-4.17(m, 1H), 4.31-4.39(m, 2H), 6.46-6.52(m , 1H), 7.11-7.17 (m, 1H), 7.30 (s, 1H), 8.28 (s, 1H), 8.31-8.34 (d, J=2.8Hz 1H).

[0616] Step 4: Synthesis of compound 18-4

[0617] Compound 18-3 (100 mg, 169.60 μmol, 1 eq) was dissolved in a mixed solvent of anhydrous tetrahydrofuran (4 mL), methanol (1 mL), and water (1 mL). Lithium hydroxide monohydrate (35.58 mg, 847.99 μmol, 5 eq) was added and stirred at 45°C for 3 hours. After completion of the reaction, the reaction system was concentrated under reduced pressure to remove the organic solvent, and the pH was adjusted to 7 with 2N HCl aqueous solution. The mixture was then directly concentrated under reduced pressure to obtain compound 18-4.

[0618] The characterization of compound 18-4 is as follows:

[0619] LCMS: m / z (ESI) = 562.1 [M+H] + .

[0620] 1H NMR (400MHz, DMSO-d6) δ: 0.71-0.81 (m, 4H), 2.21 (s, 3H), 2.44-2.46 (m, 4H), 2.57-2.63 (m, 2H), 3.09-3.15 (m, 4H), 3.17-3. 22 (m, 2H), 3.98-4.07 (m, 1H), 6.57-6.68 (m, 1H), 7.10-7.22 (m, 1H), 7.79-7.86 (d, J=2.8Hz, 1H), 7.97 (s, 1H), 8.22 (s, 1H).

[0621] Step 5: Synthesis of compound 18

[0622] Compound 18-4 (171.77 mg, 1.35 mmol, 118.46 μL, 8 eq) was dissolved in anhydrous tetrahydrofuran (3 mL), and oxalyl chloride (171.77 mg, 1.35 mmol, 118.46 μL, 8 eq) was added at 0°C. The atmosphere was replaced with nitrogen three times, and N,N-dimethylformamide (1.24 mg, 16.92 μmol, 1.30 μL, 0.1 eq) was added. The mixture was stirred at 0°C for 0.5 hour, and 25% pure ammonia water (9 mL) was added. The mixture was stirred at 20°C for 0.5 hour. After the reaction, ethyl acetate (10 mL*3) was added to the reaction system, extracted, separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by HPLC preparative chromatography (HPLC preparative method: Waters Xbridge BEH preparative chromatograph; chromatographic column: C18 75*30 mm*3 μm; mobile phase A: 10 mM ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; gradient B%: 30%-70%, 8 min) to obtain compound 18.

[0623] The characterization of compound 18 is as follows:

[0624] LCMS: m / z (ESI) = 561.2 [M+H] + .

[0625] 1H NMR (400MHz, DMSO-d6) δ: 0.79-0.85 (m, 4H), 2.21 (s, 3H), 2.43-2.47 (m, 4H), 2.66-2.70 (t, J=7.2Hz, 2H), 3.04-3.09 (t, J=7.2Hz, 2H), 3.11-3.1 5(m, 4H), 4.11-4.18(m, 1H), 6.65-6.71(m, 1H), 7.13-7.19(d, J=8.8Hz, 1H), 7.35 (s, 2H), 7.65-7.70 (d, J=2.8Hz, 1H), 8.20 (s, 1H), 8.29 (s, 1H).

[0626] Example 19

[0627]

[0628] Step 1: Synthesis of compound 19-1

[0629] Compound 6-3 (1.2 g, 5.35 mmol, 1 eq), (2-bromoethynyl)triisopropylsilane (1.47 g, 5.62 mmol, 1.05 eq), silver acetate (893.06 mg, 5.35 mmol, 273.95 μL, 1 eq), and palladium acetate (120.13 mg, 535.06 μmol, 0.1 eq) were dissolved in acetonitrile (45 mL) and stirred at 80°C for 72 hours. After the reaction, the mixture was cooled to 20°C and concentrated to dryness under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0 to 98:2) to obtain compound 19-1.

[0630] The characterization of compound 19-1 is as follows:

[0631] LCMS: m / z (ESI) = 405.2 [M+H] + .

[0632] 1H NMR (400MHz, CDCl3) δ: 4.30-4.39 (m, 2H), 3.18-3.25 (m, 2H), 2.51-2.65 (m, 2H), 1.97-2.14 (m, 2H), 1.32-1.42 (m, 3H), 1.17 (s, 21H).

[0633] Step 2: Synthesis of compound 19-2

[0634] Compound 19-1 (155 mg, 383.06 μmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (2.5 mL), followed by the addition of tert-butoxybis(dimethylamino)methane (211.00 mg, 1.21 mmol, 0.25 mL, 3.16 eq). After purging with nitrogen, the mixture was stirred at 80°C for 2 hours. After completion of the reaction, the mixture was cooled to 20°C and the solvent was concentrated to dryness under reduced pressure to obtain crude compound 19-2, which was used directly in the next reaction.

[0635] Characterization of compound 19-2:

[0636] LCMS: m / z (ESI) = 433.2 [M-26] + .

[0637] Step 3: Synthesis of compound 19-3

[0638] Compound 19-2 (170 mg, 369.79 μmol, 1 eq) was dissolved in N,N-dimethylformamide (2 mL), followed by the addition of compound 1-3 (117.34 mg, 369.79 μmol, 1 eq), and the mixture was stirred at 110°C for 20 hours. After the reaction, water (10 mL) and saturated brine (10 mL) were added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure to dryness to obtain a crude product, which was then purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-98:2) to obtain compound 19-3.

[0639] Characterization of compound 19-3:

[0640] LCMS: m / z (ESI) = 714.3 [M+H] + .

[0641] 1 H NMR (400MHz, CDCl3) δ: 8.38 (s, 1H), 8.20 (m, 1H), 7.19 (s, 1H), 7.14 (m, 1H), 6.52 (m, 1H), 4.37 (m, 2H), 3 .19-3.40 (m, 6H), 2.81 (2H), 2.53-2.70 (m, 4H), 2.39 (s, 3H), 1.40 (t, J=7.2Hz, 3H), 1.09-1.19 (m, 21H).

[0642] Step 4: Synthesis of compound 19-4

[0643] Compound 19-3 (60 mg, 84.04 μmol, 1 eq) and ammonium chloride (26.97 mg, 504.25 μmol, 6 eq) were dissolved in 1 M lithium bis(trimethylsilyl)amide in n-hexane (2.09 mL, 10 eq) and stirred at 20 °C for 1 h under nitrogen. To the reaction solution was added methanol (3 mL) to quench the reaction, and the solvent was concentrated to dryness under reduced pressure to obtain the crude compound 19-4.

[0644] Characterization of compound 19-4:

[0645] LCMS: m / z (ESI) = 685.3 [M+H]+. + .

[0646] Step 5: synthesis of compound 19

[0647] Compound 19-4 (55 mg, 80.31 μmol, 1 eq) and 1 M tetrabutylammonium fluoride in tetrahydrofuran (1.2 mL, 14.94 eq) were dissolved in anhydrous tetrahydrofuran (2 mL) and stirred at 20 °C for 20 h. To the reaction solution was added saturated brine (5 mL) and water (5 mL), and then ethyl acetate (10 mL). The solution was filtered and the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated to dryness under reduced pressure to obtain the crude product. The compound 19 formate salt was obtained by high performance liquid preparative chromatography separation and purification (high performance liquid preparative method: Waters 2767 / QDa preparative chromatograph; column: C18 75*30 mm*3 μm; mobile phase A: H2O (containing 0.2% formic acid), mobile phase B: acetonitrile; running gradient: B%: 1%-40%, running 8 min).

[0648] Characterization of compound 19:

[0649] LCMS: m / z (ESI) = 529.2 [M+H]+.

[0650] 1H NMR (400 MHz, CD3OD) δ: 9.01-9.13 (m, 1H), 8.41-8.55 (m, 1H), 7.98-8.09 (m, 1H), 7.69-7.78 (m, 1H), 7.08-7.24 (m, 1H), 6.87-6.98 (m, 1H), 6.66-6.82 (m, 1H), 4.53-4.64 (m, 1H), 3.39-3.46 (m, 2H), 3.28-3.32 (m, 4H), 3.05-3.12 (m, 2H), 2.93-3.02 (m, 4H), 2.54-2.72 (m, 3H).

[0651] Example 20

[0652]

[0653] Step 1: Synthesis of compound 20-1

[0654] Compound 6-8 (200 mg, 659.69 μmol, 1 eq), 2-(tributylstannyl)furan (235.59 mg, 659.69 μmol, 208.48 μL, 1 eq), and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (48.27 mg, 65.97 μmol, 0.1 eq) were dissolved in N,N-dimethylformamide (5 mL) and stirred at 120°C for 16 hours. Water (10 mL) and saturated brine (10 mL) were added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (gradient eluent: petroleum ether / ethyl acetate = 100:0-70:30) to obtain compound 20-1.

[0655] The characterization of compound 20-1 is as follows:

[0656] LCMS: m / z (ESI) = 291.0 [M+H] + .

[0657] Step 2: Synthesis of compound 20-2

[0658] Compound 20-1 (145 mg, 499.43 μmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (5 mL), and tert-butoxybis(dimethylamino)methane (6.12 g, 35.11 mmol, 7.25 mL, 70.30 eq) was added. The mixture was stirred at 80°C under nitrogen for 16 hours. After the reaction, the solvent was concentrated to dryness under reduced pressure to obtain compound 20-2.

[0659] Characterization of compound 20-2:

[0660] LCMS: m / z (ESI) = 319.0 [M-26] + .

[0661] Step 3: Synthesis of compound 20-3

[0662] Compound 20-2 (170 mg, 492.17 μmol, 1 eq) was dissolved in N,N-dimethylformamide (2 mL), and compound 1-3 (156.17 mg, 492.17 μmol, 1 eq) was added, and the mixture was stirred at 110°C for 20 hours. After the reaction, the temperature was lowered to 20°C, and water (10 mL) and saturated brine (10 mL) were added to the reaction solution. The mixture was extracted with ethyl acetate (20 mL). The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-98:2) to obtain compound 20-3.

[0663] Characterization of compound 20-3:

[0664] LCMS: m / z (ESI) = 600.2 [M+H] + .

[0665] 1 H NMR (400MHz, CDCl3) δ: 8.41 (s, 1H), 8.11-8.13 (m, 1H), 7.40-7.57 (m, 2H), 7.23 (s, 1H), 7.13-7.16 (m, 1H), 6.49-6.52 (m, 1H), 6.40-6.45 ( m, 1H), 4.39-4.45 (m, 2H), 3.33-3.36 (m, 2H), 3.04-3.16 (m, 4H), 2.82-2.86 (m, 2H), 2.44-2.59 (m, 4H), 2.34 (s, 3H), 1.42 (t, J=7.2Hz, 3H).

[0666] Step 4: Synthesis of compound 20

[0667] Compound 20-3 (130 mg, 216.80 μmol, 1 eq) and ammonium chloride (69.58 mg, 1.30 mmol, 6 eq) were dissolved in a 1 M solution of bis(trimethylsilyl)amino in n-hexane (1.73 mL, 8 eq) and stirred at 20°C for 2 hours under a nitrogen atmosphere. Methanol (5 mL) was added to the reaction solution, and the solvent was concentrated to dryness under reduced pressure to obtain a crude product, which was then separated and purified by preparative HPLC (preparative HPLC method: Waters 2767 / QDa preparative chromatograph; column: C18 80*40 mm*3 μm; mobile phase A: 10 mM ammonium bicarbonate in water, mobile phase B: acetonitrile; gradient: B%: 25%-55%, running time: 8 min) to obtain compound 20.

[0668] Characterization of compound 20:

[0669] LCMS: m / z (ESI) = 571.2 [M+H]+ .

[0670] 1H NMR (400MHz, CDCl3) δ: 8.41 (s, 1H), 8.11 (s, 1H), 7.45 (s, 2H), 7.24 (s, 1H), 7.13-7.16 (m, 1H), 6.50-6.55 (m, 1H), 6 .40(s, 1H), 5.66(s, 2H), 3.30-3.36(m, 2H), 3.01-3.20(m, 4H), 2.82-2.90(m, 2H), 2.54-2.60(m, 4H), 2.36(s, 3H).

[0671] Example 21

[0672]

[0673] Step 1: Synthesis of compound 21-1

[0674] Compound 5-4 (50 mg, 155.56 μmol, 1 eq) was added to anhydrous dichloromethane (2 mL), cooled to 0°C, and then 85% pure m-chloroperbenzoic acid (63.17 mg, 311.12 μmol, 2 eq) was added. The temperature was raised to 25°C and stirred for 12 hours. After the reaction, the reaction solution was slowly poured into a saturated aqueous sodium bicarbonate solution (4 mL) and extracted with dichloromethane (4 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography (gradient eluent: dichloromethane / methanol = 100:0-90:10) to obtain compound 21-1.

[0675] Characterization of compound 21-1:

[0676] LCMS: m / z (ESI) = 354.1 [M+H] + .

[0677] 1H NMR (400MHz, CDCl3) δ: 8.29 (s, 1H), 5.05 (s, 2H), 4.40 (q, J=7.2Hz, 2H), 3.76 (s, 3H), 3.33 (t, J=7.2Hz, 2H), 2.80 (t, J=7.2Hz, 2H), 1.41 (t, J=7.2Hz, 3H).

[0678] Step 2: Synthesis of compound 21-2

[0679] Compound 21-1 (50 mg, 141.48 μmol, 1 eq) and compound 7-3 (66.81 mg, 141.48 μmol, 1 eq) were added to 1,4-dioxane (2 mL), and tris(dibenzylideneacetone)dipalladium (12.96 mg, 14.15 μmol, 0.1 eq), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (8.19 mg, 14.15 μmol, 0.1 eq), and cesium carbonate (92.19 mg, 282.95 μmol, 2 eq) were added, and the mixture was heated to 100° C. and stirred for 12 hours. After the reaction, the reaction solution was slowly poured into water (3 mL) to quench the reaction, extracted with ethyl acetate (3 mL*3), and the organic phases were combined, washed with saturated brine (3 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by thin layer chromatography (developing solvent: petroleum ether / ethyl acetate = 100:100) to obtain compound 21-2.

[0680] Characterization of compound 21-2:

[0681] LCMS: m / z (ESI) = 698.2 [M+H] + .

[0682] 1H NMR (400MHz, CDCl3) δ: 8.45 (s, 1H), 7.96-8.04 (m, 1H), 7.14-7.20 (m, 1H), 7.07-7.13 (m, 1H), 6.56-6.65 (m, 1H), 4.34-4.56 (m, 2H), 3 .58-3.66(m, 4H), 3.53-3.57(m, 3H), 3.32-3.39(m, 2H), 3.17-3.24(m, 4H), 2.82-2.90(m, 2H), 1.47-1.52(m, 9H), 1.38-1.45(m, 3H).

[0683] Step 3: Synthesis of trifluoroacetate salt of compound 21-3

[0684] Compound 21-2 (80 mg, 114.66 μmol, 1 eq) was added to anhydrous dichloromethane (2 mL), and trifluoroacetic acid (273.78 mg, 2.40 mmol, 177.78 μL, 20.94 eq) was added. The mixture was stirred at 25° C. for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 21-3, and the crude product was used directly in the next step.

[0685] Characterization of compound 21-3:

[0686] LCMS: m / z (ESI) = 598.1 [M+H] + .

[0687] Step 4: Synthesis of compound 21-4

[0688] The trifluoroacetic acid salt of compound 21-3 (75 mg, 105.39 μmol, 1 eq) was added to anhydrous tetrahydrofuran (1 mL), and triethylamine (10.66 mg, 105.39 μmol, 14.67 μL, 1 eq), 37% pure formaldehyde aqueous solution (34.21 mg, 421.55 μmol, 31.38 μL, 4 eq) and glacial acetic acid (25.32 mg, 421.55 μmol, 24.11 μL, 4eq), stirred at 25 ° C for 0.5 hours, then added sodium triacetoxyborohydride (89.34 mg, 421.55 μmol, 4eq), stirred at 25 ° C for 12 hours, added saturated sodium bicarbonate aqueous solution (2 mL) to the reaction solution, extracted with ethyl acetate (2 mL*2), separated, dried, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by thin layer chromatography (developing solvent: dichloromethane / methanol = 100:10) to give compound 21-4.

[0689] Characterization of compound 21-4:

[0690] LCMS: m / z (ESI) = 612.2 [M+H] + .

[0691] 1H NMR (400MHz, CDCl3) δ: 8.41-8.46 (m, 1H), 7.91-7.95 (m, 1H), 7.09-7.18 (m, 2H), 6.55-6.63 (m, 1H), 4.34-4.44 (m, 2H), 3.50-3 .56 (m, 3H), 3.30-3.36 (m, 2H), 3.23-3.30 (m, 4H), 2.78-2.89 (m, 2H), 2.59-2.66 (m, 4H), 2.35-2.41 (m, 3H), 1.37-1.43 (m, 3H).

[0692] Step 5: Synthesis of compound 21-5

[0693] Compound 21-4 (60 mg, 98.09 μmol, 1 eq) was added to anhydrous tetrahydrofuran (1 mL) and water (1 mL), and then lithium hydroxide monohydrate (12.35 mg, 294.28 μmol, 3 eq) was added. The mixture was stirred at 25°C for 12 hours. After the reaction was completed, it was directly concentrated and the pH was adjusted to 6-7 with 2N hydrochloric acid. Then, it was extracted with dichloromethane (3*3 mL), the liquids were separated, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 21-5.

[0694] Characterization of compound 21-5:

[0695] LCMS: m / z (ESI) = 584.2 [M+H] + .

[0696] Step 6: Synthesis of compound 21

[0697] Compound 21-5 (50 mg, 85.67 μmol, 1 eq) was added to anhydrous N, N- dimethylformamide (0.5 mL), ammonium bicarbonate (8.80 mg, 111.38 μmol, 9.17 μL, 1.3 eq), 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (65.15 mg, 171.35 μmol, 2 eq) and N,N-diisopropylethylamine (33.22 mg, 257.02 μmol, 44.77 μL, 3 eq) were added, stirred at 25 °C for 12 h, after the reaction was completed, the filtrate was concentrated under reduced pressure to obtain the crude product, which was separated and purified by high performance liquid preparative chromatography (High performance liquid preparative method: Waters 2767 / QDa preparative chromatograph; column: C18 80*30mm*3μm; mobile phase A: 10 mM ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; running gradient: B%: 25%-55%, running 8 min.), to obtain compound 21.

[0698] Characterization of compound 21:

[0699] LCMS: m / z (ESI) = 583.2 [M+H] + .

[0700] 1 H NMR (400 MHz, DMSO-d6) d: 8.75-8.84 (m, 1H), 8.44-8.50 (m, 1H), 7.77-7.99 (m, 2H), 7.18-7.24 (m, 1H), 7.12-7.16 (m, 1H), 6.82-6.87 (m, 1H), 3.30-3.33 (m, 3H), 3.13-3.21 (m, 4H), 3.04-3.11 (m, 2H), 2.71-2.78 (m, 2H), 2.41-2.45 (m, 4H), 2.19-2.24 (m, 3H).

[0701] Example 22

[0702]

[0703] Step 1: Synthesis of compound 22-1

[0704] Ethylene glycol monomethyl ether (151.00 mg, 1.98 mmol, 156.47 μL, 2 eq) was dissolved in tetrahydrofuran solution (5 mL), cooled to 0°C, added with 60% pure sodium hydride (79.37 mg, 1.98 mmol, 2 eq), reacted at 0°C for 0.5 hour, and compound 2-1 (300 mg, 992.18 μmol, 1 eq) was added. The reaction was continued at 0°C for 0.5 hour. After the reaction was completed, water (20 mL) was added, extracted with ethyl acetate (10 mL*3), washed with saturated brine (20 mL), separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (gradient eluent: petroleum ether / ethyl acetate = 100:0-50:50) to give compound 22-1.

[0705] The characterization of compound 22-1 is as follows:

[0706] LCMS: m / z (ESI) = 298.9 [M+H] + .

[0707] 1H NMR (400MHz, CDCl3) δ: 1.38 (t, J=7.09Hz, 3H), 1.98-2.08 (m, 2H), 2.42-2.58 (m, 2H), 3.19-3 .23 (m, 2H), 3.46-3.55 (m, 3H), 3.81-3.95 (m, 2H), 4.33 (q, J=7.09Hz, 2H), 4.38-4.42 (m, 2H).

[0708] Step 2: Synthesis of compound 22-2

[0709] Compound 22-1 (100 mg, 335.17 μmol, 1 eq) was dissolved in toluene (3 mL), and tert-butoxybis(dimethylamino)methane (350.49 mg, 2.01 mmol, 415.27 μL, 6 eq) was added. The mixture was stirred at 90°C for 12 hours. After the reaction, saturated aqueous ammonium chloride (5 mL) was added, and the mixture was extracted with ethyl acetate (3 mL*3). The layers were separated, and the organic phase was washed with saturated aqueous sodium chloride (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 22-2.

[0710] The characterization of compound 22-2 is as follows:

[0711] LCMS: m / z (ESI) = 327.0 [M-26] + .

[0712] Step 3: Synthesis of compound 22-3

[0713] Compound 22-2 (200 mg, 565.88 μmol, 1 eq) and compound 1-3 (179.56 mg, 565.88 μmol, 1 eq) were dissolved in N,N-dimethylformamide (2 mL) and stirred at 110°C for 12 hours. After completion of the reaction, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (5 mL*3). The organic phases were combined, washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was then separated and purified by preparative HPLC (HPLC preparative method: Waters Xbridge Prep OBD preparative chromatograph; column: C18 150*40 mm*10 μm; mobile phase A: 10 mM aqueous ammonium bicarbonate solution (containing 0.05% ammonia), mobile phase B: acetonitrile; gradient B%: 50%-80% over 8 min) to obtain compound 22-3.

[0714] The characterization of compound 22-3 is as follows:

[0715] LCMS: m / z (ESI) = 608.3 [M+H] + .

[0716] 1H NMR (400MHz, CD3OD) δ: 1.38 (t, J=7.13Hz, 3H), 2.37 (s, 3H), 2.59-2.68 (m, 4H), 2.80-2.82 (m, 2H) ), 3.24-3.31(m, 9H), 3.75-3.80(m, 2H), 4.33(q, J=7.13Hz, 2H), 4.41-4.50(m, 2H), 6.60-6.70(m J=9.07, 1H), 7.15-7.23 (m, 1H), 8.20-8.24 (m, 1H), 8.32 (s, 1H).

[0717] Step 4: Synthesis of compound 22-4

[0718] Compound 22-3 (40 mg, 65.83 μmol, 1 eq) was dissolved in a mixed solvent of tetrahydrofuran (1 mL), methanol (0.25 mL) and water (0.25 mL), and lithium hydroxide monohydrate (13.81 mg, 329.14 μmol, 5 eq) was added. The mixture was stirred at 40°C for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to remove most of the solvent. The pH was adjusted to 6-7 with 2N hydrochloric acid, and the mixture was extracted with ethyl acetate (2 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 22-4.

[0719] The characterization of compound 22-4 is as follows:

[0720] LCMS: m / z (ESI) = 580.1 [M+H] + .

[0721] Step 5: Synthesis of compound 22

[0722] Compound 22-4 (35 mg, 60.39 μmol, 1 eq) was dissolved in N, N-dimethylformamide (2 mL), and N, N-diisopropylethylamine (78.05 mg, 603.88 μmol, 105.18 μL, 10 eq), 2-(7-azobenzotriazole)-N, N, N, N-tetramethyluronium hexafluorophosphate (137.77 mg, 362.33 μmol, 6 eq), and ammonium bicarbonate (47.74 mg, 603.88 μmol, 49.73 μL, 10 eq) were added in sequence, and the mixture was stirred at 20°C for 12 hours. After the reaction, saturated aqueous ammonium chloride solution (2 mL) was added, and the mixture was extracted with ethyl acetate (2 mL*3). The organic phases were combined, washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product, which was separated and purified by preparative HPLC (HPLC preparation method: Phenomenex preparative chromatograph; chromatographic column: C18 75*30 mm*3 μm; mobile phase A: 10 mM aqueous ammonium bicarbonate solution (containing 0.05% ammonia water), mobile phase B: acetonitrile; running gradient: B%: 30%-55%, running for 8 min) to obtain compound 22.

[0723] The characterization of compound 22 is as follows:

[0724] LCMS: m / z (ESI) = 579.1 [M+H] + .

[0725] 1H NMR (400MHz, DMSO-d6) δ: 2.25 (s, 3H), 2.71 (s, 2H), 3.00-3.24 (m, 9H), 3.35 (s, 4H), 3.59 (s, 2H), 4.26 (s, 2H), 6.60-6.70 (m, 1H), 7.15-7.20 (m, 1H), 7.38 (s, 2H), 7.80 (s, 1H), 8.21 (s, 1H), 8.34 (s, 1H).

[0726] Example 23

[0727]

[0728] Step 1: Synthesis of compound 23-1

[0729] Compound 1-4 (14 g, 24.15 mmol, 1 eq) was added to a mixed solution of water (140 mL), tetrahydrofuran (70 mL), and methanol (70 mL). Lithium hydroxide monohydrate (3.04 g, 72.46 mmol, 3 eq) was added, and the mixture was stirred at 25°C for 12 hours. After the reaction, the reaction solution was concentrated under reduced pressure to 1 / 2 of its original volume, 2-methyltetrahydrofuran (30 mL) was added, and the pH was adjusted to 6-7 with 6N hydrochloric acid. The mixture was stirred at 20°C for 2 hours, filtered, and dried to obtain compound 23-1.

[0730] LCMS: m / z (ESI) = 552.1 [M+H] + .

[0731] Step 2: Synthesis of compound 23-2

[0732] Compound 23-1 (50 mg, 90.64 μmol, 1 eq) was dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (68.93 mg, 181.29 μmol, 2 eq) and N,N-diisopropylethylamine (35.14 mg, 271.93 μmol, 47.36 μL, 3 eq) were added. The mixture was stirred at 20°C for 0.5 hour, and then O-(tetrahydro-2H-pyran)-2-hydroxylamine (21.24 mg, 181.29 μmol, 2 eq) was added. The mixture was stirred at 20°C for 1 hour. After the reaction, water (3 mL) was added to the reaction system, and the mixture was filtered. The filter cake was dried to obtain compound 23-2.

[0733] The characterization of compound 23-2 is as follows:

[0734] LCMS: m / z (ESI) = 651.0 [M+H] + .

[0735] Step 3: Synthesis of compound 23

[0736] Compound 23-2 (50 mg, 76.84 μmol, 1 eq) was dissolved in anhydrous methanol (5 mL), and p-toluenesulfonic acid (35.71 mg, 207.40 μmol, 2.70 eq) was added. The mixture was stirred at 20°C for 1 hour. After completion of the reaction, the reaction system was concentrated under reduced pressure, and water (5 mL) was added. The mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were separated, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative HPLC (HPLC method: Phenomenex Luna preparative chromatograph; column: C18 75 x 30 mm x 3 μm; mobile phase A: water (containing 0.05% formic acid), mobile phase B: acetonitrile; gradient: B%: 20%-60% over 8 min) to obtain the formate salt of compound 23.

[0737] Characterization of compound 23:

[0738] LCMS: m / z (ESI) = 567.1 [M+H] + .

[0739] 1 H NMR (400MHz, DMSO-d6) δ: 10.53-10.85 (m, 1H), 8.93-9.36 (m, 1H), 8.47 (s, 1H), 8.32 (s, 1H), 8.16 (s, 1H), 7.50 (d, J=2.8Hz, 1H), 7.17 (dd, J=8.8, 1 .6Hz, 1H), 6.71 (dd, J=9.2, 2.8Hz, 1H), 3.12-3.18 (m, 4H), 3.07-3.10 (m, 2H), 2.73(t, J=7.2Hz, 2H), 2.53(s, 3H), 2.43-2.46(m, 4H), 2.22(s, 3H).

[0740] Biological test data:

[0741] Experimental Example 1: Evaluation of PLK1 kinase activity in vitro

[0742] use 33 IC was determined by P isotope-labeled kinase activity assay (Reaction Biology Corp). 50 The inhibitory ability of the test compound on human PLK1 protein kinase was evaluated by PCR.

[0743] Buffer conditions: 20 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01% Brij35, 0.02 mg / ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO

[0744] Experimental steps: At room temperature, the test compound was dissolved in DMSO to prepare a 10mM solution for use. The substrate Casein was dissolved in a freshly prepared buffer (final concentration 20μM), and the PLK1 kinase to be tested (final concentration 12nM) was added thereto and mixed evenly. The DMSO-dissolved test compound stock solution was added to the above-mentioned mixed reaction solution according to the set final concentration gradient (the highest final concentration was 1μM, 3-fold dilution, 10 gradients) using the acoustic pipetting system Echo 550. After incubation at room temperature for 20 minutes, the mixture was added. 33 After incubation at room temperature for 120 minutes with 30 μM P-ATP, the reaction solution was spotted onto P81 ion exchange filter paper (Whatman #3698-915). After repeated washing with 0.75% phosphoric acid solution, the level of radioactive phosphorylated substrate remaining on the filter paper was determined. % kinase activity = kinase activity 受试化合物 / kinase activity 空白组(DMSO) × 100%, and the IC was obtained by curve fitting using Prism4 software (GraphPad). 50 The experimental results are shown in Table 1.

[0745] Table 1: Results of in vitro PLK1 kinase activity screening test of the compounds of the present invention

[0746] Compound number <![CDATA[PLK1 / IC 50 (nM)]]> 1 4.4 2 4.2 3 5.0 4 1.0 5 2.6 6 6.9 7 3.0

[0747] 8 1.7 12 4.0 13 4.9 14 7.3 15 6.4 16 5.3 17 5.9 18 4.3 20 2.8

[0748] Conclusion: The compounds of the present invention generally exhibit good inhibitory activity against PLK1.

[0749] Experimental Example 2: In vitro evaluation of PLK2 / PLK3 / PLK4 kinase activity

[0750] use 33 IC was determined by P isotope-labeled kinase activity assay (Reaction Biology Corp). 50 The inhibitory ability of the test compound on human PLK family protein kinases PLK2 / PLK3 / PLK4 was evaluated by the kinase inhibitory value.

[0751] Buffer conditions: 20 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01% Brij35, 0.02 mg / ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO.

[0752] Experimental steps: At room temperature, the test compound was dissolved in DMSO to prepare a 10mM solution for use. The substrate Casein was dissolved in a freshly prepared buffer (final concentration 20μM), and the tested PLK2 / PLK3 / PLK4 kinases (final concentrations of 15 / 10 / 150nM, respectively) were added thereto and mixed evenly. The DMSO-dissolved test compound stock solution was added to the mixed reaction solution using the acoustic pipetting system Echo 550 according to the set final concentration gradient (the highest final concentration was 1μM, 3-fold dilution, 10 gradients). After incubation at room temperature for 20 minutes, the mixture was added 33 After incubation at room temperature for 120 minutes with 10 μM of P-ATP (final concentrations of 30 / 50 / 10 μM, respectively), the reaction mixture was spotted onto P81 ion exchange filter paper (Whatman #3698-915). After repeated washing with 0.75% phosphoric acid solution, the level of radioactive phosphorylated substrate remaining on the filter paper was determined. % kinase activity = kinase activity 受试化合物 / kinase activity 空白组(DMSO) × 100%, and the IC was obtained by curve fitting using Prism4 software (GraphPad). 50 The experimental results are shown in Table 2.

[0753] Table 2: Selectivity test results of the present invention for PLK family protein kinases

[0754] Compound 1 <![CDATA[PLK2IC 50 (μM)]]> ＞10 <![CDATA[PLK3IC 50 (μM)]]> ＞10 <![CDATA[PLK4IC 50 (μM)]]> ＞10

[0755] Conclusion: The compounds of the present invention have weak inhibitory activity against PLK2 / PLK3 / PLK4 kinases, that is, they have good PLK1 selectivity.

[0756] Experimental Example 3: In vitro HCT116 cytological activity evaluation

[0757] Experimental Materials:

[0758] McCoy's 5A medium and penicillin / streptomycin antibiotics were purchased from Vicente, and fetal bovine serum was purchased from Biosera. 3D CellTiter-Glo (a chemiluminescent cell viability assay) reagent was purchased from Promega. HCT116 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd. Envision multi-label analyzer was purchased from PerkinElmer.

[0759] Experimental methods:

[0760] HCT116 cells were seeded in ultra-low attachment 96-well U-shaped plates, with 80 μL of cell suspension per well containing 1000 HCT116 cells. The plates were incubated overnight in a CO2 incubator.

[0761] The compound to be tested was diluted 5-fold to the 9th concentration, that is, from 2mM to 5.12nM, using a dispenser, and a double-well experiment was set up. 78μL of culture medium was added to the middle plate, and then 2μL of the gradient diluted compound per well was transferred to the middle plate according to the corresponding position. After mixing, 20μL of each well was transferred to the cell plate. The concentration range of the compound transferred to the cell plate was 10μM to 0.0256nM. The cell plate was placed in a carbon dioxide incubator and cultured for 5 days. Prepare another cell plate and read the signal value on the day of drug addition as the maximum value (Max value in the equation below) for data analysis.

[0762] Add 100 μL of cell viability chemiluminescent detection reagent to the cell plate and incubate at room temperature for 10 minutes to allow the luminescent signal to stabilize. Read the results using a multi-label analyzer.

[0763] Data Analysis:

[0764] The raw data were converted into inhibition rate, IC, using the equation (Sample-Min) / (Max-Min)*100%. 50 The value can be obtained by four-parameter curve fitting (obtained using the "log (inhibitor) vs. response--Variable slope" mode in GraphPad Prism). Table 3 provides the inhibitory activity of the compounds of the present invention on HCT116 cell proliferation.

[0765] Table 3: Results of in vitro screening tests of compounds of the present invention

[0766] Compound number HCT116 / IC 50 (nM)]]> 1 27 2 30.8 4 35 8 52 16 29.2 17 18.3 18 74.5 20 58.6

[0767] 23 72

[0768] Conclusion: The compounds of the present invention exhibited good inhibitory activity on cell proliferation in the HCT116 cell line.

[0769] Experimental Example 4: Pharmacokinetic study of the test compound after oral and intravenous administration in CD-1 male mice

[0770] Purpose of the experiment:

[0771] This study was designed to investigate the pharmacokinetics of the test compound in the plasma of CD-1 male mice after intravenous and oral administration.

[0772] Experimental operation:

[0773] Intravenous injection group: Dissolve the test compound in a 20% SBE-b-CD aqueous solution, adjust the pH to 4-5 with 6M hydrochloric acid, and vortex for 2 minutes to obtain a clear solution. Adjust the pH to approximately 7 with 5N sodium hydroxide and vortex for 1 minute to obtain a 1.5 mg / mL clear solution. Filter through a 0.22 μm microporous filter before use. Male CD-1 mice aged 6 to 10 weeks were administered the test compound solution intravenously. Samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours.

[0774] Oral administration: Dissolve the test compound in a 20% SBE-b-CD aqueous solution, adjust the pH to 3-4 with 6M hydrochloric acid, and vortex for 2 minutes to obtain a clear solution. Adjust the pH to approximately 7 with 5N sodium hydroxide and vortex for 1 minute to obtain a 2.0 mg / mL clear solution for later use. Male CD-1 mice aged 6 to 10 weeks were orally administered with the test compound. Samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours.

[0775] At each time point, approximately 50 μL of whole blood was collected from the jugular vein to prepare plasma for concentration determination by high-performance liquid chromatography-tandem mass spectrometry (LC-MS / MS). All animals were euthanized by CO2 anesthesia after the collection of the PK sample at the last time point. TM The plasma concentrations were processed using a non-compartmental model using the pharmacokinetic software Version 6.3 (Pharsight, Mountain View, CA). The pharmacokinetic parameters were calculated using the linear-log trapezoidal method. The experimental results are shown in Table 4.

[0776] Table 4: Pharmacokinetic results of the test compounds

[0777]

[0778]

[0779] Experimental conclusion:

[0780] The compound showed a low drug clearance rate in the CD-1 mouse pharmacokinetic study. After oral administration, it could quickly reach the peak and exhibit high oral absorption bioavailability.

[0781] Experimental Example 5: In vivo pharmacodynamic study of the test compound on a subcutaneous xenograft model of human colon cancer HCT116 cells

[0782] 1. Purpose of the experiment

[0783] This study used a BALB / c Nude mouse model with subcutaneous transplantation of human colon cancer HCT116 cells to evaluate the in vivo antitumor efficacy of the test compounds.

[0784] 2. Experimental Methods

[0785] 2.1 Model establishment

[0786] HCT116 cell culture: McCoy's 5A medium supplemented with 10% fetal bovine serum was cultured at 37°C in a 5% CO2 incubator. When cell saturation reached 80%-90% and the required number of cells was reached, the cells were harvested, counted, and inoculated subcutaneously into female BALB / c nude mice (6-7 weeks old).

[0787] 2.2 Grouping and Dosage Observation

[0788] When the tumor grows to a certain size, animals with tumors that are too large, too small, or with irregular shapes are eliminated, and animals with tumors with a size of 103.12 to 174.35 mm are selected. 3 The animals were randomly divided into 6 groups according to the tumor volume, with 6 mice in each group. The average tumor volume was about 147.12 mm 3 The experimental groups and dosing regimen are shown in Table 5 below. The health status and mortality of the animals were monitored daily. Routine examinations included observing tumor growth and the effects of drug treatment on the animals' daily behavior, such as behavioral activity, food and water intake, body weight changes (body weight was measured twice a week), tumor size (tumor volume was measured twice a week), physical signs, or other abnormalities.

[0789] Table 5 Research plan for the human colon cancer HCT116 cell BALB / c nude mouse xenograft tumor model

[0790]

[0791] Vehicle: Vehicle group, 20% SEB-β-CD

[0792] PO: Oral administration

[0793] QD: once a day, give for 5 days and rest for 2 days

[0794] 2.3 Evaluation indicators

[0795] The formula for calculating tumor volume (TV) is: 1 / 2×a×b 2, where a and b are the measured length and width of the tumor, respectively. The tumor inhibition rate (TGI) (%) was calculated as follows: TGI (%) = [1 - (average tumor volume of a treatment group at the end of dosing - average tumor volume of the treatment group at the start of dosing) / (average tumor volume of the solvent control group at the end of treatment - average tumor volume of the solvent control group at the start of treatment)] × 100%.

[0796] 2.4 Data Analysis

[0797] In this study, all experimental data are expressed as mean ± SEM. Statistical analysis was performed using IBM SPSS Statistics software based on RTV data at the end of the study. Comparisons between two groups were analyzed using the T test, and comparisons between three or more groups were analyzed using one-way ANOVA. If the variances were equal (F values ​​were not significantly different), Tukey's method was used for analysis. If the variances were unequal (F values ​​were significantly different), the Games-Howell method was used for analysis. A p value of < 0.05 was considered significant.

[0798] 3. Experimental Results and Discussion

[0799] This study evaluated the efficacy of test compounds 1, 2, and 8 in a BALB / cNude mouse model with subcutaneous transplantation of human colon cancer HCT-116 cells. No animal deaths occurred in any of the experimental groups during the entire dosing period, and the mice tolerated the drugs well. The experimental results are shown in Tables 6 and Figure 1 、 Figure 2 shown.

[0800] Table 6. Evaluation of the anti-tumor efficacy of the test compounds in the human colon cancer HCT116 cell subcutaneous xenograft tumor model (calculated based on the tumor volume on day 22 after administration)

[0801]

[0802] Experimental conclusion: In this pharmacodynamic model, the compound of the present invention exhibited dose-dependent antitumor activity and had significant antitumor effects. The changes in animal body weight during the entire experiment were similar to those in the vehicle group, and the animals had good tolerance.

Claims

1. A compound represented by formula (P) or a pharmaceutically acceptable salt thereof, in, T1 is selected from CR1 and N; T2 is selected from CH and N; R1 is selected from H; R2 is selected from H, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, S(=O)2C 1-3 Alkyl, C 2-3 Alkynyl, C 3-5 Cycloalkyl, -OC 3-5 Cycloalkyl and 5-membered heteroaryl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, S(=O)2C 1-3 Alkyl, C 2-3 Alkynyl, C 3-5 Cycloalkyl, -OC 3-5 Cycloalkyl and 5-membered heteroaryl are optionally substituted by 1, 2 or 3 R b replace; R3 is selected from C 1-4 Alkyl, piperazinyl and 7-9 membered heterocycloalkyl, the C 1-4 Alkyl, piperazinyl and 7-9 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R c replace; R4 is selected from C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted with 1, 2 or 3 R d replace; R5 is selected from H and OH; Alternatively, R1 and R3 form a ring with the atoms to which they are connected, so that the structural fragment Selected from Each R b Each independently selected from F, Cl, Br, I, OH and OCH3; Each R c are independently selected from =O, C 1-3 Alkyl, C 1-4 Alkylamino and heterocyclic butyl, the C 1-3 Alkyl, C 1-4 Alkylamino and heterocyclobutyl are optionally substituted with 1, 2 or 3 R; Each R d are independently selected from F, Cl, Br and I; Each R is independently selected from F, Cl, Br, I and OH; The heteroatom of the "heterocyclobutyl" and "7-9 membered heterocycloalkyl" is selected from N, O and S.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is selected from H, CN, SCH3, SCH2CH3, SCH(CH3)2, S(=O)2CH3、OCH3、OCH2CH3、OCH(CH3)2、CH3、CH2CH3、CH(CH3)2、cyclopropyl group、 and The SCH3, SCH2CH3, SCH(CH3)2, S(=O)2CH3, OCH3, OCH2CH3, OCH(CH3)2, CH3, CH2CH3, CH(CH3)2, cyclopropyl, Optional 1, 2 or 3 R b replace.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R2 is selected from H, CN, SCH3, SCH2CH2OH, S(=O)2CH3, OCH2CH3, OCH2CH2OH, OCH2CH2OCH3, CH3, CH2CH2OH, CH2OCH3, cyclopropyl, 4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R c Selected from =O, CH3, CH2CH3, N(CH3)2 and The CH3, CH2CH3 and N(CH3)2 are optionally substituted with 1, 2 or 3 Rs.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R c Selected from =O, CH3, CH2CH2OH, N(CH3)2 and 6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R3 is selected from CH2CH2CH3, The CH2CH2CH3, Optional 1, 2 or 3 R c replace.

7. The compound according to any one of claims 1, 4 to 6, or a pharmaceutically acceptable salt thereof, wherein: R3 is selected from 8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R4 is selected from CH3, OCH3, OCHF2 and OCF3.

9. The compound according to any one of claims 1 to 3 and 6 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from in, R2 and R3 are as defined in any one of claims 1 to 3 and 6.

10. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from in, R2 and R3 are as defined in claim 7.

11. The following compounds or pharmaceutically acceptable salts thereof, wherein the compound is selected from 12. Use of the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating solid tumors.

13. Use of the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating solid tumors associated with selective PLK1 inhibitors.

14. The use according to claim 12 or 13, wherein: Solid tumor refers to colorectal cancer.

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