POLQ inhibitors

Abstract

The present disclosure provides a novel class of compounds having POLQ inhibitory activity, pharmaceutical compositions containing the compounds, intermediates for preparing the compounds, and methods of treating cancer using the compounds of the disclosure. # imgabs0 #

Description

Technical Field

[0001] The present disclosure belongs to the field of medicinal chemistry, and relates to novel compounds having POLQ inhibitory activity, pharmaceutical compositions containing the compounds, useful intermediates for preparing the compounds, and methods for using the compounds to treat POLQ-mediated related diseases. Background Art

[0002] Targeting DNA repair defects in cancer cells has become a proven effective strategy for treating cancer. The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib is the first drug that targets the DNA repair process and is successfully marketed. It is successfully used to treat BRCA-mutated breast cancer and ovarian cancer through a synthetic lethal mechanism.

[0003] DNA polymerase θ (Polθ or POLQ) is a synthetic lethal target with homologous recombination (HR) defects. It is a key component of the alternative end joining (alt-EJ) pathway, also known as microhomology-mediated end joining (MMEJ) or PolQ-mediated end joining (TMEJ) pathway, and plays an important role in the DNA damage response (DDR) pathway of double-strand breaks (DSBs). When DNA end resection occurs, in the presence of BRCA2, BRCA2 not only recruits the recombinase RAD51 to DSBs to promote HR, but also inhibits repair pathways such as TMEJ. When homologous recombination-mediated repair is impaired (HR deficiency), such as BRCA1 or BRCA2 mutations, POLQ is highly expressed and directs DSB repair toward TMEJ, turning on the DNA repair process of TMEJ. Therefore, in the case of HR deficiency, inhibition of POLQ can lead to cell death through the accumulation of toxic RAD51 intermediates and inhibition of the TMEJ repair pathway.

[0004] POLQ is the eighth human DNA polymerase discovered in 1990 and is one of the 16 DNA polymerases in the human genome. POLQ is structurally and functionally distinct from other polymerases and consists of three domains, including a C-terminal low-fidelity DNA polymerase (A-type) and an N-terminal DNA helicase (SF2 HEL308-type), separated by a long and less conserved central domain of unknown function. It has been shown that the helicase domain of POLQ mediates the removal of RPA proteins from ssDNA ends and stimulates annealing, and this anti-recombinase activity of POLQ promotes the TMEJ pathway. In addition, the helicase domain of POLQ facilitates microhomology-mediated strand annealing, and when ssDNA overhangs contain >2 bp of microhomology, POLQ can promote end joining in the TMEJ pathway by utilizing this annealing activity. This reannealing activity is obtained through the coupling of Rad51 interaction, followed by ATPase-mediated displacement of Rad51 from the DSB damage site. After annealing, the polymerase domain extends the ssDNA ends and fills in the remaining gaps.

[0005] POLQ expression is low in normal cells, but is significantly overexpressed in HRD ovarian, uterine, and breast cancer subsets, which are associated with a poor prognosis. Recent studies have shown that cancer cells with defects in HR, NHEJ, or ATM are highly dependent on POLQ expression. POLQ inhibition can prevent the MMEJ-dependent functional reversal of BRCA1 or BRCA2 mutations, which underlies the emergence of cisplatin and PARPi resistance in tumors. Therefore, there is a theoretical basis for the application of POLQ inhibitors in cancers containing DNA repair defects, making it an attractive target for new synthetic lethal therapies.

[0006] At present, drug research targeting POLQ is hot, and there are drugs under development for both the polymerase domain and the helicase domain. The fastest progress is ART4215 developed by Artios Pharma, which has become the world's first POLQ inhibitor to enter clinical research. ART4215 targets the polymerase domain. GSK101, developed by IDEAYA and GlaxoSmithKline, has also recently been approved by the FDA to enter the clinical trial stage. GSK101 targets POLQ helicase inhibitors. Clinical development is for its combination with PARP inhibitors to treat BRCA or other homologous recombination (HR) mutations or homologous recombination deficiency (HRD) tumor patients. Although POLQ inhibitor drugs have entered the clinical stage, given the complexity, uncertainty and high risk of the drug development process, it is still of great significance to continue to promote the development of POLQ inhibitors and increase clinical candidate drugs. Summary of the invention

[0007] The present disclosure provides a POLQ inhibitor with novel structure, which has good anti-tumor activity in vitro and in vivo, and good pharmacokinetic properties, and can be used to treat tumor diseases mediated by POLQ.

[0008] The present disclosure provides a compound represented by formula (I), its stereoisomers and pharmaceutically acceptable salts thereof,

[0009]

[0010] in,

[0011] X1, X2, X3, X4, and X5 are independently CH or N;

[0012] R1 is selected from hydrogen, halogen, NO2, CN, -C(O)-N(R 1a )(R 1b ), C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl-S(O)2-, C 3-8 Cycloalkyl, C 2-6 Alkynyl, 3-8 membered heterocyclic group;

[0013] R 1a , R 1b are independently selected from hydrogen, C 1-6 alkyl;

[0014] R2 is selected from hydrogen, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl C 1-6 alkyl;

[0015] Ring A is selected from 5-6 membered heteroarylene, 3-8 membered heterocyclyl;

[0016] W is selected from O, S, CO, SO2;

[0017] L1 is selected from a bond, C 1-6 Alkylene chain, the C 1-6 The carbon atoms in the alkylene chain may be substituted with oxygen;

[0018] Ring B is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 8-10 fused ring group, phenyl, 5-6 membered heteroaryl;

[0019] R3 is selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6Alkoxy, hydroxyl C 1-6 Alkyl, hydroxyl C 3-6 Cycloalkyl, -C(O)-N(R 3a )(R 3b ), C 1-6 Alkyl-S(O)2-, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-C(O)-N(R 3a )-;

[0020] R 3a , R 3b are independently selected from hydrogen, C 1-6 alkyl;

[0021] m, n, and p are independently selected from 0, 1, 2, 3, and 4;

[0022] When W is selected from O, L1 is not a methylene group; When W is selected from O, L1 is a bond, Ring B is not C 3-8 Cycloalkyl, 4-7 membered heterocyclic group,

[0023] The present disclosure provides compounds of formula (I), stereoisomers and pharmaceutically acceptable salts thereof,

[0024]

[0025] in,

[0026] X1, X2, X3, X4, and X5 are independently CH or N;

[0027] R1 is selected from hydrogen, halogen, NO2, CN, -C(O)-N(R 1a )(R 1b ), C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl-S(O)2-, C 3-8 Cycloalkyl, C 2-6 Alkynyl;

[0028] R 1a , R 1b are independently selected from hydrogen, C 1-4 alkyl;

[0029] R2 is selected from hydrogen, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl C 1-4 alkyl;

[0030] Ring A is selected from 5-6 membered heteroarylene;

[0031] W is selected from O, S, CO, SO2;

[0032] L1 is selected from a bond, C 1-4 Alkylene chain, the C 1-4 The carbon atoms in the alkylene chain may be substituted with oxygen;

[0033] Ring B is selected from C 3-8 Cycloalkyl, 4-7 membered heterocyclic group, 9-10 fused ring group, phenyl, 5-6 membered heteroaryl;

[0034] R3 is selected from hydrogen, halogen, cyano, hydroxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl C 1-4 Alkyl, hydroxyl C 3-6 Cycloalkyl, -C(O)-N(R 3a )(R 3b ), C 1-4 Alkyl-S(O)2-, C 1-4 Alkyl-C(O)-, C 1-4 Alkyl-C(O)-N(R 3a )-;

[0035] R 3a , R 3b are independently selected from hydrogen, C 1-4 alkyl;

[0036] m, n, and p are independently selected from 0, 1, 2, 3, and 4;

[0037] When W is selected from O, L1 is not a methylene group; When W is selected from O, L1 is a bond, Ring B is not C 3-8 Cycloalkyl, 4-7 membered heterocyclic group,

[0038] The present application provides a compound of formula (I), its stereoisomers and pharmaceutically acceptable salts,

[0039]

[0040] in,

[0041] X1, X2, X3, and X4 are each independently CH or N;

[0042] X5 is CH or N;

[0043] R1 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4Alkoxy, C 1-4 Haloalkoxy, cyano, methylsulfonyl, C 3-8 cycloalkyl;

[0044] R2 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy;

[0045] Ring A is selected from 5-6 membered heteroaryl;

[0046] W is selected from O, S, CO, SO2;

[0047] L1 is selected from a bond, C 1-4 Alkylene chain, the C 1-4 The carbon atoms in the alkylene chain may be substituted with oxygen;

[0048] Ring B is selected from C 3-8 Cycloalkyl, 5-7 membered heterocyclic group, 9-10 fused ring group, phenyl, 5-6 membered heteroaryl;

[0049] R3 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, hydroxyl, C 1-4 Alkyl-OH, C 3-6 Cycloalkyl-OH, cyano, carbamoyl;

[0050] m, n, p are selected from 0, 1, 2, 3, 4;

[0051] When W is selected from O, L1 is not a methylene group; When W is selected from O, L1 is a bond, Ring B is not C 3-8 Cycloalkyl, 5-7 membered heterocyclic group; and the above structure does not include the following compounds:

[0052]

[0053] In some embodiments of the present disclosure, the compound of formula (I), its stereoisomers and pharmaceutically acceptable salts are characterized by the structural unit Selected from

[0054] In some embodiments of the present disclosure, the compound of formula (I), its stereoisomers and pharmaceutically acceptable salts are characterized by the structural unit Selected from

[0055] In some embodiments of the present disclosure, the compound, its stereoisomers and pharmaceutically acceptable salts thereof are characterized in that the structure of formula I is selected from the structure shown in the following formula IA,

[0056]

[0057] R1, R2, Ring A, W, L1, Ring B, R3, m, n, and p are as defined in any embodiment of the present disclosure.

[0058] In some embodiments of the present disclosure, the compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, characterized in that R1 is selected from F, Cl, CN, NO2, -CH3, -CHF2, -CF3, CH3O-, CHF2-O-, CF3-O-, -S(O)2CH3, -C(O)-NH2, HC≡C-.

[0059] In some embodiments of the present disclosure, the compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, characterized in that R1 is selected from F, Cl, -CH3, -CHF2, -CF3, CH3O-, CHF2-O-,

[0060] In some embodiments of the present disclosure, the compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof are characterized in that R1 is selected from CN, NO2, CF3-O-, -S(O)2CH3, -C(O)-NH2, HC≡C-.

[0061] In some embodiments of the present disclosure, the compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof are characterized in that R1 is selected from F, Cl, CH3O-, CHF2-O-, -CHF2, -CH3, CN.

[0062] In some embodiments of the present disclosure, the compound of the above formula (I), its stereoisomers and pharmaceutically acceptable salts thereof are characterized in that R2 is selected from -CH3, HO-CH2-.

[0063] In some embodiments of the present disclosure, the compound of the above formula (I), its stereoisomers and pharmaceutically acceptable salts thereof are characterized in that R2 is selected from -CH3.

[0064] In some embodiments of the present disclosure, the compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, characterized in that ring A is selected from

[0065] In some embodiments of the present disclosure, the compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof are characterized in that W is selected from S, CO, and SO2.

[0066] In some embodiments of the present disclosure, the compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof are characterized in that W is selected from S and CO.

[0067] In some embodiments of the present disclosure, the above-mentioned compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof are characterized in that L1 is selected from a chemical bond, -CH2-CO-, -CH2-, and -CH(CH3)-.

[0068] In some embodiments of the present disclosure, the compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof are characterized in that L1 is selected from -CH2-CO-, -CH2-, and -CHCH3-.

[0069] In some embodiments of the present disclosure, the compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof are characterized in that L1 is selected from a chemical bond, -CH2-.

[0070] In some embodiments of the present disclosure, the compound of the above formula (I), its stereoisomers and pharmaceutically acceptable salts thereof are characterized in that -WL- is selected from CO.

[0071] In some embodiments of the present disclosure, the compound of the above formula (I), its stereoisomers and pharmaceutically acceptable salts thereof are characterized in that -WL- is selected from S.

[0072] In some embodiments of the present disclosure, the compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, characterized in that ring B is selected from C 3-8 Cycloalkyl, 4-7 membered heterocyclyl, phenyl, benzo 5-6 membered cycloalkyl, benzo 5-6 membered heterocyclyl, 5-6 membered heteroaryl and 5-6 membered cycloalkyl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl, 5-6 membered heterocyclyl and 5-6 membered heterocyclyl, 5-6 membered heterocyclyl and 5-6 membered heterocyclyl, 5-6 membered heterocyclyl and 5-6 membered cycloalkyl, 5-6 membered heteroaryl.

[0073] In some embodiments of the present disclosure, the compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, characterized in that ring B is selected from C 3-8 Cycloalkyl, 4-7 membered heterocyclyl, phenyl, benzo 5-6 membered cycloalkyl, benzo 5-6 membered heterocyclyl, 5-6 membered heteroaryl and 5-6 membered cycloalkyl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl, 5-6 membered heterocyclyl and 5-6 membered heterocyclyl, 5-6 membered heterocyclyl and 5-6 membered cycloalkyl.

[0074] In some embodiments of the present disclosure, the compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, characterized in that ring B is selected from C 3-8 Cycloalkyl, 4-7 membered heterocyclyl, phenyl, benzo 5-6 membered cycloalkyl, 6 membered heteroaryl and 5-6 membered cycloalkyl.

[0075] In some embodiments of the present disclosure, the compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, characterized in that ring B is selected from C 5-6 Cycloalkyl, 5-6 membered heterocyclyl, phenyl, benzo 5-6 membered cycloalkyl, 6 membered heteroaryl and 5-6 membered cycloalkyl.

[0076] In some embodiments of the present disclosure, the compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, characterized in that ring B is selected from

[0077] In some embodiments of the present disclosure, the compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, characterized in that ring B is selected from

[0078] In some embodiments of the present disclosure, the compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, characterized in that ring B is selected from

[0079] In some embodiments of the present disclosure, the compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, characterized in that ring B is selected from

[0080] In some embodiments of the present disclosure, the compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, characterized in that R3 is selected from F, Cl, -CH3, CH3O-, -OH, -CH2OH, -CN, NH2-CO-.

[0081] In some embodiments of the present disclosure, the compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, are characterized in that R3 is selected from CH3-NH-C(O)-, (CH3)2N-C(O)-, -S(O)2CH3, CH3C(O)-NH-, CH3C(O)-(CH3)N-.

[0082] In some embodiments of the present disclosure, the compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof are characterized in that R3 is selected from F, Cl, -OH, -CN, CH3O-.

[0083] In some embodiments of the present disclosure, the compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof are characterized by the structural unit Selected from

[0084]

[0085]

[0086] In some embodiments of the present disclosure, the compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof are characterized in that the structural unit Selected from

[0087]

[0088] In some embodiments of the present disclosure, the compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof are characterized in that the structural unit Selected from

[0089] In some embodiments of the present disclosure, the compound of formula (I), its stereoisomers and pharmaceutically acceptable salts thereof are characterized in that the structural unit Selected from

[0090] In some embodiments of the present disclosure, the compound, its stereoisomers and pharmaceutically acceptable salts thereof are selected from the structures shown below:

[0091]

[0092] wherein X is selected from N or CH;

[0093] R1, R2, R3, L1, Ring B, m, n, and p are as defined in any of the above schemes.

[0094] In some embodiments of the present disclosure, the compound, its stereoisomers and pharmaceutically acceptable salts thereof have a structure as shown in the following formula (II-C):

[0095]

[0096] in,

[0097] X is selected from N or CH;

[0098] R1 is selected from hydrogen, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy;

[0099] R2 is selected from C 1-4 alkyl;

[0100] W is selected from C(O) or S;

[0101] L1 is selected from a chemical bond or C 1-2 Alkylene chain;

[0102] Ring B is selected from phenyl, benzo 5-6 membered cycloalkyl, 5-6 membered cycloalkyl, 5-6 membered heterocyclyl;

[0103] R3 is selected from hydroxy, cyano, halogen;

[0104] p is selected from 0, 1 or 2.

[0105] In some embodiments of the present disclosure, the compound, its stereoisomers and pharmaceutically acceptable salts thereof have a structure as shown in the following formula (II-A):

[0106]

[0107] Wherein, R1 is selected from hydrogen, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy;

[0108] R2 is selected from C 1-4 alkyl;

[0109] L1 is selected from a chemical bond or C 1-2 Alkylene chain;

[0110] Ring B is selected from phenyl, benzo 5-6 membered cycloalkyl, 5-6 membered cycloalkyl, 5-6 membered heterocyclyl;

[0111] R3 is selected from hydroxy, cyano, halogen;

[0112] p is selected from 0, 1 or 2.

[0113] In some embodiments of the present disclosure, the compound, its stereoisomers and pharmaceutically acceptable salts thereof have a structure as shown in the following formula (II-A2):

[0114]

[0115] Wherein, R1 is selected from hydrogen, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy;

[0116] R2 is selected from C 1-4 alkyl;

[0117] Ring B is selected from 5-6 membered cycloalkyl, 5-6 membered heterocyclyl;

[0118] R3 is selected from hydroxy, cyano, halogen;

[0119] p is selected from 0, 1 or 2.

[0120] In some embodiments of the present disclosure, the compound, its stereoisomers and pharmaceutically acceptable salts thereof are selected from the structures shown below:

[0121]

[0122] wherein R1, R2, R3, W, m, n, and p are as defined in any of the above schemes.

[0123] In some embodiments of the present disclosure, the compound, its stereoisomers and pharmaceutically acceptable salts thereof are selected from the structures shown below:

[0124]

[0125] wherein R1, R2, R3, W, m, n, and p are as defined in any of the above schemes.

[0126] The present disclosure also provides the following compounds, stereoisomers and pharmaceutically acceptable salts thereof,

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135] The present disclosure also provides a pharmaceutical composition, which contains a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0136] The present disclosure also provides use of the above-mentioned compound or a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition in preparing a drug for treating POLQ target-mediated related diseases.

[0137] In some embodiments of the present disclosure, the disease mediated by the POLQ target is a tumor.

[0138] In some embodiments of the present disclosure, the tumor is a tumor whose DNA repair is dependent on the TMEJ (theta-mediated end joining) repair pathway.

[0139] In some embodiments of the present disclosure, the tumor is a tumor with DNA double-strand repair defects.

[0140] In some embodiments of the present disclosure, the tumor is a tumor deficient in homologous recombination (HR) repair.

[0141] In some embodiments of the present disclosure, the tumor is a BRCA mutated tumor.

[0142] In some embodiments of the present disclosure, the tumor is a tumor with reduced or absent BRCA gene expression, absent BRCA gene, or reduced BRCA protein function.

[0143] In some embodiments of the present disclosure, the tumor is a tumor that overexpresses POLQ.

[0144] In some embodiments of the present disclosure, the tumor is a solid tumor.

[0145] In some embodiments of the present disclosure, the tumor is an advanced solid tumor or a metastatic solid tumor.

[0146] In some embodiments of the present disclosure, the tumor is breast cancer, ovarian cancer, fallopian tube cancer, cervical cancer, or peritoneal cancer.

[0147] The present disclosure also provides a pharmaceutical composition, which contains a therapeutically effective amount of the above compound, its stereoisomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0148] In some embodiments of the present disclosure, in the pharmaceutical composition, the content of the compound, stereoisomer or pharmaceutically acceptable salt thereof is selected from 0.1 mg-1000 mg.

[0149] In some embodiments of the present disclosure, in the pharmaceutical composition, the pharmaceutically acceptable carrier includes one or more of a filler, a disintegrant, a binder, a glidant, and a lubricant.

[0150] The present disclosure also provides use of the above-mentioned compound or a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition in preparing a drug for treating a disease mediated by POLQ, wherein the POLQ-related disease includes a tumor.

[0151] The present disclosure also provides use of the above-mentioned compound or a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition in treating a disease mediated by POLQ; the POLQ-mediated related disease includes a tumor.

[0152] Technical Effects

[0153] The disclosed compounds have significant POLQ enzyme inhibitory activity, good tumor cell inhibitory activity, in vivo anti-tumor activity and pharmacokinetic properties.

[0154] Description and Definition

[0155] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered ambiguous or unclear without special definition, but should be understood according to the ordinary meaning in the art.

[0156] The tumors described in the present disclosure include benign tumors and malignant tumors, and malignant tumors are generally referred to as cancers.

[0157] The "POLQ-mediated disease" mentioned in the present disclosure refers to a disease related to the POLQ target, which can be a disease caused by abnormal expression of POLQ due to mutation or deletion of POLQ itself, or a disease caused by abnormal expression of POLQ due to abnormalities in other related genes / targets (such as genes / targets with a synthetic lethal relationship with POLQ).

[0158] As used herein, "overexpression of POLQ" refers to an increase in the expression or activity of POLQ in diseased cells (e.g., cancer cells) relative to the expression or activity of POLQ in normal cells (e.g., non-disease cells of the same species). The amount of POLQ may be at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 10-fold or more relative to the expression of POLQ in normal cells.

[0159] The "homologous recombination (HR) deficient tumor" described in the present disclosure refers to a tumor characterized by a reduction or loss of a functional HR repair pathway. HR deficiency may be due to the absence of one or more HR-related genes or the presence of one or more mutations in one or more HR-related genes. Examples of HR-related genes include BRCA1, BRCA2, RAD54, RAD51B, Ct1P (choline transporter-like protein), PALB2 (chaperone and locator of BRCA2), XRCC2 (X-ray repair complement defect repair 2 in Chinese hamster cells), etc.

[0160] The compounds disclosed herein exist in geometric isomers and stereoisomers, such as cis-trans isomers, enantiomers, diastereomers, and racemic mixtures and other mixtures thereof, and all such mixtures are within the scope of the present disclosure.

[0161] The term "enantiomer" refers to stereoisomers that are mirror images of one another.

[0162] The term "diastereomer" refers to stereoisomers that have two or more chiral centers and are not mirror images of each other.

[0163] The term "cis-trans isomers" refers to configurations in which double bonds or single bonds of ring carbon atoms in a molecule cannot rotate freely.

[0164] The term "stereoisomer" refers to a molecule with one or more chiral centers, including enantiomers, diastereomers, and racemates and non-racemate mixtures thereof. "Stereoisomers" include, but are not limited to, absolute configuration R and absolute configuration S containing one chiral center, a mixture of R configuration isomers and S configuration isomers containing one chiral center, and diastereomers containing 2 to 4 chiral centers.

[0165] Stereoisomers of the disclosed compounds can be prepared by chiral synthesis or chiral reagents or other conventional techniques. For example, one enantiomer of a compound of the disclosed compounds can be prepared by asymmetric catalysis technology or chiral auxiliary derivatization technology. Alternatively, a compound of a single stereo configuration can be obtained from a mixture by chiral resolution technology. Alternatively, it can be prepared directly using chiral starting materials. The separation of optically pure compounds in the disclosed compounds is usually accomplished by preparative chromatography, using a chiral chromatographic column to achieve the purpose of separating chiral compounds.

[0166] The absolute stereo configuration of the compound can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction, the absolute configuration of the compound can also be confirmed by the chiral structure of the raw material and the reaction mechanism of asymmetric synthesis. The compounds marked as "absolute configuration not determined" herein are usually selected from a single isomer by chiral preparative SFC separation of the racemic compound, and then characterized and tested.

[0167] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0168] The term "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound prepared with a relatively non-toxic acid or base. These salts can be prepared during the synthesis, separation, and purification of the compound, or the purified free form of the compound can be used alone to react with a suitable acid or base. When the compound contains a relatively acidic functional group (e.g., -COOH, -OH, -SO3H, etc.), it reacts with a suitable inorganic or organic cation (base) to obtain a base addition salt, including salts formed with alkali metals or alkaline earth metals, ammonium salts formed with amines or their derivatives, and salts formed with amino acids. When the compound contains a relatively basic functional group (e.g., -NH2, etc.), it reacts with a suitable inorganic or organic anion (acid) to obtain an acid addition salt, including a salt formed with an inorganic acid or an organic acid (e.g., carboxylic acid, etc.). .

[0169] The term "pharmaceutically acceptable carrier" refers to a medium generally acceptable in the art for delivering biologically active agents to animals, particularly mammals, including, for example, adjuvants, excipients or excipients, such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatics, antibacterial agents, antifungal agents, lubricants and dispersants, depending on the nature of the mode of administration and dosage form. Pharmaceutically acceptable carriers are formulated within the scope of ordinary technicians in the field according to a large number of factors. They include, but are not limited to: the type and nature of the active agent to be formulated, the subject to whom the composition containing the agent is to be administered, the intended route of administration of the composition, and the target therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media and a variety of solid and semi-solid dosage forms. In addition to the active agent, such carriers include many different ingredients and additives, and such additional ingredients included in the prescription for various reasons (e.g., stabilizing the active agent, adhesives, etc.) are well known to ordinary technicians in the field.

[0170] The term "excipient" generally refers to carriers, diluents and / or vehicles required to formulate an effective pharmaceutical composition.

[0171] The term "optionally substituted" as used herein refers to two situations in which one or more hydrogen atoms of the substituted group may be "substituted" or "unsubstituted" with one or more substituents.

[0172] When the substituent appears in the structure Indicates the bonding position, e.g. Indicates that the substituent is connected to a given group or a given structural formula through a C atom on the pyrimidine ring. The presence of a dash "-" in a substituent structure indicates a point of attachment for the substituent, for example, -CH3 is connected through a C atom. Indicates the absolute configuration of a stereocenter, i.e., R or S configuration. It represents cis or trans configuration. Double real bonds or double imaginary bonds both represent cis configuration, and one real and one imaginary bond represent trans configuration.

[0173] When a substituent has a bond that can cross-link to a ring, it means that the substituent can be bonded to any atom on the ring. It means that the substituent R can be substituted at any position on the benzene ring.

[0174] When a substituent is listed without indicating the atom via which the substituent is attached to a given group or to a given formula, then the substituent may be attached via any bondable atom thereof.

[0175] When any variable (such as R d ) occurs more than once in the composition or structure of a compound, its definition in each instance is independent. For example, It means that the cyclopentyl group is substituted by 3 R d replaced, and each R d All have independent options.

[0176] The term "halogen" denotes a fluorine, chlorine, bromine or iodine atom.

[0177] The term "alkyl" refers to a group derived from a branched or straight chain saturated aliphatic alkane having a specified number of carbon atoms by removing one hydrogen. 1-10 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 Alkyl, "C 1-6 Alkyl", "C 1-4 Alkyl", "C 1-3 "Alkyl"; specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, sec-butyl, 2-methylbutyl, 1,1-dimethylbutyl, etc.

[0178] The term "alkynyl" refers to a radical derived from a straight-chain or branched alkyne (containing at least one carbon-carbon triple bond) by removing a hydrogen atom, including "C 2-5 Alkynyl", "C 2-4 Alkynyl", "C 2-3 "Alkynyl", specific examples include but are not limited to: -C≡CH, -C≡CHCH3, HC≡CHCH2-, HC≡CC≡C-, etc.

[0179] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms, preferably a haloalkyl group. 1-6 Alkyl, more preferably halogenated C 1-4Examples of haloalkyl include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like.

[0180] The term "hydroxyalkyl" refers to a group derived from an alkyl group in which one or more hydrogen atoms are replaced by a hydroxy group. The "hydroxyalkyl" described in the present disclosure includes "hydroxyC 1-6 Alkyl", "Hydroxy C 1-4 "alkyl"; specific examples include but are not limited to -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CH2CH2OH, wait.

[0181] The term "alkoxy" refers to an alkyl group attached through an oxygen bridge, i.e., "alkyl-O-", including "C 1-6 Alkoxy (structure C 1-6 Alkyl-O-), "C 1-4 "Alkoxy", specific examples include but are not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy. Preferably, the "alkoxy" described in the present disclosure is preferably C 1-4 Alkoxy, more preferably C 1-3 Alkoxy.

[0182] The term "haloalkoxy" refers to a group in which one or more hydrogen atoms in an alkoxy group are replaced by halogen. Preferably, the "haloalkoxy" described in the present disclosure is preferably a "haloC 1-6 Alkoxy", "halogenated C 1-4 Alkoxy". Specific examples of the present disclosure include: fluoromethoxy (including monofluoromethoxy, difluoromethoxy, trifluoromethoxy), -OCH2CF3, -OCHFCH3, etc. Alkoxy is as defined above.

[0183] The term "heteroaryl" refers to a monocyclic group with aromaticity in which at least one ring atom is a heteroatom and / or a heteroatom group. The heteroatom and / or heteroatom group is generally selected from N, O, S, P, NO, SO, S(O)2, P(O) and NR, and R is H or any substituent group that may exist. Preferably, the heteroatom is independently selected from 1-3 N and / or O. The heteroaryl includes "5-6 membered heteroaryl"; examples of the 5-6 membered heteroaryl 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, 2H-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.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl), pyridyl, pyrimidinyl, etc.

[0184] The term "alkylene" refers to a group derived from a branched or straight chain saturated aliphatic alkane by removing two hydrogen atoms, and the removed hydrogen atoms may be derived from the same carbon atom or different carbon atoms; the "alkylene" described in the present disclosure is preferably a "straight chain alkylene"; the "alkylene" includes "C 1-6 Alkylene", "C 1-4 Alkylene", "C 1-2 "Alkylene"; specific examples include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH2)CH2-, -CH2CH2CH2CH2-, -CH(CH2)CH2CH2-, -CH(CH2CH2)CH2-, -C(CH2)(CH2)CH2-, -CH2CH2CH2CH2CH2-, and the like.

[0185] The term "cycloalkyl" refers to a saturated cyclic group derived from a monocyclic cycloalkane by removing a hydrogen atom, wherein the carbon atoms in the cycloalkyl group may be further oxidized to form C(O). The cycloalkyl group includes "C 3-8 "C-cycloalkyl" 3-6 cycloalkyl", "C 3-5 cycloalkyl", "C 4-6 Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0186] The term "hydroxycycloalkyl" refers to a group derived from a cycloalkyl group substituted by one or more hydroxyl groups, preferably 1-2 hydroxyl groups. 3-6 Cycloalkyl", "hydroxy C 3-4 "Cycloalkyl"; specific examples include but are not limited to

[0187] The term "heterocyclic group" refers to a saturated or partially saturated cyclic group derived from the replacement of one or more ring carbon atoms in a cycloalkyl group by heteroatoms and / or heteroatomic groups. The heteroatoms and / or heteroatomic groups are generally selected from N, O, S, NO, SO, S(O)2, P(O), and NR, wherein the carbon atoms in the heterocyclic ring are optionally oxidized, i.e., -C(O); preferably, the heteroatoms are independently selected from 1-3 N and / or O. The "partially saturated heterocyclic group" refers to a group (also defined as a heterocyclic alkene group) in which one or more ring bonds are unsaturated bonds (such as double bonds) and are not aromatic. The heterocyclic groups include "3-8 membered heterocyclic groups", "3-6 membered heterocyclic groups", "3-5 membered heterocyclic groups", "4-7 membered heterocyclic groups", "4-6 membered heterocyclic groups", "5-7 membered heterocyclic groups" and "5-6 membered heterocyclic groups". Specific examples include, but are not limited to, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, wait.

[0188] The term "fused cyclic group" refers to a saturated or partially saturated non-aromatic cyclic group formed by two or more cyclic structures sharing two adjacent atoms, including fused carbocyclic groups and fused heterocyclic groups; the "fused carbocyclic group" means that all ring atoms are carbon; the "fused heterocyclic group" means that at least one ring atom is a heteroatom or a heteroatom group, and the heteroatom and / or heteroatom group is generally selected from N, O, S, NO, SO, S(O)2, P(O), and NR. The ring carbon atoms in the fused cyclic group are optionally oxidized, that is, to form -C(O). The fused cyclic groups include "8-10 membered fused cyclic groups", "9-10 membered fused cyclic groups", and "8-9 membered fused cyclic groups". The condensed form can be 4-6-membered cycloalkyl and 5-6-membered cycloalkyl, 5-6-membered heterocyclyl and 5-6-membered heterocyclyl, 5-6-membered cycloalkyl and phenyl, 5-6-membered heterocyclyl and 5-6-membered cycloalkyl, benzo 5-6-membered heterocyclyl, benzo 5-6-membered saturated heterocyclyl, 5-6-membered heteroaryl and 5-6-membered heterocyclyl, 5-6-membered heteroaryl and 5-6-membered saturated heterocyclyl, benzo 5-6-membered heterocyclyl and 5-6-membered heterocyclyl, 5-6-membered heteroaryl and 5-6-membered heterocyclyl and 5-6-membered heterocyclyl, benzo 5-6-membered cycloalkyl and 5-6-membered heterocyclyl, 5-6-membered heteroaryl and 5-6-membered heterocyclyl and 5-6-membered heterocyclyl. Specific examples of the 9-10-membered condensed ring group described in the present disclosure include, but are not limited to: This disclosure further describes The radical is defined herein as benzocyclopentyl.

[0189] The compounds disclosed herein 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 synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0190] The solvents used in the present disclosure are commercially available.

[0191] The structures of the compounds disclosed herein are determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS), or ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS). The NMR chemical shift (δ) is given in parts per million (ppm). The NMR is measured using a Bruker Neo 400M or Bruker Ascend 400 nuclear magnetic instrument, and the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3), heavy water (D2O), and the internal standard is tetramethylsilane (TMS).

[0192] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1260-6125B single quadrupole massspectrometer with a Welch Biomate column (C18, 2.7 um, 4.6*50 mm) or a Waters H-ClassSQD2 with a Welch Ultimate column (XB-C18, 1.8 um, 2.1*50 mm) mass spectrometer (the ion source was electrospray ionization).

[0193] Ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) was performed using a Waters UPLC H-class SQD mass spectrometer (with electrospray ionization as the ion source).

[0194] HPLC determination was performed using Waters e2695-2998 or Waters ARC and Agilent 1260 or Agilent Poroshell HPH high performance liquid chromatography.

[0195] Preparative HPLC used Waters 2555-2489 (10 μm, ODS 250 cm×5 cm) or GILSON Trilution LC, and the column was Welch XB-C18 column (5 um, 21.2*150 mm).

[0196] The chiral HPLC determination used waters acquity UPC2; the columns were Daicel chiralpak AD-H (5um, 4.6*250mm), Daicel chiralpak OD-H (5um, 4.6*250mm), Daicel chiralpak IG-3 (3um, 4.6*150mm), Chiral Technologies Europe AD-3 (3um, 3.0*150mm) and Trefoil TM Technology Trefoil TM AMY1 (2.5um, 3.0*150mm).

[0197] Supercritical fluid chromatography (SFC) used Waters SFC 80Q, and the column was Daicel Chiralcel OD / OJ / OZ (20×250 mm, 10 um) or Daicel Chiralpak IC / IG / IH / AD / AS (20×250 mm, 10 um).

[0198] The thin layer chromatography silica gel plate uses GF254 silica gel plate from Yantai Jiangyou Silica Gel Development Co., Ltd. or GF254 silica gel plate from Rushan Shangbang New Materials Co., Ltd. The specification used by TLC is 0.15mm-0.20mm, and the preparation type is 20x 20cm. Column chromatography generally uses 200-300 mesh silica gel from Chenghua as the carrier. DETAILED DESCRIPTION

[0199] Example 1 2'-Chloro-N-(5-(2-(4-chlorophenyl)acetyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide Reaction route:

[0200]

[0201] Steps:

[0202] Step A: Dissolve dimethylhydroxylamine hydrochloride (3.14 g, 32.24 mmol) in N,N-dimethylformamide (40 ml), add diisopropylethylamine (11.36 g, 87.93 mmol), then add p-chlorophenylacetic acid (5 g, 29.31 mmol) and HATU (12.26 g, 32.24 mmol), and stir at room temperature for 16 hours. The reaction solution is slowly poured into water (400 ml) and extracted with ethyl acetate (30 ml x 3). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue is purified by silica gel column chromatography to give 2.5 g of the product 2-(4-chlorophenyl)-N-methoxy-N-methylacetamide.

[0203] MS (ESI) M / Z: 214.1 [M+H] + .

[0204] 1 HNMR(400MHz,DMSO-d6)δ7.36-7.34(m,2H),7.26-7.24(m,2H),3.73(s,2H),3.68(s,3H),3.10(s,3H).

[0205] Step B: Dissolve tert-butyl N-(5-bromo-1,3-thiazol-2-yl)carbamate (560 mg, 2 mmol) in tetrahydrofuran (5 ml), add n-butyl lithium (1.0 M, 2.2 ml) dropwise at -78°C, maintain the temperature and stir for 15 minutes, then add 2-(4-chlorophenyl)-N-methoxy-N-methylacetamide (850 mg, 4 mmol), and stir at room temperature for 2 hours. The reaction solution is added to saturated ammonium chloride solution (50 ml), extracted with ethyl acetate (10 ml x 3), the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by silica gel column chromatography to obtain 250 mg of tert-butyl (5-(2-(4-chlorophenyl)acetyl)thiazol-2-yl)carbamate.

[0206] MS (ESI) M / Z: 353.1 [M+H] + .

[0207] 1 H NMR (400MHz, DMSO-d6) δ12.04(s,1H),8.46(s,1H),7.39-7.36(m,2H),7.33-7.30(m,2H),4.24(s,2H),1.49(s,9H).

[0208] Step C: Dissolve tert-butyl (5-(2-(4-chlorophenyl)acetyl)thiazol-2-yl)carbamate (250 mg, 0.71 mmol) in dichloromethane (3 ml), add trifluoroacetic acid (1 ml), stir the reaction solution at room temperature for 16 hours, and concentrate under reduced pressure. The residue is diluted with dichloromethane (5 ml) and concentrated under reduced pressure to obtain 250 mg of the product 1-(2-aminothiazol-5-yl)-2-(4-chlorophenyl)ethane-1-one.

[0209] MS (ESI) M / Z: 253.1 [M+H] + .

[0210] 1H NMR (400MHz, DMSO-d6) δ8.20(brs,2H),8.18(s,1H),7.37-7.34(m,2H),7.32-7.29(m,2H),4.08(s,2H).

[0211] Step D: 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (synthesized with reference to WO2022118210, 28 mg, 0.10 mmol), 1-(2-aminothiazol-5-yl)-2-(4-chlorophenyl)ethane-1-one (30.33 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (0.6 ml), followed by the addition of HATU (45.63 mg, 0.12 mmol) and diisopropylethylamine (38.77 mg, 0.30 mmol), and the reaction solution was reacted at room temperature for 3 hours. The reaction solution was purified by preparative high performance liquid chromatography to obtain 6.7 mg of 2'-chloro-N-(5-(2-(4-chlorophenyl)acetyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0212] MS (ESI) M / Z: 513.1 [M+H] + .

[0213] 1 HNMR(400MHz,DMSO-d6)δ13.21(br s,1H),8.82(s,1H),8.61(s,1H),8.15(s,1H),7.56(s,1H),7.45(s,1H),7.40-7.32(m,4H),4.30(s,2H),3.56(s,3H),2.59(s,3H).

[0214] Example 2 2'-Chloro-5'-methoxy-6-methyl-N-(5-(2-phenylacetyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide

[0215] Reaction route:

[0216]

[0217] Steps:

[0218] Step A: Dissolve dimethylhydroxylamine hydrochloride (1.95 g, 20.02 mmol) in N,N-dimethylformamide (40 ml), add diisopropylethylamine (2.59 g, 20.02 mmol), 2-((tert-butyloxycarbonyl)amino)thiazole-5-carboxylic acid (4.89 g, 20 mmol) and HATU (7.61 g, 20.02 mmol). Stir the reaction solution at room temperature for 1 hour, slowly add the reaction solution into water (200 ml), and continue stirring at room temperature for 1 hour. Filter, wash with water, and dry to obtain 5 g of product (5-(methoxy(methyl)carbamoyl)thiazol-2-yl)carbamic acid tert-butyl ester.

[0219] MS (ESI) M / Z: 288.1 [M+H] + .

[0220] 1 H NMR (400MHz, DMSO-d6) δ11.78(br s,1H),8.04(s,1H),3.76(s,3H),3.26(s,3H),1.50(s,9H).

[0221] Step B: Under nitrogen protection, tert-butyl (5-(methoxy(methyl)carbamoyl)thiazol-2-yl)carbamate (574.68 mg, 2 mmol) was dissolved in tetrahydrofuran (5 ml), and benzylmagnesium bromide (1.0 M, 8 ml) was slowly added dropwise at 0°C. After the addition was complete, the reaction solution was slowly warmed to room temperature and stirred for 16 hours. The reaction solution was slowly poured into a saturated ammonium chloride solution (30 ml) and extracted with ethyl acetate (10 ml x 3). The organic phases were combined, dried, concentrated, and the residue was purified by silica gel column chromatography to obtain 500 mg of the product (tert-butyl (5-(2-phenylacetyl)thiazol-2-yl)carbamate.

[0222] MS (ESI) M / Z: 319.2 [M+H] + .

[0223] 1 H NMR (400MHz, DMSO-d6) δ12.02(brs,1H),8.45(s,1H),7.34-7.29(m,4H),7.26-7.21(m,1H),4.21(s,2H),1.48(s,9H).

[0224] Step C: tert-Butyl (5-(2-phenylacetyl)thiazol-2-yl)carbamate (150 mg, 0.47 mmol) was dissolved in dichloromethane (2 ml), followed by the addition of trifluoroacetic acid (1 ml) and stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure, water (2 ml) was added to the residue, and the mixture was neutralized to pH 7 with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phases were combined and dried and concentrated to give 100 mg of the product 1-(2-aminothiazol-5-yl)-2-phenylethane-1-one.

[0225] MS (ESI) M / Z: 219.1 [M+H] + .

[0226] 1 H NMR(400MHz,DMSO-d6)δ8.15(s,1H),8.08(br s,2H),7.30-7.28(m,4H),7.24-7.20

[0227] (m,1H),4.04(s,2H).

[0228] Step D: 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (synthesized according to WO2022118210, 25 mg, 0.090 mmol) and 1-(2-aminothiazol-5-yl)-2-phenylethane-1-one (20 mg, 0.092 mmol) were dissolved in N,N-dimethylformamide (1 ml), followed by the addition of HATU (41.06 mg, 0.11 mmol) and diisopropylethylamine (34.89 mg, 0.27 mmol), and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was quenched by adding water (10 mL), extracted with ethyl acetate (10 mL x 3), the organic phases were combined, dried, and concentrated, and the resulting residue was purified by silica gel column chromatography to give 7.19 mg of the product 2'-chloro-5'-methoxy-6-methyl-N-(5-(2-phenylacetyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide.

[0229] MS (ESI) M / Z: 479.1 [M+H] + .

[0230] 1H NMR (400 MHz, DMSO-d6) δ 13.19 (brs, 1H), 8.82 (s, 1H), 8.60 (s, 1H), 8.15 (s, 1H), 7.56 (s, 1H), 7.45 (s, 1H), 7.33-7.31 (m, 4H), 7.26-7.23 (m, 1H), 4.26 (s, 2H), 3.56 (s, 3H), 2.59 (s, 3H). Example 3 2'-Chloro-N-(5-(2-(4-chlorophenyl))acetyl)thiazol-2-yl)-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0231] Reaction route:

[0232]

[0233] Steps:

[0234] 2'-Chloro-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (synthesized with reference to WO2022118210, 13 mg, 0.044 mmol), HATU (23.4 mg, 0.062 mmol) and triethylamine (18 μL, 0.18 mmol) were dissolved in N,N-dimethylformamide (1 ml) and stirred at room temperature for 15 minutes. Subsequently, 1-(2-aminothiazol-5-yl)-2-(4-chlorophenyl)ethane-1-one (16 mg, 0.062 mmol) was added and stirred at room temperature for 16 hours. The reaction solution was purified by preparative high performance liquid chromatography to obtain 3 mg of the product 2'-chloro-N-(5-(2-(4-chlorophenyl))acetyl)thiazol-2-yl)-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0235] MS (ESI) M / Z: 532.8 [M+H] + .

[0236] 1 H NMR(400MHz,DMSO-d6)δ13.35(s,1H),8.99(s,1H),8.61(s,1H),8.17(s,1H),7.50( s,1H),7.42-7.35(m,2H),7.35-7.29(m,2H),4.29(s,2H),3.69(s,3H),2.60(s,3H).

[0237] Example 4 N-(5-(2-(4-chlorophenyl)acetyl)thiazol-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0238] Reaction route: Steps:

[0239] 2'-(Difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (synthesized with reference to WO2022118210, 30 mg, 0.1 mmol), HATU (57 mg, 0.15 mmol), and triethylamine (42 μL, 0.3 mmol) were dissolved in N,N-dimethylformamide (1 ml) and stirred at room temperature for 15 minutes. Then 1-(2-aminothiazol-5-yl)-2-(4-chlorophenyl)ethane-1-one (16 mg, 0.062 mmol) was added and stirred at room temperature for 16 hours. The reaction solution was purified by preparative high performance liquid chromatography to obtain 3 mg of the product N-(5-(2-(4-chlorophenyl)acetyl)thiazol-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0240] MS (ESI) M / Z: 528.8 [M+H] + .

[0241] 1 HNMR(400MHz,DMSO-d6)δ13.23(brs,1H),8.84(s,1H),8.61(s,1H),8.45(s,1H),7.72(s,1H), 7.45(s,1H),7.42-7.30(m,4H),6.98(t,J=55.1Hz,1H),4.30(s,2H),3.65(s,3H),2.61(s,3H).

[0242] Example 5 2'-Chloro-N-(5-(cyclohexanecarbonyl)-1,3,4-thiadiazole-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide Reaction route:

[0243]

[0244] Steps:

[0245] Step A: 2-cyclohexyl-2-hydroxyacetic acid (500 mg, 3.16 mmol) was dissolved in phosphorus oxychloride (5 ml), and thiosemicarbazide (288.0 mg, 3.16 mmol) was added, and the mixture was reacted at 80°C for 1 hour. Water (10 ml) was slowly added to the system to quench the reaction, and 1N NaOH aqueous solution was added to adjust the pH to neutral, and the mixture was extracted with ethyl acetate (20 ml x 3), and the organic phases were combined and concentrated. The residue was purified by silica gel column chromatography to obtain 188 mg of compound (5-amino-1,3,4-thiadiazol-2-yl)(cyclohexyl)methanol.

[0246] MS (ESI) M / Z: 214.2 [M+H] + .

[0247] Step B: (5-amino-1,3,4-thiadiazol-2-yl)(cyclohexyl)methanol (373.28 mg, 0.70 mmol) was dissolved in dichloromethane, and active manganese dioxide (608.58 mg, 7.0 mmol) was added, and stirred at room temperature overnight. The reaction solution was filtered and concentrated, and the residue was purified by silica gel column chromatography to obtain 12 mg of compound 5-cyclohexanecarbonyl-1,3,4-thiadiazol-2-amine.

[0248] MS (ESI) M / Z: 212.2 [M+H] + .

[0249] 1 H NMR (400MHz, DMSO-d6) δ8.14 (s, 2H), 3.50-3.41 (m, 1H), 1.85 (dd, J = 8.3, 4.2Hz, 2H), 1.79-1.61 (m, 4H), 1.39-1.31 (m, 4H).

[0250] Step C: Dissolve 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (synthesized according to WO2022118210, 13.93 mg, 0.05 mmol) in acetonitrile (3 ml), and then add TFCH (14.03 mg, 0.05 mmol) and 1-methylimidazole (8.21 mg, 0.1 mmol) in sequence, stir at room temperature for 15 minutes, then add 5-cyclohexanecarbonyl-1,3,4-thiadiazole-2-amine (10.56 mg, 0.05 mmol), and continue stirring at room temperature overnight. Water (10 mL) was added to quench the reaction, and the product was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and concentrated. The residue was purified by preparative HPLC to give 4 mg of the product 4-(2-chloro-5-methoxypyridin-4-yl)-N-(5-cyclohexanecarbonyl-1,3,4-thiadiazol-2-yl)-6-methylpyridine-3-carboxamide.

[0251] MS (ESI) M / Z: 471.8 [M+H] + .

[0252] 1H NMR(400MHz,DMSO-d6)δ13.65(s,1H),8.86(s,1H),8.15(s,1H),7.58(s,1H),7.47(s,1H),3.60-3.50(m,4H) ,2.60(s,3H),1.95-1.91(m,2H),1.79-1.77(m,2H),1.70-1.67(m,1H),1.45-1.33(m,4H),1.25-1.22(m,1H).

[0253] Example 6 2'-Chloro-N-(5-(cyclopentanecarbonyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0254] Reaction route:

[0255]

[0256] Steps:

[0257] Referring to the preparation method in the above example, 2.2 mg of the product 2'-chloro-N-(5-(cyclopentanecarbonyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide was obtained.

[0258] MS (ESI) M / Z: 456.8 [M+H] + .

[0259] 1 H NMR(400MHz,DMSO-d6)δ13.11(s,1H),8.85(s,1H),8.39(s,1H),8.15(s,1H),7.52(s,1H),7.40(s,1H),3 .65(t,J=7.7Hz,1H),3.57(s,3H),2.58(s,3H),1.91-1.88(m,2H),1.76-1.71(m,2H),1.64-1.58(m,4H).

[0260] Example 7 2'-Chloro-5'-methoxy-6-methyl-N-(5-(tetrahydro-2H-pyran-4-carbonyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide

[0261]

[0262] Referring to the preparation method in the above example, 8.4 mg of the product 2'-chloro-5'-methoxy-6-methyl-N-(5-(tetrahydro-2H-pyran-4-carbonyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide was obtained.

[0263] MS (ESI) M / Z: 473.1 [M+H] + .

[0264] 1 HNMR(400MHz,DMSO-d6)δ13.13(brs,1H),8.84(s,1H),8.51(s,1H),8.15(s,1H),7.54(s,1H),7 .42(s,1H),3.91-3.87(m,2H),3.57(s,3H),3.54-3.39(m,3H),2.59(s,3H),1.72-1.57(m,4H).

[0265] Example 8 2'-Chloro-N-(5-(2-(2,3-dihydro-1H-inden-2-yl)acetyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0266] Reaction route:

[0267]

[0268] Steps:

[0269] Step A: 2-(2,3-dihydro-1H-inden-2-yl)acetic acid (500 mg, 2.84 mmol) was dissolved in DMF (10 ml), and HATU (1295.8 mg, 3.41 mmol) and triethylamine (632.24 mg, 6.25 mmol) were added in sequence, and the mixture was reacted at room temperature for 15 minutes. Dimethylhydroxylamine hydrochloride (304.71 mg, 3.12 mmol) was then added to the system, and the mixture was reacted at room temperature for 4 hours. Water (10 ml) was added to the system, and the mixture was extracted with ethyl acetate (30 ml x 3). The organic phase was concentrated, and the residue was purified by silica gel column chromatography to obtain 526 mg of the product 2-(2,3-dihydro-1H-inden-2-yl)-N-methoxy-N-methylacetamide.

[0270] MS (ESI) M / Z: 220.8 [M+H] + .

[0271] Step B: Dissolve tert-butyl N-(5-bromo-thiazol-2-yl)carbamate (558.3 ​​mg, 2 mmol) in anhydrous tetrahydrofuran (10 ml), cool to -78°C, slowly drop n-butyl lithium (2.4 ml, 2.5 mol / L) into the system, and continue stirring at -78°C for 1 hour after the addition. Then slowly drop a solution of 2-(2,3-dihydro-1H-inden-2-yl)-N-methoxy-N-methylacetamide (526.27 mg, 2.4 mmol) in anhydrous tetrahydrofuran (3 ml) into the reaction system, and continue to react at -78°C for 2 hours. Water (10 mL) was added to the system, and the mixture was extracted with ethyl acetate (30 mL×3). The residue was purified by silica gel column chromatography to give 262 mg of product tert-butyl N-(5-(2-(2,3-dihydro-1H-inden-2-yl)acetyl)thiazol-2-yl)carbamate.

[0272] MS (ESI) M / Z: 302.2 [M+H-Bu -t ] + .

[0273] Step C: Dissolve tert-butyl N-(5-(2-(2,3-dihydro-1H-inden-2-yl)acetyl)thiazol-2-yl)carbamate (130 mg, 0.24 mmol) in dichloromethane (2 ml), add trifluoroacetic acid (2 ml), and react at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure, and the obtained residue is used directly in the next step without purification.

[0274] MS (ESI) M / Z: 258.6 [M+H] + .

[0275] Step D: 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (synthesized according to WO2022118210, 27.87 mg, 0.1 mmol) was dissolved in acetonitrile (3 ml), and TFCH (28.06 mg, 0.1 mmol) and N-methylimidazole (24.63 mg, 0.30 mmol) were added in sequence. The mixture was stirred at room temperature for 15 minutes, and 1-(2-aminothiazol-5-yl)-2-(2,3-dihydro-1H-inden-2-yl)ethane-1-one (25.83 mg, 0.1 mmol) was added, and stirring was continued at room temperature overnight. Water (10 ml) was added to the system, extracted with ethyl acetate (10 ml×3), and the organic phase was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to give 6 mg of product 2'-chloro-N-(5-(2-(2,3-dihydro-1H-inden-2-yl)acetyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0276] MS (ESI) M / Z: 518.8 [M+H]+ .

[0277] 1 H NMR(400MHz,DMSO-d6)δ13.15(s,1H),8.83(s,1H),8.43(s,1H),8.16(s,1H),7.56(s,1H),7.45(s,1H),7.21-7.18(m,2H),7 .13-7.10(m,2H),3.58(s,3H),3.13(d,J=7.2Hz,2H),3.09-3.03(m,2H),2.90-2.80(m,1H),2.68-2.61(m,2H),2.59(s,3H).

[0278] Example 9 2'-Chloro-5'-methoxy-6-methyl-N-(5-(2-(tetrahydro-2H-pyran-4-yl)acetyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide

[0279] Reaction route:

[0280]

[0281] Steps:

[0282] Referring to the preparation method in the above example, 10.8 mg of the product 2'-chloro-5'-methoxy-6-methyl-N-(5-(2-(tetrahydro-2H-pyran-4-yl)acetyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide was obtained.

[0283] MS (ESI) M / Z: 487.1 [M+H] + .

[0284] 1 HNMR(400MHz,DMSO-d6)δ13.16(brs,1H),8.82(s,1H),8.44(s,1H),8.15(s,1H),7.55(s,1H),7.44(s,1H),3.81(dd,J=11.2,2.4Hz,2H),3.56(s,3 H),3.29(td,J=11.6,2.4Hz,2H),2.84(d,J=6.8Hz,2H),2.59(s,3H),2.08 -2.03(m,1H),1.56(dd,J=12.8,2.0Hz,2H),1.26(qd,J=12.0,4.4Hz,2H).

[0285] Example 10 2'-Chloro-N-(5-((4-chlorobenzyl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0286] Reaction route:

[0287]

[0288] Steps:

[0289] Step A: 1-chloro-4-(chloromethyl)benzene (200 mg, 1.24 mmol) was dissolved in ethanol / water (3 ml, 2 / 1), sodium hydroxide (546.6 mg, 13.6 mmol) and 5-amino-1,3,4-thiadiazole-2-thiol (165.4 mg, 1.24 mmol) were added at room temperature, and the reaction system was stirred at room temperature for 1 hour. Water (10 ml) was added to quench the reaction, the mixed solution was filtered, and the solid was washed with water and ethanol / n-hexane (1 / 1). The residue was purified by silica gel column chromatography to obtain 176 mg of 5-((4-chlorobenzyl)thio)-1,3,4-thiadiazole-2-amine.

[0290] MS (ESI) M / Z: 258.0 [M+H] + .

[0291] Step B: 5-((4-chlorobenzyl)thio)-1,3,4-thiadiazol-2-amine (50 mg, 0.20 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (50 mg, 0.18 mmol) and 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (synthesized by referring to WO2022118210, 45 mg, 0.16 mmol) were dissolved in acetonitrile / N,N-dimethylformamide (2 ml, 15 / 1), and then nitrogenmethylimidazole (29.2 mg, 0.35 mmol) was added, and the reaction solution was stirred at room temperature for 16 hours. The solid was filtered, rinsed with acetonitrile and methanol, and dried to give 44.6 mg of 2'-chloro-N-(5-((4-chlorobenzyl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0292] MS (ESI) M / Z: 518.4 [M+H] + .

[0293] 1HNMR(400MHz,DMSO-d6)δ13.23(s,1H),8.82(s,1H),8.15(s,1H),7.55(s,1H),7.48-7.34(m,5H),4.48(s,2H),3.55(s,3H),2.59(s,3H).

[0294] Example 11 2'-Chloro-5'-methoxy-6-methyl-N-(5-((tetrahydro-2H-pyran-4-yl)thio)-1,3,4-thiadiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide

[0295] Reaction route:

[0296]

[0297] Steps:

[0298] Step A: 5-amino-1,3,4-thiadiazole-2-thiol (403 mg, 3.0 mmol) was dissolved in ethanol (15 ml) at room temperature, potassium hydroxide (170 mg, 3.0 mmol) was added, the reaction system was stirred at room temperature for 10 minutes, and then 4-bromotetrahydro-2H-pyran (0.34 ml) was added, and the reaction system was stirred at 80°C for 16 hours. The reaction solution was cooled to room temperature, water (30 ml) was added to quench the reaction, and the ethanol was removed by concentration under reduced pressure, and the organic phase was extracted with ethyl acetate (30 ml × 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 420 mg of 5-((tetrahydro-2H-pyran-4-yl)thio)-1,3,4-thiadiazole-2-amine.

[0299] MS (ESI) M / Z: 218.0 [M+H] + .

[0300] 1 H NMR (400MHz, DMSO-d6) δ7.38(s,2H),3.87-3.79(m,2H),3.56-3.47(m,1H),3.43-3.34(m,2H),1.94-1.86(m,2H),1.62-1.52(m,2H).

[0301] Step B: 5-((tetrahydro-2H-pyran-4-yl)thio)-1,3,4-thiadiazol-2-amine (50 mg, 0.23 mmol), TCFH (71 mg, 0.25 mmol) and 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (64 mg, 0.23 mmol) were dissolved in acetonitrile (1.5 ml) and N,N-dimethylformamide (0.1 ml), and nitrogen methyl imidazole (0.04 ml, 0.51 mmol) was added, and the reaction solution was stirred at 30°C for 2 hours. Water (10 ml) was added to quench the reaction, filtered, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 70 mg of 2'-chloro-5'-methoxy-6-methyl-N-(5-((tetrahydro-2H-pyran-4-yl)thio)-1,3,4-thiadiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide.

[0302] MS (ESI) M / Z: 478.2 [M+H] + .

[0303] 1 H NMR (400MHz, DMSO-d6) δ13.28(s,1H),8.83(s,1H),8.16(s,1H),7.56(s,1H),7.45(s,1H),3.86-3. 78(m,2H),3.59(s,3H),3.47-3.39(m,3H),2.59(s,3H),1.98(d,J=12.3Hz,2H),1.71-1.58(m,2H).

[0304] Example 12 2'-Chloro-N-(5-((trans-4-hydroxycyclohexyl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0305] Reaction route:

[0306]

[0307] Steps:

[0308] Step A: Dissolve trans-cyclohexane-1,4-diol (2 g, 12.91 mmol) in anhydrous N,N-dimethylformamide (20 ml), cool the reaction solution to 0 degrees Celsius, and add imidazole (1.76 g, 19.37 mmol) and tert-butyldimethylsilyl chloride (2.85 g, 14.21 mmol) to the reaction solution in sequence. Stir the reaction solution at room temperature for 18 hours. Add water (100 ml) to the reaction solution to quench, extract with ethyl acetate (40 ml × 3 times), combine the organic phases, wash the organic phases with saturated brine (60 ml), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography to obtain 2.17 g of compound trans-4-((tert-butyldimethylsilyl)oxy)cyclohexane-1-ol.

[0309] MS (ESI) M / Z: 231.1 [M+H] + .

[0310] 1 H NMR (400MHz, DMSO-d6) δ4.43 (d, J = 4.2Hz, 1H), 3.64-3.54 (m, 1H), 3.45-3. 36(m,1H),1.79-1.68(m,4H),1.31-1.11(m,4H),0.84(s,9H),0.02(s,6H).

[0311] Step B: Under nitrogen protection, trans-4-((tert-butyldimethylsilyl)oxy)cyclohexane-1-ol (2.3 g, 10.0 mmol) and triphenylphosphine (3.14 g, 12.0 mmol) were dissolved in tetrahydrofuran (25 ml). The above reaction was cooled to zero degrees Celsius. Subsequently, a solution of carbon tetrabromide (3.97 g, 12.0 mmol) in tetrahydrofuran (5 ml) was slowly added dropwise to the above reaction solution, and the reaction solution was stirred for 18 hours at 0 degrees Celsius. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 730 mg of ((trans-4-bromocyclohexyl)oxy)(tert-butyl)dimethylsilane.

[0312] 1 H NMR (400MHz, DMSO-d6) δ4.52-4.32(m,1H),3.87-3.72(m,1H),2.04-1.94(m,2H),1.94-1.82(m,2H),1.66-1.46(m,4H),0.82(s,9H),0.00(s,6H).

[0313] Step C: Dissolve 5-amino-1,3,4-thiadiazole-2-thiol (331 mg, 2.49 mmol) in ethanol (9 ml), add potassium hydroxide (139 mg, 2.49 mmol) to the above solution, and stir the reaction solution at room temperature for 10 minutes. Then, add (((1R,4R)-4-bromocyclohexyl)oxy)(tert-butyl)dimethylsilane in ethanol (1 ml) dropwise to the above solution, and heat the reaction solution to 80 degrees Celsius and stir for 18 hours. The reaction solution is cooled to room temperature and quenched by adding ice water. The mixed solution was extracted with dichloromethane (30 ml × 3 times), and the organic phases were combined, washed with water (20 ml), 1 molar sodium hydroxide solution (20 ml) and saturated brine (20 ml) in sequence, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 153 mg of 5-((trans-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)thio)-1,3,4-thiadiazole-2-amine.

[0314] MS (ESI) M / Z: 346.8 [M+H] + .

[0315] 1 H NMR(400MHz,DMSO-d6)δ7.32(s,2H),3.69-3.52(m,1H),3.26-3.13(m,1H),2.02-1 .89(m,2H),1.85-1.71(m,2H),1.48-1.24(m,4H),0.89-0.74(m,9H),0.02(m,6H).

[0316] Step D: 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (synthesized by referring to WO2022118210, 20 mg, 0.06 mmol), 5-((trans-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)thio)-1,3,4-thiadiazol-2-amine (20 mg, 0.06 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (19 mg, 0.07 mmol), and N-methylimidazole (11 mg, 0.13 mmol) were dissolved in acetonitrile (1 ml) and N,N-dimethylformamide (0.07 ml) at room temperature. The reaction solution was stirred at room temperature for 16 hours, quenched by adding water (20 ml), and the mixture was extracted with ethyl acetate (15 ml × 3 times). The organic phases were combined, washed with water (20 ml) and saturated brine (20 ml) in sequence, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by thin layer silica gel plate to obtain 28 mg of N-(5-(((trans-4-(((tert-butyldimethylsilyl)oxy)cyclohexyl)thio)-1,3,4-thiadiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0317] MS (ESI) M / Z: 606.3 [M+H] + .

[0318] Step E: N-(5-(((trans-4-(((tert-butyldimethylsilyl)oxy)cyclohexyl)thio)-1,3,4-thiadiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (28 mg, 0.046 mmol) was dissolved in anhydrous tetrahydrofuran (1 ml), and tetrabutylammonium fluoride (0.23 ml, 0.23 mmol) was added to the reaction solution, and the reaction solution was stirred at room temperature overnight. The reaction solution was quenched by adding water (20 ml), extracted with ethyl acetate (15 ml x 3 times), and the organic phases were combined, washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 2 mg of 2'-chloro-N-(5-((trans-4-hydroxycyclohexyl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0319] MS (ESI) M / Z: 491.9 [M+H] + .

[0320] 1H NMR(400MHz,CD3OD)δ8.81(s,1H),8.07(s,1H),7.48(s,1H),7.42(s,1H),3.68(s,3H),3.62-3.55(m,1H),3 .52-3.46(m,1H),2.67(s,3H),2.25-2.13(m,2H),2.05-1.95(m,2H),1.62-1.46(m,2H),1.47-1.33(m,2H).

[0321] Example 13 2'-Chloro-N-(5-((cis-4-hydroxycyclohexyl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0322] Reaction route:

[0323]

[0324] Steps:

[0325] Step A: Under nitrogen protection, cis-4-((tert-butyldimethylsilyl)oxy)cyclohexane-1-ol (500 mg, 2.17 mmol), p-toluenesulfonyl chloride (433 mg, 2.28 mmol) and triethylamine (332.5 mg, 1.2 mmol) were dissolved in dichloromethane (8 ml). The reaction solution was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 430 mg of cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl 4-methylbenzenesulfonate.

[0326] 1 H NMR (400MHz, DMSO-d6) δ7.78(d,J=8.3Hz,2H),7.46(d,J=8.1Hz,2H),4.62-4.46(m,1H),3.74(d,J= 3.5Hz,1H),2.41(s,3H),1.83-1.62(m,4H),1.52-1.22(m,4H),0.83(d,J=7.3Hz,9H),0.00(s,6H).

[0327] Step B: 5-amino-1,3,4-thiadiazole-2-thiol (34.6 mg, 0.26 mmol) was dissolved in ethanol (3 ml), potassium hydroxide (14.56 mg, 0.26 mmol) was added to the above solution, and the reaction solution was stirred at room temperature for 10 minutes. Then, cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl 4-methylbenzenesulfonate (100 mg, 0.26 mmol) in ethanol (1 ml) was added dropwise to the above solution, and the reaction solution was heated to 80 degrees Celsius and stirred for 18 hours. The reaction solution was cooled to room temperature and quenched by adding ice water. The mixed solution was extracted with dichloromethane (30 ml × 3 times). The organic phases were combined and washed with water (20 ml), 1 molar sodium hydroxide solution (20 ml) and saturated brine (20 ml) in sequence, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 30 mg of 5-(((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)thio)-1,3,4-thiadiazole-2-amine.

[0328] MS (ESI) M / Z: 346.8 [M+H] + .

[0329] 1 H NMR (400MHz, DMSO-d6) δ7.31(s,2H),3.92-3.84(m,1H),3.40-3.33(m,1H),1.84-1.70(m,4H),1.65-1.50(m,4H),0.86(s,9H),0.02(m,6H).

[0330] Step C: 5-(((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)thio)-1,3,4-thiadiazol-2-amine (30 mg, 0.065 mmol), 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (synthesized with reference to WO2022118210, 20 mg, 0.06 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (41.86 mg, 0.14 mmol), N-methylimidazole (33.66 mg, 0.14 mmol) were dissolved in acetonitrile (1 ml) and N,N-dimethylformamide at room temperature. The reaction mixture was stirred at room temperature for 16 hours in a nitrogen system. Water (20 ml) was added to quench the mixture, and the mixture was extracted with ethyl acetate (15 ml × 3 times). The organic phases were combined, washed with water (20 ml) and saturated brine (20 ml) in turn, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by thin layer silica gel plate to obtain 46 mg of N-(5-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)thio)-1,3,4-thiadiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0331] MS (ESI) M / Z: 606.3 [M+H] + .

[0332] Step D: N-(5-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)thio)-1,3,4-thiadiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (40 mg, 0.066 mmol) was dissolved in anhydrous tetrahydrofuran (1 ml), and then tetrabutylammonium fluoride (0.23 ml, 0.23 mmol) was added to the reaction solution, and the reaction solution was stirred at room temperature overnight. Water (20 ml) was added to the reaction solution to quench, and ethyl acetate (15 ml × 3 times) was used for extraction, and the organic phases were combined, washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to give 10.6 mg of 2'-chloro-N-(5-((cis-4-hydroxycyclohexyl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0333] MS (ESI) M / Z: 492.0 [M+H] + .

[0334] 1H NMR(400MHz,CD3OD)δ8.80(s,1H),8.07(s,1H),7.49(s,1H),7.43(s,1H),3.83 -3.70(m,2H),3.68(s,3H),2.67(s,3H),1.96-1.89(m,4H),1.77-1.70(m,4H).

[0335] Example 14 2'-Chloro-3'-fluoro-N-(5-((cis-4-hydroxycyclohexyl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0336] Reaction route:

[0337]

[0338] Referring to the preparation method in the above example, 1.3 mg of 2'-chloro-3'-fluoro-N-(5-((cis-4-hydroxycyclohexyl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide was obtained.

[0339] MS (ESI) M / Z: 510.3 [M+H] + .

[0340] 1 H NMR (400MHz, CD3OD) δ8.94(s,1H),8.04(s,1H),7.46(s,1H),3.82-3.71(m,5H),2.67(s,3H),1.97-1.84(m,4H),1.81-1.70(m,4H).

[0341] Example 15 2'-Chloro-N-(5-((2-cyclopropyl-2-oxoethyl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0342] Reaction route:

[0343]

[0344] Referring to the preparation method in the above example, 22.4 mg of the product 2'-chloro-N-(5-((2-cyclopropyl-2-oxoethyl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide was obtained.

[0345] MS (ESI) M / Z: 476.8 [M+H] + .

[0346] 1 H NMR(400MHz,DMSO-d6)δ13.20(s,1H),8.83(s,1H),8.16(s,1H),7.54(s,1H),7.43(s,1H),4. 48(s,2H),3.59(s,3H),2.59(s,3H),2.29-2.23(m,1H),0.99-0.93(m,2H),0.91-0.87(m,2H).

[0347] Example 16 2'-Chloro-N-(5-((2-(4-chlorophenyl)-2-oxoethyl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0348] Reaction route:

[0349]

[0350] Steps:

[0351] Step A: 2-bromo-1-(4-chlorophenyl)ethane-1-one (233 mg, 1 mmol), 5-amino-1,3,4-thiadiazole-2-thiol (133 mg, 1 mmol), potassium carbonate (166 mg, 1.2 mmol) were dissolved in N,N-dimethylformamide (4 ml) and stirred at room temperature for 5 hours. Water (10 ml) was added to quench the mixture, and the mixture was extracted with ethyl acetate (10 ml x 3). The organic phases were combined, washed once with saturated sodium chloride (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 200 mg of the product 2-((5-amino-1,3,4-thiadiazole-2-yl)thio)-1-(4-chlorophenyl)ethane-1-one.

[0352] MS (ESI) M / Z: 286.0 [M+H] + .

[0353] 1 H NMR (400MHz, DMSO-d6) δ8.11-7.97(m,2H),7.72-7.60(m,2H),7.29(s,2H),4.80(s,2H).

[0354] Step B: 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (synthesized according to WO2022118210, 27.8 mg, 0.1 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (28 mg, 0.1 mmol), and N-methylimidazole (8.2 mg, 0.1 mmol) were dissolved in acetonitrile / N,N-dimethylformamide (1 ml / 1 ml), and the mixture was stirred at room temperature for 15 minutes, followed by addition of 2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-1-(4-chlorophenyl)ethane-1-one (28.6 mg, 0.1 mmol), and the mixture was stirred at room temperature overnight. The reaction was quenched by adding water, extracted with ethyl acetate (10 ml x 3), the organic phases were combined, washed once with saturated sodium chloride (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give 15 mg of 2'-chloro-N-(5-((2-(4-chlorophenyl)-2-oxoethyl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0355] MS (ESI) M / Z: 546.0 [M+H] + .

[0356] 1 H NMR(400MHz,DMSO-d6)δ13.21(s,1H),8.79(s,1H),8.14(s,1H),8.07-8.00(m,2H), 7.66-7.59(m,2H),7.54(s,1H),7.42(s,1H),5.02(s,2H),3.56(s,3H),2.56(s,3H).

[0357] Example 17 2'-Chloro-N-(5-((5-chloro-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0358] Reaction route:

[0359]

[0360] Steps:

[0361] Step A: 5-chloro-1,3-dihydro-2H-inden-2-one (1 g, 6.002 mmol) was dissolved in anhydrous methanol (20 ml) at room temperature. Then, sodium borohydride (226 mg, 6.002 mmol) was added to the above solution under an ice-water bath in a nitrogen system, and the reaction solution was stirred at room temperature for 16 hours. Water (20 ml) was added to quench, and the mixture was extracted with ethyl acetate (20 ml × 3 times). The organic phase was first washed with saturated brine (5 ml), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 945 mg of compound 5-chloro-2,3-dihydro-1H-inden-2-ol.

[0362] 1 H NMR (400MHz, DMSO-d6) δ7.33-7.04(m,3H),4.89(d,J=3.9Hz,1H),4.54-4.44(m,1H),3.10-2.95(m,2H),2.78-2.65(m,2H).

[0363] Step B: 5-chloro-2,3-dihydro-1H-inden-2-ol (200 mg, 1.19 mmol) was dissolved in dichloromethane (2 ml) at room temperature. Subsequently, pyridine (3 ml) and p-toluenesulfonyl chloride (226 mg, 1.19 mmol) were added to the above solution under an ice-water bath in a nitrogen system. The reaction solution was stirred at room temperature for 16 hours. Water (50 ml) was added to quench, and the mixed solution was extracted with ethyl acetate (20 ml × 3 times). The organic phase was first washed with saturated brine (50 ml), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 220 mg of compound 5-chloro-2,3-dihydro-1H-inden-2-yl 4-methylbenzenesulfonate.

[0364] 1 H NMR(400MHz,DMSO-d6)δ7.82(d,J=8.3Hz,2H),7.50(d,J=8.0Hz,2H),7.25(s ,3H),5.29-5.24(m,1H),3.26-3.13(m,2H),3.01-2.89(m,2H),2.44(s,3H).

[0365] Step C: Under nitrogen protection, 5-amino-1,3,4-thiadiazole-2-thiol (90.86 mg, 0.68 mmol) was dissolved in ethanol (2 ml). Potassium hydroxide (38 mg) was added to the above solution under ice-water bath, and the reaction was stirred at room temperature for 20 minutes. 5-chloro-2,3-dihydro-1H-inden-2-yl 4-methylbenzenesulfonate (220 mg, 0.68 mmol) was added to the above solution. Water (50 ml) was added to quench, and ethyl acetate (20 ml × 3 times) was used for extraction. The organic phase was first washed with saturated brine (50 ml), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 160 mg of 5-((5-chloro-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazole-2-amine.

[0366] MS (ESI) M / Z: 284.1 [M+H] + .

[0367] Step D): 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (synthesized with reference to WO2022118210, 222 mg, 0.73 mmol), 5-((5-chloro-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazole-2-amine (160 mg, 0.038 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (422.8 mg, 1.51 mmol), N-methylimidazole (423 mg, 5.1 mmol) were dissolved in acetonitrile (3 ml) and N,N-dimethylformamide (0.21 ml) at room temperature. The reaction solution was stirred at room temperature for 16 hours under a nitrogen system. Water (20 ml) was added to quench the mixture, and dichloromethane (10 ml x 3 times) was used for extraction. The organic phases were combined, washed with water (30 ml) and saturated brine (30 ml) in sequence, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography to obtain 80 mg of 2'-chloro-N-(5-((5-chloro-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0368] MS (ESI) M / Z: 544.3 [M+H] + .

[0369] 1H NMR (400MHz, DMSO-d6) δ13.29(s,1H),8.84(s,1H),8.16(s,1H),7.56(s,1H),7.45(s,1H),7.34(s,1H),7.30-7. 26(m,1H),7.24-7.20(m,1H),4.56-4.44(m,1H),3.60(s,3H),3.52-3.45(m,2H),3.06-2.94(m,2H),2.60(s,3H).

[0370] Example 18 2'-Chloro-N-(5-((trans-2-hydroxycyclohexyl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0371] Reaction route:

[0372]

[0373] Steps:

[0374] Step A: 7-Oxabicyclo[4.1.0]heptane (980 mg, 10 mmol), 5-amino-1,3,4-thiadiazole-2-thiol (1.33 g, 10 mmol) and potassium carbonate (4.15 g, 30 mmol) were dissolved in N,N-dimethylformamide (50 ml) and stirred at room temperature for 2 hours. The reaction was quenched by adding water, extracted with ethyl acetate (100 ml x 3), the organic phases were combined, washed with saturated sodium chloride (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 509 mg of the product trans-2-((5-amino-1,3,4-thiadiazole-2-yl)thio)cyclohexane-1-ol.

[0375] MS (ESI) M / Z: 232.1 [M+H] + .

[0376] 1 H NMR (400MHz, DMSO-d6) δ7.30 (s, 2H), 5.05 (d, J = 5.6Hz, 1H), 3.38-3.33 (m, 1H), 3.14-3. 03(m,1H),2.05-1.95(m,1H),1.94-1.85(m,1H),1.69-1.52(m,2H),1.43-1.13(m,4H).

[0377] Step B: 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (synthesized according to WO2022118210, 27.8 mg, 0.1 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (28 mg, 0.1 mmol) were dissolved in acetonitrile / N,N-dimethylformamide (1 ml / 1 ml), and then N-methylimidazole (8.2 mg, 0.1 mmol) was added. After stirring at room temperature for 15 minutes, (1S,2S)-2-((5-amino-1,3,4-thiadiazol-2-yl)thio)cyclohexane-1-ol (23 mg, 0.1 mmol) was added and the reaction was allowed to react overnight. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to give 15 mg of 2'-chloro-N-(5-((trans-2-hydroxycyclohexyl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0378] MS (ESI) M / Z: 491.8 [M+H] + .

[0379] 1 H NMR (400MHz, DMSO-d6) δ13.21(s,1H),8.84(s,1H),8.18(s,1H),7.56(s,1H),7.45(s,1H),5.16(d,J=5.3Hz,1H),3.60(s,3H), 3.45-3.34(m,2H),2.60(s,3H),2.15-2.04(m,1H),1.97-1.88(m,1H),1.70-1.56(m,2H),1.48-1.37(m,1H),1.36-1.21(m,3H).

[0380] Example 19 2'-Chloro-N-(5-((cis-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0381] Reaction route:

[0382]

[0383] Referring to the preparation method in the above example, 15 mg of the product 2'-chloro-N-(5-((cis-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide was obtained.

[0384] MS (ESI) M / Z: 526.1 [M+H] + .

[0385] 1 HNMR(400MHz,DMSO-d6)δ13.23(brs,1H),8.84(s,1H),8.17(s,1H),7.56(s,1H),7.44(s,1H),7.37-7.36(m,1H),7.26-7.24(m,3H),5.95(d,J= 6.0Hz,1H),5.23(t,J=6.0Hz,1H),4.54(q,J=6.0Hz,1H),3.60(s,3H),3.41(dd,J=16.4,6.8Hz,1H),3.09(dd,J=16.4,6.0Hz,1H),2.59(s,3H).

[0386] Example 20 2'-Chloro-N-(5-((trans-2-hydroxy-2,3-dihydro-1H-inden-1-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0387] Reaction route:

[0388]

[0389] Steps:

[0390] Step A: Dissolve trans-2-bromo-2,3-dihydro-1H-inden-1-ol (2.13 g, 10 mmol) in N-methylpyrrolidone (20 ml), add sodium hydroxide (1.2 g, 30 mmol) and stir at room temperature for 16 hours. Slowly add 40 ml of water to the reaction solution, extract with methyl tert-butyl ether (20 ml x 3), combine the organic phases, dry and concentrate to obtain 0.6 g of the product 1a,6a-dihydro-6H-inden[1,2-b]oxirane.

[0391] 1 HNMR (400MHz, DMSO-d6): δ7.53(d,J=7.6Hz,1H),7.25-7.24(m,2H),7.19-7.15(m,1H),4 .34(dd,J=2.8,1.2Hz,1H),4.14(t,J=2.8Hz,1H),3.12-3.04(m,1H),3.00-2.90(m,1H).

[0392] Step B: 1a,6a-dihydro-6H-inden[1,2-b]oxirane (0.22 g, 1.66 mmol) and 5-amino-1,3,4-thiadiazole-2-thiol (0.22 g, 1.66 mmol) were dissolved in N-methylpyrrolidone (1.5 ml), sodium carbonate (0.53 g, 4.98 mmol) was added and stirred at 80°C for 2 hours. After the reaction solution was returned to room temperature, water (10 ml) was added dropwise and stirred for 30 minutes, filtered, washed with water, and dried to obtain 200 mg of the product trans-1-((5-amino-1,3,4-thiadiazole-2-yl)thio)-2,3-dihydro-1H-inden-2-ol.

[0393] MS (ESI) M / Z: 266.1 [M+H] + .

[0394] 1 HNMR(400MHz,DMSO-d6)δ7.38(br s,2H),7.36-7.34(m,1H),7.25-7.21(m,3H),5.48(d,J=4.4Hz,1H),4.57(d,J=2.8Hz ,1H),4.45-4.41(m,1H),3.17(dd,J=16.4,6.0Hz,1H),2.74(dd,J=16.4,2.8Hz,1H).

[0395] Step C: 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (synthesized with reference to WO2022118210, 28 mg, 0.10 mmol) and trans-1-((5-amino-1,3,4-thiadiazol-2-yl)thio)-2,3-dihydro-1H-indene-2-ol (53.07 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (0.6 ml), HATU (45.63 mg, 0.12 mmol) and diisopropylethylamine (38.77 mg, 0.30 mmol) were added, and the mixture was stirred at room temperature for 3 hours under nitrogen protection. The reaction solution was directly purified by preparative HPLC to obtain 7.4 mg of the product 2'-chloro-N-(5-((trans-2-hydroxy-2,3-dihydro-1H-inden-1-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0396] MS (ESI) M / Z: 526.1 [M+H] + .

[0397] 1HNMR(400MHz,DMSO-d6)δ13.25(brs,1H),8.84(s,1H),8.16(s,1H),7.54(s,1H),7.43(s,1H),7.37-7.35(m,1H),7.26-7.21(m,3H),5.53(d, J=4.4Hz,1H),4.81(d,J=3.2Hz,1H),4.49-4.45(m,1H),3.55(s,3H),3.19(dd,J=16.4,6.0Hz,1H),2.76(dd,J=16.4,3.2Hz,1H),2.59(s,3H).

[0398] Example 21 2'-(Difluoromethyl)-N-(5-((cis-4-hydroxycyclohexyl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0399] Reaction route:

[0400]

[0401] Referring to the preparation method in the above example, 11.4 mg of the product 2'-(difluoromethyl)-N-(5-((cis-4-hydroxycyclohexyl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide was obtained.

[0402] MS (ESI) M / Z: 508.4 [M+H] + .

[0403] 1 H NMR(400MHz,CD3OD)δ8.81(s,1H),8.36(s,1H),7.71(s,1H),7.45(s,1H),6.75(t,J =55.4Hz,1H),3.81-3.70(m,5H),2.68(s,3H),2.02-1.85(m,4H),1.82-1.64(m,4H).

[0404] Example 22 2'-Chloro-N-(5-((trans-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0405] Reaction route:

[0406]

[0407] Steps:

[0408] Step A: 1,4-dihydronaphthalene (510 mg, 3.86 mmol) was dissolved in dichloromethane (10 ml), p-toluenesulfonic acid (1.00 g, 5.79 mmol) was added at 0°C and stirred for 5 hours. Water (40 ml) was added, and methyl tert-butyl ether (20 ml) was extracted, and the organic phases were combined, washed with saturated sodium bicarbonate solution (10 ml), water, and brine, dried, and concentrated under reduced pressure to obtain 0.5 g of the product 1a,2,7,7a-tetrahydronaphtho[2,3-b]oxirane.

[0409] 1 HNMR(400MHz,DMSO-d6)δ7.11-7.08(m,2H),7.04-7.01(m,2H),3.43-3.41(m,

[0410] 2H), 3.17-3.14 (m, 4H).

[0411] Step B: 1a,2,7,7a-tetrahydronaphtho[2,3-b]oxirane (0.20 g, 1.37 mmol) and 5-amino-1,3,4-thiadiazole-2-thiol (0.18 g, 1.37 mmol) were dissolved in N-methylpyrrolidone (3 ml), sodium carbonate (2.42 g, 4.11 mmol) was added and stirred at 80 degrees Celsius for 2 hours. After the reaction was restored to room temperature, water (10 ml) was added dropwise and stirred for 30 minutes, filtered, washed with water, and dried to obtain 0.2 g of the product trans-3-((5-amino-1,3,4-thiadiazole-2-yl)thio)-1,2,3,4-tetrahydronaphthalen-2-ol.

[0412] MS (ESI) M / Z: 280.1 [M+H] + .

[0413] 1 HNMR(400MHz,DMSO-d6)δ7.35(brs,2H),7.12-7.05(m,4H),5.38(d,J=4.4Hz,1H),3.97-3.91(m,1H),3.70-3.66(m,1H) ,3.29(dd,J=16.8,5.2Hz,1H),3.11(dd,J=16.8,4.8Hz,1H),2.85(dd,J=16.8,7.2Hz,1H),2.74(dd,J=16.8,6.4Hz,1H).

[0414] Step C: 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (synthesized with reference to WO2022118210, 28 mg, 0.10 mmol) and trans-3-((5-amino-1,3,4-thiadiazol-2-yl)thio)-1,2,3,4-tetrahydronaphthalen-2-ol (60 mg, 0.21 mmol) were dissolved in N,N-dimethylformamide (0.6 ml), followed by the addition of HATU (45.63 mg, 0.12 mmol) and diisopropylethylamine (38.77 mg, 0.30 mmol), and the mixture was stirred at room temperature for 3 hours under nitrogen protection. The reaction solution was purified by preparative high performance liquid chromatography to obtain 9.8 mg of the product 2'-chloro-N-(5-((trans-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0415] MS (ESI) M / Z: 540.1 [M+H] + .

[0416] 1 HNMR(400MHz,DMSO-d6)δ13.24(brs,1H),8.84(s,1H),8.16(s,1H),7.55(s,1H) ,7.44(s,1H),7.13-7.05(m,4H),5.48(d,J=4.8Hz,1H),4.03-3.98(m,1H),3.95 -3.91(m,1H),3.60(s,3H),3.38(dd,J=16.8,5.2Hz,1H),3.12(dd,J=16.8,4.8H z,1H),2.92(dd,J=16.8,7.2Hz,1H),2.77(dd,J=17.2,6.4Hz,1H),2.59(s,3H).

[0417] Example 23 2'-Chloro-N-(5-((cis-5-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0418] Reaction route:

[0419]

[0420] Steps:

[0421] Step A: 1-oxo-2,3-dihydro-1H-indene-5-carbonitrile (1.57 g, 10 mmol), N-bromosuccinimide (1.78 g, 10 mmol) and p-toluenesulfonic acid (0.172 g, 1 mmol) were dissolved in tetrachloride 1-oxo-2,3-dihydro-1H-indene-5-carbonitrile (10 ml) and stirred at 60 degrees Celsius for 1 hour. Water (5 ml of water) was added to quench and extracted with dichloromethane (3 ml x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried, and concentrated under reduced pressure to obtain 1.3 g of crude product 2-bromo-1-oxo-2,3-dihydro-1H-indene-5-carbonitrile.

[0422] 1 HNMR (400MHz, DMSO-d6) δ8.13(s,1H),7.95-7.90(m,2H),5.09(dd,J=7.6,2.8Hz,1H),3.93(dd,J=18.4,7.6Hz,1H),3.38(dd,J=18.4,2.8Hz,1H).

[0423] Step B: 2-bromo-1-oxo-2,3-dihydro-1H-indene-5-carbonitrile (0.5 g, 2.12 mmol) and 5-amino-1,3,4-thiadiazole-2-thiol (0.282 g, 2.12 mmol) were added to water (10 ml), sodium bicarbonate (0.213 g, 2.54 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered, washed with water, and dried to obtain 0.45 g of the product 2-((5-amino-1,3,4-thiadiazole-2-yl)thio)-1-oxo-2,3-dihydro-1H-indene-5-carbonitrile.

[0424] MS (ESI) M / Z: 289.1 [M+H] + .

[0425] Step C: 2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-1-oxo-2,3-dihydro-1H-indene-5-carbonitrile (290 mg, 1.01 mmol) was dissolved in methanol (6 ml), sodium borohydride (321.15 mg, 3.03 mmol) was added at 0°C, and stirred for 15 minutes. Water (20 ml) was added, filtered, washed with water, and dried to obtain 150 mg of the product cis-2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-1-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile.

[0426] MS (ESI) M / Z: 291.1 [M+H] + .

[0427] 1HNMR (400MHz, DMSO-d6) δ7.74(brs,1H),7.71(d,J=7.6Hz,1H),7.52(d,J=7.6Hz,1H),7.30(brs,2H),6.20( d,J=6.0Hz,1H),5.30(t,J=6.0Hz,1H),4.44-4.37(m,1H),3.39-3.33(m,1H),3.08(dd,J=16.8,4.8Hz,1H).

[0428] Step D: 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (synthesized with reference to WO2022118210, 28 mg, 0.10 mmol) and cis-2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-1-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile (58 mg, 0.23 mmol) were dissolved in N,N-dimethylformamide (0.6 ml), HATU (45.63 mg, 0.12 mmol) and diisopropylethylamine (38.77 mg, 0.30 mmol) were added, and the mixture was stirred at room temperature for 3 hours under nitrogen protection. The reaction solution was purified by preparative HPLC to obtain 9.4 mg of the product 2'-chloro-N-(5-(((1S,2R)-5-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0429] MS (ESI) M / Z: 551.1 [M+H] + .

[0430] 1 HNMR(400MHz,DMSO-d6)δ13.24(br s,1H),8.84(s,1H),8.17(s,1H),7.75(s,1H),7.72(d,J=7.9Hz,1H),7.57-7.50(m,2H),7.44(s,1H),6.26(d,J=6.1Hz,1H),5.34( d,J=6.0Hz,1H),4.62(td,J=6.1,5.2Hz,1H),3.60(s,3H),3.46(dd,J=16.7,6.7Hz,1H),3.12(dd,J=16.8,4.8Hz,1H),2.59(s,3H).

[0431] Example 24 2'-Chloro-N-(5-((trans-7-chloro-2-hydroxy-2,3-dihydro-1H-inden-1-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0432] Reaction route:

[0433]

[0434] Referring to the preparation method in the above example, 21.4 mg of the product 2'-chloro-N-(5-((trans-7-chloro-2-hydroxy-2,3-dihydro-1H-inden-1-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide was obtained.

[0435] MS (ESI) M / Z: 561.0 [M+H] + .

[0436] 1 HNMR(400MHz,DMSO-d6)δ13.33(brs,1H),8.83(s,1H),8.18(s,1H),7.56(s,1H),7.45(s,1H),7.33-7.25(m,3H),5.52(brs,1 H), 4.81 (s, 1H), 4.55 (d, J = 4.4Hz, 1H), 3.57 (s, 3H), 3.26 (dd, J = 16.8, 4.8Hz, 1H), 2.80 (dd, J = 17.2, 3.2Hz, 1H), 2.59 (s, 3H).

[0437] Example 25 2'-Chloro-N-(5-((trans-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-1-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0438] Reaction route:

[0439]

[0440] Referring to the preparation method in the above example, 5.64 mg of the product 2'-chloro-N-(5-((trans-7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-1-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide was obtained.

[0441] MS (ESI) M / Z: 544.1 [M+H] + .

[0442] 1 HNMR(400MHz,DMSO-d6)δ13.30(brs,1H),8.86(s,1H),8.17(s,1H),7.53( s,1H),7.41(s,1H),7.34-7.31(m,1H),7.13(d,J=7.6Hz,1H),7.05(d,J=9 .0Hz,1H),5.55(d,J=3.6Hz,1H),4.87(s,1H),4.55(t,J=3.6Hz,1H),3.57 (s,3H),3.23(dd,J=17.2,5.2Hz,1H),2.78(d,J=16.8Hz,1H),2.59(s,3H).

[0443] Example 26 2'-Chloro-N-(5-((trans-2-hydroxycycloheptyl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0444] Reaction route:

[0445]

[0446] Steps:

[0447] Step A: 5-amino-1,3,4-thiadiazole-2-thiol (119 mg, 0.89 mmol) and sodium carbonate (189 mg, 1.78 mmol) were dissolved in N-methylpyrrolidone (3 ml). After stirring at room temperature for 1 hour, 8-oxabicyclo[5.1.0]octane (100 mg, 0.89 mmol) was added, and the reaction solution was heated at 80°C for 2 hours. Water (20 ml) was added to quench, and then extracted with ethyl acetate (5 ml × 3 times). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography to obtain 10 mg of the compound trans-2-((5-amino-1,3,4-thiadiazole-2-yl)thio)cycloheptane-1-ol.

[0448] MS (ESI) M / Z: 246.2 [M+H] + .

[0449] 1H NMR (400MHz, DMSO-d6) δ7.30 (s, 2H), 5.02 (d, J = 5.0Hz, 1H), 3.69-3.58 (m, 1H), 3.35(d,J=3.0Hz,1H),2.00-1.90(m,1H),1.74-1.60(m,5H),1.50-1.32(m,4H).

[0450] Step B: 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (synthesized according to WO2022118210, 13 mg, 0.044 mmol), trans-2-((5-amino-1,3,4-thiadiazol-2-yl)thio)cycloheptan-1-ol (10 mg, 0.04 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (13 mg, 0.044 mmol), N-methylimidazole (7.4 mg, 0.09 mmol) were dissolved in acetonitrile (1 ml) and N,N-dimethylformamide (0.07 ml). The reaction solution was stirred at room temperature for 72 hours. Water (20 ml) was added to quench the mixture, and then extracted with ethyl acetate (5 ml × 3 times). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and filtered. The residue was purified by preparative high performance liquid chromatography to give 4 mg of 2'-chloro-N-(5-((trans-2-hydroxycycloheptyl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0451] MS (ESI) M / Z: 506.4 [M+H] + .

[0452] 1 H NMR (400MHz, DMSO-d6) δ13.21(s,1H),8.84(s,1H),8.16(s,1H),7.54(s,1H),7.43(s,1H),5.10(d,J=5.0Hz,1H),3.7 1-3.63(m,1H),3.59(s,3H),3.58-3.54(m,1H),2.59(s,3H),2.03-1.94(m,1H),1.78-1.61(m,5H),1.54-1.37(m,4H).

[0453] Example 27 2'-Chloro-N-(5-(2-(4-chlorophenyl)propionyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0454] Reaction route:

[0455]

[0456] Referring to the preparation method in the above example, 4 mg of the compound 2'-chloro-N-(5-(2-(4-chlorophenyl)propionyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide was obtained.

[0457] MS (ESI) M / Z: 527.3 [M+H] + .

[0458] 1 H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.81 (s, 1H), 8.53 (s, 1H), 8.14 (s, 1H), 7.54 (s, 1H), 7.44-7.37 (m, 5H), 4.79 (q, J = 6.7 Hz, 1H), 3.54 (s, 3H), 2.58 (s, 3H), 1.40 (d, J = 6.9 Hz, 3H). Example 28 and Example 29

[0459] (R)-2'-Chloro-N-(5-(2-(4-chlorophenyl)propionyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 28 or Compound 29)

[0460] (S)-2'-Chloro-N-(5-(2-(4-chlorophenyl)propionyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 29 or Compound 28)

[0461]

[0462] Compound 27 was separated by chiral chromatography (separation column: OZ-3 (250 mm*25 mm, 10 um); mobile phase: CO 2 / (0.2% ammonia methanol solution) = 45 / 55, flow rate: 100 ml / min, pressure: 100 bar, detection wavelength: 214 nM, obtained

[0463] Compound 28:

[0464] Analysis conditions: Daicel OZ-3 (4.6*100 mm, 3 um); CO2 / (0.2% ammonia methanol solution)=45 / 55, flow rate: 3.0 ml / min, detection wavelength: 214 nM; retention time: 0.922 min; ee: 100%; absolute configuration unknown, enantiomer of compound 29.

[0465] MS (ESI) M / Z: 527.3 [M+H] + .

[0466] 1 H NMR(400MHz,DMSO-d6)δ13.18(s,1H),8.81(s,1H),8.52(s,1H),8.13(s,1H),7.53(s,1H), 7.43-7.37(m,5H),4.78(q,J=6.8Hz,1H),3.54(s,3H),2.58(s,3H),1.40(d,J=6.9Hz,3H).

[0467] Compound 29:

[0468] Analysis conditions: Daicel OZ-3 (4.6*100mm, 3um); CO2 / (0.2% ammonia methanol solution)=45 / 55, flow rate: 3.0 ml / min, detection wavelength: 214 nM; retention time: 1.242 min; ee: 98.2%; absolute configuration unknown, enantiomer of compound 28.

[0469] MS (ESI) M / Z: 527.3 [M+H] + .

[0470] 1 H NMR(400MHz,DMSO-d6)δ13.18(s,1H),8.80(s,1H),8.54(s,1H),8.14(s,1H),7.54(s,1H), 7.45-7.35(m,5H),4.79(q,J=6.8Hz,1H),3.54(s,3H),2.58(s,3H),1.40(d,J=6.9Hz,3H).

[0471] Example 30 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(2-(4-chlorophenyl)acetyl)thiazol-2-yl)-6-methylnicotinamide

[0472]

[0473] Referring to the preparation method in the above example, 10 mg of the product 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(2-(4-chlorophenyl)acetyl)thiazol-2-yl)-6-methylnicotinamide was obtained.

[0474] MS (ESI) M / Z: 530.0 [M+H] + .

[0475] 1H NMR (400MHz, DMSO-d6) δ13.22(s,1H),8.88(s,1H),8.60(s,1H),7.60(t,J=8.8Hz,1H),7.43 -7.37(m,3H),7.36-7.32(m,2H),6.98-6.89(m,1H),4.30(s,2H),3.54(s,3H),2.59(s,3H).

[0476] Example 31 2'-Chloro-N-(5-((cis-7-chloro-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0477] Reaction route:

[0478]

[0479] Referring to the preparation method in the above example, 22 mg of 2'-chloro-N-(5-((cis-7-chloro-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide was obtained.

[0480] MS (ESI) M / Z: 561.0 [M+H] + .

[0481] 1 H NMR (400MHz, DMSO-d6) δ13.22(s,1H),8.85(s,1H),8.16(s,1H),7.54(s,1H),7.43(s,1H),7.35-7.22(m,3H),5.96(d,J=7.8Hz, 1H),5.21(dd,J=7.9,5.7Hz,1H),4.52-4.40(m,1H),3.61(s,3H),3.48(dd,J=16.0,7.8Hz,1H),3.26-3.18(m,1H),2.59(s,3H).

[0482] Example 32 2'-Chloro-N-(5-((cis-7-fluoro-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0483] Reaction route:

[0484]

[0485] Referring to the preparation method in the above example, 51 mg of 2'-chloro-N-(5-((cis-7-fluoro-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide was obtained.

[0486] MS (ESI) M / Z: 544.1 [M+H] + .

[0487] 1 HNMR(400MHz,DMSO-d6)δ13.23(brs,1H),8.84(s,1H),8.16(s,1H),7.55(s, 1H),7.44(s,1H),7.37-7.31(m,1H),7.11(d,J=7.6Hz,1H),7.04(t,J=8.8Hz ,1H),6.01(d,J=7.2Hz,1H),5.37-5.30(m,1H),4.51-4.45(m,1H),3.61(s,3 H), 3.47 (dd, J=16.0, 8.0Hz, 1H), 3.17 (dd, J=16.0, 8.8Hz, 1H), 2.59 (s, 3H).

[0488] Example 33 2'-Chloro-N-(5-((1-hydroxy-1-methyl-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0489] Reaction route:

[0490]

[0491] Referring to the preparation method in the above example, 9 mg of 2'-chloro-N-(5-((1-hydroxy-1-methyl-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide was obtained.

[0492] MS (ESI) M / Z: 540.3 [M+H] + .

[0493] 1H NMR (400MHz, DMSO-d6) δ13.27(s,1H),8.81(s,1H),8.16(s,1H),7.55(s,1H),7.44(s,1H),7.30-7.27(m,1H),7.25-7.19(m,3H),5.47(d,J= 5.2Hz,1H),4.56(dd,J=9.1,5.6Hz,1H),3.50(s,3H),3.22(dd,J=16.3,5.9Hz,1H),2.74(dd,J=16.3,3.6Hz,1H),2.59(s,3H),1.63(s,3H).

[0494] Example 34 2'-Chloro-N-(5-(2-(4-fluorophenyl)acetyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0495] Reaction route:

[0496]

[0497] Steps:

[0498] 2-(4-fluorophenyl)acetic acid was used instead of 2-(4-chlorophenyl)acetic acid, and the synthesis method of compound 1 was referred to obtain 2'-chloro-N-(5-(2-(4-fluorophenyl)acetyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0499] MS (ESI) M / Z: 496.8 [M+H] + .

[0500] 1 H NMR(400MHz,DMSO-d6)δ13.21(brs,1H),8.86(s,1H),8.56(s,1H),8.14(s,1H),7.52(s,1H),7.40( s,1H),7.34(dd,J=8.6,5.6Hz,2H),7.14(t,J=8.89Hz,2H),4.24(s,2H),3.56(s,3H),2.58(s,3H).

[0501] Example 35 2'-Chloro-N-(5-(2-(4-chloro-2-fluorophenyl)acetyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0502] Reaction route:

[0503]

[0504] Steps:

[0505] 2-(4-chloro-2-fluorophenyl)acetic acid was used instead of 2-(4-chlorophenyl)acetic acid, and the synthesis method of compound 1 was referred to obtain 2'-chloro-N-(5-(2-(4-chloro-2-fluorophenyl)acetyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0506] MS (ESI) M / Z: 531.3 [M+H] + .

[0507] 1 H NMR (400 MHz, DMSO-d6) δ 13.17 (brs, 1H), 8.87 (s, 1H), 8.56 (s, 1H), 8.15 (s, 1H), 7.53 (s, 1H), 7.44-7.35 (m, 3H), 7.27 (dd, J = 8.0, 1.7 Hz, 1H), 4.37 (s, 2H), 3.57 (s, 3H), 2.59 (s, 3H). Example 36 2'-Chloro-N-(5-(2-(4-chloro-3-fluorophenyl)acetyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0508] Reaction route:

[0509]

[0510] Steps:

[0511] 2-(4-chloro-3-fluorophenyl)acetic acid was used instead of 2-(4-chlorophenyl)acetic acid, and the synthesis method of compound 1 was referred to obtain 2'-chloro-N-(5-(2-(4-chloro-3-fluorophenyl)acetyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0512] MS (ESI) M / Z: 531.0 [M] + .

[0513] 1 H NMR(400MHz,DMSO-d6)δ13.23(s,1H),8.83(s,1H),8.61(s,1H),8.15(s,1H),7.57-7.52(m,2H),7.45(s,1H ),7.38(dd,J=10.5,1.9Hz,1H),7.17(d,J=8.3Hz,1H),4.35(s,2H),3.56(s,3H),3.30(s,5H),2.60(s,3H).

[0514] Example 37 2"-Chloro-N-(5-((cis-4-hydroxycyclohexyl)thio)-1,3,4-thiadiazol-2-yl)-5"-methoxy-4-methyl-2-oxo-2H-[1,2':4',4'-terpyridine]-5'-carboxamide

[0515] Reaction route:

[0516]

[0517] Steps:

[0518] Step A: 2',6-dichloro-5'-methoxy-[4,4'-bipyridine]-3-carboxylic acid methyl ester (synthesized according to WO2022118210, 100 mg, 0.32 mmol) and 4-methylpyridin-2(1H)-one (34.8 mg, 0.32 mmol) were dissolved in dimethyl sulfoxide (1.5 ml), potassium carbonate (44 mg) was added, and the reaction solution was stirred at 90°C for 16 hours. The reaction solution was quenched with water (5 ml), extracted with ethyl acetate (15 ml × 3), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by thin layer chromatography to obtain 67 mg of product 2"-chloro-5"-methoxy-4-methyl-2-oxo-2H-[1,2':4',4'-bipyridine]-5'-carboxylic acid methyl ester.

[0519] MS (ESI) M / Z: 386.3 [M+H] + .

[0520] 1 H NMR (400MHz, DMSO-d6) δ8.99(d,J=0.5Hz,1H),8.28(s,1H),7.97(d,J=0.5Hz,1H),7.93(d,J=7.3Hz ,1H),7.50(s,1H),6.36(s,1H),6.31(dd,J=7.3,1.8Hz,1H),3.82(s,3H),3.74(s,3H),3.31(s,3H).

[0521] Step B: Dissolve 2"-chloro-5"-methoxy-4-methyl-2-oxo-2H-[1,2':4'-4'-bipyridine]-5'-carboxylic acid methyl ester (67 mg, 0.17 mmol) in tetrahydrofuran (1 ml) and water (1 ml), add lithium hydroxide (36.4 mg, 0.87 mmol), and stir the reaction solution at room temperature for 16 hours. Concentrate under reduced pressure, add water (5 ml) to the residue, and adjust the pH value to 4-5 with dilute hydrochloric acid. Filter, wash with toluene, and concentrate under reduced pressure to obtain 46 mg of 2"-chloro-5"-methoxy-4-methyl-2-oxo-2H-[1,2':4'-,4'-bipyridine]-5'-carboxylic acid.

[0522] MS (ESI) M / Z: 372.3 [M+H] + .

[0523] 1 H NMR (400MHz, CD3OD) δ9.07(d,J=0.5Hz,1H),8.13(s,1H),7.94(d,J=7.3Hz,1H),7.84(d,J=0 .5Hz,1H),7.46(s,1H),6.46(s,1H),6.42(dd,J=7.2,1.8Hz,1H),3.86(s,3H),2.29(s,3H).

[0524] Step C: 2"-Chloro-5"-methoxy-4-methyl-2-oxo-2H-[1,2':4'-,4'-bipyridine]-5'-carboxylic acid (46 mg, 0.12 mmol), 5-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)thio)-1,3,4-thiadiazol-2-amine (39 mg, 0.11 mmol) and tetramethylchlorouronium hexafluorophosphate (34.8 mg, 0.12 mmol) were dissolved in acetonitrile (1.5 ml) and N,N,-dimethylformamide (0.1 ml), N-methylimidazole (0.02 ml, 0.24 mmol) was added, and the reaction solution was stirred at room temperature for 16 hours. Water (5 ml) was added to quench the reaction, and the mixture was extracted with ethyl acetate (15 ml x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by thin layer chromatography to give 30 mg of N-(5-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)thio)-1,3,4-thiadiazol-2-yl)-2'-chloro-5'-methoxy-4-methyl-2-oxy-2H-[1,2':4'-tripyridine]-5'-carboxamide (30 mg, colorless oil, yield 39%)

[0525] 1H NMR (400MHz, CD3OD) δ8.88(d,J=0.4Hz,1H),8.05(s,1H),7.93(d,J=0.5Hz,1H),7.89(d,J=7.2Hz,1H),7.52(s,1H),6.43(s,1H),6.38(dd,J=7.3,1 .8Hz,1H),3.65(s,3H),2.93-2.93(m,1H),2.80(d,J=0.6Hz,1H),2.25(d, J=0.7Hz,3H),1.87-1.83(m,4H),1.65(m,4H),0.84(s,9H),-0.00(s,6H).

[0526] Step D: N-(5-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)thio)-1,3,4-thiadiazol-2-yl)-2'-chloro-5'-methoxy-4-methyl-2-oxyl-2H-[1,2':4'-tripyridine]-5'-carboxamide (30 mg, 0.043 mmol) was dissolved in tetrahydrofuran (1 ml), tetrabutylammonium fluoride (0.21 ml, 0.215 mmol) was added, and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by preparative high performance liquid chromatography to give 5 mg of 2"-chloro-N-(5-((cis-4-hydroxycyclohexyl)thio)-1,3,4-thiadiazol-2-yl)-5"-methoxy-4-methyl-2-oxo-2H-[1,2':4',4'-terpyridine]-5'-carboxamide.

[0527] MS (ESI) M / Z: 585.0 [M+H] + .

[0528] 1 H NMR(400MHz,CD3OD)δ8.96(s,1H),8.10(s,1H),7.98(s,1H),7.95(d,J=7.2Hz,1H),7.58(s,1H),6.48(s,1H),6.44 (dd,J=7.3,1.7Hz,1H),3.80(s,1H),3.76(s,1H),3.70(s,3H),2.31(s,3H),1.97-1.90(m,4H),1.77-1.71(m,4H).

[0529] Example 38 2'-Chloro-N-(5-((trans-1-hydroxy-7-methyl-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0530] Reaction route:

[0531]

[0532] Referring to the preparation method in the above example, 25 mg of 2'-chloro-N-(5-((trans-1-hydroxy-7-methyl-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide was obtained.

[0533] MS (ESI) M / Z: 540.1 [M+H] + .

[0534] 1 HNMR(400MHz,DMSO-d6)δ13.28(brs,1H),8.85(s,1H),8.16(s,1H),7.55(s,1H),7 .44(s,1H),7.17(t,J=7.6Hz,1H),7.06(d,J=7.6Hz,1H),7.02(d,J=7.6Hz,1H),5.7 3(d,J=7.2Hz,1H),5.09(dd,J=7.2,3.6Hz,1H),4.06-4.02(m,1H),3.62(dd,J=17. 2,7.6Hz,1H),3.60(s,3H),2.85(dd,J=16.8,7.6Hz,1H),2.59(s,3H),2.32(s,3H).

[0535] Example 39 2'-Chloro-N-(5-((trans-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0536] Reaction route:

[0537]

[0538] Referring to the preparation method in the above example, 21 mg of the product 2'-chloro-N-(5-((trans-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide was obtained.

[0539] MS (ESI) M / Z: 526.1 [M+H] + .

[0540] 1H NMR(400MHz,DMSO-d6)δ13.28(brs,1H),8.88(s,1H),8.15(s,1H),7.52(s,1H),7.40(s,1H),7.36-7.30(m,1H),7.29-7.21(m,3H),5.96(d,J =6.8Hz,1H),5.04(t,J=6.5Hz,1H),4.00-3.87(m,1H),3.60(s,3H),3.52(dd,J=16.2,7.9Hz,1H),2.92(dd,J=16.2,7.6Hz,1H),2.59(s,3H).

[0541] Example 40 and Example 41

[0542] 2'-Chloro-N-(5-(((2S,3S)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 40 or Compound 41)

[0543] 2'-Chloro-N-(5-(((2R,3R)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-

[0544] [4,4'-Bipyridine]-3-carboxamide (Compound 41 or Compound 40)

[0545]

[0546] Compound 22 was separated by chiral chromatography (separation column: Daicel OD (250 mm*25 mm, 10 um); mobile phase: CO 2 / (0.5% ammonia ethanol solution) = 55 / 45, flow rate: 100 ml / min, pressure: 100 bar, detection wavelength: 214 nM, obtained

[0547] Compound 40:

[0548] Analysis conditions: Daicel OD (4.6*100 mm, 3 um); CO2 / (1% ammonia ethanol solution) = 55 / 45, flow rate: 3.0 ml / min, detection wavelength: 214 nM; retention time: 1.366 min; ee: 100%; absolute configuration unknown, enantiomer of compound 41.

[0549] MS (ESI) M / Z: 540.3 [M+H] + .

[0550] 1 H NMR(400MHz,DMSO-d6)δ13.25(s,1H),8.86(s,1H),8.15(s,1H),7.51(s,1 H),7.40(s,1H),7.14-7.02(m,4H),5.47(d,J=4.7Hz,1H),4.05-3.97(m,1H ),3.96-3.89(m,1H),3.60(s,3H),3.39(d,J=5.2Hz,1H),3.12(dd,J=17.0 ,4.8Hz,1H),2.91(dd,J=16.7,7.2Hz,1H),2.81-2.74(m,1H),2.58(s,3H).

[0551] Compound 41:

[0552] Analysis conditions: Analysis conditions: Daicel OD (4.6*100mm, 3um); CO2 / (1% ammonia ethanol solution) = 55 / 45, flow rate: 3.0 ml / min, detection wavelength: 214nM; retention time: 1.618min; ee: 100%; absolute configuration unknown, enantiomer of compound 40.

[0553] MS (ESI) M / Z: 540.3 [M+H + ].

[0554] 1 H NMR(400MHz,DMSO-d6)δ13.23(s,1H),8.85(s,1H),8.16(s,1H),7.53(s, 1H),7.41(s,1H),7.14-7.06(m,4H),5.48(d,J=4.7Hz,1H),4.04-3.98(m, 1H),3.95-3.90(m,1H),3.60(s,3H),3.43-3.36(m,1H),3.12(dd,J=17.0, 4.8Hz,1H),2.91(dd,J=16.9,7.2Hz,1H),2.81-2.74(m,1H),2.59(s,3H).

[0555] Example 42 2'-Chloro-N-(5-(2-cyclobutylacetyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide Reaction route:

[0556]

[0557] Referring to the preparation method in the above example, 10 mg of 2'-chloro-N-(5-(2-cyclobutylacetyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide was obtained.

[0558] MS (ESI) M / Z: 457.3 [M+H] + .

[0559] 1 H NMR(400MHz,DMSO-d6)δ13.13(s,1H),8.81(s,1H),8.42(s,1H),8.16(s,1H),7.56(s,1H),7.45(s,1H),3.56(s,3H ),3.03(d,J=7.4Hz,2H),2.68-2.65(m,1H),2.59(s,3H),2.10-1.99(m,2H),1.87-1.77(m,2H),1.76-1.65(m,2H).

[0560] Example 43 2'-Chloro-N-(5-(2-cyclobutylacetyl)thiazol-2-yl)-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0561]

[0562] 2'-Chloro-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (synthesized with reference to WO2022118210, 50 mg, 0.17 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (70 mg, 0.18 mmol) and 1-(2-aminothiazol-5-yl)-2-cyclobutylethane-1-one (30 mg, 0.15 mmol) were dissolved in N,N-dimethylformamide (1 ml), and N,N-diisopropylethylamine (0.08 ml, 0.46 mmol) was added. The reaction solution was stirred at room temperature for 16 hours under a nitrogen system. Water (20 ml) was added to quench the mixture, and the mixture was extracted with dichloromethane (5 ml × 3 times). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative high performance liquid chromatography to give 6.3 mg of 2'-chloro-N-(5-(2-cyclobutylacetyl)thiazol-2-yl)-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0563] MS (ESI) M / Z: 475.1 [M+H] + .

[0564] 1H NMR(400MHz,DMSO-d6)δ13.27(s,1H),8.98(s,1H),8.42(s,1H),8.17(s,1H),7.50(s,1H),3.69(s,3H),3.0 3(d,J=7.2Hz,2H),2.73-2.66(m,1H),2.60(s,3H),2.08-2.01(m,2H),1.87-1.80(m,2H),1.75-1.68(m,2H).

[0565] Example 44 2'-Chloro-N-(5-((2-hydroxy-2-methyl-2,3-dihydro-1H-inden-1-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0566] Reaction route:

[0567]

[0568] Referring to the preparation method in the above example, 20 mg of 2'-chloro-N-(5-((2-hydroxy-2-methyl-2,3-dihydro-1H-inden-1-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide was obtained.

[0569] MS (ESI) M / Z: 540.3 [M+H] + .

[0570] 1 H NMR (400MHz, DMSO-d6) δ13.26(s,1H),8.83(s,1H),8.18(s,1H),7.56(s,1H),7.45(s,1H),7.27(d,J=6.4Hz, 1H),7.22-7.16(m,3H),5.36(s,1H),4.98(s,1H),3.58(s,3H),2.96-2.83(m,2H),2.59(s,3H),1.38(s,3H).

[0571] Example 45 2'-Chloro-N-(5-((trans-4-(hydroxymethyl)cyclohexyl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0572] Reaction route:

[0573]

[0574] Steps:

[0575] Step A: Dissolve cis-4-hydroxycyclohexane-1-carboxylic acid methyl ester (1 g, 6.32 mmol) in tetrahydrofuran (20 ml), add lithium aluminum hydride (1.0 M in THF, 5.1 ml) dropwise at 0°C, and stir the reaction solution at 0°C for 2 hours. Add tetrahydrofuran (80 ml) to dilute the reaction, and then add sodium sulfate decahydrate until the mixture is free of bubbles. Continue stirring the reaction solution at 0°C for 1 hour. Filter and wash with ethyl acetate. Combine the organic phases, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 800 mg of (1S,4S)-4-(hydroxymethyl)cyclohexane-1-ol.

[0576] 1 H NMR (400MHz, DMSO-d6) δ4.32(brs,1H),4.21(brs,1H),3.22(brs,2H),3.17(s,1H),1.59-1.48(m,2H),1.43-1.27(m,7H).

[0577] Step B: Dissolve cis-4-(hydroxymethyl)cyclohexane-1-ol (800 mg, 6.14 mmol) and imidazole (1.3 g, 18.4 mmol) in dichloromethane (10 ml), add tert-butyldiphenylsilyl chloride (2.4 ml, 9.2 mmol) at 0°C, and stir the reaction solution at room temperature for 2 hours. Add water (10 ml) to quench, and then extract with dichloromethane (10 ml x 3 times). Combine the organic phases, wash the organic phases with saturated brine (30 ml), dry over anhydrous sodium sulfate, filter, and purify the residue by silica gel column chromatography to obtain 970 mg of cis-4-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexane-1-ol.

[0578] 1 H NMR (400MHz, DMSO-d6) δ7.63-7.59(m,4H),7.48-7.41(m,6H),4.23(d,J=3.3Hz,1H),3. 75(brs,1H),3.47(d,J=6.5Hz,2H),1.61-1.49(m,3H),1.44-1.35(m,6H),1.00(s,9H).

[0579] Step C: Dissolve cis-4-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexane-1-ol (970 mg, 2.6 mmol) in dichloromethane (13 ml), add 4-toluenesulfonyl chloride (1 g, 5.3 mmol) and pyridine (2.2 ml, 26.4 mmol) at 0°C, and stir the reaction solution at room temperature for 16 hours. Add water (10 ml), extract with ethyl acetate (10 ml x 3), combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography to obtain 782 mg of cis-4-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexyl 4-methylbenzenesulfonate.

[0580] Step D: 5-amino-1,3,4-thiadiazole-2-thiol (200 mg, 1.49 mmol) and potassium hydroxide (84 mg, 1.49 mmol) were dissolved in ethanol (7 ml), and the reaction solution was stirred at room temperature for ten minutes, and then cis-4-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexyl 4-methylbenzenesulfonate (780 mg, 1.49 mmol) was added, and the reaction solution was stirred at 80°C for 16 hours. Water (10 ml) was added to quench, and ethyl acetate (10 ml × 3 times) was used for extraction. The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 200 mg of 5-((trans-4-((tert-butyldiphenylsilyl)oxy)methyl)cyclohexyl)thio)-1,3,4-thiadiazole-2-amine.

[0581] MS (ESI) M / Z: 484.4 [M+H] + .

[0582] 1 H NMR (400MHz, DMSO-d6) δ7.59(dd,J=7.4,1.9Hz,4H),7.46-7.43(m,6H),7.34(s,2H),3.45(d,J=6.1Hz,2H),3.30(s,1H),2.04( d,J=10.3Hz,2H),1.81(d,J=13.3Hz,2H),1.36(dd,J=12.5,3.2Hz,2H),1.24(s,1H),1.08(dd,J=12.3,2.7Hz,2H),0.99(s,9H).

[0583] Step E: 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (synthesized according to WO2022118210, 115 mg, 0.41 mmol) and N,N,N',N'-tetramethyl chlorouronium hexafluorophosphate (128 mg, 0.45 mmol) were dissolved in acetonitrile (3 ml) and N,N-dimethylformamide (0.2 ml), followed by the addition of 5-((trans-4-((tert-butyldiphenylsilyl)oxy)methyl)cyclohexyl)thio)-1,3,4-thiadiazole-2-amine (200 mg, 0.41 mmol) and N-methylimidazole (0.08 ml, 0.9 mmol), and the reaction solution was stirred at room temperature under nitrogen for 16 hours. Water (10 ml) was added for quenching, and the mixture was extracted with ethyl acetate (10 ml × 3 times). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 240 mg of N-(5-((trans-4-((tert-butyldiphenylsilyl)oxy)methyl)cyclohexyl)thio)-1,3,4-thiadiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0584] MS (ESI) M / Z: 744.2 [M+H] + .

[0585] 1 H NMR (400MHz, DMSO-d6) δ13.26(brs,1H),8.83(s,1H),8.16(s,1H),7.62-7.57(m,4H),7.56(s,1H),7.47-7.39(m,7H),3.59(s,3H),3.46(d,J=6. 1Hz,2H),2.68-2.66(m,1H),2.59(s,3H),2.11(d,J=10.3Hz,2H),1.83(d ,J=11.4Hz,2H),1.49-1.36(m,3H),1.12(d,J=14.7Hz,2H),0.99(s,9H).

[0586] Step F: N-(5-((trans-4-((tert-butyldiphenylsilyl)oxy)methyl)cyclohexyl)thio)-1,3,4-thiadiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridyl]-3-carboxamide (120 mg, 0.16 mmol) was dissolved in tetrahydrofuran (1 ml), tetrabutylammonium fluoride (0.32 ml, 0.32 mmol) was added, and the reaction solution was stirred at room temperature for 16 hours. Water (10 ml) was added to quench the mixture, and the mixture was extracted with ethyl acetate (10 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to give 60 mg of 2'-chloro-N-(5-((trans-4-(hydroxymethyl)cyclohexyl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0587] MS (ESI) M / Z: 506.1 [M+H] + .

[0588] 1 H NMR (400 MHz, DMSO-d6) δ 13.25 (s, 1H), 8.83 (s, 1H), 8.16 (s, 1H), 7.56 (s, 1H), 7.45 (s, 1H), 4.4.2 (brs, 1H), 3.59 (s, 3H), 3.47 (td, J = 8.3, 4.0 Hz, 1H), 3.20 (d, J = 6.2 Hz, 2H), 2.59 (s, 3H), 2.10 (d, J = 9.9 Hz, 2H), 1.79 (d, J = 11.4 Hz, 2H), 1.47-1.29 (m, 3H), 1.08-0.90 (m, 2H). Example 46 2'-Chloro-N-(5-((cis-4-(hydroxymethyl)cyclohexyl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0589] Reaction route:

[0590]

[0591] Steps:

[0592] Using trans-4-hydroxycyclohexane-1-carboxylic acid methyl ester as raw material, the preparation method refers to Example 45, steps A to F, to obtain compound 2'-chloro-N-(5-(((1S,4S)-4-(hydroxymethyl)cyclohexyl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0593] MS (ESI) M / Z: 506.3 [M] + .

[0594] 1 H NMR(400MHz,DMSO-d6)δ13.24(s,1H),8.83(s,1H),8.16(s,1H),7.56(s,1H),7.45(s,1H),4.03(s,1H),3.59(s, 3H), 3.26 (d, J = 6.3Hz, 2H), 2.59 (s, 3H), 1.87-1.80 (m, 4H), 1.62-1.55 (m, 2H), 1.47 (brs, 1H), 1.35-1.29 (m, 2H).

[0595] Example 47 2'-Chloro-N-(5-(2-(4-chlorophenyl)acetyl)thiazol-2-yl)-5'-methoxy-[3,4'-bipyridine]-4-carboxamide

[0596]

[0597] 2'-Chloro-5'-methoxy-6-methyl-[3,4'-bipyridine]-4-carboxylic acid (synthesized by referring to WO2022118210) was used, and the synthesis method was referred to Example 1.

[0598] MS (ESI) M / Z: 499.1 [M] + .

[0599] 1 H NMR(400MHz,DMSO-d6)δ13.29(s,1H),8.86(s,1H),8.74(s,1H),8.62(s,1H),8.14(s, 1H),7.77(d,J=4.9Hz,1H),7.63(s,1H),7.40-7.32(m,4H),4.31(s,2H),3.55(s,3H).

[0600] Example 48 2'-Chloro-N-(5-(2-(4-cyanophenyl)acetyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0601] Reaction route:

[0602]

[0603] Referring to the preparation method in the above example, 17 mg of the product 4-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(2-(4-cyanophenyl)acetyl)-1,3-thiazol-2-yl)-6-methylpyridine-3-carboxamide was obtained.

[0604] MS (ESI) M / Z: 504.4 [M+H] + .

[0605] 1 H NMR(400MHz,DMSO-d6)δ13.20(s,1H),8.85(s,1H),8.60(s,1H),8.14(s,1H),7.79(d, J=8.2Hz,2H),7.55-7.49(m,3H),7.42(s,1H),4.41(s,2H),3.56(s,3H),2.59(s,3H).

[0606] Example 49 2'-Chloro-N-(5-(2-(4-hydroxycyclohexyl)acetyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0607] Reaction route:

[0608]

[0609] Referring to the preparation method in the above example, 6 mg of the product 2'-chloro-N-(5-(2-(4-hydroxycyclohexyl)acetyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide was obtained.

[0610] MS (ESI) M / Z: 501.4 [M+H] + .

[0611] 1 H NMR (400MHz, DMSO-d6) δ13.09(s,1H),8.86(s,1H),8.38(s,1H),8.15(s,1H),7.51(s,1H),7.39(s,1H),4.27(d,J=3.2Hz,1 H),3.72(s,1H),3.58(s,3H),2.76(d,J=7.0Hz,2H),2.58(s,3H),1.90-1.85(m,1H),1.560-1.53(m,2H),1.43-1.37(m,6H).

[0612] Example 50 2'-Chloro-N-(5-((trans-7-fluoro-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0613] Reaction route:

[0614]

[0615] Steps:

[0616] Using 2-bromo-7-fluoro-2,3-dihydro-1H-inden-1-one as raw material, the synthesis method was based on the reference to Example 38 to obtain compound 2'-chloro-N-(5-((trans-7-fluoro-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0617] MS (ESI) M / Z: 544.1 [M+H] + .

[0618] 1 HNMR(400MHz,DMSO-d6)δ13.28(brs,1H),8.86(s,1H),8.15(s,1H),7.53(s,1H ),7.41(s,1H),7.35-7.30(m,1H),7.11(d,J=7.2Hz,1H),7.03(t,J=7.2Hz,1H) ,6.00(d,J=6.8Hz,1H),5.34(dd,J=6.4,3.2Hz,1H),4.09-4.05(m,1H),3.66(d d,J=16.8,7.6Hz,1H),3.59(s,3H),2.92(dd,J=17.2,4.0Hz,1H),2.59(s,3H).

[0619] Example 51 and Example 52

[0620] 2'-Chloro-N-(5-((cis-3-hydroxycycloheptyl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 51 or Compound 52)

[0621] 2'-Chloro-N-(5-((trans-3-hydroxycycloheptyl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 52 or Compound 51)

[0622] Reaction route:

[0623]

[0624] Steps:

[0625] Step A: Dissolve cycloheptane-1,3-dione (800 mg, 6.34 mmol) in tetrahydrofuran (10 ml) and methanol (10 ml) at room temperature. Then, slowly add sodium borohydride (480 mg, 12.68 mmol) to the above reaction solution under an ice-water bath. Stir the reaction solution at room temperature for 2 hours. Add water (10 ml) to the reaction solution to quench. The reaction solution is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to obtain 830 mg of compound cycloheptane-1,3-diol.

[0626] 1 H NMR (400MHz, CDCl3) δ4.48-4.39(m,1H),4.17-4.03(m,1H),2.11-1.88(m,2H),1.77-1.65(m,5H),1.55-1.40(m,3H).

[0627] Step B: At room temperature, cycloheptane-1,3-diol (2 g, 15.36 mmol) was dissolved in dichloromethane (30 ml). Subsequently, triethylamine (3.11 g, 30.72 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (4.87 g, 18.43 mmol) were slowly added to the above reaction solution under an ice-water bath. The reaction solution was stirred at room temperature for 16 hours. Water (50 ml) was added to the reaction solution to quench. The mixed solution was extracted with dichloromethane (30 ml × 3 times), the organic phases were combined, the organic phases were washed with saturated brine (50 ml), and finally dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 540 mg of compound 3-((tert-butyldimethylsilyl)oxy)cycloheptane-1-ol.

[0628] 1 H NMR (400MHz, DMSO-d6) δ4.37-4.26(m,1H),4.02-3.95(m,0.5H),3.83-3.68(m,1H),3.61-3.51(m,0.5H),2.01-1.92(m,0.5H),1.88-1 .80(m,0.5H),1.77-1.65(m,2.5H),1.60-1.45(m,3.5H),1.42-1.28(m,3H),0.86(s,4.5H),0.85(s,4.5H),0.03(s,3H),0.02(s,3H).

[0629] Step C: 3-((tert-butyldimethylsilyl)oxy)cycloheptane-1-ol (540 mg, 2.21 mmol) was dissolved in dichloromethane (10 ml) at room temperature. Subsequently, p-toluenesulfonyl chloride (842 mg, 4.42 mmol) and pyridine (1.75 g, 22.1 mmol) were added to the above reaction solution under an ice-water bath. The reaction solution was stirred at room temperature for 16 hours. Water (30 ml) was added to quench the reaction, and the mixture was extracted with dichloromethane (10 ml × 3 times), and the organic phases were combined, washed with saturated brine (30 ml), and finally dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 500 mg of compound 3-((tert-butyldimethylsilyl)oxy)cycloheptyl 4-methylbenzenesulfonate.

[0630] 1 H NMR (400MHz, DMSO-d6) δ7.81-7.72(m,2H),7.46(d,J=8.0Hz,2H),4.73-4.64(m,0.5H),4.62-4.54(m,0.5H),4.03-3.93(m,0.5H),3 .79-3.56(m,0.5H),2.41(s,3H),1.94-1.61(m,5H),1.55-1.46(m,3H),1.41-1.32(m,2H),0.83-0.74(m,9H),-0.01--0.13(m,6H).

[0631] Step D: 5-amino-1,3,4-thiadiazole-2-thiol (167 mg, 1.25 mmol) and potassium hydroxide (70.4 mg, 1.25 mmol) were dissolved in ethanol (8 ml) at room temperature. After stirring at room temperature for 10 minutes, 3-((tert-butyldimethylsilyl)oxy)cycloheptyl 4-methylbenzenesulfonate (500 mg, 1.25 mmol) was added to the above reaction solution. The reaction solution was stirred at 80 degrees Celsius for 16 hours under a nitrogen system. The residue was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 300 mg of compound 5-((3-((tert-butyldimethylsilyl)oxy)cycloheptyl)thio)-1,3,4-thiadiazole-2-amine.

[0632] MS (ESI) M / Z: 360.4 [M+H] + .

[0633] Step E: 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (synthesized according to WO2022118210, 128 mg, 0.41 mmol), 5-((3-((tert-butyldimethylsilyl)oxy)cycloheptyl)thio)-1,3,4-thiadiazole-2-amine (150 mg, 0.056 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (137 mg, 0.49 mmol)) and N-methylimidazole (80 mg, 0.98 mmol) were dissolved in acetonitrile (5 ml) and N,N-dimethylformamide (0.33 ml) at room temperature. The reaction solution was stirred at room temperature for 16 hours under a nitrogen system. Water (30 ml) was added to quench the reaction, and the mixture was extracted with dichloromethane (10 ml x 3 times). The organic phases were combined, washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 230 mg of the compound N-(5-((3-((tert-butyldimethylsilyl)oxy)cycloheptyl)thio)-1,3,4-thiadiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0634] MS (ESI) M / Z: 620.4 [M+H] + .

[0635] 1 H NMR(400MHz,DMSO-d6)δ13.27(s,1H),8.82(s,1H),8.16(s,1H),7.55(s, 1H),7.44(s,1H),4.08-4.04(m,0.5H),3.93-3.85(m,1H),3.81-3.71(m,0 .5H),3.59(s,3H),2.59(s,3H),2.19-2.06(m,2H),1.98-1.82(m,2H),1. 69-1.42(m,6H),0.81-0.83(m,9H),-0.00(s,3H),-0.03(d,J=2.6Hz,3H).

[0636] Step F: N-(5-((3-((tert-butyldimethylsilyl)oxy)cycloheptyl)thio)-1,3,4-thiadiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (230 mg, 0.37 mmol) was dissolved in anhydrous tetrahydrofuran (5 ml) at room temperature. Subsequently, tetrabutylammonium fluoride (1.85 ml, 1 mol / L, 1.85 mmol) was added to the above reaction solution. The reaction solution was stirred at room temperature for 16 hours. The tetrahydrofuran was removed by concentration under reduced pressure and extracted with ethyl acetate (10 ml x 3 times). The organic phases were combined, washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to give 14.3 mg of 2'-chloro-N-(5-((cis-3-hydroxycycloheptyl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 51 or Compound 52) and 14.6 mg of 2'-chloro-N-(5-((trans-3-hydroxycycloheptyl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 52 or Compound 51).

[0637] Compound 51:

[0638] MS (ESI) M / Z: 506.3 [M+H] + .

[0639] 1 H NMR (400MHz, DMSO-d6) δ13.26(s,1H),8.84(s,1H),8.16(s,1H),7.55(s,1H),7.43(s,1H),4.60(d,J=4.2Hz,1H),3.71-3.62(m,2H),3.5 9(s,3H),2.59(s,3H),2.23-2.15(m,1H),2.05-1.98(m,1H),1.85-1.79(m,1H),1.73-1.64(m,2H),1.61-1.50(m,3H),1.47-1.38(m,2H).

[0640] Compound 52:

[0641] MS (ESI) M / Z: 506.3 [M+H] + .

[0642] 1H NMR (400MHz, DMSO-d6) δ13.25(s,1H),8.84(s,1H),8.16(s,1H),7.55(s,1H),7.44(s,1H),4.57(d,J=4.0Hz,1H),4.0 2-3.82(m,2H),3.59(s,3H),2.59(s,3H),2.11-1.92(m,3H),1.80-1.71(m,1H),1.69-1.43(m,5H),1.39-1.28(m,1H).

[0643] Example 53 2'-Chloro-N-(5-(cyclopentanecarbonyl)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0644] Reaction route:

[0645]

[0646] Step A: 2-amino-2-cyclopentenoic acid (500 mg, 3.49 mmol) was dissolved in sulfuric acid solution (7 ml, 0.5 mol / L) at room temperature. Then, sodium nitrite aqueous solution (8.7 ml, 2 mol / L, 17.45 mmol) was slowly added under ice-water bath. The reaction solution was stirred at room temperature for 16 hours. Water (30 ml) was added, and ethyl acetate (20 ml × 3 times) was extracted. The organic phases were combined, washed with saturated brine (30 ml), and finally dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 440 mg of compound 2-cyclopentyl-2-hydroxyacetic acid was obtained.

[0647] 1 H NMR (400MHz, DMSO-d6) δ12.23 (brs, 1H), 3.80 (d, J = 5.9Hz, 1H), 2.19-2.09 (m, 1H), 1.64-1.38 (m, 8H).

[0648] Step B: Dissolve 2-cyclopentyl-2-hydroxyacetic acid (440 mg, 3.05 mmol) in phosphorus oxychloride (4.5 ml) at room temperature. Then, add thiosemicarbazide (278 mg, 3.05 mmol) to the above solution. Stir at 80 degrees Celsius for 1 hour under nitrogen protection. Concentrate under reduced pressure, slowly add 1M sodium hydroxide aqueous solution to pH 7 under ice-water bath, extract with ethyl acetate (20 ml x 3 times), combine the organic phases, wash with saturated brine (50 ml), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue obtained is purified by reverse phase chromatography to obtain 23 mg of compound (5-amino-1,3,4-thiadiazol-2-yl) (cyclopentyl) methanol.

[0649] MS (ESI) M / Z: 200.2 [M+H] + .

[0650] 1 H NMR (400MHz, DMSO-d6) δ7.01(s,2H),5.89(d,J=4.9Hz,1H),4.43(dd,J=7.7,4.9Hz,1H),2.18-2.11(m,1H),1.72-1.65(m,1H),1.54-1.46(m,7H).

[0651] Step C: Dissolve (5-amino-1,3,4-thiadiazol-2-yl)(cyclopentyl)methanol (23 mg, 0.115 mmol) in 1,4-dioxane (1 ml) at room temperature. Then, add active manganese dioxide (100 mg, 1.15 mmol) to the above solution. Stir at 80 degrees Celsius for 2 hours under nitrogen protection. Filter the reaction solution, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 11 mg of compound (5-amino-1,3,4-thiadiazol-2-yl)(cyclopentyl)methanone.

[0652] MS (ESI) M / Z: 198.2 [M+H] + .

[0653] 1 H NMR (400MHz, DMSO-d6) δ8.12(s,2H),3.91-3.81(m,1H),1.94-1.86(m,2H),1.81-1.70(m,2H),1.70-1.57(m,4H).

[0654] Step D: 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (synthesized with reference to WO2022118210, 15 mg, 0.056 mmol), (5-amino-1,3,4-thiadiazol-2-yl)(cyclopentyl)methanone (11 mg, 0.056 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (18.9 mg, 0.067 mmol), N-methylimidazole (11 mg, 0.134 mmol) were dissolved in acetonitrile (1 ml) and N,N-dimethylformamide (0.07 ml) at room temperature and stirred at room temperature for 16 hours. Water (20 ml) was added to quench the mixture, and the mixture was extracted with ethyl acetate (5 ml × 3 times). The organic phases were combined, washed with water (20 ml) and saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to give 2.05 mg of 2'-chloro-N-(5-(cyclopentanecarbonyl)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0655] MS (ESI) M / Z: 458.1 [M+H] + .

[0656] 1 H NMR(400MHz,DMSO-d6)δ13.63(s,1H),8.87(s,1H),8.15(s,1H),7.57(s,1H),7.46(s,1H),4.09- 3.84(m,1H),3.56(s,3H),2.60(s,3H),2.03-1.92(m,2H),1.85-1.76(m,2H),1.69-1.59(m,4H).

[0657] Example 54 2'-Chloro-N-(5-((4-hydroxy-4-methylcyclohexyl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0658] Reaction route:

[0659]

[0660] Steps:

[0661] Step A: 5-amino-1,3,4-thiadiazole-2-thiol (555 mg, 4.17 mmol) was dissolved in ethanol (4 ml), potassium hydroxide (233.79 mg, 4.17 mmol) was added, and the mixture was reacted at room temperature for 10 minutes, and a solution of 8-bromo-1,4-dioxaspiro[4.5]decane (921.31 mg, 4.17 mmol) in ethanol (4 ml) was added. The reaction solution was reacted at 80°C for 16 hours, quenched with water (20 ml), and extracted with dichloromethane (10 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain 539 mg of compound 5-((1,4-dioxopyrazolo[4.5]dec-8-yl)thio)-1,3,4-thiadiazole-2-amine.

[0662] MS (ESI) M / Z: 274.3 [M+H] + .

[0663] 1 H NMR (400MHz, DMSO-d6) δ7.36 (s, 2H), 3.87-3.82 (m, 4H), 3.40 (dd, J = 9.3, 4.0Hz, 1H), 2.01-1.92 (m, 2H), 1.73-1.66 (m, 2H), 1.64-1.54 (m, 4H).

[0664] Step B: Dissolve 5-((1,4-dioxopyrazolo[4.5]dec-8-yl)thio)-1,3,4-thiadiazol-2-amine (20 mg, 0.073 mmol) in tetrahydrofuran (0.5 ml), add 3 mol / L hydrochloric acid (0.5 ml), and react at 50°C for 16 hours. Quench with saturated sodium bicarbonate solution, extract with ethyl acetate (20 ml x 3 times). Combine the organic phases, dry over anhydrous sodium sulfate, filter, dry, and concentrate to obtain 16 mg of compound 4-((5-amino-1,3,4-thiadiazol-2-yl)thio)cyclohexane-1-one.

[0665] MS (ESI) M / Z: 230.4 [M+H] + .

[0666] 1 H NMR (400MHz, DMSO-d6) δ7.40(s,2H),3.83-3.76(m,1H),2.47-2.41(m,2H),2.35-2.29(m,2H),2.27-2.20(m,2H),1.90-1.77(m,2H).

[0667] Step C: 4-((5-amino-1,3,4-thiadiazol-2-yl)thio)cyclohexane-1-one (460 mg, 2.01 mmol) was added to a solution of methylmagnesium bromide (16.05 ml, 16.05 mmol, 1 mol / L), and the reaction solution was stirred at room temperature for 3 hours under a nitrogen system. The reaction solution was directly concentrated, and the residue was prepared by thin layer chromatography to obtain 258 mg of 4-((5-amino-1,3,4-thiadiazol-2-yl)thio)-1-methylcyclohexane-1-ol.

[0668] MS (ESI) M / Z: 246.3 [M+H] + .

[0669] 1 H NMR(400MHz,DMSO-d6)δ7.388(s,2H),4.24-4.15(m,2H),2.05-1.94(m,1H),1.75- 1.67(m,2H),1.62-1.54(m,2H),1.44-1.31(m,2H),1.08(s,1.5H),1.06(s,1.5H).

[0670] Step D: 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (synthesized by referring to WO2022118210, 80 mg, 0.288 mmol) and N-(chloro(dimethylamino)methylene)-N-methylmethanamine hexafluorophosphate (V) (96.65 mg, 0.34 mmol) were dissolved in a solution of dry dichloromethane (4 ml) at room temperature, followed by the addition of a solution of 4-((5-amino-1,3,4-thiadiazol-2-yl)thio)-1-methylcyclohexane-1-ol (70.4 mg, 0.288 mmol) and N-methylimidazole (129.6 mg, 1.58 mmol) in dichloromethane (4 ml). The mixture was stirred at 25°C for 16 hours, quenched with water (10 ml), extracted with dichloromethane (10 ml x 3 times), the organic phases were combined, washed with water (10 ml) and saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to obtain 10 mg of 2'-chloro-N-(5-((4-hydroxy-4-methylcyclohexyl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0671] MS (ESI) M / Z: 506.3 [M+H] + .

[0672] 1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),8.84(s,1H),8.16(s,1H),7.54(s,1H ),7.43(s,1H),4.27(s,0.45H),4.14(s,0.54H),3.74-3.72(m,0.5H),3.59 (s,3H),3.45-3.33(m,0.5H),2.59(s,3H),2.06-1.98(m,1H),1.83-1.71(m ,2H),1.58-1.55(m,3H),1.50-1.24(m,2H),1.11(s,1.5H),1.08(s,1.5H).

[0673] Example 55 2'-Chloro-5'-methoxy-N-(5-((4-methoxycyclohexyl)thio)-1,3,4-thiadiazol-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0674] Reaction route:

[0675]

[0676] Referring to the preparation method in the above example, 18 mg of 2'-chloro-5'-methoxy-N-(5-((4-methoxycyclohexyl)thio)-1,3,4-thiadiazol-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide was obtained.

[0677] MS (ESI) M / Z: 506.1 [M+H] + .

[0678] 1 H NMR(400MHz,DMSO-d6)δ13.26(s,1H),8.84(s,1H),8.16(s,1H),7.54(s,1H),7.43(s,1H),3.73-3.65(m,1H),3.59(s,3H),3.2 1(d,J=4.0Hz,3H),3.18-3.11(m,1H),2.59(s,3H),2.12-1.95(m,2H),1.82-1.59(m,4H),1.55-1.41(m,1H),1.35-1.22(m,1H).

[0679] Example 56 and Example 57

[0680] 2'-Chloro-N-(5-(((2R,3S)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-

[0681] [4,4'-Bipyridine]-3-carboxamide (Compound 56 or Compound 57)

[0682] 2'-Chloro-N-(5-(((2S,3R)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-

[0683] [4,4'-Bipyridine]-3-carboxamide (Compound 57 or Compound 56)

[0684] Reaction route:

[0685]

[0686] Steps:

[0687] Step A: 1,4-dihydronaphthalene (1 g, 7.56 mmol) was dissolved in tetrahydrofuran (2 ml) and water (8 ml), N-bromosuccinimide (1.48 g, 8.32 mmol) was added and stirred at room temperature for 16 hours. Dichloromethane (4 ml x 3) was extracted, the organic phases were combined, dried and concentrated, and the residue was purified by a flash preparation apparatus to obtain 0.6 g of (2R, 3R)-3-bromo-1,2,3,4-tetrahydronaphthalene-2-ol.

[0688] 1 HNMR(400MHz,DMSO-d6)δ7.13-7.06(m,4H),5.47(brs,1H),4.41(td,J=6.8,5.2Hz,1H),4.02(q,J=6.0Hz,1H),3.5 6(dd,J=17.2,4.8Hz,1H), 3.20(dd,J=17.6,5.2Hz,1H), 3.14(dd,J=17.2,6.4Hz,1H), 2.75(dd,J=17.2,6.0Hz,1H).

[0689] Step B: (2R,3R)-3-bromo-1,2,3,4-tetrahydronaphthalen-2-ol (0.60 g, 2.64 mmol) and 2-amino-5-mercapto-1,3,4-thiadiazole (0.35 g, 2.64 mmol) were dissolved in N-methylpyrrolidone (6 ml), sodium carbonate (0.84 g, 7.92 mmol) was added and stirred at 70 degrees Celsius for 2 hours. Water (20 ml) was added, and ethyl acetate (5 ml x 3) was extracted, the organic phases were combined and dried, and concentrated, and the residue was purified by reverse phase column chromatography to obtain 0.6 g of the product (2R,3S)-3-((5-amino-1,3,4-thiadiazole-2-yl)thio)-1,2,3,4-tetrahydronaphthalen-2-ol.

[0690] MS (ESI) M / Z: 280.1 [M+H] + .

[0691] Step C: 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-4-carboxylic acid (synthesized with reference to WO2022118210, 280 mg, 1.00 mmol) and HATU (456 mg, 1.20 mmol) were dissolved in N,N-dimethylformamide (6 ml), followed by the addition of diisopropylethylamine (388 mg, 3.00 mmol). Stir at room temperature for 1 hour under nitrogen protection, then add (2R,3S)-3-((5-amino-1,3,4-thiadiazol-2-yl)thio)-1,2,3,4-tetrahydronaphthalen-2-ol (300 mg, 1.07 mmol) and continue stirring for 16 hours. The reaction solution was purified directly by high performance liquid chromatography without treatment, and then separated by chiral chromatography column preparation (separation column: Daicel IC (250mm*25mm, 10um); mobile phase: CO 2 / (0.5% ammonia ethanol solution) = 45 / 55, flow rate: 100 ml / min, pressure: 100 bar, detection wavelength: 214 nM, obtained

[0692] Compound 56:

[0693] Analysis conditions: Daicel IC (4.6*100 mm, 3 um); CO2 / (1% ammonia ethanol solution)=45 / 55, flow rate: 3.0 ml / min, detection wavelength: 214 nM; retention time: 1.784 min; ee: 100%; absolute configuration unknown, enantiomer of compound 57.

[0694] MS (ESI) M / Z: 540.1 [M+H] + .

[0695] 1 HNMR(400MHz,DMSO-d6)δ13.24(brs,1H),8.84(s,1H),8.16(s,1H),7.55(s,1H),7.44(s,1H),7.13-7.05(m,4H),5.40(d,J= 4.8Hz,1H),4.34-4.26(m,1H),4.17-4.09(m,1H),3.60(s,3H),3.24-3.02(m,3H),2.88(dd,J=17.2,6.4Hz,1H),2.59(s,3H).

[0696] Compound 57:

[0697] Analysis conditions: Daicel IC (4.6*100 mm, 3 um); CO2 / (1% ammonia ethanol solution) = 45 / 55, flow rate: 3.0 ml / min, detection wavelength: 214 nM; retention time: 2.109 min; ee: 97.1%; absolute configuration unknown, enantiomer of compound 56.

[0698] MS (ESI) M / Z: 540.1 [M+H] + .

[0699] 1 HNMR (400MHz, DMSO-d6) δ13.22(brs,1H),8.85(s,1H),8.16(s,1H),7.53(s,1H),7.42(s,1H),7.13-7.05(m,4H),5.40(d,J=4. 0Hz,1H),4.31-4.30(m,1H),4.15(t,J=6.0Hz,1H),3.60(s,3H),3.22-3.05(m,3H),2.84(dd,J=17.2,5.2Hz,1H),2.59(s,3H).

[0700] Example 58 and Example 59

[0701] 2'-Chloro-N-(5-(((1S,2R)-5-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 58 or Compound 59)

[0702] 2'-Chloro-N-(5-(((1R,2S)-5-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 59 or Compound 58)

[0703]

[0704] 2'-Chloro-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (91.97 mg, 0.31 mmol) was dissolved in DMF (2 ml), and HATU (129.66 mg, 0.34 mmol) and triethylamine (62.74 mg, 0.62 mmol) were added in sequence. The mixture was stirred at room temperature for 15 minutes, and cis-2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-1-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile (90 mg, 0.31 mmol) was added to the reaction system, and the reaction was continued overnight. Ethyl acetate (50 ml) was added to the system, and then washed with water (5 ml × 5). The organic phase was concentrated under reduced pressure, and the obtained residue was purified by preparative high performance liquid chromatography, and then separated by chiral chromatographic column (separation column: Daicel AD (25*250 mm, 10 um); mobile phase: CO 2 / (MeOH: acetonitrile (1:1) = 50 / 50, flow rate: 100 ml / min, pressure: 100 bar, detection wavelength: 214 nM, obtained

[0705] Compound 58:

[0706] Analysis conditions: Daicel AD (4.6*100mm, 10um); mobile phase: CO 2 / (MeOH:acetonitrile (1:1) = 50 / 50, flow rate: 3.0 ml / min, detection wavelength: 214 nM; retention time: 1.338 min; ee: 100%; absolute configuration unknown, enantiomer of compound 59.

[0707] MS (ESI) M / Z: 569.2 [M+H] + .

[0708] 1 H NMR (400MHz, DMSO-d6) δ13.37(s,1H),9.02(s,1H),8.18(d,J=1.2Hz,1H),7.77-7.69(m,2H),7.54(d,J=7.7Hz,1H),7.47(s,1H),6.25(dd,J=6.2 ,2.1Hz,1H),5.33(t,J=6.0Hz,1H),4.62(d,J=6.2Hz,1H),3.72(s,3H),3.45(dd,J=16.8,6.8Hz,1H),3.11(dd,J=16.7,4.9Hz,1H),2.60(s,3H).

[0709] Compound 59:

[0710] Analysis conditions: Daicel AD (4.6*100mm, 10um); mobile phase: CO 2 / (MeOH: acetonitrile (1:1) = 50 / 50, flow rate: 3.0 ml / min, detection wavelength: 214 nM; retention time: 2.038 min; ee: 100%; absolute configuration unknown, enantiomer of compound 58.

[0711] MS (ESI) M / Z: 569.2 [M+H] + .

[0712] 1 H NMR (400MHz, DMSO-d6) δ13.36(s,1H),9.05(s,1H),8.17(d,J=1.2Hz,1H),7.77-7.69(m,2H),7.54(d,J=7.7Hz,1H),7.42(s,1H),6.25(dd,J=6.2 ,2.1Hz,1H),5.33(t,J=6.0Hz,1H),4.62(d,J=6.2Hz,1H),3.73(s,3H),3.45(dd,J=16.8,6.8Hz,1H),3.12(dd,J=16.7,4.9Hz,1H),2.59(s,3H).

[0713] Example 60 2'-Chloro-N-(5-((trans-5-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0714] Reaction route:

[0715]

[0716] Steps:

[0717] Step A: Dissolve 2-bromo-1-oxo-2,3-dihydro-1H-indene-5-carbonitrile (900 mg, 3.81 mmol) in methanol (10 ml), add sodium borohydride (288.26 mg, 7.62 mmol) in batches, and stir at zero degrees for 2 hours. Add water (50 ml) and continue stirring at room temperature for 30 minutes. Filter and dry to obtain 600 mg of the product cis-2-bromo-1-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile, which is directly used in the next step.

[0718] Step B: cis-2-bromo-1-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile (300 mg, 1.26 mmol) and 2-amino-5-mercapto-1,3,4-thiadiazole (167.83 mg, 1.26 mmol) were dissolved in N-methylpyrrolidone (4 ml), sodium carbonate (400.64 mg, 3.78 mmol) was added, and the mixture was stirred at 80 degrees Celsius for 2 hours. The reaction solution was cooled to room temperature, slowly poured into water (50 ml), extracted with ethyl acetate (10 ml x 3), and the organic phases were combined, dried and concentrated to obtain 30 mg of trans-2-((5-amino-1,3,4-thiadiazole-2-yl)thio)-1-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile.

[0719] MS (ESI) M / Z: 291.1 [M+H] + .

[0720] 1 H NMR (400MHz, DMSO-d6) δ7.71-7.70(m,2H),7.50-7.48(m,1H),7.40(s,2H),6.15(d,J=6.4Hz,1H), 5.05-5.02(m,1H),3.80-3.75(m,1H),3.45(dd,J=16.8,8.0Hz,1H),2.91(dd,J=16.8,8.0Hz,1H).

[0721] Step C: 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-4-carboxylic acid (synthesized according to WO2022118210, 28 mg, 0.10 mmol), HATU (45.63 mg, 0.12 mmol) and diisopropylethylamine (38.77 mg, 0.30 mmol) were dissolved in N,N-dimethylformamide (1.0 ml), stirred at room temperature for 30 minutes, and then trans-2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-1-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile (30 mg, 0.10 mmol) was added, and stirring was continued at room temperature for 16 hours under nitrogen protection. The reaction solution was directly purified by preparative HPLC to obtain 11 mg of 2'-chloro-N-(5-((trans-5-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0722] MS (ESI) M / Z: 551.1 [M+H] + .

[0723] 1HNMR(400MHz,DMSO-d6)δ13.23(brs,1H),8.87(s,1H),8.14(s,1H),7.73(s,1H),7.73-7.71(m,1H),7.51-7.49(m,2H),7.38(s,1H),6.21(d,J= 6.8Hz,1H),5.10(t,J=6.8Hz,1H),3.96(q,J=7.6Hz,1H),3.59(s,3H),3.54(dd,J=16.4,7.6Hz,1H),2.98(dd,J=16.8,8.0Hz,1H),2.58(s,3H).

[0724] Example 61 and Example 62

[0725] 2'-Chloro-N-(5-(((1S,2S)-5-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 61 or Compound 62)

[0726] 2'-Chloro-N-(5-(((1R,2R)-5-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 62 or Compound 61)

[0727]

[0728] Compound 60 was separated by chiral chromatography (separation column: Daicel AS (250 mm*25 mm, 10 um); mobile phase: CO 2 / (0.2% ammonia methanol solution) = 70 / 30, flow rate: 100 ml / min, pressure: 100 bar, detection wavelength: 214 nM, obtained

[0729] Compound 61:

[0730] Analysis conditions: Daicel AS (4.6*100 mm, 3 um); CO2 / (0.2% ammonia methanol solution) = 70 / 30, flow rate: 3.0 ml / min, detection wavelength: 214 nM; retention time: 1.131 min; ee: 100%; absolute configuration unknown, enantiomer of compound 62.

[0731] MS (ESI) M / Z: 551.3 [M+H] + .

[0732] 1HNMR(400MHz,DMSO-d6)δ13.30(brs,1H),8.86(s,1H),8.15(s,1H),7.73(s,1H),7.73-

[0733] 7.71(m,1H),7.54(s,1H),7.51(d,J=8.0Hz,1H),7.42(s,1H),6.22(d,J=6.8Hz,1H),5.11(t ,J=6.8Hz,1H),3.99(q,J=7.6Hz,1H),3.59(s,3H),3.55(dd,J=16.8,8.0Hz,1H),2.99(dd,J

[0734] =16.4,8.0Hz,1H),2.59(s,3H).

[0735] Compound 62:

[0736] Analysis conditions: Daicel AS (4.6*100 mm, 3 um); CO2 / (0.2% ammonia methanol solution) = 70 / 30, flow rate: 3.0 ml / min, detection wavelength: 214 nM; retention time: 1.669 min; ee: 100%; absolute configuration unknown, enantiomer of compound 61.

[0737] MS (ESI) M / Z: 551.3 [M+H] + .

[0738] 1 HNMR(400MHz,DMSO-d6)δ13.31(brs,1H),8.86(s,1H),8.15(s,1H),7.73(s,1H),7.73-

[0739] 7.71(m,1H),7.55(s,1H),7.51(d,J=8.0Hz,1H),7.43(s,1H),6.22(d,J=6.8Hz,1H),5.11(t ,J=6.8Hz,1H),3.99(q,J=7.6Hz,1H),3.59(s,3H),3.55(dd,J=16.8,8.0Hz,1H),2.99(dd,J

[0740] =16.4,8.0Hz,1H),2.59(s,3H).

[0741] Example 63 2'-Chloro-N-(5-((trans-5-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0742] Reaction route:

[0743]

[0744] 2'-Chloro-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (91.9 mg, 0.31 mmol) was dissolved in DMF (2 ml), and HATU (129.6 mg, 0.34 mmol) and triethylamine (62.7 mg, 0.62 mmol) were added in sequence. The mixture was stirred at room temperature for 15 minutes, and trans-2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-1-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile (90 mg, 0.31 mmol) was added to the reaction system, and the reaction was continued overnight. Ethyl acetate (50 ml) was added to the system, and the mixture was washed with water (5 ml×5). The organic phase was concentrated under reduced pressure and the residue was purified by preparative high performance liquid chromatography to give 43 mg of 2'-chloro-N-(5-((trans-5-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0745] MS (ESI) M / Z: 569.2 [M+H] + .

[0746] 1 H NMR (400MHz, DMSO-d6) δ13.42(brs,1H),9.02(s,1H),8.17(s,1H),7.74-7.67(m,2H),7.50(d,J=8.0Hz,1H),7.46(s,1H),6.21(dd,J=6.8,1. 3Hz,1H),5.10(t,J=6.6Hz,1H),3.97(q,J=7.7Hz,1H),3.70(s,3H),3.54(dd,J=16.5,7.9Hz,1H),2.98(dd,J=16.5,8.0Hz,1H),2.59(s,3H).

[0747] Example 64 and Example 65

[0748] 2'-Chloro-N-(5-(((1R,2R)-5-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 64 or Compound 65)

[0749] 2'-Chloro-N-(5-(((1S,2S)-5-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 65 or Compound 64)

[0750]

[0751] Compound 63 was separated by chiral chromatography (separation column: Daicel OD-33 (250 mm*25 mm, 10 um); mobile phase: CO 2 / (0.2% ammonia methanol solution) = 55 / 45, flow rate: 100 ml / min, pressure: 100 bar, detection wavelength: 214 nM, obtained

[0752] Compound 64:

[0753] Analysis conditions: Daicel OD-3 (4.6*100 mm, 3 um); CO2 / (0.2% ammonia methanol solution)=55 / 45, flow rate: 3.0 ml / min, detection wavelength: 214 nM; retention time: 1.569 min; ee: 100%; absolute configuration unknown, enantiomer of compound 65.

[0754] MS (ESI) M / Z: 569.7 [M+H] + .

[0755] 1 H NMR (400MHz, DMSO-d6) δ13.43(s,1H),9.01(s,1H),8.17(d,J=1.0Hz,1H),7.74-7.69(m,2H),7.52-7.45(m,2H),6.22(dd,J=6.8,1.6Hz, 1H),5.10(t,J=6.8Hz,1H),3.98(q,J=7.8Hz,1H),3.71(s,3H),3.56(dd,J=16.6,7.9Hz,1H),2.98(dd,J=16.5,8.0Hz,1H),2.60(s,3H).

[0756] Compound 65:

[0757] Analysis conditions: Daicel OD-3 (4.6*100 mm, 3 um); CO2 / (0.2% ammonia methanol solution)=55 / 45, flow rate: 3.0 ml / min, detection wavelength: 214 nM; retention time: 2.197 min; ee: 100%; absolute configuration unknown, enantiomer of compound 64.

[0758] MS (ESI) M / Z: 569.7 [M+H] + .

[0759] 1 H NMR (400MHz, DMSO-d6) δ13.43(s,1H),9.03(s,1H),8.17-8.16(m,1H),7.74-7.69(m,2H),7.50(d,J=8.3Hz,1H),7.45(s,1H),6.22(dd,J=6.8, 1.5Hz,1H),5.10(t,J=6.7Hz,1H),3.97(q,J=7.2Hz,1H),3.71(s,3H),3.54(dd,J=16.4,8.0Hz,1H),2.97(dd,J=16.5,8.2Hz,1H),2.59(s,3H).

[0760] Example 66 and Example 67

[0761] 2'-Chloro-N-(5-((cis-6-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 66)

[0762] 2'-Chloro-N-(5-((trans-6-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 67)

[0763] Reaction route:

[0764]

[0765] Steps:

[0766] Step A: 3-Oxo-2,3-dihydro-1H-indene-5-carbonitrile (2.00 g, 12.73 mmol), NBS (2.49 g, 14.0 mmol) and p-toluenesulfonic acid (0.22 g, 1.27 mmol) were dissolved in carbon tetrachloride (4 ml) and stirred at 60 degrees Celsius for 2 hours. Water (20 ml) was added, and the mixture was extracted with dichloromethane (10 ml x 3). The organic phases were combined and dried and concentrated, and the residue was purified by silica gel column chromatography to obtain 2.0 g of 2-bromo-3-oxo-2,3-dihydro-1H-indene-5-carbonitrile.

[0767] 1 HNMR(400MHz, DMSO-d6)δ8.26(s,1H),8.18(dd,J=8.0,2.0Hz,1H),7.81(d,J=8.4Hz ,1H),5.08(dd,J=7.2,2.8Hz,1H),3.97(dd,J=18.8,7.2Hz,1H),3.45-3.40(m,1H).

[0768] Step B: 2-bromo-3-oxo-2,3-dihydro-1H-indene-5-carbonitrile (1 g, 4.24 mmol) and 2-amino-5-mercapto-1,3,4-thiadiazole (0.56 g, 4.24 mmol) were added to a solution of sodium bicarbonate (0.71 g, 8.48 mmol) in water (10 ml), stirred at room temperature for 2 hours, filtered, washed with water, and dried to obtain 1 g of 2-((5-amino-1,3,4-thiadiazole-2-yl)sulfanyl]-3-oxo-2,3-dihydro-1H-indene-5-carbonitrile.

[0769] MS (ESI) M / Z: 289.0 [M+H] + .

[0770] 1 H NMR (400MHz, DMSO-d6) δ8.18 (s, 1H), 8.15-8.10 (m, 1H), 7.78 (d, J = 8.0Hz, 1H), 7.32 (b rs,2H),4.52(dd,J=8.0,4.4Hz,1H),3.79(dd,J=18.4,8.0Hz,1H),3.30-3.23(m,1H).

[0771] Step C: Dissolve 2-((5-amino-1,3,4-thiadiazol-2-yl)sulfanyl]-3-oxo-2,3-dihydro-1H-indene-5-carbonitrile (440 mg, 1.53 mmol) in methanol (5 ml), and add sodium borohydride (86.82 mg, 2.29 mmol) in portions. Stir the reaction at zero degree for 2 hours. Add water (15 ml), filter, wash with water, and dry to obtain 210 mg of cis-2 -((5-amino-1,3,4-thiadiazol-2-yl)thio)-3-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile. The filtrate was extracted with ethyl acetate (5 ml x 3), the dried organic phases were combined and concentrated, and the residue was purified by preparative high performance liquid chromatography to obtain 40 mg of trans-2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-3-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile.

[0772] cis-2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-3-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile:

[0773] MS (ESI) M / Z: 291.1 [M+H] + .

[0774] 1 H NMR(400MHz,DMSO-d6)δ7.74-7.71(m,2H),7.47(d,J=7.6Hz,1H),7.30(brs,2H),6.13(d,J=6.0Hz,1H), 5.27(t,J=6.0Hz,1H), 4.39(q,J=6.0Hz,1H), 3.39(dd,J=17.2,6.8Hz,1H), 3.11(dd,J=17.2,4.8Hz,1H).

[0775] Trans-2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-3-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile:

[0776] MS (ESI) M / Z: 291.1 [M+H] + .

[0777] 1H NMR(400MHz,DMSO-d6)δ7.73-7.71(m,2H),7.45(d,J=8.4Hz,1H),7.40(brs,2H),6.10(d,J=6.4Hz,1H),5.0 3(t,J=6.4Hz,1H), 3.79(td,J=7.6,6.4Hz,1H), 3.51(dd,J=17.2,7.6Hz,1H), 2.96(dd,J=17.2,7.2Hz,1H).

[0778] Step D: 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-4-carboxylic acid (synthesized by referring to WO2022118210, 55.74 mg, 0.20 mmol) and HATU (91.26 mg, 0.24 mmol) were dissolved in N,N-dimethylformamide (1.0 ml), diisopropylethylamine (77.54 mg, 0.60 mmol) was added, and the mixture was stirred at room temperature for 30 minutes, and then Cis-2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-3-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile (60.00 mg, 0.21 mmol) or trans-2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-3-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile (60.00 mg, 0.21 mmol) was added, and the mixture was stirred at room temperature for 16 hours under nitrogen protection. The reaction solution was directly purified by preparative high performance liquid chromatography to obtain 50 mg of 2'-chloro-N-(5-((cis-6-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide or 51 mg of 2'-chloro-N-(5-((trans-6-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0779] Compound 66:

[0780] MS (ESI) M / Z: 551.1 [M+H] + .

[0781] 1HNMR(400MHz,DMSO-d6)δ13.23(brs,1H),8.84(s,1H),8.16(s,1H),7.77(s,1 H),7.74(dd,J=8.0,1.2Hz,1H),7.55(s,1H),7.49(d,J=8.0Hz,1H),7.44(s,1H ),6.19(d,J=6.0Hz,1H),5.31(t,J=6.0Hz,1H),4.60(q,J=6.0Hz,1H),3.60(s ,3H),3.50(dd,J=17.2,6.8Hz,1H),3.15(dd,J=17.2,5.2Hz,1H),2.59(s,3H).

[0782] Compound 67:

[0783] MS (ESI) M / Z: 551.1 [M+H] + .

[0784] 1 HNMR(400MHz,DMSO-d6)δ13.29(brs,1H),8.84(s,1H),8.16(s,1H),7.74-7 .73(m,1H),7.73(s,1H),7.55(s,1H),7.47(d,J=8.0Hz,1H),7.44(s,1H),6. 16(d,J=6.4Hz,1H),5.10(t,J=6.4Hz,1H),4.00(q,J=7.2Hz,1H),3.60(dd, J=16.8,8.0Hz,1H),3.59(s,3H),3.02(dd,J=16.8,7.6Hz,1H),2.59(s,3H).

[0785] Example 68 2'-Chloro-N-(5-((cis-6-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0786] Reaction route:

[0787]

[0788] 2'-Chloro-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (100 mg, 0.34 mmol) was dissolved in DMF (2 ml), and HATU (155.13 mg, 0.41 mmol) and triethylamine (131.82 mg, 1.02 mmol) were added in sequence. The mixture was stirred at room temperature for 15 minutes, and cis-2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-3-hydroxy-2,3-dihydro-

[0789] 1H-indene-5-carbonitrile (100 mg, 0.34 mmol) was added to the reaction system, and the reaction was continued overnight. Ethyl acetate (50 ml) was added to the system, and then washed with water (5 ml × 5), the organic phase was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain 38 mg of 2'-chloro-N-(5-((cis-6-cyano-1-hydroxy-2,3-dihydro-1H-indene-2-yl)thio)-1,3,4-thiadiazol-2-yl)-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0790] MS (ESI) M / Z: 569.1 [M+H] + .

[0791] 1 HNMR(400MHz,DMSO-d6)δ13.36(brs,1H),9.02(s,1H),8.17(s,1H),7.77(s,1H),7.74(d,J=7.6Hz,1H),7.48(d,J=8.0Hz,1H),7.46(s,1H),6.18 (d,J=5.6Hz,1H),5.30(t,J=6.0Hz,1H),4.61-4.56(m,1H),3.72(s,3H),3.49(dd,J=17.2,6.8Hz,1H),3.15(dd,J=17.2,5.2Hz,1H),2.59(s,3H).

[0792] Example 69 and Example 70

[0793] 2'-Chloro-N-(5-(((1R,2S)-6-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 69 or Compound 70)

[0794] 2'-Chloro-N-(5-(((1S,2R)-6-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 70 or Compound 69)

[0795]

[0796] Compound 68 was separated by chiral chromatography (separation column: Daicel IC (250 mm*25 mm, 10 um); mobile phase: CO 2 / (methanol / acetonitrile) = 45 / 55, flow rate: 100 ml / min, pressure: 100 bar, detection wavelength: 214 nM, obtained

[0797] Compound 69:

[0798] Analysis conditions: Daicel IC (4.6*100mm, 3um); CO 2 / (methanol / acetonitrile) = 45 / 55, flow rate: 3.0 ml / min, detection wavelength: 214 nM; retention time: 1.044 min; ee: 100%; absolute configuration unknown, enantiomer of compound 70.

[0799] MS (ESI) M / Z: 569.3 [M+H] + .

[0800] 1 HNMR (400MHz, DMSO-d6) δ13.37(brs,1H),9.01(s,1H),8.18(d,J=1.4Hz,1H),7.77(s,1H),7.75-7.72(m,1H),7.50-7.46(m,2H),6.20(dd,J=6 .1,1.5Hz,1H),5.30(t,J=6.0Hz,1H),4.64-4.52(m,1H),3.72(s,3H),3.49(dd,J=17.2,6.9Hz,1H),3.14(dd,J=17.2,5.3Hz,1H),2.60(s,3H).

[0801] Compound 70:

[0802] Analysis conditions: Daicel IC (4.6*100mm, 3um); CO 2 / (methanol / acetonitrile) = 45 / 55, flow rate: 3.0 ml / min, detection wavelength: 214 nM; retention time: 1.524 min; ee: 100%; absolute configuration unknown, enantiomer of compound 69.

[0803] MS (ESI) M / Z: 569.3 [M+H] + .

[0804] 1 HNMR (400MHz, DMSO-d6) δ13.38(brs,1H),9.00(s,1H),8.18(d,J=1.2Hz,1H),7.77(s,1H),7.75-7.73(m,1H),7.50-7.47(m,2H),6.21-6. 20(m,1H),5.31(t,J=6.0Hz,1H),4.63-4.59(m,1H),3.72(s,3H),3.49(dd,J=17.2,6.4Hz,1H),3.15(dd,J=17.2,6.0Hz,1H),2.60(s,3H).

[0805] Example 71 2'-Chloro-N-(5-((trans-6-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0806]

[0807] 2'-Chloro-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (100 mg, 0.34 mmol) was dissolved in DMF (2 ml), and HATU (155.13 mg, 0.41 mmol) and triethylamine (131.82 mg, 1.02 mmol) were added in sequence. The mixture was stirred at room temperature for 15 minutes, and trans-2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-3-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile (100 mg, 0.34 mmol) was added to the reaction system, and the reaction was continued overnight. Ethyl acetate (50 ml) was added to the system, and the mixture was washed with water (5 ml×5). The organic phase was concentrated under reduced pressure and the residue was purified by preparative high performance liquid chromatography to give 38 mg of 2'-chloro-N-(5-((trans-6-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0808] MS (ESI) M / Z: 569.1 [M+H] + .

[0809] 1HNMR(400MHz,DMSO-d6)δ13.43(brs,1H),9.01(s,1H),8.17(s,1H),7.76-7.69(m,2H),7.53-7.43(m,2H),6.16(d,J=6.8Hz,1H), 5.09(t,J=6.4Hz,1H),4.00(q,J=7.6,1H),3.71(s,3H),3.60(dd,J=17.2,8.0Hz,1H),3.02(dd,J=17.2,8.0Hz,1H),2.60(s,3H).

[0810] Example 72 and Example 73

[0811] 2'-Chloro-N-(5-(((1S,2S)-6-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 72 or Compound 73)

[0812] 2'-Chloro-N-(5-(((1R,2R)-6-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 73 or Compound 72)

[0813]

[0814] Compound 71 was separated by chiral chromatography (separation column: Daicel IC (250 mm*25 mm, 10 um); mobile phase: CO2 / (methanol / acetonitrile)=45 / 55, flow rate: 100 ml / min, pressure: 100 bar, detection wavelength: 214 nM) to obtain

[0815] Compound 72:

[0816] Analysis conditions: Daicel IC (4.6*100mm, 3um); CO 2 / (methanol / acetonitrile) = 45 / 55, flow rate: 3.0 ml / min, detection wavelength: 214 nM; retention time: 1.084 min; ee: 100%; absolute configuration unknown, enantiomer of compound 73.

[0817] MS (ESI) M / Z: 569.3 [M+H] + .

[0818] 1HNMR(400MHz,DMSO-d6)δ13.44(brs,1H),9.00(s,1H),8.17(s,1H),7.75-7.70(m,2H),

[0819] 7.51-7.43(m,2H),6.18(dd,J=6.4,1.2Hz,1H),5.09(t,J=6.4Hz,1H),4.00(q,J=7.7Hz,1H),

[0820] 3.72(s,3H),3.60(dd,J=17.2,7.6Hz,1H),3.02(dd,J=17.2,7.6Hz,1H),2.60(s,3H).

[0821] Compound 73:

[0822] Analysis conditions: Daicel IC (4.6*100mm, 3um); CO 2 / (methanol / acetonitrile) = 45 / 55, flow rate: 3.0 ml / min, detection wavelength: 214 nM; retention time: 1.576 min; ee: 100%; absolute configuration unknown, enantiomer of compound 72.

[0823] MS (ESI) M / Z: 569.3 [M+H] + .

[0824] 1 HNMR(400MHz,DMSO-d6)δ13.43(brs,1H),9.01(s,1H),8.17(s,1H),7.75-7.70(m,2H),

[0825] 7.49-7.45(m,2H),6.17(dd,J=6.4,1.2Hz,1H),5.09(t,J=6.4Hz,1H),4.00(q,J=7.7Hz,1H),

[0826] 3.71(s,3H),3.59(dd,J=17.2,7.6Hz,1H),3.02(dd,J=17.2,7.6Hz,1H),2.60(s,3H).

[0827] Example 74 and Example 75

[0828] 2'-Chloro-N-(5-((cis-7-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 74)

[0829] 2'-Chloro-N-(5-((trans-7-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 75)

[0830] Reaction route:

[0831]

[0832] Using 3-oxo-2,3-dihydro-1H-indene-4-carbonitrile as raw material, the synthesis method can be referred to Example 66 and Example 67.

[0833] Compound 74:

[0834] MS (ESI) M / Z: 551.1 [M+H] + .

[0835] 1 HNMR(400MHz,DMSO-d6)δ13.24(brs,1H),8.85(s,1H),8.16(s,1H),7.71(d,J= 7.6Hz,1H),7.62(d,J=7.6Hz,1H),7.55(s,1H),7.49(t,J=7.6Hz,1H),7.44(s, 1H),6.33(d,J=7.6Hz,1H),5.38(t,J=6.4Hz,1H),4.58(q,J=7.2Hz,1H),3.61( s,3H),3.49(dd,J=16.4,7.6Hz,1H),3.16(dd,J=16.8,7.2Hz,1H),2.59(s,3H).

[0836] Compound 75:

[0837] MS (ESI) M / Z: 551.1 [M+H] + .

[0838] 1HNMR(400MHz,DMSO-d6)δ13.27(brs,1H),8.87(s,1H),8.15(s,1H),7.70(d,J=7 .6Hz,1H),7.60(d,J=7.6Hz,1H),7.52(s,1H),7.47(t,J=7.6Hz,1H),7.40(s,1H) ,6.34(d,J=7.2Hz,1H),5.21(dd,J=7.2,4.8Hz,1H),4.58(q,J=6.0Hz,1H),3.63 (dd,J=17.2,8.0Hz,1H),3.60(s,3H),2.97(dd,J=17.2,6.0Hz,1H),2.59(s,3H).

[0839] Example 76 and Example 77

[0840] 2'-Chloro-N-(5-((cis-4-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 76)

[0841] 2'-Chloro-N-(5-((trans-4-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 77)

[0842] Reaction route:

[0843]

[0844] Using 1-oxo-2,3-dihydro-1H-indene-4-carbonitrile as raw material, the synthesis method can be referred to Example 66 and Example 67.

[0845] Compound 76:

[0846] MS (ESI) M / Z: 551.1 [M+H] + .

[0847] 1H NMR (400MHz, DMSO-d6) δ13.24(s,1H),8.88(s,1H),8.16(s,1H),7.76(d,J=7.6Hz,1H),7.71(d,J=7.6Hz,1H),7.54(s,1H),7.48(t,J=7.8Hz,1 H),7.42(s,1H),6.24(d,J=6.3Hz,1H),5.35(t,J=6.1Hz,1H),4.71-4.62(m,1H),3.65-3.54(m,4H),3.20(dd,J=17.0,5.4Hz,1H),2.60(s,3H).

[0848] Compound 77:

[0849] MS (ESI) M / Z: 551.1 [M+H] + .

[0850] 1 H NMR (400 MHz, DMSO-d6) δ 13.23 (s, 1H), 8.91 (s, 1H), 8.14 (s, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.54-7.44 (m, 2H), 7.35 (s, 1H), 6.23 (d, J = 6.7 Hz, 1H), 5.13 (t, J = 6.5 Hz, 1H), 4.06-3.94 (m, 1H), 3.69-3.57 (m, 4H), 3.09 (dd, J = 16.7, 7.6 Hz, 1H), 2.58 (s, 3H). Example 78 and Example 79

[0851] 2'-Chloro-N-(5-((cis-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-[3,4'-bipyridine]-4-carboxamide (Example 78)

[0852] 2'-Chloro-N-(5-((trans-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-[3,4'-bipyridine]-4-carboxamide (Example 79)

[0853] Reaction route:

[0854]

[0855] Using 2-bromo-2,3-dihydro-1H-inden-1-one as raw material, the synthesis method can be referred to Example 66 and Example 67.

[0856] Compound 78:

[0857] MS (ESI) M / Z: 512.1 [M+H] + .

[0858] 1 H NMR (400MHz, DMSO-d6) δ13.34(s,1H),8.85(d,J=5.0Hz,1H),8.72(s,1H),8.16(s,1H),7.78(d,J=5.0Hz,1H),7.61(s,1H),7.40-7.34(m,1 H),7.28-7.22(m,3H),5.94(d,J=6.3Hz,1H),5.24(t,J=6.0Hz,1H),4.57-4.51(m,1H),3.60(s,3H),3.46-3.37(m,1H),3.13-3.05(m,1H).

[0859] Compound 79:

[0860] MS (ESI) M / Z: 512.1 [M+H] + .

[0861] 1 H NMR (400MHz, DMSO-d6) δ13.40(s,1H),8.84(d,J=4.9Hz,1H),8.71(s,1H),8.14(s,1H),7.79(d,J=4.9Hz,1H),7.61(s,1H),7.35-7.31(m,1 H),7.28-7.22(m,3H),5.95(d,J=6.8Hz,1H),5.04(t,J=6.4Hz,1H),4.00-3.91(m,1H),3.58(s,3H),3.56-3.48(m,1H),2.96-2.87(m,1H).

[0862] Example 80 and Example 81

[0863] 2'-Chloro-N-(5-((cis-7-hydroxy-6,7-dihydro-5H-cyclopentyl[b]pyridin-6-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Example 80)

[0864] 2'-Chloro-N-(5-((trans-7-hydroxy-6,7-dihydro-5H-cyclopentyl[b]pyridin-6-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Example 81)

[0865] Reaction route:

[0866]

[0867] Using 5,6-dihydro-7H-cyclopenta[b]pyridine-7-one as raw material, the synthesis method can be referred to Example 66 and Example 67.

[0868] Compound 80:

[0869] MS (ESI) M / Z: 527.1 [M+H] + .

[0870] 1 H NMR(400MHz,DMSO-d6)δ13.31(s,1H),8.85(s,1H),8.44(d,J=3.9Hz,1H),8 .15(s,1H),7.68(d,J=7.5Hz,1H),7.54(s,1H),7.42(s,1H),7.27(dd,J=7.6 ,4.9Hz,1H),6.08(d,J=6.5Hz,1H),4.94(t,J=6.0Hz,1H),4.07-3.87(m,1H) ,3.59(s,3H),3.58-3.52(m,1H),2.93(dd,J=16.7,6.4Hz,1H),2.59(s,3H).

[0871] Compound 81:

[0872] MS (ESI) M / Z: 527.1 [M+H] + .

[0873] 1 H NMR(400MHz,DMSO-d6)δ13.24(s,1H),8.84(s,1H),8.44(d,J=4.4Hz,1H),8 .17(s,1H),7.69(d,J=7.4Hz,1H),7.56(s,1H),7.45(s,1H),7.28(dd,J=7.6 ,4.9Hz,1H),6.17(d,J=6.4Hz,1H),5.10(t,J=6.3Hz,1H),4.61-4.53(m,1H) ,3.61(s,3H),3.51-3.44(m,1H),3.11(dd,J=16.3,6.9Hz,1H),2.60(s,3H).

[0874] Example 82 and Example 83

[0875] 2'-Chloro-N-(5-((cis-5-hydroxy-6,7-dihydro-5H-cyclopentyl[b]pyridin-6-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Example 82)

[0876] 2'-Chloro-N-(5-((trans-5-hydroxy-6,7-dihydro-5H-cyclopentyl[b]pyridin-6-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Example 83)

[0877] Reaction route:

[0878]

[0879] Using 6,7-dihydro-5H-cyclopenta[b]pyridine-5-one as raw material, the synthesis method can be referred to Example 66 and Example 67.

[0880] Compound 82:

[0881] MS (ESI) M / Z: 527.2 [M+H] + .

[0882] 1 H NMR (400MHz, DMSO-d6) δ13.24(s,1H),8.85(s,1H),8.48-8.37(m,1H),8.17(s,1H),7.75(d,J=6.8Hz,1H),7.55(s,1H),7.44(s,1H),7.31-7 .21(m,1H),6.15(d,J=6.2Hz,1H),5.32(t,J=6.1Hz,1H),4.67-4.59(m ,1H),3.61(s,3H),3.49-3.40(m,1H),3.15-3.05(m,1H),2.59(s,3H).

[0883] Compound 83:

[0884] MS (ESI) M / Z: 527.2 [M+H] + .

[0885] 1H NMR (400MHz, DMSO-d6) δ13.30(s,1H),8.83(s,1H),8.47-8.39(m,1H),8.16(s,1H),7.72(d,J=7.5Hz,1H),7.57(s,1H),7.45(s,1H),7.31-7 .22(m,1H),6.13(d,J=6.7Hz,1H),5.11(t,J=6.2Hz,1H),4.09-3.96(m ,1H),3.59(s,3H),3.58-3.53(m,1H),3.05-2.98(m,1H),2.60(s,3H).

[0886] Example 84 and Example 85

[0887] 4-(5-cyano-2-methoxyphenyl)-N-(5-((cis-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide (Example 84)

[0888] 4-(5-cyano-2-methoxyphenyl)-N-(5-((trans-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide (Example 85)

[0889] Reaction route:

[0890]

[0891] Use 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid as raw material and refer to Example 66 and Example 67 for the synthesis method.

[0892] Compound 84:

[0893] MS (ESI) M / Z: 516.3 [M+H] + .

[0894] 1H NMR (400MHz, DMSO-d6) δ13.15(s,1H),8.76(s,1H),7.92-7.86(m,2H),7.41(s,1H),7.35-7.31(m,1H),7.28-7.24(m,3H),7.16(d,J=8.6Hz,1H) ,5.94(d,J=6.9Hz,1H),5.03(t,J=6.3Hz,1H),3.94(q,J=7.7Hz,1H),3. 55(s,3H),3.54-3.49(m,1H),2.92(dd,J=16.2,7.7Hz,1H),2.59(s,3H).

[0895] Compound 85:

[0896] MS (ESI) M / Z: 516.4 [M+H] + .

[0897] 1 H NMR (400MHz, DMSO-d6) δ13.09(s,1H),8.76(s,1H),7.92-7.84(m,2H),7.41(s,1H),7.39-7.34(m,1H),7.27-7.24(m,3H),7.17(d,J=8.7Hz,1H) ,5.93(d,J=6.3Hz,1H),5.23(t,J=5.9Hz,1H),4.53(q,J=6.0Hz,1H),3. 57(s,3H),3.43-3.38(m,1H),3.09(dd,J=16.1,5.9Hz,1H),2.59(s,3H).

[0898] Example 86 and Example 87

[0899] N-(5-((cis-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-4-(2-methoxy-5-(methylsulfonyl)phenyl)-6-methylnicotinamide (Example 86)

[0900] N-(5-((trans-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-4-(2-methoxy-5-(methylsulfonyl)phenyl)-6-methylnicotinamide (Example 87)

[0901] Reaction route:

[0902]

[0903] Using 4-(2-methoxy-5-(methylsulfonyl)phenyl)-6-methylnicotinic acid as raw material, the synthesis method can be referred to Example 66 and Example 67.

[0904] Compound 86:

[0905] MS (ESI) M / Z: 569.1 [M+H] + .

[0906] 1 H NMR(400MHz,DMSO-d6)δ13.14(s,1H),8.77(s,1H),7.95(dd,J=8.7,2.4Hz,1H) ,7.88(d,J=2.3Hz,1H),7.44(s,1H),7.39-7.34(m,1H),7.27-7.21(m,4H),5.94 (d,J=6.3Hz,1H),5.23(t,J=6.0Hz,1H),4.56-4.49(m,1H),3.59(s,3H),3.40( dd,J=16.2,7.0Hz,1H),3.25(s,3H),3.08(dd,J=16.2,6.0Hz,1H),2.61(s,3H).

[0907] Compound 87:

[0908] MS (ESI) M / Z: 569.2 [M+H] + .

[0909] 1 H NMR (400MHz, DMSO-d6) δ13.20 (s, 1H), 8.77 (s, 1H), 7.95 (dd, J = 8.7, 2.4Hz, 1H), 7.89 (d,J=2.4Hz,1H),7.45(s,1H),7.36-7.30(m,1H),7.28-7.23(m,3H),7.21(d,J=8.8H z,1H),5.96(d,J=6.9Hz,1H),5.04(t,J=6.6Hz,1H),3.97-3.91(m,1H),3.57(s,3H), 3.52(dd,J=16.2,7.9Hz,1H),3.25(s,3H),2.92(dd,J=16.0,7.7Hz,1H),2.61(s,3H).

[0910] Example 88 2'-Chloro-N-(5-(((1S,3aS,4R,6aS)-4-hydroxyoctahydropenten-1-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0911] Reaction route:

[0912]

[0913] Steps:

[0914] Step A: Dissolve cyclooctane-1,5-diene in acetic acid (30 ml), then add palladium acetate (0.45 g, 2 mmol) and lead acetate (8.87 g, 20.02 mmol) in sequence, replace with nitrogen three times, and react at room temperature overnight. The reaction solution is filtered through diatomaceous earth, and the filtrate is concentrated under reduced pressure to obtain a yellow oily liquid, which is directly used in the next step without purification.

[0915] Step B: Dissolve the crude product of (1S,3aR,4S,6aR)-octahydropentene-1,4-diacetyl diacetate in methanol (100 ml) and water (10 ml), add sodium hydroxide (2.4 g, 60 mmol), and react at room temperature overnight. Concentrate under reduced pressure, add water (100 ml) to the residue, extract with ethyl acetate (50 ml x 3), adjust the pH of the aqueous phase to 5-6 with 1N hydrochloric acid, and extract with ethyl acetate (100 ml x 3). Combine the organic phases and concentrate, and the resulting residue is purified by silica gel column chromatography to obtain 780 mg of the product (1S,3aR,4S,6aR)-octahydropentene-1,4-diol.

[0916] 1 H NMR (400MHz, DMSO-d6) δ4.59 (d, J = 5.4Hz, 2H), 3.91-3.82 (m, 2H), 2.40-2.26 (m, 2H), 1.76-1.64 (m, 2H), 1.61-1.44 (m, 4H), 1.38-1.29 (m, 2H).

[0917] Step C: (1S,3aR,4S,6aR)-octahydropentene-1,4-diol (400 mg) was dissolved in pyridine (10 ml), and p-toluenesulfonyl chloride (535.73 mg, 2.81 mmol) and DMAP (34.33 mg, 0.28 mmol) were added in sequence, and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 352 mg of the product (1S,3aR,4S,6aR)-4-hydroxyoctahydropentene-1-yl 4-methylbenzenesulfonate.

[0918] Step D: (1S,3aR,4S,6aR)-4-hydroxy-octahydropenten-1-yl-4-methylbenzene-1-sulfonate (350 mg, 1.18 mmol) was dissolved in DMF (10 ml), and 5-amino-1,3,4-thiadiazole-2-thiol (157.18 mg, 1.18 mmol) and potassium hydroxide (66.21 mg, 1.18 mmol) were added in sequence. After the addition, the mixture was reacted at 80°C overnight. Ethyl acetate (50 ml) was added, and the mixture was washed with water (5 ml x 5). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 177 mg of the product ((1S,3aR,4S,6aR)-4-)-4-((5-amino-1,3,4-thiadiazole-2-yl)thio)octahydropenten-1-ol.

[0919] 1 H NMR(400MHz,DMSO-d6)δ7.32(s,2H),4.55(s,1H),3.94(q,J=6.2Hz,1H),3.29(q,J=6.2Hz,1H), 2.49-2.44(m,1H),2.34-2.27(m,1H),2.08-2.01(m,1H),1.80-1.44(m,6H),1.42-1.31(m,1H).

[0920] Step E: Dissolve 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (83.61 mg, 0.3 mmol) in DMF (2 ml), then add HATU (119.77 mg, 0.32 mmol) and triethylamine (45.54 mg, 0.45 mmol) in sequence, stir at room temperature for 15 minutes, then add ((1S,3aR,4S,6aR)-4-)-((5-amino-1,3,4-thiadiazol-2-yl)sulfanyl)-octahydropentene-1-ol (77.21 mg, 0.30 mmol) to the reaction system, and continue the reaction overnight. Ethyl acetate (50 ml) was added, and the mixture was washed with water (5 ml×5). The organic phase was concentrated under reduced pressure and the residue was purified by preparative HPLC to give 56 mg of 2'-chloro-N-(5-(((1S,3aS,4R,6aS)-4-hydroxyoctahydropenten-1-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0921] MS (ESI) M / Z: 518.1 [M+H] + .

[0922] 1H NMR(400MHz,DMSO-d6)δ13.23(s,1H),8.84(s,1H),8.16(s,1H),7.54(s,1 H),7.43(s,1H),4.57(d,J=4.1Hz,1H),4.00-3.90(m,1H),3.59(s,3H),3. 53(q,J=6.1Hz,1H),2.59(s,3H),2.47-2.45(m,1H),2.38-2.31(m,1H),2. 147-2.11(m,1H),1.84-1.71(m,1H),1.71-1.49(m,5H),1.41-1.37(m,1H).

[0923] Example 89 2'-Chloro-N- ( 5-((1-(Hydroxymethyl)-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0924] Reaction route:

[0925]

[0926] Referring to the preparation method in the above embodiment, 47 mg of 2'-chloro-N- ( 5-((1-(Hydroxymethyl)-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0927] MS (ESI) M / Z: 540.1 [M+H] + .

[0928] 1 H NMR(400MHz,DMSO-d6)δ13.26(brs,1H),8.85(s,1H),8.16(s,1H),7.55(s,1H),7.44(s,1H),7.33-7.29(m,1H),7.26-7.16(m,3H ),4.94(t,J=5.2Hz,1H),4.30-4.24(m,1H),3.65-3.50(m,6H),3.25(q,J=5.6Hz,1H),2.98(dd,J=17.0,4.1Hz,1H),2.59(s,3H).

[0929] Example 90 2'-Chloro-N-(5-((cis-6-cyano-1-methoxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0930] Reaction route:

[0931]

[0932] Referring to the preparation method in the above example, 12 mg of 2'-chloro-N-(5-((cis-6-cyano-1-methoxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide was obtained.

[0933] MS (ESI) M / Z: 583.1 [M+H] + .

[0934] 1 H NMR (400MHz, DMSO-d6) δ13.46(s,1H),9.05(s,1H),8.18-8.12(m,1H),7.87(s,1H),7.78(d,J=8.7Hz,1H),7.52(d,J=7.9Hz,1H),7.42(s,1H) ,4.99(d,J=5.7Hz,1H),4.79-4.68(m,1H),3.72(s,3H),3.48(dd,J=17.1,6.7Hz,1H),3.42(s,3H),3.16(dd,J=17.1,5.5Hz,1H),2.59(s,3H).

[0935] Example 91 and Example 92

[0936] N-(5-(((1R,2S)-5-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-4-(2-methoxy-5-nitrophenyl)-6-methylnicotinamide (Compound 91 or Compound 92)

[0937] N-(5-(((1S,2R)-5-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-4-(2-methoxy-5-nitrophenyl)-6-methylnicotinamide (Compound 92 or Compound 91)

[0938] Reaction route:

[0939]

[0940] Steps:

[0941] Step A: cis-2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-1-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile was separated by SFC (separation column: Daicel IC (250mm*25mm, 10um); mobile phase: CO2 / (0.2% ammonia methanol) = 55 / 45, flow rate: 100 ml / min, pressure: 100 bar, detection wavelength: 214 nM, to obtain

[0942] (1R,2S)-2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-1-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile or (1S,2R)-2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-1-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile:

[0943] Analysis conditions: Daicel IC (4.6*100 mm, 3 um); CO2 / (0.2% ammonia methanol)=55 / 45, flow rate: 3.0 ml / min, detection wavelength: 214 nM; retention time: 1.040 min; ee: 100%; absolute configuration unknown.

[0944] (1S,2R)-2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-1-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile or (1R,2S)-2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-1-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile:

[0945] Analysis conditions: Daicel IC (4.6*100 mm, 3 um); CO2 / (0.2% ammonia methanol)=55 / 45, flow rate: 3.0 ml / min, detection wavelength: 214 nM; retention time: 1.302 min; ee: 98.6%; absolute configuration unknown.

[0946] Step B: 2'-Chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (40 mg, 0.14 mmol) and HATU (63.88 mg, 0.17 mmol) were dissolved in N,N-dimethylformamide (2 ml), diisopropylethylamine (54.28 mg, 0.42 mmol) was added and stirred at room temperature for 0.5 hours, then (1R,2S)-2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-1-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile or (1S,2R)-2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-1-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile (35 mg, 0.12 mmol) was added and stirring was continued for 16 hours. The reaction solution was purified by preparative high performance liquid chromatography to obtain 20 mg of the target product, N-(5-(((1R,2S)-5-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-4-(2-methoxy-5-nitrophenyl)-6-methylnicotinamide or.

[0947] Compound 91, whose absolute configuration is unknown, is the enantiomer of compound 92:

[0948] MS (ESI) M / Z: 561.1 [M+H] + .

[0949] 1 HNMR(400MHz,DMSO-d6)δ13.13(brs,1H),8.81(s,1H),8.33(dd,J=9.2,2.8Hz,1H),8.2 2(d,J=2.8Hz,1H),7.74(s,1H),7.72(d,J=7.6Hz,1H),7.53(d,J=7.6Hz,1H),7.44(s,1H ),7.23(d,J=9.2Hz,1H),6.25(d,J=6.0Hz,1H),5.33(t,J=6.0Hz,1H),4.63-4.58(m,1H ),3.64(s,3H),3.45(dd,J=16.8,6.8Hz,1H),3.11(dd,J=16.8,5.2Hz,1H),2.60(s,3H).

[0950] Compound 92, whose absolute configuration is unknown, is the enantiomer of compound 91:

[0951] MS (ESI) M / Z: 561.1 [M+H] + .

[0952] 1HNMR(400MHz,DMSO-d6)δ13.14(brs,1H),8.81(s,1H),8.33(dd,J=9.2,2.8Hz,1H),8.2 2(d,J=2.8Hz,1H),7.74(s,1H),7.72(d,J=8.0Hz,1H),7.54(d,J=7.6Hz,1H),7.45(s,1H ),7.23(d,J=9.2Hz,1H),6.25(d,J=6.0Hz,1H),5.33(t,J=6.0Hz,1H),4.63-4.58(m,1H ),3.64(s,3H),3.45(dd,J=16.8,6.8Hz,1H),3.11(dd,J=16.8,4.8Hz,1H),2.60(s,3H).

[0953] Example 93 2'-cyano-N-(5-(2-(4-benzonitrile)acetyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0954] Reaction route:

[0955]

[0956] 1-Methylimidazole (25 mg, 0.3 mmol) was added dropwise to a solution of 2'-cyano-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (40 mg, 0.15 mmol), 4-(2-(2-aminothiazol-5-yl))-2-oxoethyl)benzonitrile (37 mg, 0.15 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (51 mg, 0.18 mmol) in acetonitrile (1 ml), and the mixture was stirred at room temperature overnight under nitrogen protection. The mixture was cooled to 0 degrees Celsius, quenched with water, extracted with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 5 mg of 2'-cyano-N-(5-(2-(4-benzonitrile)acetyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0957] MS (ESI) M / Z: 495.0 [MH] + .

[0958] 1H NMR (400MHz, DMSO) δ13.24(s,1H),8.86(s,1H),8.64(s,1H),8.55(s,1H),8.14(d,J=7.5Hz,1H ),7.80(d,J=8.2Hz,2H),7.57-7.45(m,3H),4.44(s,2H),3.66(d,J=12.8Hz,3H),2.60(s,3H).

[0959] Example 94 2'-Chloro-3'-fluoro-5'-methoxy-6-methyl-N-(5-(tetrahydro-2H-pyran-4-carbonyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide

[0960]

[0961] 2'-Chloro-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (74.17 mg, 0.25 mmol) was dissolved in DMF (2 ml), and HATU (104.56 mg, 0.28 mmol) and triethylamine (37.95 mg, 0.38 mmol) were added in sequence. The mixture was stirred at room temperature for 15 minutes, and (2-aminothiazol-5-yl)(tetrahydro-2H-pyran-4-yl)methanone (53.07 mg, 0.25 mmol) was added to the reaction system, and the reaction was continued overnight. Ethyl acetate (50 ml) was added, and the mixture was washed with water (5 ml x 5). The organic phase was concentrated under reduced pressure and the residue was purified by preparative high performance liquid chromatography to give 17 mg of product 2'-chloro-3'-fluoro-5'-methoxy-6-methyl-N-(5-(tetrahydro-2H-pyran-4-carbonyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide.

[0962] MS (ESI) M / Z: 491.4 [M+H] + .

[0963] 1 H NMR(400MHz,DMSO-d6)δ13.31(s,1H),9.00(s,1H),8.52(s,1H),8.18(s,1H),7.48(s,1H),3 .89(dd,J=11.4,3.7Hz,2H),3.70(s,3H),3.55-3.42(m,3H),2.60(s,3H),1.73-1.58(m,4H).

[0964] Example 95 N-(5-(2-(4-chlorophenyl)acetyl)thiazol-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide

[0965]

[0966] 5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxylic acid (synthesized according to WO2022118210, 100 mg, 0.387 mmol) was dissolved in N,N-dimethylformamide (5 ml), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (191.39 mg, 0.503 mmol) and diisopropylethylamine (150.13 mg, 1.16 mmol, 0.202 ml) were added, and stirred at room temperature for 20 minutes, 1-(2-aminothiazol-5-yl)-2-(4-chlorophenyl)ethane-1-one (97.85 mg, 0.387 mmol) was added, and stirred at room temperature for 16 hours. Water was added to quench, and extracted with ethyl acetate (10 ml × 3 times). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative high performance liquid chromatography to give 1.9 mg of compound N-(5-(2-(4-chlorophenyl)acetyl)thiazol-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide.

[0967] MS (ESI) M / Z: 493.1 [M+H] + .

[0968] 1 H NMR(400MHz,DMSO-d6)δ13.15(brs,1H),8.79(s,1H),8.56(s,1H),8.13(s,1H),7.35 (dd,J=8.5Hz,5H),7.25(s,1H),4.27(s,2H),3.51(s,3H),2.58(s,3H),2.47(s,3H).

[0969] Example 96 2'-Chloro-3'-fluoro-5'-methoxy-6-methyl-N-(5-(tetrahydro-2H-pyran-3-carbonyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide

[0970] Reaction route:

[0971]

[0972] Referring to the preparation method in the above example, 8.3 mg of the compound 2'-chloro-3'-fluoro-5'-methoxy-6-methyl-N-(5-(tetrahydro-2H-pyran-3-carbonyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide was obtained.

[0973] MS (ESI) M / Z: 491.3 [M+H] + .

[0974] 1 H NMR (400MHz, DMSO-d6) δ13.31(s,1H),8.99(s,1H),8.53(s,1H),8.17(s,1H),7.49(s,1H),3.95(d,J=10.5Hz,1H),3.82(d,J =9.4Hz,1H),3.69(d,J=1.4Hz,3H),3.55-3.45(m,1H),3.41-3.34(m,2H),2.60(s,3H),1.99-1.88(m,1H),1.71-1.59(m,3H).

[0975] Example 97 and Example 98

[0976] 2'-Chloro-3'-fluoro-5'-methoxy-6-methyl-N-(5-((S)-tetrahydro-2H-pyran-2-carbonyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (Compound 97 or Compound 98)

[0977] 2'-Chloro-3'-fluoro-5'-methoxy-6-methyl-N-(5-((R)-tetrahydro-2H-pyran-2-carbonyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (Compound 98 or Compound 97)

[0978] Reaction route:

[0979]

[0980] Referring to the preparation method in the above example, 40 mg of 2'-chloro-3'-fluoro-5'-methoxy-6-methyl-N-(5-(tetrahydro-2H-pyran-2-carbonyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide was obtained.

[0981] MS (ESI) M / Z: 491.3 [M+H] + .

[0982] 2'-Chloro-3'-fluoro-5'-methoxy-6-methyl-N-(5-(tetrahydro-2H-pyran-2-carbonyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide was prepared and separated by chiral chromatographic column (separation column: Daicel AD (250mm*25mm, 10um); mobile phase: CO2 / (0.2% ammonia methanol)=45 / 55, flow rate: 100 ml / min, pressure: 100 bar, detection wavelength: 214 nM, to obtain

[0983] Compound 97:

[0984] Analysis conditions: Daicel AD (4.6*100 mm, 3 um); CO2 / (0.2% ammonia methanol)=45 / 55, flow rate: 3.0 ml / min, detection wavelength: 214 nM; retention time: 0.811 min; ee: 100%; absolute configuration unknown, enantiomer of compound 98.

[0985] MS (ESI) M / Z: 491.3 [M+H] + .

[0986] 1 H NMR (400MHz, DMSO-d6) δ13.33(s,1H),8.99(s,1H),8.48(s,1H),8.18(s,1H),7.50(s,1H),4.43(d,J=10.6Hz,1 H),3.99(d,J=11.5Hz,1H),3.70(s,3H),3.60-3.50(m,1H),2.60(s,3H),1.86-1.76(m,2H),1.68-1.49(m,4H).

[0987] Compound 98:

[0988] Analysis conditions: Daicel AD (4.6*100 mm, 3 um); CO2 / (0.2% ammonia methanol)=45 / 55, flow rate: 3.0 ml / min, detection wavelength: 214 nM; retention time: 1.046 min; ee: 98.4%; absolute configuration unknown, enantiomer of compound 97.

[0989] MS (ESI) M / Z: 491.3 [M+H] + .

[0990] 1 H NMR (400MHz, DMSO-d6) δ13.34(s,1H),8.97(s,1H),8.48(s,1H),8.18(s,1H),7.51(s,1H),4.43(d,J=10.5Hz,1 H),3.99(d,J=11.4Hz,1H),3.70(s,3H),3.61-3.50(m,1H),2.60(s,3H),1.87-1.76(m,2H),1.68-1.48(m,4H).

[0991] Example 99 2'-Chloro-N-(5-(2-(4-chlorophenyl)acetyl)thiazol-2-yl)-6-(hydroxymethyl)-5'-methoxy-[4,4'-bipyridine]-3-carboxamide

[0992] Reaction route:

[0993]

[0994] Referring to the preparation method in the above example, 17 mg of the product 2'-chloro-N-(5-(2-(4-chlorophenyl)acetyl)thiazol-2-yl)-6-(hydroxymethyl)-5'-methoxy-[4,4'-bipyridine]-3-carboxamide was obtained.

[0995] MS (ESI) M / Z: 530.0 [M+H] + .

[0996] 1 H NMR (400MHz, DMSO-d6) δ13.21(s,1H),8.90(s,1H),8.58(s,1H),8.16(s,1H),7.51(d,J=2.3Hz,2H),7.38(d, J=8.5Hz,2H),7.33(d,J=8.5Hz,2H),5.60(t,J=5.9Hz,1H),4.68(d,J=5.4Hz,2H),4.27(s,2H),3.58(s,3H).

[0997] Example 100 N-(5-(2-(4-chlorophenyl)acetyl)thiazol-2-yl)-2'-cyclopropyl-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0998]

[0999] 2'-Cyclopropyl-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (synthesized with reference to WO2022259204, 40 mg, 0.14 mmol), 1-(2-aminothiazol-5-yl)-2-(4-chlorophenyl)ethane-1-one (35.5 mg, 0.14 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (47 mg, 0.17 mmol), and N-methylimidazole (28 mg, 0.34 mmol) were dissolved in dichloromethane (2 ml). The mixture was stirred at room temperature for 3 hours, quenched with water (20 ml), and extracted with dichloromethane (5 ml × 3 times). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by preparative HPLC to give 5 mg of N-(5-(2-(4-chlorophenyl)acetyl)thiazol-2-yl)-2'-cyclopropyl-5'-methoxy-6-methyl-

[1000] [4,4'-Bipyridine]-3-carboxamide.

[1001] MS (ESI) M / Z: 519.1 [M+H] + .

[1002] 1 H NMR(400MHz,DMSO-d6)δ13.17(s,1H),8.76(s,1H),8.60(s,1H),8.13(s,1H),7.43-7.37(m,3H), 7.35-7.30(m,3H),4.30(s,2H),3.49(s,3H),2.59(s,3H),2.19-2.09(m,1H),0.97-0.84(m,4H).

[1003] Example 101 N-(5-(2-(4-chlorophenyl)acetyl)thiazol-2-yl)-3'-fluoro-5'-methoxy-2'-,6-dimethyl-[4,4'-bipyridine]-3-carboxamide

[1004] Reaction route:

[1005]

[1006] Referring to the preparation method in the above example, 7 mg of N-(5-(2-(4-chlorophenyl)acetyl)thiazol-2-yl)-3'-fluoro-5'-methoxy-2'-,6-dimethyl-[4,4'-bipyridine]-3-carboxamide was obtained.

[1007] MS (ESI) M / Z: 511.2 [M+H] + .

[1008] 1 H NMR(400MHz,DMSO-d6)δ13.29(s,1H),8.92(s,1H),8.61(s,1H),8.16(s,1H),7.42(s,1H),7.40 -7.36(m,2H),7.34-7.30(m,2H),4.30(s,2H),3.63(s,3H),2.59(s,3H),2.42(d,J=3.1Hz,3H).

[1009] Example 102 and Example 103

[1010] 2'-Chloro-3'-fluoro-5'-methoxy-6-methyl-N-(5-(((R)-tetrahydro-2H-pyran-3-carbonyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (Compound 102 or Compound 103)

[1011] 2'-Chloro-3'-fluoro-5'-methoxy-6-methyl-N-(5-(((S)-tetrahydro-2H-pyran-3-carbonyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (Example 103 or Compound 102)

[1012]

[1013] Compound 96 was separated by chiral chromatography (separation column: Daicel AD (250 mm*25 mm, 10 um); mobile phase: CO 2 / (0.2% ammonia methanol solution) = 45 / 55, flow rate: 100 ml / min, pressure: 100 bar, detection wavelength: 214 nM, obtained

[1014] Compound 102:

[1015] Analysis conditions: Daicel AD (4.6*100 mm, 3 um); CO2 / (0.2% ammonia methanol solution) = 45 / 55, flow rate: 3.0 ml / min, detection wavelength: 214 nM; retention time: 0.811 min; ee: 100%; absolute configuration unknown, enantiomer of compound 103.

[1016] MS (ESI) M / Z: 491.2 [M+H] + .

[1017] 1 H NMR (400MHz, DMSO-d6) δ13.33(s,1H),8.98(s,1H),8.54(s,1H),8.18(s,1H),7.50(s,1H),3.96(d,J=13.3Hz,1H),3.82(d,J= 10.9Hz,1H),3.69(d,J=1.5Hz,3H),3.55-3.46(m,1H),3.44-3.34(m,2H),2.57(s,3H),2.00-1.89(m,1H),1.71-1.59(m,3H).

[1018] Compound 103:

[1019] Analysis conditions: Daicel AD (4.6*100 mm, 3 um); CO2 / (0.2% ammonia methanol solution) = 45 / 55, flow rate: 3.0 ml / min, detection wavelength: 214 nM; retention time: 2.146 min; ee: 100%; absolute configuration unknown, enantiomer of compound 102.

[1020] MS (ESI) M / Z: 491.2 [M+H] +.

[1021] 1 H NMR (400MHz, DMSO-d6) δ13.33(s,1H),8.99(s,1H),8.54(s,1H),8.17(s,1H),7.49(s,1H),3.95(d,J=10.6Hz,1H),3.82(d,J= 10.8Hz,1H),3.69(d,J=1.4Hz,3H),3.54-3.45(m,1H),3.45-3.35(m,2H),2.60(s,3H),1.99-1.88(m,1H),1.71-1.58(m,3H).

[1022] Example 104 and Example 105

[1023] 2'-Chloro-3'-fluoro-5'-methoxy-6-methyl-N-(5-((S)-tetrahydrofuran-2-carbonyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (Compound 104 or Compound 105)

[1024] 2'-Chloro-3'-fluoro-5'-methoxy-6-methyl-N-(5-((R)-tetrahydrofuran-2-carbonyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (Compound 105 or Compound 104)

[1025] Reaction route:

[1026]

[1027] Steps:

[1028] Step A: Tetrahydrofuran-2-carboxylic acid (2 g, 17.2 mmol) was dissolved in N,N-dimethylformamide (40 ml), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (7.854 g, 20.7 mmol), N,O-dimethylhydroxylamine hydrochloride (2.016 g, 20.7 mmol) and N,N-diisopropylethylamine (9 ml, 51.7 mmol) were added in sequence. The reaction solution was stirred at room temperature for 16 hours. Water (80 ml) was added to quench the mixture, and the mixture was extracted with ethyl acetate (80 ml x 6). The organic phases were combined, washed with water (80 ml x 2), then with saturated brine (80 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.2 g of N-methoxy-N-methyltetrahydrofuran-2-carboxamide.

[1029] 1H NMR (400MHz, DMSO-d6) δ4.74-4.62(m,1H),3.83-3.75(m,2H),3.67(s,3H),3.09(s,3H),2.16-2.01(m,1H),1.89-1.76(m,3H).

[1030] Step B: Dissolve tert-butyl (5-bromothiazol-2-yl)carbamate (878 mg, 3.1 mmol) in tetrahydrofuran (10 ml), add n-butyl lithium (3.8 ml, 9.4 mmol) at -78°C, stir the reaction solution at -78°C for 1 hour, then slowly dropwise add a solution of N-methoxy-N-methyltetrahydrofuran-2-carboxamide (500 mg, 3.1 mmol) in tetrahydrofuran (1 ml) to the above reaction solution, and stir at room temperature for 2 hours. Add saturated ammonium chloride solution (15 ml) to quench, and extract with ethyl acetate (15 ml x 3 times). Combine the organic phases, wash the organic phases with saturated brine (30 ml), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography to obtain 150 mg of compound (tert-butyl 5-(tetrahydrofuran-2-carbonyl)thiazol-2-yl)carbamate.

[1031] 1 H NMR(400MHz,DMSO-d6)δ12.02(s,1H),8.30(s,1H),4.92(dd,J=8.3,5.8Hz, 1H),3.93-3.80(m,2H),2.29-2.17(m,1H),2.00-1.81(m,3H),1.50(s,9H).

[1032] Step C: Dissolve tert-butyl (5-(tetrahydrofuran-2-carbonyl)thiazol-2-yl)carbamate (35 mg, 0.12 mmol) in formic acid solution (1 ml), and stir the reaction solution at room temperature for 2 hours. Concentrate under reduced pressure and adjust the pH to weak alkalinity with saturated sodium bicarbonate solution, extract with ethyl acetate (10 ml x 3), wash the combined organic phases with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain 16 mg of compound (2-aminothiazol-5-yl)(tetrahydrofuran-2-yl)methanone.

[1033] MS (ESI) M / Z: 199.2 [M+H] + .

[1034] Step D: 2'-chloro-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (26 mg, 0.09 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (37 mg, 0.1 mmol) and (2-aminothiazol-5-yl)(tetrahydrofuran-2-yl)methanone (16 mg, 0.08 mmol) were dissolved in N,N-dimethylformamide (1 ml), and N,N-diisopropylethylamine (0.04 ml, 0.24 mmol) was added. The reaction solution was stirred at room temperature for 16 hours. Water (10 ml) was added to quench the mixture, and the mixture was extracted with ethyl acetate (5 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to give 3 mg of compound 2'-chloro-3'-fluoro-5'-methoxy-6-methyl-N-(5-tetrahydrofuran-2-carbonyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide.

[1035] MS (ESI) M / Z: 477.1 [M+H] + .

[1036] 1 H NMR(400MHz,CD3OD)δ8.91(s,1H),8.37(s,1H),8.05(s,1H),7.47(s,1H),4.93-4.90(m, 1H),4.03-3.94(m,2H),3.75(s,3H),2.67(s,3H),2.38-2.31(m,1H),2.11-1.96(m,3H).

[1037] Step E: 2'-chloro-3'-fluoro-5'-methoxy-6-methyl-N-(5-tetrahydrofuran-2-carbonyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide was prepared and separated by chiral chromatographic column (separation column: Daicel AD (250mm*25mm, 10um); mobile phase: CO 2 / (0.5% ammonia ethanol solution) = 60 / 40, flow rate: 100 ml / min, pressure: 100 bar, detection wavelength: 214 nM, obtained

[1038] Compound 104:

[1039] Analysis conditions: Daicel AD (4.6*100 mm, 3 um); CO2 / (0.5% ammonia ethanol solution) = 60 / 40, flow rate: 3.0 ml / min, detection wavelength: 214 nM; retention time: 1.072 min; ee: 100%; absolute configuration unknown, enantiomer of compound 105.

[1040] MS (ESI) M / Z: 477.3 [M+H] + .

[1041] 1 H NMR (400MHz, DMSO-d6) δ13.34(s,1H),8.98(s,1H),8.45(d,J=1.0Hz,1H),8.19(s,1H),7.51(s,1H),5.01- 4.90(m,1H),3.92-3.81(m,2H),3.70(d,J=2.0Hz,3H),2.60(s,3H),2.30-2.19(m,1H),2.03-1.79(m,3H).

[1042] Compound 105:

[1043] Analysis conditions: Daicel AD (4.6*100 mm, 3 um); CO2 / (0.5% ammonia methanol solution) = 60 / 40, flow rate: 3.0 ml / min, detection wavelength: 214 nM; retention time: 1.421 min; ee: 97.46%; absolute configuration unknown, enantiomer of compound 104.

[1044] MS (ESI) M / Z: 477.3 [M+H] + .

[1045] 1 H NMR(400MHz,DMSO-d6)δ13.33(s,1H),8.99(s,1H),8.44(s,1H),8.18(s,1H),7.50(s,1H),5.02-4.90 (m,1H),3.95-3.77(m,2H),3.70(d,J=1.8Hz,3H),2.60(s,3H),2.28-2.19(m,1H),2.04-1.78(m,3H).

[1046] Example 106 and Example 107

[1047] 2'-Chloro-3'-fluoro-5'-methoxy-N-(5-((1S,4S)-4-methoxycyclohexane-1-carbonyl)thiazol-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 106 or Compound 107)

[1048] 2'-Chloro-3'-fluoro-5'-methoxy-N-(5-((1R,4R)-4-methoxycyclohexane-1-carbonyl)thiazol-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 107 or Compound 106)

[1049] Reaction route:

[1050]

[1051] Referring to the preparation method in the above example, 80 mg of N-(5-(4-methoxycyclohexane-1-carbonyl)thiazol-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide was obtained. The product was separated by SFC (separation column: Daicel OJ (250 mm*25 mm, 10 um); mobile phase: CO 2 / (0.2% ammonia ethanol solution) = 665 / 35, flow rate: 100 ml / min, pressure: 100 bar, detection wavelength: 214 nM, obtained

[1052] Compound 106:

[1053] Analysis conditions: Daicel OJ (4.6*100mm, 3um); CO2 / (0.2% ammonia ethanol solution)=65 / 35, flow rate: 3.0 ml / min, detection wavelength: 214 nM; retention time: 1.153 min; purity: 100%; relative configuration unknown, diastereomer of compound 107.

[1054] MS (ESI) M / Z: 519.4 [M+H] + .

[1055] 1 H NMR(400MHz,DMSO-d6)δ13.32(s,1H),8.98(s,1H),8.51(s,1H),8.18(s,1H),7.50(s,1H),3.70(s,3H),3.24(s,3H),3.19(d ,J=11.6Hz,1H),3.14-3.05(m,1H),2.60(s,3H),2.10-1.99(m,2H),1.89-1.79(m,2H),1.49-1.34(m,2H),1.33-1.18(m,2H).

[1056] Compound 107:

[1057] Analysis conditions: Daicel OJ (4.6*100mm, 3um); CO2 / (0.2% ammonia ethanol solution)=65 / 35, flow rate: 3.0 ml / min, detection wavelength: 214 nM; retention time: 1.786 min; purity: 99.1%; relative configuration unknown, diastereoisomer of compound 106.

[1058] MS (ESI) M / Z: 519.2 [M+H]+ .

[1059] 1 H NMR (400MHz, DMSO-d6) δ13.29(s,1H),8.98(s,1H),8.48(s,1H),8.18(s,1H),7.51(s,1H),3.70(s,3H),3.46-3. 40(m,1H),3.27-3.24(m,1H),3.21(s,3H),2.60(s,3H),1.89-1.87(m,2H),1.72-1.59(m,2H),1.56-1.53(m,4H).

[1060] Example 108 2'-Chloro-3'-fluoro-5'-methoxy-6-methyl-N-(5-(tetrahydrofuran-3-carbonyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide

[1061] Reaction route:

[1062]

[1063] Steps:

[1064] Step A: Tetrahydrofuran-3-carboxylic acid (4.65 g, 40.05 mmol) was dissolved in N,N-dimethylformamide (100 ml), N,O-dimethylhydroxylamine hydrochloride (4.10 g, 42.05 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate (19.8 g, 52.06 mmol) were added, and then diisopropylethylamine (20.70 g, 160.18 mmol) was added. The reaction solution was reacted at room temperature for 16 hours. Water (50 ml) was added to quench, and ethyl acetate (50 ml × 3 times) was used for extraction. The organic phases were combined, washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 6 g of compound N-methoxy-N-methyltetrahydrofuran-3-carboxamide.

[1065] MS (ESI) M / Z: 160.1 [M+H] + .

[1066] Step B: Dissolve tert-butyl (5-bromothiazol-2-yl)carbamate (2.5 g, 8.96 mmol) in tetrahydrofuran (15 ml), add n-butyl lithium (1.72 g, 26.87 mmol, 10.75 ml). The reaction solution is reacted at -78°C for 1.5 hours. Then, a solution of N-methoxy-N-methyltetrahydrofuran-3-carboxamide (1.43 g, 8.96 mmol) in tetrahydrofuran (10 ml) is added dropwise, and the reaction is allowed to proceed overnight at room temperature. Ammonium chloride solution is added to quench, and ethyl acetate (20 ml x 3 times) is used for extraction. The organic phases are combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to obtain 716 mg of the compound (tert-butyl 5-(tetrahydrofuran-3-carbonyl)thiazol-2-yl)carbamate.

[1067] 1 H NMR (400MHz, DMSO-d6) δ12.04(s,1H),8.36(s,1H),4.05-3.93(m,2H),3.79-3.68(m,3H),2.19-2.00(m,2H),1.50(s,9H).

[1068] Step C: Dissolve the compound (5-(tetrahydrofuran-3-carbonyl)thiazol-2-yl)carbamic acid tert-butyl ester (716.4 mg, 2.40 mmol) in hydrochloric acid / dioxane solution (5 ml, 4 mol / L) and react at 50°C for 16 hours. Concentrate under reduced pressure, dissolve the residue in ethyl acetate (10 ml), add sodium bicarbonate (10 ml) and ethyl acetate (10 ml x 3) in an ice bath, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain 400 mg of (2-aminothiazol-5-yl)(tetrahydrofuran-3-yl)methanone

[1069] MS (ESI) M / Z: 199.2 [M+H] + .

[1070] 1 H NMR (400MHz, DMSO-d6) δ8.09(s,2H),8.03(s,1H),4.07-3.79(m,2H),3.78-3.58(m,3H),2.12-1.98(m,2H).

[1071] Step D: 2'-chloro-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (120 mg, 0.404 mmol) was dissolved in N,N-dimethylformamide (5 ml), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (199.93 mg, 0.526 mmol) and diisopropylethylamine (313.7 mg, 2.43 mmol, 0.423 ml) were added. The reaction solution was stirred at room temperature for 20 minutes, (2-aminothiazol-5-yl)(tetrahydrofuran-3-yl)methanone (80.18 mg, 0.404 mmol) was added, and the reaction solution was stirred at room temperature for 16 hours under nitrogen system. The reaction solution was quenched with water and extracted with ethyl acetate (10 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to give 57 mg of compound 2'-chloro-3'-fluoro-5'-methoxy-6-methyl-N-(5-(tetrahydrofuran-3-carbonyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide.

[1072] MS (ESI) M / Z: 477.3 [M+H] + .

[1073] 1 H NMR(400MHz,DMSO-d6)δ13.35(s,1H),8.98(s,1H),8.50(s,1H),8.18(s,1H),7.51(s,1H),4.08-3 .99(m,1H),3.96(t,J=8.1Hz,1H),3.80-3.71(m,3H),3.70(s,3H),2.60(s,3H),2.20-2.01(m,2H).

[1074] Example 109 and Example 110

[1075] 2'-Chloro-3'-fluoro-5'-methoxy-6-methyl-N-(5-(((R)-tetrahydrofuran-3-carbonyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (Compound 109 or Compound 110)

[1076] 2'-Chloro-3'-fluoro-5'-methoxy-6-methyl-N-(5-(((S)-tetrahydrofuran-3-carbonyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (Compound 110 or Compound 109)

[1077]

[1078] Compound 108 was separated by chiral chromatography (separation column: Daicel AD (250 mm*25 mm, 10 um); mobile phase: CO 2 / (0.2% ammonia methanol solution) = 55 / 45, flow rate: 100 ml / min, pressure: 100 bar, detection wavelength: 214 nM, obtained

[1079] Compound 109:

[1080] Analysis conditions: Daicel AD (4.6*100 mm, 3 um); CO2 / (0.2% ammonia methanol solution) = 55 / 45, flow rate: 3.0 ml / min, detection wavelength: 214 nM; retention time: 1.276 min; ee: 100%; absolute configuration unknown, enantiomer of compound 110.

[1081] MS (ESI) M / Z: 477.3 [M+H] + .

[1082] 1 H NMR(400MHz,DMSO-d6)δ13.34(s,1H),8.99(s,1H),8.50(s,1H),8.18(s,1H),7.50(s,1H),4.07-4 .00(m,1H),3.96(t,J=8.1Hz,1H),3.79-3.71(m,3H),3.70(s,3H),2.60(s,3H),2.17-2.03(m,2H).

[1083] Compound 110:

[1084] Analysis conditions: Daicel AD (4.6*100mm, 3um); CO2 / (0.2% ammonia methanol solution) = 55 / 45, flow rate: 3.0 ml / min, detection wavelength: 214 nM; retention time: 2.641 min; ee: 100%; absolute configuration unknown, enantiomer of compound 109

[1085] MS (ESI) M / Z: 477.3 [M+H] +.

[1086] 1 H NMR(400MHz,DMSO-d6)δ13.35(s,1H),9.00(s,1H),8.49(s,1H),8.18(s,1H),7.49(s,1H),4.06-3 .99(m,1H),3.97(t,J=8.1Hz,1H),3.79-3.71(m,3H),3.69(s,3H),2.60(s,3H),2.17-2.04(m,2H).

[1087] Example 111 and Example 112

[1088] 2'-Chloro-3'-fluoro-N-(5-((cis-7-hydroxy-6,7-dihydro-5H-cyclopentyl[b]pyridin-6-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 111)

[1089] 2'-Chloro-3'-fluoro-N-(5-((trans-7-hydroxy-6,7-dihydro-5H-cyclopentyl[b]pyridin-6-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 112)

[1090] Reaction route:

[1091]

[1092] Using 2'-chloro-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid as raw material, the synthesis method can be referred to Example 66 and Example 67.

[1093] Compound 111:

[1094] MS (ESI) M / Z: 545.1 [M+H] + .

[1095] 1 H NMR (400MHz, DMSO-d6) δ13.39 (s, 1H), 9.00 (s, 1H), 8.43 (d, J = 3.6Hz, 1H), 8.18 (d,J=0.9Hz,1H),7.68(d,J=7.6Hz,1H),7.50(s,1H),7.27(dd,J=7.6,4.9Hz,1H ),6.17(dd,J=6.4,1.3Hz,1H),4.94(t,J=6.2Hz,1H),4.04-3.96(m,1H),3.72( s,3H),3.56(dd,J=16.8,7.8Hz,1H),2.93(dd,J=16.9,6.3Hz,1H),2.60(s,3H).

[1096] Compound 112:

[1097] MS (ESI) M / Z: 545.1 [M+H] + .

[1098] 1H NMR (400MHz, DMSO-d6) δ13.37(s,1H),9.00(s,1H),8.44(d,J=4.2Hz,1H),8.18( d,J=1.2Hz,1H),7.69(d,J=6.6Hz,1H),7.50(s,1H),7.27(dd,J=7.6,4.9Hz,1H) ,6.17(dd,J=6.4,1.3Hz,1H),5.09(t,J=6.2Hz,1H),4.58(q,J=6.0Hz,1H),3.72 (s,3H),3.46(dd,J=16.4,7.6Hz,1H),3.10(dd,J=16.4,6.9Hz,1H),2.60(s,3H).

[1099] Example 113 N-(5-(2-(4-cyanophenyl)acetyl)thiazol-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[1100] Reaction route:

[1101]

[1102] 2'-(Difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (15 mg, 0.051 mmol) and 4-(2-(2-amino-1,3-thiazol-5-yl)-2-oxoethyl)benzonitrile (12.41 mg, 0.051 mmol) were dissolved in N,N-dimethylformamide (0.5 ml), HATU (23.27 mg, 0.061 mmol) and diisopropylethylamine (19.77 mg, 0.15 mmol) were added, and stirred at room temperature for 16 hours. The reaction solution was purified by preparative high performance liquid chromatography to obtain 6.2 mg of N-(5-(2-(4-cyanophenyl)acetyl)thiazol-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[1103] MS (ESI) M / Z: 520.1 [M+H] + .

[1104] 1HNMR(400MHz,DMSO-d6)δ8.86(s,1H),8.588(s,1H),8.43(s,1H),7.79(d,J=7.3Hz,2H),7.67(s,1H) ,7.51(d,J=7.3Hz,2H),7.40(s,1H),6.97(t,J=55.0Hz,1H),4.40(s,2H),3.63(s,3H),2.59(s,3H).

[1105] Example 114 and Example 115

[1106] 2'-Chloro-N-(5-((cis-2-chloro-7-hydroxy-6,7-dihydro-5H-cyclopentyl[b]pyridin-6-yl)thio)-1,3,4-thiadiazol-2-yl)-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 114)

[1107] 2'-Chloro-N-(5-((trans-2-chloro-7-hydroxy-6,7-dihydro-5H-cyclopentyl[b]pyridin-6-yl)thio)-1,3,4-thiadiazol-2-yl)-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 115)

[1108] Reaction route:

[1109]

[1110] Referring to the preparation method in the above example, 8 mg of 2'-chloro-N-(5-((cis-2-chloro-7-hydroxy-6,7-dihydro-5H-cyclopentyl[b]pyridin-6-yl)thio)-1,3,4-thiadiazol-2-yl)-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 114) or 4 mg of 2'-chloro-N-(5-((trans-2-chloro-7-hydroxy-6,7-dihydro-5H-cyclopentyl[b]pyridin-6-yl)thio)-1,3,4-thiadiazol-2-yl)-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 115) were obtained.

[1111] Compound 114:

[1112] MS (ESI) M / Z: 579.3 [M+] + .

[1113] 1H NMR (400MHz, DMSO-d6) δ13.38(s,1H),9.00(s,1H),8.18(s,1H),7.77(d,J=8.0Hz,1H),7.50(s,1H),7.40(d,J=8.0Hz,1H),6.35(d,J =6.4Hz,1H),5.10(t,J=6.3Hz,1H),4.62(q,J=6.3Hz,1H),3.72(s,3H),3.49-3.43(m,1H),3.06(dd,J=16.7,6.5Hz,1H),2.60(s,3H).

[1114] Compound 115:

[1115] MS (ESI) M / Z: 579.3 [M+] + .

[1116] 1 H NMR (400MHz, DMSO-d6) δ13.43(s,1H),9.02(s,1H),8.17(s,1H),7.75(d,J=8.1Hz,1H),7.48(s,1H),7.39(d,J=8.0Hz,1H),6.24(d,J=6. 6Hz,1H),4.95(t,J=6.3Hz,1H),4.05-3.96(m,1H),3.71(s,3H),3.53(dd,J=16.7,7.9Hz,1H),2.92(dd,J=16.6,7.0Hz,1H),2.60(s,3H).

[1117] Example 116 and Example 117

[1118] 2'-Chloro-N-(5-(((6R,7S)-2-chloro-7-hydroxy-6,7-dihydro-5H-cyclopentyl[b]pyridin-6-yl)thio)-1,3,4-thiadiazol-2-yl)-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 116 or Compound 117)

[1119] 2'-Chloro-N-(5-(((6S,7R)-2-chloro-7-hydroxy-6,7-dihydro-5H-cyclopentyl[b]pyridin-6-yl)thio)-1,3,4-thiadiazol-2-yl)-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 117 or Compound 116)

[1120]

[1121] Compound 114 was separated by chiral chromatography (separation column: Daicel IG-3 (250 mm*25 mm, 10 um); mobile phase: CO 2 / (methanol / acetonitrile=1 / 1)=45 / 55, flow rate: 100 ml / min, pressure: 100 bar, detection wavelength: 214 nM, obtained

[1122] Compound 116:

[1123] Analysis conditions: Daicel IG-3 (4.6*100mm, 3um); CO 2 / (methanol / acetonitrile=1 / 1)=45 / 55, flow rate: 3.0 ml / min, detection wavelength: 214 nM; retention time: 2.399 min; ee: 100%; absolute configuration unknown, enantiomer of compound 117.

[1124] MS (ESI) M / Z: 579.0 [M+] + .

[1125] 1 H NMR (400MHz, DMSO-d6) δ13.37(s,1H),8.99(s,1H),8.18(d,J=1.1Hz,1H),7.77(d,J=8.0Hz,1H),7.50(s,1H),7.40(d,J=8.0Hz,1H),6.35(d,J= 5.7Hz,1H),5.10(t,J=5.8Hz,1H),4.63(q,J=6.4Hz,1H),3.72(s,3H),3.46(dd,J=16.9,7.3Hz,1H),3.07(dd,J=16.9,6.6Hz,1H),2.60(s,3H).

[1126] Compound 117:

[1127] Analysis conditions: Daicel IG-3 (4.6*100mm, 3um); CO 2 / (methanol / acetonitrile=1 / 1)=45 / 55, flow rate: 3.0 ml / min, detection wavelength: 214 nM; retention time: 3.273 min; ee: 98.44%; absolute configuration unknown, enantiomer of compound 116.

[1128] 1H NMR (400MHz, DMSO-d6) δ13.36(s,1H),9.00(s,1H),8.18(d,J=1.1Hz,1H),7.77(d,J=8.1Hz,1H),7.50(s,1H),7.40(d,J=8.0Hz,1H),6.35(d,J= 6.0Hz,1H),5.10(t,J=6.2Hz,1H),4.63(d,J=6.6Hz,1H),3.72(s,3H),3.48(dd,J=15.6,8.4Hz,1H),3.07(dd,J=16.7,6.8Hz,1H),2.61(s,3H).

[1129] Example 118 2'-Chloro-3'-fluoro-N-(5-(trans-4-hydroxycyclohexane-1-carbonyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[1130] Reaction route:

[1131]

[1132] Steps:

[1133] Step A: Dissolve trans-4-hydroxycyclohexane-1-carboxylic acid methyl ester (205 mg, 1.3 mmol) in water / methanol / tetrahydrofuran (1 ml / 1 ml / 1 ml), add lithium hydroxide monohydrate (272 mg, 6.48 mmol), and react at room temperature for 16 hours. Add water (20 ml) to quench, adjust the pH to 4-5 with 2M dilute hydrochloric acid, and extract with ethyl acetate (5 ml x 3 times). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 168 mg of compound trans-4-hydroxycyclohexane-1-carboxylic acid.

[1134] MS (ESI) M / Z: 145.2 [M+H] + .

[1135] Step B: Dissolve trans-4-hydroxycyclohexane-1-carboxylic acid (163 mg, 1.13 mmol), N,O-dimethylhydroxylamine hydrochloride (144 mg, 1.47 mmol), diisopropylethylamine (438 mg, 3.39 mmol) and HATU (456 mg, 1.2 mmol) in N,N-dimethylformamide (1 ml) and react overnight at room temperature. Add water to quench, extract with ethyl acetate (5 ml x 3 times). Combine the organic phases, wash with saturated brine (5 ml), dry with anhydrous sodium sulfate, filter and concentrate. The residue obtained is purified by silica gel column chromatography to obtain 59.9 mg of the compound trans-4-hydroxy-N-methoxy-N-methylcyclohexane-1-carboxamide.

[1136] MS (ESI) M / Z: 188.3 [M+H] + .

[1137] 1 H NMR(400MHz,DMSO-d6)δ3.66(s,3H),3.32-3.29(m,1H),3.07(s,3H),2.60-2.52(m ,1H),1.90-1.79(m,2H),1.73-1.61(m,2H),1.41-1.29(m,2H),1.21-1.09(m,2H).

[1138] Step C: Dissolve trans-4-hydroxy-N-methoxy-N-methylcyclohexane-1-carboxamide (984 mg, 5.26 mmol) in dichloromethane (10 ml), add triethylamine (1.33 g, 13.14 mmol), add tert-butyldimethylsilyl trifluoromethanesulfonate (1.81 g, 6.83 mmol) dropwise under ice bath, and stir the reaction solution at room temperature for 16 hours. Quench with ice water, extract with dichloromethane (10 ml x 3 times), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate. The residue is purified by silica gel column chromatography to obtain 109.3 mg of trans-4-((tert-butyldimethylsilyl)oxy)-N-methoxy-N-methylcyclohexane-1-carboxamide.

[1139] MS (ESI) M / Z: 302.5 [M+H] + .

[1140] 1 H NMR (400MHz, DMSO-d6) δ3.66 (s, 3H), 3.61-3.52 (m, 1H), 3.07 (s, 3H), 2.56 (d, J = 14.1Hz, 1H), 1.83(dd,J=12.5,3.7Hz,2H),1.76-1.63(m,2H),1.46-1.26(m,4H),0.85(s,9H),0.04(s,6H).

[1141] Step D: tert-Butyl (5-bromothiazol-2-yl)carbamate (855 mg, 3.06 mmol) was dissolved in tetrahydrofuran (8 ml), and n-butyl lithium (588.5 mg, 9.19 mmol) was added at -78°C and reacted for 1.5 hours. A solution of trans-4-((tert-butyldimethylsilyl)oxy)-N-methoxy-N-methylcyclohexane-1-carboxamide (923.45 mg, 3.06 mmol) in tetrahydrofuran (7 ml) was added. The reaction was carried out at room temperature for 16 hours. The reaction was quenched with a saturated ammonium chloride solution and then reacted, and extracted with ethyl acetate (10 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography to obtain 297 mg of tert-butyl (5-(trans-4-((tert-butyldimethylsilyl)oxy)cyclohexane-1-carbonyl)thiazol-2-yl)carbamate.

[1142] MS (ESI) M / Z: 441.5 [M+H] + .

[1143] Step E: Tert-butyl (5-(trans-4-((tert-butyldimethylsilyl)oxy)cyclohexane-1-carbonyl)thiazol-2-yl)carbamate (50 mg, 0.113 mmol) was dissolved in a solution of hydrochloric acid / 1,4-dioxane (1 ml, 4 mol) and stirred at 50°C for 16 hours. The mixture was concentrated under reduced pressure to give 33.8 mg of (2-aminothiazol-5-yl)(trans-4-hydroxycyclohexyl)methanone dihydrochloride.

[1144] MS (ESI) M / Z: 227.1 [M+H] + .

[1145] Step F: (2-aminothiazol-5-yl)(trans-4-hydroxycyclohexyl)methanone (219.58 mg, 0.97 mmol) was dissolved in dichloromethane (8 ml). The reaction solution was added with triethylamine (245.48 mg, 2.43 mmol) under nitrogen protection at 0°C, and tert-butyldimethylsilyl trifluoromethanesulfonate (333.44 mg, 1.26 mmol) was added dropwise. The reaction was allowed to react at room temperature for 16 hours. Water (20 ml) was added, and the pH value was adjusted to 8-9 with a saturated sodium bicarbonate solution, and then extracted with dichloromethane (10 ml x 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography to obtain 276 mg of (2-aminothiazol-5-yl)(trans-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)methanone.

[1146] MS (ESI) M / Z: 341.1 [M+H] + .

[1147] Step G: 2'-chloro-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (104 mg, 0.35 mmol) and (2-aminothiazol-5-yl)(trans-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)methanone (119.38 mg, 0.35 mmol) were dissolved in a solution of N,N-dimethylformamide (2.5 ml), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (173.28 mg, 0.45 mmol) was added, the reaction solution was reacted at room temperature for 1 hour, diisopropylethylamine (181.28 mg, 0.244 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Water was added to quench the mixture, and the mixture was extracted with ethyl acetate (10 ml x 3). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative high performance liquid chromatography to give 112 mg of N-(5-(trans-4-((tert-butyldimethylsilyl)oxy)cyclohexane-1-carbonyl)thiazol-2-yl)-2'-chloro-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[1148] MS (ESI) M / Z: 619.5 [M+H] + .

[1149] 1 H NMR(400MHz,DMSO-d6)δ13.30(brs,1H),8.98(s,1H),8.50(s,1H),8.17(s,1H),7.50(s,1H),3.69(s,3H),3.65 -3.53(m,1H),3.23-3.12(m,1H),2.60(s,3H),1.91-1.77(m,4H),1.51-1.34(m,4H),0.86(s,9H),0.04(s,6H).

[1150] Step H: Dissolve N-(5-(trans-4-((tert-butyldimethylsilyl)oxy)cyclohexane-1-carbonyl)thiazol-2-yl)-2'-chloro-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (112 mg, 0.181 mmol) in tetrahydrofuran (2 ml), add tetrabutylammonium fluoride (189.17 mg, 0.723 mmol), and react at room temperature for 16 hours. Quench with water, extract with ethyl acetate (10 ml x 3 times). Combine the organic phases, wash with saturated brine (20 ml), dry over anhydrous sodium sulfate, filter, and concentrate. The resulting residue was purified by preparative HPLC to give 23 mg of 2'-chloro-3'-fluoro-N-(5-(trans-4-hydroxycyclohexane-1-carbonyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[1151] MS (ESI) M / Z: 505.4 [M+H] + .

[1152] 1 H NMR (400MHz, DMSO-d6) δ13.30(brs,1H),8.98(s,1H),8.51(s,1H),8.18(s,1H),7.50(s,1H),4.61(d,J=5.3Hz,1H),3.70(s,3H) ,3.40-3.35(m,1H),3.19-3.12(m,1H),2.60(s,3H),1.91-1.84(m,2H),1.83-1.75(m,2H),1.47-1.35(m,2H),1.34-1.26(m,2H).

[1153] Example 119 2'-Chloro-3'-fluoro-N-(5-(cis-4-hydroxycyclohexane-1-carbonyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[1154] Reaction route:

[1155]

[1156] Using cis-4-hydroxycyclohexane-1-carboxylic acid methyl ester as raw material, the synthesis method was referenced to Example 118 to obtain the compound 2'-chloro-3'-fluoro-N-(5-((1S,4S)-4-hydroxycyclohexane-1-carbonyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[1157] MS (ESI) M / Z: 505.3 [M+H] + .

[1158] 1 H NMR (400MHz, DMSO-d6) δ13.23(brs,1H),9.02(s,1H),8.41(s,1H),8.17(s,1H),7.45(s,1H),4.34(d,J=2.7Hz,1H),3 .82(brs,1H),3.70(s,3H),3.22-3.17(m,1H),2.59(s,3H),1.85-1.76(m,2H),1.69-1.65(m,2H),1.58-1.48(m,4H).

[1159] Example 120 2'-Chloro-N-(5-(2-(4-cyanophenyl)acetyl)thiazol-2-yl)-6-(hydroxymethyl)-5'-methoxy-[4,4'-bipyridine]-3-carboxamide

[1160] Reaction route:

[1161]

[1162] Steps:

[1163] Step A: 2'-chloro-5'-methoxy-6-((tetrahydro-2H-pyran-2-yl)oxy)methyl)-[4,4'-bipyridine]-3-carboxylic acid (140 mg, 0.37 mmol) was dissolved in anhydrous DMF (2 ml), HATU (168.82 mg, 0.44 mmol) and diisopropylethylamine (143.46 mg, 1.11 mmol) were added in sequence, and stirred at room temperature for 30 minutes. 4-(2-(2-aminothiazol-5-yl)-2-oxoethyl)benzonitrile (90.01 mg, 0.37 mmol) was added, and stirring was continued at room temperature for 16 hours. The reaction solution was purified by reverse phase column chromatography to obtain 80 mg of 2'-chloro-N-(5-(2-(4-cyanophenyl)acetyl)thiazol-2-yl)-5'-methoxy-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-[4,4'-bipyridine]-3-carboxamide.

[1164] MS (ESI) M / Z: 605.2 [M+H] + .

[1165] 1H NMR (400MHz, DMSO-d6) δ13.28(s,1H),8.91(s,1H),8.64(s,1H),8.17(s,1H),7.80(d,J=8.0Hz,2H),7.58(s,1H),7.55-7.50(m,3H),4.85- 4.79(m,2H),4.68(d,J=13.6Hz,1H),4.45(s,2H),3.83-3.77(m,1H), 3.58(s,3H),3.52-3.47(m,1H),1.78-1.66(m,2H),1.61-1.47(m,4H).

[1166] Step B: 2'-chloro-N-(5-(2-(4-cyanophenyl)acetyl)thiazol-2-yl)-5'-methoxy-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-[4,4'-bipyridine]-3-carboxamide (80 mg, 0.13 mmol) was dissolved in tetrahydrofuran (2 ml), and 1N hydrochloric acid (1 ml) was added, and the mixture was reacted at room temperature for 1 hour. The reaction system was directly concentrated, and the resulting residue was purified by preparative high performance liquid chromatography to obtain 12 mg of 2'-chloro-N-(5-(2-(4-cyanophenyl)acetyl)thiazol-2-yl)-6-(hydroxymethyl)-5'-methoxy-[4,4'-bipyridine]-3-carboxamide.

[1167] MS (ESI) M / Z: 520.1 [M+H] + .

[1168] 1 H NMR (400MHz, DMSO-d6) δ13.20(brs,1H),8.91(s,1H),8.60(s,1H),8.17-8.13(m,1H),7.79(d,J=8. 0Hz,2H),7.53-7.45(m,4H),5.60(t,J=5.8Hz,1H),4.67(d,J=5.5Hz,2H),4.41(s,2H),3.58(s,3H).

[1169] Embodiment 121

[1170] N-(5-((cis-6-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[1171]

[1172] 4-(2-(Difluoromethyl)-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxylic acid (20 mg, 0.068 mmol) and HATU (31.03 mg, 0.082 mmol) were dissolved in N,N-dimethylformamide (0.5 ml), diisopropylethylamine (26.36 mg, 0.20 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. Then, cis-2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-1-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile (19.74 mg, 0.068 mmol) was added and stirring was continued at room temperature for 16 hours. The reaction solution was purified by preparative high performance liquid chromatography to obtain 24 mg of N-(5-(((1R,2S)-6-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[1173] MS (ESI) M / Z: 567.1 [M+H] + .

[1174] 1 H NMR(400MHz,DMSO-d6)δ13.20(brs,1H),8.86(s,1H),8.45(s,1H),7.76(s,1H),7. 73(d,J=7.8Hz,1H),7.68(s,1H),7.48(d,J=7.8Hz,1H),7.41(s,1H),6.98(t,J=55 .1Hz,1H),6.18(d,J=6.1Hz,1H),5.30(t,J=5.8Hz,1H),4.58(q,J=5.9Hz,1H),3.6 8(s,3H),3.49(dd,J=17.3,6.9Hz,1H),3.15(dd,J=17.2,5.4Hz,1H),2.60(s,3H).

[1175] Example 122 N-(5-((trans-6-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[1176]

[1177] 4-(2-(Difluoromethyl)-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxylic acid (20 mg, 0.068 mmol) and HATU (31.03 mg, 0.082 mmol) were dissolved in N,N-dimethylformamide (0.5 ml), diisopropylethylamine (26.36 mg, 0.20 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. Then, trans-2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-1-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile (19.74 mg, 0.068 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was purified by preparative high performance liquid chromatography to obtain 29 mg of N-(5-((trans-6-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[1178] MS (ESI) M / Z: 567.1 [M+H] + .

[1179] 1 H NMR(400MHz,DMSO-d6)δ13.28(brs,1H),8.86(s,1H),8.44(s,1H),7.75-7 .61(m,3H),7.46(d,J=8.2Hz,1H),7.41(s,1H),6.98(t,J=55.0Hz,1H),6.1 6(d,J=6.6Hz,1H),5.09(t,J=6.5Hz,1H),3.98(q,J=7.3Hz,1H),3.66(s,3H ), 3.59(dd,J=17.2,7.9Hz,1H), 3.02(dd,J=17.1,7.6Hz,1H), 2.60(s,3H).

[1180] Example 123 N-(5-((cis-5-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[1181]

[1182] 4-(2-(Difluoromethyl)-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxylic acid (20 mg, 0.068 mmol) and HATU (31.03 mg, 0.082 mmol) were dissolved in N,N-dimethylformamide (0.5 ml), diisopropylethylamine (26.36 mg, 0.20 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. Then, cis-2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-1-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile (19.74 mg, 0.068 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was purified by preparative high performance liquid chromatography to obtain 16 mg of N-(5-((cis-5-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[1183] MS (ESI) M / Z: 567.1 [M+H] + .

[1184] 1 H NMR(400MHz,DMSO-d6)δ13.21(brs,1H),8.86(s,1H),8.45(s,1H),7.77-7 .62(m,3H),7.53(d,J=7.8Hz,1H),7.41(s,1H),6.98(t,J=55.1Hz,1H),6.2 4(d,J=6.1Hz,1H),5.33(t,J=6.0Hz,1H),4.60(q,J=5.7Hz,1H),3.68(s,3H ), 3.45 (dd, J=16.6, 6.8Hz, 1H), 3.11 (dd, J=16.9, 4.9Hz, 1H), 2.60 (s, 3H).

[1185] Example 124 N-(5-((trans-5-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[1186]

[1187] 4-(2-(Difluoromethyl)-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxylic acid (20 mg, 0.068 mmol) and HATU (31.03 mg, 0.082 mmol) were dissolved in N,N-dimethylformamide (0.5 ml), diisopropylethylamine (26.36 mg, 0.20 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. Then, trans-2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-1-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile (19.74 mg, 0.068 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was purified by preparative high performance liquid chromatography to obtain 11.5 mg of N-(5-((trans-5-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[1188] MS (ESI) M / Z: 567.1 [M+H] + .

[1189] 1 H NMR (400MHz, DMSO-d6) δ13.31(brs,1H),8.86(s,1H),8.44(s,1H),7.75-7.64(m,3H),7.50(d,J=8.2Hz,1H),7.41(s,1H),6.97(t,J=55.0Hz,1H),6. 21(d,J=6.8Hz,1H),5.10(t,J=6.9Hz,1H),4.01-3.89(m,1H),3.66(s,3H) ,3.54(dd,J=16.3,7.8Hz,1H),2.98(dd,J=16.7,8.2Hz,1H),2.59(s,3H).

[1190] Example 125 N-(5-(2-(4-cyanophenyl)acetyl)thiazol-2-yl)-5'-methoxy-2'-,6-dimethyl-[4,4'-bipyridine]-3-carboxamide

[1191]

[1192] 4-(5-methoxy-2-methylpyridin-4-yl)-6-methylpyridine-3-carboxylic acid (5 mg, 0.019 mmol) was dissolved in DMF (0.5 ml), and HATU (7.224 mg, 0.019 mmol) and triethylamine (3.845 mg, 0.038 mmol) were added in sequence, and stirred at room temperature for 15 minutes. 4-(2-(2-amino-1,3-thiazol-5-yl)-2-oxoethyl)benzonitrile (4.622 mg, 0.099 mmol) was then added to the reaction system, and the reaction was continued overnight. Ethyl acetate (20 ml) was added to the system, washed with water (5 ml x 5), and the organic phase was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 25 mg of the product N-(5-(2-(4-cyanophenyl)acetyl)thiazol-2-yl)-5'-methoxy-2'-,6-dimethyl-[4,4'-bipyridine]-3-carboxamide.

[1193] MS (ESI) M / Z: 484.1 [M+H] + .

[1194] 1 H NMR(400MHz,DMSO-d6)δ13.12(brs,1H),8.78(s,1H),8.61(s,1H),8.16(s,1H),7.82-7.78(m,2H) ,7.53-7.49(m,2H),7.37(s,1H),7.26(s,1H),4.42(s,2H),3.51(s,3H),2.58(s,3H),2.47(s,3H).

[1195] Example 126 2'-Chloro-5'-methoxy-6-methyl-N-(5-(2-(1-methyl-1H-pyrazol-4-yl)acetyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide

[1196]

[1197] Taking methyl 2-(1-methyl-1H-pyrazol-4-yl)acetate as starting material, the synthetic method was referred to Example 48 to obtain the compound 2'-chloro-5'-methoxy-6-methyl-N-(5-(2-(1-methyl-1H-pyrazol-4-yl)acetyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide.

[1198] MS (ESI) M / Z: 483.1 [M+H] + .

[1199] 1H NMR(400MHz,DMSO-d6)δ13.14(s,1H),8.85(s,1H),8.50(s,1H),8.14(s,1H),7.54(s,1H), 7.53(s,1H),7.41(s,1H),7.31(s,1H),4.04(s,2H),3.78(s,3H),3.56(s,3H),2.58(s,3H).

[1200] Example 127 2'-Chloro-5'-methoxy-6-methyl-N-(5-(2-(4-(methylcarbamoyl)phenyl)acetyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide

[1201]

[1202] Referring to the preparation method in the above example, 19 mg of 2'-chloro-5'-methoxy-6-methyl-N-(5-(2-(4-(methylcarbamoyl)phenyl)acetyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide was obtained.

[1203] MS (ESI) M / Z: 536.0 [M+H] + .

[1204] 1 H NMR (400MHz, DMSO-d6) δ13.23(s,1H),8.85(s,1H),8.60(s,1H),8.39(d,J=4.6Hz,1H),8.14(s,1H),7.77(d,J=8.3Hz ,2H),7.54(s,1H),7.42(s,1H),7.38(d,J=8.3Hz,2H),4.32(s,2H),3.56(s,3H),2.77(d,J=4.5Hz,3H),2.59(s,3H).

[1205] Example 128 2'-Chloro-N-(5-(2-(4-(dimethylcarbamoyl)phenyl)acetyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[1206]

[1207] Using dimethylamine as raw material, the synthesis method was similar to Example 48 to obtain the compound 2'-chloro-N-(5-(2-(4-(dimethylcarbamoyl)phenyl)acetyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[1208] MS (ESI) M / Z: 550.2 [M+H] + .

[1209] 1 H NMR(400MHz,DMSO-d6)δ13.23(s,1H),8.83(s,1H),8.62(s,1H),8.15(s,1H),7.56(s,1H), 7.44(s,1H),7.36(s,4H),4.32(s,2H),3.56(s,3H),2.97(s,3H),2.91(s,3H),2.59(s,3H).

[1210] Example 129 2'-Chloro-5'-methoxy-6-methyl-N-(5-(2-(4-(methylsulfonyl)phenyl)acetyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide

[1211]

[1212] Using 2-(4-iodophenyl)-N-methoxy-N-methylacetamide dimethylamine as raw material, the synthetic method was based on Example 127 to obtain compound 2'-chloro-5'-methoxy-6-methyl-N-(5-(2-(4-(methylsulfonyl)phenyl)acetyl)thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide.

[1213] MS (ESI) M / Z: 557.0 [M+H] + .

[1214] 1 H NMR (400MHz, DMSO-d6) δ13.24(s,1H),8.84(s,1H),8.64(s,1H),8.15(s,1H),7.88(d,J=8.4Hz,2H), 7.58(d,J=8.4Hz,2H),7.55(s,1H),7.43(s,1H),4.44(s,2H),3.56(s,3H),3.21(s,3H),2.59(s,3H).

[1215] Example 130 2'-Chloro-N-(5-((cis-6-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-ethynyl-6-methyl-[4,4'-bipyridine]-3-carboxamide

[1216]

[1217] Steps:

[1218] Step A: 2-chloro-5-iodopyridin-4-amine (1 g, 3.93 mmol) was dissolved in N,N-dimethylformamide (10 ml) at room temperature. Subsequently, trimethylethynylsilane (579 mg, 5.89 mmol), cuprous iodide (150 mg, 0.79 mmol), bis(triphenylphosphine)palladium dichloride (276 mg, 0.39 mmol) and triethylamine (1.19 g, 11.79 mmol) were added to the above solution in sequence. Stir at room temperature for 16 hours under nitrogen protection. Water (50 ml) was added to quench the mixture, and the mixture was extracted with ethyl acetate (20 ml × 3 times). The organic phases were combined, washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 800 mg of 2-chloro-5-((trimethylsilyl)ethynyl)pyridin-4-amine.

[1219] 1 H NMR (400MHz, DMSO-d6) δ7.96(s,1H),6.64(s,1H),6.52(brs,2H),0.24(s,9H).

[1220] Step B: 2-chloro-5-((trimethylsilyl)ethynyl)pyridin-4-amine (350 mg, 1.56 mmol) was dissolved in acetonitrile (10 ml) at room temperature. Subsequently, tert-butyl nitrite (241 mg, 2.34 mmol) and diiodomethane (748 mg, 2.8 mmol) were slowly added to the above solution under nitrogen protection while cooling in an ice-water bath. The mixture was reacted at 60 degrees Celsius for 1 hour, cooled to room temperature, and quenched with water (30 ml). The mixture was extracted with ethyl acetate (10 ml x 3 times), and the organic phases were combined, washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 490 mg of 2-chloro-4-iodo-5-((trimethylsilyl)ethynyl)pyridine.

[1221] MS (ESI) M / Z: 335.9 [M+H] + .

[1222] 1 H NMR (400MHz, DMSO-d6) δ8.42(s,1H),8.19(s,1H),0.28(s,9H).

[1223] Step C: 2-chloro-4-iodo-5-((trimethylsilyl)ethynyl)pyridine (490 mg, 1.46 mmol), 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (1.2 g, 4.38 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (106.8 mg, 0.146 mmol) and potassium carbonate (403.6 mg, 2.92 mmol) were dissolved in 1,4-dioxane (5 ml) and water (1 ml) at room temperature. The reaction solution was reacted at 85 degrees Celsius for 16 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 310 mg of methyl 2'-chloro-6-methyl-5'-(trimethylsilyl)ethynyl)-[4,4'-bipyridine]-3-carboxylate.

[1224] MS (ESI) M / Z: 359.3 [M+H] + .

[1225] 1 H NMR (400MHz, DMSO-d6) δ8.98(s,1H),8.51(d,J=0.5Hz,1H),7.67(d,J=0.5Hz,1H),7.35(s,1H),3.65(s,3H),2.56(s,3H),0.00(s,9H).

[1226] Step D: Methyl 2'-chloro-6-methyl-5'-(trimethylsilyl)ethynyl)-[4,4'-bipyridine]-3-carboxylate (310 mg, 0.87 mmol) was dissolved in tetrahydrofuran (2 ml) and water (2 ml) at room temperature. Subsequently, lithium hydroxide monohydrate (141 mg, 3.36 mmol) was added to the above solution. The reaction solution was stirred at room temperature for 16 hours and concentrated under reduced pressure to remove tetrahydrofuran. The residue was adjusted to pH 4 with 1 mol / L dilute hydrochloric acid. After concentration under reduced pressure, the residue was purified by reverse phase preparative column to obtain 100 mg of 2'-chloro-5'-ethynyl-6-methyl-[4,4'-bipyridine]-3-carboxylic acid.

[1227] MS (ESI) M / Z: 273.2 [M+H] + .

[1228] 1 H NMR (400MHz, DMSO-d6) δ13.20(s,1H),9.01(s,1H),8.57(s,1H),7.63(s,1H),7.32(s,1H),4.38(s,1H),2.58(s,3H).

[1229] Step E: 2'-Chloro-5'-ethynyl-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (50 mg, 0.18 mmol), cis-2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-3-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile (53.2 mg, 0.18 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (61.7 mg, 0.22 mmol), N-methylimidazole (35.5 mg, 0.43 mmol) were dissolved in acetonitrile (3 ml) and N,N-dimethylformamide (0.2 ml) at room temperature. The mixture was stirred at room temperature for 16 hours and quenched with water (20 ml). The mixed solution was extracted with dichloromethane (10 ml x 3 times), and the organic phases were combined and washed with water (30 ml) and saturated brine (30 ml) in sequence, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography to obtain 13.6 mg of 2'-chloro-N-(5-((cis-6-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-ethynyl-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[1230] MS (ESI) M / Z: 545.1 [M+H] + .

[1231] 1 H NMR(400MHz,DMSO-d6)δ13.38(s,1H),9.03(s,1H),8.56(s,1H),7.77(s,1H) ,7.73(dd,J=7.6,1.5Hz,1H),7.67(s,1H),7.48(d,J=7.9Hz,1H),7.43(s,1H ),6.20(d,J=6.1Hz,1H),5.30(t,J=5.9Hz,1H),4.71-4.54(m,1H),4.32(s,1 H), 3.50 (dd, J=17.3, 6.8Hz, 1H), 3.15 (dd, J=17.2, 5.4Hz, 1H), 2.61 (s, 3H).

[1232] Example 131 2'-Chloro-N-(5-(2-(6-cyanopyridin-3-yl)acetyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[1233]

[1234] Using tert-butyl N-(5-(carbonylchloro)-1,3-thiazol-2-yl)carbamate as raw material, the synthesis method was based on Example 48 to obtain the compound 2'-chloro-N-(5-(2-(6-cyanopyridin-3-yl)acetyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[1235] MS (ESI) M / Z: 505.1 [M+H] + .

[1236] 1 H NMR (400MHz, DMSO-d6) δ13.22(s,1H),8.85(s,1H),8.69(d,J=2.1Hz,1H),8.62(s,1H),8.15(s,1H),8.02(d, J=7.9Hz,1H),7.97(dd,J=8.0,2.1Hz,1H),7.55(s,1H),7.43(s,1H),4.52(s,2H),3.57(s,3H),2.59(s,3H).

[1237] Example 132 2'-Chloro-N-(5-((trans-6-cyano-1-hydroxy-2,3-dihydro-1H-inden-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-ethynyl-6-methyl-[4,4'-bipyridine]-3-carboxamide

[1238]

[1239] Using trans-2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-3-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile as raw material, the synthetic method was based on the reference example 130 to obtain compound 2'-chloro-N-(5-((trans-6-cyano-1-hydroxy-2,3-dihydro-1H-indene-2-yl)thio)-1,3,4-thiadiazol-2-yl)-5'-ethynyl-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[1240] MS (ESI) M / Z: 544.8 [M+H] + .

[1241] 1H NMR (400MHz, DMSO-d6) δ13.45(s,1H),9.04(s,1H),8.56(s,1H),7.72(d,J=6.9Hz,2H),7.66(s,1H),7.50(d,J=8.2Hz,1H),7.43(s,1 H),6.22(d,J=6.8Hz,1H),5.10(t,J=6.8Hz,1H),4.31(s,1H),4.05-3.93(m,1H),3.59-3.48(m,1H),3.05-2.92(m,1H),2.61(s,3H).

[1242] Example 133 2'-Chloro-3'-fluoro-N-(5-(3-hydroxycyclohexane-1-carbonyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[1243]

[1244] Using 3-hydroxycyclohexanecarboxylic acid as raw material, the synthesis method was similar to that in Example 1 to obtain the compound 2'-chloro-3'-fluoro-N-(5-(3-hydroxycyclohexane-1-carbonyl)thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[1245] MS (ESI) M / Z: 505.1 [M+H] + .

[1246] 1 H NMR (400MHz, DMSO-d6) δ13.29(s,1H),8.99(s,1H),8.49(s,1H),8.19(s,1H),7.51(s,1H),4.64(dd,J=4.8,2.3Hz,1H),3.71(s,3H),3.62-3 .48(m,1H),3.31-3.24(m,1H),2.61(s,3H),1.99-1.82(m,2H),1.80- 1.68(m,2H),1.47-1.35(m,1H),1.29-1.18(m,2H),1.14-1.02(m,1H).

[1247] Biological test evaluation

[1248] Test Example 1: Evaluation of the inhibitory effect of the compounds of the present invention on POLQ enzyme activity

[1249] Experimental principle: This experiment uses ADP-Glo TMKinase Assay method detects kinase activity by measuring the amount of ADP generated in the kinase reaction. Determine the inhibitory activity of the compound on DNA polymerase theta (POLQ) protein and obtain the half inhibitory concentration IC of the compound on POLQ activity inhibition 50 .

[1250] Experimental instruments: incubator (Shanghai Boxun, SPX-100B-Z), centrifuge (Eppendorf, 5810R), Envision (Perkin Elmer, 2104 Multi-label Reader), Echo (LABCYTE, Echo650)

[1251] Experimental Materials:

[1252]

[1253] Experimental method: Compounds were dispensed into each well of a white Greiner 384-well plate using an Echo, with 1:3 serial dilutions and 10 concentration points. 2x POLQ (10nM) mixture and 2x ssDNA & ATP (20nM & 300μM ATP) mixture were prepared; 2.5μl enzyme mixture (40mM Tris-Hcl pH7.6, 20mM MgCl2, 1mM DTT, 0.01% BSA) was added, centrifuged for 30 seconds, and incubated at room temperature for 15 minutes. 2.5μl substrate mixture was added to the 384-well plate to initiate the reaction, centrifuged for 30 seconds, and incubated at 28 degrees for 60 minutes. ADP-GLO reagent was added and incubated at room temperature for 2 hours. After the incubation, 10μl of detection solution was added to each well, and the luminescent signal was detected on an Envision microplate reader (PerkinElmer) after a further incubation of 60 minutes.

[1254] Data analysis: The percentage inhibition was calculated using the formula below and the IC was analyzed by XLFit excel plugin version 4.3.1. 50 Data. Inhibition rate % = (Max-Data) / (Max-Min)*100, wherein Max is the average relative luminescent signal reading of the control without compound and POLQ protein, Min is the average signal reading of the blank control without compound and POLQ protein, and Data is the signal reading of the reaction samples containing the test compound with varying doses.

[1255] IC 50 Calculation equation: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope))

[1256] The experimental results are shown in Table 1, which show that the representative compounds disclosed herein have good enzyme inhibitory activity.

[1257] Test Example 2: Evaluation of the inhibitory effect of the compounds of the present invention on the proliferation of human colorectal cancer cell line DLD-1BRCA2(-,-)

[1258] Experimental principle: This experiment uses chemiluminescence to determine the intracellular ATP content to detect the inhibitory effect of the compound on the proliferation of human colorectal cancer cell line DLD-1BRCA2(-,-), and obtains the half inhibitory concentration IC of the compound on the inhibition of proliferation of human colorectal cancer cell line DLD-1BRCA2(-,-) 50 .

[1259] Experimental instruments: CO2 incubator (ESCO, CLM-240B-8-TC), cell counter (Invitrogen, AMQAX1000), centrifuge (Eppendorf, 5810R), BMG multifunctional microplate reader (BMG, PHERAstar FSX

[1260] Experimental Materials:

[1261] Reagents brand Part Number RPMI 1640 medium Hyclone SH30809.01 <![CDATA[TrypLE TM Express Enzyme (1X), Phenol Red Free]]> Gibco 12604-021 Penicillin-Streptomycin (10,000U / mL) Gibco 15140122 Phosphate-balanced saline, calcium-free, magnesium-free Gibco 14190144 Cell viability detection reagent based on luciferase system Vazyme DD1101-03 T75 culture flask Corning 430641 96-well plate, black, transparent, flat bottom, with lid Corning 3603

[1262] Experimental method: DLD-1BRCA2(-,-) was counted with a cell counter, and the cells were inoculated into 96-well culture plates at a density of 500 cells per well, with 100 μL per well. Incubate in an incubator (37°C, 5% CO2) overnight. The compound was dissolved in dimethyl sulfoxide, and the dilution was 1:3 serial dilution with 10 concentration points. Day 0: Add the compound to the cell culture plate and incubate at 37°C, 5% CO2. Change the medium on the fourth and seventh days, and incubate for a total of 10 days. Day 10: Add 100 μL CellTiter-Glo reagent to each well, shake at 500 rpm for 2 minutes, and incubate at room temperature in the dark for 10 minutes to stabilize the luminescent signal. The luminescent signal was detected by BMG microplate reader.

[1263] Data analysis: Calculate compound inhibition and use GraphPad Prism 6 software for data analysis and calculation of compound IC 50 .

[1264] 1) Assay robustness checks using DMSO and medium control data:

[1265] H = mean (DMSO); L = mean (medium); SD (H) = STDEV (DMSO); SD (L) = STDEV (medium); CV%

[1266] (DMSO)=100*(SD_H / Ave_H); CV% (middle)=100*SD_L / Ave_L Z'=1-3*(SD_H+SD_L) / (Ave_H-Ave_L)

[1267] Inhibition rate % = (Ave_H-sample) / (Ave_H-Ave_L)

[1268] 2) Fitting the compound IC50 using the nonlinear regression equation:

[1269] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[1270] X: compound concentration; Y: inhibition rate %

[1271] The experimental results are shown in Table 1, which show that the compounds disclosed herein have good inhibitory activity against BRCA-deficient cells.

[1272] Table 1 The enzyme inhibitory activity of the disclosed compounds on POLQ and the results of inhibition of BRCA2(-,-) cell proliferation

[1273]

[1274]

[1275]

[1276]

[1277]

[1278] “ / ” means not tested.

[1279] Test Example 3: Evaluation of the liver microsomal stability of the compound of the present invention

[1280] The purpose of this study is to study the in vitro metabolic stability of the test compound in liver microsomes of different species. The concentration of the parent drug in the incubation system is detected by LC / MS / MS, and the intrinsic clearance rate of the test compound in the microsome system is calculated to evaluate its stability.

[1281] 1. Experimental Materials

[1282] Human, rat and mouse liver microsomes were purchased from BD Gentest at a concentration of 20 mg / mL; potassium phosphate buffer, 100 mM; NADPH (nicotinamide adenine dinucleotide phosphate), 1 mM; stop solution, acetonitrile (containing internal standard 100 ng / mL tolbutamide).

[1283] 2. Experimental Methods

[1284] 1) Liver microsomes were diluted with 100 mM potassium phosphate buffer to a suitable concentration of microsome working solution, a certain amount of NADPH was added to the above microsome working solution, and then an appropriate amount of the test substance was added to start the reaction, so that the final incubation system had a compound concentration of 1 uM, and the concentrations of NADPH and liver microsomes were 1 mM and 0.5 mg / mL, respectively.

[1285] 2) Take 30 μL of the suspension at 0.5, 5, 15, 30 and 60 minutes, add 150 μL of acetonitrile containing internal standard to terminate the reaction, and vortex for 10 minutes.

[1286] 3) Then centrifuge at 3220g for 400 minutes to precipitate the protein. Transfer 100 μL of the supernatant to the sample injection plate, add 100 μL of pure water and mix well for UPLC-MS / MS analysis.

[1287] 4) Data analysis was performed using Microsoft Excel software. The in vitro half-life (t 1 / 2 The results of metabolic stability of the compounds of the present invention in liver microsomes are shown in Table 2.

[1288] Table 2 Metabolic stability results of the compounds of the present invention in liver microsomes

[1289]

[1290]

[1291] NV:not available

[1292] Conclusion: From Table 2, it can be seen that the compounds of the present invention have good metabolic stability in human and mouse liver microsomes. Test Example 4: Pharmacokinetics of the compounds of the present invention in SD rats

[1293] SD rats were used as test animals to study the pharmacokinetic behavior of the compound of the present invention in the plasma of SD rats after oral administration. Plasma samples were collected at specific time points, and the concentration of the compound in plasma was detected by LC-MS / MS. PK parameters were calculated to reflect the pharmacokinetic behavior of the compound of the present invention in the plasma of SD rats.

[1294] 1. Experimental plan

[1295] 1.1 Trial Drugs:

[1296] Some of the compounds of the present invention.

[1297] 1.2 Experimental animals

[1298] SD rats, male, supplied by JH Laboratory Animal Co.LTD.

[1299] 1.3 Administration

[1300] Administration information of the compounds in the examples: PO (oral) experimental groups consisted of 3 rats, the PO administration dose was 5 mg / kg, the administration volume was 0.5 mL / kg, and the administration solvent was 10% DMSO + 30% Solutol + 60% Saline (physiological saline).

[1301] 1.4 Experimental Equipment

[1302] The centrifuge and pipette were purchased from Eppendorf.

[1303] 1.5 Sample collection

[1304] After administration to rats, 150uL of venous blood was collected at 0.25, 0.5, 1, 2, 4, 8 and 24 hours, placed in EDTA-K2 tubes, centrifuged at 4°C, 2000g for 5 min to separate plasma, and stored at -80°C.

[1305] 1.6 Sample processing

[1306] Rat plasma sample processing:

[1307] 1) 30 μL of plasma sample was added to 300 μL of acetonitrile for precipitation, vortexed and centrifuged for 10 minutes.

[1308] 2) The supernatant after treatment was diluted with water and the concentration of the test compound was analyzed by LC / MS / MS.

[1309] 2. Experimental results

[1310] The pharmacokinetic parameters were calculated using WinNonlin 6.1. The pharmacokinetic parameters of oral drugs in rats are shown in Table 3. max represents the maximum blood drug concentration, T 1 / 2 AUC represents the terminal elimination half-life, AUC represents the area under the concentration-time curve, and F represents bioavailability.

[1311] Table 3 Pharmacokinetic parameters of some compounds of the present invention in rats after oral administration

[1312]

[1313]

[1314] Conclusion: It can be seen from Table 3 that the compounds of the present invention have good oral exposure and half-life in rats.

Claims

1. A compound represented by formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, in, X1, X2, X3, X4, and X5 are independently CH or N; R1 is selected from hydrogen, halogen, NO2, CN, -C(O)-N(R 1a )(R 1b ), C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl-S(O)2-, C 3-8 Cycloalkyl, C 2-6 Alkynyl; R 1a , R 1b are independently selected from hydrogen, C 1-4 alkyl; R2 is selected from hydrogen, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl C 1-4 alkyl; Ring A is selected from 5-6 membered heteroarylene; W is selected from O, S, CO, SO2; L1 is selected from a bond, C 1-4 Alkylene chain, the C 1-4 The carbon atoms in the alkylene chain may be substituted with oxygen; Ring B is selected from C 3-8 Cycloalkyl, 4-7 membered heterocyclic group, 9-10 fused ring group, phenyl, 5-6 membered heteroaryl; R3 is selected from hydrogen, halogen, cyano, hydroxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl C 1-4 Alkyl, hydroxyl C 3-6 Cycloalkyl, -C(O)-N(R 3a )(R 3b ), C 1-4 Alkyl-S(O)2-, C 1-4 Alkyl-C(O)-, C 1-4 Alkyl-C(O)-N(R 3a )-; R 3a , R 3b are independently selected from hydrogen, C 1-4 alkyl; m, n, and p are independently selected from 0, 1, 2, 3, and 4; When W is selected from O, L1 is not a methylene group; When W is selected from O, L1 is a bond, Ring B is not C 3-8 Cycloalkyl, 4-7 membered heterocyclic group, 2. The compound according to claim 1, its stereoisomers and pharmaceutically acceptable salts thereof, characterized in that: The structure of formula I is selected from the structure shown in the following formula IA, 3. The compound according to claim 1 or 2, its stereoisomer and pharmaceutically acceptable salt thereof, characterized in that R1 is selected from F, Cl, CN, NO2, -CH3, -CHF2, -CF3, CH3O-, CHF2-O-, CF3-O-, -S(O)2CH3, -C(O)-NH2, HC≡C-; Alternatively, R1 is selected from F, Cl, CH3O-, CHF2-O-, -CHF2, -CH3, CN.

4. The compound according to any one of claims 1 to 3, its stereoisomers and pharmaceutically acceptable salts thereof, characterized in that R2 is selected from -CH3, HO-CH2-; Alternatively, R2 is selected from -CH3.

5. The compound according to any one of claims 1 to 4, its stereoisomers and pharmaceutically acceptable salts thereof, characterized in that Ring A is selected from 6. The compound according to any one of claims 1 to 5, its stereoisomers and pharmaceutically acceptable salts thereof, characterized in that W is selected from S, CO, SO2; Alternatively, W is selected from S, CO.

7. The compound according to any one of claims 1 to 6, its stereoisomers and pharmaceutically acceptable salts thereof, characterized in that L1 is selected from a chemical bond, -CH2-CO-, -CH2-, -CH(CH3)-; Alternatively, L1 is selected from a chemical bond, -CH2-.

8. The compound according to any one of claims 1 to 7, its stereoisomers and pharmaceutically acceptable salts thereof, characterized in that Ring B is selected from C 3-8 Cycloalkyl, 4-7 membered heterocyclyl, phenyl, benzo 5-6 membered cycloalkyl, benzo 5-6 membered heterocyclyl, 5-6 membered heteroaryl and 5-6 membered cycloalkyl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl, 5-6 membered heterocyclyl and 5-6 membered heterocyclyl, 5-6 membered heterocyclyl and 5-6 membered heterocyclyl, 5-6 membered heterocyclyl and 5-6 membered cycloalkyl, 5-6 membered heteroaryl; Alternatively, ring B is selected from C 3-8 Cycloalkyl, 4-7 membered heterocyclyl, phenyl, benzo 5-6 membered cycloalkyl, 6 membered heteroaryl and 5-6 membered cycloalkyl.

9. The compound according to any one of claims 1 to 8, its stereoisomers and pharmaceutically acceptable salts thereof, characterized in that Ring B is selected from Alternatively, ring B is selected from 10. The compound according to any one of claims 1 to 9, its stereoisomers and pharmaceutically acceptable salts thereof, characterized in that R3 is selected from F, Cl, -OH, -CN, -CH3, CH3O-, -CH2OH, NH2-CO-, CH3-NH-C(O)-, (CH3)2N-C(O)-, -S(O)2CH3, CH3C(O)-NH-, CH3C(O)-(CH3)N-; Alternatively, R3 is selected from F, Cl, -OH, -CN, CH3O-.

11. The compound according to any one of claims 1 to 10, its stereoisomers and pharmaceutically acceptable salts thereof, characterized in that Structural unit Selected from 12. The compound according to any one of claims 1 to 11, its stereoisomers and pharmaceutically acceptable salts thereof, selected from the following structures, in, X is selected from N or CH; R1, R2, R3, L1, W, Ring B, m, n, and p are as defined in any one of claims 1 to 12.

13. The compound according to any one of claims 1 to 12, its stereoisomers and pharmaceutically acceptable salts thereof, characterized in that R1 is selected from hydrogen, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy; R2 is selected from C 1-4 alkyl; L1 is selected from a chemical bond or C 1-2 Alkylene chain; Ring B is selected from phenyl, benzo 5-6 membered cycloalkyl, 5-6 membered cycloalkyl, 5-6 membered heterocyclyl; R3 is selected from hydroxy, cyano, halogen; p is selected from 0, 1 or 2.

14. A compound, a stereoisomer thereof, and a pharmaceutically acceptable salt thereof, 15 . A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

16. Use of the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 12 in the preparation of a drug for treating diseases mediated by POLQ target.

17. The use according to claim 16, characterized in that The POLQ target-mediated related disease is tumor; Preferably, the tumor is a tumor with DNA double-strand break repair deficiency; preferably, the tumor is a tumor with homologous recombination repair deficiency; more preferably, the tumor is a tumor with BRCA mutation; Preferably, the tumor is breast cancer, ovarian cancer, fallopian tube cancer, cervical cancer, or peritoneal cancer.

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