N-sulfonyl carboxamide compound, and preparation method therefor and use thereof

Abstract

Disclosed are a N-sulfonyl carboxamide compound as shown in a formula (I) for treating cancers, an isotopic marker, an enantiomer, a diastereoisomer, a solvate or a pharmaceutically acceptable salt thereof. The compound in the present invention has a good inhibitory activity on DNA polymerase θ, and has good application prospects.

Description

A class of N-sulfonyl formamide compounds and their preparation method and application

[0001] This application claims priority to Chinese Patent Application No. 2023112025210, filed on September 18, 2023, and Chinese Patent Application No. 2024103752865, filed on March 29, 2024. The entire text of the above-mentioned Chinese patent application is incorporated herein by reference. Technical Field

[0002] The present invention relates to a DNA polymerase θ inhibitor, a preparation method and application thereof, and in particular to a class of N-sulfonylformamide compounds, compositions thereof and their use in treating and preventing cancer. Background Art

[0003] Tumor cells have unstable genomes and often harbor mutations in genes involved in DNA damage repair, requiring compensatory DNA repair to maintain survival (Hanahan, D.; Weinberg, RA. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674.). Targeting DNA damage repair has also been clinically proven to be an effective cancer treatment. For example, PARP (poly(ADP-nbose) polymerase) inhibitors, developed using the concept of synthetic lethality, have been successfully used in the clinical treatment of breast, prostate, and ovarian cancers harboring germline BRCA1 / 2 mutations (Maddison Rose et al. PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance. Front. Cell Dev. Biol. 8:564-601.).

[0004] Normal DNA damage repair is crucial for mammalian cells to maintain genomic genetic stability and cell survival. Among them, DNA double-strand breaks (DSBs) are the most serious type of DNA damage. There are three main repair methods. Most DSBs are repaired by canonical nonhomologous end joining (c-NHEJ), which does not require a homology template or only requires a small amount of homology template, and connects the DNA ends by inserting and deleting a few bases at the break site (Chang HHY et al. Non-homologous DNA end joining and alternative pathways to double-strand break repair. Nat Rev Mol Cell Biol. 2017, 18 (8): 495-506). In the S and G2 phases of cell mitosis, sister chromatids can serve as repair templates, mainly performing the second error-free repair method, homologous recombination (HR). Recombination); the third DSBs repair method is mainly mediated by DNA polymerase θ (Polθ, encoded by POLQ) mediated microhomology mediated end joining (TMEJ / MMEJ, polymerase theta-mediated end joining / Microhomology-mediated end joining), which was originally named alternative non-homologous end joining (alt-EJ, Alternative Pathway for Non-Homologous End Joining) as a backup pathway for DSBs repair when c-NHEJ or HR is impaired. However, more and more studies have shown that TMEJ also plays a role in other DNA repair methods and is indispensable in certain specific types of DNA damage, such as sister chromatids containing lesions that hinder replication (for example, interchain crosslinks), resulting in the collapse of the replication fork. (Sfeir A, Symington LS. Microhomology-Mediated End Joining: A Back-up Survival Mechanism or Dedicated Pathway? Trends Biochem Sci. 2015, 40(11): 701-714).

[0005] Polθ is a multifunctional DNA polymerase of the A family and has been identified as a key protein in the TMEJ pathway (Kent T et al. Mechanism of microhomology-mediated end-joining promoted by human DNA polymeraseθ. Nat Struct Mol Biol. 2015, 22(3): 230-7;). The human Polθ protein (2590 amino acids) is mainly composed of three domains: a polymerase domain (POLθ-pol, 1819-2590aa) with DNA polymerase activity at the C-terminus, a helicase-like domain (POLθ-hel, 32-899aa) with both ATP hydrolase and helicase activities at the N-terminus, and an unstructured central domain connecting the two. Currently, POLθ is the only polymerase in eukaryotic animals with helicase activity. Both POLθ-hel and POLθ-pol are required for TMEJ repair. Inhibiting the activity of either enzyme will inhibit the activity of TMEJ. These are the two main directions of POLθ inhibitors currently under development (Beagan K et al. Drosophila DNA polymerase theta utilizes both helicase-like and polymerase domains during microhomology-mediated end joining and interstrand crosslink repair. PLoS Genet. 2017, 13(5): e1006813).

[0006] POLθ-hel has ATPase and helicase activities and contains a Rad51 binding site. POLθ-hel dissociates Rad51 or RPA proteins bound to ssDNA protrusions in an ATP-dependent manner, thereby promoting the annealing of ssDNA chains (a key step in TMEJ), ultimately leading to the inhibition of the HR pathway and effectively promoting the TMEJ process (Mateos-Gomez et al. The Helicase Domain of Polθ Counteracts RPA to Promote Alt-NHEJ. Nat. Struct. Mol. Biol. 2017, 24(12), 1116-1123). Therefore, inhibiting the ATPase activity of POLθ-hel can effectively inhibit the TMEJ repair activity of POLθ and has become an important development direction for POLθ inhibitors (Ceccaldi, R. et al. Homologous-recombination-deficient tumors are dependent on Polθ-mediated repair. Nature 2015, 518, 258–262)

[0007] Polθ is not essential in healthy cells, but its expression is upregulated in breast cancer, lung cancer and ovarian cancer, and its overexpression is associated with HR repair defects and poor clinical outcomes (Ceccaldi R et al. Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair. Nature. 2015, 518(7538):258-62). In the context of HR deficiency, the loss of POLθ has been shown to impair cell viability, revealing a synthetic lethal relationship between POLθ and HR factors (e.g., POLθ and FA / BRCA deficiency are synthetic lethal) (Shima N et al. The mouse genomic instability mutation chaos1 is an allele of Polq that exhibits genetic interaction with Atm. Mol Cell Biol. 2004, 24(23): 10381-9; Wang Z et al., DNA polymeraseθ (POLQ) is important for repair of DNA double-strand breaks caused by fork collapse. J Biol Chem. 2019, 294(11): 3909-3919). More importantly, Polθ inhibition / depletion has shown synergistic effects with PARP inhibitors in killing HR-deficient tumor cells, and does not overlap with the PARP resistance mechanism, which is expected to expand the clinical application range of PARP inhibitors and overcome their resistance problem (Ceccaldi R et al. Homologous-recombination-deficient tumors are dependent on Polθ-mediated repair. Nature. 2015, 518(7538):258-62; Mateos-Gomez PA et al. Nature. 2015, 518(7538):254-7). In addition, inhibition of POLθ promotes the accumulation of DNA damage at replication forks, thereby enhancing sensitivity to inhibitors such as ATR or topoisomerase.In addition, since p53-deficient tumors tend to use NHEJ and TMEJ to repair DSBs, POLθ inhibitors combined with DNA-PK inhibitors have become an important combination drug strategy for targeting P53 mutant tumors (Z. Wang, et al. DNA polymerase (POLQ) is important for repair of DNA double-strand breaks caused by fork collapse. J. Biol. Chem., 294 (2019), pp. 3909-3919; RJ Kumar, et al. Hyperactive end joining repair mediates resistance to DNA damaging therapy in p53-deficient cells. bio Rxiv., Published online April 3, 2020).

[0008] Therefore, for cancer types with DNA repair defects, Polθ is a very attractive new target for synthetic lethal therapy. The development of small molecule inhibitors that inhibit Polθ-hel / ATPase activity is an effective means of targeting Polθ and is of great significance.

[0009] Summary of the Invention

[0010] In order to overcome the defects in the prior art, the present invention provides a class of compounds and their preparation methods and applications. The compounds of the present invention have good inhibitory activity against DNA polymerase θ.

[0011] The present invention provides a compound represented by formula (I), its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt, wherein the compound of formula (I) is selected from the following structures:

[0012] in,

[0013] X 1 is CH or N;

[0014] Ring A is a phenyl group or a six-membered heteroaryl group containing 1 to 3 nitrogen atoms;

[0015] m is 0, 1, 2, 3 or 4;

[0016] Each R 1Each is independently selected from deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyloxy, halogenated C1-C6 alkoxy, deuterated C1-C6 alkoxy, hydroxy, cyano, C2-C6 alkynyl, -NR 1x R 1y ; R 1x and R 1y Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

[0017] R 2 Selected from hydrogen, cyano, hydroxyl, -NR 2x R 2y 、-CONR 2x R 2y 、-NR 2x COR 2y , C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group A, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group A, C2-C6 alkenyl which is unsubstituted or substituted by one or more substituents selected from Group A, C2-C6 alkynyl which is unsubstituted or substituted by one or more substituents selected from Group A, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group A, C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group A, 5-6 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A;

[0018] The substituents in group A include: oxo, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from group A1, C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from group A1, 3-8 membered heterocyclic group which is unsubstituted or substituted by one or more substituents selected from group A1, 5-6 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from group A1, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyloxy, halogenated C1-C6 alkoxy, deuterated C1-C6 alkoxy, hydroxyl, cyano, -NR 3x R 3y 、-CONR 3x R 3z 、-NR 3x COR 3z ;

[0019] The substituents of group A1 include: halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy;

[0020] R 2x 、R 2y 、R 3x 、R 3y and R 3z Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, or C3-C6 cycloalkyl;

[0021] or R 2x and R 2y and the nitrogen atoms connected to them together form a 4-6 membered heterocyclic group containing 1-2 nitrogen atoms; the 4-6 membered heterocyclic group may be unsubstituted or substituted by one or more selected from oxo, C1-C6 alkyl, C3-C6 cycloalkyl, hydroxyl, amino, halogen, and cyano;

[0022] or R 3x and R 3y and the nitrogen atoms connected to them together form a 4-6 membered heterocyclic group containing 1-2 nitrogen atoms; the 4-6 membered heterocyclic group may be unsubstituted or substituted by one or more selected from oxo, C1-C6 alkyl, C3-C6 cycloalkyl, hydroxyl, amino, halogen, and cyano;

[0023] R 3 For-(CR4R5) n R 6 ;

[0024] R 4 and R 5 Each is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl;

[0025] n is 0, 1, 2, or 3;

[0026] R 6 is C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group B, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group B, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group B, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group B, or C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group B;

[0027] The substituents of Group B include: oxo, deuterium, halogen, hydroxyl, cyano, mercapto, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group C, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group C, -(CH2) i NR 7 R 8 、-(CH2) i CONR 7 R 8 、-(CH2) i NR 7 CO-R 8 、-(CH2) i SO2R 7 、-(CH2) i SO2NR 7 R 8 、-(CH2) i OR 7 , C6-C10 aryl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl;

[0028] i is 0, 1, 2, or 3;

[0029] R 7 and R 8 Each is independently H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

[0030] The C group substituents include: deuterium, halogen, hydroxyl, C1-C6 alkoxy, cyano, amino, C3-C6 cycloalkyl, deuterated C1-C6 alkoxy;

[0031] The heteroatoms in the 3-8 membered heterocyclic group, 5-10 membered heteroaryl group and 5-6 membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S.

[0032] As a preferred technical solution, ring A is phenyl or pyridyl.

[0033] As a preferred technical solution,

[0034] for Preferably, for

[0035] W 1 、W 2 、W 3 、W 4independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyloxy, halogenated C1-C6 alkoxy, deuterated C1-C6 alkoxy, hydroxy, cyano, C2-C6 alkynyl, -NR 1x R 1y ; R 1x and R 1y Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

[0036] More preferably, for

[0037] Preferably, for

[0038] As a preferred technical solution, R 2 C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group A, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group A, C2-C6 alkynyl which is unsubstituted or substituted by one or more substituents selected from Group A, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group A, C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group A, 5-6 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A;

[0039] The substituents in group A include: oxo, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from group A1, C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from group A1, 3-8 membered heterocyclic group which is unsubstituted or substituted by one or more substituents selected from group A1, 5-6 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from group A1, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyloxy, halogenated C1-C6 alkoxy, deuterated C1-C6 alkoxy, hydroxyl, cyano, -NR 3x R 3y 、-CONR 3x R 3z 、-NR 3x COR 3z ;

[0040] The substituents of group A1 include: halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy;

[0041] R 3x 、R 3y and R 3z Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, or C3-C6 cycloalkyl;

[0042] or R 3x and R 3y and the nitrogen atoms connected to them together constitute a 4-6 membered heterocyclic group containing 1-2 nitrogen atoms; the 4-6 membered heterocyclic group may be unsubstituted or substituted by one or more selected from oxo, C1-C6 alkyl, C3-C6 alkyl, hydroxyl, amino, halogen, and cyano.

[0043] As a preferred technical solution, R 2 C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group A, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group A, C2-C6 alkynyl which is unsubstituted or substituted by one or more substituents selected from Group A, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group A,

[0044] in,

[0045] The substituents in group A include: deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from group A1, C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from group A1, 3-8 membered heterocyclic group which is unsubstituted or substituted by one or more substituents selected from group A1, 5-6 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from group A1, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, C3-C6 cycloalkyloxy, halogenated C1-C6 alkoxy, hydroxyl, cyano, -NR 3x R 3y 、-CONR 3x R 3z 、-NR 3x COR 3z ;

[0046] The substituents of group A1 include: halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy;

[0047] R 3x 、R 3y and R 3z Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, or C3-C6 cycloalkyl;

[0048] or R 3x and R 3y and the nitrogen atoms connected to them together form a 4-6 membered heterocyclic group containing 1-2 nitrogen atoms; the 4-6 membered heterocyclic group may be unsubstituted or substituted by one or more selected from oxo, C1-C6 alkyl, C3-C6 alkyl, hydroxyl, amino, halogen, and cyano;

[0049] R a Selected from hydrogen, halogen, hydroxy, amino, cyano, C1-C6 alkyl, halogenated C1-C6 alkoxy, C1-C6 alkoxy;

[0050] p is 1, 2, or 3.

[0051] As a preferred technical solution, R 2 Selected from C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxy substituted C1-C6 alkyl,

[0052] in,

[0053] R a is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy; p is 1, 2 or 3; R 3x It is H, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, or C3-C6 cycloalkyl.

[0054] As a preferred technical solution, R 2 Selected from methyl, methoxy, -CF3, -CD3, -CH2CF3, -CH2OCH3,

[0055] As a preferred technical solution, R 2 Selected from methyl, -CD3.

[0056] As a preferred technical solution,

[0057] R 3 -(CH2) n R 6 ;

[0058] n is 0, 1, 2, or 3;

[0059] R 6 is a 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group B, a 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group B, a C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group B, or a C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group B;

[0060] The substituents of Group B include: oxo, deuterium, halogen, hydroxyl, cyano, mercapto, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group C, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group C, -(CH2) i NR 7 R 8 、-(CH2) i CONR 7 R 8 、-(CH2) i NR 7 CO-R 8 、-(CH2) i SO2R 7 、-(CH2) i SO2NR 7 R 8 、-(CH2) i OR 7 ;

[0061] i is 0, 1, 2, or 3;

[0062] R 7 and R 8 Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, or C3-C6 cycloalkyl;

[0063] The C group substituents include: deuterium, halogen, hydroxyl, cyano, amino, C1-C6 alkoxy, C3-C6 cycloalkyl, deuterated C1-C6 alkoxy;

[0064] The heteroatoms in the 5-10 membered heteroaryl and 5-6 membered heteroaryl are independently selected from 1, 2 or 3 of N, O and S.

[0065] As a preferred technical solution,

[0066] R 3 -(CH2) n R 6 ;

[0067] n is 1 or 2;

[0068] R 6 is unsubstituted or refers to a C6-C10 aryl group (such as phenyl) substituted by one or more substituents selected from Group B;

[0069] The substituents of Group B include: oxo, deuterium, halogen, hydroxyl, cyano, mercapto, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group C, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group C, -(CH2) i NR 7 R 8 、-(CH2) i CONR 7 R 8 、-(CH2) i NR 7 CO-R 8 、-(CH2) i SO2R 7 、-(CH2) i SO2NR 7 R 8 、-(CH2) i OR 7 ;

[0070] i is 0, 1, 2, or 3;

[0071] R 7 and R 8 Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, or C3-C6 cycloalkyl;

[0072] The C group substituents include: deuterium, halogen, hydroxyl, cyano, amino, C1-C6 alkoxy, C3-C6 cycloalkyl, deuterated C1-C6 alkoxy;

[0073] The heteroatoms in the 5-10 membered heteroaryl and 5-6 membered heteroaryl are independently selected from 1, 2 or 3 of N, O and S.

[0074] As a preferred technical solution, R 3 Selected from -C1-C3 alkyl, (like ),

[0075] As a preferred technical solution, R 3 for

[0076] As a preferred technical solution, the compound of formula (I) is selected from the following structures:

[0077] in,

[0078] R a Selected from hydrogen, halogen, hydroxy, amino, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy;

[0079] R b C1-C6 alkyl, which is unsubstituted or substituted by one or more substituents selected from Group A, and C1-C6 alkoxy, which is unsubstituted or substituted by one or more substituents selected from Group A; wherein the substituents in Group A include: deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, deuterated C1-C6 alkoxy, hydroxyl, cyano, amino, -CONR 3x R 3z 、-NR 3x COR 3z , a 5-6 membered heteroaryl group which is unsubstituted or substituted with a C1-C6 alkyl group;

[0080] Ring A, R 1 、R 3 、R 3x 、R 3z and m are defined as above.

[0081] As a preferred technical solution, the compound of formula (I) is selected from the following structures:

[0082] in,

[0083] R b C1-C6 alkyl, which is unsubstituted or substituted by one or more substituents selected from Group A, and C1-C6 alkoxy, which is unsubstituted or substituted by one or more substituents selected from Group A; wherein the substituents in Group A include: deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, deuterated C1-C6 alkoxy, hydroxyl, cyano, amino, -CONR 3x R 3z 、-NR 3x COR 3z , 5-6 membered heteroaryl which is unsubstituted or substituted by C1-C6 alkyl; R 3x and R 3z Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, or C3-C6 cycloalkyl;

[0084] R 3 For-(CR4R5) n R 6;

[0085] R 4 and R 5 Each is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl;

[0086] n is 0, 1, 2, or 3;

[0087] R 6 is C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group B, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group B, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group B, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group B, or C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group B;

[0088] The substituents of Group B include: oxo, deuterium, halogen, hydroxyl, cyano, mercapto, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group C, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group C, -(CH2) i NR 7 R 8 、-(CH2) i CONR 7 R 8 、-(CH2) i NR 7 CO-R 8 、-(CH2) i SO2R 7 、-(CH2) i SO2NR 7 R 8 、-(CH2) i OR 7 , C6-C10 aryl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl;

[0089] i is 0, 1, 2, or 3;

[0090] R 7 and R 8 Each is independently H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

[0091] The C group substituents include: deuterium, halogen, hydroxyl, cyano, amino, C1-C6 alkoxy, C3-C6 cycloalkyl, deuterated C1-C6 alkoxy;

[0092] The heteroatoms in the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S.

[0093] As a further preferred technical solution,

[0094] R b C1-C6 alkyl, which is unsubstituted or substituted by one or more substituents selected from Group A, and C1-C6 alkoxy, which is unsubstituted or substituted by one or more substituents selected from Group A; wherein the substituents in Group A include: deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, hydroxyl, cyano, amino, -CONR 3x R 3z 、-NR 3x COR 3z , 5-6 membered heteroaryl which is unsubstituted or substituted by C1-C6 alkyl; R 3x and R 3z Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, or C3-C6 cycloalkyl;

[0095] R 3 For-(CR4R5) n R 6 ;

[0096] R 4 and R 5 are each independently selected from hydrogen, deuterium, halogen, and methyl;

[0097] n is 0, 1, 2, or 3;

[0098] R 6 is C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group B, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group B, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group B, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group B, or C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group B;

[0099] The substituents of Group B include: oxo, deuterium, halogen, hydroxyl, cyano, mercapto, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group C, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group C, -(CH2) i NR 7 R 8 、-(CH2)i CONR 7 R 8 、-(CH2) i NR 7 CO-R 8 、-(CH2) i SO2R 7 、-(CH2) i SO2NR 7 R 8 、-(CH2) i OR 7 ;

[0100] i is 0, 1, 2, or 3;

[0101] R 7 and R 8 Each is independently H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

[0102] The C group substituents include: deuterium, halogen, hydroxyl, cyano, amino, C1-C6 alkoxy, C3-C6 cycloalkyl, deuterated C1-C6 alkoxy;

[0103] The heteroatoms in the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S.

[0104] As a further preferred technical solution,

[0105] R b C1-C6 alkyl, which is unsubstituted or substituted by one or more substituents selected from Group A, and C1-C6 alkoxy, which is unsubstituted or substituted by one or more substituents selected from Group A; wherein the substituents in Group A include: deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, -CONR 3x R 3z 、-NR 3x COR 3z , 5-6 membered heteroaryl which is unsubstituted or substituted by C1-C6 alkyl; R 3x and R 3z Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, or C3-C6 cycloalkyl;

[0106] R 3 -(CH2) n R 6 ;

[0107] n is 0, 1, or 2;

[0108] R 6is C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group B, 3-6 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group B, 6-membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group B, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group B, or phenyl which is unsubstituted or substituted by one or more substituents selected from Group B;

[0109] The substituents of Group B include: deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, deuterated C1-C6 alkoxy, amino, -(CH2) i OR 7 The C group substituents include: deuterium, halogen, hydroxyl, cyano, amino, C1-C6 alkoxy, C3-C6 cycloalkyl, deuterated C1-C6 alkoxy; i is 1 or 2; R 7 is a halogenated C1-C6 alkyl group;

[0110] The heteroatoms in the 3-6 membered heterocyclic group and the 6-membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S.

[0111] As a further preferred technical solution,

[0112] R b C1-C6 alkyl, which is unsubstituted or substituted by one or more substituents selected from Group A, and C1-C6 alkoxy, which is unsubstituted or substituted by one or more substituents selected from Group A; wherein the substituents in Group A include: deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, -CONR 3x R 3z 、-NR 3x COR 3z ; R 3x and R 3z Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl; preferably, R b C1-C6 alkyl, deuterated C1-C6 alkyl, such as CH3, CD3;

[0113] R 3 -(CH2) n R 6 ;

[0114] n is 0 or 1;

[0115] R 6is C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group B, 3-6 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group B, 6-membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group B, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group B, or phenyl which is unsubstituted or substituted by one or more substituents selected from Group B;

[0116] Group B substituents include: deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl,

[0117] The heteroatoms in the 3-6 membered heterocyclic group and the 6-membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S.

[0118] As a preferred technical solution, the compound of formula (I) is selected from the following structures:

[0119] in,

[0120] X 1 and Y are each independently N or CH; preferably, X 1 is CH, Y is N;

[0121] R 4a and R 5a Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl;

[0122] s is 0, 1, 2, 3, or 4;

[0123] Each R c independently selected from deuterium, halogen, hydroxyl, cyano, mercapto, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group C, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group C, -(CH2) i NR 7 R 8 、-(CH2) i CONR 7 R 8 、-(CH2) i NR 7 CO-R 8 、-(CH2) i SO2R 7 、-(CH2) i SO2NR 7 R 8 、-(CH2) i OR7 ;

[0124] i is 0, 1, 2, or 3;

[0125] R 7 and R 8 Each is independently H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

[0126] The C group substituents include: deuterium, halogen, hydroxyl, cyano, amino, C1-C6 alkoxy, C3-C6 cycloalkyl, deuterated C1-C6 alkoxy;

[0127] R 2 The definition is the same as above; preferably, R 2 It is CH3 or CD3.

[0128] As a preferred technical solution, the compound of formula (I) is selected from the following structures:

[0129] in,

[0130] X 1 and Y are each independently N or CH; preferably, X 1 is CH, Y is N;

[0131] R c selected from halogen, hydroxy, cyano, mercapto, C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group C, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group C, -(CH2) i OR 7 ;

[0132] i is 0, 1, 2, or 3;

[0133] R 7 and R 8 Each is independently H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

[0134] The C group substituents include: deuterium, halogen, hydroxyl, cyano, amino, C1-C6 alkoxy, C3-C6 cycloalkyl, deuterated C1-C6 alkoxy;

[0135] R 2 The definition is the same as above; preferably, R 2 It is CH3 or CD3.

[0136] As a preferred technical solution, the compound represented by formula (I) is selected from the following compounds:

[0137] As a preferred technical solution, the compound represented by formula (I) can also be selected from the following compounds:

[0138] The present invention also provides methods for preparing the compound represented by formula (I), its isotope-labeled products, enantiomers, diastereomers, solvates, or pharmaceutically acceptable salts thereof, including the following methods:

[0139] Method 1 includes the following steps:

[0140] (1) In the presence of a catalyst and / or a base, coupling or nucleophilic substitution reaction is performed on the compound represented by formula (I-1) and the compound represented by (I-1-A) to obtain the compound represented by formula (I-2);

[0141] (2) In the presence of a catalyst and / or a base, the compound shown in formula (I-2) and compound R 2 -X 5 A coupling or nucleophilic substitution reaction occurs to obtain a compound as shown in formula (I-3);

[0142] (3) hydrolyzing the compound represented by formula (I-3) in the presence of a base to obtain the compound represented by formula (I-4);

[0143] (4) reacting the compound represented by formula (I-4) and the compound represented by formula (I-5) in a solvent in the presence of a condensing agent or a base to obtain the compound represented by formula (I);

[0144] Among them, ring A, R 1 、R 2 、R 3 , m and X 1 The definition of is the same as above; X 2 and X 3 Each is independently halogen or triflate; X 4 is a boronic acid group, a boronic ester group, a zinc bromide group or a tributyltin group; X 5 It is hydrogen, boric acid group, borate ester group, potassium trifluoroborate salt or zinc bromide group or halogen, etc.

[0145] Preferably,

[0146] The catalyst in step (1) is a palladium catalyst, such as [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; the base can be an inorganic base (such as potassium acetate) or an organic base (such as N,N-diisopropylethylamine);

[0147] The catalyst in step (2) is a palladium catalyst, such as [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; the base can be an inorganic base (such as potassium acetate) or an organic base (such as N,N-diisopropylethylamine);

[0148] The base in step (3) is selected from sodium hydroxide, lithium hydroxide or potassium hydroxide;

[0149] The condensing agent in step (4) is selected from (3H-1,2,3-triazolo[4,5-b]pyridine-3-oxy)tris-1-pyrrolidinylphosphonium hexafluorophosphate or 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; the base is selected from N,N-diisopropylethylamine; the solvent is selected from N,N-dimethylformamide.

[0150] Method 2 includes the following steps:

[0151] (1) reacting the compound represented by formula (I-4) with an acyl chloride reagent to produce a carboxylic acid chlorination reaction to obtain a compound represented by formula (I-6);

[0152] (2) reacting the compound represented by formula (I-6) and the compound represented by formula (I-5) in a solvent in the presence of a base to obtain the compound represented by formula (I);

[0153] Among them, ring A, R 1 、R 2 、R 3 , m and X 1 The definition of is the same as above; X 2 and X 3 Each is independently halogen or triflate.

[0154] Preferably,

[0155] The acyl chloride reagent in step (1) is selected from thionyl chloride, phosphorus oxychloride or oxalyl chloride;

[0156] In step (2), the base is selected from N,N-diisopropylethylamine or pyridine; and the solvent is selected from N,N-dimethylformamide or pyridine.

[0157] The present invention also provides a pharmaceutical composition comprising the compound represented by formula (I), its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, and pharmaceutical excipients.

[0158] In the composition, the amount of the compound represented by formula (I), its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof can be an effective therapeutic amount.

[0159] The present invention also provides a use of the compound represented by formula (I), its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt in the preparation of a DNA polymerase θ inhibitor or a drug; the drug is a drug for treating and / or preventing diseases by inhibiting DNA polymerase θ.

[0160] The present invention also provides a use of the compound represented by formula (I), its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt in the preparation of a drug for treating and / or preventing cancer.

[0161] The present invention also provides a method for treating and / or preventing cancer, which comprises administering to a patient a therapeutically effective amount of the compound of formula (I), its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof.

[0162] The term "pharmaceutically acceptable" means relatively non-toxic, safe, and suitable for use by patients.

[0163] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. For details, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0164] The term "solvate" refers to a substance formed by the combination of a compound and a solvent (including but not limited to water, methanol, ethanol, etc.). Solvates are divided into stoichiometric solvates and non-stoichiometric solvates.

[0165] The term "pharmaceutically acceptable salt solvate" refers to a compound formed by combining with a pharmaceutically acceptable acid or base and a solvent (including but not limited to water, methanol, ethanol, etc.). The amount of solvent may be stoichiometric or non-stoichiometric.

[0166] A "-" at the end of a group means that the group is attached to the rest of the molecule through that site. For example, CH3-C(=O)- means an acetyl group.

[0167] When the group valence bond has a wavy line When, for example, In the example, the wavy line indicates the point of attachment of the group to the rest of the molecule.

[0168] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0169] The term "oxo" refers to =0, an oxygen atom replacing two hydrogens on the same carbon atom, ie, a carbonyl replacing a methylene group.

[0170] The term "alkyl" refers to a linear or branched, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C1-C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.

[0171] The term "alkoxy" refers to a group R X -O-, R X The same definition as the term "alkyl". Alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.

[0172] The term "alkenyl" refers to a linear or branched, unsaturated, monovalent hydrocarbon radical having a specified number of carbon atoms (e.g., C2-C6) and having one or more (e.g., one, two, or three) carbon-carbon sp 2 Double bond. Alkenyl groups include but are not limited to: vinyl, wait.

[0173] The term "alkynyl" refers to a linear or branched, unsaturated, monovalent hydrocarbon radical having a specified number of carbon atoms (e.g., C2-C6) and having one or more (e.g., one, two, or three) carbon-carbon triple bonds. Alkenyl groups include, but are not limited to, ethynyl, wait.

[0174] The term "cycloalkyl" refers to a cyclic, saturated, monovalent hydrocarbon radical having a specified number of carbon atoms (e.g., C3-C6) that is a single ring. Cycloalkyl groups include, but are not limited to: wait.

[0175] The term "cycloalkoxy" refers to a group R Y -O-, R Y The same definition as the term "cycloalkyl". Cycloalkoxy includes but is not limited to cyclopropyloxy and the like.

[0176] The term "aryl" refers to a group having the specified number of carbon atoms (e.g., C6-C 10) is a cyclic, unsaturated, monovalent hydrocarbon group, which may be monocyclic or polycyclic (e.g., 2 or 3). In the case of polycyclic rings, the monocyclic rings share two atoms and one bond, and each ring is aromatic. Aryl groups include, but are not limited to, phenyl, naphthyl, and the like.

[0177] In the present invention, the term "heterocyclic group" refers to a non-aromatic cyclic group containing at least one carbon atom and at least one (e.g., 1-3) ring heteroatom selected from N, O, and S, wherein the sulfur atom may be optionally oxidized or aminated. Examples of "heterocyclic groups" include cycloalkyl groups as defined in the present invention in which one or more ring carbon atoms are selected from -O-, -N=, -NR-, -S-, -S(=O)-, and -S(=O)2-, The group formed by partial replacement of 1-4 Alkyl, C 3-6 Cycloalkyl or nitrogen protecting group (for example, benzyloxycarbonyl, p-methoxybenzylcarbonyl, tert-butoxycarbonyl, acetyl, benzoyl, benzyl, p-methoxy-benzyl, p-methoxy-phenyl, 3,4-dimethoxybenzyl, etc.). "Heterocyclic group" includes monocyclic and bicyclic structures such as fused rings, bridged rings, and spirocyclic rings and may be partially or completely saturated, such as 4-10 membered saturated or unsaturated heterocyclic groups, 4-6 membered saturated or unsaturated heterocyclic groups, 3-8 membered heterocyclic groups, 3-6 membered heterocyclic groups, etc.; such as tetrahydrofuranyl, pyrrolidinyl, oxetanyl, oxetanyl, azetidinyl, oxiranyl, aziridine, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, azepanyl, oxetanyl, etc. For example, the heterocyclic group of the present invention may be preferably selected from the following groups:

[0178] In the present invention, the term "heteroaryl" refers to a monocyclic or bicyclic or condensed polycyclic aromatic hydrocarbon group having a specified number of ring atoms (e.g., 5-10 members), which contains at least one (e.g., 1-3) ring heteroatom independently selected from N, O and S (e.g., N) in the ring, and the remaining ring atoms are carbon atoms; such as imidazolyl, pyridyl, pyrrolyl, thiazolyl, furyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, pyrimidinyl, 1,2,4-triazolyl, benzoxazolyl, imidazopyridinyl, triazolopyridinyl, benzofuranyl, pyrazolopyrimidinyl, benzodioxolyl, indolyl, quinolinyl, isoquinolinyl, etc.

[0179] The term "isotopically labeled" refers to an isotopically labeled compound in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature, compared to the nitrogen-containing compound of formula (I). Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of H, C, N, O, S, F, and Cl, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 32 P. 35 S. 18 F and 36 Cl. Compounds of the present invention, pharmaceutically acceptable salts thereof, solvates thereof, solvates of pharmaceutically acceptable salts thereof, or prodrugs thereof containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, for example, those incorporating radioactive isotopes (such as 3 H and 14 C) compounds can be used in drug and / or substrate tissue distribution assays. 3 H) and carbon 14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. 2 Substitution with hydrogen (H or D) may provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) derived from greater metabolic stability and may therefore be preferred in certain circumstances. The compounds of the present invention as claimed in the claims may be specifically limited to substitution with deuterium or tritium. Furthermore, the absence of separate listing of the term deuterium or tritium for hydrogen present in a substituent does not exclude deuterium or tritium, but rather may also include deuterium or tritium.

[0180] The term "therapeutically effective amount" refers to an amount administered to a patient that is sufficient to effectively treat a disease. The therapeutically effective amount will vary depending on the type of compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted by those skilled in the art as appropriate.

[0181] The term "pharmaceutical excipients" refers to all substances contained in pharmaceutical preparations other than the active pharmaceutical ingredient (API). These substances are generally classified into two categories: excipients and additives. For details, see the Pharmacopoeia of the People's Republic of China (2020 Edition) and the Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0182] The term "treat" refers to eliminating the cause or alleviating the symptoms of a disease.

[0183] The term "prevent" refers to reducing the risk of developing a disease.

[0184] The term "patient" refers to any animal, typically a mammal, such as a human, that needs to be treated or prevented. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like.

[0185] The term "PG" represents a protecting group, such as a Boc protecting group and the like.

[0186] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0187] The reagents and raw materials used in the present invention are commercially available.

[0188] The positive improvement effect of the present invention is that the compounds of the present invention have better inhibitory activity on DNA polymerase θ. DETAILED DESCRIPTION

[0189] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0190] In each embodiment, 1 HNMR was recorded by a BRUKER AVANCE NEO 400 MHz, JNM-ECZ400s nuclear magnetic resonance instrument, and the chemical shift is expressed in δ (ppm); liquid chromatography-mass spectrometry (LCMS) was recorded by Shimadzu LC-20AD, Agilent 1260 and Agilent 1200 mass spectrometers; preparative HPLC separations were performed using a WATERS Autop, Shimadzu LC20AR liquid chromatograph.

[0191] In the following experimental descriptions, the following abbreviations may be used:

[0192] Preparation of intermediate compound INT-1

[0193] Step 1: 4-Bromo-2-(difluoromethyl)-5-methoxypyridine

[0194] To a solution of 4-bromo-5-methoxymethylpyridinecarboxaldehyde (1.0 g, 4.63 mmol) in dichloromethane (10 mL) at 0°C was added diethylaminosulfur trifluoride (1.49 g, 9.26 mmol) dropwise. The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, water (10 mL) was added, followed by extraction with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 10% to 20%) to obtain 4-bromo-2-(difluoromethyl)-5-methoxypyridine (800 mg, yield 85.2%). LCMS calc. for C7H7BrF2NO[M+H] + :m / z=238.0; Found:237.9,239.9.

[0195] Step 2: 2-(Difluoromethyl)-5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (INT-1)

[0196] To a solution of 4-bromo-2-(difluoromethyl)-5-methoxypyridine (800 mg, 3.36 mmol) in 1,4-dioxane (10 mL) at room temperature were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.7 g, 6.72 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (244 mg, 0.336 mmol), and potassium acetate (989 mg, 10.1 mmol). The atmosphere was replaced three times with nitrogen. The reaction mixture was heated to 100°C for 16 hours and then cooled to room temperature. The reaction mixture was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 20% to 50%) to give 2-(difluoromethyl)-5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (INT-1) (700 mg, yield 65.8%). LCMS calc. for C 13 H 19 BF2NO3[M+H] + m / z = 286.1; Found: 204.1. (The molecular ion peak detected is (2-(difluoromethyl)-5-methoxypyridin-4-yl)boronic acid)

[0197] Preparation of intermediate compound INT-2

[0198] Step 1: Methyl 6-chloro-4-iodonitrile

[0199] To a solution of 6-chloro-4-iodonicotinoic acid (2.0 g, 7.1 mmol) and potassium carbonate (2.94 g, 21.3 mmol) in N,N-dimethylformamide (10 mL) was added dropwise iodomethane (1.6 g, 11.3 mmol) at 0°C. The mixture was allowed to react at room temperature for 4 hours. After completion of the reaction, water (30 mL) was added, followed by extraction with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 5% to 10%) to obtain methyl 6-chloro-4-iodonicotinoic acid ester (2.05 g, yield 97.8%). LCMS calc. for C7H5ClINO2[M+H] + :m / z=297.9;Found:297.7.

[0200] Step 2: Methyl 6-chloro-2'-(difluoromethyl)-5'-methoxy-[4,4'-bipyridine]-3-carboxylate

[0201] To a solution of methyl 6-chloro-4-iodonitrile (711 mg, 2.49 mmol) and 2-(difluoromethyl)-5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (700 mg, 2.35 mmol) in 1,4-dioxane (10 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (171 mg, 0.235 mmol) and potassium carbonate (813 mg, 5.88 mmol) at room temperature. The atmosphere was replaced with nitrogen three times, and the reaction mixture was heated to 80°C for 1.5 hours before being cooled to room temperature. The reaction mixture was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 20% to 50%) to give methyl 6-chloro-2'-(difluoromethyl)-5'-methoxy-[4,4'-bipyridine]-3-carboxylate (600 mg, yield 69.8%). LCMS calc. for C 14 H 12 ClF2N2O3[M+H] + :m / z=329.0;Found:329.0.

[0202] Step 3: Methyl 2"-(difluoromethyl)-5"-methoxy-4-methyl-2-carbonyl-2H-[1,2':4',4"-terpyridine]-5'-carboxylate

[0203] To a solution of methyl 6-chloro-2'-(difluoromethyl)-5'-methoxy-[4,4'-bipyridyl]-3-carboxylate (300 mg, 0.913 mmol) and 4-methylpyridin-2(1H)-one (99.6 mg, 0.913 mmol) in dimethyl sulfoxide (4 mL) was added potassium carbonate (253 mg, 1.73 mmol) at room temperature. The atmosphere was replaced three times with nitrogen. The reaction mixture was heated to 90°C for 16 hours and then cooled to room temperature. Saturated aqueous ammonium chloride (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to yield a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0% to 10%) to give methyl 2"-(difluoromethyl)-5"-methoxy-4-methyl-2-carbonyl-2H-[1,2':4',4"-terpyridine]-5'-carboxylate (200 mg, yield 49.1%). LCMS calc. for C 20 H 18 F2N3O4[M+H] + :m / z=402.1;Found:402.0.

[0204] Step 4: 2"-(difluoromethyl)-5"-methoxy-4-methyl-2-carbonyl-2H-[1,2':4',4"-terpyridine]-5'-carboxylic acid (INT-2)

[0205] Methyl 2"-(difluoromethyl)-5"-methoxy-4-methyl-2-carbonyl-2H-[1,2':4',4"-terpyridine]-5'-carboxylate (150 mg, 0.374 mmol) was dissolved in 1,4-dioxane (3 mL), methanol (1 mL), and water (1 mL), and lithium hydroxide (57.2 mg, 2.39 mmol) was added. The reaction solution was reacted at room temperature for 3 hours. After the reaction, the solution was adjusted to pH 4-5 with 1N dilute hydrochloric acid. The solid precipitated, filtered, and vacuum dried to obtain 2"-(difluoromethyl)-5"-methoxy-4-methyl-2-carbonyl-2H-[1,2':4',4"-terpyridine]-5'-carboxylic acid (INT-2) (90 mg, yield: 62.3%). LCMS calc. for C 19 H 16 F2N3O4[M+H] + :m / z=388.1;Found:388.0.

[0206] Preparation of intermediate compound INT-3

[0207] Step 1: 4-Isopropylbenzylcarbamoyl sulfate

[0208] 1-(Chloromethyl)-4-isopropylbenzene (2.0 g, 11.9 mmol) was dissolved in ethanol (20 mL). Thiourea (0.99 g, 13.0 mmol) was added to the reaction solution. The reaction solution was heated to 80°C and the reaction was continued for 1 hour. After the reaction was completed, the reaction solution was concentrated to obtain 4-isopropylbenzylcarbamoyl sulfate (2.47 g, crude yield: >99%). LCMS calculation for C 11 H 17 N2S[M+H] + :m / z=209.1;Found:209.2.

[0209] Step 2: (4-isopropylphenyl)methanesulfonyl chloride

[0210] N-chlorosuccinimide (6.33 g, 47.4 mmol) was dissolved in acetonitrile (20 mL) and 1N dilute hydrochloric acid (5 mL). The reaction mixture was allowed to react at 0°C for 15 minutes. 4-Isopropylbenzylcarbamoyl sulfate (2.47 g, 11.8 mmol) was then added to the reaction mixture. The reaction mixture was allowed to react at room temperature for 1 hour. After completion of the reaction, the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to yield (4-isopropylphenyl)methanesulfonyl chloride (2.5 g, crude yield: 90.6%).

[0211] Step 3: (4-isopropylphenyl)methanesulfonamide

[0212] (4-isopropylphenyl)methanesulfonyl chloride (2.5 g, 10.7 mmol) was dissolved in tetrahydrofuran (10 mL) and aqueous ammonia (10 mL), and the reaction mixture was reacted at room temperature for 1 hour. After the reaction was completed, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 0% to 5%) to obtain (4-isopropylphenyl)methanesulfonamide (2.0 g, yield: 87.3%). LCMS calc. for C 10 H 14 NO2S[MH] - :m / z=212.1;Found:212.1.

[0213] Example 1 Preparation of Compound CPD-1

[0214] Step 1: N-((4-chlorobenzyl)sulfonyl)-2"-(difluoromethyl)-5"-methoxy-4-methyl-2-carbonyl-2H-[1,2':4',4"-terpyridine]-5'-carboxamide

[0215] To a solution of 2"-(difluoromethyl)-5"-methoxy-4-methyl-2-carbonyl-2H-[1,2':4',4"-terpyridine]-5'-carboxylic acid (INT-2) (60 mg, 0.15 mmol), (7-azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (105 mg, 0.20 mmol), and (4-chlorophenyl)methanesulfonamide (38 mg, 0.19 mmol) in N,N-dimethylformamide (2 mL) was added dropwise N,N-diisopropylethylamine (40 mg, 0.31 mmol) at room temperature. The reaction was allowed to proceed at 25°C for 3 hours, and the reaction solution was concentrated. The residue was purified by preparative HPLC (C18 column, Mobile Phase A: water (0.01% HCOOH), Mobile Phase B:acetonitrile, Gradient: 5%-90% (% B)) was purified to give N-((4-chlorobenzyl)sulfonyl)-2"-(difluoromethyl)-5"-methoxy-4-methyl-2-carbonyl-2H-[1,2':4',4"-terpyridine]-5'-carboxamide (30 mg, yield: 33.6%). LCMS calc. for C 26 H 22 ClF2N4O5S[M+H] + :m / z=575.1;Found:575.1. 1 H NMR(400MHz,DMSO-d6)δ12.31(br s,1H),8.70(s,1H),8.53(s,1H),7.91-7.85(m,2H),7.61(s,1H),7.44-7.42(m,2H),7.33-7.31(m,2H) ,6.97(t,J=55.2Hz,1H),6.35(s,1H),6.30-6.28(m,1H),4.72-4.43(m,2H),3.90(s,3H),2.21(s,3H).

[0216] Example 2 Preparation of Compound CPD-2

[0217] The same synthetic route was used as for compound cpd-2, except that the starting material was replaced by ethylsulfonamide instead of the original (4-chlorophenyl)methanesulfonamide.

[0218] 2"-(Difluoromethyl)-N-(ethylsulfonyl)-5"-methoxy-4-methyl-2-carbonyl-2H-[1,2':4',4"-terpyridine]-5'-carboxamide

[0219] LCMS calc.for C 21 H 21 F2N4O5S[M+H] + :m / z=479.1;Found:478.8 1 H NMR (400MHz, DMSO-d6) δ12.81-12.12(m,1H),8.86(s,1H),8.48(s,1H),7.90(d,J=6.8Hz,1H),7.76(s,1H),7.54(s,1H),6 .95(t,J=55.2Hz,1H),6.33(s,1H),6.29-6.27(m,1H),3.88(s,3H),3.06-3.04(m,2H),2.20(s,3H),1.10(t,J=7.2Hz,3H).

[0220] Example 3 Preparation of Compound CPD-3

[0221] Step 1: 2-Bromo-4-(difluoromethyl)-1-methoxybenzene

[0222] 3-Bromo-4-methoxybenzaldehyde (20 g, 93.0 mmol) was dissolved in 1,2-dichloroethane (100 mL) at room temperature. Diethylaminosulfur trifluoride (60 g, 372 mmol) was added to the reaction solution, which was heated to 60°C and allowed to react for 48 hours. After completion of the reaction, the reaction solution was slowly poured into ice water and extracted with ethyl acetate (200 mL x 2). The organic phase was washed once with saturated sodium bicarbonate solution, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0% to 10%) to yield 2-bromo-4-(difluoromethyl)-1-methoxybenzene (15.0 g, yield: 68%).

[0223] Step 2: Methyl 4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

[0224] Methyl 2-bromo-4-methylbenzoate (6.0 g, 26.2 mmol) was dissolved in dioxane (60 mL). Pinacol borate (9.98 g, 39.3 mmol), potassium acetate (5.14 g, 52.4 mmol), and 1,1'-bis(diphenylphosphinoferrocenedichloropalladium) (1.92 g, 2.62 mmol) were added to the reaction solution. The reaction solution was heated to 100°C under an argon atmosphere for 1 hour. After the reaction, the reaction solution was concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0% to 20%) to obtain methyl 4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (5.5 g, yield: 76%). LCMS calculation for C 15 H 22 BO4[M+H] + :m / z=277.2;Found:277.2

[0225] Step 3: 5'-(difluoromethyl)-2'-methoxy-5-methyl-[1,1'-biphenyl]-2-carboxylic acid methyl ester

[0226] Methyl 4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (5.5 g, 19.9 mmol) was dissolved in dioxane (50 mL) and water (10 mL). 2-Bromo-4-(difluoromethyl)-1-methoxybenzene (5.67 g, 23.9 mmol), potassium carbonate (8.26 g, 59.8 mmol), and 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride (1.46 g, 1.99 mmol) were added to the reaction mixture. The reaction mixture was heated to 80°C and reacted under an argon atmosphere for 2 hours. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (100 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0% to 30%) to give 5'-(difluoromethyl)-2'-methoxy-5-methyl-[1,1'-biphenyl]-2-carboxylic acid methyl ester (5.4 g, yield: 88.5%).

[0227] Step 4: 5'-(difluoromethyl)-2'-methoxy-5-methyl-[1,1'-biphenyl]-2-carboxylic acid

[0228] 5'-(Difluoromethyl)-2'-methoxy-5-methyl-[1,1'-biphenyl]-2-carboxylic acid methyl ester (5.4 g, 17.6 mmol) was dissolved in methanol (50 mL) and water (8 mL). Sodium hydroxide (2.12 g, 52.9 mmol) was added to the reaction solution, and the reaction solution was heated to 50°C for 16 hours. After the reaction, the reaction solution was adjusted to pH = 5 with 1N dilute hydrochloric acid, extracted with ethyl acetate (100 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 0% to 10%) to obtain 5'-(difluoromethyl)-2'-methoxy-5-methyl-[1,1'-biphenyl]-2-carboxylic acid (5.0 g, yield: 97%). LCMS calc. for C 16 H 13 F2O3[MH] + :m / z=291.1;Found:291.2.

[0229] Step 5: (S)-methyl 4-(1-methoxyethyl)benzoate

[0230] Methyl (S)-4-(1-hydroxyethyl)benzoate (1.0 g, 5.55 mmol) was dissolved in N,N-dimethylformamide (10 mL). Sodium hydride (0.33 g, 8.32 mmol, 60%) was then added to the solution at 0°C. The reaction mixture was allowed to react under nitrogen at 0°C for 0.5 hours. Methyl iodide (1.58 g, 11.1 mmol) was added to the reaction mixture, and the reaction mixture was allowed to react under nitrogen at 20°C for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to yield a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0% to 20%) to yield methyl (S)-4-(1-methoxyethyl)benzoate (0.8 g, yield: 74.3%).

[0231] Step 6: (S)-(4-(1-methoxyethyl)phenyl)methanol

[0232] Methyl (S)-4-(1-methoxyethyl)benzoate (0.8 g, 4.12 mmol) was dissolved in tetrahydrofuran (10 mL). A solution of lithium aluminum hydride in tetrahydrofuran (8.3 mL, 8.3 mmol, 1 mol / L) was then added to the solution at 0°C. The reaction mixture was allowed to react under nitrogen at 0°C for 1 hour. After completion, sodium sulfate decahydrate was slowly added to the reaction mixture to quench the reaction. The mixture was filtered, and the filter cake was washed three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to yield a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0% to 30%) to yield (S)-(4-(1-methoxyethyl)phenyl)methanol (0.7 g, yield: 93%).

[0233] Step 7: (S)-1-(Chloromethyl)-4-(1-methoxyethyl)benzene

[0234] (S)-(4-(1-methoxyethyl)phenyl)methanol (0.7 g, 4.21 mmol) was dissolved in dichloromethane (10 mL), and thionyl chloride (0.92 mL, 12.6 mmol) was added to the reaction solution. The mixture was reacted at room temperature for 1 hour, and concentrated under reduced pressure to give the crude product (S)-1-(chloromethyl)-4-(1-methoxyethyl)benzene (0.8 g, crude yield: >99%).

[0235] Step 8: (S)-(4-(1-methoxyethyl)benzyl)acetic acid benzyl thioester

[0236] (S)-1-(Chloromethyl)-4-(1-methoxyethyl)benzene (0.78 g, 4.22 mmol) was dissolved in acetone (15 mL), followed by the addition of potassium thioacetate (0.58 g, 5.07 mmol). The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the mixture was filtered and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0% to 20%) to obtain (S)-(4-(1-methoxyethyl)benzyl)acetic acid benzyl thioester (0.8 g, yield: 84.4%).

[0237] Step 9: (S)-(4-(1-methoxyethyl)phenyl)methanesulfonamide

[0238] (S)-(4-(1-methoxyethyl)benzyl)acetic acid benzyl thioester (0.8 g, 3.57 mmol) was dissolved in dichloromethane (10 mL), and 1N dilute hydrochloric acid (21.4 mL, 21.4 mmol) was added. Then, 10% aqueous sodium hypochlorite (15.9 g, 21.4 mmol) was added to the reaction solution. After reacting for 1 hour, concentrated aqueous ammonia was added to the reaction solution to adjust the pH to 11, and the reaction was continued for 0.5 hour. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0% to 10%) to obtain (S)-(4-(1-methoxyethyl)phenyl)methanesulfonamide (0.35 g, yield: 47.5%). LCMS calculation for C 10 H 14 NO3S[MH] + :m / z=228.1;Found:228.2.

[0239] Step 10: (S)-5'-(difluoromethyl)-2'-methoxy-N-(4-(1-methoxyethyl)benzyl)sulfonyl)-5-methyl-[1,1'-biphenyl]-2-carboxamide

[0240] 5'-(Difluoromethyl)-2'-methoxy-5-methyl-[1,1'-biphenyl]-2-carboxylic acid (100 mg, 0.34 mmol) was dissolved in dichloromethane (6 mL), and (S)-(4-(1-methoxyethyl)phenyl)methanesulfonamide (94.1 mg, 0.41 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (78.7 mg, 0.41 mmol), and 4-dimethylaminopyridine (83.6 mg, 0.68 mmol) were added. The mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 0-10%) and preparative high performance liquid chromatography (Column: XBridge Prep C18 5μm OBD 19*150mm, Mobile phase: A (10mM NH4HCO3 in The product was purified by filtration using a 5-mL aqueous solution of B (ACN), 0-3 min: 40% B, 3-7 min: 40-85% B, 7-11 min: 85-90% B, 11-13 min: 90-95% B, 13-16 min: 95% B, 16-16.5 min: 95-40% B, 16.5-21 min: 40% B, Flow rate = 15 mL / min) to give (S)-5'-(difluoromethyl)-2'-methoxy-N-(4-(1-methoxyethyl)benzyl)sulfonyl)-5-methyl-[1,1'-biphenyl]-2-carboxamide (58 mg, yield: 33.7%). LCMS calc. for C 26 H 26 F2NO5S[MH] - :m / z=502.2;Found:502.3. 1 H NMR (400MHz, DMSO-d6) δ11.79 (s, 1H), 7.62-7.52 (m, 1H), 7.43 (d, J = 2.1Hz, 1H), 7.34-7.19 (m, 6H), 7.17-6. 86(m,3H),4.64(s,2H),4.33(q,J=6.4Hz,1H),3.72(s,3H),3.13(s,3H),2.38(s,3H),1.33(d,J=6.4Hz,3H).

[0241] Example 4 Preparation of Compound CPD-4

[0242] The same synthetic route was used as for compound cpd-8, except that the starting material in step three was replaced by (S)-4-(1-methoxyethyl)phenyl)methanesulfonamide instead of the original (R)-4-(1-methoxyethyl)phenyl)methanesulfonamide.

[0243] (S)-2-(2-(Difluoromethyl)-5-methoxypyridin-4-yl)-N-((4-(1-methoxyethyl)benzyl)sulfonyl)-4-methylbenzamide

[0244] LCMS calc.for C 25 H 27 F2NO5S[M+H] + :m / z=505.2;Found:505.4. 1 H NMR (400MHz, DMSO-d6) δ11.91(s,1H),8.44(s,1H),7.56(s,1H),7.39-7.21(m,7H),6.96(t,J=55.1Hz, 1H), 4.66 (s, 2H), 4.33 (q, J = 6.4Hz, 1H), 3.86 (s, 3H), 3.13 (s, 3H), 2.39 (s, 3H), 1.32 (d, J = 6.4Hz, 3H).

[0245] Example 5 Preparation of Compound CPD-5

[0246] The same synthetic route was used as for compound cpd-9, except that the starting material in step three was replaced by (S)-4-(1-methoxyethyl)phenyl)methanesulfonamide instead of the original (R)-4-(1-methoxyethyl)phenyl)methanesulfonamide.

[0247] (S)-4-(5-(difluoromethyl)-2-methoxyphenyl)-N-((4-(1-methoxyethyl)benzyl)sulfonyl)-6-methylnicotinamide

[0248] LCMS calc.for C 25 H 27 F2NO5S[M+H] + :m / z=505.2;Found:505.3. 1 H NMR (400MHz, DMSO-d6) δ12.03(s,1H),8.35(s,1H),7.62(d,J=8.6Hz,1H),7.50(s,1H),7.32-6.89(m, 7H), 4.67 (s, 2H), 4.33 (q, J = 6.4Hz, 1H), 3.74 (s, 3H), 3.13 (s, 3H), 2.54 (s, 3H), 1.33 (d, J = 6.4Hz, 3H).

[0249] Example 6 Preparation of Compound CPD-6

[0250] The same synthetic route was used as for compound cpd-10, except that the starting material in step 3 was replaced by (S)-4-(1-methoxyethyl)phenyl)methanesulfonamide instead of the original (R)-4-(1-methoxyethyl)phenyl)methanesulfonamide.

[0251] (S)-2'-(Difluoromethyl)-5'-methoxy-N-((4-(1-methoxyethyl)benzyl)sulfonyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0252] LCMS calc.for C 24 H 26 F2N3O5S[M+H] + :m / z=506.2;Found:506.3 1 H NMR(400MHz,DMSO-d6)δ12.16(s,1H),8.52(s,1H),8.45(s,1H),7.65(s,1H),7.38(s,1H),7.35-7.27(m,4H),6.99( t,J=55.1Hz,1H),4.69(s,2H),4.33(q,J=6.4Hz,1H),3.88(s,3H),3.13(s,3H),2.57(s,3H),1.32(d,J=6.4Hz,3H).

[0253] Example 7 Preparation of Compound CPD-7

[0254] Step 1: Methyl (R)-4-(1-methoxyethyl)benzoate

[0255] Methyl (R)-4-(1-hydroxyethyl)benzoate (1.0 g, 5.55 mmol) was dissolved in N,N-dimethylformamide (10 mL). Sodium hydride (0.33 g, 8.32 mmol, 60%) was then added to the solution at 0°C. The reaction was continued under nitrogen at 0°C for 0.5 hours. Methyl iodide (1.58 g, 11.1 mmol) was added to the reaction solution, and the reaction was continued under nitrogen at 20°C for 2 hours. Water (40 mL) was added, and the mixture was extracted twice with ethyl acetate (50 mL). The combined organic phases were washed sequentially with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0% to 30%) to obtain methyl (R)-4-(1-methoxyethyl)benzoate (0.8 g, yield: 74.3%).

[0256] Step 2: (R)-4-(1-methoxyethyl)phenyl)methanol

[0257] To a solution of methyl (R)-4-(1-methoxyethyl)benzoate in tetrahydrofuran (40 mL) was added lithium aluminum hydride (0.31 g, 8.24 mmol) under a nitrogen atmosphere at 0°C. The mixture was allowed to react at 0°C for 2 hours. After completion of the reaction, the temperature was lowered to -10°C, and 0.31 mL of water, 0.31 mL of 20% sodium hydroxide solution, and 0.93 mL of water were slowly added in sequence. The mixture was allowed to react at room temperature for 30 minutes. The mixture was filtered under reduced pressure, and the filtrate was concentrated to afford (R)-4-(1-methoxyethyl)phenyl)methanol (0.7 g, crude yield: >99%).

[0258] Step 3: (R)-1-(chloromethyl)-4-(1-methoxyethyl)benzene

[0259] Dissolve (R)-4-(1-methoxyethyl)phenyl)methanol (0.7 g, 4.21 mmol) in dichloromethane (10 mL). Add thionyl chloride (1.76 g, 14.8 mmol) at 20°C. The mixture is reacted at 20°C for 1 hour. Concentrate under reduced pressure to obtain (R)-1-(chloromethyl)-4-(1-methoxyethyl)benzene (0.8 g, crude yield: >99%). (The crude product is directly used in the next step.)

[0260] Step 4: (R)-4-(1-methoxyethyl)phenyl)methanesulfonamide

[0261] (R)-1-(Chloromethyl)-4-(1-methoxyethyl)benzene (0.72 g, 4.21 mmol) was dissolved in acetone (15 mL), followed by the addition of potassium thioacetate (0.5 g, 5.05 mmol). The mixture was reacted at 60°C under nitrogen for 1 hour. The reaction solution was diluted with water (30 mL), and the aqueous phase was extracted twice with ethyl acetate (30 mL). The combined organic phases were washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. Dichloromethane (10 mL) and 1N dilute hydrochloric acid (10 mL) were added to the concentrated residue, cooled to 0°C, and 10% aqueous sodium hypochlorite (14 mL) was slowly added dropwise. After 1 hour of reaction, concentrated aqueous ammonia was added to adjust the pH of the reaction solution to 13, and the reaction was continued for 0.5 hours. The reaction mixture was diluted with water (50 mL), and the aqueous phase was extracted twice with ethyl acetate (50 mL). The combined organic phases were washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0% to 5%) to obtain (R)-4-(1-methoxyethyl)phenyl)methanesulfonamide (0.4 g, yield: 43.5%). LCMS calc. for C 10 H 16 NO3S[M+H] +:m / z=230.1;Found:230.2.

[0262] Step 5: (R)-5'-(difluoromethyl)-2'-methoxy-N-(4-(1-methoxyethyl)benzyl)sulfonyl)-5-methyl-[1,1'-biphenyl]-2-carboxamide

[0263] (R)-4-(1-methoxyethyl)phenyl)methanesulfonamide and 5'-(difluoromethyl)-2'-methoxy-5-methyl-[1,1'-biphenyl]-2-carboxylic acid (100 mg, 0.34 mmol) were dissolved in dichloromethane (6 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (131 mg, 0.68 mmol) and 4-dimethylaminopyridine (83.6 mg, 0.68 mmol) were added and reacted at 20°C for 10 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 0-10%) and preparative high performance liquid chromatography (Column: XBridge Prep C18 5μm OBD 19*150mm, Mobile phase: A (10mM NH4HCO3 in The mixture was stirred for 1 h at 40 ℃ for 2 h (15 min). The mixture was stirred for 1 h (15 min). The mixture was stirred for 2 h (15 min). The mixture was stirred for 1 h (15 min). The mixture was stirred for 2 h (15 min). The mixture was stirred for 3 h (15 min). The mixture was stirred for 1 h (15 min). The mixture was stirred for 2 h (15 min). The mixture was stirred for 3 h (15 min). The mixture was stirred for 2 h (15 min). The mixture was stirred for 3 h (15 min). The mixture was stirred for 2 h (15 min). The mixture was stirred for 3 h (15 min). The mixture was stirred for 2 h (15 min). The mixture was stirred for 3 h (15 min). The mixture was stirred for 2 h (15 min). The mixture was stirred for 3 h (15 min). The mixture was stirred for 3 h 26 H 26 F2NO5S[MH] - :m / z=502.2;Found:502.1 1 H NMR (400MHz, DMSO-d6) δ11.78(s,1H),7.56(dd,J=7.6,2.4Hz,1H),7.43(d,J=2.4Hz,1H),7.3 3-7.11(m,8H),7.02(t,J=56.0Hz,1H),4.64(s,2H),4.34-4.30(m,1H),3.72(s,3H),3.13(s, 3H)2.38(s,3H),1.33(d,J=6.4Hz,3H).

[0264] Example 8 Preparation of Compound CPD-8

[0265] Step 1: Methyl 2-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-4-methylbenzoate

[0266] (2-(Difluoromethyl)-5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.5 g, 1.75 mmol) and methyl 2-bromo-4-methylbenzoate (0.48 g, 2.1 mmol) were dissolved in dioxane (15 mL), and then 1,1'-bis(diphenylphosphinodiphenylferrocenepalladium dichloride) (0.13 g, 0.18 mmol), potassium carbonate ( 0.73 g, 5.26 mmol) and water (3 mL). The reaction was continued at 100 ° C under nitrogen for 2 hours. After cooling, the reaction solution was filtered through celite, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0% to 30%) to obtain methyl 2-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-4-methylbenzoate (0.5 g, yield: 92.3%). LCMS calc. for C 16 H 16 F2NO3[M+H] + :m / z=308.1;Found:308.2

[0267] Step 2: 2-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-4-methylbenzoic acid

[0268] To a solution of methyl 2-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-4-methylbenzoate (0.5 g, 1.63 mmol) in methanol (20 mL) were added water (3 mL) and lithium hydroxide (0.19 g, 8.14 mmol) and reacted at 40°C for 2 hours. After completion of the reaction, the pH of the reaction solution was adjusted to 4 with 4N dilute hydrochloric acid and extracted twice with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 0% to 10%) to obtain 2-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-4-methylbenzoic acid (0.32 g, yield: 67.1%). LCMS calc. for C 15 H 14 F2NO3[M+H] + :m / z=294.1;Found:294.2

[0269] Step 3: (R)-2-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-N-((4-(1-methoxyethyl)benzyl)sulfonyl)-4-methylbenzamide

[0270] (R)-4-(1-methoxyethyl)phenyl)methanesulfonamide (94 mg, 0.41 mmol) and 2-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-4-methylbenzoic acid (80 mg, 0.27 mmol) were dissolved in dichloromethane (5 mL), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (104 mg, 0.55 mmol) and 4-dimethylaminopyridine (66.6 mg, 0.55 mmol) were added. The mixture was reacted at 20°C for 10 hours. The reaction solution was concentrated under reduced pressure and analyzed by silica gel column chromatography (dichloromethane:methanol = 0-10%) and preparative high performance liquid chromatography (Column: XBridge Prep C18 5μm OBD 19*150mm, Mobile phase: A (10mM NH4HCO3 in The product was purified by adding 4-nitropropane-2-ol (4-nitropropane-2-ol) (5-nitropropane-2-ol, 4-nitropropane-3-ol) (Water) (ACN, 0-3 min: 40% B, 3-7 min: 40-85% B, 7-11 min: 85-90% B, 11-13 min: 90-95% B, 13-16 min: 95% B, 16-16.5 min: 95-40% B, 16.5-21 min: 40% B, Flow rate = 15 mL / min) to afford (R)-2-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-N-((4-(1-methoxyethyl)benzyl)sulfonyl)-4-methylbenzamide (46.2 mg, yield: 33.4%). LCMS calc. for C 25 H 27 F2N2O5S [M+H] + :m / z=505.2;Found:505.3 1 H NMR (400MHz, DMSO-d6) δ11.92(s,1H),8.44(s,1H),7.54(s,1H),7.48-7.09(m,7H),7.02(t,J=55.2H z,1H),4.63(s,2H),4.30-4.25(m,1H),3.85(s,3H),3.12(s,3H)2.39(s,3H),1.33(d,J=6.4Hz,3H).

[0271] Example 9 Preparation of Compound CPD-9

[0272] Step 1: 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methylnicotinate

[0273] 2-Bromo-4-(difluoromethyl)-1-methoxybenzene (0.62 g, 2.61 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (0.83 g, 3.26 mmol) were dissolved in dioxane (15 mL). 1,1'-bis(diphenylphosphinoferrocenepalladium chloride) (0.16 g, 0.22 mmol) and potassium acetate (0.64 g, 6.52 mmol) were then added. The reaction was continued at 100°C under nitrogen for 1 hour. After the reaction solution was cooled to room temperature, methyl 4-bromo-6-methylnicotinate (0.5 g, 2.17 mmol), 1,1'-bis(diphenylphosphinoferrocenepalladium chloride) (0.16 g, 0.22 mmol), potassium carbonate (0.9 g, 6.52 mmol), and water (2 mL) were added. The reaction was continued at 100°C under nitrogen for 2 hours. After cooling, the reaction solution was filtered through celite, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0% to 100%) to obtain methyl 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methylnicotinate (0.6 g, yield: 89.8%). LCMS calculation for C 16 H 16 F2NO3[M+H] + :m / z=308.1;Found:308.3

[0274] Step 2: 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methylnicotinic acid

[0275] To a solution of methyl 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methylnicotinate (0.6 g, 1.95 mmol) in methanol (10 mL) were added water (3 mL) and lithium hydroxide (0.28 g, 11.7 mmol) and reacted at 40°C for 2 hours. After completion of the reaction, the pH of the reaction solution was adjusted to 5 with 4N dilute hydrochloric acid and extracted twice with ethyl acetate (20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 0% to 10%) to obtain 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methylnicotinic acid (0.4 g, yield: 69.9%). LCMS calc. for C 15 H 14 F2NO3[M+H] + :m / z=294.1;Found:294.2

[0276] Step 3: (R)-4-(5-(difluoromethyl)-2-methoxyphenyl)-N-((4-(1-methoxyethyl)benzyl)sulfonyl)-6-methylnicotinamide

[0277] To a solution of (R)-4-(1-methoxyethyl)phenyl)methanesulfonamide (80 mg, 0.35 mmol) and 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methylnicotinic acid (80 mg, 0.27 mmol) in dichloromethane (5 mL) were added 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (105 mg, 0.55 mmol) and 4-dimethylaminopyridine (66.7 mg, 0.55 mmol), and the reaction solution was reacted at 20°C for 10 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol=0-10%) and preparative high performance liquid chromatography (Column: SHIMADZU Prep C18 10 μm 20*250 mm Mobile phase: A(0.1% FA in H2O)B(ACN)0-2 min: 40% B, 2-3.5 min: 40-75% B, 3.5-6 min: 75% B, 6-9 min: 75-95% B, 9-11 min: 95% B, 11-11.01 min: 95-40% B, 11.01-14 min: 40% B (Flow rate = 20 mL / min)) to give (R)-4-(5-(difluoromethyl)-2-methoxyphenyl)-N-((4-(1-methoxyethyl)benzyl)sulfonyl)-6-methylnicotinamide (10.2 mg, yield: 7.4%). LCMS calc.for C 25 H 27 F2N2O5S[M+H] + :m / z=505.2;Found:505.3 1 H NMR(400MHz,DMSO-d6)δ12.03(s,1H),8.35(s,1H),8.46(s,1H),7.62(s,1H),7.50(s,1H),7.40-7.18(m,6H),7.0 3(t,J=56.0Hz,1H),4.68(s,2H),4.30-4.25(m,1H),3.74(s,3H),3.13(s,3H)2.54(s,3H),1.32(d,J=6.4Hz,3H).

[0278] Example 10 Preparation of Compound CPD-10

[0279] Step 1: 2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid methyl ester

[0280] (2-(Difluoromethyl)-5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.0 g, 3.51 mmol) and methyl 4-bromo-6-methylnicotinate (0.97 g, 4.21 mmol) were dissolved in dioxane (15 mL), and then 1,1'-bis(diphenylphosphino)ferrocenedichlorid palladium (0.26 g, 0.35 mmol), potassium carbonate (1.4 5g, 10.5mmol) and water (3mL). The reaction was continued at 100°C under nitrogen for 2 hours. After cooling, the reaction solution was filtered through celite, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0% to 100%) to obtain 2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid methyl ester (0.7g, yield: 64.7%). LCMS calc.for C 15 H 15 F2N2O3[M+H] + :m / z=309.1;Found:309.3

[0281] Step 2: 2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid

[0282] To a solution of methyl 2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (0.7 g, 2.27 mmol) in methanol (10 mL) were added water (3 mL) and lithium hydroxide (0.33 g, 13.6 mmol), and the reaction system was reacted at 40°C for 2 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 5 with 4N dilute hydrochloric acid and extracted twice with ethyl acetate (20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0% to 10%) to obtain 2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (0.4 g, yield: 59.9%). LCMS calc. for C 14 H 13 F2N2O3[M+H] + :m / z=295.1;Found:295.2

[0283] Step 3: (R)-2'-(difluoromethyl)-5'-methoxy-N-((4-(1-methoxyethyl)benzyl)sulfonyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0284] To a solution of (R)-4-(1-methoxyethyl)phenyl)methanesulfonamide (93.8 mg, 0.41 mmol) and 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methylnicotinic acid (80 mg, 0.27 mmol) in dichloromethane (5 mL) were added 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (105 mg, 0.55 mmol) and 4-dimethylaminopyridine (66.7 mg, 0.55 mmol). The reaction mixture was reacted at 20°C for 10 hours. The reaction mixture was concentrated under reduced pressure and analyzed by silica gel column chromatography (dichloromethane:methanol = 0-10%) and preparative high performance liquid chromatography (Column: SHIMADZU Prep C18 10 μm 20*250 mm Mobile phase: A (0.1% FA in The mixture was purified by HPLC (H2O) using B (ACN) (0-2 min: 40% B, 2-3.5 min: 40-75% B, 3.5-6 min: 75% B, 6-9 min: 75-95% B, 9-11 min: 95% B, 11-11.01 min: 95-40% B, 11.01-14 min: 40% B, Flow rate = 20 mL / min) to afford (R)-2'-(difluoromethyl)-5'-methoxy-N-((4-(1-methoxyethyl)benzyl)sulfonyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (20.2 mg, yield: 14.5%). LCMS calc. for C 24 H 26 F2N3O5S[M+H] + :m / z=506.2;Found:506.3 1 H NMR(400MHz,DMSO-d6)δ12.15(s,1H),8.51(s,1H),8.46(s,1H),7.63(s,1H),7.50-7.25(m,5H),6.98(t,J =54.8Hz,1H),4.68(s,2H),4.30-4.25(m,1H),3.88(s,3H),3.12(s,3H)2.56(s,3H),1.32(d,J=6.8Hz,3H).

[0285] Example 11 Preparation of Compound CPD-11

[0286] Step 1: Methyl 2-bromo-4-(cyanomethyl)benzoate

[0287] Methyl 2-bromo-4-(bromomethyl)benzoate (13 g, 42.2 mmol) was dissolved in acetonitrile (100 mL). Trimethylsilyl cyanide (15.8 mL, 127 mmol) and a solution of tetrabutylammonium fluoride in tetrahydrofuran (127 mL, 1.00 mol / L, 127 mmol) were added. The reaction was allowed to react at room temperature for 3 hours. After completion, water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (200 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0% to 30%) to obtain methyl 2-bromo-4-(cyanomethyl)benzoate (8.0 g, yield: 74.6%).

[0288] Step 2: Methyl 2-bromo-4-(2-methoxy-2-carbonylethyl)benzoate

[0289] Methyl 2-bromo-4-(cyanomethyl)benzoate (5.0 g, 19.7 mmol) was dissolved in methanol (20 mL) and 4N hydrochloric acid in dioxane (30 mL), heated to 80°C, and the reaction was continued for 2 hours. After the reaction, the reaction solution was poured into a saturated sodium bicarbonate solution and extracted with ethyl acetate (100 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0% to 30%) to obtain methyl 2-bromo-4-(2-methoxy-2-carbonylethyl)benzoate (4.5 g, yield: 79.7%). LCMS calculation for C 11 H 12 BrO4[M+H] + :m / z=287.0 / 289.0; Found:287.1 / 289.1.

[0290] Step 3: 2-(3-bromo-4-(carbomethoxy)phenyl)acetic acid

[0291] Methyl 2-bromo-4-(2-methoxy-2-carbonylethyl)benzoate (4.5 g, 15.7 mmol) was dissolved in tetrahydrofuran (40 mL) and water (8 mL), and lithium hydroxide (1.13 g, 47.0 mmol) was added and reacted at room temperature for 1 hour. After the reaction was completed, the pH was adjusted to 5 with 1N dilute hydrochloric acid, extracted with ethyl acetate (100 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 0% to 10%) to obtain 2-(3-bromo-4-(methyl ester) phenyl) acetic acid (2.8 g, yield: 88.8%). LCMS calc. for C 10 H 10 BrO4[M+H]+ :m / z=273.0 / 275.0; Found:273.0 / 275.0.

[0292] Step 4: Methyl 2-bromo-4-(2-(dimethylamino)-2-carbonylethyl)benzoate

[0293] Dissolve 2-(3-bromo-4-(carbomethoxy)phenyl)acetic acid (0.7 g, 2.56 mmol) in N,N-dimethylformamide (8 mL), and add dimethylamine hydrochloride (0.31 g, 3.85 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.17 g, 3.08 mmol), and N,N-diisopropylethylamine (0.99 g, 7.69 mmol). The reaction was allowed to proceed at room temperature for 1 hour. After completion of the reaction, the reaction solution was quenched with water and extracted with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0% to 50%) to give methyl 2-bromo-4-(2-(dimethylamino)-2-carbonylethyl)benzoate (0.7 g, yield: 91%). LCMS calc. for C 12 H 15 BrNO3[M+H] + :m / z=300.0 / 302.0; Found:300.1 / 302.1.

[0294] Step 5: 5'-(difluoromethyl)-5-(2-(dimethylamino)-2-carbonylethyl)-2'-methoxy-[1,1'-biphenyl]-2-carboxylic acid methyl ester

[0295] Methyl 2-bromo-4-(2-(dimethylamino)-2-carbonylethyl)benzoate (0.63 g, 2.11 mmol) was dissolved in dioxane (8 mL) and water (2 mL). 2-(5-(difluoromethyl)-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.6 g, 2.11 mmol), potassium carbonate (0.88 g, 6.34 mmol), and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (0.15 g, 0.21 mmol) were added. The mixture was heated to 80°C and the reaction was continued under an argon atmosphere for 2 hours. After completion of the reaction, the reaction solution was quenched with water and extracted with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0% to 50%) to give 5'-(difluoromethyl)-5-(2-(dimethylamino)-2-carbonylethyl)-2'-methoxy-[1,1'-biphenyl]-2-carboxylic acid methyl ester (0.5 g, yield: 62.7%). LCMS calc. for C 20 H 22 F2NO4[M+H] + :m / z=378.1;Found:378.3.

[0296] Step 6: 5'-(difluoromethyl)-5-(2-(dimethylamino)-2-carbonylethyl)-2'-methoxy-[1,1'-biphenyl]-2-carboxylic acid

[0297] Dissolve methyl 5'-(difluoromethyl)-5-(2-(dimethylamino)-2-carbonylethyl)-2'-methoxy-[1,1'-biphenyl]-2-carboxylate (0.5 g, 1.32 mmol) in methanol (8 mL) and water (2 mL). Add sodium hydroxide (0.16 g, 3.97 mmol) to the reaction solution, and heat to 50°C for 16 hours. After completion of the reaction, adjust the pH to 5 with 1N dilute hydrochloric acid and extract with ethyl acetate (50 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 0% to 10%) to give 5'-(difluoromethyl)-5-(2-(dimethylamino)-2-carbonylethyl)-2'-methoxy-[1,1'-biphenyl]-2-carboxylic acid (0.35 g, yield: 72.7%). LCMS calc. for: C 19 H 20 F2NO4[M+H] + :m / z=364.1;Found:364.2.

[0298] Step 7: 5'-(difluoromethyl)-5-(2-(dimethylamino)-2-carbonylethyl)-N-((4-isopropylbenzyl)sulfonyl)-2'-methoxy-[1,1'-biphenyl]-2-carboxamide

[0299] 5'-(Difluoromethyl)-5-(2-(dimethylamino)-2-carbonylethyl)-2'-methoxy-[1,1'-biphenyl]-2-carboxylic acid (100 mg, 0.28 mmol) was dissolved in N,N-dimethylformamide (3 mL), and carbonyldiimidazole (53.5 mg, 0.33 mmol) was added. The mixture was reacted at 80°C for 10 minutes, followed by the addition of (4-isopropylphenyl)methanesulfonamide (88 mg, 0.41 mmol) and 1,8-diazabicyclo(5,4,0)-7-undecene (0.08 mL, 0.55 mmol). The reaction was continued at 80°C for 1 hour. After completion of the reaction, the mixture was quenched with water and extracted with ethyl acetate (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by preparative high performance liquid chromatography (Column: XBridge Prep C18 5μm OBD 19*150mm, Mobile phase: A(10mM NH4HCO3 in Water)B(ACN), 0-3min: 40% B, 3-7min: 40-85% B, 7-11min: 85-90% B, 11-13min: 90-95% B, 13-16min: 95% B, 16-16.5min: 95-40% B, 16.5-21min: 40% B, Flow=15mL / min) to give 5'-(difluoromethyl)-5-(2-(dimethylamino)-2-carbonylethyl)-N-((4-isopropylbenzyl)sulfonyl)-2'-methoxy-[1,1'-biphenyl]-2-carboxamide (51.0mg, yield: 33.2%). LCMS calc.for C 29 H 33 F2N2O5S[M+H] + :m / z=559.2;Found:559.2. 1 H NMR (400MHz, DMSO-d6) δ11.80(s,1H),7.56(d,J=8.5Hz,1H),7.41(s,1H),7.31-6.89(m,9H),4.60(s, 2H),3.79(s,2H),3.73(s,3H),3.04(s,3H),2.90(p,J=6.9Hz,1H),2.83(s,3H),1.20(d,J=6.9Hz,6H)

[0300] Example 12 Preparation of Compound CPD-12

[0301] The same synthetic route was used as for compound CPD-11, except that the starting material in step 4 was replaced by N-methylcyclopropaneamine hydrochloride instead of dimethylamine hydrochloride.

[0302] 5-(2-(cyclopropyl(methyl)amino)-2-oxoethyl)-5'-(difluoromethyl)-N-((4-isopropylbenzyl)sulfonyl)-2'-methoxy-[1,1'-biphenyl]-2-carboxamide

[0303] LCMS calc.for C 31 H 35 F2N2O5S[M+H] + :m / z=585.2;Found:585.1 1 H NMR (400MHz, DMSO-d6) δ11.80 (s, 1H), 7.58-7.54 (m, 1H), 7.41 (d, J = 2.1Hz, 1H), 7.31-7.17 (m, 7H), 7.15 -6.89(m,2H),4.61(s,2H),3.96(s,2H),3.73(s,3H),2.85-2.75(m,4H),2.81(s,3H),1.20(d,J=6.9Hz,6H),0.97-0.66(m,4H).

[0304] Example 13 Preparation of Compound CPD-13

[0305] Step 1: Methyl 4-(2-(2-acetylhydrazine)-2-carbonylethyl)-2-bromobenzoate

[0306] To a solution of 2-(3-bromo-4-(carbomethoxy)phenyl)acetic acid (0.5 g, 1.83 mmol) in N,N-dimethylformamide (8.00 mL) was added acetic hydrazide (0.15 g, 2.01 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.84 g, 2.2 mmol), and triethylamine (0.53 mL, 3.66 mmol) at room temperature. The reaction was continued at room temperature for 30 minutes. Water (10 mL) was added, and the pH was adjusted to 5 with 1N aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (50 mL x 3), washed sequentially with saturated brine (50 mL x 2) and water (50 mL x 2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0% to 10%) to give methyl 4-(2-(2-acetylhydrazine)-2-carbonylethyl)-2-bromobenzoate (0.3 g, yield: 49.8%). LCMS calc. for C 12 H 14 BrN2O4[M+H] + :m / z=329.0 / 331.0; Found:329.1 / 331.1.

[0307] Step 2: Methyl 2-bromo-4-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)benzoate

[0308] Phosphorus oxychloride (0.11 mL, 1.18 mmol) was added to a solution of methyl 4-(2-(2-acetylhydrazine)-2-carbonylethyl)-2-bromobenzoate (0.3 g, 0.91 mmol) in dioxane (8 mL) at room temperature. The mixture was reacted at 90°C for 1 hour. Water (10 mL) was added, and the pH was adjusted to 7 with aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate (50 mL x 3), washed sequentially with saturated brine (50 mL x 2) and water (50 mL x 2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0% to 10%) to obtain methyl 2-bromo-4-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)benzoate (0.27 g, yield: 95.2%). LCMS calc. for C 12 H 12 BrN2O3[M+H] + :m / z=311.0 / 313.0; Found:311.1 / 313.1.

[0309] Step 3: 5'-(difluoromethyl)-2'-methoxy-5-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid methyl ester

[0310] To a solution of methyl 2-bromo-4-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)benzoate (0.27 g, 0.87 mmol) in dioxane (8 mL) and water (1 mL) was added 2-[5-(difluoromethyl)-2-methoxyphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.49 g, 1.74 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.07 g, 0.09 mmol), and potassium carbonate (0.36 g, 2.6 mmol) at room temperature. The reaction was allowed to proceed at 90°C under an argon atmosphere for 2 hours. Water (10 mL) was added, the pH was adjusted to 5 with 1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate (50 mL x 3). After washing with saturated brine (50 mL x 2) and water (50 mL x 2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 0% to 10%) to obtain 5'-(difluoromethyl)-2'-methoxy-5-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid methyl ester (0.3 g, yield: 89%). LCMS calc. for C 20 H 19 F2N2O4[M+H] + :m / z=389.1;Found:389.2.

[0311] Step 4: 5'-(difluoromethyl)-2'-methoxy-5-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid

[0312] To a solution of methyl 5'-(difluoromethyl)-2'-methoxy-5-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-[1,1'-biphenyl]-2-carboxylate (0.27 g, 0.7 mmol) in methanol (3 mL) / tetrahydrofuran (3 mL) / water (3 mL) was added lithium hydroxide (0.08 g, 3.48 mmol) at room temperature. The mixture was reacted at 50°C for 3 hours. Water (10 mL) was added, and the pH was adjusted to 5 with 1N aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (50 mL x 3), washed sequentially with saturated brine (50 mL x 2) and water (50 mL x 2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0% to 10%) to give 5'-(difluoromethyl)-2'-methoxy-5-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid (0.27 g, yield: 98.6%). LCMS calc. for C 19 H 17 F2N2O4[M+H] + :m / z=375.1;Found:375.1.

[0313] Step 5: 5'-(difluoromethyl)-N-((4-isopropylbenzyl)sulfonyl)-2'-methoxy-5-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-[1,1'-biphenyl]-2-carboxamide

[0314] To a solution of 5'-(difluoromethyl)-2'-methoxy-5-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid (100 mg, 0.27 mmol) in tetrahydrofuran (3 mL) was added 1,1-carbonyldiimidazole (65 mg, 0.4 mmol) at room temperature. The reaction mixture was reacted at 50°C for 15 minutes, cooled to room temperature, and (4-isopropylphenyl)methanesulfonamide (114 mg, 0.53 mmol) and 1,8-diazabicycloundec-7-ene (0.08 mL, 0.53 mmol) were added. The reaction mixture was heated to 75°C and reacted for 2 hours. Water (10 mL) was added, and the pH was adjusted to 5 with 1N aqueous hydrochloric acid solution. The mixture was extracted with ethyl acetate (50 mL x 3), and washed successively with saturated brine (50 mL x 2) and water (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by preparative high performance liquid chromatography (Column: SHIMADZU Prep C18 10 μm 20*250 mm; Mobile phase: A (0.1% FA in H2O) B (ACN); 0-2 min: 40% B, 2-4 min: 40-80% B, 4-6 min: 80% B, 6-8 min: 80-95% B, 8-12 min: 95% B, 12-12.01 min: 95-40% B, 12.01-15 min: 40% B, Flow = 20 mL / min) to give 5'-(difluoromethyl)-N-((4-isopropylbenzyl)sulfonyl)-2'-methoxy-5-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-[1,1'-biphenyl]-2-carboxamide (30.4 mg, yield: 19.8%). LCMS calc.for C 29 H 30 F2N3O5S[M+H] + :m / z=570.2;Found:570.2. 1 H NMR (400MHz, DMSO-d6) δ11.84(s,1H),7.60-7.53(m,1H),7.46-7.39(m,1H),7.35(s,2H),7.31(s,1H),7.25(d,J=8.0Hz,2H),7.20 (d,J=8.0Hz,2H),7.18-6.86(m,2H),4.60(s,2H),4.34(s,2H),3.72(s,3H),2.97-2.80(m,1H),2.45(s,3H),1.20(d,J=6.8Hz,6H).

[0315] Example 14 Preparation of Compound CPD-14

[0316] Step 1: 1-Bromo-4-(2,2,2-trifluoro-1-methoxyethyl)benzene

[0317] 1-(4-Bromophenyl)-2,2,2-trifluoroethane-1-ol (2.5 g, 9.8 mmol) was dissolved in N,N-dimethylformamide (20 mL), and sodium hydride (0.59 g, 14.7 mmol, 60% purity) was added at 0°C. The reaction was continued at 0°C under nitrogen for 0.5 hours. Iodomethane (0.92 mL, 14.7 mmol) was then added, and the reaction was continued at 20°C under nitrogen for 2 hours. The reaction solution was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (100 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0% to 20%) to yield 1-bromo-4-(2,2,2-trifluoro-1-methoxyethyl)benzene (1.6 g, yield: 60.7%).

[0318] Step 2: (4-(2,2,2-trifluoro-1-methoxyethyl)phenyl)methanol

[0319] 1-Bromo-4-(2,2,2-trifluoro-1-methoxyethyl)benzene (1.6 g, 6.27 mmol) was dissolved in dioxane (20 mL). (tributyltin)methanol (3.02 g, 9.41 mmol) and tetrakis(triphenylphosphine)palladium (0.72 g, 0.63 mmol) were added to the reaction mixture. After completion, the reaction mixture was quenched with aqueous potassium fluoride solution and extracted with ethyl acetate (100 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0% to 30%) to obtain (4-(2,2,2-trifluoro-1-methoxyethyl)phenyl)methanol (0.9 g, yield: 65.2%).

[0320] Step 3: 1-(Chloromethyl)-4-(2,2,2-trifluoro-1-methoxyethyl)benzene

[0321] Dissolve (4-(2,2,2-trifluoro-1-methoxyethyl)phenyl)methanol (0.5 g, 2.27 mmol) in dichloromethane (8 mL), add thionyl chloride (0.82 mL, 11.4 mmol), and continue to react at room temperature for 1 hour. Concentrate under reduced pressure to give the crude product 1-(chloromethyl)-4-(2,2,2-trifluoro-1-methoxyethyl)benzene (0.54 g, crude yield: 99.7%).

[0322] Step 4: S-(4-(2,2,2-trifluoro-1-methoxyethyl)benzyl)ethyl sulfate

[0323] 1-(Chloromethyl)-4-(2,2,2-trifluoro-1-methoxyethyl)benzene (0.54 g, 2.26 mmol) was dissolved in acetone (10 mL), followed by the addition of potassium thioacetate (0.39 g, 3.39 mmol). The reaction was continued at room temperature for 2 hours. After completion, the product was filtered and the filtrate concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0% to 20%) to obtain S-(4-(2,2,2-trifluoro-1-methoxyethyl)benzyl)ethylsulfate (0.5 g, yield: 79.4%).

[0324] Step 5: (4-(2,2,2-trifluoro-1-methoxyethyl)phenyl)methanesulfonamide

[0325] S-(4-(2,2,2-trifluoro-1-methoxyethyl)benzyl)ethylsulfate (0.5 g, 1.8 mmol) was dissolved in dichloromethane (8 mL). 1N dilute hydrochloric acid (10.8 mL, 10.8 mmol) was added, followed by the addition of 10% aqueous sodium hypochlorite (8.02 g, 10.8 mmol). After 1 hour of reaction, concentrated aqueous ammonia was added to adjust the pH of the reaction solution to 11, and the reaction was continued for 0.5 hour. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0% to 10%) to obtain (4-(2,2,2-trifluoro-1-methoxyethyl)phenyl)methanesulfonamide (0.3 g, yield: 59.4%). LCMS calculation for C 10 H 11 F3NO3S[MH] - :m / z=282.0;Found:282.1.

[0326] Step 6: 5'-(difluoromethyl)-2'-methoxy-5-methyl-N-((4-(2,2,2-trifluoro-1-methoxyethyl)benzyl)sulfonyl)-[1,1'-biphenyl]-2-carboxamide

[0327] 5'-(Difluoromethyl)-2'-methoxy-5-methyl-[1,1'-biphenyl]-2-carboxylic acid (100 mg, 0.34 mmol) was dissolved in dichloromethane (3 mL), and (4-(2,2,2-trifluoro-1-methoxyethyl)phenyl)methanesulfonamide (116 mg, 0.41 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (78.7 mg, 0.41 mmol), and 4-dimethylaminopyridine (83.6 mg, 0.68 mmol) were added. The mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 0% to 10%) and preparative high performance liquid chromatography (Column: XBridge Prep C18 5μm OBD 19*150mm, Mobile phase: A (10mM NH4HCO3 in The product was purified by adding 4-[[(4-(2,2,2-trifluoro-1-methoxyethyl)phenylmethyl)sulfonyl]-[1,1'-biphenyl]-2-carboxamide]-1,4'-difluoromethyl-2'-methoxy-5-methyl-N-((4-(2,2,2-trifluoro-1-methoxyethyl)phenylmethyl)sulfonyl)-[1,1'-biphenyl]-2-carboxamide) (68.9 mg, yield: 36.1%). LCMS calc. for C 26 H 25 F5NO5S[M+H] + :m / z=558.1;Found:558.4. 1 H NMR (400MHz, DMSO-d6) δ11.84(s,1H),7.59-7.53(m,1H),7.49-7.41(m,3H),7.38(d,J=8.0Hz,2H ),7.22-6.87(m,5H),5.10(q,J=7.0Hz,1H),4.69(s,2H),3.72(s,3H),3.35(s,3H),2.38(s,3H).

[0328] Example 15 Preparation of Compound CPD-15

[0329] Step 1: Methyl 4-(difluoromethoxy)methylbenzoate

[0330] Methyl 4-(hydroxymethyl)benzoate (1.0 g, 6.02 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of potassium bifluoride (1.88 g, 24.1 mmol), (bromodifluoromethyl)trimethylsilane (2.44 g, 12 mmol), and water (10 mL). The mixture was reacted at 25°C for 16 hours. Water (40 mL) was added and the mixture was extracted twice with dichloromethane (50 mL). The combined organic phases were washed sequentially with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0% to 10%) to obtain methyl 4-(difluoromethoxy)methylbenzoate (0.32 g, yield: 24.6%). LCMS calc. for C 10 H 11 F2O3[M+H] + :m / z=217.1;Found:217.1.

[0331] Step 2: (4-((difluoromethoxy)methyl)phenyl)methanol

[0332] To a solution of methyl 4-(difluoromethoxy)methylbenzoate (0.32 g, 1.48 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (67.4 mg, 1.78 mmol) under a nitrogen atmosphere at 0°C, followed by reaction at 0°C for 2 hours. After completion of the reaction, the temperature was lowered to -10°C, and 0.1 mL of water, 0.1 mL of 20% sodium hydroxide solution, and 0.3 mL of water were slowly added in sequence. The mixture was stirred at room temperature for 30 minutes, filtered under reduced pressure, and the filtrate was concentrated to give (4-((difluoromethoxy)methyl)phenyl)methanol (0.23 g, yield: 82.6%).

[0333] Step 3: 1-(Chloromethyl)-4-(difluoromethoxy)methyl)benzene

[0334] Dissolve (4-((difluoromethoxy)methyl)phenyl)methanol (0.7 g, 4.21 mmol) in dichloromethane (50 mL), add thionyl chloride (330 mg, 2.8 mmol), and react at 20°C for 1 hour. Concentrate under reduced pressure to obtain a residue, 1-(chloromethyl)-4-(difluoromethoxy)methyl)benzene (0.32 g, crude product). (The crude product is directly used in the next step.)

[0335] Step 4: (4-((difluoromethoxy)methyl)phenyl)methanesulfonamide

[0336] 1-(Chloromethyl)-4-(difluoromethoxymethyl)benzene (0.32 g, crude) was dissolved in acetone (10 mL), followed by the addition of potassium thioacetate (170 mg, 1.49 mmol). The mixture was reacted at 60°C for 1 hour under nitrogen. The reaction solution was diluted with water (30 mL), and the aqueous phase was extracted twice with ethyl acetate (30 mL). The combined organic phases were washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. Dichloromethane (5 mL) and 1N dilute hydrochloric acid (5 mL) were added to the residue, cooled to 0°C, and 10% aqueous sodium hypochlorite (7 mL) was slowly added dropwise. After 1 hour of reaction, concentrated aqueous ammonia was added to adjust the pH to 13, and the reaction was continued for 0.5 hours. The reaction solution was diluted with water (50 mL), and the aqueous phase was extracted twice with ethyl acetate (50 mL). The combined organic phases were washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0% to 5%) to obtain (4-((difluoromethoxy)methyl)phenyl)methanesulfonamide (0.21 g, yield: 67.5%). LCMS calc. for C9H 12 F2NO3S[M+H] + :m / z=252.0;Found:252.1.

[0337] Step 5: N-((4-(difluoromethoxy)methyl)benzyl)sulfonyl)-5'-(difluoromethyl)-2'-methoxy-5-methyl-[1,1'-biphenyl]-2-carboxamide

[0338] (4-((Difluoromethoxy)methyl)phenyl)methanesulfonamide (150 mg, 0.6 mmol) and 5'-(difluoromethyl)-2'-methoxy-5-methyl-[1,1'-biphenyl]-2-carboxylic acid (145 mg, 0.5 mmol) were dissolved in dichloromethane (6 mL), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (143 mg, 0.75 mmol) and 4-dimethylaminopyridine (122 mg, 0.99 mmol) were added. The mixture was reacted at 20°C for 10 hours. The reaction solution was concentrated under reduced pressure and analyzed by silica gel column chromatography (dichloromethane:methanol = 0% to 10%) and preparative high performance liquid chromatography (Column: XBridge Prep C18 5μm OBD 19*150mm, Mobile phase: A (10mM NH4HCO3 in The product was purified by adding 4-(4-(difluoromethoxy)methyl)benzyl)sulfonyl)-5'-(difluoromethyl)-2'-methoxy-5-methyl-[1,1'-biphenyl]-2-carboxamide (126 mg, yield: 40.2%). LCMS calculation for C 25 H 24 F4NO5S[M+H] + : m / z=526.1;Found:526.3 1 H NMR(400MHz,DMSO-d6)δ11.78(s,1H),7.60-7.50(m,1H),7.45-7.19(m,7H) ),7.17-6.60(m,4H),4.93(s,2H),4.66(s,2H),3.72(s,3H),2.38(s,3H).

[0339] Example 16 Preparation of Compound CPD-16

[0340] Step 1: Methyl (S)-4-(1-(methoxy-d3)ethyl)benzoate

[0341] Methyl (S)-4-(1-hydroxyethyl)benzoate (4.0 g, 22.2 mmol) was dissolved in N,N-dimethylformamide (30 mL). Sodium hydride (0.80 g, 33.3 mmol, 60%) was then added to the solution at 0°C. The reaction mixture was stirred under nitrogen for 0.5 hours. Deuterated iodomethane (4.83 g, 33.3 mmol) was added to the reaction mixture, and the reaction mixture was stirred under nitrogen at 20°C for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0% to 20%) to obtain methyl (S)-4-(1-(methoxy-d3)ethyl)benzoate (2.7 g, yield: 61.7%).

[0342] Step 2: (S)-(4-(1-(methoxy-d3)ethyl)phenyl)methanol

[0343] (S)-4-(1-(Methoxy-d3)ethyl)benzoate (2.7 g, 13.7 mmol) was dissolved in tetrahydrofuran (30 mL). Lithium aluminum hydride (11 mL, 27.5 mmol, 2.5 mol / L) was then added at 0°C. The reaction mixture was stirred under nitrogen at 0°C for 1 hour. After completion of the reaction, sodium sulfate decahydrate was slowly added to the reaction mixture to quench the reaction. The mixture was filtered, and the filter cake was washed three times with ethyl acetate (100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0% to 30%) to yield (S)-(4-(1-(methoxy-d3)ethyl)phenyl)methanol (2.0 g, yield: 86.3%).

[0344] Step 3: (S)-1-(chloromethyl)-4-(1-(methoxy-d3)ethyl)benzene

[0345] (S)-(4-(1-(methoxy-d3)ethyl)phenyl)methanol (2.0 g, 11.8 mmol) was dissolved in dichloromethane (20 mL). Thionyl chloride (2.57 mL, 35.5 mmol) was added to the reaction solution. The reaction solution was stirred at room temperature for 1 hour, quenched with saturated sodium carbonate solution, and extracted with dichloromethane (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product (S)-1-(chloromethyl)-4-(1-(methoxy-d3)ethyl)benzene (2.1 g, crude product).

[0346] Step 4: (S)-S-(4-(1-(methoxy-d3)ethyl)benzyl)ethyl sulfate

[0347] (S)-1-(Chloromethyl)-4-(1-(methoxy-d3)ethyl)benzene (2.1 g, 11.2 mmol) was dissolved in acetone (20 mL), followed by the addition of potassium thioacetate (1.92 g, 16.8 mmol). The reaction mixture was stirred at room temperature for 2 hours. After completion, the mixture was filtered and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0% to 20%) to obtain (S)-S-(4-(1-(methoxy-d3)ethyl)benzyl)ethylsulfate (2.0 g, yield: 78.6%).

[0348] Step 5: (S)-(4-(1-(methoxy-d3)ethyl)phenyl)methanesulfonamide

[0349] (S)-S-(4-(1-(methoxy-d3)ethyl)benzyl)ethylsulfate (2.0 g, 8.8 mmol) was dissolved in dichloromethane (20 mL). 1N dilute hydrochloric acid (35.2 mL, 35.2 mmol) was added, followed by the addition of 10% aqueous sodium hypochlorite (26.2 g, 35.2 mmol). After stirring for 1 hour, concentrated aqueous ammonia was added to adjust the pH to 12, and stirring was continued for 0.5 hour. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50.00 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0% to 10%) to obtain (S)-(4-(1-(methoxy-d3)ethyl)phenyl)methanesulfonamide (1.0 g, yield: 54.2%). LCMS calculation for C 10 H 11 D3NO3S[MH] - :m / z=231.1;Found:231.2. 1 HNMR (400MHz, DMSO) δ7.31(d,J=8.1Hz,2H),7.26(d,J=8.1Hz,2H).6.82(s,2H),4.28(q,J=6.4Hz,1H),4.21(s,2H),1.29(d,J=6.4Hz,3H).

[0350] Step 6: 3-Bromo-4-(methoxycarbonyl)phenyl)boronic acid

[0351] Methyl 2-bromo-4-iodobenzoate (11.0 g, 32.3 mmol) was dissolved in tetrahydrofuran (100 mL). Isopropylmagnesium chloride / lithium chloride complex (27.3 mL, 1.30 mol / L, 35.5 mmol) was slowly added to the reaction mixture at -30°C. The reaction mixture was stirred at this temperature for 0.5 hours. Trimethyl borate (6.71 g, 64.5 mmol) was then added to the reaction mixture. The reaction mixture was stirred at -30°C for 2 hours. After the reaction, 1N dilute hydrochloric acid (20 mL) was added to the reaction mixture. After stirring for 10 minutes, the mixture was extracted with ethyl acetate (200 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was slurried with dichloromethane (20 mL) and filtered to obtain the crude product 3-bromo-4-(methoxycarbonyl)phenyl)boronic acid (8.0 g, yield: 95.8%).

[0352] Step 7: Methyl 2-bromo-4-(methyl-d3)benzoate

[0353] 3-Bromo-4-(methoxycarbonyl)phenyl)boronic acid (8.0 g, 30.9 mmol) was dissolved in dioxane (80 mL) and water (8.0 mL). Deuterated iodomethane (6.72 g, 46.6 mmol), 1,1'-bis(diphenylphosphinoferrocenepalladium)dichloride (2.26 g, 3.09 mmol), and potassium phosphate (16.4 g, 77.3 mmol) were added. The reaction mixture was heated to 50°C and stirred under an argon atmosphere for 2 hours. After completion of the reaction, the mixture was quenched with water and extracted with ethyl acetate (100 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0% to 20%) to obtain methyl 2-bromo-4-(methyl-d3)benzoate (3.0 g, yield: 41.8%).

[0354] Step 8: Methyl 2-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-4-(methyl-d3)benzoate

[0355] Methyl 2-bromo-4-(methyl-d3)benzoate (3.0 g, 13.0 mmol) was dissolved in dioxane (30 mL) and water (5.0 mL). 2-(difluoromethyl)-5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.7 g, 13.0 mmol), potassium carbonate (4.76 g, 34.5 mmol), and 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride (1.01 g, 1.3 mmol) were added to the reaction solution. The reaction solution was heated to 80°C and stirred under an argon atmosphere for 2 hours. After completion of the reaction, the mixture was quenched with water and extracted with ethyl acetate (100 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0% to 30%) to give methyl 2-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-4-(methyl-d3)benzoate (4.0 g, yield: 93.5%).

[0356] Step 9: 2-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-4-(methyl-d3)benzoic acid

[0357] Methyl 2-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-4-(methyl-d3)benzoate (4.0 g, 12.9 mmol) was dissolved in methanol (30 mL) and water (5.0 mL). Lithium hydroxide (0.93 g, 38.7 mmol) was added to the reaction solution, and the reaction solution was heated to 50°C and stirred for 16 hours. After the reaction, the reaction solution was adjusted to pH 5 with 1N dilute hydrochloric acid and extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0% to 10%) to obtain 2-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-4-(methyl-d3)benzoic acid (3.0 g, yield: 78.6%). LCMS calculation for C 15 H9D3F2NO3[MH] - :m / z=295.1;Found:295.1. 1 HNMR(400MHz,DMSO)δ12.65(s,1H),8.43(s,1H),7.79(d,J=7.9Hz,1H),7.49(s,1H),7 .34(dd,J=7.9,1.7Hz,1H),7.15(d,J=1.6Hz,1H),6.94(t,J=55.1Hz,1H),3.83(s,3H).

[0358] Step 10: (S)-2-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-N-((4-(1-(methoxy-d3)ethyl)benzyl)sulfonyl)-4-(methyl-d3)benzamide

[0359] 2-(2-(Difluoromethyl)-5-methoxypyridin-4-yl)-4-(methyl-d3)benzoic acid (100 mg, 0.34 mmol) was dissolved in dichloromethane (4.0 mL), and (S)-(4-(1-(methoxy-d3)ethyl)phenyl)methanesulfonamide (94.1 mg, 0.41 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (78.7 mg, 0.41 mmol), and 4-dimethylaminopyridine (83.6 mg, 0.68 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column (dichloromethane:methanol = 0-10%) and preparative HPLC (Column: XBridge Prep C18 5μm OBD 19*150mm, Mobile phase: A (10mM NH4HCO3 in The mixture was stirred for 2 h at 4 ℃ for 1 h (15 min). The mixture was stirred for 2 h at 4 ℃ for 3 h (15 min). The mixture was stirred for 2 h (15 min). The mixture was stirred for 3 h (15 min). The mixture was stirred for 2 h (15 min). The mixture was stirred for 3 h (15 min). The mixture was stirred for 3 h (15 min). The mixture was stirred for 2 h (15 min). The mixture was stirred for 3 h (15 min). The mixture was stirred for 3 h (15 min). The mixture was stirred for 2 h (15 min). The mixture was stirred for 3 h (15 min). The mixture was stirred for 3 h (15 min). The mixture was stirred for 3 h (15 min). The mixture was stirred for 2 h (15 min). The mixture was stirred for 3 h (15 min). The mixture was stirred for 3 h (15 min). The mixture was stirred for 3 h 25 H 21 D6F2N2O5S[M+H] + :m / z=511.2; Found:511.3.1H NMR(400MHz,DMSO-d6)δ11.92(s,1H),8.45(s,1H),7.56(s,1H),7.37-7.22(m,7H),6.96( t,J=55.1Hz,1H),4.66(s,2H),4.33(q,J=6.4Hz,1H),3.86(s,3H),1.32(d,J=6.4Hz,3H).

[0360] Example 17 Preparation of Compound CPD-17

[0361] Step 1: Methyl 2-(2-chloro-5-methoxypyridin-4-yl)-4-(methyl-d3)benzoate

[0362] Methyl 2-bromo-4-(methyl-d3)benzoate (250 mg, 1.07 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL), followed by the addition of (2-chloro-5-methoxypyridin-4-yl)boronic acid (202 mg, 1.07 mmol), potassium carbonate (447 mg, 3.23 mmol), and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (78.8 mg, 0.11 mmol). The mixture was reacted at 90°C for 2 hours. Water (20 mL) was added, and the mixture was extracted three times with ethyl acetate (20 mL). The combined organic phases were washed sequentially with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give methyl 2-(2-chloro-5-methoxypyridin-4-yl)-4-(methyl-d3)benzoate (300 mg, crude product). LCMS calc. for C 15 H 12 D3ClNO3[M+H] + :m / z=295.1;Found:295.1.

[0363] Step 2: 2-(2-chloro-5-methoxypyridin-4-yl)-4-(methyl-d3)benzoic acid

[0364] To a solution of methyl 2-(2-chloro-5-methoxypyridin-4-yl)-4-(methyl-d3)benzoate (300 mg, 1.02 mmol) in methanol (10 mL) was added sodium hydroxide (201 mg, 5.1 mmol), and the mixture was reacted at 80°C for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, water (20 mL) was added, and the mixture was extracted three times with ethyl acetate and petroleum ether (20 mL, 1:1). 1N dilute hydrochloric acid (20 mL) was added to the aqueous phase to adjust the pH to 5, and the aqueous phase was extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-(2-chloro-5-methoxypyridin-4-yl)-4-(methyl-d3)benzoic acid (210 mg, yield: 76.3%). LCMS calc. for C 14 H 10 D3ClNO3[M+H] + :m / z=281.1;Found:281.1.

[0365] Step 3: (S)-2-(2-chloro-5-methoxypyridin-4-yl)-N-((4-(1-(methoxy-d3)ethyl)benzyl)sulfonyl)-4-(methyl-d3)benzamide

[0366] 2-(2-Chloro-5-methoxypyridin-4-yl)-4-(methyl-d3)benzoic acid (65 mg, 0.23 mmol) and (S)-(4-(1-(methoxy-d3)ethyl)phenyl)methanesulfonamide (53.8 mg, 0.23 mmol) were dissolved in dichloromethane (4 mL), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (66.6 mg, 0.35 mmol) and 4-dimethylaminopyridine (42.4 mg, 0.35 mmol) were added, and the reaction was carried out at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by preparative high performance liquid chromatography (Gemini-C18 150 x 21.2 mm, 5 μm, Mobile phase: A (0.1% FA in Water) B (ACN), 0-10 min: 40% B, 10-10.5 min: 40-95% B, 10.5-12.5 min: 95-90% B, 12.5-13 min: 95-10% B, 13-15 min: 40% B, Flow rate = 20 mL / min) to give (S)-2-(2-chloro-5-methoxypyridin-4-yl)-N-((4-(1-(methoxy-d3)ethyl)benzyl)sulfonyl)-4-(methyl-d3)benzamide (21.5 mg, yield: 18.6%). LCMS calc. for C 24 H 20 D6ClN2O5S[M+H] + :m / z=495.2;Found:495.3. 1 H NMR(400MHz,)δ11.87(s,1H),8.12(s,1H),7.34(s,1H),7.30(t,J=5.7Hz,2H),7.27(d,J=1.7Hz,2H),7.24(d ,J=8.2Hz,2H),7.21(d,J=1.5Hz,1H),4.64(s,2H),4.29(q,J=6.4Hz,1H),3.75(s,3H),1.28(d,J=6.4Hz,3H).

[0367] Example 18 Preparation of Compound CPD-18

[0368] Step 1: Methyl 2-(4,5-dimethyl-1,3,2-dioxaborolan-2-yl)-4-(methyl-d3)benzoate

[0369] Dissolve methyl 2-bromo-4-(methyl-d3)benzoate (1 g, 4.32 mmol) in 1,4-dioxane (10 mL). Add pinacol diboron (2 g, 8.64 mmol), potassium acetate (1.50 g, 13.0 mmol), and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (158 mg, 0.22 mmol). React at 100°C for 2 hours. Add water (30 mL) and extract three times with ethyl acetate (30 mL). The combined organic phase was washed with water (20 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 0% to 25%) to obtain methyl 2-(4,5-dimethyl-1,3,2-dioxaborolan-2-yl)-4-(methyl-d3)benzoate (1 g, yield: 82.8%). LCMS calc. for C 15 H 19 D3BO4[M+H] + :m / z=280.2;Found:280.3.

[0370] Step 2: 2-(Hydroxymethyl)-5-(methoxy-d3)-4H-pyran-4-one

[0371] 5-Hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (5.0 g, 35.2 mmol), deuterated iodomethane (6.0 g, 42.2 mmol), and potassium carbonate (15.0 g, 106 mmol) were dissolved in N,N-dimethylformamide (10 mL) and reacted at 25°C for 16 h. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure to give 2-(hydroxymethyl)-5-(methoxy-d3)-4H-pyran-4-one (3.0 g, crude product). LCMS calc. for C7H6D3O4[M+H] + :m / z=160.1;Found:160.1

[0372] Step 3: 2-(Hydroxymethyl)-5-(methoxy-d3)pyridin-4(1H)-one

[0373] 2-(Hydroxymethyl)-5-(methoxy-d3)-4H-pyran-4-one (3.0 g, 18.9 mmol) was dissolved in aqueous ammonia (30 mL) and reacted at 90°C for 6 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to give 2-(hydroxymethyl)-5-(methoxy-d3)pyridin-4(1H)-one (2.0 g, yield: 60%). LCMS calc. for C7H7D3NO3[M+H] + :m / z=159.1;Found:159.1.

[0374] Step 4: 5-(Methoxy-d3)-4-carbonyl-1,4-dihydropyridine-2-carboxylic acid

[0375] 2-(Hydroxymethyl)-5-(methoxy-d3)pyridin-4(1H)-one (2.0 g, 12.7 mmol) was dissolved in methanol and 1,4-dioxane (20 mL). Manganese dioxide (11 g, 127 mmol) was added and the mixture was allowed to react at 75°C for 16 hours. After completion of the reaction, the mixture was filtered under reduced pressure and the filtrate was concentrated to give 5-(methoxy-d3)-4-carbonyl-1,4-dihydropyridine-2-carboxylic acid (2.0 g, 73%). LCMS calc. for C7H5D3NO4[M+H] + :m / z=173.1;Found:173.1.

[0376] Step 5: Methyl 5-(methoxy-d3)-4-carbonyl-1,4-dihydropyridine-2-carboxylate

[0377] Dissolve 5-(methoxy-d3)-4-carbonyl-1,4-dihydropyridine-2-carboxylic acid (2 g, 11.6 mmol) in methanol (20 mL), add thionyl chloride (1.66 g, 14.0 mmol), and react at 40°C for 3 hours. Concentrate to give methyl 5-(methoxy-d3)-4-carbonyl-1,4-dihydropyridine-2-carboxylate (3.0 g, crude product). LCMS calc. for C8H7D3NO4[M+H] + :m / z=187.1;Found:187.0.

[0378] Step 6: Methyl 5-(methoxy-d3)-4-(((trifluoromethyl)sulfonyl)oxy)methyl picolinate

[0379] Under a nitrogen atmosphere at 0°C, methyl 5-(methoxy-d3)-4-carbonyl-1,4-dihydropyridine-2-carboxylate (3.0 g, 16.0 mmol) and triethylamine (5.0 mL, 32.1 mmol) were dissolved in dichloromethane (30 mL), followed by the addition of trifluoromethanesulfonic anhydride (4.0 mL, 19.3 mmol). The reaction was allowed to proceed at 25°C for 2 hours under nitrogen. The reaction solution was diluted with water (50 mL) and extracted three times with dichloromethane (50 mL). The combined organic phases were washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0% to 10%) to afford methyl 5-(methoxy-d3)-4-(((trifluoromethyl)sulfonyl)oxy)methylpicolinate (270 mg, yield: 5.3%). LCMS calc.for C9H6D3F3NO6S[M+H] +:m / z=319.0;Found:319.0.

[0380] Step 7: 2-Formyl-5-(methoxy-d3)pyridin-4-yl trifluoromethanesulfonate

[0381] To a solution of methyl 5-(methoxy-d3)-4-(((trifluoromethyl)sulfonyl)oxy)picolinate (270 mg, 0.85 mmol) in dichloromethane (5 mL) was slowly added dropwise diisobutylaluminum hydride (1 mL, 1.0 mmol, 1 mol / L) under a nitrogen atmosphere at -78°C. The reaction was allowed to react at 25°C for 1 hour. The reaction mixture was cooled to -78°C and quenched with saturated aqueous ammonium chloride (10 mL). The mixture was allowed to return to room temperature and the aqueous phase was extracted three times with dichloromethane (20 mL). The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 20% to 50%) to provide 2-formyl-5-(methoxy-d3)pyridin-4-yl trifluoromethanesulfonate (80 mg, yield: 26.3%). LCMS calc.for C8H4D3F3NO5S[M+H] + :m / z=289.0;Found:289.0.

[0382] Step 8: 2-(Difluoromethyl)-5-(methoxy-d3)pyridin-4-yl trifluoromethanesulfonate

[0383] To a solution of 2-formyl-5-(methoxy-d3)pyridin-4-yl trifluoromethanesulfonate (80 mg, 0.27 mmol) in dichloromethane (4 mL) was slowly added dropwise diethylaminosulfur trifluoride (130 mg, 0.81 mmol) under a nitrogen atmosphere at 0°C. The mixture was allowed to react at 25°C for 2 hours. The reaction solution was diluted with water (20 mL), and the aqueous phase was extracted three times with dichloromethane (20 mL). The combined organic phases were washed with water (20 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0% to 30%) to give 2-(difluoromethyl)-5-(methoxy-d3)pyridin-4-yl trifluoromethanesulfonate (50 mg, yield: 53.7%). LCMS calc. for C8H4D3F5NO4S[M+H] + :m / z=311.0;Found:311.0.

[0384] Step 9: Methyl 2-(2-(difluoromethyl)-5-(methoxy-d3)pyridin-4-yl)-4-(methyl-d3)benzoate

[0385] 2-(Difluoromethyl)-5-(methoxy-d3)pyridin-4-yl trifluoromethanesulfonate (50 mg, 0.16 mmol) was dissolved in 1,4-dioxane (5.0 mL) and water (0.5 mL). Methyl 2-(4,5-dimethyl-1,3,2-dioxaborolan-2-yl)-4-(methyl-d3)benzoate (61 mg, 0.24 mmol), potassium carbonate (66 mg, 0.48 mmol), and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (12 mg, 0.016 mmol) were then added. The mixture was reacted at 90°C for 2 hours. Water (20 mL) was added, and the mixture was extracted three times with ethyl acetate (20 mL). The combined organic phases were washed sequentially with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 0% to 10%) to give methyl 2-(2-(difluoromethyl)-5-(methoxy-d3)pyridin-4-yl)-4-(methyl-d3)benzoate (45 mg, yield: 80.8%). LCMS calc. for C 16 H 10 D6F2NO3[M+H] + :m / z=314.1;Found:314.1.

[0386] Step 10: 2-(2-(difluoromethyl)-5-(methoxy-d3)pyridin-4-yl)-4-(methyl-d3)benzoic acid

[0387] Methyl 2-(2-(difluoromethyl)-5-(methoxy-d3)pyridin-4-yl)-4-(methyl-d3)benzoate (45 mg, 0.14 mmol) was dissolved in methanol (3.0 mL), and then sodium hydroxide (17 mg, 0.42 mmol) was added. The mixture was reacted at 80°C for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, water (20 mL) was added, and the mixture was extracted three times with ethyl acetate (20 mL). 2N dilute hydrochloric acid (20 mL) was added to the aqueous phase to adjust the pH to 6, and the aqueous phase was extracted three times with ethyl acetate (20 mL). The combined organic phases were washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2-(2-(difluoromethyl)-5-(methoxy-d3)pyridin-4-yl)-4-(methyl-d3)benzoic acid (40 mg, yield: 95.5%). LCMS calc. for C 15 H8D6F2NO3[M+H] + :m / z=300.1;Found:300.1.

[0388] Step 11: (S)-2-(2-(difluoromethyl)-5-(methoxy-d3)pyridin-4-yl)-N-((4-(1-(methoxy-d3)ethyl)benzyl)sulfonyl)-4-(methyl-d3)benzamide

[0389] 2-(2-Chloro-5-methoxypyridin-4-yl)-4-(methyl-d3)benzoic acid (40 mg, 0.13 mmol) and (S)-(4-(1-(methoxy-d3)ethyl)phenyl)methanesulfonamide (37 mg, 0.16 mmol) were dissolved in dichloromethane (4 mL), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (31 mg, 0.16 mmol) and 4-dimethylaminopyridine (20 mg, 0.16 mmol) were added and reacted at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by preparative high performance liquid chromatography (Gemini-C18 150 x 21.2 mm, 5 μm, Mobile phase: A (0.1% FA in Water) B (ACN), 0-10 min: 50% B, 10-10.5 min: 50-95% B, 10.5-12.5 min: 95-95% B, 12.5-13 min: 95-50% B, 13-15 min: 50% B, Flow rate = 20 mL / min) to give (S)-2-(2-(difluoromethyl)-5-(methoxy-d3)pyridin-4-yl)-N-((4-(1-(methoxy-d3)ethyl)benzyl)sulfonyl)-4-(methyl-d3)benzamide (22 mg, yield: 32.9%). LCMS calc. for C 25 H 18 D9F2N2O5S[M+H] + :m / z=514.2;Found:514.2. 1 HNMR (400MHz, DMSO) δ = 11.92 (s, 1H), 8.44 (s, 1H), 7.56 (s, 1H), 7.36-7.25 (m, 6H), 7 .23(s,1H),7.10-6.83(m,1H),4.66(s,2H),4.33(q,J=6.4,1H),1.32(d,J=6.4,3H).

[0390] Example 19 Preparation of Compound CPD-19

[0391] Step 1: (S)-2-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-N-((4-(1-(methoxy-d3)ethyl)benzyl)sulfonyl)-4-methylbenzamide

[0392] 2-(2-(Difluoromethyl)-5-methoxypyridin-4-yl)-4-methylbenzoic acid (100 mg, 0.34 mmol) and (S)-(4-(1-(methoxy-d3)ethyl)phenyl)methanesulfonamide (79 mg, 0.34 mmol) were dissolved in dichloromethane (5.0 mL), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (78 mg, 0.41 mmol) and 4-dimethylaminopyridine (50 mg, 0.41 mmol) were added, and the reaction was carried out at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate (30 mL), washed sequentially with 1N dilute hydrochloric acid (5 mL) and saturated brine (10 mL), dried, concentrated, and purified by preparative HPLC (Gemini-C18 150 x 21.2 mm, 5 um, Mobile phase: A (0.1% FA in Water) B (ACN), 0-10 min: 49% B, 10-10.5 min: 49-95% B, 10.5-12.5 min: 95-95% B, 12.5-13 min: 95-49% B, 13-15 min: 49% B, Flow = 20 mL / min) to give (S)-2-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-N-((4-(1-(methoxy-d3)ethyl)benzyl)sulfonyl)-4-methylbenzamide (46 mg, yield: 26.2%). LCMS calc.for C 25 H 24 D3F2N2O5S[M+H] + :m / z=508.2;Found:508.2. 1 HNMR(400MHz,DMSO)δ11.93(s,1H),8.45(s,1H),7.56(s,1H),7.36-7.26(m,6H),7.24(s,1H),6.97(t ,J=55.1Hz,1H),4.67(s,2H),4.33(q,J=6.4Hz,1H),3.86(s,3H),2.39(s,3H),1.32(d,J=6.4Hz,3H).

[0393] Example 20 Preparation of Compound CPD-20

[0394] Step 1: 1-(5-bromopyridin-2-yl)ethan-1-ol

[0395] Under a nitrogen atmosphere at 0°C, methylmagnesium bromide (28 mL, 28.2 mmol) was slowly added to a solution of 5-bromomethylpyridinaldehyde (3.5 g, 18.8 mmol) in tetrahydrofuran (40 mL), followed by reaction at 25°C for 4 hours. A saturated aqueous ammonium chloride solution (20 mL) was added, and the mixture was extracted three times with dichloromethane (50 mL). The combined organic phases were washed sequentially with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 1-(5-bromopyridin-2-yl)ethane-1-ol (3.0 g, yield: 71.2%). LCMS calc. for C7H9BrNO[M+H] + :m / z=202.0 / 204.0; Found:202.0 / 204.0.

[0396] Step 2: 5-Bromo-2-(1-methoxyethyl)pyridine

[0397] Under a nitrogen atmosphere at 0°C, 1-(5-bromopyridin-2-yl)ethane-1-ol (3.0 g, 14.8 mmol) was dissolved in tetrahydrofuran (30 mL), and sodium hydride (1.0 g, 22.2 mmol, 60%) was added. The mixture was reacted at 0°C for 30 minutes. Iodomethane (3 g, 22.20 mmol) was added to the reaction solution, and the reaction was continued at 25°C for 4 hours. Saturated aqueous ammonium chloride solution (30 mL) was added, and the mixture was extracted three times with ethyl acetate (50 mL). The combined organic phases were washed sequentially with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0% to 10%) to obtain 5-bromo-2-(1-methoxyethyl)pyridine (2.0 g, yield: 56.6%). LCMS calc. for C8H 11 BrNO[M+H] + :m / z=216.0 / 218.0; Found:216.1 / 218.1.

[0398] Step 3: (6-(1-methoxyethyl)pyridin-3-yl)methanol

[0399] 5-Bromo-2-(1-methoxyethyl)pyridine (2.0 g, 9.3 mmol) and (tributylstannyl)methanol (3.6 g, 11.2 mmol) were dissolved in anhydrous toluene (20 mL), and tetrakistriphenylphosphine palladium (537 mg, 0.46 mmol) was added. The mixture was reacted at 100°C for 4 hours. Water (30 mL) was added, and the mixture was extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 20% to 50%) to give (6-(1-methoxyethyl)pyridin-3-yl)methanol (800 mg, yield: 46.6%). LCMS calc. for C9H 14 NO2[M+H] + :m / z=168.1;Found:168.2.

[0400] Step 4: 5-(Bromomethyl)-2-(1-methoxyethyl)pyridine

[0401] Under a nitrogen atmosphere at 0°C, (6-(1-methoxyethyl)pyridin-3-yl)methanol (800mg, 4.78mmol) was dissolved in dichloromethane (10mL), phosphorus tribromide (2.0g, 7.18mmol) was added, and the mixture was reacted at 25°C for 4 hours. The reaction solution was poured into a sodium bicarbonate solution (20mL) and extracted three times with dichloromethane (30mL). The combined organic phase was washed with water (30mL) and saturated brine (30mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 5-(bromomethyl)-2-(1-methoxyethyl)pyridine (850mg, 69.5%). LCMS calc. for C9H 13 BrNO[M+H] + :m / z=230.0 / 232.0; Found:230.0 / 232.0.

[0402] Step 5: S-((6-(1-methoxyethyl)pyridin-3-yl)methyl)ethyl sulfate

[0403] 5-(Bromomethyl)-2-(1-methoxyethyl)pyridine (850 mg, 3.71 mmol) was dissolved in acetone (10 mL), and potassium thioacetate (595 mg, 5.22 mmol) was added. The mixture was reacted at 25°C for 1 hour under nitrogen protection. The reaction solution was diluted with water (30 mL) and extracted three times with ethyl acetate (30 mL). The combined organic phase was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0% to 20%) to give S-((6-(1-methoxyethyl)pyridin-3-yl)methyl)ethylsulfate (580 mg, yield: 51.8%). LCMS calc. for C 11 H 16 NO2S[M+H] + :m / z=226.1;Found:226.1.

[0404] Step 6: (6-(1-methoxyethyl)pyridin-3-yl)methanesulfonyl chloride

[0405] To a solution of S-((6-(1-methoxyethyl)pyridin-3-yl)methyl)ethylsulfate (580 mg, 2.57 mmol) in dichloromethane (10 mL) under a nitrogen atmosphere at 0°C was added 2N dilute hydrochloric acid (1 mL), and aqueous sodium hypochlorite (1.40 g, 15.44 mmol) was slowly added dropwise. The mixture was allowed to react for 2 hours. The reaction solution was diluted with water (20 mL), and the aqueous phase was extracted three times with dichloromethane (20 mL). The combined organic phases were washed with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to provide (6-(1-methoxyethyl)pyridin-3-yl)methanesulfonyl chloride (360 mg, yield: 50.4%).

[0406] Step 7: (S)-(4-(1-(methoxy-d3)ethyl)phenyl)methanesulfonamide

[0407] Under a nitrogen atmosphere at 0°C, a solution of (6-(1-methoxyethyl)pyridin-3-yl)methanesulfonyl chloride (360 mg, 1.44 mmol) in tetrahydrofuran (4.0 mL) was added dropwise to aqueous ammonia (2 mL). The mixture was reacted at 25°C for 1 hour. The reaction solution was directly concentrated to obtain a residue. The residue was purified by reverse phase column chromatography (acetonitrile:water (0.1% FA) = 0% to 20%) to give (S)-(4-(1-(methoxy-d3)ethyl)phenyl)methanesulfonamide (80 mg, yield: 21.6%). LCMS calc. for C9H 15 N2O3S[M+H] + :m / z=231.1;Found:231.0.

[0408] Step 8: 5'-(difluoromethyl)-2'-methoxy-N-(((6-(1-methoxyethyl)pyridin-3-yl)methyl)sulfonyl)-5-methyl-[1,1'-biphenyl]-2-carboxamide

[0409] (S)-(4-(1-(methoxy-d3)ethyl)phenyl)methanesulfonamide (80 mg, 0.34 mmol) and 5'-(difluoromethyl)-2'-methoxy-5-methyl-[1,1'-biphenyl]-2-carboxylic acid (79 mg, 0.34 mmol) were dissolved in dichloromethane (3.0 mL), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (80 mg, 0.42 mmol) and 4-dimethylaminopyridine (85 mg, 0.69 mmol) were added, and the reaction was carried out at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by preparative high performance liquid chromatography (Gemini-C18 150 x 21.2 mm, 5 μm, Mobile phase: A (0.1% FA in Water) B (ACN), 0-10 min: 40-60% B, 10-10.5 min: 60-95% B, 10.5-12.5 min: 95-95% B, 12.5-13 min: 95-40% B, 13-15 min: 40% B, Flow = 20 mL / min) to give 5'-(difluoromethyl)-2'-methoxy-N-(((6-(1-methoxyethyl)pyridin-3-yl)methyl)sulfonyl)-5-methyl-[1,1'-biphenyl]-2-carboxamide (70 mg, yield: 39.2%). LCMS calc. for C 25 H 27 F2N2O5S[M+H] + :m / z=505.2;Found:505.2. 1 H NMR (400MHz, DMSO) δ11.88(s,1H),8.39(s,1H),7.73(d,J=7.9Hz,1H),7.56(d,J=8.3Hz,1H),7.44(d,J=7.7Hz,2H),7.26(dd,J=22.2,7.7Hz,2H),7.1 7-6.89(m,1H),7.14(dd,J=16.5,6.7Hz,2H),4.72(s,2H),4.38(dd,J=12.9 ,6.4Hz,1H),3.73(s,3H),3.21(s,3H),2.38(s,3H),1.36(d,J=6.5Hz,3H).

[0410] Example 21 Preparation of Compound CPD-21

[0411] Step 1: 5-bromo-2-fluoro-4-methoxybenzaldehyde

[0412] Under a nitrogen atmosphere at 0°C, bromine (4.0 g, 26.0 mmol) was slowly added dropwise to a 30 mL aqueous solution of 2-fluoro-4-methoxybenzaldehyde (2.0 g, 13.0 mmol) and potassium bromide (8.0 g, 64.9 mmol). The mixture was allowed to react at 25°C for 16 h. After completion, the reaction was quenched by the addition of saturated aqueous sodium thiosulfate (30 mL). The aqueous phase was extracted three times with ethyl acetate (40 mL). The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0% to 30%) to yield 5-bromo-2-fluoro-4-methoxybenzaldehyde (2.0 g, yield: 59.5%). LCMS calc. for C8H7BrFO2 [M+H] + :m / z=233.0 / 235.0; Found:233.0 / 235.0.

[0413] Step 2: 1-Bromo-5-(difluoromethyl)-4-fluoro-2-methoxybenzene

[0414] Dissolve 5-bromo-2-fluoro-4-methoxybenzaldehyde (1.0 g, 4.31 mmol) in 1,2-dichloromethane (12 mL), and slowly add diethylaminosulfur trifluoride (2.0 g, 12.9 mmol) dropwise. Reaction mixture was stirred at 60°C for 12 hours. The reaction mixture was poured into water (30 mL) and extracted three times with dichloromethane (30 mL). The combined organic phases were washed with water (20 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0% to 40%) to afford 1-bromo-5-(difluoromethyl)-4-fluoro-2-methoxybenzene (1.0 g, yield: 68.5%). 1 HNMR (400MHz, CDCl3) δ7.75(d,J=7.5Hz,1H),6.80(t,J=56Hz,1H),6.66(d,J=2.1Hz,1H),3.92(s,3H).

[0415] Step 3: Methyl 5'-(difluoromethyl)-4'-fluoro-2'-methoxy-5-(methyl-d3)-[1,1'-biphenyl]-2-carboxylate

[0416] 1-Bromo-5-(difluoromethyl)-4-fluoro-2-methoxybenzene (300 mg, 1.17 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL). Methyl 4-(methyl-d3)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (394 mg, 1.41 mmol), potassium carbonate (325 mg, 2.35 mmol), and di(tri-tert-butylphosphine)palladium(0) (60 mg, 0.12 mmol) were then added. The mixture was reacted at 100°C for 2 hours. Water (20 mL) was added, and the mixture was extracted three times with ethyl acetate (20 mL). The combined organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 0% to 40%) to obtain methyl 5'-(difluoromethyl)-4'-fluoro-2'-methoxy-5-(methyl-d3)-[1,1'-biphenyl]-2-carboxylate (160 mg, yield: 37.4%). LCMS calc. for C 17 H 13 D3F3O3[M+H] + :m / z=328.1;Found:328.1.

[0417] Step 4: 5'-(difluoromethyl)-4'-fluoro-2'-methoxy-5-(methyl-d3)-[1,1'-biphenyl]-2-carboxylic acid

[0418] Methyl 5'-(difluoromethyl)-4'-fluoro-2'-methoxy-5-(methyl-d3)-[1,1'-biphenyl]-2-carboxylate (160 mg, 0.49 mmol) was dissolved in methanol (3 mL) and water (1 mL), followed by the addition of sodium hydroxide (117 mg, 2.93 mmol). The reaction was allowed to proceed at 80°C for 2 hours. After completion, the reaction was concentrated under reduced pressure, water (20 mL) was added, and the mixture was extracted three times with ethyl acetate (20 mL). 1N dilute hydrochloric acid was added to the aqueous phase to adjust the pH to 5, and the aqueous phase was extracted three times with ethyl acetate (30 mL). The organic phases were combined, washed sequentially with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 5'-(difluoromethyl)-4'-fluoro-2'-methoxy-5-(methyl-d3)-[1,1'-biphenyl]-2-carboxylic acid (110 mg, yield: 64.6%). LCMS calc.for C 16 H 11 D3F3O3[M+H] + :m / z=314.1;Found:314.1.

[0419] Step 5: (S)-5'-(difluoromethyl)-4'-fluoro-2'-methoxy-N-((4-(1-(methoxy-d3)ethyl)phenylmethyl)sulfonyl)-5-(methyl-d3)-[1,1'-biphenyl]-2-carboxamide

[0420] 5'-(Difluoromethyl)-4'-fluoro-2'-methoxy-5-(methyl-d3)-[1,1'-biphenyl]-2-carboxylic acid (110 mg, 0.35 mmol) and (S)-(4-(1-(methoxy-d3)ethyl)phenyl)methanesulfonamide (82 mg, 0.35 mmol) were dissolved in dichloromethane (4 mL), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (134 mg, 0.7 mmol) and 4-dimethylaminopyridine (51 mg, 0.42 mmol) were added, and the reaction was carried out at 25°C for 3 hours. After the reaction was complete, the mixture was diluted with dichloromethane (30 mL), washed with 1N dilute hydrochloric acid (10 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by preparative high performance liquid chromatography (Gemini-C18 150 x 21.2 mm, 5 μm, Mobile phase: A (0.1% FA in The product was purified by HPLC (5% NaHCO 4 HCl, 0-10 min: 55% B, 10-10.5 min: 55-95% B, 10.5-12.5 min: 95-95% B, 12.5-13 min: 95-55% B, 13-15 min: 55% B, Flow = 20 mL / min) to give (S)-5'-(difluoromethyl)-4'-fluoro-2'-methoxy-N-((4-(1-(methoxy-d3)ethyl)benzyl)sulfonyl)-5-(methyl-d3)-[1,1'-biphenyl]-2-carboxamide (82 mg, yield: 42.0%). LCMS calc. for C 26 H 21 D6F3NO5S[M+H] + :m / z=528.2;Found:528.1. 1 HNMR (400MHz, DMSO) δ11.77 (s, 1H), 7.45 (d, J = 8.0Hz, 1H), 7.32-7.21 (m, 6H), 7.31-7.03 (m, 1H), 7.15 ( s,1H),7.09(d,J=12.5Hz,1H),4.65(s,2H),4.32(q,J=6.4Hz,1H),3.73(s,3H),1.32(d,J=6.4Hz,3H).

[0421] Example 22 Preparation of Compound CPD-22

[0422] Step 1: 1-(4-bromophenyl-2,3,5,6-d4)ethan-1-one

[0423] Under a nitrogen atmosphere at -78°C, 1,4-dibromobenzene-2,3,5,6-d4 (10 g, 41.7 mmol) and n-butyllithium hexane solution (17 mL, 41.7 mmol, 2.5 mol / L) were dissolved in tetrahydrofuran (60 mL) and stirred at -78°C for 30 minutes. Then, N-methoxy-N-methylacetamide (3.8 g, 37.5 mmol) was added and reacted at 25°C for 2 hours. After completion of the reaction, saturated aqueous ammonium chloride solution (20 mL) was added and extracted three times with dichloromethane (50 mL). The combined organic phases were washed with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 0% to 30%) to give 1-(4-bromophenyl-2,3,5,6-d4)ethan-1-one (6.0 g, yield: 65.2%). 1 H NMR (400MHz, CDCl3) δ2.59 (s, 3H).

[0424] Step 2: (S)-1-(4-bromophenyl-2,3,5,6-d4)ethan-1-ol

[0425] Under a nitrogen atmosphere at -18°C, 1-(4-bromophenyl-2,3,5,6-d4)ethan-1-one (6.0 g, 29.7 mmol) was dissolved in tetrahydrofuran (60 mL). A toluene solution of (R)-2-methyl-CBS-oxazaborolidine (3.1 mL, 3.1 mmol, 1 mol / L) and borane dimethyl sulfide complex (22 mL, 22.0 mmol, 1 mol / L) were slowly added. The mixture was then reacted at 25°C for 3 hours. After completion, methanol (50 mL) was added to quench the reaction solution and the mixture was concentrated to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 0% to 30%) to obtain (S)-1-(4-bromophenyl-2,3,5,6-d4)ethan-1-ol (3.0 g, yield: 44.7%). 1 HNMR (400MHz, DMSO) δ5.22 (s, 1H), 4.70 (q, J = 6.5Hz, 1H), 1.29 (d, J = 6.5Hz, 3H).

[0426] Step 3: (S)-1-bromo-4-(1-(methoxy-d3)ethyl)benzene-2,3,5,6-d4

[0427] Under a nitrogen atmosphere at 0°C, (S)-1-(4-bromophenyl-2,3,5,6-d4)ethan-1-ol (3.0 g, 14.60 mmol) was dissolved in N,N-dimethylformamide (30 mL). Sodium hydride (530 mg, 21.9 mmol, 60%) was then added and the mixture was allowed to react at 0°C for 30 minutes. Iodomethane-d3 (3.0 g, 21.9 mmol) was added to the reaction mixture, and the mixture was allowed to react at 25°C for 4 hours. Saturated aqueous ammonium chloride (30 mL) was added, and the mixture was extracted three times with ethyl acetate (50 mL). The combined organic phases were washed sequentially with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 0% to 10%) to give (S)-1-bromo-4-(1-(methoxy-d3)ethyl)benzene-2,3,5,6-d4 (2.7 g, yield: 74.6%). 1 HNMR (400MHz, DMSO) δ4.31 (q, J=6.4Hz, 1H), 1.30 (d, J=6.4Hz, 3H).

[0428] Step 4: (S)-(4-(1-(methoxy-d3)ethyl)phenyl-2,3,5,6-d4)methanol

[0429] (S)-1-Bromo-4-(1-(methoxy-d3)ethyl)benzene-2,3,5,6-d4 (2.7 g, 12.2 mmol) was dissolved in 1,4-dioxane (30 mL), and (tributyltin)methanol (5.8 g, 18.3 mmol) and tetrakistriphenylphosphine palladium (1.4 g, 1.22 mmol) were added. The mixture was reacted at 100°C for 12 hours. After completion of the reaction, water (50 mL) was added, and the mixture was extracted three times with ethyl acetate (50 mL). The combined organic phases were washed sequentially with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 0% to 30%) to obtain (S)-(4-(1-(methoxy-d3)ethyl)phenyl-2,3,5,6-d4)methanol (1.3 g, yield: 55.7%). LCMS calc.for C 10 H8D7O2[M+H] + :m / z=174.1; Found:139.2.[M-OCD3] +

[0430] Step 5: (S)-1-(chloromethyl)-4-(1-(methoxy-d3)ethyl)benzene-2,3,5,6-d4

[0431] (S)-(4-(1-(methoxy-d3)ethyl)phenyl-2,3,5,6-d4)methanol (1.3 g, 7.47 mmol) was dissolved in dichloromethane (15 mL), and thionyl chloride (1.06 g, 8.96 mmol) was added. The mixture was reacted at 25°C for 2 hours. Water (30 mL) was added, and the mixture was extracted three times with dichloromethane (30 mL). The combined organic phases were washed sequentially with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield (S)-1-(chloromethyl)-4-(1-(methoxy-d3)ethyl)benzene-2,3,5,6-d4 (1.4 g, crude product). (The crude product was directly used in the next step.)

[0432] Step 6: (S)-S-(4-(1-(methoxy-d3)ethyl)benzyl)ethylsulfate-2,3,5,6-d4

[0433] (S)-1-(Chloromethyl)-4-(1-(methoxy-d3)ethyl)benzene-2,3,5,6-d4 (1.4 g, crude product) was dissolved in acetone (20 mL), followed by the addition of potassium thioacetate (1.26 g, 11.0 mmol) and the reaction was carried out at 25°C for 1 hour under nitrogen protection. The reaction solution was diluted with water (30 mL) and extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give (S)-S-(4-(1-(methoxy-d3)ethyl)benzyl)ethylsulfate-2,3,5,6-d4 (1.2 g, yield: 56.1%). LCMS calc. for C 12 H 10 D7O2S[M+H] + :m / z=232.1; Found:198.1[M-OCD3] + .

[0434] Step 7: (S)-(4-(1-(methoxy-d3)ethyl)phenyl-2,3,5,6-d4)methanesulfonyl chloride

[0435] To a solution of (S)-S-(4-(1-(methoxy-d3)ethyl)benzyl)ethylsulfate-2,3,5,6-d4 (1.2 g, 5.19 mmol) in dichloromethane (20 mL) under a nitrogen atmosphere at 0°C was added 2N dilute hydrochloric acid (16 mL), followed by the slow dropwise addition of aqueous sodium hypochlorite (2.32 g, 31.1 mmol). The mixture was allowed to react for 1 hour. The reaction mixture was diluted with water (30 mL), and the aqueous phase was extracted three times with dichloromethane (30 mL). The combined organic phases were washed with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford (S)-(4-(1-(methoxy-d3)ethyl)phenyl-2,3,5,6-d4)methanesulfonyl chloride (1.2 g, yield: 72.4%).

[0436] Step 8: (S)-(4-(1-(methoxy-d3)ethyl)phenyl-2,3,5,6-d4)methanesulfonamide

[0437] Under a nitrogen atmosphere at 0°C, (S)-(4-(1-(methoxy-d3)ethyl)phenyl-2,3,5,6-d4)methanesulfonyl chloride (1.2 g, 4.7 mmol) was added to a mixed solution of tetrahydrofuran (16 mL) and ammonia water (8 mL). The reaction was allowed to proceed at 25°C for 1 hour. The reaction solution was diluted with water (30 mL) and extracted three times with dichloromethane (30 mL). The combined organic phases were washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 0% to 50%) to give (S)-(4-(1-(methoxy-d3)ethyl)phenyl-2,3,5,6-d4)methanesulfonamide (270 mg, yield: 23.4%). LCMS calc.for C 10 H9D7NO3S[M+H] + :m / z=237.1; Found:254.2[M+NH4] + .1HNMR (400MHz, DMSO) δ6.84 (s, 2H), 4.32 (q, J = 6.4Hz, 1H), 4.25 (s, 2H), 1.33 (d, J = 6.4Hz, 3H).

[0438] Step 9: (S)-2-(2-chloro-5-methoxypyridin-4-yl)-N-(4-(1-(methoxy-d3)ethyl)(phenyl-2,3,5,6-d4)methylsulfonyl)-4-(methyl-d3)benzamide

[0439] 2-(2-Chloro-5-methoxypyridin-4-yl)-4-(methyl-d3)benzoic acid (40 mg, 0.14 mmol) and (S)-(4-(1-(methoxy-d3)ethyl)phenyl-2,3,5,6-d4)methanesulfonamide (34 mg, 0.14 mmol) were dissolved in dichloromethane (3 mL), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (33 mg, 0.17 mmol) and 4-dimethylaminopyridine (21 mg, 0.17 mmol) were added and reacted at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by preparative high performance liquid chromatography (Gemini-C18 150 x 21.2 mm, 5 μm, Mobile phase: A (0.1% FA in Water) B (ACN), 0-10 min: 50% B, 10-10.5 min: 50-95% B, 10.5-12.5 min: 95-95% B, 12.5-13 min: 95-50% B, 13-15 min: 50% B, Flow = 20 mL / min) to give (S)-2-(2-chloro-5-methoxypyridin-4-yl)-N-(4-(1-(methoxy-d3)ethyl)(phenyl-2,3,5,6-d4)methylsulfonyl)-4-(methyl-d3)benzamide (30 mg, yield: 40.1%). LCMS calc. for C 24 H 16 D 10 ClN2O5S[M+H] + :m / z=499.2;Found:499.2. 1 H NMR (400MHz, DMSO) δ = 11.91 (s, 1H), 8.16 (s, 1H), 7.38 (s, 1H), 7.36-7.28 (m, 2H) ,7.24(s,1H),4.68(s,2H),4.33(q,J=6.4,1H),3.78(s,3H),1.32(d,J=6.4,3H).

[0440] Example 23 Preparation of Compound CPD-23

[0441] Step 1: 2-chloro-5-fluoro-6-iodopyridin-3-ol

[0442] 2-Chloro-5-fluoropyridin-3-ol (900 mg, 6.10 mmol), iodine (1.70 g, 6.71 mmol), and potassium carbonate (1.70 g, 12.2 mmol) were dissolved in water (10 mL) and reacted at 25°C for 2 h. After completion of the reaction, the reaction solution was diluted with water (30 mL), and the aqueous phase was extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0% to 30%) to obtain 2-chloro-5-fluoro-6-iodopyridin-3-ol (1.0 g, yield: 53.9%). LCMS calc. for C5H3ClFINO[M+H] + :m / z=273.9;Found:273.9.

[0443] Step 2: 2-chloro-5-fluoro-6-iodo-3-methoxypyridine

[0444] Under a nitrogen atmosphere at 0°C, 2-chloro-5-fluoro-6-iodopyridin-3-ol (1.0 g, 3.70 mmol) was dissolved in N,N-dimethylformamide (10 mL). Sodium hydride (190 mg, 4.80 mmol, 60%) was added portionwise and allowed to react at 0°C for 30 minutes. Iodomethane (346 mL, 5.55 mmol, 2.28 g / L) was added to the reaction mixture and allowed to react at room temperature for 1 hour. After completion, the reaction was quenched with saturated ammonium chloride solution (10 mL). The aqueous phase was extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0% to 30%) to yield 2-chloro-5-fluoro-6-iodo-3-methoxypyridine (780 mg, yield: 64.8%). LCMS calc.for C6H5ClFINO[M+H] + :m / z=287.9;Found:287.9.

[0445] Step 3: 2-chloro-5-fluoro-3-methoxy-6-vinylpyridine

[0446] 2-Chloro-5-fluoro-6-iodo-3-methoxypyridine (580 mg, 2.02 mmol) was dissolved in acetonitrile (5 mL) and water (1 mL). Potassium ethylene trifluoroborate (405 mg, 3.03 mmol), potassium carbonate (558 mg, 4.04 mmol), and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (148 mg, 0.2 mmol) were then added. The mixture was reacted at 80°C for 3 hours. Water (20 mL) was added, and the mixture was extracted three times with ethyl acetate (20 mL). The combined organic phases were washed sequentially with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 0% to 30%) to provide 2-chloro-5-fluoro-3-methoxy-6-vinylpyridine (300 mg, yield: 71.3%). LCMS calc.for C8H8ClFNO[M+H] + :m / z=188.0;Found:188.1.

[0447] Step 4: 6-chloro-3-fluoro-5-methoxymethylpyridine aldehyde

[0448] Dissolve 2-chloro-5-fluoro-3-methoxy-6-vinylpyridine (300 mg, 1.60 mmol) in dichloromethane (5 mL), cool to -78°C, purge with ozone, and allow to react for 10 minutes. After completion, add dimethyl sulfide (1 mL) dropwise to quench the reaction. Concentrate the reaction mixture to yield 6-chloro-3-fluoro-5-methoxymethylpyridine aldehyde (400 mg, crude), which is used directly in the next step. LCMS calc. for C7H6ClFNO2[M+H] + :m / z=190.0;Found:190.0.

[0449] Step 5: 2-chloro-6-(difluoromethyl)-5-fluoro-3-methoxypyridine

[0450] 6-Chloro-3-fluoro-5-methoxymethylpyridine aldehyde (400 mg, 2.12 mmol) was dissolved in 1.2-dichloromethane (5 mL), and diethylaminosulfur trifluoride (1.40 g, 8.48 mmol) was slowly added dropwise. The mixture was reacted at 60°C for 2 hours. The reaction solution was diluted with water (20 mL), and the aqueous phase was extracted three times with dichloromethane (20 mL). The combined organic phases were washed with water (20 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0% to 60%) to obtain 2-chloro-6-(difluoromethyl)-5-fluoro-3-methoxypyridine (250 mg, yield: 50.4%). LCMS calculation for C7H6ClF3NO[M+H]+ :m / z=212.0;Found:212.0.

[0451] Step 6: Methyl 2-(6-(difluoromethyl)-5-fluoro-3-methoxypyridin-2-yl)-4-(methyl-d3)benzoate

[0452] 2-Chloro-6-(difluoromethyl)-5-fluoro-3-methoxypyridine (140 mg, 0.66 mmol) was dissolved in 1,4-dioxane (4 mL) and water (0.5 mL). Methyl 4-(methyl-d3)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (203 mg, 0.73 mmol), potassium carbonate (183 mg, 1.32 mmol), and di(tri-tert-butylphosphine)palladium (34 mg, 0.07 mmol) were then added. The mixture was reacted at 100°C for 3 hours. Water (20 mL) was added, and the mixture was extracted three times with ethyl acetate (20 mL). The combined organic phases were washed sequentially with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 0% to 30%) to give methyl 2-(6-(difluoromethyl)-5-fluoro-3-methoxypyridin-2-yl)-4-(methyl-d3)benzoate (150 mg, yield: 62.1%). LCMS calc. for C 16 H 12 D3F3NO3[M+H] + :m / z=329.1;Found:329.1.

[0453] Step 7: 2-(6-(difluoromethyl)-5-fluoro-3-methoxypyridin-2-yl)-4-(methyl-d3)benzoic acid

[0454] Methyl 2-(6-(difluoromethyl)-5-fluoro-3-methoxypyridin-2-yl)-4-(methyl-d3)benzoate (120 mg, 0.37 mmol) was dissolved in methanol (2 mL) and water (0.5 mL), and then sodium hydroxide (88 mg, 2.19 mmol) was added. The reaction was allowed to proceed at 60°C for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, water (20 mL) was added, and the mixture was extracted three times with ethyl acetate (20 mL). 2N dilute hydrochloric acid (20 mL) was added to the aqueous phase to adjust the pH to 6, and the aqueous phase was extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2-(6-(difluoromethyl)-5-fluoro-3-methoxypyridin-2-yl)-4-(methyl-d3)benzoic acid (120 mg, crude product). LCMS calc. for C 15 H10 D3F3NO3[M+H] + :m / z=315.1;Found:315.1.

[0455] Step 8: (S)-2-(6-(difluoromethyl)-5-fluoro-3-methoxypyridin-2-yl)-N-((4-(1-(methoxy-d3)ethyl)benzyl)sulfonyl)-4-(methyl-d3)benzamide

[0456] 2-(6-(Difluoromethyl)-5-fluoro-3-methoxypyridin-2-yl)-4-(methyl-d3)benzoic acid (50 mg, 0.16 mmol) and (S)-(4-(1-(methoxy-d3)ethyl)phenyl)methanesulfonamide (37 mg, 0.16 mmol) were dissolved in dichloromethane (4 mL), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (61 mg, 0.32 mmol) and 4-dimethylaminopyridine (23 mg, 0.19 mmol) were added, and the reaction was carried out at 25°C for 2 hours. After the reaction was completed, 1N dilute hydrochloric acid (10 mL) was added to dilute and adjust the pH to 4. The aqueous phase was extracted three times with dichloromethane (20 mL). The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by preparative high performance liquid chromatography (Gemini-C18 150 x 21.2 mm, 5 μm, Mobile phase: A (0.1% FAin The reaction mixture was purified by adding 4-nitropropane-2-ol (5-nitropropane-2-ol) (5-nitropropane-2-ol, 4-nitropropane-2-ol, 4-nitropropane-2-ol, 2 ... 25 H 20 D6F3N2O5S[M+H] + :m / z=529.1;Found:529.1. 1 HNMR(400MHz,DMSO)δ12.03(s,1H),7.70(d,J=12.1Hz,1H),7.39-7.24(m,7H),7.21- 6.92(m,1H),4.64(s,2H),4.33(q,J=6.4Hz,1H),3.82(s,3H),1.33(d,J=6.4Hz,3H).

[0457] Example 24 Preparation of Compound CPD-24

[0458] Step 1: 2-Fluoro-6-methoxynicotinonitrile

[0459] To a solution of 3-bromo-2-fluoro-6-methoxypyridine (6.0 g, 29.1 mmol) in N,N-dimethylformamide (40 mL) were added zinc cyanide (2.05 g, 14.5 mmol) and tetrakistriphenylphosphine palladium (1.68 g, 1.46 mmol). The reaction mixture was stirred at 130°C under a nitrogen atmosphere for 3 hours. After completion of the reaction, the reaction mixture was poured into water (400 mL) and extracted twice with ethyl acetate (50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 5% to 10%) to provide 2-fluoro-6-methoxynicotinonitrile (3.91 g, yield: 88.3%). 1 H NMR (400MHz, DMSO-d6) δ8.36 (t, J=9.3, 8.5Hz, 1H), 6.99 (d, J=8.5, 1.4Hz, 1H), 3.94 (s, 3H).

[0460] Step 2: 5-Bromo-2-fluoro-6-methoxynicotinonitrile

[0461] To a solution of 2-fluoro-6-methoxynicotinonitrile (2.91 g, 19.1 mmol) and sodium acetate (3.14 g, 38.3 mmol) in acetic acid (10 mL) was added liquid bromine (2.94 mL, 57.4 mmol). The mixture was stirred at 80°C under a nitrogen atmosphere for 48 hours. After completion of the reaction, the reaction solution was poured into a saturated sodium sulfite solution (100 mL), stirred for ten minutes, and then extracted twice with ethyl acetate (30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 5% to 10%) to yield 5-bromo-2-fluoro-6-methoxynicotinonitrile (1.8 g, yield: 40.7%). 1 H NMR (400MHz, DMSO-d6) δ8.80 (d, J=8.0Hz, 1H), 4.01 (s, 3H).

[0462] Step 3: 5-Bromo-2-fluoro-6-methoxynicotinaldehyde

[0463] To a solution of 5-bromo-2-fluoro-6-methoxynicotinonitrile (1.8 g, 7.79 mmol) in dichloromethane (20 mL) at -78°C was added diisobutylaluminum hydride (1.69 mL, 9.35 mmol). The reaction mixture was stirred at -78°C for 1 hour. After completion of the reaction, the reaction mixture was poured into a saturated aqueous ammonium chloride solution (100 mL) and extracted twice with dichloromethane (30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 5% to 10%) to yield 5-bromo-2-fluoro-6-methoxynicotinaldehyde (0.98 g, yield: 53.8%). 1 H NMR (400MHz, DMSO-d6) δ9.98 (s, 1H), 8.47 (d, J = 8.4Hz, 1H), 4.04 (s, 3H).

[0464] Step 4: 3-Bromo-5-(difluoromethyl)-6-fluoro-2-methoxypyridine

[0465] To a solution of 5-bromo-2-fluoro-6-methoxynicotinaldehyde (980 mg, 4.19 mmol) in dichloromethane (10 mL) at 0°C was added diethylaminosulfur trifluoride (2.03 g, 12.6 mmol). The reaction mixture was stirred at 0°C for 3 hours. After the reaction was complete, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (100 mL) and extracted twice with dichloromethane (50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 5% to 10%) to give 3-bromo-5-(difluoromethyl)-6-fluoro-2-methoxypyridine (757 mg, yield: 70.6%). 1 H NMR (400MHz, DMSO-d6) δ8.41 (dt, J=8.4, 0.9Hz, 1H), 7.12 (t, J=54.0Hz, 1H), 3.97 (s, 3H).

[0466] Step 5: Methyl 2-(5-(difluoromethyl)-6-fluoro-2-methoxypyridin-3-yl)-4-(methyl-d3)benzoate

[0467] To a solution of 3-bromo-5-(difluoromethyl)-6-fluoro-2-methoxypyridine (300 mg, 1.17 mmol) in 1,4-dioxane (4 mL) were added bis-pinacol boronate (387 mg, 1.52 mmol), potassium acetate (345 mg, 3.52 mmol), and 1,1'-bis(diphenylphosphinoferrocenepalladium dichloride) (85.8 mg, 0.12 mmol). The reaction mixture was stirred at 90°C under a nitrogen atmosphere for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, and 1,1'-bis(diphenylphosphinoferrocenepalladium dichloride) (85.8 mg, 0.12 mmol), methyl 2-bromo-4-(methyl-d3)benzoate (272 mg, 1.17 mmol), water (1.0 mL), and potassium carbonate (486 mg, 3.52 mmol) were added. The reaction mixture was stirred at 90°C under a nitrogen atmosphere for 1 hour. After the reaction was completed, the reaction solution was concentrated and purified by silica gel column chromatography (ethyl acetate:petroleum ether=5% to 10%) to obtain methyl 2-(5-(difluoromethyl)-6-fluoro-2-methoxypyridin-3-yl)-4-(methyl-d3)benzoate (260 mg, yield: 67.6%). LCMS calc. for C 16 H 12 D3F3NO3[M+H] + :m / z=329.1;Found:329.1.

[0468] Step 6: 2-(5-(difluoromethyl)-6-fluoro-2-methoxypyridin-3-yl)-4-(methyl-d3)benzoic acid

[0469] To a solution of methyl 2-(5-(difluoromethyl)-6-fluoro-2-methoxypyridin-3-yl)-4-(methyl-d3)benzoate (260 mg, 0.79 mmol) in methanol (4.0 mL) were added lithium hydroxide (37.9 mg, 1.58 mmol) and water (1.0 mL). The reaction solution was stirred at 25°C for 1 hour. After the reaction was completed, the reaction solution was poured into water (20 mL). The pH was adjusted to 6 with 1M hydrochloric acid solution. The aqueous phase was extracted twice with ethyl acetate (30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (methanol:dichloromethane = 5% to 10%) to give 2-(5-(difluoromethyl)-6-fluoro-2-methoxypyridin-3-yl)-4-(methyl-d3)benzoic acid (220 mg, yield: 30.9%). LCMS calc.for C 15 H8D3F3NO3[MH] - :m / z=313.1;Found:313.1.

[0470] Step 7: (S)-2-(5-(difluoromethyl)-6-fluoro-2-methoxypyridin-3-yl)-N-((4-(1-(methoxy-d3)ethyl)benzyl)sulfonyl)-4-(methyl-d3)benzamide

[0471] To a solution of 2-(5-(difluoromethyl)-6-fluoro-2-methoxypyridin-3-yl)-4-(methyl-d3)benzoic acid (150 mg, 0.48 mmol) in dichloromethane (5.0 mL) were added (S)-(4-(1-(methoxy-d3)ethyl)phenyl)methanesulfonamide (131 mg, 0.57 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (137 mg, 0.72 mmol), and 4-dimethylaminopyridine (116 mg, 0.95 mmol). The reaction solution was stirred at 25°C for 3 hours. After completion of the reaction, the reaction solution was purified by silica gel column chromatography (methanol:dichloromethane = 5% to 10%) to obtain a crude product. Further preparative high performance liquid chromatography (SHIMADZU Prep C18 10μm 20*250mm Mobile phase: A(0.1% FA in water)B(ACN): 40% B, 0.5-2min: 60% B, 2-4min: 60-75% B, 4-6min: 75% B, 6-7min: 75-95% B, 7-12min: 95% B, 12-12.01min: 95-40% B, 12.01-15.5min: 40% B (Flow=20mL / min)) gave (S)-2-(5-(difluoromethyl)-6-fluoro-2-methoxypyridin-3-yl)-N-((4-(1-(methoxy-d3)ethyl)benzyl)sulfonyl)-4-(methyl-d3)benzamide (18 mg, 14.0%). LCMS calc.for C 25 H 18 D6F3N2O5S[MH] - :m / z=527.2;Found:527.1 1 H NMR (400MHz, DMSO-d6) δ11.87(s,1H),8.01(d,J=9.1Hz,1H),7.37-7.07(m,8H),4.68(s,2H),4.42-4.17(m,1H),3.82(s,3H),1.32(d,J=6.4Hz,3H).

[0472] Biological experiments

[0473] Polθ ATPase activity assay

[0474] The inhibitory effect of the compound of formula (I) on Polθ ATPase activity was detected using ADP-Glo ​​enzyme activity detection reagent (Promega, V9101).

[0475] Compounds were dissolved in 100% DMSO and serially diluted (0.1 μL) into a 384-well plate. The starting and final concentrations were 100 nM, and three-fold dilutions were performed for a total of 10 concentration points in duplicate. 5 μL of purified truncated POLQ-N protein (aa 1-894, N-terminal 6 His tag) was added to each well. After centrifugation at 1000 rpm for 1 minute, the cells were incubated at 25°C for 10 minutes. 5 μL of substrate reaction solution (containing ATP and ssDNA) was added to each well and the cells were reacted at 25°C for 60 minutes. 5 μL of ADP-Glo ​​Reagent was added to each well. After centrifugation at 1000 rpm for 1 minute, the cells were incubated at 25°C for 40 minutes. 10 μL of detection solution was added to each well. After centrifugation at 1000 rpm for 1 minute, the cells were incubated at 25°C for 40 minutes. Fluorescence was read using a microplate reader (BMG, PHERAstar FSX). The final reaction system contains 1 nM POLQ-N enzyme, 50 nM ssDNA (5'-CCAGTGAATTGTTGCTCGGTACCTGCTAAC-3'), 50 μM ATP, and 1% DMSO.

[0476] The inhibition percentage (%) of each concentration of compound was calculated using the RFU value normalized by the control well value in each assay plate, and curve fitting was performed using XLfit. The specific results are shown in Table 1.

[0477] Table 1 Inhibitory activity of compounds on Polθ ATPase

[0478] Ref.1 is Selected from WO 2023233295 Al.

[0479] *+ refers to IC 50 ≤2nM,++ means 2nM <IC 50 ≤10nM,+++ means 10nM <IC 50 ≤100nM,++++ means 100nM <IC 50 ≤1000nM.

[0480] The specific values ​​of the inhibitory activity of the compounds in Table 1 against Polθ ATPase are as follows:

[0481] The above data show that the compounds of the present invention have good inhibitory activity against Polθ ATPase, especially some compounds have better inhibitory activity against Polθ ATPase than compound Ref.1.

[0482] DLD-1BRCA2 - / -Cell proliferation assay:

[0483] The CellTiter-Glo (CTG) method was used to evaluate the effects of compounds on the human colorectal adenocarcinoma cell line DLD-1BRCA2 - / - anti-proliferative effect.

[0484] Instruments and equipment:

[0485] Reagents and consumables:

[0486] DLD-1 (purchased from ATCC, product number: CCL-221, batch number: 70033255)

[0487] RPMI1640 (purchased from Invitrogen, cat. no.: 11875-085)

[0488] 0.25% Trypsine-EDTA (purchased from Invitrogen, cat. no.: 25200-072)

[0489] Penicillin-Streptomycin solution (purchased from Hyclone, product number: SV30010)

[0490] FBS (purchased from BI, product number: 04-002-1A)

[0491] DMSO (purchased from Sigma, product number: D4540-1L)

[0492] 96-well plate (purchased from Corning, catalog number: CLS3903)

[0493] CellTiter-Glo reagent (purchased from Promega, product number: G7558)

[0494] Experimental methods:

[0495] The antiproliferative effect of the compound on human colorectal adenocarcinoma cell lines was evaluated by ATP quantification, and the activity was well correlated with the number of viable cells. - / -The cells were cultured in RPMI 1640 (Invitrogen, 11875-085) medium supplemented with 10% (v / v) fetal bovine serum (BI, 04-002-1A). Cell lines were cultured according to the standard instructions of the American Type Culture Collection. Cell lines were authenticated by their short tandem repeat profiles.

[0496] In the proliferation experiment, collect the cells and resuspend them in cell culture medium. Use a cell counter to determine the cell density. Pipette an appropriate amount of cell suspension from the centrifuge tube to prepare the seed plate working solution (DLD-1BRCA2 - / - Cell line 150 cells / 100 μL). 100 μL of cell suspension was plated in each well of a 96-well plate (Corning, 3603) and incubated overnight in an incubator. The diluted test compound solution was added to the well plate. Fresh culture medium was replaced and the compound was re-treated on the fourth and seventh days of incubation, for a total incubation time of 10 days. After the incubation, the cell culture plate was removed and equilibrated to room temperature. 100 μL of CellTiter-Glo (Promega, G7558) was added to each well and incubated at room temperature for 30 minutes. The data on the plate was read using a microplate reader in 96-well Luminescence mode (Perkinelme, Enspire). Data analysis, curve fitting, and reporting were performed using the Dose-response one-site 205 model of IDBS XLfit. Specific results are shown in Table 2.

[0497] Table 2: Effects of compounds on DLD1 BRCA2 - / - Cell proliferation inhibitory activity

[0498] The above data show that the compounds of the present invention have an effect on DLD-1BRCA2 - / - It has good inhibitory activity on cell proliferation.

[0499] TMEJ reporter experiments:

[0500] Compounds were evaluated for their inhibitory effects on theta-mediated end joining (TMEJ) process.

[0501] Experimental instruments:

[0502] Experimental Materials:

[0503] Experimental methods:

[0504] 1) HEK293T cells were cultured in DMEM supplemented with 10% heat-inactivated fetal bovine serum (FBS) and 1% penicillin-streptomycin (PS).

[0505] 2) Before starting, sterilize the Neon transfection system and equilibrate the E2 and R buffers to room temperature.

[0506] 3) Preheat the culture medium without antibiotics.

[0507] 4) The cells in the flask with a confluence of 80-90% were treated with trypsin, neutralized with culture medium, centrifuged, and counted.

[0508] 5) Take 2×10 6 The cells were transfected with a 100 μL electroporation pipette tip and washed with DPBS (without Mg). 2+ and Ca 2+ ) Wash once, centrifuge at 1000 rpm for 5 min, and discard the supernatant. Increase the number of cells and volume as needed.

[0509] 6) Set up the neon tube system, insert the neon tube into the neon tube pipette, and add E2 buffer.

[0510] 7) Add 10 μg of TMEJ substrate to 100 μl of R solution. Increase the volume as needed.

[0511] 8) Resuspend the cells in DNA buffer and start electroporation using the following parameters:

[0512] 9) Place the cells in culture medium without antibiotics and mix gently

[0513] 10) Repeat steps 8)-9) as needed and seed the cells into a 384-well plate at 40,000 cells / well in 40 μl of culture medium.

[0514] 11) Culture in a 37°C humidified CO2 incubator for 24 hours.

[0515] 12) Warm the NanoGlo reagent to room temperature and mix the NanoGlo buffer with the substrate at a ratio of 50:1.

[0516] 13) The cell culture plate was equilibrated at room temperature for 10 minutes.

[0517] 14) Add 40 μL of NanoGlo substrate buffer to each well and shake at 300 rpm for 3 minutes in the dark.

[0518] 15) Read the signal via BMG PHERAstar FSX.

[0519] See Table 3 for specific results.

[0520] Table 3: Inhibitory activity of compounds on theta-mediated end joining (TMEJ) process in HEK293T cells

[0521] The above data show that the example compounds of the present invention have good inhibitory activity on the Theta-mediated end-joining (TMEJ) process in HEK293T cells and are superior to the reference compound Ref.1.

[0522] Thermodynamic solubility determination:

[0523] Experimental Materials

[0524] 1.) The control compound, diclofenac sodium, was purchased from Sigma.

[0525] 2.) FaSSIF, FeSSIF & FaSSGF (FFF02) powders were purchased from Biorelevant.

[0526] 3. 1.5 mL flat-bottom glass vials (purchased from a local supplier); Teflon / silicone stoppers (BioTech Solutions); Teflon-coated stir bars (V&P Scientific); MultiScreen HTS HV (0.45 μm) 96-well plates (Millipore, MSHVN4510 or MSHVN4550); Eppendorf Thermomixer Comfort; and Vacuum Manifold ORVMN96 (Orochem).

[0527] Experimental methods:

[0528] 1) Configure FaSSIF

[0529] a. Configure buffer A

[0530] Dissolve 0.420 g of NaOH, 3.438 g of NaH2PO4, and 6.186 g of NaCl in approximately 900 mL of ultrapure water and adjust the pH of the solution to 6.5 with 1 N NaOH or 1 N HCl. Then dilute the solution to 1000 mL with ultrapure water at room temperature.

[0531] b. Add powder

[0532] Add 2.240 g of FaSSIF, FeSSIF, and FaSSGF powder to approximately 500 mL of Buffer A. Stir until the powder is completely dissolved. Then, dilute the solution to 1000 mL with Buffer A at room temperature.

[0533] c. Prepare for use

[0534] Let the solution sit for 2 hours. It will become slightly milky and ready to use. Note: Use within 48 hours at room temperature and within 24 hours at 37°C.

[0535] 2) Test and control compounds were weighed out to measure solubility (approximately 1.0 mg each in three separate 1.5 mL glass vials).

[0536] 3) For each compound, one vial was used as a standard and the other two vials were used to measure solubility in duplicate.

[0537] 4) Place each compound into its appropriate 96-well plate in order. One plate is used as a standard and the other plate is used as a sample.

[0538] 5) Use a pipette to add an appropriate volume (approximately 1000 μL) of FaSSIF to each vial of the solubility plate, based on the mass of sample in each vial. Place a stir bar in each vial and seal with a Teflon / silicone stopper.

[0539] 6) Transfer the solubility sample plate to an Eppendorf Thermomixer Comfort shaker and shake at 37°C and 1100 rpm for 24 hours.

[0540] 7) After 24 hours, remove the stopper, then use a large magnet to remove the stir bar and transfer the sample from the solubility sample plate to the filter plate. Filter the sample using a vacuum pump. Dilute the filtrate 1000-fold with a mixture of water and acetonitrile (1:1 by volume) (take 5 μL of sample from the filtrate to a new plate, then add 5 μL of DMSO and 490 μL of a mixture of water and acetonitrile (1:1 by volume), mix thoroughly, then take 50 μL of sample from the diluted sample to a new plate, then add 450 μL of a mixture of water and acetonitrile (1:1 by volume)). Transfer 200 μL of the diluted sample to a new 96-well plate for LC-MS / MS analysis. The dilution factor can vary depending on the solubility value and LC-MS signal response.

[0541] 8) For the standards, dissolve each standard to a concentration of 1.0 mg / mL based on the mass of sample in each vial on the standards plate. Use a pipette to add the appropriate volume of DMSO to each standard vial.

[0542] 9) Cover the standard vial with a 96-well plate lid, place the standard plate in an Eppendorf Thermomixer Comfort, and shake at 1100 rpm at 25°C for 5 minutes.

[0543] 10) After 5 minutes, each compound should be completely dissolved.

[0544] 11) From the 1.0 mg / mL DMSO standard plate, transfer 5 μL to a new plate. Then, add 5 μL of FaSSIF and 490 μL of a 1:1 water / acetonitrile mixture to a 10 μg / mL concentration of the standard. From the 10 μg / mL standard plate, transfer 50 μL to a new plate. Add 450 μL of a 1:1 water / acetonitrile mixture to a 1 μg / mL concentration of the standard. Transfer 200 μL of this diluted sample to a new 96-well plate for LC-MS / MS analysis. The concentration of the standard can be varied based on the LC-MS signal response.

[0545] 12) The solubility sample plate and standard plate were placed in an autosampler at 4°C and evaluated by LC-MS / MS analysis.

[0546] Data Analysis:

[0547] All calculations were performed using Microsoft Excel. The analysis and quantification of the sample filtrate were performed by qualitative and quantitative analysis of the known concentrations of the standard peak using a liquid chromatography mass spectrometer. The solubility values ​​of the control drug and the test substance were calculated as follows:

[0548] DF refers to the dilution factor.

[0549] See Table 4 for specific results.

[0550] Table 4: Thermodynamic solubility of compounds

[0551] The above data show that the thermodynamic solubility of the example compounds of the present invention is significantly better than that of the reference compound Ref.1.

[0552] Pharmacokinetic studies in rats:

[0553] 1. Experimental purpose: To test the pharmacokinetics of the compound in Wistar-Han rats.

[0554] 2. Experimental instruments and materials:

[0555] Animals: Wistar-Han rats (male)

[0556] instrument:

[0557] Reagents:

[0558] Solvent:

[0559] Oral gavage: 1% methyl cellulose aqueous solution.

[0560] 3. Experimental methods:

[0561] Six male rats were enrolled. They were fasted in the evening before dosing and had free access to water. Mice were allowed to eat and drink freely during the experimental process. The animals were administered intravenously or orally. After administration, the animals were observed and any abnormalities were recorded. Blood was collected by jugular vein puncture at 0.0833, 0.25, 1, 2, 4, 8, and 24 hours after intravenous injection; and by jugular vein puncture at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after oral gavage. A 50 μL plasma sample was collected, and 500 μL of acetonitrile (containing dexamethasone as an internal standard) was added to precipitate the protein. The sample was centrifuged at 4000 rpm for 20 minutes at 4°C. 300 μL of the supernatant was mixed with 300 μL of Watson's aqueous solution in a 96-well plate. Another 5 μL sample was collected for LC-MS / MS analysis.

[0562] 4. Data processing methods and results:

[0563] The internal standard method was used to establish a standard curve, with the theoretical standard curve concentration as the horizontal axis and the peak area ratio as the vertical axis (test compound peak area / internal standard peak area). Linear regression was used (weighting factor 1 / X2), with R2>0.9900. Unknown samples were calculated using the standard curve. Pharmacokinetic parameters were calculated using the non-compartmental analysis model of WinNonlin 8.2 software and presented in the report, including T 1 / 2 , Tmax, Cmax and AUC, etc.

[0564] See Table 5 for specific results.

[0565] Table 5: Compound PK in rats

[0566] The compounds of the present invention showed a higher exposure in rats, and their AUC was significantly better than that of the prodrug compound Example 1 reported in patent WO 2023233295 Al (AUC 0-t 8.5ug*hr / mL).

[0567] Example 1 is Selected from WO 2023233295 Al.

Claims

1. A compound as represented by formula (I), its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt, characterized in that: The compound of formula (I) is selected from the following structures: in, X 1 is CH or N; Ring A is phenyl or a six-membered heteroaryl group containing 1 to 3 N atoms; m is 0, 1, 2, 3 or 4; Each R 1 Each is independently selected from deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyloxy, halogenated C1-C6 alkoxy, deuterated C1-C6 alkoxy, hydroxyl, cyano, C2-C6 alkynyl, -NR 1x R 1y ; R 1x and R 1y Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; R 2 Selected from hydrogen, cyano, hydroxyl, -NR 2x R 2y 、-CONR 2x R 2y 、-NR 2x COR 2y , C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group A, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group A, C2-C6 alkenyl which is unsubstituted or substituted by one or more substituents selected from Group A, C2-C6 alkynyl which is unsubstituted or substituted by one or more substituents selected from Group A, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group A, C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group A, 5-6 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A; The substituents of group A include: oxo, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from group A1, C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from group A1, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from group A1, 5-6 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from group A1, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyloxy, halogenated C1-C6 alkoxy, deuterated C1-C6 alkoxy, hydroxyl, cyano, -NR 3x R 3y 、-CONR 3x R 3z 、-NR 3x COR 3z ; The substituents of the A1 group include: halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy; R 2x , R 2y , R 3x , R 3y and R 3z Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl; or R 2x and R 2y and the N atoms connected to them together constitute a 4-6 membered heterocyclic group containing 1-2 N atoms; the 4-6 membered heterocyclic group may be unsubstituted or substituted by one or more selected from oxo, C1-C6 alkyl, C3-C6 cycloalkyl, hydroxyl, amino, halogen, cyano; or R 3x and R 3y and the N atoms connected to them together form a 4-6 membered heterocyclic group containing 1-2 N atoms; the 4-6 membered heterocyclic group may be unsubstituted or selected from oxo, C1-C6 alkyl, C3-C6 cycloalkyl, hydroxyl, amino, halogen, cyano or more than one; R 3 For -(CR4R5) n R 6 ; R 4 and R 5 Each is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl; n is 0, 1, 2 or 3; R 6 is C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group B, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group B, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group B, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group B, C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group B; The substituents of Group B include: oxo, deuterium, halogen, hydroxyl, cyano, mercapto, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group C, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group C, -(CH2) i NR 7 R 8 、-(CH2) i CONR 7 R 8 、-(CH2) i NR 7 CO-R 8 、-(CH2) i S02R 7 、-(CH2) i SO2NR 7 R 8 、-(CH2) i OR 7 , C6-C10 aryl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl; i is 0, 1, 2, or 3; R 7 and R 8 Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl; The substituents of group C include: deuterium, halogen, hydroxyl, cyano, amino, C1-C6 alkoxy, C3-C6 cycloalkyl, deuterated C1-C6 alkoxy; The heteroatoms in the 3-8 membered heterocyclic group, 5-10 membered heteroaryl group and 5-6 membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S.

2. The compound of formula (I) according to claim 1, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, characterized in that: Ring A is phenyl or pyridyl.

3. The compound of formula (I) according to claim 1, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, characterized in that: for Among them, W 1 , W 2 , W 3 , W 4 independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyloxy, halogenated C1-C6 alkoxy, deuterated C1-C6 alkoxy, hydroxy, cyano, C2-C6 alkynyl, -NR 1x R 1y ; R 1x and R 1y Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; Preferably, for W 1 , W 2 , W 3 independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, deuterated C1- C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C1-C6 alkoxy, deuterated C1-C6 alkoxy, hydroxy, cyano, C2-C6 alkynyl, -NR 1x R 1y ; R 1x and R 1y Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, or C3-C6 cycloalkyl.

4. The compound of formula (I) according to claim 1, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, characterized in that: for Preferably, for 5. The compound of formula (I) according to claim 1, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, characterized in that: R 2 C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group A, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group A, C2-C6 alkynyl which is unsubstituted or substituted by one or more substituents selected from Group A, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group A, C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group A, 5-6 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A; The substituents of group A include: oxo, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from group A1, C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from group A1, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from group A1, 5-6 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from group A1, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, C3-C6 cycloalkyloxy, halogenated C1-C6 alkoxy, hydroxyl, cyano, -NR 3x R 3y 、-CONR 3x R 3z 、-NR 3x COR 3z ; The substituents of the A1 group include: halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy; R 3x , R 3y and R 3z Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl; or R 3x and R 3y and the N atoms connected to them together constitute a 4-6 membered heterocyclic group containing 1-2 N atoms; the 4-6 membered heterocyclic group may be unsubstituted or substituted by one or more selected from oxo, C1-C6 alkyl, C3-C6 cycloalkyl, hydroxyl, amino, halogen, and cyano.

6. The compound of formula (I) according to claim 1, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, characterized in that: R 2 C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group A, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group A, C2-C6 alkynyl which is unsubstituted or substituted by one or more substituents selected from Group A, in, The substituents of group A include: deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from group A1, C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from group A1, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from group A1, 5-6 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from group A1, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, C3-C6 cycloalkyloxy, halogenated C1-C6 alkoxy, hydroxyl, cyano, -NR 3x R 3y 、-CONR 3x R 3z 、-NR 3x COR 3z ; The substituents of the A1 group include: halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy; R 3x , R 3y and R 3z Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl; or R 3x and R 3y and the N atoms connected to them together constitute a 4-6 membered heterocyclic group containing 1-2 N atoms; the 4-6 membered heterocyclic group may be unsubstituted or substituted by one or more selected from oxo, C1-C6 alkyl, C3-C6 alkyl, hydroxyl, amino, halogen, cyano; R a is selected from hydrogen, halogen, hydroxy, amino, cyano, C1-C6 alkyl, halogenated C1-C6 alkoxy, C1-C6 alkoxy; p is 1, 2 or 3.

7. The compound of formula (I) according to claim 1, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, characterized in that: R 2 is selected from C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxy substituted C1-C6 alkyl, in, R a is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy; p is 1, 2 or 3; R 3x H, C1-C6 alkane C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl.

8. The compound of formula (I) according to claim 1, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, characterized in that: R 2 Selected from methyl, methoxy, -CF3, -CD3, -CH2CF3, -CH2OCH3, 9. The compound of formula (I) according to claim 1, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, characterized in that: R 3 -(CH2) n R 6 ; n is 0, 1, 2 or 3; R 6 is a 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group B, a 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group B, a C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group B, or a C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group B; The substituents of Group B include: oxo, deuterium, halogen, hydroxyl, cyano, mercapto, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group C, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group C, -(CH2) i NR 7 R 8 、-(CH2) i CONR 7 R 8 、-(CH2) i NR 7 CO-R 8 、-(CH2) i S02R 7 、-(CH2) i SO2NR 7 R 8 、-(CH2) i OR 7 ; i is 0, 1, 2, or 3; R 7 and R 8 Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl; The substituents of group C include: deuterium, halogen, hydroxyl, cyano, amino, C1-C6 alkoxy, C3-C6 cycloalkyl, deuterated C1-C6 alkoxy; The heteroatoms in the 5-10 membered heteroaryl and 5-6 membered heteroaryl are independently selected from 1, 2 or 3 of N, O and S.

10. The compound of formula (I) according to claim 1, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, characterized in that: R 3 Selected from -C1-C3 alkyl, 11. The compound of formula (I) according to claim 1, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, characterized in that: The compound of formula (I) is selected from the following structures: in, R a Selected from hydrogen, halogen, hydroxy, amino, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy; R b C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group A, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group A; the substituents of Group A include: deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, deuterated C1-C6 alkoxy, hydroxyl, cyano, amino, -CONR 3x R 3z 、-NR 3x COR 3z , a 5-6 membered heteroaryl group which is unsubstituted or substituted by a C1-C6 alkyl group; Ring A, R 1 , R 3 , R 3x , R 3z The definitions of m and m are the same as those in claim 1.

12. The compound of formula (I) according to claim 1, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, characterized in that: The compound of formula (I) is selected from the following structures: in, R b C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group A, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group A; the substituents of Group A include: deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, deuterated C1-C6 alkoxy, hydroxyl, cyano, amino, -CONR 3x R 3z 、-NR 3x COR 3z , a 5-6 membered heteroaryl group which is unsubstituted or substituted by a C1-C6 alkyl group; R 3x and R 3z Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl; R 3 For -(CR4R5) n R 6 ; R 4 and R 5 Each is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl; n is 0, 1, 2 or 3; R 6 is C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group B, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group B, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group B, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group B, C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group B; The substituents of Group B include: oxo, deuterium, halogen, hydroxyl, cyano, mercapto, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group C, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group C, -(CH2) i NR 7 R 8 、-(CH2) i CONR 7 R 8 、-(CH2) i NR 7 CO-R 8 、-(CH2) i S02R 7 、-(CH2) i SO2NR 7 R 8 、-(CH2) i OR 7 , C6-C10 aryl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl; i is 0, 1, 2, or 3; R 7 and R 8 Each is independently H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; The substituents of group C include: deuterium, halogen, hydroxyl, cyano, amino, C1-C6 alkoxy, C3-C6 cycloalkyl, deuterated C1-C6 alkoxy; The heteroatoms in the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S.

13. The compound of formula (I) according to claim 12, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, characterized in that: R b C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group A, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group A; the substituents of Group A include: deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, hydroxyl, cyano, amino, -CONR 3x R 3z 、-NR 3x COR 3z , a 5-6 membered heteroaryl group which is unsubstituted or substituted by a C1-C6 alkyl group; R 3x and R 3z Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl; R 3 For -(CR4R5) n R 6 ; R 4 and R 5 Each is independently selected from hydrogen, deuterium, halogen, methyl; n is 0, 1, 2 or 3; R 6 is C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group B, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group B, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group B, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group B, C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group B; The substituents of Group B include: oxo, deuterium, halogen, hydroxyl, cyano, mercapto, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group C, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group C, -(CH2) i NR 7 R 8 、-(CH2) i CONR 7 R 8 、-(CH2) i NR 7 CO-R 8 、-(CH2) i S02R 7 、-(CH2) i SO2NR 7 R 8 、-(CH2) i OR 7 ; i is 0, 1, 2, or 3; R 7 and R 8 Each is independently H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; The substituents of group C include: deuterium, halogen, hydroxyl, cyano, amino, C1-C6 alkoxy, C3-C6 cycloalkyl, deuterated C1-C6 alkoxy; The heteroatoms in the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S.

14. The compound of formula (I) according to claim 12, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, characterized in that: R b C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group A, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group A; the substituents of Group A include: deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, -CONR 3x R 3z 、-NR 3x COR 3z , a 5-6 membered heteroaryl group which is unsubstituted or substituted by a C1-C6 alkyl group; R 3x and R 3z Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl; R 3 -(CH2) n R 6 ; n is 0, 1 or 2; R 6 is C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group B, 3-6 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group B, 6-membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group B, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group B, phenyl which is unsubstituted or substituted by one or more substituents selected from Group B; The substituents of Group B include: deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, deuterated C1-C6 alkoxy, amino, -(CH2) i OR 7 The substituents of group C include: deuterium, halogen, hydroxyl, cyano, amino, C1-C6 alkoxy, C3-C6 cycloalkyl, deuterated C1-C6 alkoxy; i is 1 or 2; R 7 is a halogenated C1-C6 alkyl group; The heteroatoms in the 3-6 membered heterocyclic group and the 6-membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S.

15. The compound of formula (I) according to claim 12, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, characterized in that: R b C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group A, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group A; the substituents of Group A include: deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, -CONR 3x R 3z 、-NR 3x COR 3z ; R 3x and R 3z Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl; R 3 -(CH2) n R 6 ; n is 0 or 1; R 6 is C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group B, 3-6 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group B, 6-membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group B, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group B, phenyl which is unsubstituted or substituted by one or more substituents selected from Group B; The substituents of Group B include: deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, The heteroatoms in the 3-6 membered heterocyclic group and the 6-membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S.

16. The compound of formula (I) according to any one of claims 1 to 10, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, characterized in that: The compound of formula (I) is selected from the following structures: in, X 1 and Y are each independently N or CH; R 4a and R 5a Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl; s is 0, 1, 2, 3, or 4; Each R c independently selected from deuterium, halogen, hydroxyl, cyano, mercapto, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group C, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group C, -(CH2) i NR 7 R 8 、-(CH2) i CONR 7 R 8 、-(CH2) i NR 7 CO-R 8 、-(CH2) i S02R 7 、-(CH2) i SO2NR 7 R 8 、-(CH2) i OR 7 ; i is 0, 1, 2, or 3; R 7 and R 8 Each is independently H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; The substituents of group C include: deuterium, halogen, hydroxyl, cyano, amino, C1-C6 alkoxy, C3-C6 cycloalkyl, deuterated C1-C6 alkoxy; R 2 The definition is the same as that of the corresponding claims.

17. The compound of formula (I) according to claim 16, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, characterized in that: The compound of formula (I) is selected from the following structures: in, X 1 and Y are each independently N or CH; preferably, X 1 is CH, Y is N; R c selected from halogen, hydroxyl, cyano, mercapto, C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group C, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group C, -(CH2) i OR 7 ; i is 0, 1, 2, or 3; R 7 and R 8 Each is independently H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; The substituents of group C include: deuterium, halogen, hydroxyl, cyano, amino, C1-C6 alkoxy, C3-C6 cycloalkyl, deuterated C1-C6 alkoxy; R 2 The same definition as in claim 16; preferably, R 2 It is CH3 or CD3.

18. The compound of formula (I) according to claim 1, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) is selected from the following compounds:

19. A pharmaceutical composition comprising a compound of formula (I) as described in any one of claims 1 to 18, its isotope-labeled substance, enantiomer, diastereomer, solvate or a pharmaceutically acceptable salt thereof and a pharmaceutical excipient.

20. Use of a compound of formula (I) as described in any one of claims 1 to 18, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt in the preparation of a DNA polymerase θ inhibitor or a drug; the drug is a drug for treating and / or preventing a disease by inhibiting DNA polymerase θ.

21. Use of a compound of formula (I) as described in any one of claims 1 to 18, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt in the preparation of a drug for treating and / or preventing cancer.

22. A method for treating and / or preventing cancer, characterized in that: The method comprises administering to the patient a therapeutically effective amount of a compound of formula (I) as described in any one of claims 1 to 18, an isotope-labeled substance, an enantiomer, a diastereomer, a solvate or a pharmaceutically acceptable salt thereof.

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