Heterocyclic amide derivatives and pharmaceutical use thereof

Abstract

This invention relates to the field of pharmaceutical technology, specifically to Polθ inhibitors, their preparation methods, and their applications in medicine. This invention provides a Polθ inhibitor of formula (Ia) or (Ib), a composition thereof, and its uses. This compound can be used to treat or prevent Polθ-mediated diseases or conditions and related diseases or conditions.

Description

[Technical Field]

[0001] This invention relates to the field of pharmaceutical technology, and more specifically to a heterocyclic amide compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof, and its use in the preparation of medicaments for treating related diseases. [Previous Technology]

[0002] Common forms of DNA damage include single-strand breaks, double-strand breaks (DSBs), and base damage, among which DSB damage is the most serious. If DSBs are not repaired in time, chromosomes will exhibit abnormalities such as breaks, deletions, and rearrangements. Therefore, timely repair of DSBs plays an important role in maintaining genome stability, ensuring cell survival, and inhibiting tumor development and progression. Double-stranded DNA break repair can be broadly categorized into three main pathways: homologous recombination (HR), a repair process that uses homologous double-stranded DNA as a template to synthesize DNA, offering high fidelity and a low mismatch repair rate; non-homologous end joining (NHEJ), which directly joins the damaged ends of the broken double-stranded DNA by capturing the damaged ends and utilizing protein interactions, but is an error-prone repair process; and microhomology-mediated end joining (MMEJ), a more widespread and error-prone end-joining mechanism, also known as alternative end-joining (ALT-EJ), driven by the annealing of microhomological sequences at the DNA ends.

[0003] Under normal circumstances, homologous recombination repair (MMEJ) occurs at a very low rate as a substitute for HR repair. However, in HR-deficient cells, MMEJ becomes the main DSB repair pathway. For example, in cancer cells with BRCA gene defects, HR repair is impaired, and MMEJ becomes the main DSB repair pathway. DNA polymerase θ (Polθ) plays a crucial role in this process. Polθ replaces RPA at the excised DSB site to promote the annealing of microhomologous ssDNA, subsequently synthesizing DNA to fill the excised gap and complete the ligation of the damaged ends. Polθ is almost not expressed in normal tissues, but is highly expressed in various tumor types (such as breast cancer, ovarian cancer, colorectal cancer, and lung cancer), and its upregulation is associated with poor cancer prognosis. Homologous recombination deficiency (HRD) is prevalent in these tumors, with the loss of tumor suppressor genes related to DNA repair (including BRCA1, BRCA2, ATM, and FANCD2).

[0004] Research on Polθ provides a new targeted strategy for cancer treatment. In cancer cells with damaged or inactivated HR and NHEJ, DSB repair is highly dependent on the MMEJ process. If Polθ activity is inhibited, cells will lose the ability to perform MMEJ, preventing timely DSB repair and leading to cancer cell death over time. Therefore, for cancer patients carrying HRD (e.g., BRCA1 / 2 mutations), Polθ inhibitors can be used in combination with PARP inhibitors to achieve a synergistic tumor-killing effect. In addition, patients receiving PARP inhibitor maintenance therapy may develop resistance, possibly due to gene mutations that partially restore HR pathway activity, such as the loss of TP53BP1. In this case, HR repair mainly occurs through Polθ-dependent MMEJ. Therefore, Polθ inhibitors can also overcome resistance to PARP inhibitors, bringing benefits to more patients.

[0005] In summary, Polθ inhibitors can provide a new strategy for targeted therapy of tumors with homologous recombination repair defects, representing a significant unmet clinical need. Developing novel and highly effective Polθ inhibitors has immense scientific research significance and clinical value. The purpose of this invention is to provide a novel heterocyclic amide derivative and its uses. The described compound exhibits excellent Polθ inhibitory activity and can be used as a Polθ inhibitor for the treatment of related tumors or cancers. [Summary of the Invention]

[0006] The technical problem to be solved by the present invention is to provide a novel heterocyclic amide compound, which can be used as a Polθ inhibitor for the preparation of drugs for treating Polθ-mediated diseases or symptoms and related diseases or symptoms. To solve the above technical problem, the technical solution provided by the present invention is as follows:

[0007] A heterocyclic amide compound is a compound, isomer, or pharmaceutically acceptable salt thereof having the following general structural formula (I): wherein: ring C is selected from; U', V', Z', W' are each independently selected from, and at least one of U', V', Z', W' is selected from; Rv, Rw, Rx are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 alkylthio, substituted or unsubstituted C1-6 alkylamine, substituted or unsubstituted 4-10 membered heterocyclic, substituted or unsubstituted 5-14 membered heteroaryl, substituted or unsubstituted C6-12 aryl; when C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylthio, C1-6 alkylamine, 4-10 membered heterocyclic, 5 When a -14-membered heteroaryl or C6-12 aryl group has substituents, it may be substituted by at least one of the following groups: deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C1-6 alkylthio, substituted or unsubstituted C1-6 alkylthio. Substituted or unsubstituted C1-6 alkylamino, substituted or unsubstituted C1-6 alkylester, substituted or unsubstituted C1-6 alkylacryl, substituted or unsubstituted C1-6 alkylacrylamino, substituted or unsubstituted C1-6 alkylsulfonyl, substituted or unsubstituted C1-6 alkylsulfonylamino, substituted or unsubstituted C1-6 phosphatidyl, substituted or unsubstituted 3-8 membered heterocyclic, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C6-14 aryl;Furthermore, when C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamine, C1-6 alkylesteryl, C1-6 alkylacrylyl, C1-6 alkylacrylamide, C1-6 alkylsulfonyl, C1-6 alkylsulfonamide, C1-6 phosphatyl, 3-8 membered heterocyclic, 5-10 membered heteroaryl, or C6-14 aryl have substituents, it can be at least as follows: Substitution of the following groups: deuterium, halogen, cyano, nitro, hydroxyl, amino, mercapto, oxo, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C1-6 alkylthio, substituted or unsubstituted C1-6 alkylamine, substituted or unsubstituted C1-6 alkylester, etc. Substituted or unsubstituted C1-6 alkylamide, substituted or unsubstituted C1-6 alkylsulfonyl, substituted or unsubstituted C1-6 alkylsulfonylamine, substituted or unsubstituted C1-6 phospholipid, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted 5-14 membered heteroaryl, substituted or unsubstituted C6-12 aryl; furthermore, when C1-6 alkyl, C2-6 alkenyl, C2-6 ynynyl, C3-6 cyclic When alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C1-6 alkylester, C1-6 alkylacryl, C1-6 alkylacrylamide, C1-6 alkylsulfonyl, C1-6 alkylsulfonylamide, C1-6 phospholipid, 3-8 membered heterocyclic, 5-14 membered heteroaryl, and C6-12 aryl are present with substituents, they may be substituted by at least one of the following groups: deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, and C1-6 alkyl. Ry and Rz are interconnected with a common carbon atom to form a 3-8 membered aliphatic ring or heterocycle, wherein the aforementioned aliphatic ring or heterocycle may be substituted with at least one of the following groups: deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamine, 4-10 membered heterocyclic group, 5-14 membered heteroaryl, or C6-12 aryl; n1 is selected from 0, 1, 2, or 3; X', Ya, and Yb are each independently selected from N or CR1a;R1a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C1-6 alkylthio, substituted or unsubstituted C1-6 alkylamine, substituted or unsubstituted C1-6 alkylester, substituted or unsubstituted C1-6 alkylamide, substituted or unsubstituted C1-6 alkylsulfonyl, substituted or unsubstituted C1-6 alkylsulfonylamide, substituted or unsubstituted C1-6 alkylsulfonylamide, substituted or unsubstituted The C1-6 phosphatyl group, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted 5-10 membered heteroaryl group, and substituted or unsubstituted C6-14 aryl group; when the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylazyl, C1-6 alkylthio, C1-6 alkylamine, C1-6 alkylesteryl, C1-6 alkylpyridyl, C1-6 alkylpyridinyl, C1-6 alkylsulfonyl, C1-6 alkylsulfoninyl, C1-6 phosphatyl, 3-8 membered heterocyclic group, 5-10 membered heteroaryl group, and C6-14 aryl group have substituents, they may be substituted by at least one of the following groups: deuterium, halogen, cyano, nitro, hydroxyl, or ammonia. alkyl, mercapto, oxo, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C1-6 alkylthio, substituted or unsubstituted C1-6 alkylamine, substituted or unsubstituted C1-6 alkylester, substituted or unsubstituted C1-6 alkylamide, substituted or unsubstituted C1-6 alkylsulfonyl, substituted or unsubstituted C1-6 alkylsulfonylamide, substituted or unsubstituted C1-6 phospholipid, substituted or unsubstituted 3- The 8-membered heterocyclic group, substituted or unsubstituted 5-14-membered heteroaryl group, substituted or unsubstituted C6-12 aryl group; furthermore, when the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylenyl, C1-6 alkylthio, C1-6 alkylamine, C1-6 alkylesteryl, C1-6 alkylacrylyl, C1-6 alkylsulfonyl, C1-6 alkylsulfonylamine, C1-6 phospholipidyl, 3-8-membered heterocyclic group, 5-14-membered heteroaryl group, and C6-12 aryl group have substituents, they can be substituted by at least one of the following groups: deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, and C1-6 alkyl. Ring B is a 3-18 membered heterocyclic group, a 5-10 membered heteroaryl group, a C6-14 aryl group, or a 4-10 membered cycloalkenyl group;When ring B has substituents, it can be substituted by at least one of the following groups: deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C1-6 alkylthio, substituted or unsubstituted C1-6 alkylamine, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C1-6 alkylesteryl, substituted or unsubstituted C1-6 alkylacrylyl, substituted or unsubstituted C1-6 alkyl The C1-6 alkylsulfonyl group, substituted or unsubstituted C1-6 alkylsulfonyl group, substituted or unsubstituted C1-6 alkylsulfonyl group; when the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylenyl, C1-6 alkylthio, C1-6 alkylamine, 3-8 membered heterocyclic group, C1-6 alkylesteryl, C1-6 alkylamide, C1-6 alkylsulfonyl, C1-6 alkylsulfonyl group, C1-6 alkylsulfonyl group are substituents, they may be substituted by at least one of the following groups: deuterium, halogen, cyano, nitro, hydroxyl, amino, mercapto, oxo, substituted or unsubstituted C1-6 alkyl ... Substituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C1-6 alkylthio, substituted or unsubstituted C1-6 alkylamine, substituted or unsubstituted C1-6 alkylester, substituted or unsubstituted C1-6 alkylacryl, substituted or unsubstituted C1-6 alkylacrylamine, substituted or unsubstituted C1-6 alkylsulfonyl, substituted or unsubstituted C1-6 alkylsulfonylamine, substituted or unsubstituted C1-6 phospholipid, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted 5-14-membered heteroaryl, substituted or unsubstituted C6-12 aryl; furthermore, when C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamine, C1-6 alkylesteryl, C1-6 alkylacryl, C1-6 alkylacrylamide, C1-6 alkylsulfonyl, C1-6 alkylsulfonamide, C1-6 phospholipidyl, 3-8-membered heterocyclic, 5-14-membered heteroaryl, or C6-12 aryl have substituents, they may be substituted by at least one of the following groups: deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or C1-6 alkyl;L is a covalent bond, and can be a substituted or unsubstituted C1-6 alkylene group, a substituted or unsubstituted C2-6 alkenyl group, a substituted or unsubstituted C2-6 ynylene group, a substituted or unsubstituted C3-8 cycloalkylene group, a substituted or unsubstituted C6-10 arylene group, a substituted or unsubstituted C1-6 alkoxy group, a substituted or unsubstituted C1-6 alkylene group, a substituted or unsubstituted C1-6 alkylthio group, or a substituted or unsubstituted C1-6 alkylamine group. When C1-6 alkylene, C2-6 alkenyl, or C2- When 6-alkynyl, C3-8 cycloalkylene, C6-10 arylene, C1-6 alkoxy, C1-6 alkylene, C1-6 alkylthio, and C1-6 alkylamine are present with substituents, they may be substituted by at least one of the following groups: deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylene, C1-6 alkylthio, C1-6 alkylamine, or 3-8 membered heterocyclic groups; RL is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C1-6 alkylenyl, substituted or unsubstituted C1-6 alkylthioyl, substituted or unsubstituted C1-6 alkylamine, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C2-9 heterocyclic, substituted or Unsubstituted C6-10 aryl, substituted or unsubstituted C2-10 heteroaryl; when C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, C1-6 alkylenyl, C1-6 alkylthio, C1-6 alkylamine, C3-8 cycloalkyl, C2-9 heterocyclic, C6-10 aryl, or C2-10 heteroaryl are substituents, they may be substituted by at least one of the following groups: deuterium, halogen, cyanide. alkyl, nitro, hydroxyl, amino, mercapto, oxo, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C1-6 alkylthio, substituted or unsubstituted C1-6 alkylamine, substituted or unsubstituted Substituted C1-6 alkyl esters, substituted or unsubstituted C1-6 alkyl acetyl groups, substituted or unsubstituted C1-6 alkyl acetylamine groups, substituted or unsubstituted C1-6 alkyl sulfonyl groups, substituted or unsubstituted C1-6 alkyl sulfonylamine groups, substituted or unsubstituted C1-6 phospholipid groups, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted 5-14 membered heteroaryl groups, substituted or unsubstituted C6-12 aryl groups;Furthermore, when a substituent is present in the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamine, C1-6 alkylesteryl, C1-6 alkylacrylyl, C1-6 alkylsulfonyl, C1-6 alkylsulfonamide, C1-6 phospholipidyl, 3-8 membered heterocyclic, 5-14 membered heteroaryl, or C6-12 aryl group, it may be substituted by at least one of the following groups: deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or C1-6 alkyl; and the heterocyclic or heteroaryl group contains at least one heteroatom selected from N, O, or S.

[0008] Preferably, it is a heterocyclic amide compound, which may be a compound represented by general structural formula (II) or a pharmaceutically acceptable salt thereof: wherein U', V', Z', W', ring B, L and RL are defined as in general formula (I).

[0009] More preferably, it is a heterocyclic amide compound, which may be a compound represented by the general structural formula (IIA) or a pharmaceutically acceptable salt thereof: wherein, ring B is selected from; RL is selected from substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted 3-8-membered heterocyclic group, substituted or unsubstituted 5-10-membered heteroaryl, substituted or unsubstituted C6-14 aryl; when there are substituents in the C3-6 cycloalkyl, 3-8-membered heterocyclic group, 5-10-membered heteroaryl, and C6-14 aryl groups, they may be substituted by at least one of the following groups: halogen, hydroxyl, amino, cyano, oxo, C1-6 alkyl; Ru is selected from hydrogen, deuterium, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-6 cycloalkyl, and substituted or unsubstituted 3-8 membered heterocyclic groups; when C1-6 alkyl, C3-6 cycloalkyl, and 3-8 membered heterocyclic groups have substituents, they can be substituted by at least one of the following groups: hydroxyl, amino, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C1-6 alkylamine, substituted or unsubstituted C1-6 alkylanthyl, and substituted or unsubstituted 3-8 membered heterocyclic groups; furthermore, when C1-6 alkoxy, C1-6 alkylamine, C1-6 alkylanthyl, and 3-8 membered heterocyclic groups have substituents, they can be substituted by at least one of the following groups: halogen, hydroxyl, amino, cyano, and oxo. RB and RB' are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C1-6 alkylthio, substituted or unsubstituted C1- 6-alkylamino, substituted or unsubstituted C1-6 alkyl ester, substituted or unsubstituted C1-6 alkyl acetylated, substituted or unsubstituted C1-6 alkyl acetylated, substituted or unsubstituted C1-6 alkyl sulfonylated, substituted or unsubstituted C1-6 alkyl sulfonylated, substituted or unsubstituted C1-6 phosphatylated, substituted or unsubstituted 3-8-membered heterocyclic, substituted or unsubstituted 5-10-membered heteroaryl, substituted or unsubstituted C6-14 aryl;When a substituent is present in the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C1-6 alkylesteryl, C1-6 alkylacrylyl, C1-6 alkylacrylamide, C1-6 alkylsulfonyl, C1-6 alkylsulfonamide, C1-6 phosphatyl, 3-8 membered heterocyclic, 5-10 membered heteroaryl, or C6-14 aryl group, it can be replaced by at least one of the following groups. Substituted: deuterium, halogen, cyano, nitro, hydroxyl, amino, mercapto, oxo, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C1-6 alkylthio, substituted or unsubstituted C1-6 alkylamine, substituted or unsubstituted C1-6 alkylester, substituted or Unsubstituted C1-6 alkylamide, substituted or unsubstituted C1-6 alkylamide, substituted or unsubstituted C1-6 alkylsulfonamide, substituted or unsubstituted C1-6 alkylsulfonamide, substituted or unsubstituted C1-6 phospholipid, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted 5-14 membered heteroaryl, substituted or unsubstituted C6-12 aryl; furthermore, when C1-6 alkyl, C2-6 alkenyl, C2-6 ynynyl, C3-6 cycloalkyl The C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamine, C1-6 alkylester, C1-6 alkylacryl, C1-6 alkylacrylamide, C1-6 alkylsulfonyl, C1-6 alkylsulfonylamide, C1-6 phospholipid, 3-8 membered heterocyclic, 5-14 membered heteroaryl, and C6-12 aryl groups, when substituents are present, may be substituted by at least one of the following groups: deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or C1-6 alkyl; the heterocyclic and heteroaryl groups contain at least one heteroatom selected from N, O, or S; and Ry and Rz are defined as in general formula (I).

[0010] More preferably, it is a heterocyclic amide compound, which may be a compound represented by the general structural formula (IIB) or a pharmaceutically acceptable salt thereof: wherein RL is selected from substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted 3-8-membered heterocyclic group, substituted or unsubstituted 5-10-membered heteroaryl, substituted or unsubstituted C6-14 aryl, substituted or unsubstituted C2-6 alkynyl; when the C3-6 cycloalkyl, 3-8-membered heterocyclic group, 5-10-membered heteroaryl, C6-14 aryl, and C2-6 alkynyl have substituents, they may be substituted by at least one of the following groups: halogen, hydroxyl, amino, cyano, oxo, or C1-6 alkyl; the heterocyclic group or heteroaryl group contains at least one heteroatom selected from N, O, or S; and Ry, Rz, cycloB, and Ru are defined as in general formula (IIA).

[0011] Preferably, it is a heterocyclic amide compound, which may be a compound represented by the general structural formula (IIC) or a pharmaceutically acceptable salt thereof: wherein, L is selected from -OCH2-, -CH2-; RL is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C6-14 aryl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C6-14 aryl, and substituted or unsubstituted C2-6 ynyl. When C3-6 cycloalkyl, 3-8 membered heterocyclic, 5-10 membered heteroaryl, C6-14 aryl, or C2-6 ynyl have substituents, they may be substituted by at least one of the following groups: halogen, hydroxyl, amino, cyano, oxo, or substituted or unsubstituted C1-6 alkyl. Furthermore, when C1-6 alkyl has substituents, it may be substituted by at least one of the following groups: hydroxyl. The heterocyclic group and the heteroaryl group contain at least one heteroatom selected from N, O or S; and Ry, Rz, ring B and Ru are defined as in general formula (IIA).

[0012] Preferably, it is a heterocyclic amide compound, which may be a compound represented by the general structural formula (IID) or a pharmaceutically acceptable salt thereof: wherein U', V', Z', W' are each independently selected, and at least one of U', V', Z', W' is selected; n1 is 1; Ru, Rv, Rw, Rx, Ry and Rz are defined as in general formula (I); and rings B and RL are defined as in general formula (IIA).

[0013] Preferably, it is a heterocyclic amide compound, which may be a compound represented by the general structural formula (III) or a pharmaceutically acceptable salt thereof: wherein U', V', Z', W' are each independently selected, and at least one of U', V', Z', W' is selected from n1, which is selected from 0, 1, 2 or 3; Ru, Rv, Rw, Rx are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C1-6 alkylthio, substituted or unsubstituted C1-6 alkylthio, substituted or unsubstituted The C1-6 alkylamine group, substituted or unsubstituted 4-10-membered heterocyclic group, substituted or unsubstituted 5-14-membered heteroaryl group, and substituted or unsubstituted C6-12 aryl group; when C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamine, 4-10-membered heterocyclic group, 5-14-membered heteroaryl group, and C6-12 aryl group have substituents. When substituted, it may be replaced by at least one of the following groups: deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C1-6 alkylthio, substituted or unsubstituted C1- 6-alkylamino, substituted or unsubstituted C1-6 alkyl ester, substituted or unsubstituted C1-6 alkyl acetylated, substituted or unsubstituted C1-6 alkyl acetylated, substituted or unsubstituted C1-6 alkyl sulfonylated, substituted or unsubstituted C1-6 alkyl sulfonylated, substituted or unsubstituted C1-6 phosphatylated, substituted or unsubstituted 3-8-membered heterocyclic group, substituted or unsubstituted 5-10-membered heteroaryl, substituted or unsubstituted C6-14 aryl; the heterocyclic group and heteroaryl contain at least one heteroatom selected from N, O or S; and Ry, Rz, ring B and RL are defined as in general formula (IIA).

[0014] In one aspect, the present invention provides a heterocyclic amide compound of general formula (Ia) or (Ib), the stereoisomer, tautomer, deuterated derivative or pharmaceutical salt thereof: wherein ring A is selected from 3-14-membered heterocyclic group, 5-14-membered heteroaryl group, C6-14 aryl group or 4-10-membered cycloalkenyl group; the 3-14-membered heterocyclic group, 5-14-membered heteroaryl group, C6-C14 aryl group or 4-10-membered cycloalkenyl group may optionally be further substituted by one or more Ra groups; X is selected from N or CR2; each R2 is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl or C1-6 haloalkyl; Y1 and Y2 are each independently selected from N or CR4; R4 is each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, or C1-6 haloalkyl; U, V, W, and Z are each independently selected from -(C=O)-, -SO2-, -O-, -NRb-, -(CRcRd)n-, or -CReRf-, and at least one of U, V, W, and Z is selected from -CReRf-; n is selected from 0, 1, 2, or 3; Re, Rf, and the atoms they are attached to together form a C3-12 cycloalkyl or a 3-12 membered heterocyclic group; the C3-12 cycloalkyl or 3-12 membered heterocyclic group may optionally be further substituted by one or more Ra; Ra, Rb, Rc, and Rd are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylenyl, C1-6 alkylthio, C1-6 alkylamine, C1-6 alkylester, C1-6 alkylacryl, C1-6 alkylacrylamide, C1-6 alkylsulfonyl, C1-6 alkylsulfonylamide, C1-6 phosphatyl, 3-8 membered heterocyclic, 5-14 membered heteroaryl, or C6-12 aryl; Ra, Rb, Rc, and Rd are each selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C1-6 alkyl, C2-6 alkenyl, C1-6 alkylenyl, C1-6 alkylthio, C1-6 alkylyl group, C2-6 alkenyl group, C1-6 alkylthio group, C1-6 alkylyl group, C1-6 alkylamino ... The 1-6 alkylamino, C1-6 alkylester, C1-6 alkylacryl, C1-6 alkylacrylamino, C1-6 alkylsulfonyl, C1-6 alkylsulfonylamino, C1-6 phosphatyl, 3-8-membered heterocyclic, 5-14-membered heteroaryl or C6-12 aryl may optionally be further substituted with one or more hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C1-6 alkylacryl, 4-10-membered heterocyclic, 5-14-membered heteroaryl or C6-12 aryl;The R1 is selected from halogen, cyano, amino, -ORg-, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 3-8 heterocyclic, 5-14 heteroaryl, C6-10 aryl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkylenyl, C1-6 alkylthio, or C1-6 alkylamine. The Rg is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkylazinyl, C1-6 alkylthio, C1-6 alkylamino, C1-6 alkylesteryl, C1-6 alkylacrylyl, C1-6 alkylazinyl, C1-6 alkylsulfonyl, C1-6 phosphatyl, C6-12 aryl, 3-8 membered heterocyclic, or 5-14 membered heteroaryl; the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkylazinyl, C1-6 alkylazinyl, C1-6 alkylamino The C1-6 alkyl ester group, C1-6 alkyl acetyl group, C1-6 alkyl acetylamine group, C1-6 alkyl sulfonyl group, C1-6 phosphatyl group, C6-12 aryl group, 3-8 membered heterocyclic group, or 5-14 membered heteroaryl group may optionally be further substituted with one or more hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo group, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamine, C1-6 alkyl acetyl, 4-10 membered heterocyclic group, 5-14 membered heteroaryl, or C6-12 aryl group.

[0015] In a further preferred embodiment, the compound represented by formula (Ia) or (Ib), or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, wherein R1 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 3-8-membered heterocyclic, 5-14-membered heteroaryl, C6-10 aryl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylthio, or C1- 6-alkylamino; and Rg is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkylazinyl, C1-6 alkylthio, C1-6 alkylamino, C1-6 alkylesteryl, C1-6 alkylacrylyl, C1-6 alkylazinyl, C1-6 alkylsulfonyl, C1-6 phosphatyl, C6-12 aryl, 3-8 membered heterocyclic or 5-14 membered heteroaryl; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkylazinyl, C1-6 alkylthio, C1-6 The alkylamine, C1-6 alkyl ester, C1-6 alkyl acetyl, C1-6 alkyl acetylamine, C1-6 alkyl sulfonyl, C1-6 phosphatyl, C6-12 aryl, 3-8 membered heterocyclic or 5-14 membered heteroaryl may optionally be further substituted with one or more hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-6 alkoxy, C1-6 alkyl thio, C1-6 alkylamine, C1-6 alkyl acetyl, 4-10 membered heterocyclic, 5-14 membered heteroaryl or C6-12 aryl.

[0016] In some specific embodiments, the compound has a structure as shown in formula (IIa) or (IIb), or a stereoisomer, tautomer, deuterated product or pharmaceutical salt thereof: wherein the rings A, Y1, Y2, U, V, W, Z, R1 are defined as in general formula (Ia) or (Ib).

[0017] In some specific embodiments, the compound has a structure as shown in formula (IIIa) or (IIIb), or a stereoisomer, tautomer, deuterated product or pharmaceutical salt thereof: wherein U, V, W are each independently selected from -(C=O)-, -SO2-, -O-, -NRb-, -CRcRd- or -CReRf-, and at least one of U, V, W is selected from -CReRf-; and the rings A, Y1, Y2, R1, Rb, Rc, Rd, Re, Rf are defined as described in general formula (Ia) or (Ib).

[0018] In some specific embodiments, the compound has a structure of (IVa), (IVb), (IVc), (IVd), (IVe) or (IVf), or a stereoisomer, tautomer, deuterated product or pharmaceutical salt thereof: wherein U, V, W are each independently selected from -(C=O)-, -SO2-, -O-, -NRb- or -CRcRd-; m and t are each independently selected from 0, 1, 2, 3, 4 or 5, and m and t are not simultaneously 0; Q is selected from O, S, SO2, C(R3)2 or NR3; R3 is each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl or C1-6 haloalkyl; and the rings A, Y1, Y2, R1, Rb, Rc, Rd are defined as in general formula (Ia) or (Ib).

[0019] In some specific embodiments, the compound has the following structure: (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), (Vk), (Vl), (Vm), (Vn), (Vo), (Vp), (Vq), (Vr), (Vs), (Vt), (Vu), (Vv) or (Vw), or a stereoisomer, tautomer, deuterated product or pharmaceutical salt thereof: wherein R3 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl or C1-6 haloalkyl; and the definitions of ring A, R1, Rb are as described in general formula (Ia) or (Ib).

[0020] In some specific embodiments, the compound has the structure shown in formula (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), (Vk), (Vl), (Vm), (Vn), (Vo), (Vp), (Vq), (Vr), (Vs), (Vt), (Vu) or (Vv): wherein R3 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl or C1-6 haloalkyl; and the definitions of ring A, R1, Rb are as described in general formula (Ia) or (Ib).

[0021] In some specific embodiments, the compound has a structure as shown in formula (IIIc) or (IIId), or a stereoisomer, tautomer, deuterated product or pharmaceutical salt thereof: wherein U, V, W, Z are each independently selected from -(C=O)-, -SO2-, -O-, -NRb-, -CRcRd- or -CReRf-, and at least one of U, V, W, Z is selected from -CReRf-; and the rings A, Y1, Y2, R1, Rb, Rc, Rd, Re, Rf are defined as described in general formula (Ia) or (Ib).

[0022] In some specific embodiments, the compound has a structure as shown in formula (IVg), (IVh), (IVVi), (IVj) or (IVk), or a stereoisomer, tautomer, deuterated product or pharmaceutical salt thereof: wherein U, V, W, Z are each independently selected from -(C=O)-, -SO2-, -O-, -NRb- or -CRcRd-; m and t are each independently selected from 0, 1, 2, 3, 4 or 5, and m and t are not simultaneously 0; Q is selected from O, S, SO2, C(R3)2 or NR3; R3 is each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl or C1-6 haloalkyl; and the rings A, Y1, Y2, R1, Rb, Rc, Rd are defined as described in general formula (Ia) or (Ib).

[0023] In some specific embodiments, the compound has the following structure: (VIa), (VIb), (VIc), (VId), (VIe), (VIIf), (VIg), (VIh), (VIi), (VIj), (VIk), (VIl), (VIm), (VIn), (VIo), (VIp), (VIq), (VIr), (VIs), (VIt), (VIu), (VIv) or (VIw), or a stereoisomer, tautomer, deuterated product or pharmaceutical salt thereof: wherein the rings A, R1, and Rb are defined as in general formula (Ia) or (Ib).

[0024] In some specific embodiments, the ring A is selected from phenyl, pyridinyl, morpholinyl, pyridoneyl or cyclohexenyl; the phenyl, pyridinyl, morpholinyl, pyridoneyl or cyclohexenyl may optionally be further substituted by one or more Ra, each Ra being independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, C2-6 ynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylenyl or 3-8 membered heterocyclic group.

[0025] In some specific embodiments, the ring A is selected from phenyl, which may optionally be further substituted by one or more Ra, which is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylene or 3-8 membered heterocyclic groups.

[0026] In some specific embodiments, the ring A is selected from pyridinyl, which may optionally be further substituted by one or more Ra, which is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylenyl or 3-8 membered heterocyclic group.

[0027] In some specific embodiments, the ring A is selected from...

[0028] In some specific embodiments, the ring A is selected from...

[0029] In some specific embodiments, the ring A is selected from […].

[0030] In some specific embodiments, R1 is selected from an acetylene group substituted with Rg, and Rg is selected from hydrogen, deuterium, C1-6 alkyl, C3-12 cycloalkyl, C6-12 aryl, 3-8 heterocyclic or 5-14 heteroaryl, wherein the C1-6 alkyl, C3-12 cycloalkyl, C6-12 aryl, 3-8 heterocyclic or 5-14 heteroaryl may optionally be further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 acetylene, C3-6 cycloalkyl, C1-6 alkylene or 3-8 heterocyclic.

[0031] In some specific embodiments, R1 is selected from cyclopropyl groups substituted with one or more Rg groups, wherein Rg is selected from hydrogen, deuterium, C1-6 alkyl, C2-6 alkynyl, C6-12 aryl, 3-8 heterocyclic or 5-14 heteroaryl groups, wherein the C1-6 alkyl, C2-6 alkynyl, C6-12 aryl, 3-8 heterocyclic or 5-14 heteroaryl groups may optionally be further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkylene or 3-8 heterocyclic groups.

[0032] In some specific embodiments, R1 is selected from methyl groups substituted with one or more Rg groups, wherein Rg is selected from hydrogen, deuterium, halogen, C1-6 alkyl, C3-12 cycloalkyl, C6-12 aryl, 3-8 heterocyclic or 5-14 heteroaryl groups, wherein the C1-6 alkyl, C3-12 cycloalkyl, C6-12 aryl, 3-8 heterocyclic or 5-14 heteroaryl groups may optionally be further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkylene or 3-8 heterocyclic groups.

[0033] In some specific embodiments, R1 is selected from ethyl groups substituted with one or more Rg groups, wherein Rg is selected from hydrogen, deuterium, halogen, C1-6 alkyl, C3-12 cycloalkyl, C6-12 aryl, 3-8 heterocyclic or 5-14 heteroaryl groups, wherein the C1-6 alkyl, C3-12 cycloalkyl, C6-12 aryl, 3-8 heterocyclic or 5-14 heteroaryl groups may optionally be further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkylene or 3-8 heterocyclic groups.

[0034] In some specific embodiments, R1 is selected from -O(CH2)pRg-, p is selected from 0, 1, 2, 3 or 4, and Rg is selected from hydrogen, deuterium, halogen, hydroxyl, C1-6 alkyl, C3-12 cycloalkyl, C1-6 alkylamine, C6-12 aryl, 3-8 heterocyclic or 5-14 heteroaryl. The C1-6 alkyl, C3-12 cycloalkyl, C1-6 alkylamine, C6-12 aryl, 3-8 heterocyclic or 5-14 heteroaryl may optionally be further substituted by one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkylazine, C1-6 hydroxyalkyl or 3-8 heterocyclic.

[0035] In some specific embodiments, R1 is selected from -O(CH2)pRg-, p is selected from 0, 1, 2, 3 or 4, and Rg is selected from hydrogen, deuterium, halogen, hydroxyl, C1-6 alkyl, C3-12 cycloalkyl, C1-6 alkylamine, C6-12 aryl, 3-8 heterocyclic or 5-14 heteroaryl. The C1-6 alkyl, C3-12 cycloalkyl, C1-6 alkylamine, C6-12 aryl, 3-8 heterocyclic or 5-14 heteroaryl may optionally be further substituted by one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkylene or 3-8 heterocyclic.

[0036] In some specific embodiments, R1 is selected from -(CH2)qORg-, q is selected from 0, 1, 2, 3 or 4, and Rg is selected from hydrogen, deuterium, halogen, hydroxyl, C1-6 alkyl, C6-12 aryl, 3-8 heterocyclic or 5-14 heterocyclic. The C1-6 alkyl, C6-12 aryl, 3-8 heterocyclic or 5-14 heterocyclic may optionally be further substituted by one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkylenyl or 3-8 heterocyclic.

[0037] In some specific embodiments, R1 is selected from […].

[0038] In some specific embodiments, R1 is selected from...

[0039] In some specific embodiments, the compound of the present invention, or its stereoisomers, tautomers, deuterated derivatives or pharmaceutical salts, are selected from the following compounds:

[0040] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh), (IVi), (IVj), (IVk), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), ( The compounds or their stereoisomers, tautomers, deuterated derivatives or pharmaceutical salts represented by Vi), (Vj), (Vk), (Vl), (Vm), (Vn), (Vo), (Vp), (Vq), (Vr), (Vs), (Vt), (Vu), (Vv), (Vw), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VIi), (VIj), (VIk), (VIl), (VIm), (VIn), (VIo), (VIp), (VIq), (VIr), (VIs), (VIt), (VIu), (VIv) or (VIw) are shown.

[0041] In another aspect, the present invention provides formulas (I), (II), (IIA), (IIB), (IIC), (IID), (III), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh), (IVi), (IVj), (IVk), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), (Vk), (Vl), (Vm), (V Use of the compounds (n), (Vo), (Vp), (Vq), (Vr), (Vs), (Vt), (Vu), (Vv), (Vw), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VIi), (VIj), (VIk), (VIl), (VIm), (VIn), (VIo), (VIp), (VIq), (VIr), (VIs), (VIt), (VIu), (VIv) or (VIw) or their stereoisomers, tautomers, deuterated derivatives or pharmaceutical salts thereof in the preparation of medicaments for the treatment of POLθ-mediated diseases or conditions and related diseases or conditions.

[0042] In another aspect, the present invention provides formulas (I), (II), (IIA), (IIB), (IIC), (IID), (III), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh), (IVi), (IVj), (IVk), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), (Vk), (Vl), (Vm) as described above. The compounds (Vn), (Vo), (Vp), (Vq), (Vr), (Vs), (Vt), (Vu), (Vv), (Vw), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VIi), (VIj), (VIk), (VIl), (VIm), (VIn), (VIo), (VIp), (VIq), (VIr), (VIs), (VIt), (VIu), (VIv), or (VIw), or their stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts thereof, are used for the treatment and / or prevention of POLθ-mediated diseases or conditions and related diseases or conditions.

[0043] The present invention also provides a method for treating a disease or symptom, the method comprising administering to a patient in need a therapeutically effective amount of the formulas (I), (II), (IIA), (IIB), (IIC), (IID), (III), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh), (IVi), (IVj), (IVk), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg). The compounds represented by (Vh), (Vi), (Vj), (Vk), (Vl), (Vm), (Vn), (Vo), (Vp), (Vq), (Vr), (Vs), (Vt), (Vu), (Vv), (Vw), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VIi), (VIj), (VIk), (VIl), (VIm), (VIn), (VIo), (VIp), (VIq), (VIr), (VIs), (VIt), (VIu), (VIv), or (VIw), or their stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts thereof.

[0044] In some specific embodiments, the disease for which the treatment and / or prevention is performed is selected from POLθ-mediated diseases or conditions and related diseases or conditions.

[0045] In some specific embodiments, the POLθ-mediated disease or condition and related diseases or conditions are selected from tumors or cancer.

[0046] In some specific embodiments, the cancer is characterized by homologous recombination (HR) deficiency, reduced or absent expression of HR-related genes.

[0047] In some specific embodiments, the cancer is characterized by reduced or absent BRCA gene expression, absence of BRAC genes, or reduced function of BRCA proteins.

[0048] In some specific embodiments, the cancer is characterized by the absence of the 53BP1 / Shieldin complex.

[0049] In some specific embodiments, the cancer is characterized by an increased dependence on MMEJ DSB repair.

[0050] In some specific embodiments, the cancer is characterized by receiving or not receiving PARPi drug treatment and having resistance to PARPi treatment.

[0051] In some specific embodiments, the tumor or cancer is selected from hematologic malignancies or solid tumors, including, but not limited to, soft tissue cancer, rhabdomyosarcoma, multiple myeloma, uterine cancer, gastric cancer, peripheral nervous system cancer, rhabdomyosarcoma, bone cancer, colorectal cancer, mesothelioma, breast cancer, ovarian cancer, lung cancer, fibroblastic cancer, central nervous system cancer, urinary tract cancer, upper gastrointestinal cancer, kidney cancer, skin cancer, esophageal cancer, and pancreatic cancer; the hematologic malignancies include, but are not limited to, lymphoma and leukemia.

[0052] In another aspect, the present invention provides a compound represented by formula (M), or a stereoisomer, tautomer, deuterated product or pharmaceutical salt thereof: wherein RM1 is selected from iodine, pinacol diboronic acid ester group (Bpin) or ring A, the ring A being defined as described in general formula (Ia) or (Ib), and RM2 is selected from hydrogen or C1-6 alkyl.

[0053] In some specific embodiments, the present invention provides an intermediate compound M1, chemically named methyl 5'-iodo-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid, with the following structural formula:

[0054] In some specific embodiments, the present invention provides an intermediate compound M2, chemically named methyl 1'-methyl-2'-oxo-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid methyl ester, with the following structural formula:

[0055] In some specific embodiments, the present invention provides an intermediate compound M3, the structural formula of which is as follows: wherein the ring A is defined as described in general formula (Ia) or (Ib).

[0056] In another aspect, the present invention provides compounds of formula (M) as described above, or their stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts thereof, for the preparation of compounds of formulas (I), (II), (IIA), (IIB), (IIC), (IID), (III), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh), (IVi), (IVj), (IVk), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg) as described above. Use in the compounds shown in (Vh), (Vi), (Vj), (Vk), (Vl), (Vm), (Vn), (Vo), (Vp), (Vq), (Vr), (Vs), (Vt), (Vu), (Vv), (Vw), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VIi), (VIj), (VIk), (VIl), (VIm), (VIn), (VIo), (VIp), (VIq), (VIr), (VIs), (VIt), (VIu), (VIv), or (VIw), or their stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts.

[0057] Unless otherwise stated, the general chemical terms used in this structural formula have their usual meanings.

[0058] For example, unless otherwise stated, the term "halogen" as used in this invention refers to fluorine, chlorine, bromine or iodine.

[0059] In this invention, unless otherwise stated, "alkyl" includes a straight-chain or branched monovalent saturated hydrocarbon group. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, "1-6" in "C1-6 alkyl" refers to a group containing 1, 2, 3, 4, 5, or 6 carbon atoms arranged in a straight-chain or branched form.

[0060] The term "alkoxy" refers to the oxygen ether form of the aforementioned straight-chain or branched alkyl group, i.e., -O-alkyl.

[0061] The term “halogenated alkyl” refers to an alkyl group in which one or more H atoms have been replaced by halogen atoms.

[0062] The term “oxo” or “oxo group” refers to an oxygen atom in the form of a divalent substituent, which forms a carbonyl group when attached to C, and forms a ternary or ternary or N-oxide group when attached to a heteroatom.

[0063] The term "cycloalkyl" refers to a ring system having at least one cycloalkyl group. Preferably, it is a C3-12 cycloalkyl group, where "C3-12" means that the cycloalkyl group can have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 cyclic atoms. The cycloalkyl group can include monocyclic and polycyclic groups (e.g., having 2, 3, or 4 fused rings, spirocyclic, bridged rings, etc.). In some embodiments, the cycloalkyl group includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, etc.; the cycloalkyl group can also be fused to an aryl, heterocyclic, or heteroaryl ring, wherein the ring connected to the parent structure is a cycloalkyl group.

[0064] The term "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds, such as vinyl, propenyl, 1,3-butadiene, cis-butenyl, trans-butenyl, etc.

[0065] The term "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds, such as ethynyl, propynyl, etc.

[0066] The term “hydroxyalkyl” refers to a hydroxyl group that is further substituted with an alkyl group as defined above, i.e., -alkyl-OH, such as C1-6 hydroxyalkyl, including, but not limited to, -CH2OH, -C2H5OH, -CH2CH2CH2OH or -CH(CH3)2OH, etc.

[0067] The term "alkylthio" refers to a straight-chain or branched alkyl group linked through a sulfur atom, i.e., -S-alkyl, such as C1-6 alkylthio, including, but not limited to, methylthio, ethylthio, propylthio (including n-propylthio and isopropylthio), butylthio (including n-butylthio, isobutylthio, sec-butylthio, and tert-butylthio), pentylthio (including n-pentylthio, isopentylthio, and neopentylthio), hexylthio (n-hexylthio, 2-methylpentylthio, 3-methylpentylthio, 2,3-dimethylbutylthio, and 2,2-dimethylbutylthio), etc.

[0068] The term "alkyl alkyl" refers to a straight-chain or branched alkyl group linked by an alkyl group, i.e., -SO2-alkyl, such as C1-6 alkyl alkyl, including, but not limited to, methyl alkyl, ethyl alkyl, propanyl (including n-propanyl and isopropanyl), butylthio (including n-butyl, isobutyl, sec-butyl, and tert-butyl), pentanyl (including n-pentanyl, isopentanyl, and neopentanyl), hexanyl (n-hexanyl, 2-methylpentanyl, 3-methylpentanyl, 2,3-dimethylbutyl, and 2,2-dimethylbutyl), etc.

[0069] The term “alkylamino” refers to an open-chain alkyl group containing a nitrogen atom, such as C1-6 alkylamino, including, but not limited to, methylamino, ethylamino, isopropylamino, dimethylamino, methylethylamino, diethylamino, etc.

[0070] The term "alkyl ester" refers to a straight-chain or branched alkyl group linked through an ester group, i.e., -alkyl-CO2-, such as C1-6 alkyl ester, including, but not limited to, methyl ester, ethyl ester, propyl ester (including n-propyl ester and isopropyl ester), butyl ester (including n-butyl ester, isobutyl ester, sec-butyl ester, and tert-butyl ester), pentyl ester (including n-pentyl ester, isopentyl ester, and neopentyl ester), hexyl ester (n-hexyl ester, 2-methylpentyl ester, 3-methylpentyl ester, 2,3-dimethylbutyl ester, and 2,2-dimethylbutyl ester), etc.

[0071] The term "alkyl acyl" refers to a straight-chain or branched alkyl group linked by an acyl group, i.e., -alkyl-CO-, such as C1-6 alkyl acyl, including, but not limited to, methyl, ethyl, propionic (including n-propionic and isopropionic), butyl (including n-butyl, isobutyl, sec-butyl, and tert-butyl), pentayl (including n-pentyl, isopentyl, and neopentyl), hexyl (n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl, and 2,2-dimethylbutyl), etc.

[0072] The term “alkylamino” refers to a straight-chain or branched alkyl group linked by an amino group, i.e., -alkyl-CONH-, such as C1-6 alkylamino, including, but not limited to, methylamino, acetamino, propylamino (including n-propylamino and isopropylamino), butylamino (including n-butylamino, isobutylamino, sec-butylamino, and tert-butylamino), pentaamino (including n-pentaamino, isopentaamino, and neopentaamino), hexamido (n-hexamido, 2-methylpentaamino, 3-methylpentaamino, 2,3-dimethylbutylamino, and 2,2-dimethylbutylamino), etc.

[0073] The term "alkylsulfonyl" refers to a straight-chain or branched alkyl group linked by a sulfonyl group, i.e., -alkyl-SO2-, such as C1-6 alkylsulfonyl, including, but not limited to, methanesulfonyl, ethanesulfonyl, propanesulfonyl (including n-propanesulfonyl and isopropanesulfonyl), butanesulfonyl (including n-butanesulfonyl, isobutanesulfonyl, sec-butanesulfonyl, tert-butanesulfonyl), pentasulfonyl (including n-pentanesulfonyl, isopentanesulfonyl, neopentanesulfonyl), hexanesulfonyl (n-hexanesulfonyl, 2-methylpentanesulfonyl, 3-methylpentanesulfonyl, 2,3-dimethylbutanesulfonyl, 2,2-dimethylbutanesulfonyl), etc.

[0074] The term "alkylsulfonamide" refers to a straight-chain or branched alkyl group linked by a sulfonamide group, i.e., -alkyl-SO2N-, such as C1-6 alkylsulfonamide, including, but not limited to, methanesulfonamide, ethanesulfonamide, propanesulfonamide (including n-propanesulfonamide and isopropanesulfonamide), and butanesulfonamide (including n-butanesulfonamide). (e.g., isobutyridine, sec-butyridine, tert-butyridine), pentyridine (including n-pentylsulfonidine, isopentylsulfonidine, neopentylsulfonidine), hexylsulfonidine (n-hexylsulfonidine, 2-methylpentylsulfonidine, 3-methylpentylsulfonidine, 2,3-dimethylbutyridine, 2,2-dimethylbutyridine), etc.)

[0075] The term "phosphatidyl" is -PO2-, such as C1-6 phosphatidyl, including, but not limited to, methoxyphosphatidyl, ethoxyphosphatidyl, propionic phosphatidyl (including n-propionic phosphatidyl and isopropionic phosphatidyl), butylphosphatidyl (including n-butylphosphatidyl, isobutylphosphatidyl, sec-butylphosphatidyl, tert-butylphosphatidyl), pentaphosphatidyl (including n-pentaphosphatidyl, isopentaphosphatidyl, neopentaphosphatidyl), hexapionic phosphatidyl (n-hexapionic phosphatidyl, 2-methylpentaphosphatidyl, 3-methylpentaphosphatidyl, 2,3-dimethylbutylphosphatidyl, 2,2-dimethylbutylphosphatidyl), etc.

[0076] The term "aryl" in this invention, unless otherwise stated, refers to an unsubstituted or substituted monocyclic or fused-ring aromatic group comprising a carbon ring atom. Preferably, it is a C6-12 aryl group, more preferably a C6-10 monocyclic or bicyclic aromatic ring group. Phenyl or naphthyl are preferred. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl group, wherein the ring attached to the parent structure is an aryl ring. Non-limiting examples include, but are not limited to, benzocyclopentyl.

[0077] The term "heteroaryl" in this invention, unless otherwise stated, refers to a monocyclic or polycyclic (e.g., fused bicyclic) aromatic heterocycle having at least one heteroatom selected from N, O, and / or S, wherein the nitrogen or sulfur heteroatom may be selectively oxidized, and the nitrogen heteroatom may be selectively quaternized. Preferably, it is a 5-14-membered heteroaryl, wherein "5-14" in 5-14-membered heteroaryl means a heteroaryl consisting of 5-14 cyclic atoms of C, N, O, or S. More preferably, it is a 5-10-membered heteroaryl, and even more preferably, it is a 5-6-membered heteroaryl. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrroloyl, thiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, indolyl, azaindolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiophene, benzoisoxazolyl, benzothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladenine, quinolinyl, or isoquinolinyl. The heteroaryl group may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring.

[0078] The term "heterocyclic group" refers to a ring system having at least one cyclic alkyl or cyclic alkenyl group containing a heterocycle, the heteroatom being selected from N, O, and / or S. The heterocyclic group may include monocyclic or polycyclic groups (e.g., having 2, 3, or 4 fused rings, spirocyclic, bridged rings, etc.). The heterocyclic group may be connected to other parts of the compound via cyclic carbon atoms or cyclic heteroatoms. Preferably, it is a 3-14 membered heterocyclic group, where "3-14" refers to a heterocyclic group consisting of 3-14 cyclic atoms of C, N, O, or S; more preferably, it is a 3-8 membered heterocyclic group, and even more preferably, it is a 5-6 membered heterocyclic group; wherein the nitrogen or sulfur heteroatom may be selectively oxidized, and the nitrogen heteroatom may be selectively quaternized. Examples of these heterocyclic groups include, but are not limited to, azacyclic butyl, pyrrolyl, piperidinyl, 1,2,3,6-tetrahydropyridine, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxopentyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl urethane, thiomorpholinyl urethane, and tetrahydrooxadiazolyl. The heterocyclic group may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group.

[0079] The term "medicinal salt" refers to salt prepared from a pharmaceutically acceptable, non-toxic alkali or acid.

[0080] When the compound provided by the present invention is an acid, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (high and low valence), ferric iron, ferrous iron, lithium, magnesium, manganese (high and low valence), potassium, sodium, zinc, etc. Salts of ammonium, calcium, magnesium, potassium, and sodium are particularly preferred. Non-toxic organic bases capable of being derived into pharmaceutically acceptable salts include primary amines, secondary amines, and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents. Other pharmaceutically acceptable non-toxic organic bases that can form salts include ion exchange resins, as well as arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylguanidine, reduced glucosamine, glucosamine, histidine, isopropylamine, lysine, methylglucosamine, morpholine, guanidine, guanidine, polyamine resins, procaine, chloroprocaine, purine, cocoa base, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0081] When the compound provided by the present invention is a base, pharmaceutically acceptable non-toxic acids, including inorganic and organic acids, can be used to conveniently prepare their corresponding salts. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucilage, nitric acid, pyric acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, cyclohexanesulfonic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluoroacetic acid, tartaric acid, and p-toluenesulfonic acid, etc.

[0082] The drug precursors of the compounds of the present invention are included within the scope of protection of the present invention. Generally, the drug precursor refers to a functional derivative that is readily converted into the desired compound in vivo. For example, any pharmaceutically acceptable salt, ester, salt of ester, or other derivative of the compounds of the present invention, which, upon administration to a receptor, can directly or indirectly provide the compounds of the present invention or their pharmaceutically active metabolites or residues.

[0083] The compounds of the present invention may contain one or more asymmetric centers, and may thereby produce diastereomers and optical isomers. The present invention includes all possible diastereomers and their racemic mixtures, their substantially pure enantiomers, all possible geometric isomers and their pharmaceutical salts.

[0084] When formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), (IVc), ( IVd), (IVe), (IVf), (IVg), (IVh), (IVi), (IVj), (IVk), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), (Vk), (Vl), (Vm), (Vn) Unless otherwise stated, this invention includes any possible tautomers and their pharmaceutical salts, and mixtures thereof, when the compounds shown in (Vo), (Vp), (Vq), (Vr), (Vs), (Vt), (Vu), (Vv), (Vw), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VIi), (VIj), (VIk), (VIl), (VIm), (VIn), (VIo), (VIp), (VIq), (VIr), (VIs), (VIt), (VIu), (VIv), or (VIw) are present in tautomers.

[0085] This invention also includes atoms of all isotopes, whether in intermediates or final compounds. Isotopic atoms include those having the same number of atoms but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0086] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present invention or their pharmaceutical salts with a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of the present invention to an organism.

[0087] In this invention, the terms "a", "an", "the", "at least one", and "one or more" are used interchangeably. Thus, for example, a mixture comprising "a" pharmaceutically acceptable excipient can be interpreted as indicating that the pharmaceutical composition includes "one or more" pharmaceutically acceptable excipients.

[0088] The term "pharmaceuticalally acceptable excipient" refers to those excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0089] The pharmaceutical compositions of the present invention can be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0090] Typical routes of administration of the compounds of the present invention or their pharmaceutical salts or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intralingual, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous or intravenous administration.

[0091] The term “treatment” generally refers to achieving the desired pharmacological and / or physiological effect. This effect may be therapeutic, depending on whether it partially or completely stabilizes or cures the disease and / or causes side effects due to the disease. As used herein, “treatment” covers any treatment of a patient’s disease, including: (a) suppressing the symptoms of the disease, i.e., preventing its progression; or (b) alleviating the symptoms of the disease, i.e., causing the disease or symptoms to regress.

[0092] The term “effective amount” means the amount of the compound of the present invention used to (i) treat or prevent a particular disease, condition, or disorder; (ii) alleviate, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of the present invention constituting a “therapeutic effective amount” varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by those skilled in the art based on their own knowledge and the contents of this disclosure.

[0093] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0094] Based on the target design of Polθ inhibitors, this invention has developed a series of novel heterocyclic amide compounds. Related biological experiments show that the compounds of this invention can significantly inhibit cell proliferation and Polθ ATPase activity, exhibit excellent in vivo antitumor efficacy, and demonstrate low hERG toxicity, stable in vitro liver microsomal metabolism, and favorable pharmacokinetic properties. Furthermore, the synthetic routes provided by this invention are novel, safe, environmentally friendly, and have good production feasibility.

Implementation Method

[0095] To make the above content clearer and more explicit, the technical solution of the present invention will be further illustrated by the following embodiments. The following embodiments are only used to illustrate specific implementation methods of the present invention so that those skilled in the art can understand the present invention, but are not intended to limit the scope of protection of the present invention. In the specific implementation methods of the present invention, the technical means or methods, etc., not specifically described are conventional technical means or methods in the art.

[0096] Unless otherwise stated, all temperatures in this invention refer to Celsius.

[0097] The following abbreviations were used in the examples: H2SO4: sulfuric acid; HNO3: nitric acid; Na2SO4: sodium sulfate; EA: ethyl acetate; DMSO: dimethyl sulfoxide; K2CO3: potassium carbonate; NaCl: sodium chloride; PE: petroleum ether; DMF: N,N-dimethylformamide; AcOH: acetic acid; Fe: iron powder; NaHCO3: sodium bicarbonate; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride; THF: tetrahydrofuran; HCl: hydrochloric acid; MeOH: methanol; N2: nitrogen; DCM: dichloromethane; NaH: sodium hydride; MeCN: acetonitrile; Pd / C: palladium / carbon; Pd(PPh3)4: tetratetraphenylphosphine palladium; TEA: triethylamine; TCFH: N,N,N',N' -Tetramethylchloromethylammonium hexafluorophosphate; NMI: N-methylimidazolium; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; H2O: water; Cs2CO3: cesium carbonate; dioxane: dioxane; NBS: N-bromobutyldioxane; Pd2(dpa)3: tris(dibenzylacetone)dipalladium; BIDIME: (S)-3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[d][1,3]oxophosphazenecyclopentadiene; K3PO4: potassium phosphate; xylene: xylene; LiOH: lithium hydroxide; Bpin: pinacolyl diboronate group; Boc: tert-butoxycarbonyl protecting group; LC-MS: liquid chromatography-mass spectrometry; in the embodiments of the present invention, x mL × y: indicates y times, x mL each time. For example, if dichloromethane is used for extraction three times (20 mL × 3), it means that 20 mL of dichloromethane is used for extraction each time, and the extraction is repeated 3 times. In the embodiments of this invention, the amount of eluent is a volume ratio. For example, a petroleum ether solution containing 10% ethyl acetate indicates that the volume ratio of petroleum ether to ethyl acetate is 9:1. PE:EA=5:1 indicates that the volume ratio of petroleum ether to ethyl acetate is 5:1.

[0098] Furthermore, all operations involving easily oxidized or hydrolyzed raw materials are performed under nitrogen protection. Unless otherwise stated, the raw materials used in this invention are commercially available and can be used directly without further purification.

[0099] All reaction raw materials and common intermediates involved in the embodiments of the present invention can be purchased commercially or obtained in-house. The preparation process of raw materials and common intermediates that need to be obtained in-house is detailed below.

[0100] Preparation route: Preparation of key intermediate M1

[0101] Step 1: Synthesis of 1-(tert-butyl)6-methyl-2-oxoindoline-1,6-dicarboxylic acid ester (M1-2)

[0102] M1-1 (500 mg, 2.62 mmol) was dissolved in tetrahydrofuran (10 mL), sodium bicarbonate (1.3 g, 15.71 mmol) and di-tert-butyl dicarbonate (860 mg, 3.93 mmol) were added, and the mixture was heated to 70°C and stirred for 3 hours. The system was cooled to room temperature, quenched with water (20 mL), and extracted three times with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using petroleum ether solution containing 10% ethyl acetate as the eluent to give compound M1-2 (400 mg) in a yield of 52.5%.

[0103] LC-MS(m / z): 292.0 [M+H]+.

[0104] Step 2: Synthesis of 1'-(tert-butyl)6'-methyl2'-oxospiro[cyclopropane-1,3'-indoline]-1',6'-dicarboxylic acid ester (M1-3)

[0105] Compound M1-2 (1.40 g, 4.81 mmol) was dissolved in DMSO (10 mL), and potassium carbonate (1.70 g, 1.23 mmol) and dibromoethane (500 μL, 5.77 mmol) were added. The mixture was stirred at room temperature for 16 hours. The system was quenched with water (20 mL), extracted three times with ethyl acetate (20 mL × 3), and the organic phases were combined. The organic phases were washed three times with water (20 mL × 3), washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using petroleum ether solution containing 6% ethyl acetate as the eluent to give compound M1-3 (400 mg) in a yield of 26.3%.

[0106] LC-MS(m / z): 318.0 [M+H]+.

[0107] Step 3: Synthesis of methyl 2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (M1-4)

[0108] Compound M1-3 (400 mg, 1.26 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was added dropwise. The system was stirred at room temperature for 2 hours. The pH was adjusted to neutral by adding saturated sodium bicarbonate solution, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the de-Boc product (crude extract), which was used directly in the next reaction.

[0109] LC-MS(m / z): 218.0 [M+H]+.

[0110] Step 4: Synthesis of methyl 1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid ester (M1-5)

[0111] The crude extract obtained in the previous step was dissolved in DMF (5 mL), and cesium carbonate (760 mg, 2.33 mmol) and methyl iodide (200 μL, 3.21 mmol) were added. The system was stirred at room temperature for 16 hours. The mixture was quenched with water and extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined, washed three times with water (20 mL × 3), washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The mixture was then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using petroleum ether solution containing 20% ​​ethyl acetate as the eluent to give compound M1-5 (130 mg). The overall yield of the two steps (3 and 4) was 44.6%.

[0112] LC-MS(m / z): 232.0 [M+H]+.

[0113] Step 5: Synthesis of methyl 5'-iodo-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (M1)

[0114] Compound M1-5 (100 mg, 0.43 mmol) was dissolved in acetonitrile (5 mL), and three drops of trifluoroacetic acid and N-iodosuccinimide (166 mg, 0.73 mmol) were added. The system was heated to 70°C and stirred for 16 hours. The system was cooled to room temperature, quenched with water (20 mL), concentrated under reduced pressure, and extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using petroleum ether solution containing 5% ethyl acetate as the eluent to give compound M1-6 (133 mg) in 86.1% yield.

[0115] LC-MS(m / z): 358.0 [M+H]+.

[0116] Preparation of key intermediate M2

[0117] Step 1: Synthesis of methyl 5'-bromo-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (M2-1)

[0118] Methyl 1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (1.7 g, 7.34 mmol) was dissolved in DMF (10 mL), cooled to 0°C, and N-bromobutadieneimide (1.6 g, 8.83 mmol) was added. The reaction was carried out at room temperature for 16 hours. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 5:1) to give compound M2-1 (1.7 g) in 74.9% yield.

[0119] LC-MS(m / z): 310.0 [M+H]+.

[0120] Step 2: Synthesis of methyl 1'-methyl-2'-oxo-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid ester (M2)

[0121] Compound M2-1 (1.7 g, 5.50 mmol), pinacol diborate (2.8 g, 11.00 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (402 mg, 0.55 mmol), and potassium acetate (1.35 g, 13.75 mmol) were added to a reaction flask, followed by the addition of dioxane (20 mL). The system was replaced with N2 atmosphere, and the reaction was carried out at 90°C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 5:1) to give compound M2 (700 mg), with a yield of 39.6%.

[0122] LC-MS(m / z): 358.0 [M+H]+.

[0123] Preparation of key intermediate M3

[0124] Compound M1 and substituted boric acid (or compound M2 and substituted halogen) undergo Suziki coupling in the presence of a palladium catalyst to give compound M3-1, and compound M3-1 undergoes alkaline hydrolysis to give compound M3.

[0125] wherein, X is selected from bromine or iodine.

[0126] Example 1: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (1)

[0127] Step 1: Synthesis of methyl 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (1-1)

[0128] Intermediate M1 (50 mg, 0.14 mmol) was dissolved in dioxane / water (5 mL / 1 mL), and (2-chloro-5-methoxypyridin-4-yl)boronic acid (26 mg, 0.14 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (10 mg, 0.01 mmol), and potassium carbonate (40 mg, 0.28 mmol) were added sequentially. The system was purged under a nitrogen atmosphere and heated to 80°C with stirring for 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, quenched with water, and extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using petroleum ether solution containing 20% ​​ethyl acetate as the eluent to give compound 1-1 (21 mg) in a yield of 40.3%.

[0129] LC-MS(m / z): 373.0 [M+H]+.

[0130] Step 2: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (1-2)

[0131] Compound 1-1 (500 mg, 1.34 mmol) was dissolved in tetrahydrofuran / water (5 mL / 5 mL), and lithium hydroxide monohydrate (200 mg, 4.03 mmol) was added. The mixture was stirred at room temperature for 16 hours. The solution was concentrated under reduced pressure, and the pH was adjusted to 5 with 2N hydrochloric acid. The mixture was filtered, and the filter cake was dried to give compound 1-2 (460 mg) in 95.6% yield.

[0132] LC-MS (m / z): 357.0 [MH]-.

[0133] Step 3: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (1)

[0134] Compounds 1-2 (200 mg, 0.56 mmol) were dissolved in DMF (10 mL), and 5-(cyclopropylethynyl)-1,3,4-thiadiazole-2-amine (100 mg, 0.61 mmol), HATU (200 mg, 0.53 mmol), and triethylamine (200 mg, 1.98 mmol) were added sequentially. The mixture was stirred at room temperature for 4 hours, and then cesium carbonate (398 mg, 1.22 mmol) was added. The mixture was stirred at room temperature for another 2 hours. The mixture was quenched with water (20 mL), extracted three times with ethyl acetate (20 mL × 3), and the organic phases were combined. The organic phases were washed three times with water (20 mL × 3), washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The mixture was then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with dichloromethane solution containing 2.5% methanol as the eluent, and then purified by preparative liquid chromatography to obtain target compound 1 (10 mg) in a yield of 3.5%.

[0135] LC-MS(m / z): 506.0 [M+H]+.

[0136] 1H NMR (400 MHz, DMSO-d 6): δ 13.17 (s, 1H), 8.02 (s, 1H), 7.57 (s, 1H), 7.45 (s, 1H), 7.17 (s, 1H), 3.51 (s, 3H), 3.31 (s, 3H), 1.83 (s, 2H), 1.71-1.66 (m, 1H), 1.61 (d,J= 4.4 Hz, 2H), 1.01-0.96 (m, 2H), 0.88-0.84 (m, 2H).

[0137] Example 2: Synthesis of 6'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-methamide (2)

[0138] Step 1: Synthesis of tert-butyl 6-bromo-2-oxoindoline-1-carboxylic acid (2-2)

[0139] Compound 2-1 (414 mg, 2.00 mmol) was dissolved in tetrahydrofuran (10 mL), sodium bicarbonate (1.01 g, 12.00 mmol) and di-tert-butyl dicarbonate (532 mg, 2.40 mmol) were added, and the mixture was heated to 70°C and stirred for 3 hours. After cooling to room temperature, the mixture was quenched with water and extracted three times with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using petroleum ether solution containing 10% ethyl acetate as the eluent to give compound 2-2 (422 mg), in 80.7% yield.

[0140] LC-MS (m / z): 312.0, 314.0 [M+H]+.

[0141] Step 2: Synthesis of 6'-bromo-2'-oxospiro[cyclopropane-1,3'-dihydroindole]-1'-carboxylic acid tert-butyl ester (2-3)

[0142] Compound 2-2 (100 mg, 0.32 mmol) was dissolved in DMSO (3 mL), and potassium carbonate (110 mg, 0.80 mmol) and dibromoethane (40 μL, 0.39 mmol) were added. The mixture was stirred at room temperature for 16 hours. The solution was quenched with water, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined, washed three times with water (20 mL × 3), washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The mixture was then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using petroleum ether solution containing 6% ethyl acetate as the eluent to give compound 2-3 (85 mg), in 78.4% yield.

[0143] LC-MS(m / z): 338.0, 340.0 [M+H]+.

[0144] Step 3: Synthesis of 6'-bromospiro[cyclopropane-1,3'-indoline]-2'-one (2-4)

[0145] Compounds 2-3 (400 mg, 1.19 mmol) were dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was added dropwise. The system was stirred at room temperature for 2 hours. The pH was adjusted to neutral by adding saturated sodium bicarbonate, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the deBoc product, which was used directly in the next reaction.

[0146] LC-MS(m / z): 238.0, 240.0 [M+H]+.

[0147] Step 4: Synthesis of 6'-bromo-1'-methylspiro[cyclopropane-1,3'-indoline]-2'-one (2-5)

[0148] The crude extract obtained in the previous step was dissolved in DMF (5 mL), and cesium carbonate (760 mg, 2.33 mmol) and methyl iodide (200 μL, 3.21 mmol) were added. The system was stirred at room temperature for 16 hours. The mixture was quenched with water and extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined, washed three times with water (20 mL × 3), washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The mixture was then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using petroleum ether solution containing 20% ​​ethyl acetate as the eluent to give compound 2-5 (147 mg). The overall yield of the two-step reaction was 49.2%.

[0149] LC-MS(m / z): 252.0, 254.0 [M+H]+.

[0150] Step 5: Synthesis of 6'-bromo-5'-(2-chloroacetyl)-1'-methylspiro[cyclopropane-1,3'-indoline]-2'-one (2-6)

[0151] Compound 2-5 (100 mg, 0.40 mmol) was dissolved in 1,2-dichloroethane (3 mL), and chloroacetyl chloride (70 μL, 0.80 mmol) and aluminum trichloride (210 mg, 1.60 mmol) were added sequentially under ice bath conditions, followed by heating and stirring for 3 hours. The mixture was quenched with water, extracted three times with dichloromethane (20 mL × 3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using petroleum ether solution containing 25% ethyl acetate as the eluent to give compound 2-6 (57 mg), in a yield of 43.6%.

[0152] LC-MS(m / z): 328.0, 330.0 [M+H]+.

[0153] Step 6: Synthesis of 6'-bromo-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carboxylic acid (2-7)

[0154] Compound 2-6 (50 mg, 0.15 mmol) was dissolved in pyridine (3 mL), heated to 90°C and stirred for 3 hours, then cooled to 50°C and reacted for 16 hours. The mixture was filtered, and the filter cake was added to a 4N sodium hydroxide solution (5 mL). The mixture was heated to 80°C and stirred for 16 hours. After cooling to room temperature, the pH of the system was adjusted to 3-4 with 2N hydrochloric acid, and a solid precipitated. The solid was filtered, the filter cake was washed with water, and dried to obtain compound 2-7, which could be used in the next reaction without purification.

[0155] LC-MS(m / z): 294.0, 296.0 [MH]-.

[0156] Step 7: Synthesis of methyl 6'-bromo-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carboxylic acid (2-8)

[0157] Compounds 2-7 obtained in the previous step were dissolved in dry dichloromethane (3 mL). Oxalic acid chloride (22 μL, 0.17 mmol) and one drop of DMF were added under ice bath conditions. After stirring at room temperature for 3 hours, 1 mL of methanol was added dropwise, and stirring continued for 1 hour. The mixture was quenched with water and extracted three times with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 2-8 (27 mg). The overall yield of the two-step reaction was 57.2%.

[0158] LC-MS(m / z): 310.0, 312.0 [M+H]+.

[0159] Step 8: Synthesis of methyl 6'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carboxylic acid (2-9)

[0160] Compound 2-8 (310 mg, 1.00 mmol) was dissolved in dioxane / water (5 mL / 1 mL), and compound (2-chloro-5-methoxypyridin-4-yl)boric acid (200 mg, 1.10 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (73 mg, 0.10 mmol), and potassium carbonate (276 g, 2.00 mmol) were added sequentially. The system was heated to 100°C and stirred for 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, quenched with water, and extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using petroleum ether solution containing 20% ​​ethyl acetate as the eluent to give compound 2-9 (340 mg), in 91.4% yield.

[0161] LC-MS(m / z): 373.0 [M+H]+.

[0162] Step 9: Synthesis of 6'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carboxylic acid (2-10)

[0163] Compound 2-9 (340 mg, 0.91 mmol) was dissolved in tetrahydrofuran / water (5 mL / 5 mL), and lithium hydroxide monohydrate (154 mg, 3.66 mmol) was added. The mixture was stirred at room temperature for 16 hours. The solution was concentrated under reduced pressure, and the pH was adjusted to 5 with 2 N hydrochloric acid. The solution was filtered, and the filter cake was dried to give compound 2-10 (320 mg), with a yield of 97.9%.

[0164] LC-MS(m / z): m / z = 357.0 [MH]-.

[0165] Step 10: Synthesis of 6'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-methamide (2)

[0166] Compound 2-10 (150 mg, 0.42 mmol) was dissolved in DMF (5 mL), and 5-(cyclopropylethynyl)-1,3,4-thiadiazole-2-amine (80 mg, 0.46 mmol), HATU (145 mg, 0.38 mmol), and triethylamine (85 mg, 0.84 mmol) were added sequentially. The mixture was stirred at room temperature for 4 hours, and then cesium carbonate (145 mg, 0.44 mmol) was added. The mixture was stirred at room temperature for another 2 hours. The mixture was quenched with water, extracted three times with ethyl acetate (20 mL × 3), and the organic phases were combined. The organic phases were washed three times with water (20 mL × 3), washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The mixture was then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with dichloromethane solution containing 3% methanol as the eluent, and then purified by preparative liquid chromatography to obtain target compound 2 (20 mg) in a yield of 9.4%.

[0167] LC-MS(m / z): 506.0 [M+H]+.

[0168] 1H NMR (400 MHz, DMSO-d 6): δ 12.97 (s, 1H), 8.07 (s, 1H), 7.57 (s, 1H), 7.48 (s, 1H), 7.17 (s, 1H), 3.54 (s, 3H), 3.28 (s, 3H), 1.80-1.79 (m, 2H), 1.71-1.65 (m, 1H), 1.64-1.62 (m, 2H), 1.00-0.96 (m, 2H), 0.86-0.82 (m, 2H).

[0169] Example 24: Synthesis of 7-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-4-methyl-3-oxo-3,4-dihydrospirocyclic [benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-methamide (24)

[0170] Step 1: Synthesis of methyl 2-bromo-4-fluoro-5-nitrobenzene (24-1)

[0171] Methyl 2-bromo-4-fluorobenzoate (10.0 g, 43.10 mmol) was dissolved in H2SO4 (20 mL), and HNO3 (20 mL) was added dropwise under ice bath conditions. The reaction was carried out at room temperature for 4 hours. The reaction solution was poured into ice water (200 mL), the pH was adjusted to above 7 with saturated sodium carbonate aqueous solution (200 mL), and extracted with EA (200 mL × 3). The organic phases were combined, washed with saturated brine (200 mL), dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give compound 24-1 (3.0 g), with a yield of 25.1%.

[0172] LC-MS (m / z): 278.0 [M+H]+.

[0173] Step 2: Synthesis of methyl 2-bromo-4-hydroxy-5-nitrobenzene (24-2)

[0174] Compound 24-1 (2.5 g, 9.09 mmol) was dissolved in DMSO (20 mL), followed by the addition of acetoxyxamic acid (2.8 g, 10.18 mmol) and K₂CO₃ (2.51 g, 18.18 mmol) and reacted at 80°C for 2 hours. The reaction was quenched with water (10 mL), extracted with EA (30 mL × 3), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to give compound 24-2 (2.5 g) in 93.3% yield.

[0175] LC-MS (m / z): 276.0 [M+H]+.

[0176] Step 3: Synthesis of methyl 2-bromo-4-(1-(ethoxycarbonyl)cyclopropoxy)-5-nitrobenzene (24-3)

[0177] Compound 24-2 (2.5 g, 9.02 mmol) was dissolved in DMF (20 mL), and ethyl 2,4-dibromobutyrate (3.0 g, 10.82 mmol) and K2CO3 (3.8 g, 27.14 mmol) were added sequentially. The reaction mixture was reacted at 80°C for 10 hours. The reaction solution was quenched with water (10 mL), extracted with EA (30 mL × 3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 5:1) to give compound 24-3 (0.7 g), with a yield of 19.8%.

[0178] LC-MS(m / z): 388.1 [M+H]+.

[0179] Step 4: Synthesis of methyl 7-bromo-3-oxo-3,4-dihydrospirocyclic [benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-carboxylic acid (24-4)

[0180] Compound 24-3 (0.7 g, 1.80 mmol) was dissolved in AcOH (10 mL), and reduced iron powder (304 mg, 5.42 mmol) was added under ice bath conditions. The reaction was carried out at 90°C for 0.5 h. The reaction solution was concentrated under reduced pressure, water (10 mL) was added, and the pH was adjusted to above 7 with saturated NaHCO3 aqueous solution (100 mL). The solution was extracted with EA (100 mL × 3), the organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give compound 24-4 (0.3 g) in a yield of 53.3%.

[0181] LC-MS(m / z): 312.1 [M+H]+.

[0182] Step 5: Synthesis of methyl 7-bromo-4-methyl-3-oxo-3,4-dihydrospirocyclic [benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-carboxylic acid (24-5)

[0183] Compound 24-4 (300 mg, 0.96 mmol) was dissolved in DMF (5 mL), and iodomethane (980 mg, 6.50 mmol) and cesium carbonate (656 mg, 1.92 mmol) were added sequentially. The reaction mixture was reacted at room temperature for 16 hours. The reaction mixture was diluted with water (10 mL), extracted with EA (30 mL × 3), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 5:1) to give compound 24-5 (300 mg) in 95.6% yield.

[0184] LC-MS(m / z): 326.1 [M+H]+.

[0185] Step 6: Synthesis of methyl 7-(2-chloro-5-methoxypyridin-4-yl)-4-methyl-3-oxo-3,4-dihydrospirocyclic [benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-carboxylic acid (24-6)

[0186] Compound 24-5 (300 mg, 0.92 mmol), (2-chloro-5-methoxypyridin-4-yl)boronic acid (206 mg, 1.10 mmol), K₂CO₃ (381 mg, 2.76 mmol), and Pd(dppf)Cl₂ (68 mg, 0.09 mmol) were added sequentially to a flask. Dioxane (5 mL) and water (5 mL) were added to dissolve the compounds. The system was reacted at 80°C for 1 hour under nitrogen protection. After the reaction was complete, the mixture was diluted with water (10 mL), extracted with EA (30 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (40 mL) and dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to give compound 24-6 (240 mg) in 87.6% yield.

[0187] LC-MS(m / z): 389.0 [M+H]+.

[0188] Step 7: Synthesis of 7-(2-chloro-5-methoxypyridin-4-yl)-4-methyl-3-oxo-3,4-dihydrospirocyclic [benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-carboxylic acid (24-7)

[0189] Compound 24-6 (240 mg, 1.80 mmol) was dissolved in a mixed solution of methanol (2 mL), water (2 mL), and THF (2 mL), and lithium hydroxide (432 mg, 18.0 mmol) was added. The reaction was carried out at room temperature for 16 hours. The solvent was removed by vacuum distillation, water (10 mL) was added, the pH was adjusted to below 7 with 1 mol / L HCl solution, and the mixture was extracted with EA (100 mL × 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give compound 24-7 (180 mg) in a yield of 77.9%.

[0190] LC-MS (m / z): 375.0 [M+H]+.

[0191] Step 8: Synthesis of 7-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-4-methyl-3-oxo-3,4-dihydrospirocyclic [benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-methamide (24)

[0192] Compound 24-7 (180 mg, 0.48 mmol) was dissolved in DMF (5 mL), and 5-(cyclopropylethynyl)-1,3,4-thiadiazole-2-amine (119 mg, 0.72 mmol), N,N,N',N'-tetramethylchloromethamphicanine hexafluorophosphate (202 mg, 0.72 mmol), and N-methylimidazole (118 mg, 1.44 mmol) were added sequentially. The reaction mixture was reacted at room temperature for 16 hours. The reaction mixture was quenched with water (10 mL), extracted with EA (30 mL × 3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to give target compound 24 (25 mg), in a yield of 10.1%.

[0193] LC-MS (m / z): 522.0 [M+H]+.

[0194] 1H NMR (600 MHz, DMSO-d 6): δ 13.21 (s, 1H), 8.06 (s, 1H), 7.64 (s, 1H), 7.45 (s, 1H), 7.06 (s, 1H), 3.54 (s, 3H), 3.42 (s, 3H), 1.71-1.68 (m, 1H), 1.35 (s, 2H), 1.28 (s, 2H), 1.01-0.98 (m, 2H), 0.87 (s, 2H).

[0195] Example 43: Synthesis of N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-5'-(2-methoxy-5-(trifluoromethyl)phenyl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (43)

[0196] Step 1: Synthesis of methyl 5'-(2-methoxy-5-(trifluoromethyl)phenyl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (43-1)

[0197] Intermediate M1 (100 mg, 0.28 mmol), 2-methoxy-5-trifluoromethylphenylboronic acid (123 mg, 0.56 mmol), K2CO3 (77 mg, 0.56 mmol), and Pd(dppf)Cl2 (22 mg, 0.03 mmol) were added sequentially to a flask. Dioxane (2 mL) and water (1 mL) were added, and the mixture was reacted at 80°C for 2 hours under nitrogen protection. After the reaction was complete, the system was diluted with water (10 mL), extracted with EA (30 mL × 3), the organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 5:1) to give compound 43-1 (90 mg), with a yield of 79.3%.

[0198] LC-MS(m / z): 406.0 [M+H]+.

[0199] Step 2: Synthesis of 5'-(2-methoxy-5-(trifluoromethyl)phenyl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (43-2)

[0200] Compound 43-1 (90 mg, 0.22 mmol) was dissolved in a mixed solution of methanol (2 mL), water (2 mL), and THF (2 mL). Lithium hydroxide (91 mg, 2.22 mmol) was added at room temperature, and the reaction was carried out at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, water (5 mL) was added, the pH was adjusted to below 7 with 1 mol / L HCl solution (30 mL), and extracted with EA (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give compound 43-2 (80 mg), with a yield of 92.0%.

[0201] LC-MS(m / z): 392.0 [M+H]+.

[0202] Step 3: Synthesis of N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-5'-(2-methoxy-5-(trifluoromethyl)phenyl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (43)

[0203] Compound 43-2 (80 mg, 0.20 mmol) was dissolved in DMF (2 mL), and 5-(cyclopropylethynyl)-1,3,4-thiadiazole-2-amine (50 mg, 0.30 mmol), N,N,N',N'-tetramethylchloromethamphicanine hexafluorophosphate (84 mg, 0.30 mmol), and N-methylimidazole (49 mg, 0.60 mmol) were added sequentially. The reaction was carried out at room temperature for 16 hours. The system was diluted with water (10 mL), extracted with EA (30 mL × 3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to give compound 43 (6 mg), with a yield of 5.4%.

[0204] LC-MS(m / z): 539.0 [M+H]+.

[0205] 1H NMR (600 MHz, DMSO-d 6): δ 13.03 (s, 1H), 7.65 (dd,J 1= 9.0 Hz,J 2= 2.4 Hz, 1H), 7.58 (s, 1H), 7.51 (s, 1H), 7.11 (s, 1H), 7.07 (d,J= 8.4 Hz, 1H), 3.49 (s, 3H), 3.29 (s, 3H), 1.69-1.66 (m,1H), 1.58 (d,J= 4.8 Hz, 2H), 1.26-1.23 (m, 2H), 1.00-0.96 (m, 2H), 0.86-0.83 (m, 2H).

[0206] Example 45: Synthesis of 5'-(5-cyano-2-methoxyphenyl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (45)

[0207] Step 1: Synthesis of methyl 5'-(5-cyano-2-methoxyphenyl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (45-1)

[0208] Intermediate M1 (100 mg, 0.60 mmol) was dissolved in dioxane (6 mL) and water (1 mL), followed by the addition of (5-cyano-2-methoxyphenyl)boronic acid (200 mg, 1.20 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (40 mg, 0.06 mmol), and potassium carbonate (160 mg, 1.20 mmol). The reaction mixture was incubated at 80°C for 2 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give compound 45-1 (190 mg), with a yield of 87.4%.

[0209] LC-MS(m / z): 363.0 [M+H]+.

[0210] Step 2: Synthesis of 5'-(5-cyano-2-methoxyphenyl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (45-2)

[0211] Compound 45-1 (190 mg, 0.52 mmol), lithium hydroxide monohydrate (110 mg, 0.60 mmol), THF (6 mL), MeOH (3 mL), and H2O (1.8 mL) were added sequentially to a flask, and the mixture was reacted at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was added with water (1.8 mL), and the pH was adjusted to weakly acidic with 1N HCl. The mixture was then filtered to give compound 45-2 (80 mg), with a yield of 44.2%.

[0212] LC-MS(m / z): 349.0 [M+H]+.

[0213] Step 3: Synthesis of 5'-(5-cyano-2-methoxyphenyl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (45)

[0214] Compound 45-2 (80 mg, 0.23 mmol) was dissolved in ultradry dichloromethane (3 mL), and 5-(cyclopropylethynyl)-1,3,4-thiadiazole-2-amine (45 mg, 0.27 mmol), N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (193 mg, 0.69 mmol), and N-methylimidazole (94 mg, 1.15 mmol) were added sequentially. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 50:1), followed by reversed-phase chromatography to obtain the target compound 45 (7 mg), with a yield of 6.1%.

[0215] LC-MS(m / z): 496.0 [M+H]+.

[0216] Example 47: Synthesis of N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-5'-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (47)

[0217] Step 1: Synthesis of 4-bromo-2-(difluoromethyl)-5-methoxypyridine (47-1)

[0218] 4-Bromo-5-methoxypyridinecarboxaldehyde (950 mg, 4.37 mmol) was dissolved in dichloromethane (10 mL) under nitrogen protection. Diethylaminosulfur trifluoride (915 mg, 5.68 mmol) was slowly added in an ice-water bath, and the reaction was brought to room temperature for 16 hours. After the reaction was completed, the temperature was lowered to 0°C, and methanol was slowly added to quench the reaction. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to give compound 47-1 (700 mg), with a yield of 67.3%.

[0219] LC-MS(m / z): 238.0 [M+H]+.

[0220] Step 2: Synthesis of methyl 5'-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (47-2)

[0221] Intermediate M2 (250 mg, 0.7 mmol), compound 47-1 (166 mg, 0.70 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (51 mg, 0.07 mmol), and potassium carbonate (290 mg, 2.10 mmol) were added to a reaction flask, along with dioxane (10 mL) and water (2 mL). The reaction was carried out at 100°C for 2 hours under a N2 atmosphere. After the reaction was completed, the mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (20 mL) and dried over anhydrous Na2SO4. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 3:1) to give compound 47-2 (130 mg) in a yield of 48.0%.

[0222] LC-MS(m / z): 389.0 [M+H]+.

[0223] Step 3: Synthesis of 5'-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (47-3)

[0224] Compound 47-2 (130 mg, 0.34 mmol) was dissolved in 10 mL of a mixed solvent (methanol:tetrahydrofuran:water = 2:2:1), and lithium hydroxide hydrate (140 mg, 3.35 mmol) was added. The reaction was carried out at room temperature for 16 hours. After the reaction was completed, the organic solvent was removed by concentration, and the pH was adjusted to 5-6 by adding 4N hydrochloric acid. The mixture was filtered, and the residue was thoroughly dried to give compound 47-3 (100 mg) in 80.0% yield.

[0225] LC-MS(m / z): 375.0 [M+H]+.

[0226] Step 4: Synthesis of N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-5'-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (47)

[0227] Compound 47-3 (50 mg, 0.14 mmol), 5-(cyclopropylethynyl)-1,3,4-thiadiazole-2-amine (30 mg, 0.16 mmol), N,N,N',N'-tetramethylchloromethamphicanine hexafluorophosphate (77 mg, 0.27 mmol), and N-methylimidazole (33 mg, 0.41 mmol) were added to DCM (5 mL) and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give the target compound 47 (38 mg), with a yield of 53.5%.

[0228] LC-MS(m / z): 522.0 [M+H]+.

[0229] 1H NMR (600 MHz, DMSO-d 6): δ 13.20 (s, 1H), 8.32 (s, 1H), 7.64 (s, 1H), 7.56 (s, 1H), 7.20 (s, 1H), 7.04 (t,J= 55.2 Hz, 1H), 3.59 (s, 3H), 3.30 (s, 3H), 1.86 (d,J= 4.8 Hz, 2H), 1.72-1.67 (m, 1H), 1.61 (d,J= 4.8 Hz, 2H), 1.01-0.98 (m, 2H), 0.88-0.85 (m, 2H).

[0230] Example 81: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-((tetrahydrofuran-3-yl)methoxy)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-methamide (81)

[0231] Step 1: Synthesis of 5-((tetrahydrofuran-3-yl)methoxy)-1,3,4-thiadiazole-2-amine (81-1)

[0232] (Tetrahydrofuran-3-yl)methanol (245 mg, 2.40 mmol) was added to the flask, followed by tetrahydrofuran (4 mL). The mixture was allowed to cool to 0°C under nitrogen protection. NaH (120 mg, 3.00 mmol) was then added to the system, and the reaction was continued at 0°C for 1 hour. Next, 5-bromo-1,3,4-thiadiazol-2-amine (360 mg, 2.00 mmol) was added to the system, and the reaction was continued at 0°C for 1 hour. After the reaction was complete, the reaction mixture was quenched with saturated ammonium chloride aqueous solution (10 mL), extracted with EA (30 mL × 3), and the organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to give compound 81-1 (40 mg), with a yield of 9.8%.

[0233] LC-MS(m / z): 202.0 [M+H]+.

[0234] Step 2: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-((tetrahydrofuran-3-yl)methoxy)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-methamide (81)

[0235] Compounds 1-2 (72 mg, 0.20 mmol) were dissolved in DMF (2 mL), and compound 81-1 (40 mg, 0.20 mmol), N,N,N',N'-tetramethylchloromethamidine hexafluorophosphate (56 mg, 0.30 mmol), and N-methylimidazole (49 mg, 0.60 mmol) were added sequentially. The mixture was reacted at room temperature for 16 hours. The system was diluted with water (10 mL), extracted with EA (30 mL × 3), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to give target compound 81 (6 mg), with a yield of 5.7%.

[0236] LC-MS(m / z): 542.0 [M+H]+.

[0237] 1H NMR (600 MHz, DMSO-d 6): δ 12.64 (s, 1H), 8.05 (s, 1H), 7.52 (s, 1H), 7.44 (s, 1H), 7.17 (s, 1H), 4.40-4.31 (m, 2H), 3.78-3.74 (m, 2H), 3.67 (q,J= 7.8 Hz, 1H), 3.58 (s, 3H), 3.54-3.51 (m, 1H), 3.29 (s, 3H), 2.03-1.96 (m, 1H), 1.83 (s, 2H), 1.61 (d,J= 4.8 Hz, 2H), 1.26-1.23 (m, 2H).

[0238] Example 83: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-((tetrahydrofuran-3-yl)methoxy)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-methamide (83)

[0239] Step 1: Synthesis of 5-((tetrahydro-2H-pyran-4-yl)methoxy)-1,3,4-thiadiazole-2-amine (83-1)

[0240] (Tetrahydro-2H-pyran-4-yl)methanol (348.0 mg, 3.00 mmol) was added to the flask, followed by tetrahydrofuran (10 mL). The system was protected under nitrogen and cooled to 0°C. NaH (120 mg, 3.00 mmol) was added, and the reaction was carried out at 0°C for 1 hour. Then, 5-bromo-1,3,4-thiadiazol-2-amine (360 mg, 2.00 mmol) was added to the system, and the reaction was carried out at 0°C for 1 hour. After the reaction was completed, the reaction mixture was quenched with saturated ammonium chloride solution (10 mL), extracted with EA (30 mL × 3), the organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to give compound 83-1 (40 mg), with a yield of 5.8%.

[0241] LC-MS(m / z): 216.0 [M+H]+.

[0242] Step 2: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-((tetrahydrofuran-3-yl)methoxy)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-methamide (83)

[0243] Compound 1-2 (68 mg, 0.19 mmol) was dissolved in dichloromethane (2 mL), and compound 83-1 (40 mg, 0.19 mmol), N,N,N',N'-tetramethylchloromethamine hexafluorophosphate (56 mg, 0.30 mmol), and NMI (37 mg, 0.45 mmol) were added sequentially. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH=20:1) to give the target compound 83 (6 mg), with a yield of 5.7%.

[0244] LC-MS(m / z): 556.0 [M+H]+.

[0245] 1H NMR (600 MHz, DMSO-d 6): δ 12.64 (s, 1H), 8.05 (s, 1H), 7.51 (s, 1H), 7.45 (s, 1H), 7.17 (s, 1H), 4.28 (d,J= 6.6 Hz, 2H), 3.88 (dd,J 1= 11.6 Hz,J 2= 4.2 Hz, 2H), 3.58 (s, 3H), 3.31 (s,3H), 3.33 (m, 2H), 2.09-2.05 (m, 1H), 1.83 (s, 2H), 1.65-1.60 (m, 4H), 1.35-1.28 (m, 2H).

[0246] Example 96: Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (96)

[0247] Step 1: Synthesis of 2-chloro-3-fluoro-5-methoxypyridine (96-1)

[0248] 6-Chloro-5-fluoropyridin-3-ol (1.0 g, 6.80 mmol) was dissolved in MeCN (10 mL), and iodomethane (2.9 g, 20.40 mmol) and potassium carbonate (2.8 g, 20.40 mmol) were added. The mixture was reacted at room temperature for 3 hours. After the reaction was completed, the mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated NaCl aqueous solution (10 mL × 3), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give compound 96-1 (800 mg), with a yield of 72.7%.

[0249] LC-MS (m / z): 162.0 [M+H]+.

[0250] Step 2: Synthesis of 2-chloro-3-fluoro-4-iodo-5-methoxypyridine (96-2)

[0251] Compound 96-1 (800 mg, 4.94 mmol) was dissolved in THF (10 mL), cooled to -78°C under a N2 atmosphere, and a solution of n-butyllithium (37 mL, 7.41 mmol) was slowly added dropwise. The mixture was stirred at -78°C for 30 minutes, followed by the addition of I2 (1.25 g, 4.94 mmol), and the reaction was allowed to proceed to room temperature for 2 hours. After the reaction was complete, the reaction mixture was quenched with saturated ammonium chloride aqueous solution (15 mL), washed with sodium thiosulfate aqueous solution (20 mL), and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography (PE:EA = 10:1) to give compound 96-2 (370 mg), with a yield of 26.5%.

[0252] LC-MS (m / z): 288.0 [M+H]+.

[0253] Step 3: Synthesis of methyl 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (96-3)

[0254] Intermediate M2 (150 mg, 0.56 mmol), compound 96-2 (144 mg, 0.50 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (40 mg, 0.06 mmol), and potassium carbonate (200 mg, 1.40 mmol) were dissolved in dioxane (10 mL) and water (2 mL), and reacted at 80°C for 2 hours under a N2 atmosphere. After the reaction was complete, the mixture was extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 3:1) to give compound 96-3 (48 mg), in a yield of 24.6%.

[0255] LC-MS (m / z): 391.0 [M+H]+.

[0256] Step 4: Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (96-4)

[0257] Compound 96-3 (48 mg, 0.12 mmol) was dissolved in 10 mL of a mixed solvent (methanol:tetrahydrofuran:water = 2:2:1), and lithium hydroxide hydrate (52 mg, 1.23 mmol) was added. The reaction was carried out at room temperature for 16 hours. After the reaction was completed, the organic solvent was removed by concentration, and the pH was adjusted to 5-6 by adding 4M hydrochloric acid aqueous solution. The mixture was filtered, and the residue was thoroughly dried to give compound 96-4 (28 mg), with a yield of 60.8%.

[0258] LC-MS (m / z): 377.0 [M+H]+.

[0259] Step 5: Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (96)

[0260] Compound 96-4 (20 mg, 0.05 mmol), 5-(cyclopropylethynyl)-1,3,4-thiadiazole-2-amine (12 mg, 0.06 mmol), N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (30 mg, 0.11 mmol), and N-methylimidazole (13 mg, 0.16 mmol) were dissolved in DCM (10 mL) and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give the target compound 96 (6 mg) in a yield of 22.2%.

[0261] LC-MS(m / z): 524.0 [M+H]+.

[0262] 1H NMR (600 MHz, DMSO-d 6): δ 13.31 (s, 1H), 8.06 (s, 1H), 7.71 (s, 1H), 7.22 (s, 1H), 3.64 (s, 3H), 3.30 (s, 3H), 1.76 – 1.72 (m, 2H), 1.69 (m, 1H), 1.63 (m, 2H), 0.99 (m, 2H), 0.86 (m, 2H).

[0263] Example 97: Synthesis of (R)-N-(5-((1,4-dioxane-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (97)

[0264] Step 1: Synthesis of (R)-5-((1,4-dioxane-2-yl)methoxy)-1,3,4-thiadiazol-2-amine (97-1)

[0265] (S)-(1,4-dioxane-2-yl)methanol (200 mg, 1.68 mmol) was dissolved in tetrahydrofuran (10 mL). Under nitrogen protection, sodium hydride (70 mg, 2.25 mmol) was added in an ice-water bath. The reaction mixture was reacted at 0°C for 1 hour under nitrogen protection, followed by the addition of 5-bromo-1,3,4-thiadiazol-2-amine (200 mg, 1.12 mmol). The reaction mixture was further reacted at 0°C for 2 hours under nitrogen protection. The reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to give compound 97-1 (50 mg) in a yield of 20.5%.

[0266] LC-MS (m / z): 218.0 [M+H]+.

[0267] Step 2: Synthesis of (R)-N-(5-(((1,4-dioxane-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (97)

[0268] Compounds 1-2 (110 mg, 0.3 mmol) were dissolved in ultradry dichloromethane (10 mL), and compound 97-1 (50 mg, 0.23 mmol), HATU (110 mg, 0.25 mmol), and triethylamine (70 mg, 0.69 mmol) were added. The reaction mixture was reacted at room temperature for 16 hours. After the reaction was completed, the reaction mixture was quenched with water (10 mL), extracted with dichloromethane (10 mL × 3), the organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to give target compound 97 (20 mg) in a yield of 15.7%.

[0269] LC-MS(m / z): 558.0 [M+H]+.

[0270] 1H NMR (600 MHz, DMSO-d 6): δ 12.65 (s, 1H), 8.05 (s, 1H), 7.51 (s, 1H), 7.45 (s, 1H), 7.17 (s, 1H), 4.42-4.37 (m, 2H), 3.93-3.89 (m, 1H), 3.80-3.75 (m, 2H), 3.67-3.58 (m, 2H), 3.58 (s, 3H), 3.51-3.47 (m, 1H), 3.39-3.36 (m, 1H), 3.31 (m, 3H), 1.83 (s, 2H), 1.61 (d,J= 4.8 Hz, 2H).

[0271] Example 98: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(2-cyclopropylethyl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (98)

[0272] Step 1: Synthesis of (5-(2-cyclopropylethyl)-1,3,4-thiadiazol-2-yl) tert-butyl carbamate (98-1)

[0273] 100 mg (0.38 mmol) of tert-butyl (5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)carbamate was dissolved in 10 mL of ethanol, and 60 mg of 10% Pd / C was added at room temperature. The reaction was carried out at room temperature for 24 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 98-1 (40 mg) in a yield of 39.4%.

[0274] LC-MS (m / z): 270.0 [M+H]+.

[0275] Step 2: Synthesis of 5-(2-cyclopropylethyl)-1,3,4-thiadiazole-2-amine (98-2)

[0276] Compound 98-1 (80 mg, 0.30 mmol) was dissolved in DCM (2 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was reacted at room temperature for 2 hours. The system was concentrated under reduced pressure to give compound 98-2 (20 mg) in a yield of 39.8%.

[0277] LC-MS (m / z): 170.0 [M+H]+.

[0278] Step 3: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(2-cyclopropylethyl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (98)

[0279] Compounds 1-2 (43 mg, 0.12 mmol) were dissolved in DMF (2 mL), and compound 98-2 (20 mg, 0.12 mmol), N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (67 mg, 0.24 mmol), and N-methylimidazole (29 mg, 0.36 mmol) were added sequentially. The reaction mixture was reacted at room temperature for 16 hours. The reaction mixture was diluted with water (10 mL), extracted with EA (30 mL × 3), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to give target compound 98 (6 mg) in 10.1% yield.

[0280] LC-MS(m / z): 510.0 [M+H]+.

[0281] 1H NMR (600 MHz, DMSO-d 6): δ 12.74 (s, 1H), 8.04 (s, 1H), 7.54 (s, 1H), 7.45 (s, 1H), 7.18 (s, 1H), 3.53 (s, 3H), 3.29 (s, 3H), 3.07 (t,J= 7.2 Hz, 2H), 1.83 (s, 2H), 1.63-1.60 (m, 2H), 1.26-1.23 (m, 2H), 0.78-0.72 (m, 1H), 0.42-0.39 (m, 2H), 0.08-0.05 (m, 2H).

[0282] Example 99: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(3,3-dimethylbut-1-yn-1-yl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (99)

[0283] Step 1: Synthesis of tert-butyl carbamate (5-(3,3-dimethylbut-1-yn-1,3,4-thiadiazol-2-yl)carbamate (99-1)

[0284] Tert-butyl(5-bromo-1,3,4-thiadiazol-2-yl)carbamate (1.0 g, 3.60 mmol) was dissolved in DMF (20 mL), and Pd(PPh3)4 (200 mg, 1.20 mmol), cuprous iodide (40 mg, 0.06 mmol), and triethylamine (160 mg, 1.20 mmol) were added sequentially. The reaction was carried out at 60°C for 6 hours under nitrogen protection. After the reaction was completed, water (40 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with water and then with saturated brine (20 mL), concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give compound 99-1 (400 mg), with a yield of 39.5%.

[0285] LC-MS(m / z): 282.0 [M+H]+.

[0286] Step 2: Synthesis of 5-(3,3-dimethylbut-1-en-1-yl)-1,3,4-thiadiazol-2-amine (99-2)

[0287] Compound 99-1 (250 mg, 0.89 mmol) was added to a flask, dissolved in DCM (10 mL), and trifluoroacetic acid (3 mL) was added. The reaction was carried out at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give compound 99-2 (120 mg), with a yield of 74.5%.

[0288] LC-MS(m / z): 182.0 [M+H]+.

[0289] Step 3: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(3,3-dimethylbut-1-yn-1-yl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (99)

[0290] Compound 1-2 (72 mg, 0.20 mmol) was dissolved in ultradry DCM (3 mL), and compound 99-2 (43 mg, 0.24 mmol), N,N,N',N'-tetramethylchloromethamidine hexafluorophosphate (84 mg, 0.30 mmol), and N-methylimidazole (50 mg, 0.60 mmol) were added sequentially. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 50:1), followed by reversed-phase chromatography to obtain target compound 99 (7 ​​mg), with a yield of 6.7%.

[0291] LC-MS (m / z): 522.0 [M+H]+.

[0292] 1H NMR (600 MHz, DMSO-d 6): δ 13.19 (s, 1H), 8.02 (s, 1H), 7.57 (s, 1H), 7.47 (s, 1H), 7.20 (s, 1H), 3.51 (s, 3H), 3.31 (s, 3H), 1.84 (s, 2H), 1.61 (d,J= 4.2 Hz, 2H), 1.32 (s, 9H).

[0293] Example 100: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-((tetrahydro-2H-pyran-4-yl)ethynyl)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-methamide (100)

[0294] Step 1: Synthesis of (5-((tetrahydro-2H-pyran-4-yl)ethynyl)-1,3,4-thiadiazol-2-yl)tert-butyl carbamate (100-1)

[0295] (5-Bromo-1,3,4-thiadiazol-2-yl)carbamate tert-butyl ester (500 mg, 1.78 mmol) was dissolved in DMF (5 mL), and 4-ethynyltetrahydro-2H-pyran (589 mg, 5.35 mmol), tetraphenylphosphine palladium (206 mg, 0.18 mmol), cuprous iodide (17 mg, 0.09 mmol), and triethylamine (542 mg, 5.35 mmol) were added sequentially. The reaction was carried out at 60°C for 12 hours under nitrogen protection. The system was quenched with water (20 mL), extracted with EA (15 mL × 3), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 2:1) to give compound 100-1 (180 mg), with a yield of 32.6%.

[0296] LC-MS (m / z): 310.0 [M+H]+.

[0297] Step 2: Synthesis of 5-(tetrahydro-2H-pyran-4-yl)ethyl)-1,3,4-thiadiazole-2-amine (100-2)

[0298] Compound 100-1 (180 mg, 0.58 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was reacted at room temperature for 3 hours. After the reaction was complete, the mixture was concentrated, and the residue was extracted with dichloromethane (10 mL × 3) in saturated sodium bicarbonate solution. The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (100% EA) to give compound 100-2 (92 mg) in a yield of 75.6%.

[0299] LC-MS (m / z): 210.0 [M+H]+.

[0300] Step 3: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-((tetrahydro-2H-pyran-4-yl)ethynyl)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-methamide (100)

[0301] Compounds 1-2 (120 mg, 0.33 mmol) were dissolved in dichloromethane (10 mL), and compound 100-2 (84 mg, 0.40 mmol), N-methylimidazole (82 mg, 1.0 mmol), and N,N,N',N'-tetramethylchloromethanesulfonyl hexafluorophosphate (140.0 mg, 0.50 mmol) were added. The reaction was carried out at room temperature for 12 hours. After the reaction was completed, the system was quenched with water (10 mL), extracted with dichloromethane (10 mL × 3), the organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 50:1) to give target compound 100 (20 mg), with a yield of 10.9%.

[0302] LC-MS(m / z): 550.0 [M+H]+.

[0303] 1H NMR (600 MHz, DMSO-d 6): δ 13.22 (s, 1H), 8.03 (s, 1H), 7.57 (s, 1H), 7.48 (s, 1H), 7.20 (s, 1H), 3.82-3.78 (m, 2H), 3.52 (s, 3H), 3.48-3.44 (m, 2H), 3.31 (s, 3H), 3.06-3.03 (m, 1H), 1.91-1.82 (m, 4H), 1.67-1.61 (m, 4H).

[0304] Example 101: Synthesis of (R)-5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-N-(5-((4-methylmorpholin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (101)

[0305] Step 1: Synthesis of (R)-5-((4-methylmorpholin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine (101-1)

[0306] (R)-(4-methylmorpholin-2-yl)methanol (393 mg, 3.00 mmol) was added to the flask, followed by tetrahydrofuran (10 mL). The mixture was allowed to cool to 0°C under nitrogen protection. NaH (120 mg, 3.00 mmol) was then added to the system, and the reaction was continued at 0°C for one hour. Next, 5-bromo-1,3,4-thiadiazol-2-amine (360 mg, 2.00 mmol) was added to the system, and the reaction was continued for another hour. The mixture was quenched with saturated ammonium chloride aqueous solution (10 mL), extracted with EA (30 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (40 mL) and dried over anhydrous Na₂SO₄, then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to give compound 101-1 (40 mg), with a yield of 9.8%.

[0307] LC-MS(m / z): 231.0 [M+H]+.

[0308] Step 2: Synthesis of (R)-5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-((tetrahydrofuran-3-yl)methoxy)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-methamide (101)

[0309] Compounds 1-2 (54 mg, 0.15 mmol) were dissolved in DCM (2 mL), and compound 101-1 (35 mg, 0.15 mmol), TCFH (56 mg, 0.30 mmol), and NMI (37 mg, 0.45 mmol) were added sequentially. The reaction mixture was reacted at room temperature for 16 hours. The reaction mixture was diluted with water (10 mL), extracted with EA (30 mL × 3), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to give target compound 101 (12 mg), with a yield of 13.3%.

[0310] LC-MS(m / z): 571.0 [M+H]+.

[0311] 1H NMR (600 MHz, DMSO-d 6): δ 12.72 (s, 1H), 8.05 (s, 1H), 7.51 (s, 1H), 7.46 (s, 1H), 7.19 (s, 1H), 4.56-4.47 (m, 2H), 4.12-4.02 (m, 2H), 3.79 (t,J= 12.6 Hz, 1H), 3.58 (s, 3H), 3.53-3.51 (m, 1H), 3.31 (s, 3H), 3.05 (s, 2H), 2.83 (s, 3H), 2.02-1.96 (m, 1H), 1.84 (s, 2H), 1.61 (d, J = 4.8 Hz, 2H).

[0312] Example 102: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-N-(5-(3-morpholinylpropoxy)-1,3,4-thiadiazol-2-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (102)

[0313] Step 1: Synthesis of 5-(3-morpholinylpropoxy)-1,3,4-thiadiazole-2-amine (102-1)

[0314] 3-morpholinylpropane-1-ol 5-bromo-1,3,4-thiadiazole-2-amine (725 mg, 5.00 mmol) was dissolved in THF (20 mL), and NaH (200 mg, 5.00 mmol) was added at 0°C. The mixture was stirred at 0°C for 30 minutes, and then 5-bromo-1,3,4-thiadiazole-2-amine (597 g, 3.33 mmol) was added to the reaction solution. The reaction was carried out at room temperature for 1 hour. After the reaction was completed, MeOH (5 mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to give compound 102-1 (110 mg), with a yield of 13.5%.

[0315] LC-MS(m / z): 245.0 [M+H]+.

[0316] Step 2: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-N-(5-(3-morpholinylpropoxy)-1,3,4-thiadiazol-2-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (102)

[0317] Compound 1-2 (143 mg, 0.20 mmol) was added to a flask and dissolved in DCM (3 mL). Compound 102-1 (110 mg, 0.43 mmol), N,N,N',N'-tetramethylchloromethamidine hexafluorophosphate (182 mg, 0.48 mmol), and N-methylimidazole (88 mg, 0.80 mmol) were added sequentially, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 50:1), followed by reversed-phase chromatography to obtain the target compound 102 (8 mg), with a yield of 3.4%.

[0318] LC-MS(m / z): 585.0 [M+H]+.

[0319] 1H NMR (600 MHz, DMSO-d 6): δ 12.64 (s, 1H), 8.04 (s, 1H), 7.53 (s, 1H), 7.42 (s, 1H), 7.14 (s, 1H), 4.44 (t,J= 6.6 Hz, 2H), 3.58 (s, 3H), 3.57 (t,J= 4.8 Hz, 4H), 3.30 (s, 3H), 2.41 (t,J= 7.2 Hz, 2H), 2.35 (s, 4H), 1.94 (p,J= 6.6 Hz, 2H), 1.82 (s, 2H), 1.60 (d,J= 4.2 Hz, 2H).

[0320] Example 103: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(3-(dimethylamino)propoxy)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (103)

[0321] Step 1: Synthesis of 5-(3-(dimethylamino)propoxy)-1,3,4-thiadiazole-2-amine (103-1)

[0322] 3-(dimethylamino)prop-1-ol (2.9 g, 27.77 mmol) was dissolved in THF (20 mL). Under nitrogen protection, NaH (1.7 g, 41.66 mmol) was added in an ice-water bath. The reaction was carried out at 0°C for 1 hour under nitrogen protection. Then, 5-bromo-1,3,4-thiadiazol-2-amine (5.0 g, 27.77 mmol) was added, and the reaction was carried out at 0°C for another 3 hours under nitrogen protection. The reaction mixture was diluted with water (20 mL), extracted with EA (20 mL × 3), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to give compound 103-1 (180 mg) in a yield of 32.6%.

[0323] LC-MS(m / z): 203.0 [M+H]+.

[0324] Step 2: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(3-(dimethylamino)propoxy)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (103)

[0325] Compounds 1-2 (100 mg, 0.27 mmol) were dissolved in ultradry dichloromethane (10 mL), and compound 103-1 (55 mg, 0.27 mmol), HATU (102 mg, 0.27 mmol), and triethylamine (55 mg, 0.54 mmol) were added. The reaction mixture was reacted at room temperature for 12 hours. After the reaction was complete, the reaction mixture was diluted with water (10 mL), extracted with dichloromethane (10 mL × 3), the organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to give the target compound 103 (2 mg), with a yield of 1.3%.

[0326] LC-MS(m / z): 543.0 [M+H]+.

[0327] Example 104: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-((tetrahydrofuran-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-methamide (104)

[0328] Step 1: Synthesis of 5-((tetrahydrofuran-2-yl)methoxy)-1,3,4-thiadiazole-2-amine (104-1)

[0329] (Tetrahydrofuran-2-yl)methanol (750 mg, 7.26 mmol) was dissolved in tetrahydrofuran (10 mL). Under nitrogen protection, sodium hydride (340 mg, 8.39 mmol) was added in an ice-water bath. The reaction was carried out at 0°C for 1 hour under nitrogen protection, followed by the addition of 5-bromo-1,3,4-thiadiazol-2-amine (1.0 g, 5.59 mmol). The reaction was continued at 0°C for 2 hours under nitrogen protection. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to give compound 104-1 (300 mg) in a yield of 26.7%.

[0330] LC-MS(m / z): 202.0 [M+H]+.

[0331] Step 2: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-((tetrahydrofuran-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-methamide (104)

[0332] Compounds 1-2 (400 mg, 1.50 mmol) were dissolved in ultradry dichloromethane (10 mL), and compound 104-1 (300 mg, 1.50 mmol), HATU (570 mg, 1.50 mmol), and triethylamine (454 mg, 4.50 mmol) were added. The reaction mixture was reacted at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with water (10 mL), extracted with dichloromethane (10 mL × 3), the organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to give the target compound 104 (30 mg) in a yield of 3.7%.

[0333] LC-MS(m / z): 542.0 [M+H]+.

[0334] 1H NMR (600 MHz, DMSO-d 6): δ 12.97 (s, 1H), 8.07 (s, 1H), 7.57 (s, 1H), 7.48 (s, 1H), 7.17 (s, 1H), 3.54 (s, 3H), 3.33 (s, 5H), 3.28 (s, 3H), 1.80 (d,J= 4.8 Hz, 2H), 1.63 (d,J= 4.8 Hz, 2H), 1.00-0.96 (m, 2H), 0.86-0.82 (m, 2H).

[0335] Example 105: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-methamide (105)

[0336] Step 1: Synthesis of 5-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)-1,3,4-thiadiazole-2-amine (105-1)

[0337] 2-(tetrahydro-2H-pyran-4-yl)ethanol-1-ol (1.3 g, 10.00 mmol) was dissolved in THF (20 mL), and NaH (480 mg, 12.00 mmol) was added at 0°C. The mixture was stirred at 0°C for 30 minutes. 5-bromo-1,3,4-thiadiazol-2-amine (1.4 g, 7.82 mmol) was added to the reaction solution, and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction solution was quenched with MeOH (5 mL), concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 10:1) to give compound 105-1 (115 mg), with a yield of 4.9%.

[0338] LC-MS(m / z): 230.0 [M+H]+.

[0339] Step 2: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-methamide (105)

[0340] Compound 1-2 (143 mg, 0.40 mmol) was added to a flask and dissolved in DCM (3 mL). Compound 105-1 (115 mg, 0.49 mmol), N,N,N',N'-tetramethylchloromethamidine hexafluorophosphate (182 mg, 0.48 mmol), and N-methylimidazole (88 mg, 0.80 mmol) were added sequentially, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 50:1), followed by reversed-phase chromatography and lyophilization to obtain the target compound 105 (8 mg), with a yield of 3.5%.

[0341] LC-MS(m / z): 570.0 [M+H]+.

[0342] 1H NMR (600 MHz, DMSO-d 6): δ 12.65 (s, 1H), 8.05 (s, 1H), 7.52 (s, 1H), 7.43 (s, 1H), 7.16 (s, 1H), 4.47 (t,J= 6.0 Hz, 2H), 3.84-3.81 (m, 2H), 3.58 (s, 3H), 3.31 (s, 3H), 3.28 (dd,J 1= 11.4 Hz,J2= 2.4 Hz, 2H), 1.82 (s, 2H), 1.73-1.70 (m, 3H), 1.62-1.59 (m, 4H), 1.24-1.18 (m, 2H).

[0343] Example 106: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-1'-methylspiro[cyclopropane-1,3'-indoline]-6'-methamide (106)

[0344] Step 1: Synthesis of methyl 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methylspiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (106-1)

[0345] Compound 1-7 (200 mg, 0.54 mmol) was added to the flask, followed by tetrahydrofuran (5 mL). The mixture was allowed to cool to 0°C under nitrogen protection. Borane dimethyl sulfide (5.4 mL, 5.40 mmol) was then added to the system, and the reaction was carried out at 60°C for 6 hours. After the reaction was complete, the reaction mixture was quenched with saturated ammonium chloride solution (10 mL), extracted with EA (30 mL × 3), and the organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to give compound 10⁶⁻¹ (40 mg), with a yield of 20.8%.

[0346] LC-MS (m / z): 359.0 [M+H]+.

[0347] Step 3: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methylspiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (106-2)

[0348] Compound 106-1 (40 mg, 0.11 mmol) was dissolved in a mixed solution of methanol (2 mL), water (2 mL), and THF (2 mL). LiOH (26 mg, 1.10 mmol) was added at room temperature, and the reaction was carried out at room temperature for 16 hours. After the reaction was completed, the system was concentrated under reduced pressure, water (10 mL) was added, the pH was adjusted to below 7 with 1 mol / L HCl solution (15 mL), and extracted with EA (30 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude extract of compound 106-2 (40 mg).

[0349] LC-MS (m / z): 345.0 [M+H]+.

[0350] Step 4: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-1'-methylspiro[cyclopropane-1,3'-indoline]-6'-methamide (106)

[0351] The crude extract of compound 106-2 was dissolved in dichloromethane (2 mL), and 5-(cyclopropylethynyl)-1,3,4-thiadiazole-2-amine (30 mg, 0.18 mmol), N,N,N',N'-tetramethylchloromethamphicanine hexafluorophosphate (50 mg, 0.18 mmol), and N-methylimidazole (29 mg, 0.36 mmol) were added sequentially. The reaction mixture was reacted at room temperature for 2 hours. After the reaction was completed, the reaction mixture was diluted with water (10 mL), extracted with EA (30 mL × 3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to give the target compound 106 (1.2 mg), with a two-step yield of 2.2%.

[0352] LC-MS(m / z): 492.0 [M+H]+.

[0353] Example 107: Synthesis of N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-5'-(3-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (107)

[0354] Step 1: Synthesis of methyl 5'-(3-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (107-1)

[0355] Intermediate M1 (180 mg, 0.50 mmol) was dissolved in dioxane (6 mL) and water (1 mL), followed by the addition of (3-methoxypyridin-4-yl)boronic acid (92 mg, 0.60 mmol), Pd(dppf)Cl2 (36 mg, 0.05 mmol), and K2CO3 (138 mg, 1.00 mmol). The reaction mixture was then reacted at 80°C for 2 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 50:1) to give compound 107-1 (80 mg) in 47.3% yield.

[0356] LC-MS (m / z): 339.0 [M+H]+.

[0357] Step 2: Synthesis of 5'-(3-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (107-2)

[0358] Compound 107-1 (80 mg, 0.24 mmol), lithium hydroxide monohydrate (110 mg, 2.40 mmol), THF (5 mL), MeOH (1.5 mL), and H2O (1 mL) were added sequentially to a flask, and the mixture was reacted at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was added with H2O (2 mL), the pH was adjusted to weakly acidic with 1N HCl, and the mixture was concentrated under reduced pressure to give compound 107-2 (45 mg), with a yield of 57.9%.

[0359] LC-MS (m / z): 325.0 [M+H]+.

[0360] Step 3: Synthesis of N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-5'-(3-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (107)

[0361] Compound 107-2 (45 mg, 0.12 mmol) was dissolved in ultradry DCM (3 mL), and 5-(cyclopropylethynyl)-1,3,4-thiadiazole-2-amine (23 mg, 0.14 mmol), N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (50 mg, 0.18 mmol), and N-methylimidazole (30 mg, 0.36 mmol) were added sequentially. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 50:1) to give the target compound 107 (53 mg), with a yield of 93.7%.

[0362] LC-MS (m / z): 472.0 [M+H]+.

[0363] 1H NMR (600 MHz, DMSO-d 6): δ 13.15 (s, 1H), 8.28 (d,J= 4.8 Hz, 1H), 8.23 ​​(s, 1H), 7.53 (s, 1H), 7.34 (d,J= 4.8 Hz, 1H), 7.14 (s, 1H), 3.53 (s, 3H), 3.32 (s, 3H), 1.82-1.80 (m, 2H), 1.71-1.67 (m, 1H), 1.62 (q,J= 3.6 Hz, 2H), 1.01-0.98 (m, 2H), 0.88-0.86 (m, 2H).

[0364] Example 108: Synthesis of N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-5'-(5-methoxy-2-methylpyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (108)

[0365] The preparation method of target compound 108 is the same as that of compound 107 in Example 107, except that the raw material (3-methoxypyridin-4-yl)boronic acid is replaced with (5-methoxy-2-methylpyridin-4-yl)boronic acid. The other intermediate raw materials and preparation methods are the same as in Example 107, and target compound 108 (4 mg) is obtained with a total yield of 0.9%.

[0366] LC-MS(m / z): 486.0 [M+H]+.

[0367] 1H NMR (600 MHz, DMSO-d 6): δ 13.13 (s, 1H), 8.07 (s, 1H), 7.52 (s, 1H), 7.25 (s, 1H), 7.14 (s, 1H), 3.48 (s, 3H), 3.31 (s, 3H), 2.47 (s, 3H), 1.82-1.80 (m, 2H), 1.71-1.68 (m, 1H), 1.62-1.60 (m, 2H), 1.01-0.98 (m, 2H), 0.88-0.85 (m, 2H).

[0368] Example 109: Synthesis of N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-5'-(5-methoxy-2-cyclopropylpyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (109)

[0369] The preparation method of target compound 109 is the same as that of compound 107 in Example 107, except that the raw material (3-methoxypyridin-4-yl)boronic acid is replaced with (5-methoxy-2-cyclopropylpyridin-4-yl)boronic acid. The other intermediate raw materials and preparation methods are the same as in Example 107, and target compound 109 (9 mg) is obtained with a total yield of 1.8%.

[0370] LC-MS(m / z): 512.0 [M+H]+.

[0371] 1H NMR (600 MHz, DMSO-d 6): δ 13.11 (s, 1H), 8.01 (s, 1H), 7.51 (s, 1H), 7.23 (s, 1H), 7.15 (s, 1H), 3.45 (s, 3H), 3.31 (s, 3H), 2.10-2.06 (m, 1H), 1.82-1.80 (m, 2H), 1.71-1.67 (m, 1H), 1.61 (d,J= 4.8 Hz, 2H), 1.00-0.97 (m, 2H), 0.91-0.89 (m, 2H), 0.88-0.84 (m, 4H).

[0372] Example 110: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (110)

[0373] Compounds 1-2 (120 mg, 0.34 mmol), 5-methoxy-1,3,4-thiadiazol-2-amine (45 mg, 0.34 mmol), N,N,N',N'-tetramethylchloromethamidine hexafluorophosphate (280 mg, 1.0 mmol), and N-methylimidazole (135 mg, 1.65 mmol) were dissolved in DCM and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give the target compound 110 (8 mg) in a yield of 5.1%.

[0374] LC-MS (m / z): 472.0 [M+H]+.

[0375] 1H NMR (600 MHz, DMSO-d 6): δ 12.65 (s, 1H), 8.05 (s, 1H), 7.52 (s, 1H), 7.45 (s, 1H), 7.17 (s, 1H), 4.07 (s, 3H), 3.58 (s, 3H), 3.31 (s, 3H), 1.83 (s, 2H), 1.61 (d,J= 4.8 Hz, 2H).

[0376] Example 112: Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (112)

[0377] The preparation method of target compound 112 is the same as that of compound 110 in Example 110, except that compound 1-2 is replaced with compound 96-4. Other raw materials and preparation methods are the same as in Example 110, and target compound 112 (7 mg) is obtained with a yield of 10.8%.

[0378] LC-MS(m / z): 490.0 [M+H]+.

[0379] 1H NMR (600 MHz, DMSO-d 6): δ 12.79 (s, 1H), 8.07 (s, 1H), 7.68 (s, 1H), 7.17 (s, 1H), 4.06 (s, 3H), 3.68 (s, 3H), 3.31 (s, 3H), 1.72 (s, 2H), 1.62 (s, 2H).

[0380] Example 113: Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-N-(5-ethoxy-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (113)

[0381] The preparation method of target compound 113 is the same as that of compound 112 in Example 112, except that the raw material 5-methoxy-1,3,4-thiadiazole-2-amine is replaced with 5-ethoxy-1,3,4-thiadiazole-2-amine. The other raw materials and preparation methods are the same as in Example 112, and target compound 113 (6 mg) is obtained with a yield of 9.0%.

[0382] LC-MS(m / z): 504.0 [M+H]+.

[0383] 1H NMR (600 MHz, DMSO-d 6): δ 12.77 (s, 1H), 8.07 (s, 1H), 7.69 (s, 1H), 7.15 (s, 1H), 4.44-4.42 (m, 2H), 3.68 (s, 3H), 3.30 (s, 3H), 1.72 (s, 2H), 1.61 (s, 2H), 1.37 (t,J= 7.2 Hz, 3H).

[0384] Example 114: Synthesis of 5'-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (114)

[0385] The preparation method of target compound 114 is the same as that of compound 110 in Example 110, except that compound 1-2 is replaced with compound 47-2, and other raw materials and preparation methods are the same as in Example 110, to obtain target compound 114 (15 mg) with a yield of 38.5%.

[0386] LC-MS(m / z): 488.0 [M+H]+.

[0387] 1H NMR (600 MHz, DMSO-d 6): δ 12.69 (s, 1H), 8.33 (s, 1H), 7.61 (s, 1H), 7.53 (s, 1H), 7.15 (s, 1H), 7.03 (t,J= 55.2 Hz, 1H), 4.06 (s, 3H), 3.65 (s, 3H), 3.30 (s, 3H), 1.85-1.81 (m, 2H), 1.60 (d,J= 4.8 Hz, 2H).

[0388] Example 115: Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-N-(5-ethyl-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (115)

[0389] The preparation method of target compound 115 is the same as that of compound 112 in Example 112, except that 5-methoxy-1,3,4-thiadiazole-2-amine is replaced with 5-ethyl-1,3,4-thiadiazole-2-amine. The other intermediate raw materials and preparation methods are the same as in Example 112, and target compound 115 (13 mg) is obtained with a yield of 25.1%.

[0390] LC-MS (m / z): 488.0 [M+H]+.

[0391] 1H NMR (600 MHz, DMSO-d 6): δ 12.90 (s, 1H), 8.08 (s, 1H), 7.70 (s, 1H), 7.19 (s, 1H), 3.66 (s, 3H), 3.33 (s, 3H), 2.98 (q,J= 7.2 Hz, 2H), 1.76-1.71 (m, 2H), 1.65-1.60 (m, 2H), 1.30 (t,J= 7.8 Hz, 3H).

[0392] Example 116: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(methoxy-d3)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (116)

[0393] Step 1: Synthesis of 5-(methoxy-d3)-1,3,4-thiadiazole-2-amine (116-1)

[0394] Deuterated methanol (0.5 mL) was added to the reaction flask under nitrogen protection. Sodium hydride (40 mg, 1.20 mmol) was added in an ice-water bath, and the reaction was carried out at 0°C for 0.5 h. Then, 5-bromo-1,3,4-thiadiazol-2-amine (179 mg, 1.00 mmol) was added, and the reaction was continued for 2 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give compound 116-1 (80 mg), with a yield of 59.7%.

[0395] LC-MS (m / z): 135.0 [M+H]+.

[0396] Step 2: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(methoxy-d3)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (116)

[0397] Compounds 1-2 (220 mg, 0.60 mmol) were dissolved in ultradry acetonitrile (10 mL), and compound 116-1 (80 mg, 0.60 mmol), N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (252 mg, 0.90 mmol) and N-methylimidazole (160 mg, 1.80 mmol) were added. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH=20:1) to give the target compound 116 (45 mg), with a yield of 15.8%.

[0398] LC-MS (m / z): 475.0 [M+H]+.

[0399] Example 117: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-6'-methamide (117)

[0400] Step 1: Synthesis of methyl 5-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (117-1)

[0401] Methyl 5-bromo-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (1.0 g, 3.94 mmol) was added to the flask, followed by DMF (13 mL). The system was cooled to 0°C under nitrogen protection, and NaH (192 mg, 4.80 mmol) was added. The reaction was allowed to proceed for 0.5 hours. Iodomethane (740 mg, 5.21 mmol) was then added, and the mixture was slowly allowed to return to room temperature for 1 hour. After the reaction was complete, 10 mL of saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with EA (30 mL × 3), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to give compound 117-1 (800 mg), with a yield of 75.8%.

[0402] LC-MS(m / z): 269.0, 271.0 [M+H]+.

[0403] Step 2: Synthesis of methyl 3,3,5-tribromo-1-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid (117-2)

[0404] To compound 117-1 (700 mg, 2.61 mmol), tert-butanol (8 mL) and water (2 mL) were added. Pyridinium tribromide (2.5 g, 7.81 mmol) was added under nitrogen protection, and the reaction was carried out at 40°C for 4 hours. After the reaction was complete, the system was concentrated under reduced pressure, water (10 mL) was added, and the mixture was extracted with EA (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 20:1) to give compound 117-2 (700 mg) in a yield of 60.8%.

[0405] LC-MS(m / z): 441.0 [M+H]+.

[0406] Step 3: Synthesis of methyl 5-bromo-1-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (117-3)

[0407] Compound 117-2 (700 mg, 1.59 mmol) was dissolved in a mixed solution of ACN (9 mL) and AcOH (6 mL). Zinc powder (104 mg, 1.86 mmol) was added at room temperature, and the reaction was carried out for 16 hours at room temperature. After the reaction was completed, the system was concentrated under reduced pressure, diluted with water (5 mL), and the pH was adjusted to 7 with saturated NaHCO3 solution (5 mL). The mixture was extracted with EA (20 mL × 3), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 3:1) to give compound 117-3 (350 mg), with a yield of 77.4%.

[0408] LC-MS(m / z): 285.0, 287.0 [M+H]+.

[0409] Step 4: Synthesis of methyl 5'-bromo-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-6'-carboxylic acid (117-4)

[0410] Compound 117-3 (100 mg, 0.35 mmol) was dissolved in DMSO (2 mL), and K2CO3 (97 mg, 0.7 mmol) and 1,2-dibromoethane (79 mg, 0.42 mmol) were added sequentially. The reaction mixture was reacted at room temperature for 16 hours. After the reaction was completed, the reaction mixture was diluted with water (10 mL), extracted with EA (20 mL × 3), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to give compound 117-4 (50 mg), with a yield of 45.8%.

[0411] LC-MS(m / z): 311.0, 313.0 [M+H]+.

[0412] Step 5: Synthesis of methyl 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-6'-carboxylic acid (117-5)

[0413] Compound 117-4 (31 mg, 0.10 mmol), (2-chloro-5-methoxypyridin-4-yl)boronic acid (20 mg, 0.12 mmol), K2CO3 (27 mg, 0.20 mmol), and Pd(dppf)Cl2 (8 mg, 0.01 mmol) were added sequentially to a flask. Dioxane (5 mL) and water (1 mL) were added, and the mixture was reacted at 80°C for 1 hour under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with water (5 mL), extracted with EA (10 mL × 3), the organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10: 1) to give compound 117-5 (30 mg) in 80.4% yield.

[0414] LC-MS(m / z): 374.0 [M+H]+.

[0415] Step 6: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-6'-carboxylic acid (117-6)

[0416] Compound 117-5 (30.0 mg, 0.08 mmol) was dissolved in a mixed solution of methanol (1 mL), water (1 mL), and THF (1 mL). LiOH (34.4 mg, 0.80 mmol) was added at room temperature, and the reaction was carried out at room temperature for 16 hours. After the reaction was completed, the system was concentrated under reduced pressure, water (5 mL) was added, the pH was adjusted to below 7 with 1 mol / L HCl solution (8 mL), and extracted with EA (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude extract of compound 117-6 (25 mg).

[0417] LC-MS(m / z): 360.0 [M+H]+.

[0418] Step 7: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-6'-methamide (117)

[0419] Compound 117-6 (25 mg, 0.07 mmol) was dissolved in DMF (2 mL), and 5-methoxy-1,3,4-thiadiazol-2-amine (9.2 mg, 0.07 mmol), HATU (26.6 mg, 0.07 mmol), and DIPEA (25 mg, 0.21 mmol) were added sequentially. The reaction mixture was reacted at room temperature for 16 hours. After the reaction was completed, the reaction mixture was diluted with water (5 mL), extracted with EA (10 mL × 3), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to give the target compound 117 (7 mg), with a yield of 21.9%.

[0420] LC-MS (m / z): 473.0 [M+H]+.

[0421] 1H-NMR (600 MHz, DMSO-d 6): δ 12.70 (s, 1H), 8.14 (s, 1H), 7.58 (s, 1H), 7.46 (s, 1H), 4.08 (s, 3H), 3.65 (s, 3H), 3.42 (s, 3H), 1.91 (q,J= 4.2 Hz, 2H), 1.70 (d,J= 4.8 Hz, 2H).

[0422] Example 118: Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-N-(5-(methoxy-d3)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (118)

[0423] Compound 96-4 (100 mg, 0.27 mmol), 5-(methoxy-d3)-1,3,4-thiadiazole-2-amine (37 mg, 0.27 mmol), N,N,N',N'-tetramethylchloromethamidine hexafluorophosphate (91 mg, 0.32 mmol), and N-methylimidazole (66 mg, 0.81 mmol) were dissolved in DCM (5 mL) and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give the target compound 118 (50 mg) in a yield of 38.3%.

[0424] LC-MS(m / z): 493.0 [M+H]+.

[0425] 1H NMR (600 MHz, DMSO-d 6): δ 12.80 (s, 1H), 8.08 (s, 1H), 7.67 (s, 1H), 7.19 (s, 1H), 3.68 (s, 3H), 3.30 (s, 3H), 1.76-1.71 (m, 2H), 1.64-1.61 (m, 2H).

[0426] Example 119: Synthesis of 5'-(2-chloro-3-fluoro-5-(methoxy-d3)pyridin-4-yl)-N-(5-(methoxy-d3)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (119)

[0427] Step 1: Synthesis of 2-chloro-3-fluoro-5-(methoxy-d3)pyridine (119-1)

[0428] 6-Chloro-5-fluoropyridin-3-ol (1.0 g, 6.80 mmol) was dissolved in acetonitrile (20 mL), and K₂CO₃ (1.5 g, 13.60 mmol) and deuterated iodomethane (1.5 g, 10.20 mmol) were added sequentially at room temperature, and the reaction was carried out at room temperature for 16 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to give compound 119-1 (1.1 g) in 98.6% yield.

[0429] LC-MS (m / z): 165.0 [M+H]+.

[0430] Step 2: Synthesis of 2-chloro-3-fluoro-4-iodo-5-(methoxy-d3)pyridine (119-2)

[0431] Compound 119-1 (1.14 g, 6.95 mmol) was dissolved in THF (30 mL) and cooled to -78°C under nitrogen protection. Butyllithium (3.5 mL, 8.34 mmol) was slowly added dropwise to the system, which was then stirred at -78°C for 0.5 h. Iodine (267.0 mg, 10.43 mmol) was added, followed by slow restoration to room temperature, and the reaction was allowed to proceed for 2 h. After the reaction was complete, saturated ammonium chloride solution (20 mL) was added to quench the reaction. The mixture was extracted with EA (20 mL × 3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to give compound 119-2 (1.2 g), with a yield of 59.7%.

[0432] LC-MS(m / z): 291.0 [M+H]+.

[0433] Step 3: Synthesis of methyl 5'-(2-chloro-3-fluoro-5-(methoxy-d3)pyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (119-3)

[0434] Compound 119-2 (400 mg, 1.37 mmol), methyl 1'-methyl-2'-oxo-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (587 mg, 1.64 mmol), K2CO3 (378 mg, 2.74 mmol), and Pd(dppf)Cl2 (102 mg, 0.14 mmol) were added sequentially to a flask. Dioxane (10 mL) and water (2 mL) were then added, and the reaction was carried out at 100°C for 4 hours under nitrogen protection. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 2:1) to give compound 119-3 (80 mg), with a yield of 14.9%.

[0435] LC-MS(m / z): 394.0 [M+H]+.

[0436] Step 4: Synthesis of 5'-(2-chloro-3-fluoro-5-(methoxy-d3)pyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (119-4)

[0437] Compound 119-3 (80 mg, 0.20 mmol) was dissolved in a mixed solution of methanol (1 mL), water (1 mL), and THF (2 mL). LiOH (90 mg, 2.10 mmol) was added at room temperature, and the reaction was carried out at room temperature for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, water (5 mL) was added to the system, and the pH was adjusted to below 7 with 1 mol / L HCl solution (10 mL). The mixture was filtered, and the filter cake was dried to obtain the crude extract of compound 119-4 (80 mg).

[0438] LC-MS(m / z): 380.0 [M+H]+.

[0439] Step 5: Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-N-(5-(methoxy-d3)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (119)

[0440] Compound 119-4 (80 mg, 0.21 mmol) was dissolved in DMF (2 mL), and 5-(methoxy-d3)-1,3,4-thiadiazol-2-amine (28 mg, 0.21 mmol), HATU (80 mg, 0.21 mmol), and DIPEA (75 mg, 0.63 mmol) were added sequentially. The reaction was carried out at room temperature for 16 hours. After the reaction was completed, water (10 mL) was added, and the mixture was extracted with EA (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to give the target compound 119 (7 mg), with a two-step yield of 7.1%.

[0441] LC-MS(m / z): 496.0 [M+H]+.

[0442] 1H-NMR (600 MHz, DMSO-d 6): δ 12.80 (s, 1H), 8.07 (s, 1H), 7.68 (s, 1H), 7.17 (s, 1H), 3.31 (s, 3H), 1.75-1.70 (m, 2H), 1.64-1.59 (m, 2H).

[0443] Example 120: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-1',4'-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (120)

[0444] Step 1: Synthesis of methyl 4-bromo-1-methyl-1H-indole-6-carboxylate (120-1)

[0445] Methyl 4-bromo-1H-indole-6-carboxylate (5.06 g, 20.00 mmol) was added to the flask, followed by DMF (50 mL), then cesium carbonate (13.04 g, 40.00 mmol) and iodomethane (5.68 g, 40.00 mmol), and the reaction was allowed to proceed for 16 hours. After the reaction was complete, the mixture was extracted with EA (30 mL × 3), the organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to give compound 120-1 (5.0 g), with a yield of 93.6%.

[0446] LC-MS(m / z): 268.0, 270.0 [M+H]+.

[0447] Step 2: Synthesis of methyl 1,4-dimethyl-1H-indole-6-carboxylate (120-2)

[0448] Compound 120-1 (5.32 g, 20.00 mmol), methylboric acid (3.6 g, 60.00 mmol), K2CO3 (5.52 g, 40.00 mmol), and Pd(dppf)Cl2 (1.56 g, 2.00 mmol) were added sequentially to a flask. Dioxane (50 mL) and water (10 mL) were added, and the mixture was reacted at 90°C for 8 hours under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with water (50 mL), extracted with EA (100 mL × 3), the organic phases were combined, washed with saturated NaCl (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to give compound 120-2 (2.84 g) in 70.0% yield.

[0449] LC-MS(m / z): 204.0 [M+H]+.

[0450] Step 3: Synthesis of methyl 1,4-dimethyl-2-oxoindole-6-carboxylic acid (120-3)

[0451] Compound 120-2 (2.03 g, 10.00 mmol) was dissolved in tert-butanol (40 mL), and NBS (1.98 g, 11.00 mmol) was added at room temperature. The reaction mixture was then reacted at 85°C for 24 hours under nitrogen protection. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 3:1) to give compound 120-3 (1.16 g) in 52.3% yield.

[0452] LC-MS (m / z): 220.0 [M+H]+.

[0453] Step 4: Synthesis of methyl 1',4'-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (120-4)

[0454] Compound 120-3 (5.0 g, 22.83 mmol) was dissolved in DMSO (70 mL), and K2CO3 (7.6 g, 55.07 mmol) and 1,2-dibromoethane (4.91 g, 26.40 mmol) were added sequentially. The reaction mixture was reacted at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with water (50 mL), extracted with EA (100 mL × 3), the organic phases were combined, washed with saturated NaCl (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to give compound 120-4 (4.0 g) in 71.5% yield.

[0455] LC-MS (m / z): 246.0 [M+H]+.

[0456] Step 5: Synthesis of methyl 5'-bromo-1',4'-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (120-5)

[0457] Compound 120-4 (500 mg, 2.04 mmol) was dissolved in DMF (10 mL), and NBS (542 mg, 3.04 mmol) was added at room temperature. The reaction mixture was reacted at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with water (10 mL), extracted with EA (10 mL × 3), the organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to give compound 120-5 (400 mg), with a yield of 60.7%.

[0458] LC-MS(m / z): 324.0, 326.0 [M+H]+.

[0459] Step 6: Synthesis of methyl 5'-(2-chloro-5-methoxypyridin-4-yl)-1',4'-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (120-6)

[0460] Compound 120-5 (1.0 g, 3.10 mmol), (2-chloro-5-methoxypyridin-4-yl)boronic acid (870 mg, 4.65 mmol), K3PO4 (1.32 g, 6.23 mmol), Pd2(dba)3 (284 mg, 0.31 mmol), and BIDIME (205 mg, 0.62 mmol) were added sequentially to a flask. Xylene (20 mL) was added, and the system was heated to 95°C under nitrogen protection for 8 hours. After the reaction was completed, the reaction mixture was diluted with water (20 mL), extracted with EA (40 mL × 3), the organic phases were combined, washed with saturated NaCl (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to give compound 120-6 (80 mg), with a yield of 6.7%.

[0461] LC-MS(m / z): 387.0 [M+H]+.

[0462] Step 7: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1',4'-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (120-7)

[0463] Compound 120-6 (80 mg, 0.21 mmol) was dissolved in a mixed solution of methanol (1 mL), water (1 mL), and THF (3 mL). LiOH (50 mg, 2.08 mmol) was added at room temperature, and the reaction was allowed to proceed for 16 hours at room temperature. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. Water (5 mL) was added to the system, and the pH was adjusted to below 7 with 1 mol / L HCl solution (8 mL). The mixture was extracted with EA (10 mL × 3), the organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude extract of compound 120-7 (70 mg).

[0464] LC-MS(m / z): 373.0 [M+H]+.

[0465] Step 8: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-1',4'-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-methamide (120)

[0466] Compound 120-7 (70 mg, 0.19 mmol) was dissolved in DMF (2 mL), and 5-methoxy-1,3,4-thiadiazol-2-amine (25 mg, 0.19 mmol), HATU (72 mg, 0.19 mmol), and DIPEA (74 mg, 0.57 mmol) were added sequentially. The reaction mixture was reacted at room temperature for 16 hours. After the reaction was completed, the reaction mixture was diluted with water (5 mL), extracted with EA (10 mL × 3), the organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to give the target compound 120 (7 mg), with a yield of 21.9%.

[0467] LC-MS(m / z): 486.0 [M+H]+.

[0468] 1H-NMR (600 MHz, DMSO-d 6): δ 8.09 (s, 1H), 7.34 (s, 1H), 7.23 (s, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.20 (s, 3H), 2.18 (s, 3H), 2.10-2.07 (m, 2H), 1.47-1.45 (m, 2H).

[0469] Example 121: 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-N-(5-(methoxy-d3)-1,3,4-thiadiazol-2-yl)-1'-(methyl-d3)-2'-oxospiro[cyclopropane-1,3'-indole]-6'-methamide (121)

[0470] The preparation method of compound 121-1 is the same as that of intermediate M2, except that iodomethane is replaced with deuterated iodomethane, and the other intermediate raw materials are the same as those in the preparation method.

[0471] The preparation method of target compound 121 is the same as that of compound 119 in Example 119, except that intermediate M2 is replaced with compound 121-1 and compound 119-2 is replaced with compound 96-2. Other raw materials and preparation methods are the same as in Example 119, and target compound 121 (15 mg) is obtained with a three-step yield of 3.6%.

[0472] LC-MS(m / z): 496.0 [M+H]+.

[0473] 1H-NMR (600 MHz, DMSO-d 6): δ 12.81 (s, 1H), 8.08 (s, 1H), 7.67 (s, 1H), 7.19 (s, 1H), 3.68 (s, 3H), 1.75-1.71 (m, 2H), 1.64-1.60 (m, 2H).

[0474] Example 122: Synthesis of 7-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-N-(5-(methoxy-d3)-1,3,4-thiadiazol-2-yl)-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-methamide (122)

[0475] Step 1: Synthesis of methyl 4-methyl-3-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-carboxylic acid ester (122-1)

[0476] Compound 24-5 (622 mg, 1.91 mmol) was dissolved in dioxane (5 mL), and pinacol diboronate (533 mg, 2.1 mmol), potassium acetate (374 mg, 2.81 mmol), and Pd(dppf)Cl2 (139 mg, 0.19 mmol) were added. The system was substituted under N2, and the temperature was raised to 100°C for 2 hours. After the reaction was completed, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 4:1) to give compound 122-1 (520 mg), with a yield of 73.1%.

[0477] LC-MS (m / z): 374.0 [M+H]+.

[0478] Step 2: Synthesis of methyl 7-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-carboxylic acid (122-2)

[0479] Compound 122-1 (520 mg, 1.39 mmol) was dissolved in dioxane (5 mL) and water (1 mL). 2-chloro-3-fluoro-4-iodo-5-methoxypyridine (320 mg, 1.11 mmol), cesium carbonate (1.36 g, 4.18 mmol), and Pd(dppf)Cl2 (102 mg, 0.14 mmol) were added. The system was substituted with N2, and the temperature was raised to 100°C for 3 hours. After the reaction, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give compound 122-2 (300 mg), with a yield of 52.9%.

[0480] LC-MS(m / z): 407.0 [M+H]+.

[0481] Step 3: Synthesis of 7-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-carboxylic acid (122-3)

[0482] Compound 122-2 (300 mg, 1.39 mmol) was dissolved in methanol (2 mL) and water (2 mL), and LiOH (88 mg, 3.69 mmol) was added. The reaction was carried out at room temperature for 24 hours. After the reaction was completed, the filtrate was concentrated under reduced pressure, and the pH of the residue was adjusted to 5 with 2N hydrochloric acid. The residue was filtered, and the solid was dried to give compound 122-3 (280 mg), with a yield of 96.7%.

[0483] LC-MS(m / z): 393.0 [M+H]+.

[0484] Step 4: Synthesis of 7-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-N-(5-(methoxy-d3)-1,3,4-thiadiazol-2-yl)-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-methamide (122)

[0485] Compound 122-3 (100 mg, 0.25 mmol) was dissolved in DMF (2 mL), and HATU (95 mg, 0.25 mmol), triethylamine (51 mg, 0.51 mmol), and 5-(methoxy-d3)-1,3,4-thiadiazole-2-amine (34 mg, 0.25 mmol) were added. The mixture was reacted at room temperature for 12 hours. After the reaction was completed, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give the target compound 122 (100 mg) in 77.2% yield.

[0486] LC-MS(m / z): 509.0 [M+H]+.

[0487] 1H NMR (600 MHz, DMSO-d 6): δ 12.83 (s, 1H), 8.10 (s, 1H), 7.72 (s, 1H), 7.09 (s, 1H), 3.71 (s, 3H), 3.44 (s, 3H), 1.39-1.37 (m, 1H), 1.35-1.32 (m, 1H), 1.28-1.26 (m, 2H).

[0488] Example 127: Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-1'-methyl-N-(5-(oxacyclobutane-3-yloxy)-1,3,4-thiadiazol-2-yl)-2'-oxospiro[cyclopropane-1,3'-indole]-6'-methamide (127)

[0489] Step 1: Synthesis of 5-(oxetane-3-yloxy)-1,3,4-thiadiazole-2-amine (127-1)

[0490] Oxycyclobutane-3-ol (1.24 g, 16.76 mmol) was dissolved in tetrahydrofuran (10 mL) and DMF (0.5 mL). Under nitrogen protection, sodium hydride (900 mg, 22.34 mmol) was added in an ice-water bath. The reaction was carried out at 0°C for 1 hour under nitrogen protection, followed by the addition of 5-bromo-1,3,4-thiadiazol-2-amine (2.0 g, 11.17 mmol). The reaction was continued at 0°C for 2 hours under nitrogen protection. The reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to give compound 127-1 (400 mg) in a yield of 20.7%.

[0491] LC-MS (m / z): 174.0 [M+H]+.

[0492] Step 2: Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-1'-methyl-N-(5-(oxacyclobutane-3-yloxy)-1,3,4-thiadiazol-2-yl)-2'-oxospiro[cyclopropane-1,3'-indole]-6'-methamide (127)

[0493] Compound 127-1 (50 mg, 0.29 mmol) was dissolved in ultradry dichloromethane (10 mL), and compound 96-4 (109 mg, 0.29 mmol), HATU (110 mg, 0.29 mmol), and triethylamine (59 mg, 0.58 mmol) were added. The reaction mixture was reacted at room temperature for 12 hours. After the reaction was complete, the reaction mixture was diluted with water (10 mL), extracted with dichloromethane (10 mL × 3), the organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to give the target compound 127 (60 mg) in a yield of 39.0%.

[0494] LC-MS (m / z): 532.0 [M+H]+.

[0495] 1H-NMR (600 MHz, DMSO-d 6): δ 12.89 (s, 1H), 8.09 (s, 1H), 7.66 (s, 1H), 7.20 (s, 1H), 5.68-5.64 (m, 1H), 4.90 (t,J= 7.2 Hz, 2H), 4.65 (dd,J 1= 8.4 Hz,J 2= 4.8 Hz, 2H), 3.68 (s, 3H), 3.32 (s, 3H), 1.76-1.71 (m, 2H), 1.65-1.60 (m, 2H).

[0496] Example 129: Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-((tetrahydrofuran-3-yl)oxy)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indole]-6'-methamide (129)

[0497] The preparation method of target compound 129 is the same as that of compound 127 in Example 127, except that oxetane-3-ol is replaced with 3-hydroxytetrahydrofuran. Other raw materials and preparation methods are the same as in Example 127, and target compound 129 (100 mg) is obtained with a two-step yield of 1.6%.

[0498] LC-MS (m / z): 546.0 [M+H]+.

[0499] 1H-NMR (600 MHz, DMSO-d 6): δ 12.82 (s, 1H), 8.08 (s, 1H), 7.67 (s, 1H), 7.20 (s, 1H), 5.51 (t,J= 4.8 Hz, 1H), 3.93 (d,J= 10.8 Hz, 1H), 3.88-3.83 (m, 2H), 3.77-3.69 (m, 1H), 3.69 (s, 3H), 3.33 (s, 3H), 2.30-2.23 (m, 1H), 2.14-2.09 (m, 1H), 1.75-1.71 (m, 2H), 1.65-1.60 (m, 2H).

[0500] Biological Test

[0501] Example 1 Evaluation of Polθ's in vitro ATPase inhibitory activity

[0502] The ability of compounds to bind to and inhibit Polθ helicase activity in vitro was tested using the ADP-Glo ​​assay. The ADP-Glo™ Kinase Assay kit was provided by Zhejiang Promeg Biotechnology Co., Ltd., model V9102.

[0503] The compound was first dissolved in DMSO, and then the compound was serially diluted 3-fold with sterile deionized ultrapure water to obtain 8 concentrations of compound solution. A 2× helicase domain Polθ enzyme and DNA mixture was prepared in buffer (25 mM Tris-HCl pH 7.5, 6 mM NaCl, 1.5 mM MgCl2, 5% (v / v) glycerol, 0.01% (v / v) Triton X-100, 0.01% (w / v) Bovine γ-Globulin, 1 mM dithiothreitol). A matrix solution containing 2× ATP was prepared in buffer. 1 μL of each concentration of compound solution was added to a 384-well plate, centrifuged, and then 2 μL of the 2× helicase domain Polθ enzyme and DNA mixture and the enzyme-free buffer containing DNA were added. The mixture was centrifuged and pre-treated for 30 minutes. Subsequently, 2 μL of 2× ATP solution was added to each well, mixed, centrifuged, and incubated at room temperature for 60 minutes. 5 μL of ADP-Glo ​​reagent was added to each well to stop the reaction, mixed, centrifuged, and incubated at room temperature for 60 minutes. Then, 10 μL of ADP-Glo ​​Kinase Detection Reagent was added to each well, centrifuged, and equilibrated for 60 minutes. The readings were then taken on a microplate analyzer, and the inhibition rate of each compound was determined.

[0504] Table 1 Inhibitory activity of compounds against Polθ ATPase compound IC 50 (nM) compound IC 50 (nM) compound IC 50 (nM) 1 0.78 101 14.5 113 4.8 2 12.16 102 14.9 114 37.4 twenty four 12.62 103 408.0 115 41.7 43 23.71 104 14.3 116 27.04 45 13.66 83 <4.57 118 1.47 47 0.84 105 <4.57 119 1.37 96 0.80 106 24.0 120 15.38 97 17.21 107 17.2 121 4.74 81 27.59 108 17.7 122 53.98 98 13.6 109 14.8 127 12.17 99 7.5 110 28.7 129 28.27 100 6.8 112 2.8

[0505] As can be seen from the data in Table 1, the compound of the present invention has excellent in vitro inhibitory activity against Polθ.

[0506] Example 2 Evaluation of the inhibitory effect of HCT116 BRCA2- / - cell viability

[0507] The compounds were first dissolved in DMSO, and then the test compounds were serially diluted 3-fold with culture medium to obtain 8 concentrations of compound solutions. HCT116 BRCA2- / - cells (provided by Guangzhou Yuanjing Biotechnology Co., Ltd., model YKO-H668) in logarithmic growth phase were seeded at 800 cells / well in 96-well cell culture dishes and cultured at 37°C, 5% CO2 for 24 hours. Then, the compound solutions of each concentration were added, and the cells were incubated at 37°C, 5% CO2 for another 7 days. After 7 days, 10 μL of CCK8 solution was added to the cell culture dish, and the dish was incubated at 37°C for 2 hours. After 2 hours, the absorbance at 450 nM was measured using a microplate analyzer, and the inhibition rate of each compound was calculated. The results are shown in Table 2 below.

[0508] Table 2 Inhibitory activity of compounds against HCT116 BRCA2- / - cells compound IC 50 (nM) compound IC 50 (nM) 110 21.58 119 53.74 112 13.92 121 14.1 118 9.4

[0509] Example 3: Investigation of Pharmacokinetic Characteristics in Mice

[0510] SPF-grade female Balb / c mice, 3 mice per group, were administered a single dose of the compound by gavage at 10 mg / kg. Blood samples were collected at specified time points, plasma was separated, and stored at -80°C for later use. The plasma samples were thawed at room temperature and vortexed (2500 rpm, 1 min). 30.0 µL of plasma sample was transferred to a 1.5 mL centrifuge tube, 6.00 μL of internal standard (ramelteinamide, 500.0 ng / mL) was added, followed by 1000 µL of methanol. The mixture was vortexed (2500 rpm, 1 min) and centrifuged (17000 g, 4°C) for 10 min. 180 µL of the supernatant was added to a 96-well plate, sealed, and analyzed by LC-MS / MS with an injection volume of 1.00 μL. The results are shown below.

[0511] Table 3 Pharmacokinetic parameters of the compound in vivo (po) compound T 1 / 2 (h) C max (ng / mL) AUC last (h*ng / mL) CL (mL / min / kg) F (%) 1 5.74 7105 27930 5.86 74.05 2 2.96 8896 30932 5.63 95.55 110 4.59 6998 42205 4.02 126.74 112 6.93 5049 39792 3.87 78.92 118 7.53 4941 58719 1.05 91.16

[0512] As can be seen from the data in Table 3, the compounds of the present invention have good plasma exposure and oral bioavailability after oral administration, showing excellent oral administration potential.

[0513] Example 4 hERG Toxicity

[0514] The inhibitory effect of the compound on human hERG ion channels stably expressed in HEK293 cells (provided by Deqing Aolifu Biotechnology Co., Ltd.) was tested using conventional patch-clamp techniques. The compound was prepared at a concentration of 10 μM. Each cell served as a control. Perfusion was performed using a gravity-based perfusion system. After the current stabilized, the hERG current before and after the addition of the compound was compared, and the blocking effect of the compound on the hERG current was calculated. The results are shown in Table 4 below.

[0515] Table 4. Blocking effect of compounds on hERG current (10 μM) compound Inhibition compound Inhibition 1 7.14 113 -1.18 107 -3.42 116 1.75 110 9.37 118 0.23 112 9.63

[0516] Example 5 In vitro metabolic stability

[0517] Main Reagent Materials: reagents batch number content source Human (mixed) liver microsomes OUP 20 mg / mL BIOIVT, USA SD rat (mixed) liver microsomes YYMG 20 mg / mL RILD, Reid Liver Disease Research (Shanghai) Co., Ltd. CD mouse (mixed) liver microsomes TZZL 20 mg / mL RILD, Reid Liver Disease Research (Shanghai) Co., Ltd. NADPH A2305348 95.0% Shanghai Aladdin Biochemical Technology Co., Ltd. testosterone G1217507 98.33% Provided by Dr. Ehrenstorfer

[0518] System of Action: Element Final concentration Liver microsomes 0.5 mg·mL -1 working buffer 100 mM, pH = 7.4 MgCl2 3 mM Test compound or positive control 1 μM Actual volume 100 µL Duration of action 0, 120 minutes (positive control); 120 minutes (negative control); 120 minutes (for testing compounds) NADPH 1 mM

[0519] Experimental Method:

[0520] 1 μM of the test sample and positive control testosterone were incubated with microsomes under NADPH for 120 minutes, and a negative control group was set up (the test sample was incubated with microsomes for 120 minutes without any coenzymes). Samples were taken at 0 minutes and 120 minutes, and 300 μL of pre-cooled methanol solution containing internal standard (ramelteinamide: 1.000 ng / mL) was added to the sample. The mixture was vortexed (2500 rpm, 1 minute), centrifuged (4700 rpm, 4C) for 10 minutes, and 50.0 µL of the supernatant was added to 200 µL of pure water and vortexed (1000 rpm, 10 minutes). The membrane was sealed and analyzed by LC-MS / MS. The parent remaining amount of the test substance or probe matrix was detected by LC-MS / MS. The metabolic stability of the test substance was expressed as a percentage of the parent remaining amount of the test substance at each time point relative to the parent amount before treatment (0 minutes). The data were calculated according to the following formula: Parent remaining percentage (%) = Tx parent amount / T0 parent amount × 100; Tx: any treatment time point; T0: 0-minute treatment time point. The test results are shown in Table 5 below.

[0521] Table 5 Results of in vitro metabolic stability of the compounds compound Compound Residual Rate (%) compound Compound Residual Rate (%) people rats mice people rats mice 1 92.52 116.07 95.18 111 63.54 88.84 76.88 2 88.76 91.46 83.41 112 84.59 92.36 96.10 47 85.68 103.26 91.02 113 87.84 87.85 91.11 96 95.68 82.11 75.84 118 92.67 95.11 95.95 108 93.57 89.49 76.04 127 48.59 75.32 89.07 109 90.65 97.64 77.50 testosterone 1.28 0.04 0.15 110 80.15 100.12 99.10

[0522] As can be seen from the data in Table 5, the compounds of the present invention have good in vitro metabolic stability and little difference between species.

[0523] The foregoing embodiments and examples provided in this invention are for illustrative purposes only and are not intended to limit the scope of the invention. Based on this disclosure, various changes and modifications to the disclosed embodiments will be readily apparent to those skilled in the art, and such changes and modifications can be made without departing from the spirit and scope of the invention.

Claims

1. A heterocyclic amide compound of general formula (Ia) or (Ib) or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts thereof: wherein, Ring A is selected from a 6-membered heterocyclic group, a 6-membered heteroaryl group, a phenyl group, or a 6-membered cycloalkenyl group; the 6-membered heterocyclic group, 6-membered heteroaryl group, phenyl group, or 6-membered cycloalkenyl group may optionally be further substituted by one or more Ra groups; the Ra group is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkyl-thio, C1-6 alkylamine, C1-6 alkyl ester; the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkyl-thio, C1-6 alkylamine, or C1-6 alkyl ester may optionally be further substituted by one or more hydrogen, deuterium, halogen, cyano, hydroxyl, or amino groups; the X group is selected from N; Y1 and Y2 are each independently selected from N or CH; U, V, W, and Z are each independently selected from -(C=O)-, -O-, -NRb-, -(CRcRd)n-, or -CReRf-, and at least one of U, V, W, and Z is selected from -CReRf-; n is selected from 0 or 1; Re, Rf, and the atoms they are attached to together form a C3-6 cycloalkyl or a 3-6 membered heterocyclic group; the C3-6 cycloalkyl or 3-6 membered heterocyclic group may optionally be further substituted by one or more hydrogens, deuteriums, halogens, amino groups, cyano groups, hydroxyl groups, C1-6 alkyl groups, C1-6 alkoxy groups, C3-6 cycloalkyl groups, or C1-6 haloalkyl groups; Rb is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or 3-8 membered heterocyclic groups; the C1-6 alkyl, C3-6 cycloalkyl, or 3-8 membered heterocyclic group may optionally be further substituted by one or more hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylazine, C1-6 alkylamine, or 4-10 membered heterocyclic groups; Rc and Rd are each independently selected from hydrogen, deuterium, halogen, oxo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, or 3-8 membered heterocyclic groups; the C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, or 3-8 membered heterocyclic group may optionally be further substituted by one or more hydrogen, deuterium, halogen, or oxo. R1 is selected from halogen, cyano, amino, -ORg-, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 3-8 heterocyclic, 5-14 heteroaryl, C6-10 aryl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkylanthryl, C1-6 alkylthio, or C1-6 alkylamine;And Rg is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkylenyl, C1-6 alkylthio, C1-6 alkylamine, C1-6 alkylester, C1-6 alkylacryl, C1-6 alkylacrylamide, C1-6 alkylsulfonyl, C1-6 phosphatyl, C6-12 aryl, 3-8 membered heterocyclic or 5-14 membered heteroaryl; and the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkylenyl, C1-6 alkylthio, C1-6 alkylamine The C1-6 alkyl ester group, C1-6 alkyl acetyl group, C1-6 alkyl acetamino group, C1-6 alkyl sulfonyl group, C1-6 phosphatyl group, C6-12 aryl group, 3-8 membered heterocyclic group, or 5-14 membered heteroaryl group may optionally be further substituted with one or more hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo group, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamine, C1-6 alkyl acetyl, 4-10 membered heterocyclic group, 5-14 membered heteroaryl, or C6-12 aryl group.

2. The compound as claimed in claim 1, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts thereof, wherein R1 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 3-8 heterocyclic, 5-14 heteroaryl, C6-10 aryl, C1-6 alkoxy, C1-6 alkylenyl, C1-6 alkylthio, or C1-6 alkylamine; Rg is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamine, C1-6 alkylester, C1-6 alkylamide, C1-6 alkylamide, C1-6 alkylsulfonyl Acryl, C1-6 phosphatyl, C6-12 aryl, 3-8 membered heterocyclic or 5-14 membered heteroaryl; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamine, C1-6 alkylester, C1-6 alkylacryl, C1-6 alkylacrylamine The C1-6 alkylsulfonyl, C1-6 phosphatyl, C6-12 aryl, 3-8 heterocyclic or 5-14 heteroaryl groups may optionally be further substituted with one or more hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamine, C1-6 alkylacyl, 4-10 heterocyclic, 5-14 heteroaryl or C6-12 aryl groups; and the rings A, X, Y1, Y2, U, V, W, Z, n, Re, Rf, Ra, Rb, Rc, Rd are as defined in claim 1.

3. The compound or its stereoisomers, tautomers, deuterated derivatives or pharmaceutical salts as described in claim 1 or 2, wherein the compound has a structure as shown in formula (IIa) or (IIb): wherein the rings A, Y1, Y2, U, V, W, Z, R1 are defined as described in claim 1 or 2.

4. The compound as claimed in claim 3, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutical salt thereof, wherein the compound has a structure as shown in formula (IIIa) or (IIIb): where, The U, V, and W are each independently selected from -(C=O)-, -O-, -NRb-, -CRcRd-, or -CReRf-, and at least one of U, V, and W is selected from -CReRf-; and the rings A, Y1, Y2, R1, Rb, Rc, Rd, Re, and Rf are defined as described in request item 1 or 2.

5. The compound as claimed in claim 4, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutical salt thereof, wherein the compound has a structure as shown in formula (IVa), (IVb), (IVc), (IVd), (IVe), or (IVf): wherein, U, V, and W are each independently selected from -(C=O)-, -O-, -NRb-, or -CRcRd-; m and t are each independently selected from 0, 1, 2, 3, 4, or 5, and m and t are not both 0; Q is selected from O, S, SO2, C(R3)2, or NR3; R3 is each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, or C1-6 haloalkyl; and the definitions of cycloA, Y1, Y2, R1, Rb, Rc, and Rd are as described in claim 1 or 2.

6. The compound as claimed in claim 5, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutical salt thereof, wherein the compound has a structure as shown in formula (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), (Vk), (Vl), (Vm), (Vn), (Vo), (Vp), (Vq), (Vr), (Vs), (Vt), (Vu), (Vv), or (Vw): wherein, R3 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, or C1-6 haloalkyl; and cycloA, R1, and Rb are defined as described in claim 1 or 2.

7. The compound as claimed in claim 5, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutical salt thereof, wherein the compound has a structure as shown in formula (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), (Vk), (Vl), (Vm), (Vn), (Vo), (Vp), (Vq), (Vr), (Vs), (Vt), (Vu), or (Vv): wherein, R3 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, or C1-6 haloalkyl; and cycloA, R1, and Rb are defined as described in claim 1 or 2.

8. The compound as claimed in claim 3, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutical salt thereof, wherein the compound has a structure as shown in formula (IIIc) or (IIId): where, U, V, W, Z are each independently selected from -(C=O)-, -O-, -NRb-, -CRcRd- or -CReRf-, and at least one of U, V, W, Z is selected from -CReRf-; and the rings A, Y1, Y2, R1, Rb, Rc, Rd, Re, Rf are defined as described in request item 1 or 2.

9. The compound as claimed in claim 8, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutical salt thereof, wherein the compound has a structure as shown in formula (IVg), (IVh), (IVVi), (IVj), or (IVk): where, U, V, W, Z are each independently selected from -(C=O)-, -O-, -NRb-, or -CRcRd-; m and t are each independently selected from 0, 1, 2, 3, 4, or 5, and m and t are not both 0; Q is selected from O, S, SO2, C(R3)2, or NR3; R3 is each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, or C1-6 haloalkyl; and the definitions of cycloA, Y1, Y2, R1, Rb, Rc, and Rd are as described in claim 1 or 2.

10. The compound as claimed in claim 9, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutical salt thereof, wherein the compound has a structure as shown in formulas (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VIi), (VIj), (VIk), (VIl), (VIm), (VIn), (VIo), (VIp), (VIq), (VIr), (VIs), (VIt), (VIu), (VIv), or (VIw): wherein, The definitions of rings A, R1, and Rb are as described in request item 1 or 2.

11. The compound as claimed in claim 3, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutical salt thereof, wherein ring A is selected from phenyl, pyridinyl, morpholinyl, pyridoneyl, or cyclohexenyl; wherein the phenyl, pyridinyl, morpholinyl, pyridoneyl, or cyclohexenyl may optionally be further substituted by one or more Ra, each Ra being independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, C2-6 ynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylenyl, or 3-8 membered heterocyclic groups.

12. The compound as claimed in claim 11, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutical salt thereof, wherein ring A is selected from phenyl, and the phenyl may optionally be further substituted by one or more Ra groups selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylenyl, or 3-8 membered heterocyclic groups.

13. The compound as claimed in claim 11, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutical salt thereof, wherein ring A is selected from pyridinyl, which may optionally be further substituted by one or more Ra groups, wherein Ra is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, C2-6 ynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylenyl, or 3-8 membered heterocyclic groups.

14. The compound as claimed in claim 11, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutical salt thereof, wherein ring A is selected from...

15. The compound as claimed in claim 11, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutical salt thereof, wherein ring A is selected from...

16. The compound as claimed in claim 11, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutical salt thereof, wherein ring A is selected from...

17. The compound as claimed in claim 11, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutical salt thereof, wherein R1 is selected from an ethynyl group substituted with Rg, and Rg is selected from hydrogen, deuterium, C1-6 alkyl, C3-12 cycloalkyl, C6-12 aryl, 3-8 heterocyclic, or 5-14 heteroaryl, wherein the C1-6 alkyl, C3-12 cycloalkyl, C6-12 aryl, 3-8 heterocyclic, or 5-14 heteroaryl may optionally be further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 ethynyl, C3-6 cycloalkyl, C1-6 alkylenyl, or 3-8 heterocyclic.

18. The compound of claim 11 or a stereoisomer, tautomer, deuterated derivative or pharmaceutical salt thereof, wherein R1 is selected from a cyclopropyl group substituted with one or more Rg groups, wherein Rg is selected from hydrogen, deuterium, C1-6 alkyl, C2-6 alkynyl, C6-12 aryl, 3-8 heterocyclic or 5-14 heteroaryl groups, wherein the C1-6 alkyl, C2-6 alkynyl, C6-12 aryl, 3-8 heterocyclic or 5-14 heteroaryl groups may optionally be further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkylenyl or 3-8 heterocyclic groups.

19. The compound as claimed in claim 11, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutical salt thereof, wherein R1 is selected from a methyl group substituted with one or more Rg groups, wherein Rg is selected from hydrogen, deuterium, halogen, C1-6 alkyl, C3-12 cycloalkyl, C6-12 aryl, 3-8 heterocyclic, or 5-14 heteroaryl groups, wherein the C1-6 alkyl, C3-12 cycloalkyl, C6-12 aryl, 3-8 heterocyclic, or 5-14 heteroaryl groups may optionally be further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkylenyl, or 3-8 heterocyclic groups.

20. The compound of claim 11 or a stereoisomer, tautomer, deuterated derivative or pharmaceutical salt thereof, wherein R1 is selected from an ethyl group substituted with one or more Rg groups, wherein Rg is selected from hydrogen, deuterium, halogen, C1-6 alkyl, C3-12 cycloalkyl, C6-12 aryl, 3-8 heterocyclic or 5-14 heteroaryl groups, wherein the C1-6 alkyl, C3-12 cycloalkyl, C6-12 aryl, 3-8 heterocyclic or 5-14 heteroaryl groups may optionally be further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkylenyl or 3-8 heterocyclic groups.

21. The compound as claimed in claim 11, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutical salt thereof, wherein R1 is selected from -O(CH2)pRg-, p is selected from 0, 1, 2, 3, or 4, and Rg is selected from hydrogen, deuterium, halogen, hydroxyl, C1-6 alkyl, C3-12 cycloalkyl, C1-6 alkylamino, C6-12 aryl, 3-8 membered heterocyclic, or 5-14 membered heteroaryl, wherein C1- The 6-alkyl, C3-12 cycloalkyl, C1-6 alkylamino, C6-12 aryl, 3-8 heterocyclic or 5-14 heteroaryl groups may optionally be further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkane, C1-6 hydroxyalkyl or 3-8 heterocyclic groups.

22. The compound as claimed in claim 11, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutical salt thereof, wherein R1 is selected from -O(CH2)pRg-, p is selected from 0, 1, 2, 3, or 4, and Rg is selected from hydrogen, deuterium, halogen, hydroxyl, C1-6 alkyl, C3-12 cycloalkyl, C1-6 alkylamino, C6-12 aryl, 3-8 heterocyclic, or 5-14 heteroaryl, wherein the C1-6 alkyl, C3-12 cycloalkyl, C1-6 alkylamino, C6-12 aryl, 3-8 heterocyclic, or 5-14 heteroaryl may optionally be further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkylenyl, or 3-8 heterocyclic.

23. The compound as claimed in claim 11, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutical salt thereof, wherein R1 is selected from -(CH2)qORg-, q is selected from 0, 1, 2, 3, or 4, and Rg is selected from hydrogen, deuterium, halogen, hydroxyl, C1-6 alkyl, C6-12 aryl, 3-8 heterocyclic, or 5-14 heteroaryl, wherein the C1-6 alkyl, C6-12 aryl, 3-8 heterocyclic, or 5-14 heteroaryl may optionally be further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkylenyl, or 3-8 heterocyclic.

24. The compound as claimed in claim 11, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutical salt thereof, wherein R1 is selected from...

25. The compound as claimed in claim 11, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutical salt thereof, wherein R1 is selected from...

26. The compound as claimed in claim 11, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutical salt thereof, wherein the compound is selected from the following compounds:

27. A pharmaceutical composition comprising a therapeutically effective amount of a compound as claimed in any one of claims 1-26, or a stereoisomer, tautomer, deuterated compound, or pharmaceutical salt thereof.

28. Use of a compound or stereoisomer, tautomer, deuterated compound or pharmaceutical salt thereof, as described in any one of claims 1-26, or a pharmaceutical composition as described in claim 27, in the preparation of a medicament for treating POLθ-mediated diseases or conditions and related diseases or conditions.

29. The use as described in claim 28, wherein the POLθ-mediated disease or condition and related diseases or conditions are selected from tumors or cancer.

30. The use as described in claim 29, wherein the cancer is characterized by any one or more of the following: 1) the cancer is characterized by homologous recombination (HR) deficiency, reduced or absent expression of HR-related genes; 2) the cancer is characterized by reduced or absent expression of BRCA genes, absence of BRAC genes, or reduced function of BRCA proteins; 3) the cancer is characterized by absence of the 53BP1 / Shieldin complex; 4) the cancer is characterized by increased dependence on MMEJ DSB repair; 5) the cancer is characterized by treatment with or without PARPi drugs, or resistance to PARPi treatment.

31. The use as described in claim 29 or 30, wherein the tumor or cancer is selected from soft tissue cancer, rhabdomyosarcoma, multiple myeloma, uterine cancer, peripheral nervous system cancer, rhabdomyosarcoma, bone cancer, colorectal cancer, mesothelioma, breast cancer, ovarian cancer, lung cancer, fibroblastic cancer, central nervous system cancer, urinary tract cancer, upper gastrointestinal cancer, skin cancer, pancreatic cancer, lymphoma, and leukemia.

32. Use of a compound of formula (M), or a stereoisomer, tautomer, deuterated derivative, or pharmaceutical salt thereof, in the preparation of a compound or a stereoisomer, tautomer, deuterated derivative, or pharmaceutical salt thereof as described in any one of claims 1-26: wherein, RM1 is selected from iodine, pinacol diboronic acid ester (Bpin) or ring A, as defined in claim 1; and RM2 is selected from hydrogen or C1-6 alkyl.