Heterocyclic amide compound and use thereof in medicine

Abstract

The present invention relates to the technical field of medicine, and in particular to a Polθ inhibitor, a preparation method therefor and a use thereof in medicine. The present invention provides a Polθ inhibitor represented by formula (Ia) or (Ib), a composition comprising same and a use thereof, wherein the compound can be used for treating or preventing Polθ-mediated diseases or disorders and related diseases or disorders.

Description

Heterocyclic amide compound and medical use thereof TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a heterocyclic amide compound represented by formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof, and use thereof in the preparation of a medicament for treating related diseases. BACKGROUND

[0002] DNA damage is commonly in the form of single-strand break, double-strand break (DSB) and base damage, among which DSB is the most serious. If DSB cannot be repaired in time, chromosome will appear abnormal such as breakage, deletion and rearrangement. Therefore, timely repair of DSB plays an important role in maintaining the stability of genome, ensuring cell survival and inhibiting the occurrence and development of tumor. Repair of double-strand DNA break can be roughly divided into three main ways: homologous recombination repair (HR), a repair process using homologous double-strand DNA as a template to synthesize DNA, which has high fidelity and low mismatch repair rate; non-homologous end joining (NHEJ), which captures the damaged end of double-strand DNA break, and directly connects the damaged end by protein interaction, which is an error-prone repair process; microhomology-mediated end joining (MMEJ), a more extensive and error-prone end joining mechanism, also known as alternative end-joining (alt-EJ), which is driven by the annealing of microhomologous sequences on the DNA end.

[0003] Under normal circumstances, MMEJ occurs as an alternative repair to HR at a very low proportion, but in HR-deficient cells, MMEJ becomes the main DSB repair method. For example, in BRCA gene-deficient cancer cells, the HR repair method is impaired, and MMEJ becomes the main repair pathway of DSB. In this process, DNA polymerase theta (Polθ) plays a very key role. Polθ replaces RPA at the excised DSB to facilitate the annealing of microhomologous ssDNA, and then synthesizes DNA to fill the excised gap, completing the ligation of the damaged end. 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 expression up-regulation is associated with poor prognosis of cancer. Homologous recombination repair deficiency (HRD) is prevalent in these tumors, and tumor suppressor genes related to DNA repair (including BRCA1, BRCA2, ATM and FANCD2) are deleted.

[0004] Research on Polθ provides a new targeting strategy for tumor treatment. In cancer cells with impaired or inactivated HR and NHEJ, the repair of DSB is highly dependent on the MMEJ process, and if the activity of Polθ is inhibited, the cell will lose the ability to perform MMEJ, so that DSB cannot be repaired in time, and long-term accumulation leads to death of cancer cells. Therefore, for tumor patients carrying HRD such as BRCA1 / 2 mutations, Polθ inhibitors can be used in combination with PARP inhibitors to achieve a synergistic effect of killing tumors; in addition, patients receiving PARP inhibitor maintenance therapy will develop drug resistance, which may be due to the occurrence of genetic mutations that partially restore the activity of the HR pathway, for example, the loss of TP53BP1, at this time, the HR repair method is mainly Polθ-dependent MMEJ, so Polθ inhibitors can also overcome the resistance to PARP inhibitors, bringing good news to more patients.

[0005] In summary, Polθ inhibitors can provide a new strategy for targeted therapy of tumors with homologous recombination repair deficiency, and there is a huge unmet clinical need, and the development of new and efficient Polθ inhibitors has great scientific research significance and clinical value. The present application aims to provide a novel heterocyclic amide derivative and its use, and the described compound has excellent Polθ inhibitory activity and can be used as a Polθ inhibitor for the treatment of related tumors or cancers. SUMMARY

[0006] The technical problem solved by the present application is to provide a novel heterocyclic amide compound, which can be used as a Polθ inhibitor, for preparing a drug for treating Polθ-mediated diseases or disorders and related diseases or disorders.

[0007] A heterocyclic amide compound is a compound having the following general structure (I), an isomer or a pharmaceutically acceptable salt thereof:

[0008] Among them:

[0009] Ring C is selected from

[0010] U', V', Z', and W' are each independently selected from and at least one of U', V', Z', and W' is selected from

[0011] R u , R v , R w , R x are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylsulfone, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, substituted or unsubstituted C 6-12 aryl; when C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfone, C 1-6 alkylthio, C 1-6 alkylamino, 4-10 membered heterocyclyl, 5-14 membered heteroaryl, C 6-12 aryl is substituted by at least one of deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylsulfone, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted C 1-6 alkylaliphatic, substituted or unsubstituted C 1-6 alkylacyl, substituted or unsubstituted C 1-6 alkylamido, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 alkylsulfonamido, substituted or unsubstituted C 1-6 phosphoryl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, C 6- 14 aryl; further, when C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfone, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylaliphatic, C 1-6 alkylacyl, C 1-6 alkylamido, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamido, C 1-6 phosphoryl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, C 6-14 aryl, when substituted, can be substituted with at least one of the following: deuterium, halogen, cyano, nitro, hydroxyl, amino, thiol, oxo, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylsulfone, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted C 1-6 alkylaliphatic, substituted or unsubstituted C 1-6 alkylacyl, substituted or unsubstituted C 1-6 alkylamido, substituted or unsubstituted C 1-6alkylsulfonyl, substituted or unsubstituted C 1-6 alkylsulfonamido, substituted or unsubstituted C 1-6 phospholipidyl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, substituted or unsubstituted C 6-12 aryl; further, when C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfone, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylaliphatic, C 1-6 alkylacyl, C 1-6 alkylamido, C 1-6 alkylsulfonyl, C 1- 6alkylsulfonamido, C 1-6 phospholipidyl, 3-8 membered heterocyclyl, 5-14 membered heteroaryl, C 6-12 aryl, when substituted, can be substituted with at least one of deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C 1-6 alkyl;

[0012] R y and R z are connected to each other and to a common carbon atom to form a 3-8 membered aliphatic or heterocyclic ring, which can be substituted with at least one of deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1- 6alkoxy, C 1-6 alkylsulfone, C 1-6 alkylthio, C 1-6 alkylamino, 4-10 membered heterocyclyl, 5-14 membered heteroaryl, or C 6-12 aryl;

[0013] n1 is selected from 0, 1, 2, or 3;

[0014] X’, Y a and Y b are each independently selected from N or CR 1a ;

[0015] R 1a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylsulfone, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted C 1-6 alkylaliphatic, substituted or unsubstituted C 1-6 alkylacyl, substituted or unsubstituted C 1-6 alkylamido, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 alkylsulfonamido, substituted or unsubstituted C 1-6 phosphoryl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, C 6-14 aryl; when C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfone, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylaliphatic, C 1-6 alkylacyl, C 1-6 alkylamido, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamido, C 1-6 phosphoryl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, C 6-14 aryl, when substituted, can be substituted with at least one of the following: deuterium, halogen, cyano, nitro, hydroxyl, amino, thiol, oxo, C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylsulfone, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted C 1-6 alkylaliphatic, substituted or unsubstituted C 1-6 alkylacyl, substituted or unsubstituted C 1-6 alkylamido, substituted or unsubstituted C 1-6alkylsulfonyl, substituted or unsubstituted C 1-6 alkylsulfonamido, substituted or unsubstituted C 1-6 phosphatidyl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, substituted or unsubstituted C 6-12 aryl; further, when C 1-6 alkyl, C 2-6 alkenyl, C 2- alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfone, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkanoid, C 1-6 alkylacyl, C 1-6 alkylamido, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamido, C 1-6 phosphatidyl, 3-8 membered heterocyclyl, 5-14 membered heteroaryl, C 6-12 aryl; further, when C 1-6 alkyl;

[0016] ring B is 3-18 membered heterocyclyl, 5-10 membered heteroaryl, C 6-14 aryl or 4-10 membered cycloalkenyl; further, when ring B is substituted, it can be substituted with at least one of deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylsulfone, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C 1-6 alkanoid, substituted or unsubstituted C 1-6 alkylacyl, substituted or unsubstituted C 1-6 alkylamido, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 alkylsulfonamido; further, when C 1-6 alkyl, C 2-6 alkenyl, C 2- alkynyl, C 3-6cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfone, C 1-6 alkylthio, C 1-6 alkylamino, 3-8 membered heterocyclyl, C 1-6 alkylaliphatic, C 1-6 alkylacyl, C 1-6 alkylamido, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamido, when substituted, can be substituted with at least one of deuterium, halogen, cyano, nitro, hydroxyl, amino, thiol, oxo, C 1-6 alkyl, substituted or unsubstituted C 2- alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylsulfone, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted C 1-6 alkylaliphatic, substituted or unsubstituted C 1-6 alkylacyl, substituted or unsubstituted C 1-6 alkylamido, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 alkylsulfonamido, substituted or unsubstituted C 1-6 phospholipid, 3-8 membered heterocyclyl, 5-14 membered heteroaryl, C 6-12 aryl; further, when C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfone, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylaliphatic, C 1-6 alkylacyl, C 1-6 alkylamido, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamido, C 1-6 phospholipid, 3-8 membered heterocyclyl, 5-14 membered heteroaryl, C 6-12 aryl, when substituted, can be substituted with at least one of deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C 1-6 alkyl;

[0017] L is a covalent bond, substituted or unsubstituted C 1-6 alkylene, substituted or unsubstituted C 2-6 alkenylene, substituted or unsubstituted C 2-6 alkynylene, substituted or unsubstituted C 3-8 cycloalkylene, substituted or unsubstituted C 6-10 arylene, substituted or unsubstituted C 1-6 alkyleneoxy, substituted or unsubstituted C 1-6 alkylene sulfone, substituted or unsubstituted C 1-6 alkylene sulfide, substituted or unsubstituted C 1-6 alkylene amine, when C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 3-8 cycloalkylene, C 6-10 arylene, C 1-6 alkyleneoxy, C 1-6 alkylene sulfone, C 1-6 alkylene sulfide, C 1-6 alkylene amine, when substituted, can be substituted with at least one of deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkyl sulfone, C 1-6 alkyl sulfide, C 1-6 alkyl amine, 3-8 membered heterocyclyl;

[0018] R L selected from substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkyl sulfone, substituted or unsubstituted C 1-6 alkyl sulfide, substituted or unsubstituted C 1-6 alkyl amine, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 2-9 heterocyclyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 2-10 heteroaryl; when C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl, C 2-10 heteroaryl, when substituted, can be substituted with at least one of deuterium, halogen, cyano, nitro, hydroxyl, amino, thiol, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylcarboxy, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonylamino, C 1-6 phospholipid, 3-8 membered heterocyclyl, 5-14 membered heteroaryl, or C 6-12 aryl; further, when C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1- alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylcarboxy, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonylamino, C 1-6 phospholipid, 3-8 membered heterocyclyl, 5-14 membered heteroaryl, or C 6-12 aryl, when substituted, can be substituted with at least one of deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C 1-6 alkyl;

[0019] heterocyclyl, heteroaryl contain at least one heteroatom selected from N, O, or S.

[0020] Preferably, a heterocyclic amide compound can be a compound of structural formula (II) or a pharmaceutically acceptable salt thereof:

[0021] wherein U', V', Z', W', ring B, L and R L are defined as in formula (I).

[0022] More preferably, a heterocyclic amide compound can be a compound of structural formula (IIA) or a pharmaceutically acceptable salt thereof:

[0023] wherein ring B is selected from

[0024] R L is selected from substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 6-14 aryl; when C 3-6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, C 6-14 aryl is substituted, it can be substituted with at least one of halogen, hydroxyl, amino, cyano, oxo, C 1-6 alkyl;

[0025] R u is selected from hydrogen, deuterium, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl; when C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl is substituted, it can be substituted with at least one of hydroxyl, amino, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted 3-8 membered heterocyclyl; further, when C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylsulfonyl, 3-8 membered heterocyclyl is substituted, it can be substituted with at least one of halogen, hydroxyl, amino, cyano, oxo;

[0026] R B , R B are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylsulfone, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted C 1-6 alkylaliphatic, substituted or unsubstituted C 1-6 alkylacyl, substituted or unsubstituted C 1-6 alkylamido, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 alkylsulfonamido, substituted or unsubstituted C 1-6 phosphoryl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, C 6-14 aryl; when C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfone, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylaliphatic, C 1-6 alkylacyl, C 1-6 alkylamido, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamido, C 1-6 phosphoryl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, C 6-14 aryl, when substituted, can be substituted with at least one of the following: deuterium, halogen, cyano, nitro, hydroxyl, amino, thiol, oxo, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylsulfone, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted C 1-6 alkylaliphatic, substituted or unsubstituted C 1-6 alkylacyl, substituted or unsubstituted C 1-6 alkylamido, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C1-6 alkylsulfonamide group, substituted or unsubstituted C 1-6 phospholipid group, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, substituted or unsubstituted C 6-12 aryl; further, when C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfone group, C 1-6 alkylthio group, C 1-6 alkylamino group, C 1-6 alkylaliphatic group, C 1-6 alkylacyl group, C 1-6 alkylamide group, C 1-6 alkylsulfonyl group, C 1-6 alkylsulfonamide group, C 1-6 phospholipid group, 3-8 membered heterocyclyl, 5-14 membered heteroaryl, C 6-12 aryl, when substituted, can be substituted with at least one of deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C 1-6 alkyl;

[0027] heterocyclyl, heteroaryl contain at least one heteroatom selected from N, O or S;

[0028] R y and R z are as defined in general formula (I).

[0029] More preferably, a heterocyclic amide compound can be a compound shown in general structural formula (IIB) or a pharmaceutically acceptable salt thereof:

[0030] wherein R L is selected from substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 6-14 aryl, substituted or unsubstituted C 2-6 alkynyl; when C 3-6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, C 6-14 aryl, C 2-6 alkynyl, when substituted, can be substituted with at least one of halogen, hydroxyl, amino, cyano, oxo, C 1-6 alkyl;

[0031] heterocyclyl, heteroaryl contain at least one heteroatom selected from N, O or S;

[0032] R y , R z , ring B and R u are as defined in general formula (IIA).

[0033] More preferably, a heterocyclic amide compound can be a compound shown in general formula (IIC) or a pharmaceutically acceptable salt thereof:

[0034] wherein L is selected from -OCH2-, -CH2-;

[0035] R L is selected from substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 6-14 aryl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 6- 14 aryl, substituted or unsubstituted C 2-6 alkynyl; when C 3-6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, C 6-14 aryl, C 2-6 alkynyl is substituted, it can be substituted by at least one of halogen, hydroxyl, amino, cyano, oxo, substituted or unsubstituted C 1-6 alkyl; further, when C 1-6 alkyl is substituted, it can be substituted by at least one of hydroxyl;

[0036] the heterocyclyl and heteroaryl contain at least one heteroatom selected from N, O or S;

[0037] R y , R z , ring B and R u are as defined in general formula (IIA).

[0038] More preferably, a heterocyclic amide compound can be a compound shown in general formula (IID) or a pharmaceutically acceptable salt thereof:

[0039] wherein U', V', Z', W' are each independently selected from and at least one of U', V', Z', W' is selected from

[0040] n1 is 1;

[0041] Ru , R v , R w , R x , R y , and R z are defined as in general formula (I);

[0042] ring B and R L are defined as in general formula (IIA).

[0043] Preferably, the heterocyclic amide compound can be a compound as shown in general formula (III) or a pharmaceutically acceptable salt thereof:

[0044] wherein U', V', Z', and W' are each independently selected from and at least one of U', V', Z', and W' is selected from

[0045] n1 is selected from 0, 1, 2, or 3;

[0046] R u , R v , R w , R x are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylsulfone, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, substituted or unsubstituted C 6-12 aryl; when C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfone, C 1-6 alkylthio, C 1-6 alkylamino, 4-10 membered heterocyclyl, 5-14 membered heteroaryl, C 6-12 aryl is substituted with at least one of deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, substituted or unsubstituted C 1-6alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylsulfone, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted C 1-6 alkyl ester, substituted or unsubstituted C 1-6 alkyl acyl, substituted or unsubstituted C 1-6 alkyl amide, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 alkylsulfonamide, substituted or unsubstituted C 1-6 phosphoryl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 6- 14 aryl;

[0047] heterocyclyl, heteroaryl containing at least one heteroatom selected from N, O or S;

[0048] R y , R z , ring B and R L are as described in general formula (IIA).

[0049] In one aspect, the present application provides a heterocyclic amide compound represented by general formula (Ia) or (Ib), stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof:

[0050] wherein ring A is selected from 3-14 membered heterocyclyl, 5-14 membered heteroaryl, C 6-14 aryl or 4-10 membered cycloalkenyl; said 3-14 membered heterocyclyl, 5-14 membered heteroaryl, C6-C 14 aryl or 4-10 membered cycloalkenyl can be optionally further substituted by one or more R a ;

[0051] said X is selected from N or CR2; each R2is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or C 1-6 haloalkyl;

[0052] The Y1 and Y2 are each independently selected from N or CR4; the R4 are each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1- 6 alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or C 1-6 alkyl halide;

[0053] The U, V, W, and Z are each independently selected from -(C=O)-, -SO2-, -O-, -NR b -、-(CR c R d ) n -or-CR e R f -, and at least one of U, V, W, Z is selected from -CR e R f -;

[0054] Said n is selected from 0, 1, 2 or 3;

[0055] The R e 、R f and the atoms it is connected to together form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group; said C 3-12 The cycloalkyl or 3-12 membered heterocyclic group may be further optionally substituted by one or more R a replaced by;

[0056] The R a 、R b 、R c 、R d are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Alkyl ester, C 1-6 Alkyl acyl, C 1-6 Alkylamide, C 1-6 Alkylsulfonyl, C 1-6 Alkylsulfonamide, C 1-6 Phosphoryl, 3-8 membered heterocyclic group, 5-14 membered heteroaryl or C 6-12 Aryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C1-6 alkoxy, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkyl ester, C 1-6 alkyl acyl, C 1-6 alkyl amide, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide, C 1-6 phosphoryl, 3-8 membered heterocyclyl, 5-14 membered heteroaryl or C 6-12 aryl can be optionally further substituted by one or more hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkyl acyl, 4-10 membered heterocyclyl, 5-14 membered heteroaryl or C 6-12 aryl substituted;

[0057] said R1is selected from halogen, cyano, amino, -OR g -, C g alkyl substituted by one or more R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 8cycloalkyl, 3-8 membered heterocyclyl, 5-14 membered heteroaryl, C 6-10 aryl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio or C 1-6 alkylamino;

[0058] said R g is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 12 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6alkylsulfonyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl, C 6-12 aryl, 3-8 membered heterocyclyl, or 5-14 membered heteroaryl; said C 1-6 alkylsulfonyl, C 2-6 alkylsulfonyl, C 2-6 alkylsulfonyl, C 3-12 alkylsulfonyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl, C 6-12 aryl, 3-8 membered heterocyclyl, or 5-14 membered heteroaryl; said C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl, C 2-6 alkylsulfonyl, C 2-6 alkylsulfonyl, C 3-10 alkylsulfonyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl, C 6-12 aryl, 3-8 membered heterocyclyl, or 5-14 membered heteroaryl; said C

[0059] In a further preferred aspect is a compound according to Formula (Ia) or (Ib), or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein R1is selected from C g alkylsulfonyl, C 1-6 alkylsulfonyl, C 2-6 alkylsulfonyl, C 2-6 alkylsulfonyl, C 3-8 alkylsulfonyl, C 6-10 alkylsulfonyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl, C

[0060] alkylsulfonyl, C gselected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 12 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfone, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkyl ester, C 1-6 alkyl acyl, C 1-6 alkyl amide, C 1-6 alkyl sulfonyl, C 1-6 phosphoryl, C 6-12 aryl, 3-8 membered heterocyclyl, or 5-14 membered heteroaryl; said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfone, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkyl ester, C 1-6 alkyl acyl, C 1-6 alkyl amide, C 1-6 alkyl sulfonyl, C 1-6 phosphoryl, C 6-12 aryl, 3-8 membered heterocyclyl, or 5-14 membered heteroaryl can be optionally further substituted with one or more hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfone, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkyl acyl, 4-10 membered heterocyclyl, 5-14 membered heteroaryl, or C 6-12 aryl.

[0061] In some embodiments, the compound is a compound of Formula (IIa) or (IIb), or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof:

[0062] wherein the definitions of ring A, Y1, Y2, U, V, W, Z, R1are as described in general formula (Ia) or (Ib).

[0063] In some embodiments, the compound is a compound having the following formula (IIIa) or (IIIb), or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof:

[0064] wherein each of U, V, and W is independently selected from -(C=O)-, -SO2-, -O-, -NR b -CR c R d - or -CR e R f -; and at least one of U, V, and W is selected from -CR e R f -;

[0065] the definitions of ring A, Y1, Y2, R1, R b , R c , R d , R e , R f are as described in general formula (Ia) or (Ib).

[0066] In some embodiments, the compound is a compound having the following formula (IVa), (IVb), (IVc), (IVd), (IVe), or (IVf), or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof:

[0067] wherein each of U, V, and W is independently selected from -(C=O)-, -SO2-, -O-, -NR b -CR c R d -;

[0068] each of m and t is independently selected from 0, 1, 2, 3, 4, or 5, and m and t are not simultaneously 0;

[0069] Q is selected from O, S, SO2, C(R3)2, or NR3; each R3is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, or C 1-6 haloalkyl;

[0070] the definitions of ring A, Y1, Y2, R1, R b , R c , R dThe definition of is as described in the general formula (Ia) or (Ib).

[0071] In some embodiments, the compound has a structure represented by 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), or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof:

[0072] Wherein, R3 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or C 1-6 alkyl halide;

[0073] Ring A, R1, R b The definition of is as described in the general formula (Ia) or (Ib).

[0074] In some embodiments, the compound has a structure represented by Formula (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), (Vk), (Vl), (Vm), (Vn), (Vo), (Vp), (Vq), (Vr), (Vs), (Vt), (Vu), or (Vv):

[0075] Wherein, R3 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or C 1-6 alkyl halide;

[0076] Ring A, R1, R b The definition of is as described in the general formula (Ia) or (Ib).

[0077] In some embodiments, the compound has a structure represented by the following formula (IIIc) or (IIId), or a stereoisomer, tautomer, deuterated compound, or pharmaceutically acceptable salt thereof:

[0078] Wherein, U, V, W, and Z are each independently selected from -(C=O)-, -SO2-, -O-, -NR b -、-CR c R d -or-CR e Rf - and at least one of U, V, W, Z is selected from -CR e R f -;

[0079] ring A, Y1, Y2, R1, R b , R c , R d , R e , R f are as described in Formula (la) or (lb).

[0080] In some embodiments, the compound is a compound of Formula (IVg), (IVh), (IVi), (IVj), or (IVk), or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof:

[0081] wherein each of U, V, W, Z is independently selected from -(C=0)-, -SO2-, -0-, -NR b - or -CR c R d -;

[0082] each of m and t is independently selected from 0, 1, 2, 3, 4, or 5, and m and t are not simultaneously 0;

[0083] Q is selected from O, S, SO2, C(R3)2, or NR3; each R3is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, or C 1-6 haloalkyl;

[0084] ring A, Y1, Y2, R1, R b , R c , R d are as described in Formula (la) or (lb).

[0085] In some embodiments, the compound is a compound of Formula (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 a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof:

[0086] wherein ring A, R1, Rb The definition of is as described in the general formula (Ia) or (Ib).

[0087] In some embodiments, the ring A is selected from phenyl, pyridyl, morpholinyl, pyridonyl or cyclohexenyl; the phenyl, pyridyl, morpholinyl, pyridonyl or cyclohexenyl may be further optionally substituted with one or more R a Substituted, the R a Each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 an alkylsulfone group or a 3-8 membered heterocyclic group.

[0088] In some embodiments, the ring A is selected from phenyl, which may be further optionally substituted with one or more R a Substituted, the R a Selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 an alkylsulfone group or a 3-8 membered heterocyclic group.

[0089] In some embodiments, the ring A is selected from pyridyl, which may be further optionally substituted with one or more R a Substituted, the R a Selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 an alkylsulfone group or a 3-8 membered heterocyclic group.

[0090] In some embodiments, the ring A is selected from

[0091] In some embodiments, the ring A is selected from

[0092] In some embodiments, the ring A is selected from

[0093] In some embodiments, said R1is selected from substituted ethynyl, said R g substituted ethynyl, said R g is selected from hydrogen, deuterium, C 1-6 alkyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-8 membered heterocyclyl, or 5-14 membered heteroaryl, said C 1-6 alkyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-8 membered heterocyclyl, or 5-14 membered heteroaryl can be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfone, or 3-8 membered heterocyclyl.

[0094] In some embodiments, said R1is selected from substituted cyclopropyl, said R g substituted cyclopropyl, said R g is selected from hydrogen, deuterium, C 1-6 alkyl, C 2- 6alkynyl, C 6-12 aryl, 3-8 membered heterocyclyl, or 5-14 membered heteroaryl, said C 1-6 alkyl, C 2-6 alkynyl, C 6-12 aryl, 3-8 membered heterocyclyl, or 5-14 membered heteroaryl can be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfone, or 3-8 membered heterocyclyl.

[0095] In some embodiments, said R1is selected from substituted methyl, said R g substituted methyl, said R g is selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-8 membered heterocyclyl, or 5-14 membered heteroaryl, said C 1-6 alkyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-8 membered heterocyclyl, or 5-14 membered heteroaryl can be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfone or 3-8 membered heterocyclyl substituted.

[0096] In some embodiments, said R1is selected from -O(CH2) g substituted ethyl, said R g selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, said C 1-6 alkyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl can be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfone or 3-8 membered heterocyclyl substituted.

[0097] In some embodiments, said R1is selected from -O(CH2) p R g -, said p is selected from 0, 1, 2, 3 or 4, said R g selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 3-12 cycloalkyl, C 1-6 alkylamino, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, said C 1-6 alkyl, C 3-12 cycloalkyl, C 1-6 alkylamino, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl can be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfone, C 1-6 hydroxyalkyl or 3-8 membered heterocyclyl substituted.

[0098] In some embodiments, said R1is selected from -O(CH2) p Rg - p is selected from 0, 1, 2, 3, or 4, and R g is selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 3-12 cycloalkyl, C 1-6 alkylamino, C 6-12 aryl, 3-8 membered heterocyclyl, or 5-14 membered heteroaryl, which C 1-6 alkyl, C 3-12 cycloalkyl, C 1-6 alkylamino, C 6-12 aryl, 3-8 membered heterocyclyl, or 5-14 membered heteroaryl can be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfone, or 3-8 membered heterocyclyl.

[0099] In some embodiments, the R1is selected from -(CH2) q OR g - q is selected from 0, 1, 2, 3, or 4, and R g is selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 6-12 aryl, 3-8 membered heterocyclyl, or 5-14 membered heteroaryl, which C 1-6 alkyl, C 6-12 aryl, 3-8 membered heterocyclyl, or 5-14 membered heteroaryl can be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfone, or 3-8 membered heterocyclyl.

[0100] In some embodiments, the R1is selected from

[0101] In some embodiments, the R1is selected from

[0102] In some embodiments, the compound of the present application, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof is selected from the following compounds:

[0103] In another aspect, the present application provides a pharmaceutical composition containing a therapeutically effective amount of a compound 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), (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 a stereoisomer, tautomer, deuterated version, or pharmaceutically acceptable salt thereof.

[0104] In another aspect, the present application provides use of a compound 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), (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) as described above, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a POLQ mediated disease or disorder and related diseases or disorders.

[0105] In another aspect, the present application provides use of a compound 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), (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) as described above, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a POLQ mediated disease or disorder and related diseases or disorders.

[0106] The present application also provides a method of treating a disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound 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), (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) as described above or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof.

[0107] In some embodiments, the disease treated and / or prevented is selected from a POLQ-mediated disease or disorder and related diseases or disorders.

[0108] In some embodiments, the POLQ-mediated disease or disorder and related diseases or disorders are selected from a tumor or cancer.

[0109] In some embodiments, the cancer is characterized by a deficiency in homologous recombination (HR), a decrease or loss of expression of HR-associated genes.

[0110] In some embodiments, the cancer is characterized by a decrease or loss of expression of BRCA genes, a loss of BRAC genes, or a decrease in function of BRCA proteins.

[0111] In some embodiments, the cancer is characterized by a loss of 53BP1 / Shieldin complex.

[0112] In some embodiments, the cancer is characterized by an increased dependence on MMEJ DSB repair.

[0113] In some embodiments, the cancer is characterized by receiving or not receiving PARPi drug treatment, or is resistant to PARPi treatment.

[0114] In some embodiments, the tumor or cancer is selected from a hematological tumor or a solid tumor, including but not limited to soft tissue carcinoma, rhabdoid carcinoma, multiple myeloma, uterine carcinoma, gastric carcinoma, peripheral nervous system carcinoma, rhabdomyosarcoma, bone carcinoma, colorectal carcinoma, mesothelioma, breast carcinoma, ovarian carcinoma, lung carcinoma, fibroblast, central nervous system carcinoma, urinary tract carcinoma, upper gastrointestinal tract carcinoma, kidney carcinoma, skin carcinoma, esophageal carcinoma, and pancreatic carcinoma; the hematological tumor including but not limited to lymphoma and leukemia.

[0115] In another aspect, the present application provides a compound represented by Formula (M), or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof:

[0116] wherein, R M1 is selected from iodo, a pinacolato boronic acid group (Bpin), or ring A, which is defined as in Formula (la) or (lb), R M2 is selected from hydrogen or C 1-6 alkyl.

[0117] In some embodiments, the present application provides an intermediate compound M1, which is 5'-iodo-l'-methyl-2'-oxospiro[cyclopropane-l,3'-indolin]-6'-carboxylic acid methyl ester, and has the following structural formula:

[0118] In some embodiments, the present application provides an intermediate compound M2, which is l'-methyl-2'-oxo-5'-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)spiro[cyclopropane-l,3'-indolin]-6'-carboxylic acid methyl ester, and has the following structural formula:

[0119] In some embodiments, the present application provides an intermediate compound M3, and has the following structural formula:

[0120] wherein, ring A is defined as in Formula (la) or (lb).

[0121] In another aspect, the present application provides use of a compound of Formula (M), or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, as described above, in the manufacture of a compound 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), (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 a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, as described above.

[0122] Unless otherwise indicated, the general chemical terms used in the structural formulae have the usual meanings.

[0123] For example, unless otherwise indicated, the term "halogen" as used herein means fluorine, chlorine, bromine, or iodine.

[0124] In the present application, unless otherwise indicated, "alkyl" includes straight-chain or branched-chain monovalent saturated hydrocarbon groups. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, and the like. Similarly, "C 1-6 " in "alkyl" means a straight-chain or branched-chain group containing 1, 2, 3, 4, 5, or 6 carbon atoms. 1-6

[0125] The term "alkoxy" means the oxygen ether form of the straight-chain or branched-chain alkyl groups described above, i.e., -O-alkyl.

[0126] The term "haloalkyl" means an alkyl group in which one or more H's have been replaced by a halogen atom.

[0127] ​The term "oxo" or "oxo group" refers to an oxygen atom in a bivalent substituent form, which forms a carbonyl group when attached to a C and a sulfoxide or sulfone group or an N-oxide group when attached to a heteroatom.

[0128] The term "cycloalkyl" refers to a ring system having at least one ring of alkyl groups. Preferred C 3-12 cycloalkyl, wherein "C 3-12 " means that the cycloalkyl group can have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring-forming atoms. The cycloalkyl group can include single rings and multiple rings (e.g., having 2, 3, or 4 fused rings, spiro rings, bridged rings, etc.). In some embodiments, cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like; the cycloalkyl group can also be fused to an aryl, heterocyclyl, or heteroaryl ring, where the ring that is attached to the parent structure together is a cycloalkyl group.

[0129] The term "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds, such as ethenyl, propenyl, 1,3-butadienyl, cis-butenyl, trans-butenyl, and the like.

[0130] The term "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds, such as ethynyl, propynyl, and the like.

[0131] The term "hydroxyalkyl" refers to a hydroxyl group further substituted with an alkyl group as defined above, i.e., -alkyl-OH, such as C 1-6 hydroxyalkyl, including but not limited to -CH2OH, -C2H5OH, -CH2CH2CH2OH, or -CH(CH3)2OH, and the like.

[0132] The term "alkylthio" refers to a straight or branched chain alkyl group attached through a sulfur atom, i.e., -S-alkyl, such as C 1-6 alkylthio, including but not limited to methylthio, ethylthio, propylthio (including n-propylthio, isopropylthio), butylthio (including n-butylthio, isobutylthio, sec-butylthio, t-butylthio), pentylthio (including n-pentylthio, isopentylthio, neopentylthio), hexylthio (n-hexylthio, 2-methylpentylthio, 3-methylpentylthio, 2,3-dimethylbutylthio, 2,2-dimethylbutylthio), and the like.

[0133] The term "alkylsulfonyl" refers to a straight or branched chain alkyl group attached through a sulfonyl group, i.e., -SO2-alkyl, such as C 1-6 alkylsulfonyl, including but not limited to methylsulfonyl, ethylsulfonyl, propylsulfonyl (including n-propylsulfonyl, isopropylsulfonyl), butylsulfonyl (including n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, t-butylsulfonyl), pentylsulfonyl (including n-pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl), hexylsulfonyl (n-hexylsulfonyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl, 2,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl), and the like.

[0134] The term "alkylamino" refers to an open-chain alkyl group containing a nitrogen atom, such as -NH-alkyl, -N(alkyl)2, -N(alkyl)3, and the like. 1-6 alkylamino groups include, but are not limited to, methylamino, ethylamino, isopropylamino, dimethylamino, methylethylamino, diethylamino, and the like.

[0135] The term "alkylcarbonyl" refers to a straight-chain or branched alkyl group attached through a carbonyl group, i.e., -alkyl-CO-, such as 1-6 alkylcarbonyl groups include, but are not limited to, formyl, acetyl, propionyl (including n-propionyl, isopropionyl), butyryl (including n-butyryl, isobutyryl, sec-butyryl, t-butyryl), valeryl (including n-valeryl, isovaleryl, neovaleryl), hexanoyl (n-hexanoyl, 2-methylvaleryl, 3-methylvaleryl, 2,3-dimethylbutanoyl, 2,2-dimethylbutanoyl), and the like.

[0136] The term "alkylcarbonyl" refers to a straight-chain or branched alkyl group attached through a carbonyl group, i.e., -alkyl-CO-, such as 1-6 alkylcarbonyl groups include, but are not limited to, formyl, acetyl, propionyl (including n-propionyl, isopropionyl), butyryl (including n-butyryl, isobutyryl, sec-butyryl, t-butyryl), valeryl (including n-valeryl, isovaleryl, neovaleryl), hexanoyl (n-hexanoyl, 2-methylvaleryl, 3-methylvaleryl, 2,3-dimethylbutanoyl, 2,2-dimethylbutanoyl), and the like.

[0137] The term "alkylcarbonyl" refers to a straight-chain or branched alkyl group attached through a carbonyl group, i.e., -alkyl-CO-, such as 1-6 alkylcarbonyl groups include, but are not limited to, formyl, acetyl, propionyl (including n-propionyl, isopropionyl), butyryl (including n-butyryl, isobutyryl, sec-butyryl, t-butyryl), valeryl (including n-valeryl, isovaleryl, neovaleryl), hexanoyl (n-hexanoyl, 2-methylvaleryl, 3-methylvaleryl, 2,3-dimethylbutanoyl, 2,2-dimethylbutanoyl), and the like.

[0138] The term "alkylcarbonyl" refers to a straight-chain or branched alkyl group attached through a carbonyl group, i.e., -alkyl-CO-, such as 1-6 alkylcarbonyl groups include, but are not limited to, formyl, acetyl, propionyl (including n-propionyl, isopropionyl), butyryl (including n-butyryl, isobutyryl, sec-butyryl, t-butyryl), valeryl (including n-valeryl, isovaleryl, neovaleryl), hexanoyl (n-hexanoyl, 2-methylvaleryl, 3-methylvaleryl, 2,3-dimethylbutanoyl, 2,2-dimethylbutanoyl), and the like.

[0139] The term "alkylsulfonamido" refers to straight or branched chain alkyl groups attached through a sulfonamido group, i.e., -alkyl-SO2N-, such as C 1-6 alkylsulfonamido groups include, but are not limited to, methanesulfonamido, ethanesulfonamido, propanesulfonamido (including n-propanesulfonamido, isopropanesulfonamido), butanesulfonamido (including n-butanesulfonamido, isobutanesulfonamido, sec-butanesulfonamido, t-butanesulfonamido), pentanesulfonamido (including n-pentanesulfonamido, isopentanesulfonamido, neopentanesulfonamido), hexanesulfonamido (n-hexanesulfonamido, 2-methylpentanesulfonamido, 3-methylpentanesulfonamido, 2,3-dimethylbutanesulfonamido, 2,2-dimethylbutanesulfonamido), and the like.

[0140] The term "phosphoryl" refers to -PO2-, such as C 1-6 phosphoryl groups include, but are not limited to, methanephosphoryl, ethanephosphoryl, propanephosphoryl (including n-propanephosphoryl, isopropanephosphoryl), butanephosphoryl (including n-butanephosphoryl, isobutanephosphoryl, sec-butanephosphoryl, t-butanephosphoryl), pentanephosphoryl (including n-pentanephosphoryl, isopentanephosphoryl, neopentanephosphoryl), hexanephosphoryl (n-hexanephosphoryl, 2-methylpentanephosphoryl, 3-methylpentanephosphoryl, 2,3-dimethylbutanephosphoryl, 2,2-dimethylbutanephosphoryl), and the like.

[0141] The term "aryl", unless otherwise specified, refers to a monocyclic or fused ring aromatic group, including carbon atoms, which is unsubstituted or substituted, in the present application. Preferably C 6-12 aryl groups, more preferably aryl groups are C 6-10 monocyclic or bicyclic aromatic ring groups. Preferably phenyl, naphthyl. The aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl group wherein the ring which is attached to the parent structure together with the parent structure is an aryl ring, non-limiting examples include, but are not limited to, benzocyclopentyl.

[0142] The term "heteroaryl," as used herein, unless otherwise indicated, refers to a monocyclic or polycyclic (e.g., fused bicyclic) aromatic heterocycle having at least one heteroatom selected from N, O, and / or S, and wherein the nitrogen or sulfur heteroatoms can optionally be oxidized, and the nitrogen heteroatoms can optionally be quaternized. Preferred are 5-14 membered heteroaryl, wherein "5-14 membered" in 5-14 membered heteroaryl refers to a heteroaryl group having 5-14 ring-forming C, N, O, or S atoms. More preferred are 5-10 membered heteroaryl, and even more preferred are 5-6 membered heteroaryl. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adenine, quinolinyl, or isoquinolinyl. The heteroaryl group can be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heteroaryl ring.

[0143] The term "heterocyclyl" refers to a ring system having at least one ring cyclized alkyl or cyclized alkenyl group having a heterocycle, the heteroatom selected from N, O, and / or S. The heterocyclyl group can include a single ring or multiple rings (e.g., having 2, 3, or 4 fused rings, spiro rings, bridged rings, etc.). The heterocyclyl group can be attached to the rest of the compound via a ring-forming carbon atom or a ring-forming heteroatom. Preferred are 3-14 membered heterocyclyl, wherein "3-14 membered" in 3-14 membered heterocyclyl refers to a heterocyclyl group having 3-14 ring-forming C, N, O, or S atoms; more preferred are 3-8 membered heterocyclyl, and even more preferred are 5-6 membered heterocyclyl; wherein the nitrogen or sulfur heteroatoms can optionally be oxidized, and the nitrogen heteroatoms can optionally be quaternized. Examples of these heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, 1,2,3,6-tetrahydropyridine, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and tetrahydrooxadiazolyl. The heterocyclyl group can be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heterocyclyl ring.

[0144] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid.

[0145] When the compounds provided herein are acids, their corresponding salts can be conveniently formed from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, as well as salts of cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable non-toxic organic bases from which salts can be derived include ion exchange resins as well as arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0146] When the compounds provided herein are bases, their corresponding salts can be conveniently formed from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. 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, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, cyclohexanesulfamic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluoroacetic acid, tartaric acid, p-toluenesulfonic acid, and the like.

[0147] Prodrugs of the compounds of the present application are included within the scope of the present application. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired compound. Thus, for example, any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of this application which is readily convertible in vivo into the desired compound or its pharmaceutically acceptable salt or solvate is a prodrug within the scope of this application. Prodrugs of the present application can, for example, be biohydrolyzed in vivo by hydrolysis of a carboxylate ester, ether, or amide bond, or other group to form the parent drug. Examples of prodrugs include, but are not limited to, choline ester prodrugs (e.g., choline phosphate), phosphate ester prodrugs, and sulfate ester prodrugs.

[0148] The compounds described herein can contain one or more asymmetric centers and can thus give rise to diastereomers and optical isomers. The present application includes all possible diastereomers and optical isomers and racemic mixtures thereof, substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.

[0149] When tautomers exist for compounds 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), (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), the present application includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, unless otherwise specified.

[0150] The present application also includes all isotopes of atoms occurring in the instant compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0151] The term "pharmaceutical composition" means a mixture of one or more compounds of the present application or pharmaceutically acceptable salts thereof with a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application to an organism.

[0152] In the present application, "a," "an," "the," "at least one," and "one or more" are used interchangeably. Thus, for example, a mixture comprising "a" pharmaceutically acceptable carrier can be interpreted to mean that the pharmaceutical composition includes "one or more" pharmaceutically acceptable carriers.

[0153] The term "pharmaceutically acceptable carrier" means a carrier that does not cause a significant, adverse, toxic, or allergic reaction when administered to an organism. Suitable carriers are well known to persons of ordinary skill in the art, such as carbohydrates, waxes, water soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0154] The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres, aerosols, and the like.

[0155] Typical routes of administering the compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0156] The term "treatment" generally refers to obtaining a desired pharmacologic and / or physiologic effect. The effect can be therapeutic in terms of partially or completely arresting or reversing the symptoms of a disease and / or side effects resulting from the disease. As used herein, "treatment" covers any treatment of a patient, including: (a) inhibiting the symptoms, i.e., arresting their development; or (b) relieving the symptoms, i.e., causing regression of the disease or symptoms.

[0157] The term "effective amount" means the amount of a compound of the present application which (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compound of the present application that will constitute an "effective amount" will vary depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but can be determined routinely by the artisan without undue experimentation.

[0158] Compared with the prior art, the present application has the following advantages:

[0159] Based on the target design of Polθ inhibitors, the present application develops a series of structurally novel heterocyclic amide compounds. The relevant biological tests show that the compounds of the present application can significantly inhibit cell proliferation and Polθ ATPase activity, have excellent anti-tumor in vivo efficacy, and have low hERG toxicity, in vitro liver microsomal metabolism stability, and good pharmacokinetic properties. In addition, the synthesis route of the compounds provided by the present application is novel, safe, environmentally friendly, and has good production feasibility. DETAILED DESCRIPTION

[0160] In order to make the above content clearer and more explicit, the technical solutions of the present application will be further illustrated by the following examples. The following examples are only used to illustrate the specific embodiments of the present application, so that those skilled in the art can understand the present application, but are not used to limit the protection scope of the present application. In the specific embodiments of the present application, the technical means or methods not specifically described are conventional technical means or methods in the art.

[0161] Unless otherwise indicated, all temperatures are in degrees Celsius.

[0162] The following abbreviations are used in the examples:

[0163] 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(diphenylphosphino)ferrocene]dichloropalladium; THF: tetrahydrofuran; HCl: hydrochloric acid; MeOH: methanol; N2: nitrogen; DCM: dichloromethane; NaH: sodium hydride; MeCN: acetonitrile; Pd / C: palladium on carbon; Pd(PPh3)4: tetrakis(triphenylphosphine)palladium; TEA: triethylamine; TCFH: N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate; NMI: N-methylimidazole; HATU: 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; H2O: water; Cs2CO3: cesium carbonate; dioxane: dioxane; NBS: N-bromosuccinimide; Pd2(dpa)3: tris(dibenzylideneacetone)dipalladium; BIDIME: (S)-3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[d][1,3]oxazaphosphinine; K3PO4: potassium phosphate; xylene: xylene; LiOH: lithium hydroxide; Bpin: pinacolato boronic acid group; Boc: tert-butyloxycarbonyl protecting group; LC-MS: liquid chromatography-mass spectrometry; x mL x y in the examples of the present application means repeating y times, each time x mL, for example, extracting with dichloromethane three times (20 mL x 3) means extracting with 20 mL of dichloromethane each time, repeating 3 times; the amount of eluent in the examples of the present application is by volume, for example, a solution of petroleum ether containing 10% ethyl acetate means that the volume ratio of petroleum ether and ethyl acetate is 9:1, PE:EA = 5:1 means that the volume ratio of petroleum ether and ethyl acetate is 5:1.

[0164] In addition, all operations involving easily oxidizable or easily hydrolyzable raw materials are carried out under nitrogen protection. Unless otherwise specified, the raw materials used in the present application are commercially available raw materials, which can be used directly without further purification.

[0165] The raw materials and common intermediates involved in the examples of the present application can be obtained by purchase or self-preparation, and the raw materials and common intermediates that need to be obtained by self-preparation are prepared as follows.

[0166] Preparation route: preparation of key intermediate M1

[0167] Step 1: Synthesis of 1-(tert-butyl) 6-methyl-2-oxoindoline-1,6-dicarboxylate (M1-2)

[0168] 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, the system was warmed to 70 °C and stirred for 3 hours. The system was cooled to room temperature, quenched with water (20 mL), extracted with dichloromethane three times (20 mL x 3), the organic phase was 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, eluent was 10% ethyl acetate in petroleum ether, to give compound M1-2 (400 mg) with a yield of 52.5%.

[0169] LC-MS (m / z): 292.0 [M+H] + .

[0170] Step 2: Synthesis of 1'-(tert-butyl) 6'-methyl 2'-oxospiro[cyclopropane-1,3'-indoline]-1',6'-dicarboxylate (M1-3)

[0171] Compound M1-2 (1.40 g, 4.81 mmol) was dissolved in DMSO (10 mL), potassium carbonate (1.70 g, 1.23 mmol) and dibromoethane (500 μL, 5.77 mmol) were added, the system was stirred at room temperature for 16 hours. The system was quenched with water (20 mL), extracted with ethyl acetate three times (20 mL x 3), the organic phase was combined, washed with water three times (20 mL x 3), 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, eluent was 6% ethyl acetate in petroleum ether, to give compound M1-3 (400 mg) with a yield of 26.3%.

[0172] LC-MS (m / z): 318.0 [M+H] + .

[0173] Step 3: Synthesis of 2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid methyl ester (M1-4)

[0174] Compound M1-3 (400 mg, 1.26 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was added dropwise, the system was stirred at room temperature for 2 hours. The system was added with saturated sodium bicarbonate solution to adjust pH to neutral, extracted with ethyl acetate for three times (20 mL x 3), the organic phase was combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure to obtain the de-Boc product (crude product), which was directly used in the next step reaction.

[0175] LC-MS (m / z): 218.0 [M+H] + .

[0176] Step 4: Synthesis of methyl 1'-methyl-2'-oxospiro[cyclopropane-1,3'-indolin]-6'- carboxylate (M1-5)

[0177] The crude product obtained in the previous step was dissolved in DMF (5 mL), 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. Quench with water, extracted with ethyl acetate for three times (20 mL x 3), the organic phase was combined, washed with water for three times (20 mL x 3), saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography, eluent was 20% ethyl acetate in petroleum ether, to obtain compound M1-5 (130 mg), the total yield of two steps of step 3 and step 4 was 44.6%.

[0178] LC-MS (m / z): 232.0 [M+H] + .

[0179] Step 5: Synthesis of methyl 5'-iodo-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indolin]-6'- carboxylate (M1)

[0180] Compound M1-5 (100 mg, 0.43 mmol) was dissolved in acetonitrile (5 mL), 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, extracted with ethyl acetate for three times (20 mL x 3), the organic phase was combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography, eluent was 5% ethyl acetate in petroleum ether, to obtain compound M1-6 (133 mg), yield 86.1%.

[0181] LC-MS (m / z): 358.0 [M+H] + .

[0182] Preparation of key intermediate M2

[0183] Step 1: Synthesis of methyl 5'-bromo-1'-methyl-2'-oxospiro[cyclopropane-1,3'- indolin]-6'-carboxylate (M2-1)

[0184] Methyl 1'-methyl-2'-oxospiro[cyclopropane-1,3'-indolin]-6'-carboxylate (1.7 g, 7.34 mmol) was dissolved in DMF (10 mL), cooled to 0 °C, and N-bromosuccinimide (1.6 g, 8.83 mmol) was added. The reaction was stirred at room temperature for 16 h. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 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.

[0185] LC-MS (m / z): 310.0 [M+H] + .

[0186] Step 2: Synthesis of methyl 1'-methyl-2'-oxo-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3'-indolin]-6'-carboxylate (M2)

[0187] Compound M2-1 (1.7 g, 5.50 mmol), pinacol diboronic acid (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 an N2 atmosphere and stirred at 90 °C for 2 h. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 5:1) to give compound M2 (700 mg) in 39.6% yield.

[0188] LC-MS (m / z): 358.0 [M+H] + .

[0189] Preparation of key intermediate M3

[0190] Compound M1 undergoes Suzuki coupling with a substituted boronic acid (or compound M2 with a substituted halogen) in the presence of a palladium catalyst to give compound M3-1, which undergoes basic hydrolysis to give compound M3.

[0191] wherein X is selected from bromine or iodine.

[0192] 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'-indolin]-6'-carboxamide (1)

[0193] Step 1: Synthesis of methyl 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[ cyclopropane-1,3'-indolin]-6'-carboxylate (1-1)

[0194] Intermediate M1 (50 mg, 0.14 mmol) was dissolved in dioxane / water (5 mL / 1 mL), (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 successively, the system was replaced with nitrogen atmosphere, and was stirred at 80 °C for 2 hours. It was cooled to room temperature, concentrated under reduced pressure, quenched with water, extracted with ethyl acetate for three times (20 mL x 3), the combined organic phase was 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 with 20% ethyl acetate in petroleum ether as eluent to give compound 1-1 (21 mg) in 40.3% yield.

[0195] LC-MS (m / z): 373.0 [M+H] + .

[0196] Step 2: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane- 1,3'-indolin]-6'-carboxylic acid (1-2)

[0197] Compound 1-1 (500 mg, 1.34 mmol) was dissolved in tetrahydrofuran / water (5 mL / 5 mL), lithium hydroxide monohydrate (200 mg, 4.03 mmol) was added, and the system was stirred at room temperature for 16 hours. It was concentrated under reduced pressure, adjusted to pH 5 with 2N hydrochloric acid, filtered, and the filter cake was dried to give compound 1-2 (460 mg) in 95.6% yield.

[0198] LC-MS (m / z): 357.0 [M-H] - .

[0199] 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'-indolin]-6'-carboxamide (1)

[0200] Compound 1-2 (200 mg, 0.56 mmol) was dissolved in DMF (10 mL), 5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-amine (100 mg, 0.61 mmol), HATU (200 mg, 0.53 mmol) and triethylamine (200 mg, 1.98 mmol) were added successively, the system was stirred at room temperature for 4 hours, then cesium carbonate (398 mg, 1.22 mmol) was added, and the stirring was continued at room temperature for 2 hours. Water (20 mL) was added for quenching, and extraction was performed with ethyl acetate three times (20 mL x 3), the organic phase was combined, washed with water three times (20 mL x 3), 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 with 2.5% methanol in dichloromethane as the eluent, and then purified by preparative liquid chromatography to obtain the target compound 1 (10 mg) with a yield of 3.5%.

[0201] LC-MS (m / z): 506.0 [M+H] + .

[0202] 1 H NMR (400 MHz, DMSO-d6): 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).

[0203] 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'-indolin]-5'-carboxamide (2)

[0204] Step 1: Synthesis of 6-bromo-2-oxoindoline-1-carboxylic acid tert-butyl ester (2-2)

[0205] 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 stirred at 70 °C for 3 h. After cooling to room temperature, the reaction was quenched with water and extracted with dichloromethane (20 mL x 3). The combined organic phase was 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 10% ethyl acetate in petroleum ether as eluent to give compound 2-2 (422 mg) in 80.7% yield.

[0206] LC-MS (m / z): 312.0, 314.0 [M+H] + .

[0207] Step 2: Synthesis of tert-butyl 6'-bromo-2'-oxospiro[cyclopropane-l,3'- dihydroindol]-l'-carboxylate (2-3)

[0208] Compound 2-2 (100 mg, 0.32 mmol) was dissolved in DMSO (3 mL), potassium carbonate (110 mg, 0.80 mmol) and dibromoethane (40 μL, 0.39 mmol) were added, and the mixture was stirred at room temperature for 16 h. The reaction was quenched with water and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with water (20 mL x 3), 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 6% ethyl acetate in petroleum ether as eluent to give compound 2-3 (85 mg) in 78.4% yield.

[0209] LC-MS (m / z): 338.0, 340.0 [M+H] + .

[0210] Step 3: Synthesis of 6'-bromospiro[cyclopropane-l,3'-indolin]-2'-one (2-4)

[0211] Compound 2-3 (400 mg, 1.19 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was added dropwise, and the mixture was stirred at room temperature for 2 h. The pH was adjusted to neutral with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the de-Boc product, which was used directly in the next step.

[0212] LC-MS (m / z): 238.0, 240.0 [M+H] + .

[0213] Step 4: Synthesis of 6'-bromo-l'-methylspiro[cyclopropane-l,3'-indolin]-2'-one (2-5)

[0214] The crude product from the previous step was dissolved in DMF (5 mL), cesium carbonate (760 mg, 2.33 mmol) and iodomethane (200 μί, 3.21 mmol) were added, and the mixture was stirred at room temperature for 16 h. The reaction was quenched with water and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with water (20 mL x 3), 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 20% ethyl acetate in petroleum ether as the eluent to give compound 2-5 (147 mg). The overall yield for the two steps was 49.2%.

[0215] LC-MS (m / z): 252.0, 254.0 [M+H] + .

[0216] Step 5: Synthesis of 6'-bromo-5'-(2-chloroacetyl)-l'-methylspiro[cyclopropane-l,3'- indolin]-2'-one (2-6)

[0217] Compound 2-5 (100 mg, 0.40 mmol) was dissolved in 1,2-dichloroethane (3 mL), and chloroacetyl chloride (70 μί, 0.80 mmol) and aluminum trichloride (210 mg, 1.60 mmol) were added successively under ice-bath cooling, followed by warming and stirring for 3 h. The reaction was quenched with water and extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with 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 25% ethyl acetate in petroleum ether as the eluent to give compound 2-6 (57 mg). The yield was 43.6%.

[0218] LC-MS (m / z): 328.0, 330.0 [M+H] + .

[0219] Step 6: Synthesis of 6'-bromo-l'-methyl-2'-oxospiro[cyclopropane-l,3'-indolin]-5'- carboxylic acid (2-7)

[0220] Compound 2-6 (50 mg, 0.15 mmol) was dissolved in pyridine (3 mL), and the mixture was warmed to 90 °C and stirred for 3 h, and then cooled to 50 °C and stirred for 16 h. The mixture was filtered, and the filter cake was added to 4 N sodium hydroxide solution (5 mL), and the mixture was warmed to 80 °C and stirred for 16 h. The mixture was cooled to room temperature, and the pH was adjusted to 3-4 with 2 N hydrochloric acid. The solid was collected by suction filtration, washed with water, and dried to give compound 2-7, which was used in the next step without further purification.

[0221] LC-MS (m / z): 294.0, 296.0 [M-H] - .

[0222] Step 7: Synthesis of methyl 6'-bromo-l'-methyl-2'-oxospiro[cyclopropane-l,3'- indolin]-5'-carboxylate (2-8)

[0223] The compound 2-7 obtained from above step was dissolved in dry dichloromethane (3 mL), oxalyl chloride (22 μί, 0.17 mmol) and one drop of DMF were added under ice-bath, after stirring at room temperature for 3 hours, 1 mL of methanol was added dropwise, and stirring was continued for 1 hour. Quenching with water, extraction with dichloromethane for three times (20 mL x 3), combined organic phase, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure to give compound 2-8 (27 mg), the total yield of two steps was 57.2%.

[0224] LC-MS (m / z): 310.0, 312.0 [M+H] + .

[0225] Step 8: Synthesis of methyl 6'-(2-chloro-5-methoxypyridin-4-yl)-l'-methyl-2'- oxospiro[cyclopropane-l,3'-indolin]-5'-carboxylate (2-9)

[0226] Compound 2-8 (310 mg, 1.00 mmol) was dissolved in dioxane / water (5 mL / 1 mL), compound (2-chloro-5-methoxypyridin-4-yl)boronic acid (200 mg, 1.10 mmol), l,l'-bis(diphenylphosphino)ferrocene palladium dichloride (73 mg, 0.10 mmol) and potassium carbonate (276 g, 2.00 mmol) were added successively, the system was warmed to 100 °C and stirred for 2 hours. Cooled to room temperature, concentrated under reduced pressure, quenched with water, extracted with ethyl acetate for three times (20 mL x 3), combined organic phase, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography, eluent was 20% ethyl acetate in petroleum ether, to give compound 2-9 (340 mg), yield 91.4%.

[0227] LC-MS (m / z): 373.0 [M+H] + .

[0228] Step 9: Synthesis of 6'-(2-chloro-5-methoxypyridin-4-yl)-l'-methyl-2'-oxospiro[ cyclopropane-l,3'-indolin]-5'-carboxylic acid (2-10)

[0229] Compound 2-9 (340 mg, 0.91 mmol) was dissolved in tetrahydrofuran / water (5 mL / 5 mL), lithium hydroxide monohydrate (154 mg, 3.66 mmol) was added, the system was stirred at room temperature for 16 hours. Concentrated under reduced pressure, adjusted to pH 5 with 2N hydrochloric acid, filtered, the filter cake was dried to obtain compound 2-10 (320 mg), yield 97.9%.

[0230] LC-MS (m / z): m / z = 357.0 [M-H] - .

[0231] 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'-indolin]-5'-formamide (2)

[0232] Compound 2-10 (150 mg, 0.42 mmol) was dissolved in DMF (5 mL), 5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-amine (80 mg, 0.46 mmol), HATU (145 mg, 0.38 mmol) and triethylamine (85 mg, 0.84 mmol) were added in turn, cesium carbonate (145 mg, 0.44 mmol) was added after the system was stirred at room temperature for 4 hours, and the stirring was continued at room temperature for 2 hours. Quench with water, extract with ethyl acetate three times (20 mL x 3), combine the organic phases, wash with water three times (20 mL x 3), wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography, eluent was 3% methanol in dichloromethane, and then purified by full-preparation liquid chromatograph to obtain the target compound 2 (20 mg), yield 9.4%.

[0233] LC-MS (m / z): 506.0 [M+H] + .

[0234] 1 H NMR (400 MHz, DMSO-d6): 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).

[0235] 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-dihydrospiro[cyclo[b][1,4]oxazepine-2,1'- cyclopropane]-6-carboxamide (24)

[0236] Step 1: Synthesis of methyl 2-bromo-4-fluoro-5-nitrobenzoate (24-1)

[0237] Methyl 2-bromo-4-fluorobenzoate (10.0 g, 43.10 mmol) was dissolved in H2SO4(20 mL), HNO3(20 mL) was added dropwise under ice bath condition, and the reaction was allowed to react at room temperature for 4 hours. The reaction solution was poured into ice water (200 mL), the pH was adjusted to more than 7 with saturated aqueous Na2CO3solution (200 mL), and extracted with EA (200 mL x 3), the organic phase was washed with saturated brine (200 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give compound 24-1 (3.0 g) in a yield of 25.1%.

[0238] LC-MS (m / z): 278.0 [M+H] + .

[0239] Step 2: Synthesis of methyl 2-bromo-4-hydroxy-5-nitrobenzoate (24-2)

[0240] Compound 24-1 (2.5 g, 9.09 mmol) was dissolved in DMSO (20 mL), acetoxyhydroxamic acid (2.8 g, 10.18 mmol) and K2CO3(2.51 g, 18.18 mmol) were added successively, and the reaction was allowed to react at 80°C for 2 hours. Water (10 mL) was added to quench, extracted with EA (30 mL x 3), the organic phase was 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 a yield of 93.3%.

[0241] LC-MS (m / z): 276.0 [M+H] + .

[0242] Step 3: Synthesis of methyl 2-bromo-4-(1-(ethoxycarbonyl)cyclopropoxy)-5-nitrobenzoate (24-3)

[0243] Compound 24-2 (2.5 g, 9.02 mmol) was dissolved in DMF (20 mL), and 2,4- dibromobutyl ethyl ether (3.0 g, 10.82 mmol) and K2CO3 (3.8 g, 27.14 mmol) were added successively, and the mixture was reacted at 80 °C for 10 h. The reaction solution was quenched with water (10 mL) and extracted with EA (30 mL x 3). The combined organic phase was 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%.

[0244] LC-MS (m / z): 388.1 [M+H] + .

[0245] Step 4: Synthesis of methyl 7-bromo-3-oxo-3,4-dihydrospiro[benzo[b][l,4]oxazine-2,l’- cyclopropan]-6-carboxylate (24-4)

[0246] 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 condition, and the mixture was reacted 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 more than 7 with saturated NaHCO3 aqueous solution (100 mL). The mixture was extracted with EA (100 mL x 3), and the combined organic phase was 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) with a yield of 53.3%.

[0247] LC-MS (m / z): 312.1 [M+H] + .

[0248] Step 5: Synthesis of methyl 7-bromo-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][l,4]oxazine-2,l’- cyclopropan]-6-carboxylate (24-5)

[0249] 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 successively, and the mixture was reacted at room temperature for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EA (30 mL x 3). The combined organic phase was 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) with a yield of 95.6%.

[0250] LC-MS (m / z): 326.1 [M+H] + .

[0251] Step 6: Synthesis of methyl 7-(2-chloro-5-methoxypyridin-4-yl)-4-methyl-3-oxo- 3,4-dihydrospiro[cyclopropane-1,4'-benzo[b][1,4]oxazine]-6-carboxylate (24-6)

[0252] To the flask was added 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) successively, dissolved with dioxane (5 mL) and water (5 mL), and the system was reacted at 80 °C for 1 h under nitrogen protection. After the reaction was completed, water (10 mL) was added for dilution, EA (30 mL x 3) was used for extraction, the combined organic phase was 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 obtain compound 24-6 (240 mg) with a yield of 87.6%.

[0253] LC-MS (m / z): 389.0 [M+H] + .

[0254] Step 7: Synthesis of 7-(2-chloro-5-methoxypyridin-4-yl)-4-methyl-3-oxo-3,4- dihydrospiro[cyclopropane-1,4'-benzo[b][1,4]oxazine]-6-carboxylic acid (24-7)

[0255] 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, and the reaction was carried out at room temperature for 16 h. The solvent was removed by distillation under reduced pressure, water (10 mL) was added, the pH was adjusted to less than 7 with 1 mol / L HC1 solution, and EA (100 mL x 3) was used for extraction, the combined organic phase was washed with saturated brine (200 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 24-7 (180 mg) with a yield of 77.9%.

[0256] LC-MS (m / z): 375.0 [M+H] + .

[0257] Step 8: Synthesis of 7-(2-chloro-5-methoxy-pyridin-4-yl)-N-(5-(cyclopropylethynyl)- 1,3,4-thiadiazol-2-yl)-4-methyl-3-oxo-3,4-dihydro-spiro[benzo[b][1,4]oxazin-2,1 '- cyclopropane]-6-carboxamide (24)

[0258] Compound 24-7 (180 mg, 0.48 mmol) was dissolved in DMF (5 mL), 5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-amine (119 mg, 0.72 mmol), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (202 mg, 0.72 mmol) and N-methylimidazole (118 mg, 1.44 mmol) were added successively, and the reaction was allowed to proceed at room temperature for 16 hours. The reaction mixture was quenched by adding water (10 mL), extracted with EA (30 mL x 3), and the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous Na2S04, 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 24 (25 mg) with a yield of 10.1%.

[0259] LC-MS (m / z): 522.0 [M+H] + .

[0260] 1 H NMR (600 MHz, DMSO-d6): 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).

[0261] 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'-indolin]-6'- carboxamide (43)

[0262] Step 1 : Synthesis of 5'-(2-methoxy-5-(trifluoromethyl)phenyl)-1 '-methyl-2'-oxospiro[ cyclopropane-1,3'-indolin]-6'-carboxylic acid methyl ester (43-1 )

[0263] Into a flask, was placed intermediate M1 (100 mg, 0.28 mmol), 2-methoxy-5- trifluoromethylbenzoic acid (123 mg, 0.56 mmol), K2CO3 (77 mg, 0.56 mmol) and Pd(dppf)Cl2 (22 mg, 0.03 mmol), dioxane (2 mL) and water (1 mL) were added, and the mixture was stirred at 80 °C for 2 h under nitrogen. After the reaction was completed, water (10 mL) was added to dilute the system, and EA (30 mL x 3) was used for extraction. The combined organic phase was 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) in a yield of 79.3%.

[0264] LC-MS (m / z): 406.0 [M+H] + .

[0265] Step 2: Synthesis of 5'-(2-methoxy-5-(trifluoromethyl)phenyl)-1'-methyl-2'- oxospiro[cyclopropane-1,3'-indolin]-6'-carboxylic acid (43-2)

[0266] Compound 43-1 (90 mg, 0.22 mmol) was dissolved in a mixture of methanol (2 mL), water (2 mL) and THF (2 mL), and lithium hydroxide (91 mg, 2.22 mmol) was added at room temperature. The reaction was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, water (5 mL) was added, the pH was adjusted to less than 7 with 1 mol / L HCl solution (30 mL), and EA (50 mL x 3) was used for extraction. The combined organic phase was 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) in a yield of 92.0%.

[0267] LC-MS (m / z): 392.0 [M+H] + .

[0268] 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'-indolin]-6'-carboxamide (43)

[0269] Compound 43-2 (80 mg, 0.20 mmol) was dissolved in DMF (2 mL), 5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-amine (50 mg, 0.30 mmol), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (84 mg, 0.30 mmol) and N-methylimidazole (49 mg, 0.60 mmol) were added successively, and the reaction was allowed to proceed at room temperature for 16 hours. The system was diluted with water (10 mL), extracted with EA (30 mL x 3), and the combined organic phases were 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) in a yield of 5.4%.

[0270] LC-MS (m / z): 539.0 [M+H] + .

[0271] 1 H NMR (600 MHz, DMSO-d6): δ 13.03 (s, 1H), 7.65 (dd, J1= 9.0 Hz, J2= 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).

[0272] 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'-indolin]-6'-formamide (45)

[0273] Step 1: Synthesis of 5'-(5-cyano-2-methoxyphenyl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indolin]-6'-carboxylic acid methyl ester (45-1)

[0274] Intermediate M1 (100 mg, 0.60 mmol) was dissolved in dioxane (6 mL) and water (1 mL), and (5-cyano-2-methoxyphenyl)boronic acid (200 mg, 1.20 mmol), [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) dichloride (40 mg, 0.06 mmol) and potassium carbonate (160 mg, 1.20 mmol) were added successively. The system was protected by nitrogen and reacted at 80 °C for 2 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to obtain compound 45-1 (190 mg) with a yield of 87.4%.

[0275] LC-MS (m / z): 363.0 [M+H] + .

[0276] Step 2: Synthesis of 5'-(5-cyano-2-methoxyphenyl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'- indolin]-6'-carboxylic acid (45-2)

[0277] Compound 45-1 (190 mg, 0.52 mmol), lithium hydroxide monohydrate (110 mg, 0.60 mmol) were added successively into a bottle, and THF (6 mL), MeOH (3 mL) and H2O (1.8 mL) were added, and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was added with water (1.8 mL), and 1N HCl was added to adjust the pH to weakly acidic. Filtration under suction was performed to obtain compound 45-2 (80 mg) with a yield of 44.2%.

[0278] LC-MS (m / z): 349.0 [M+H] + .

[0279] 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'-indolin]-6'-carboxamide (45)

[0280] Compound 45-2 (80 mg, 0.23 mmol) was dissolved in super dry dichloromethane (3 mL), and 5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-amine (45 mg, 0.27 mmol), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (193 mg, 0.69 mmol) and N-methylimidazole (94 mg, 1.15 mmol) were added successively, and the reaction was carried out at room temperature for 2 h. 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) and then by reverse phase chromatography to obtain the target compound 45 (7 mg) with a yield of 6.1%.

[0281] LC-MS (m / z): 496.0 [M+H] + .

[0282] 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'- indolin]-6'-formamide (47)

[0283] Step 1: Synthesis of 4-bromo-2-(difluoromethyl)-5-methoxypyridine (47-1)

[0284] 4-bromo-5-methoxypyridinecarboxaldehyde (950 mg, 4.37 mmol) was dissolved in dichloromethane (10 mL) under nitrogen protection, diethylamine sulfide trifluoride (915 mg, 5.68 mmol) was slowly added under ice water bath, and the reaction was allowed to react at room temperature for 16 h. After the reaction was completed, it was cooled to 0 °C, and methanol was slowly added to quench the reaction. Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 10:1) to obtain compound 47-1 (700 mg) with a yield of 67.3%.

[0285] LC-MS (m / z): 238.0 [M+H] + .

[0286] Step 2: Synthesis of 5'-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-1'-methyl-2'- oxospiro[cyclopropane-1,3'-indolin]-6'-carboxylic acid methyl ester (47-2)

[0287] Intermediate M2 (250 mg, 0.7 mmol), compound 47-1 (166 mg, 0.70 mmol), [1,1'- bis(diphenylphosphino)ferrocene]palladium dichloride (51 mg, 0.07 mmol) and potassium carbonate (290 mg, 2.10 mmol) were added to a reaction bottle, dioxane (10 mL) and water (2 mL) were added, and the reaction was allowed to react at 100 °C for 2 h under N2 atmosphere. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), and the combined organic phase was 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 = 3:1) to obtain compound 47-2 (130 mg) with a yield of 48.0%.

[0288] LC-MS (m / z): 389.0 [M+H] + .

[0289] Step 3: Synthesis of 5'-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-1'-methyl-2'- oxospiro[cyclopropane-1,3'-indolin]-6'-carboxylic acid (47-3)

[0290] Compound 47-2 (130 mg, 0.34 mmol) was dissolved in 10 mL of mixed solvent (methanol: tetrahydrofuran: water = 2:2:1), lithium hydroxide hydrate (140 mg, 3.35 mmol) was added, and the reaction was allowed to proceed at room temperature for 16 h. After the reaction was completed, the organic solvent was removed by concentration, 4N hydrochloric acid was added to the system to adjust the pH to 5-6, and then filtered. The filter residue was dried to obtain compound 47-3 (100 mg) with a yield of 80.0%.

[0291] LC-MS (m / z): 375.0 [M+H] + .

[0292] 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'-indolin]-6'-carboxamide (47)

[0293] Compound 47-3 (50 mg, 0.14 mmol), 5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-amine (30 mg, 0.16 mmol), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (77 mg, 0.27 mmol), and N-methylimidazole (33 mg, 0.41 mmol) were added to DCM (5 mL), and the reaction was allowed to proceed at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to obtain the target compound 47 (38 mg) with a yield of 53.5%.

[0294] LC-MS (m / z): 522.0 [M+H] + .

[0295] 1 H NMR (600 MHz, DMSO-d6): 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).

[0296] 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'- indolin]-6'-formamide (81)

[0297] Step 1: Synthesis of 5-((tetrahydrofuran-3-yl)methoxy)-1,3,4-thiadiazol-2-amine (81-1)

[0298] Into a flask, (tetrahydrofuran-3-yl)methanol (245 mg, 2.40 mmol) was added, then tetrahydrofuran (4 mL) was added, the system was cooled to 0 °C under nitrogen protection, NaH (120 mg, 3.00 mmol) was added, and the reaction was carried out at 0 °C for 1 h. 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 h. After the reaction was completed, the reaction mixture was added to saturated aqueous ammonium chloride solution (10 mL) to quench, extracted with EA (30 mL x 3), the combined organic phase was 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) in 9.8% yield.

[0299] LC-MS (m / z): 202.0 [M+H] + .

[0300] 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'- indolin]-6'-formamide (81)

[0301] Compound 1-2 (72 mg, 0.20 mmol) was dissolved in DMF (2 mL), and compound 81-1 (40 mg, 0.20 mmol), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (56 mg, 0.30 mmol), and N-methylimidazole (49 mg, 0.60 mmol) were added in turn, and the reaction was carried out at room temperature for 16 h. The system was diluted with water (10 mL), extracted with EA (30 mL x 3), and the combined organic phase was 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 81 (6 mg) in 5.7% yield.

[0302] LC-MS (m / z): 542.0 [M+H]+ .

[0303] 1 H NMR (600 MHz, DMSO-d6): 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).

[0304] 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'- indolin]-6'-formamide (83)

[0305] Step 1: Synthesis of 5-((tetrahydro-2H-pyran-4-yl)methoxy)-1,3,4-thiadiazol-2- amine (83-1)

[0306] To a flask was added (tetrahydro-2H-pyran-4-yl)methanol (348.0 mg, 3.00 mmol), then tetrahydrofuran (10 mL), and the system was protected by nitrogen and cooled to 0 °C, then NaH (120 mg, 3.00 mmol) was added, and the reaction was carried out at 0 °C for 1 h. To the system was added 5-bromo-1,3,4-thiadiazol-2-amine (360 mg, 2.00 mmol), and the reaction was carried out at 0 °C for 1 h. After the reaction was completed, the reaction mixture was added to saturated ammonium chloride solution (10 mL) for quenching, extracted with EA (30 mL x 3), and the combined organic phase was 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) in a yield of 5.8%.

[0307] LC-MS (m / z): 216.0 [M+H] + .

[0308] 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'- indolin]-6'-formamide (83)

[0309] 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'-tetramethylchloroformamidium hexafluorophosphate (56 mg, 0.30 mmol), and NMI (37 mg, 0.45 mmol) were added sequentially, and the reaction was allowed to proceed at room temperature for 2 h. 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 obtain the target compound 83 (6 mg) at a yield of 5.7%.

[0310] LC-MS (m / z): 556.0 [M+H] + .

[0311] 1 H NMR (600 MHz, DMSO-d6): 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, J1 = 11.6 Hz, J2 = 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).

[0312] 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'-indolin]-6'-formamide (96)

[0313] Step 1: Synthesis of 2-chloro-3-fluoro-5-methoxypyridine (96-1)

[0314] 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, and the reaction was allowed to proceed at room temperature for 3 h. After the reaction was completed, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated NaCl aqueous solution (10 mL x 3), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 96-1 (800 mg) at a yield of 72.7%.

[0315] LC-MS (m / z): 162.0 [M+H] + .

[0316] Step 2: Synthesis of 2-chloro-3-fluoro-4-iodo-5-methoxypyridine (96-2)

[0317] Compound 96-1 (800 mg, 4.94 mmol) was dissolved in THF (10 mL) under N2 atmosphere, cooled to -78 °C, n-butyllithium (37 mL, 7.41 mmol) was added dropwise slowly, stirred at -78 °C for 30 min, then I2 (1.25 g, 4.94 mmol) was added, the reaction was allowed to warm to room temperature for 2 h. After the reaction was completed, saturated aqueous ammonium chloride solution was added to quench the reaction (15 mL), aqueous sodium thiosulfate solution was added to wash (20 mL), ethyl acetate was used to extract (20 mL x 3), the organic phase was combined, 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 96-2 (370 mg) in 26.5% yield.

[0318] LC-MS (m / z): 288.0 [M+H] + .

[0319] Step 3: Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-1'-methyl-2'- oxospiro[cyclopropane-1,3'-indolin]-6'-carboxylic acid methyl ester (96-3)

[0320] 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), potassium carbonate (200 mg, 1.40 mmol) were dissolved in dioxane (10 mL) and water (2 mL) and the reaction was carried out at 80 °C for 2 h under N2 atmosphere. After the reaction was completed, ethyl acetate was used to extract (10 mL x 3), the organic phase was combined and washed with saturated brine (20 mL x 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 24.6% yield.

[0321] LC-MS (m / z): 391.0 [M+H] + .

[0322] Step 4: Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-1'-methyl-2'- oxospiro[cyclopropane-1,3'-indolin]-6'-carboxylic acid (96-4)

[0323] Compound 96-3 (48 mg, 0.12 mmol) was dissolved in 10 mL of mixed solvent (methanol: tetrahydrofuran: water = 2:2:1), lithium hydroxide hydrate (52 mg, 1.23 mmol) was added, and the reaction was allowed to proceed at room temperature for 16 h. After the reaction was completed, the organic solvent was removed by concentration, 4M aqueous hydrochloric acid was added to the system to adjust the pH to 5-6, and then filtered. The filter residue was dried to obtain compound 96-4 (28 mg) with a yield of 60.8%.

[0324] LC-MS (m / z): 377.0 [M+H] + .

[0325] 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'-indolin]-6'-formamide (96)

[0326] Compound 96-4 (20 mg, 0.05 mmol), 5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-amine (12 mg, 0.06 mmol), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (30 mg, 0.11 mmol), and N-methylimidazole (13 mg, 0.16 mmol) were dissolved in DCM (10 mL), and the reaction was allowed to proceed at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to obtain the target compound 96 (6 mg) with a yield of 22.2%.

[0327] LC-MS (m / z): 524.0 [M+H] + .

[0328] 1 H NMR (600 MHz, DMSO-d6): 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).

[0329] Example 97: Synthesis of (R)-N-(5-((1,4-dioxan-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indolin]-6'-formamide (97)

[0330] Step 1: Synthesis of (R)-5-((l,4-dioxan-2-yl)methoxy)-l,3,4-thiadiazol-2- amine (97-1)

[0331] (S)-(l,4-dioxan-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 under ice water bath, and the reaction was continued at 0 °C for 1 h under nitrogen protection. Then 5-bromo-l,3,4-thiadiazol-2-amine (200 mg, 1.12 mmol) was added, and the reaction was continued at 0 °C for 2 h under nitrogen protection. The reaction mixture was quenched by water (20 mL), extracted with ethyl acetate (20 mL x 3), and the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous Na2S04, 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) with a yield of 20.5%.

[0332] LC-MS (m / z): 218.0 [M+H] + .

[0333] Step 2: Synthesis of (R)-N-(5-(((l,4-dioxan-2-yl)methoxy)-l,3,4-thiadiazol-2-yl)-5'-(2- chloro-5-methoxypyridin-4-yl)-l'-methyl-2'-oxospiro[cyclopropane-l,3'-indolin]-6'- formamide (97)

[0334] Compound 1-2 (110 mg, 0.3 mmol) was dissolved in super dry dichloromethane (10 mL), compound 97-1 (50 mg, 0.23 mmol), HATU (110 mg, 0.25 mmol) and triethylamine (70 mg, 0.69 mmol) were added, and the reaction was continued at room temperature for 16 h. After the reaction was completed, the reaction mixture was quenched by water (10 mL), extracted with dichloromethane (10 mL x 3), and the combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous Na2S04, 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) with a yield of 15.7%.

[0335] LC-MS (m / z): 558.0 [M+H] + .

[0336] 1H NMR (600 MHz, DMSO-d6): 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).

[0337] Example 98: Synthesis of 5'-(2-chloro-5-methoxy-pyridin-4-yl)-N-(5-(2- cyclopropylethyl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'- indolin]-6'-formamide (98)

[0338] Step 1: Synthesis of tert-butyl (5-(2-cyclopropylethyl)-1,3,4-thiadiazol-2- yl)carbamate (98-1)

[0339] Tert-butyl (5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)carbamate (100 mg, 0.38 mmol) was dissolved in ethanol (10 mL), 10% Pd / C (60 mg) was added at room temperature, and the reaction was allowed to proceed at room temperature for 24 hours. Filtration and concentration of the filtrate under reduced pressure gave compound 98-1 (40 mg) in a yield of 39.4%.

[0340] LC-MS (m / z): 270.0 [M+H] + .

[0341] Step 2: Synthesis of 5-(2-cyclopropylethyl)-1,3,4-thiadiazol-2-amine (98-2)

[0342] Compound 98-1 (80 mg, 0.30 mmol) was dissolved in DCM (2 mL), and trifluoroacetic acid (0.5 mL) was added at room temperature, and the reaction was allowed to proceed at room temperature for 2 hours. Concentration of the system under reduced pressure gave compound 98-2 (20 mg) in a yield of 39.8%.

[0343] LC-MS (m / z): 170.0 [M+H] + .

[0344] 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'- indolin]-6'-formamide (98)

[0345] Compound 1-2 (43 mg, 0.12 mmol) was dissolved in DMF (2 mL), and compound 98-2 (20 mg, 0.12 mmol), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (67 mg, 0.24 mmol) and N-methylimidazole (29 mg, 0.36 mmol) were added successively, and the reaction was allowed to proceed at room temperature for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (30 mL x 3), and the combined organic phase was 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 98 (6 mg) with a yield of 10.1%.

[0346] LC-MS (m / z): 510.0 [M+H] + .

[0347] 1 H NMR (600 MHz, DMSO-d6): 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).

[0348] 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'- indolin]-6'-formamide (99)

[0349] Step 1: Synthesis of tert-butyl (5-(3,3-dimethylbut-1-yn-1-yl-1,3,4-thiadiazol-2- yl)carbamate (99-1)

[0350] To a flask was added compound 99-1 (250 mg, 0.89 mmol) and dissolved with DCM (10 mL), trifluoroacetic acid (3 mL) was added, and the reaction was allowed to proceed at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue obtained was purified by column chromatography (DCM:MeOH = 20:1) to obtain compound 99-2 (120 mg) with a yield of 74.5%.

[0351] LC-MS (m / z): 282.0 [M+H] + .

[0352] Step 2: Synthesis of 5-(3,3-dimethylbut-1-en-1-yl)-1,3,4-thiadiazol-2-amine (99-2)

[0353] To a flask was added compound 99-1 (250 mg, 0.89 mmol) and dissolved with DCM (10 mL), trifluoroacetic acid (3 mL) was added, and the reaction was allowed to proceed at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue obtained was purified by column chromatography (DCM:MeOH = 20:1) to obtain compound 99-2 (120 mg) with a yield of 74.5%.

[0354] LC-MS (m / z): 282.0 [M+H] + .

[0355] 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'-indolin]-6'-formamide (99)

[0356] To a flask was added compound 1-2 (72 mg, 0.20 mmol) and dissolved with super dry DCM (3 mL), compound 99-2 (43 mg, 0.24 mmol), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (84 mg, 0.30 mmol), and N-methylimidazole (50 mg, 0.60 mmol) were sequentially added, and the reaction was allowed to proceed at room temperature for 2 h. 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) and then by reverse phase chromatography to obtain the target compound 99 (7 mg) with a yield of 6.7%.

[0357] LC-MS (m / z): 522.0 [M+H]+ .

[0358] 1 H NMR (600 MHz, DMSO-d6): 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).

[0359] 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'-indolin]-6'-formamide (100)

[0360] Step 1: Synthesis of tert-butyl (5-((tetrahydro-2H-pyran-4-yl)ethynyl)-1,3,4-thiadiazol-2-yl)carbamate (100-1)

[0361] Tert-butyl (5-bromo-1,3,4-thiadiazol-2-yl)carbamate (500 mg, 1.78 mmol) was dissolved in DMF (5 mL), 4-ethynyltetrahydro-2H-pyran (589 mg, 5.35 mmol), tetrakis(triphenylphosphine)palladium (206 mg, 0.18 mmol), cuprous iodide (17 mg, 0.09 mmol) and triethylamine (542 mg, 5.35 mmol) were added successively, and the reaction was carried out at 60 °C for 12 h under nitrogen protection. The system was quenched with water (20 mL), extracted with EA (15 mL x 3), and the combined organic phase was 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) in a yield of 32.6%.

[0362] LC-MS (m / z): 310.0 [M+H] + .

[0363] Step 2: Synthesis of 5-(tetrahydro-2H-pyran-4-yl)ethyl)-1,3,4-thiadiazol-2-amine (100-2)

[0364] Compound 100-1 (180 mg, 0.58 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added and reacted at room temperature for 3 hours. After the reaction was completed, the residue was added to saturated sodium bicarbonate solution (15 mL) and extracted with dichloromethane (10 mL x 3), the combined organic phase was 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 obtain compound 100-2 (92 mg) with a yield of 75.6%.

[0365] LC-MS (m / z): 210.0 [M+H] + .

[0366] 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'-indolin]-6'- formamide (100)

[0367] Compound 1-2 (120 mg, 0.33 mmol) was dissolved in dichloromethane (10 mL), compound 100-2 (84 mg, 0.40 mmol), N-methylimidazole (82 mg, 1.0 mmol) and N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (140.0 mg, 0.50 mmol) were added and reacted at room temperature for 12 hours. After the reaction was completed, the system was quenched with water (10 mL) and extracted with dichloromethane (10 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 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 obtain the target compound 100 (20 mg) with a yield of 10.9%.

[0368] LC-MS (m / z): 550.0 [M+H] + .

[0369] 1 H NMR (600 MHz, DMSO-d6): 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).

[0370] 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'- indolin]-6'-formamide (101)

[0371] Step 1: Synthesis of (R)-5-((4-methylmorpholin-2-yl)methoxy)-1,3,4-thiadiazol-2- amine (101-1)

[0372] Into a flask, was placed (R)-(4-methylmorpholin-2-yl)methanol (393 mg, 3.00 mmol), then tetrahydrofuran (10 mL), the system was cooled to 0 °C under nitrogen protection, NaH (120 mg, 3.00 mmol) was added, and the reaction was continued at 0 °C for one hour. 5-Bromo-1,3,4-thiadiazol-2-amine (360 mg, 2.00 mmol) was added to the system, and the reaction was continued for one hour. Saturated aqueous ammonium chloride solution (10 mL) was added to quench, extracted with EA (30 mL x 3), the combined organic phase was 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 101-1 (40 mg) in 9.8% yield.

[0373] LC-MS (m / z): 231.0 [M+H] + .

[0374] 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'-indolin]-6'- formamide (101)

[0375] Compound 1-2 (54 mg, 0.15 mmol) was 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 in turn, and the reaction was continued at room temperature for 16 hours. The reaction mixture was diluted with water (10 mL), extracted with EA (30 mL x 3), and the combined organic phase was 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 101 (12 mg) in 13.3% yield.

[0376] LC-MS (m / z): 571.0 [M+H]+ .

[0377] 1 H NMR (600 MHz, DMSO-d6): 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).

[0378] Example 102: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-N-(5-(3- morpholinopropoxy)-1,3,4-thiadiazol-2-yl)-2'-oxospiro[cyclopropane-1,3'-indolin]-6'- carboxamide (102)

[0379] Step 1: Synthesis of 5-(3-morpholinopropoxy)-1,3,4-thiadiazol-2-amine (102-1)

[0380] To a solution of 3-morpholinopropane-1-ol (725 mg, 5.00 mmol) in THF (20 mL) was added 5-bromo-1,3,4-thiadiazol-2-amine (597 g, 3.33 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched by the addition of MeOH (5 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to give compound 102-1 (110 mg) in 13.5% yield.

[0381] LC-MS (m / z): 245.0 [M+H] + .

[0382] Step 2: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-N-(5-(3- morpholinopropoxy)-1,3,4-thiadiazol-2-yl)-2'-oxospiro[cyclopropane-1,3'-indolin]-6'- carboxamide (102)

[0383] To a flask was added compound 1-2 (143 mg, 0.20 mmol), dissolved with DCM (3 mL), and added compound 102-1 (110 mg, 0.43 mmol), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (182 mg, 0.48 mmol), and N-methylimidazole (88 mg, 0.80 mmol) sequentially, and reacted at room temperature for 2 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH=50:1) and reverse phase chromatography to obtain the target compound 102 (8 mg) at a yield of 3.4%.

[0384] LC-MS (m / z): 585.0 [M+H] + .

[0385] 1 H NMR (600 MHz, DMSO-d6): 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).

[0386] 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'-indolin]-6'-formamide (103)

[0387] Step 1: Synthesis of 5-(3-(dimethylamino)propoxy)-1,3,4-thiadiazol-2-amine (103-1)

[0388] Compound 103-1 (180 mg) was obtained by the procedure described above. MS (m / z): 203.0 [M+H].

[0389] LC-MS (m / z): 203.0 [M+H] + .

[0390] 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'-indolin]-6'-formamide (103)

[0391] Compound 1-2 (100 mg, 0.27 mmol) was dissolved in super dry dichloromethane (10 mL), compound 103-1 (55 mg, 0.27 mmol), HATU (102 mg, 0.27 mmol) and triethylamine (55 mg, 0.54 mmol) were added, and the reaction was allowed to proceed at room temperature for 12 hours. After the reaction was completed, the reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 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 obtain the target compound 103 (2 mg) with a yield of 1.3%.

[0392] LC-MS (m / z): 543.0 [M+H] + .

[0393] 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'-indolin]-6'-formamide (104)

[0394] Step 1: Synthesis of 5-((tetrahydrofuran-2-yl)methoxy)-1,3,4-thiadiazol-2-amine (104-1)

[0395] Compound 104-1 (300 mg) was obtained by the procedure described above in Example 1, Step 2. LC-MS (m / z): 202.0 [M+H]

[0396] LC-MS (m / z): 542.0 [M+H] + .

[0397] 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'-indolin]-6'-formamide (104)

[0398] Compound 1-2 (400 mg, 1.50 mmol) was dissolved in super dry dichloromethane (10 mL), compound 104-1 (300 mg, 1.50 mmol), HATU (570 mg, 1.50 mmol) and triethylamine (454 mg, 4.50 mmol) were added, and the reaction was allowed to proceed at room temperature for 16 hours. After the reaction was completed, the reaction mixture was diluted with water (10 mL), extracted with dichloromethane (10 mL x 3), and the combined organic phase was washed with saturated brine (20 mL x 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 obtain the target compound 104 (30 mg) with a yield of 3.7%.

[0399] LC-MS (m / z): 542.0 [M+H] + .

[0400] 1H NMR (600 MHz, DMSO-d6): 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).

[0401] 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'-indolin]-6'-carboxamide (105)

[0402] Step 1: Synthesis of 5-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)-1,3,4-thiadiazol-2-amine (105-1)

[0403] THF (20 mL), NaH (480 mg, 12.00 mmol) was added at 0 °C, and the mixture was stirred at 0 °C for 30 min. 5-Bromo-1,3,4-thiadiazol-2-amine (1.4 g, 7.82 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 h. 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 105-1 (115 mg) in 4.9% yield.

[0404] LC-MS (m / z): 230.0 [M+H] + .

[0405] 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'-indolin]-6'-carboxamide (105)

[0406] To a flask was added compound 1-2 (143 mg, 0.40 mmol), dissolved with DCM (3 mL), and added compound 105-1 (115 mg, 0.49 mmol), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (182 mg, 0.48 mmol), and N-methylimidazole (88 mg, 0.80 mmol) sequentially, and reacted at room temperature for 2 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH=50:1), and then purified by reverse phase chromatography, and lyophilized to obtain the target compound 105 (8 mg) at a yield of 3.5%.

[0407] LC-MS (m / z): 570.0 [M+H] + .

[0408] 1 H NMR (600 MHz, DMSO-d6): 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, J1=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).

[0409] 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'-indolin]-6'-formamide (106)

[0410] Step 1: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methylspiro[cyclopropane-1,3'-indolin]-6'-carboxylate (106-1)

[0411] Into a flask, was placed compound 1-7 (200 mg, 0.54 mmol), then tetrahydrofuran (5 mL), the system was cooled to 0 °C under nitrogen protection, then borane dimethyl sulfide (5.4 mL, 5.40 mmol) was added, and the reaction was carried out at 60 °C for 6 h. After the reaction was completed, the reaction mixture was added to saturated ammonium chloride solution (10 mL) for quenching, extracted with EA (30 mL x 3), the combined organic phase was 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%.

[0412] LC-MS (m / z): 359.0 [M+H] + .

[0413] Step 3: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methylspiro[cyclopropane-1,3'- indolin]-6'-carboxylic acid (106-2)

[0414] Compound 106-1 (40 mg, 0.11 mmol) was dissolved in a mixture solution of methanol (2 mL), water (2 mL) and THF (2 mL), and LiOH (26 mg, 1.10 mmol) was added at room temperature, and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the system was concentrated under reduced pressure, water (10 mL) was added, the pH was adjusted to less than 7 with 1 mol / L HCl solution (15 mL), and extraction was carried out with EA (30 mL x 3), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give compound 106-2 (40 mg) as a crude product.

[0415] LC-MS (m / z): 345.0 [M+H] + .

[0416] Step 4: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(cyclopropylethynyl)-1,3,4- thiazol-2-yl)-1'-methylspiro[cyclopropane-1,3'-indolin]-6'-carboxamide (106)

[0417] The crude compound 106-2 was dissolved in dichloromethane (2 mL), 5- (cyclopropylethynyl)-1,3,4-thiadiazol-2-amine (30 mg, 0.18 mmol), N,N,N',N'- tetramethylchloroformamidium hexafluorophosphate (50 mg, 0.18 mmol) and N- methylimidazole (29 mg, 0.36 mmol) were added successively, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, the reaction mixture was diluted with water (10 mL) and extracted with EA (30 mL x 3). The combined organic phase was 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) in a two-step yield of 2.2%.

[0418] LC-MS (m / z): 492.0 [M+H] + .

[0419] 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'-indolin]-6'-formamide (107)

[0420] Step 1: Synthesis of methyl 5'-(3-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane- 1,3'-indolin]-6'-carboxylate (107-1)

[0421] Intermediate M1 (180 mg, 0.50 mmol) was dissolved in dioxane (6 mL) and water (1 mL), and (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) were added successively. The reaction was carried out at 80 °C for 2 h 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 a yield of 47.3%.

[0422] LC-MS (m / z): 339.0 [M+H] + .

[0423] Step 2: Synthesis of 5'-(3-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'- indolin]-6'-carboxylic acid (107-2)

[0424] To a flask, was added compound 107-1 (80 mg, 0.24 mmol), lithium hydroxide monohydrate (110 mg, 2.40 mmol) sequentially, THF (5 mL), MeOH (1.5 mL) and H2O (1 mL) were added, and the reaction mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, the residue was added with H2O (2 mL), and the pH was adjusted to weakly acidic with 1N HCl, and concentrated under reduced pressure to obtain compound 107-2 (45 mg) in a yield of 57.9%.

[0425] LC-MS (m / z): 325.0 [M+H] + .

[0426] 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'-indolin]-6'-formamide (107)

[0427] Compound 107-2 (45 mg, 0.12 mmol) was dissolved in super dry DCM (3 mL), and 5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-amine (23 mg, 0.14 mmol), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (50 mg, 0.18 mmol) and N-methylimidazole (30 mg, 0.36 mmol) were sequentially added, and the reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 50:1) to obtain the target compound 107 (53 mg) in a yield of 93.7%.

[0428] LC-MS (m / z): 472.0 [M+H] + .

[0429] 1 H NMR (600 MHz, DMSO-d6): 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).

[0430] 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'-indolin]-6'- carboxamide (108)

[0431] The preparation method of the target compound 108 refers to the preparation method of compound 107 in Example 107, only the raw material (3-methoxypyridin-4-yl)boronic acid is replaced with (5-methoxy-2-methylpyridin-4-yl)boronic acid, and other intermediate raw materials and preparation methods are the same as those in Example 107, to obtain the target compound 108 (4 mg), with a total yield of 0.9%.

[0432] LC-MS (m / z): 486.0 [M+H] + .

[0433] 1 H NMR (600 MHz, DMSO-d6): 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).

[0434] 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'-indolin]-6'- carboxamide (109)

[0435] The preparation method of the target compound 109 refers to the preparation method of compound 107 in Example 107, only the raw material (3-methoxypyridin-4-yl)boronic acid is replaced with (5-methoxy-2-cyclopropylpyridin-4-yl)boronic acid, and other intermediate raw materials and preparation methods are the same as those in Example 107, to obtain the target compound 109 (9 mg), with a total yield of 1.8%.

[0436] LC-MS (m / z): 512.0 [M+H] + .

[0437] 1H NMR (600 MHz, DMSO-d6): 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).

[0438] 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'-indolin]-6'-carboxamide (110)

[0439] Compound 1-2 (120 mg, 0.34 mmol), 5-methoxy-1,3,4-thiadiazol-2-amine (45 mg, 0.34 mmol), N,N,N',N'-tetramethylchloroformamidium 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 h. 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 obtain the target compound 110 (8 mg) with a yield of 5.1%.

[0440] LC-MS (m / z): 472.0 [M+H] + .

[0441] 1 H NMR (600 MHz, DMSO-d6): 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).

[0442] 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'-indolin]-6'-carboxamide (112)

[0443] The preparation method of the target compound 112 refers to the preparation method of compound 110 in Reference Example 110, only compound 1-2 is replaced by compound 96-4, and the other raw materials and preparation methods are the same as those in Example 110, to obtain the target compound 112 (7 mg) with a yield of 10.8%.

[0444] LC-MS (m / z): 490.0 [M+H] + .

[0445] 1 H NMR (600 MHz, DMSO-d6): 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).

[0446] 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'-indolin]-6'-formamide (113)

[0447] The preparation method of the target compound 113 refers to the preparation method of compound 112 in Example 112, only replacing the raw material 5-methoxy-1,3,4-thiadiazol-2-amine with 5-ethoxy-1,3,4-thiadiazol-2-amine, and the other raw materials and preparation methods are the same as those in Example 112, to obtain the target compound 113 (6 mg) with a yield of 9.0%.

[0448] LC-MS (m / z): 504.0 [M+H] + .

[0449] 1 H NMR (600 MHz, DMSO-d6): 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).

[0450] 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'-indolin]-6'-formamide (114)

[0451] The preparation method of the target compound 114 refers to the preparation method of compound 110 in Reference Example 110, only replacing compound 1-2 with compound 47-2, and the other raw materials and preparation methods are the same as those in Example 110, to obtain the target compound 114 (15 mg) with a yield of 38.5%.

[0452] LC-MS (m / z): 488.0 [M+H] + .

[0453] 1 H NMR (600 MHz, DMSO-d6): 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).

[0454] 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'-indolin]-6'- formamide (115)

[0455] The preparation method of the target compound 115 refers to the preparation method of compound 112 in Reference Example 112, only replacing 5-methoxy-1,3,4-thiadiazol-2-amine with 5-ethyl-1,3,4-thiadiazol-2-amine, and the other intermediate raw materials and preparation methods are the same as those in Example 112, to obtain the target compound 115 (13 mg) with a yield of 25.1%.

[0456] LC-MS (m / z): 488.0 [M+H] + .

[0457] 1 H NMR (600 MHz, DMSO-d6): 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).

[0458] 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'-indolin]-6'-carboxamide (116)

[0459] Step 1: Synthesis of 5-(methoxy-d3)-1,3,4-thiadiazol-2-amine (116-1)

[0460] Into a reaction vial was added deuterated methanol (0.5 mL) under nitrogen protection, sodium hydride (40 mg, 1.20 mmol) was added under 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 obtain compound 116-1 (80 mg) with a yield of 59.7%.

[0461] LC-MS (m / z): 135.0 [M+H] + .

[0462] 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'-indolin]-6'-carboxamide (116)

[0463] Compound 1-2 (220 mg, 0.60 mmol) was dissolved in super-dry acetonitrile (10 mL), compound 116-1 (80 mg, 0.60 mmol), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (252 mg, 0.90 mmol), and N-methylimidazole (160 mg, 1.80 mmol) were added, and the reaction was carried out at room temperature for 2 h. 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 obtain the target compound 116 (45 mg) with a yield of 15.8%.

[0464] LC-MS (m / z): 475.0 [M+H] + .

[0465] 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'-carboxamide (117)

[0466] Step 1: Synthesis of methyl 5-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridine-6-carboxylate (117-1)

[0467] Into a flask, was placed methyl 5-bromo-lH-pyrrolo[2,3-b]pyridine-6-carboxylate (1.0 g, 3.94 mmol), DMF (13 mL), the system was cooled to 0 °C under nitrogen protection, NaH (192 mg, 4.80 mmol) was added, and the reaction was carried out for 0.5 h. Then iodomethane (740 mg, 5.21 mmol) was added, and the system was slowly warmed to room temperature, and the reaction was carried out for 1 h. After the reaction was completed, saturated ammonium chloride solution (10 mL) was added for quenching, and EA was used for extraction (30 mL x 3), the combined organic phase was 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) in a yield of 75.8%.

[0468] LC-MS (m / z): 269.0, 271.0 [M+H] + .

[0469] Step 2: Synthesis of methyl 3,3,5-tribromo-l-methyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3-b]pyridine-6-carboxylate (117-2)

[0470] Into a flask, was placed compound 117-1 (700 mg, 2.61 mmol), t-butanol (8 mL) and water (2 mL), and pyridinium tribromide (2.5 g, 7.81 mmol) was added under nitrogen protection, and the reaction was carried out at 40 °C for 4 h. After the reaction was completed, the system was concentrated under reduced pressure, water (10 mL) was added, and EA was used for extraction (20 mL x 3), the combined organic phase was 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%.

[0471] LC-MS (m / z): 441.0 [M+H] + .

[0472] Step 3: Synthesis of methyl 5-bromo-l-methyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3-b]pyridine-6-carboxylate (117-3)

[0473] 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 allowed to proceed at room temperature for 16 h. After the reaction was completed, the system was concentrated under reduced pressure, diluted with water (5 mL), and the pH was adjusted to 7 by adding a saturated NaHCO3 solution (5 mL), and extracted with EA (20 mL x 3), the combined organic phase was 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%.

[0474] LC-MS (m / z): 285.0, 287.0 [M+H] + .

[0475] Step 4: Synthesis of methyl 5'-bromo-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-6'-carboxylate (117-4)

[0476] Compound 117-3 (100 mg, 0.35 mmol) was dissolved in DMSO (2 mL), K2CO3 (97 mg, 0.7 mmol) and 1,2-dibromoethane (79 mg, 0.42 mmol) were added successively, and the reaction was allowed to proceed at room temperature for 16 h. After the reaction was completed, the reaction mixture was diluted with water (10 mL) and extracted with EA (20 mL x 3), the combined organic phase was 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%.

[0477] LC-MS (m / z): 311.0, 313.0 [M+H] + .

[0478] 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'-carboxylate (117-5)

[0479] Into a flask, was placed 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), dioxane (5 mL) and water (1 mL) were added, and the mixture was stirred at 80 °C for 1 h under nitrogen. After the reaction was completed, the reaction mixture was diluted with water (5 mL) and extracted with EA (10 mL x 3). The combined organic phase was 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.

[0480] LC-MS (m / z): 374.0 [M+H] + .

[0481] 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)

[0482] Compound 117-5 (30.0 mg, 0.08 mmol) was dissolved in a mixture of methanol (1 mL), water (1 mL) and THF (1 mL), and LiOH (34.4 mg, 0.80 mmol) was added at room temperature. The mixture was stirred at room temperature for 16 h. After the reaction was completed, the system was concentrated under reduced pressure, water (5 mL) was added, the pH was adjusted to less than 7 with 1 mol / L HC1 solution (8 mL), and the mixture was extracted with EA (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give compound 117-6 (25 mg) as a crude product.

[0483] LC-MS (m / z): 360.0 [M+H] + .

[0484] 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'- carboxamide (117)

[0485] Compound 117-6 (25 mg, 0.07 mmol) was dissolved in DMF (2 mL), 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 successively, and the reaction was allowed to proceed at room temperature for 16 h. After the reaction was completed, the reaction mixture was diluted with water (5 mL) and extracted with EA (10 mL x 3). The combined organic phase was 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) in a yield of 21.9%.

[0486] LC-MS (m / z): 473.0 [M+H] + .

[0487] 1 H-NMR (600MHz, DMSO-d6): 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).

[0488] 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'-indolin]-6'-formamide (118)

[0489] Compound 96-4 (100 mg, 0.27 mmol), 5-(methoxy-d3)-1,3,4-thiadiazol-2-amine (37 mg, 0.27 mmol), N,N,N',N'-tetramethylchloroformamidium 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 h. 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%.

[0490] LC-MS (m / z): 493.0 [M+H] + .

[0491] 1H NMR (600 MHz, DMSO-d6): 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).

[0492] 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'- indolin]-6'-formamide (119)

[0493] Step 1: Synthesis of 2-chloro-3-fluoro-5-(methoxy-d3)pyridine (119-1)

[0494] Dissolve 6-chloro-5-fluoropyridin-3-ol (1.0 g, 6.80 mmol) in acetonitrile (20 mL), add K2CO3 (1.5 g, 13.60 mmol) and deuterated methyl iodide (1.5 g, 10.20 mmol) successively at room temperature, and react at room temperature for 16 hours. After the reaction is completed, filter, and concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (PE:EA = 10:1) to obtain compound 119-1 (1.1 g) with a yield of 98.6%.

[0495] LC-MS (m / z): 165.0 [M+H] + .

[0496] Step 2: Synthesis of 2-chloro-3-fluoro-4-iodo-5-(methoxy-d3)pyridine (119-2)

[0497] Dissolve compound 119-1 (1.14 g, 6.95 mmol) in THF (30 mL), cool to -78 °C under nitrogen protection, and slowly add n-butyllithium (3.5 mL, 8.34 mmol) dropwise to the system. Keep the system stirring at -78 °C for 0.5 hours. Add iodine (267.0 mg, 10.43 mmol), then slowly restore to room temperature, and react for 2 hours. After the reaction is completed, add saturated ammonium chloride solution (20 mL) to quench, extract with EA (20 mL x 3), wash the combined organic phase with saturated brine (20 mL), dry over anhydrous Na2SO4, filter, and concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (PE:EA = 10:1) to obtain compound 119-2 (1.2 g) with a yield of 59.7%.

[0498] LC-MS (m / z): 291.0 [M+H] + .

[0499] Step 3: Synthesis of 5'-(2-chloro-3-fluoro-5-(methoxy-d3)pyridin-4-yl)-1'- methyl-2'-oxospiro[cyclopropane-1,3'-indolin]-6'-carboxylic acid methyl ester (119-3)

[0500] To a flask was added compound 119-2 (400 mg, 1.37 mmol), 1'-methyl-2'-oxo-5'-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3'-indolin]-6'-carboxylic acid methyl ester (587 mg, 1.64 mmol), K2CO3 (378 mg, 2.74 mmol) and Pd(dppf)Cl2 (102 mg, 0.14 mmol) sequentially, dioxane (10 mL) and water (2 mL) were added, and the mixture was stirred at 100 °C for 4 h 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) in 14.9% yield.

[0501] LC-MS (m / z): 394.0 [M+H] + .

[0502] Step 4: Synthesis of 5'-(2-chloro-3-fluoro-5-(methoxy-d3)pyridin-4-yl)-1'-methyl-2'- oxospiro[cyclopropane-1,3'-indolin]-6'-carboxylic acid (119-4)

[0503] Compound 119-3 (80 mg, 0.20 mmol) was dissolved in a mixture of methanol (1 mL), water (1 mL) and THF (2 mL), and LiOH (90 mg, 2.10 mmol) was added at room temperature. The mixture was stirred at room temperature for 16 h. 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 less than 7 with 1 mol / L HCl solution (10 mL). The mixture was filtered, and the filter cake was dried to give compound 119-4 (80 mg) as a crude product.

[0504] LC-MS (m / z): 380.0 [M+H] + .

[0505] Step 5: Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-N-(5-(methoxy-d3)-1,3,4- thiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indolin]-6'-carboxamide (119)

[0506] Compound 119-4 (80 mg, 0.21 mmol) was dissolved in DMF (2 mL), 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 successively, and the reaction was carried out at room temperature for 16 h. After the reaction was completed, water (10 mL) was added, and extraction was performed with EA (10 mL x 3). The combined organic phase was 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 obtain the target compound 119 (7 mg) with a two-step yield of 7.1%.

[0507] LC-MS (m / z): 496.0 [M+H] + .

[0508] 1 H-NMR (600MHz, DMSO-d6): 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).

[0509] 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'-indolin]-6'-formamide (120)

[0510] Step 1: Synthesis of methyl 4-bromo-1-methyl-1H-indole-6-carboxylate (120-1)

[0511] Into a flask was added methyl 4-bromo-1H-indole-6-carboxylate (5.06 g, 20.00 mmol), DMF (50 mL), cesium carbonate (13.04 g, 40.00 mmol) and iodomethane (5.68 g, 40.00 mmol) were added successively, and the reaction was carried out for 16 h. After the reaction was completed, extraction was performed with EA (30 mL x 3), the combined organic phase was 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 obtain compound 120-1 (5.0 g) with a yield of 93.6%.

[0512] LC-MS (m / z): 268.0, 270.0 [M+H] + .

[0513] Step 2: Synthesis of methyl 1,4-dimethyl-1H-indole-6-carboxylate (120-2)

[0514] To a flask was added compound 120-1 (5.32 g, 20.00 mmol), methylboronic acid (3.6 g, 60.00 mmol), K2CO3(5.52 g, 40.00 mmol) and Pd(dppf)Cl2(1.56 g, 2.00 mmol) successively, added dioxane (50 mL) and water (10 mL), and reacted at 90 °C for 8 hours under nitrogen protection. After the reaction was completed, the reaction mixture was diluted with water (50 mL), extracted with EA (100 mL x 3), and the combined organic phases were 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 obtain compound 120-2 (2.84 g) in a yield of 70.0%.

[0515] LC-MS (m / z): 204.0 [M+H] + .

[0516] Step 3: Synthesis of methyl 1,4-dimethyl-2-oxoindoline-6-carboxylate (120-3)

[0517] 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 was carried out 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 obtain compound 120-3 (1.16 g) in a yield of 52.3%.

[0518] LC-MS (m / z): 220.0 [M+H] + .

[0519] Step 4: Synthesis of methyl 1',4'-dimethyl-2'-oxospiro[cyclopropane-1,3'-indolin]-6'- carboxylate (120-4)

[0520] Compound 120-3 (5.0 g, 22.83 mmol) was dissolved in DMSO (70 mL), K2CO3 (7.6 g, 55.07 mmol) and 1,2-dibromoethane (4.91 g, 26.40 mmol) were added successively, and the reaction was allowed to proceed at room temperature for 16 h. After the reaction was completed, the reaction mixture was diluted with water (50 mL) and extracted with EA (100 mL x 3). The combined organic phase was 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 obtain compound 120-4 (4.0 g) with a yield of 71.5%.

[0521] LC-MS (m / z): 246.0 [M+H] + .

[0522] Step 5: Synthesis of methyl 5'-bromo-1',4'-dimethyl-2'-oxospiro[cyclopropane-1,3'- indolin]-6'-carboxylate (120-5)

[0523] 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 was allowed to proceed at room temperature for 16 h. After the reaction was completed, the reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic phase was 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 obtain compound 120-5 (400 mg) with a yield of 60.7%.

[0524] LC-MS (m / z): 324.0, 326.0 [M+H] + .

[0525] Step 6: Synthesis of methyl 5'-(2-chloro-5-methoxypyridin-4-yl)-1',4'-dimethyl-2'- oxospiro[cyclopropane-1,3'-indolin]-6'-carboxylate (120-6)

[0526] Into a flask, was placed 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), then added xylene (20 mL), and the system was heated to 95 °C for 8 h under nitrogen protection. After the reaction was completed, the reaction mixture was diluted with water (20 mL), extracted with EA (40 mL x 3), the combined organic phase was 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) in 6.7% yield.

[0527] LC-MS (m / z): 387.0 [M+H] + .

[0528] Step 7: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1',4'-dimethyl-2'- oxospiro[cyclopropane-1,3'-indolin]-6'-carboxylic acid (120-7)

[0529] Compound 120-6 (80 mg, 0.21 mmol) was dissolved in a mixture of methanol (1 mL), water (1 mL) and THF (3 mL), and LiOH (50 mg, 2.08 mmol) was added at room temperature. The reaction was allowed to proceed at room temperature for 16 h. 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 less than 7 with 1 mol / L HCl solution (8 mL). The mixture was extracted with EA (10 mL x 3), the combined organic phase was washed with saturated NaCl (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. Compound 120-7 (70 mg) was obtained as a crude product.

[0530] LC-MS (m / z): 373.0 [M+H] + .

[0531] Step 8: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-methoxy-1,3,4- thiazol-2-yl)-1',4'-dimethyl-2'-oxospiro[cyclopropane-1,3'-indolin]-6'-carboxamide (120)

[0532] Compound 120-7 (70 mg, 0.19 mmol) was dissolved in DMF (2 mL), 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 successively, and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the reaction mixture was diluted with water (5 mL) and extracted with EA (10 mL x 3). The combined organic phase was 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 obtain the target compound 120 (7 mg) with a yield of 21.9%.

[0533] LC-MS (m / z): 486.0 [M+H] + .

[0534] 1 H-NMR (600MHz, DMSO-d6): 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).

[0535] Example 121: 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-N-(5-(methoxy-d3)-1,3,4- thiazol-2-yl)-1'-(methyl-d3)-2'-oxospiro[cyclopropane-1,3'-indole]-6'-carboxamide (121)

[0536] The preparation method of compound 121-1 refers to that of intermediate M2, only replacing iodomethane with deuterated iodomethane, and the other intermediate raw materials and preparation methods are the same.

[0537] The preparation method of the target compound 121 refers to that of compound 119 in Example 119, only replacing intermediate M2 with compound 121-1, and compound 119-2 with compound 96-2, and the other raw materials and preparation methods are the same as those in Example 119, to obtain the target compound 121 (15 mg) with a three-step yield of 3.6%.

[0538] LC-MS (m / z): 496.0 [M+H] + .

[0539] 1H-NMR (600 MHz, DMSO-d6): 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).

[0540] Example 122: Synthesis of 7-(2-chloro-3-fluoro-5-methoxy-pyridin-4-yl)-N-(5-(methoxy-d3)- 1,3,4-thiadiazol-2-yl)-4-methyl-3-oxo-3,4-dihydro-spiro[benzo[b][1,4]oxazine-2,1’- cyclopropane]-6-carboxamide (122)

[0541] Step 1: Synthesis of methyl 4-methyl-3-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,4-dihydro-spiro[benzo[b][1,4]oxazine-2,1’-cyclopropane]-6-carboxylate (122-1)

[0542] Compound 24-5 (622 mg, 1.91 mmol) was dissolved in dioxane (5 mL), pinacol diboronic acid (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 replaced with N2, and the temperature was raised to 100 °C for 2 h. 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 obtain compound 122-1 (520 mg) with a yield of 73.1%.

[0543] LC-MS (m / z): 374.0 [M+H] + .

[0544] Step 2: Synthesis of methyl 7-(2-chloro-3-fluoro-5-methoxy-pyridin-4-yl)-4-methyl-3-oxo- 3,4-dihydro-spiro[benzo[b][1,4]oxazine-2,1’-cyclopropane]-6-carboxylate (122-2)

[0545] 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 replaced by N2, and the temperature was raised to 100 °C for 3 h. After the reaction was completed, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH = 50:1) to obtain compound 122-2 (300 mg) with a yield of 52.9%.

[0546] LC-MS (m / z): 407.0 [M+H] + .

[0547] Step 3: Synthesis of 7-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-4-methyl-3-oxo-3,4- dihydrospiro[benzo[b][l,4]oxazine-2,l'-cyclopropane]-6-carboxylic acid (122-3)

[0548] 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, and the reaction was carried out at room temperature for 24 h. After the reaction was completed, the filtrate was concentrated under reduced pressure, the residue was adjusted to pH 5 with 2N hydrochloric acid, filtered, and the solid was dried to obtain compound 122-3 (280 mg) with a yield of 96.7%.

[0549] LC-MS (m / z): 393.0 [M+H] + .

[0550] Step 4: Synthesis of 7-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-N-(5-(methoxy-d3)-l,3,4- thiazol-2-yl)-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][l,4]oxazine-2,l'-cyclopropane]-6- carboxamide (122)

[0551] Compound 122-3 (100 mg, 0.25 mmol) was dissolved in DMF (2 mL), HATU (95 mg, 0.25 mmol), triethylamine (51 mg, 0.51 mmol) and 5-(methoxy-d3)-l,3,4-thiazol-2-amine (34 mg, 0.25 mmol) were added, and the reaction was carried out at room temperature for 12 h. 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 obtain the target compound 122 (100 mg) with a yield of 77.2%.

[0552] LC-MS (m / z): 509.0 [M+H] + .

[0553] 1 H NMR (600 MHz, DMSO-d6): 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).

[0554] Example 127: Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-1'-methyl-N-(5-(oxetan-3-yloxy)-1,3,4-thiadiazol-2-yl)-2'-oxospiro[cyclopropane-1,3'-indole]-6'- carboxamide (127)

[0555] Step 1: Synthesis of 5-(oxetan-3-yloxy)-1,3,4-thiadiazol-2-amine (127-1)

[0556] Oxetan-3-ol (1.24 g, 16.76 mmol) was dissolved in tetrahydrofuran (10 mL) and DMF (0.5 mL), sodium hydride (900 mg, 22.34 mmol) was added under nitrogen protection at ice water bath, and the reaction was continued at 0 °C for 1 h under nitrogen protection, then 5-bromo-1,3,4-thiadiazol-2-amine (2.0 g, 11.17 mmol) was added, and the reaction was continued at 0 °C for 2 h under nitrogen protection. The reaction mixture was quenched by adding water (20 mL), extracted with ethyl acetate (20 mL x 3), the combined organic phase was 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) with a yield of 20.7%.

[0557] LC-MS (m / z): 174.0 [M+H] + .

[0558] Step 2: Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-1'-methyl-N-(5-(oxetan-3-yloxy)-1,3,4-thiadiazol-2-yl)-2'-oxospiro[cyclopropane-1,3'-indole]-6'- carboxamide (127)

[0559] Compound 127-1 (50 mg, 0.29 mmol) was dissolved in super dry dichloromethane (10 mL), compound 96-4 (109 mg, 0.29 mmol), HATU (110 mg, 0.29 mmol) and triethylamine (59 mg, 0.58 mmol) were added, and the reaction was allowed to proceed at room temperature for 12 hours. After the reaction was completed, the reaction mixture was diluted with water (10 mL), extracted with dichloromethane (10 mL x 3), and the combined organic phase was washed with saturated brine (20 mL x 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 obtain the target compound 127 (60 mg) with a yield of 39.0%.

[0560] LC-MS (m / z): 532.0 [M+H] + .

[0561] 1 H-NMR (600MHz, DMSO-d6): 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, J1 = 8.4 Hz, J2 = 4.8 Hz, 2H), 3.68 (s, 3H), 3.32 (s, 3H), 1.76-1.71 (m, 2H), 1.65-1.60 (m, 2H).

[0562] 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'-carboxamide (129)

[0563] The preparation method of the target compound 129 refers to the preparation method of compound 127 in Example 127, only replacing the oxetan-3-ol with 3-hydroxytetrahydrofuran, and the other raw materials and preparation methods are the same as those in Example 127, to obtain the target compound 129 (100 mg) with a two-step yield of 1.6%.

[0564] LC-MS (m / z): 546.0 [M+H] + .

[0565] 1H-NMR (600 MHz, DMSO-d6): 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).

[0566] Biological test

[0567] Example 1 Evaluation of PolQ ATPase inhibitory activity in vitro

[0568] The ability of the compounds to bind to and inhibit the PolQ helicase activity in vitro was tested using the ADP Glo assay.

[0569] ADP-Glo TM The ADP-Glo Kinase Assay kit was provided by Zhejiang Promega Biotech Co., Ltd., model number V9102.

[0570] The compound was first dissolved in DMSO, and then the test compound was sequentially diluted 3-fold to obtain 8 concentrations of compound solutions. The 2x helicase domain PolQ enzyme and DNA mixed solution 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 gamma-Globulin, 1 mM dithiothreitol), and the substrate solution containing 2x ATP was prepared in buffer. 1 μL of each gradient concentration of compound solution was added to a 384-well plate, centrifuged, and then 2 μL of 2x helicase domain PolQ enzyme and DNA mixed solution and DNA-containing buffer without enzyme were added, centrifuged, and pre-incubated for 30 minutes. Then 2 μL of 2x ATP solution was added to each well, mixed and 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 and 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 reading was then taken on a microplate reader to determine the inhibition rate of each compound.

[0571] Table 1 Inhibitory activity of compounds on Polθ ATPase

[0572] The data in Table 1 show that the compounds of the present invention have excellent in vitro inhibitory activity against Polθ.

[0573] Example 2 HCT116 BRCA2 - / - Evaluation of the inhibitory effect on cell viability

[0574] First, dissolve the compound in DMSO, then dilute the compound to be tested in 3-fold gradient with culture medium to obtain 8 concentrations of compound solution. - / - Cells (provided by Guangzhou Yuanjing Biotechnology Co., Ltd., model YKO-H668) were seeded at 800 cells / well in a 96-well cell culture plate and incubated in a 37°C, 5% CO2 incubator for 24 hours. Compound solutions were then added at varying concentrations and incubated for a further 7 days at 37°C, 5% CO2. After 7 days, 10 μL of CCK8 solution was added to the cell culture plate and incubated in a 37°C incubator for 2 hours. After 2 hours, the absorbance at a wavelength of 450 nM was measured using a microplate reader, and the inhibition rate of each compound was calculated. The results are shown in Table 2.

[0575] Table 2 Effects of Compounds on HCT116 BRCA2 - / - Cell inhibitory activity

[0576] Example 3 Investigation of Pharmacokinetic Characteristics in Mice

[0577] SPF female Balb / c mice, 3 per group, were given a single oral gavage of 10 mg / kg of the compound. Blood was collected at the specified time points, plasma was separated, and stored in a -80°C refrigerator for later use. The plasma sample to be tested was thawed at room temperature and vortexed (2500 rpm, 1 min). 30.0 μL of plasma sample was taken into a 1.5 mL centrifuge tube, 6.00 μL of internal standard (ramelteon, 500.0 ng / mL) was added, and 1000 μL of methanol was added. The tube was vortexed (2500 rpm, 1 min) and centrifuged (17000 g, 4°C) for 10 min. 180 μL of the supernatant was taken and placed in a 96-well plate, sealed, and subjected to LC-MS / MS analysis with an injection volume of 1.00 μL. The experimental data are shown in the following table:

[0578] Table 3 Pharmacokinetic parameters of compounds in vivo (po)

[0579] 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.

[0580] Example 4 hERG toxicity

[0581] The inhibitory effect of the compound on human hERG ion channel stably expressed in HEK293 cells (provided by Deqing Olive Biotechnology Co., Ltd.) was tested by traditional patch clamp. The compound was prepared at a concentration of 10 μM. Each cell was used as a control. The compound was perfused using a perfusion system using its own gravity. After the current was stable, the size of 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, and the results are shown in Table 4 below.

[0582] Table 4 Blocking effect of the compound on hERG current (10 μM)

[0583] Example 5 in vitro metabolic stability

[0584] Main reagent materials:

[0585] Incubation system:

[0586] Experimental method:

[0587] 1 μM of the test and positive control testosterone were incubated with microsomes under the condition of NADPH for 120 min, and a negative control group (test under the condition of no coenzyme incubated with microsomes for 120 min) was set; sample at 0 min and 120 min, add 300 μL of pre-cooled methanol solution containing internal standard (ramelteon: 1.000 ng / mL) sample, vortex (2500 rpm, 1 min), centrifuge (4700 rpm, 4℃) for 10 min, take 50.0 μL of supernatant + 200 μL of pure water in a 96-well plate, vortex (1000 rpm, 10 min), seal the film, and perform LC-MS / MS analysis. The parent remaining amount of the test or probe substrate was detected by LC-MS / MS, and the metabolic stability of the test was represented by the percentage of the parent remaining amount at each time point relative to the parent amount before incubation (0 min), and the data was calculated according to the following formula: parent remaining percentage (%) = T x parent amount / T0parent amount x 100; T x : any incubation time point; T0: 0 min incubation time point. The test results are shown in Table 5 below.

[0588] Table 5 in vitro metabolic stability results of the compound

[0589] From the data in Table 5, it can be seen that the compound of the present application has good in vitro metabolic stability, and the species difference is small.

[0590] The foregoing embodiments and examples provided by the present application are for illustration only and are not intended to limit the scope of the present application. Various changes and modifications will be apparent to those skilled in the art based on the disclosure, and such changes and modifications can be made without departing from the spirit and scope of the present application.

Claims

1. A heterocyclic amide compound represented by general formula (Ia) or (Ib), its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts: wherein, A is selected from 3-14 membered heterocyclyl, 5-14 membered heteroaryl, C 6-14 aryl or 4-10 membered cycloalkenyl; said 3-14 membered heterocyclyl, 5-14 membered heteroaryl, C 6-14 aryl or 4-10 membered cycloalkenyl can be optionally further substituted by one or more R a substituents; said X is selected from N or CR2; said R2is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, or C 1-6 haloalkyl; Y1, Y2are each independently selected from N or CR4; R4is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or C 1-6 haloalkyl; U, V, W, Z are each independently selected from -(C=0)-, -SO2-, -0-, -NR b - (CR c R d ) n - or -CR e R f - and at least one of U, V, W, Z is selected from -CR e R f -; n is selected from 0, 1, 2, or 3; R e R f and the atom to which they are attached together form a C 3-12 cycloalkyl or 3-12 membered heterocyclyl; said C 3-12 cycloalkyl or 3-12 membered heterocyclyl can optionally be further substituted by one or more R a R The R a 、R b 、R c 、R d are independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Alkyl ester, C 1-6 Alkyl acyl, C 1-6 Alkylamide, C 1-6 Alkylsulfonyl, C 1-6 Alkylsulfonamide, C 1-6 Phosphoryl, 3-8 membered heterocyclic group, 5-14 membered heteroaryl or C 6-12 Aryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Alkyl ester, C 1-6 Alkyl acyl, C 1-6 Alkylamide, C 1-6 Alkylsulfonyl, C 1-6 Alkylsulfonamide, C 1-6 Phosphoryl, 3-8 membered heterocyclic group, 5-14 membered heteroaryl or C 6-12 The aryl group may be further optionally substituted with one or more hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Alkyl, 4-10 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 substituted with aryl; Said R1 is selected from halogen, cyano, amino, -OR g -, by one or more R g Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3- 8-membered cycloalkyl, 3-8-membered heterocyclic group, 5-14-membered heteroaryl, C 6-10 Aryl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino; said R g selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 12 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfone, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkyl ester, C 1-6 alkyl acyl, C 1-6 alkyl amide, C 1-6 alkyl sulfonyl, C 1-6 phosphoryl, C 6-12 aryl, 3-8 membered heterocyclyl, or 5-14 membered heteroaryl; said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfone, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkyl ester, C 1-6 alkyl acyl, C 1-6 alkyl amide, C 1-6 alkyl sulfonyl, C 1-6 phosphoryl, C 6-12 aryl, 3-8 membered heterocyclyl, or 5-14 membered heteroaryl can be optionally further substituted with one or more hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfone, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkyl acyl, 4-10 membered heterocyclyl, 5-14 membered heteroaryl, or C 6-12 aryl.

2. The compound of claim 1 of Formula (la) or (lb): or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof. The R1 is selected from one or more R g Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 5-14 membered heteroaryl, C 6-10 Aryl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino; said R g selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 12 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfone, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkyl ester, C 1-6 alkyl acyl, C 1-6 alkyl amide, C 1-6 alkyl sulfonyl, C 1-6 phosphoryl, C 6-12 aryl, 3-8 membered heterocyclyl, or 5-14 membered heteroaryl; said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfone, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkyl ester, C 1-6 alkyl acyl, C 1-6 alkyl amide, C 1-6 alkyl sulfonyl, C 1-6 phosphoryl, C 6-12 aryl, 3-8 membered heterocyclyl, or 5-14 membered heteroaryl can be optionally further substituted with one or more hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfone, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkyl acyl, 4-10 membered heterocyclyl, 5-14 membered heteroaryl, or C 6-12 aryl substituted; Ring A, X, Y1, Y2, U, V, W, Z, n, R e 、R f 、R a 、R b 、R c 、R d The definition is as stated in claim 1.

3. The compound of claim 1 or 2, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein, The compounds have the following formula (IIa) or (IIb): wherein, the definitions of ring A, Y1, Y2, U, V, W, Z, R1are as described in claim 1 or 2.

4. The compound of claim 3, or a stereoisomer, tautomer, deuterated isomer, or pharmaceutically acceptable salt thereof. The compounds have the following formula (IIIa) or (IIIb): wherein U, V, W are each independently selected from the group consisting of -(C=0)-, -SO2-, -0-, -NR b -CH2-, -CR c R d - and at least one of U, V, W is selected from -CR e R f -; and R e R f - is selected from the group consisting of H, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, haloalkyl, haloalkenyl, -ORa, -NRaRa, -SRa, -CN, -C(O)Ra, -C(O)ORa, -C(O)NRaRa, -S said ring A, Y1, Y2, R1, R b , R c , R d , R e , R f are defined as in claim 1 or 2.

5. The compound of claim 4, or a stereoisomer, tautomer, deuterated isomer, or pharmaceutically acceptable salt thereof. The compounds have the following formula (IVa), (IVb), (IVc), (IVd), (IVe) or (IVf): wherein U, V, W are each independently selected from -(C=0)-, -SO2-, -0-, -NR b - or -CR c R d -; m and t are each independently selected from 0, 1, 2, 3, 4, or 5, m and t are not simultaneously 0; Q is selected from O, S, SO2, C(R3)2, or NR3; each R3is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, or C 1-6 haloalkyl; A, Y1, Y2, R1, R b , R c , R d are as defined in claim 1 or 2.

6. The compound of claim 5, or a stereoisomer, tautomer, deuterated isomer, or pharmaceutically acceptable salt thereof. The compounds have the following 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 R3is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, or C 1-6 haloalkyl; Rings A, R1, R b are as defined in claim 1 or 2.

7. The compound of claim 5, or a stereoisomer, tautomer, deuterated isomer, or pharmaceutically acceptable salt thereof. The compounds have the following 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 R3is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, or C 1-6 haloalkyl; Ring A, R1, R b The definition as in claim 1 or 2.

8. The compound of claim 3, or a stereoisomer, tautomer, deuterated analog, or pharmaceutically acceptable salt thereof, wherein, The compounds have the following formula (IIIc) or (IIId): wherein U, V, W, Z are each independently selected from the group consisting of -(C=0)-, -SO2-, -0-, -NR b -; -CR c R d -; -CR e R f -; and at least one of U, V, W, Z is selected from the group consisting of -CR e R f -; Ring A, Y1, Y2, R1, R b 、R c 、R d 、R e 、R f The definition as in claim 1 or 2.

9. The compound of claim 8, or a stereoisomer, tautomer, deuterated isomer, or pharmaceutically acceptable salt thereof. The compounds have the following formula (IVg), (IVh), (IVi), (IVj) or (IVk): wherein U, V, W, Z are each independently selected from -(C=0)-, -SO2-, -0-, -NR b - or -CR c R d -; m and t are each independently selected from 0, 1, 2, 3, 4, or 5, m and t are not simultaneously 0; Q is selected from O, S, SO2, C(R3)2, or NR3; each R3is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, or C 1-6 haloalkyl; A, Y1, Y2, R1, R b , R c , R d are as defined in claim 1 or 2.

10. The compound of claim 9, or a stereoisomer, tautomer, deuterated isomer, or pharmaceutically acceptable salt thereof. The compounds have the following formula (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 ring A, R1, R b are as defined in claim 1 or 2.

11. The compound of any one of claims 1-10, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein, The ring A is selected from phenyl, pyridyl, morpholinyl, pyridone or cyclohexenyl; the phenyl, pyridyl, morpholinyl, pyridone or cyclohexenyl may be further optionally substituted with one or more R a Substituted, the R a Each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 an alkylsulfone group or a 3-8 membered heterocyclic group.

12. The compound of claim 11, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof. The ring A is selected from phenyl, and the phenyl may be further optionally substituted with one or more R a Substituted, the R a Selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 an alkylsulfone group or a 3-8 membered heterocyclic group.

13. The compound of claim 11, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein, said ring A is selected from pyridyl, which can be optionally further substituted by one or more R a substituents, said R a substituents are selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfone or 3-8 membered heterocyclyl.

14. The compound of any one of claims 11-13, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein, said ring A is selected from 15. The compound of any one of claims 11-13, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein, said ring A is selected from 16. The compound of any one of claims 11-13, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein, said ring A is selected from 17. The compound of any one of claims 1-16, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein, said R1is selected from the group consisting of hydrogen, deuterium, C g substituted alkynyl, said R g is selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-8 membered heterocyclyl, or 5-14 membered heteroaryl, said C 1-6 alkyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-8 membered heterocyclyl, or 5-14 membered heteroaryl can be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfone, or 3-8 membered heterocyclyl.

18. The compound of any one of claims 1-16, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein, said R1is selected from one or more R g substituted cyclopropyl, said R g selected from hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkynyl, C 6-12 aryl, 3-8 membered heterocyclyl, or 5-14 membered heteroaryl, said C 1-6 alkyl, C 2-6 alkynyl, C 6-12 aryl, 3-8 membered heterocyclyl, or 5-14 membered heteroaryl can be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2- alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfone, or 3-8 membered heterocyclyl.

19. The compound of any one of claims 1-16, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein, said R1is selected from one or more R g substituted methyl, said R g is selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-8 membered heterocyclyl, or 5-14 membered heteroaryl, said C 1-6 alkyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-8 membered heterocyclyl, or 5-14 membered heteroaryl can be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfone, or 3-8 membered heterocyclyl.

20. The compound of any one of claims 1-16, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, said R1is selected from one or more R g substituted ethyl, said R g is selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-8 membered heterocyclyl, or 5-14 membered heteroaryl, said C 1-6 alkyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-8 membered heterocyclyl, or 5-14 membered heteroaryl can be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfone, or 3-8 membered heterocyclyl.

21. The compound of any one of claims 1-16, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein, said R1is selected from -O(CH2) p R g -, said p is selected from 0, 1, 2, 3 or 4, said R g is selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 3-12 cycloalkyl, C 1-6 alkylamino, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, said C 1-6 alkyl, C 3-12 cycloalkyl, C 1-6 alkylamino, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl can be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfone, C 1-6 hydroxyalkyl or 3-8 membered heterocyclyl.

22. The compound of any one of claims 1-16, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein, said R1is selected from -O(CH2) p R g -, said p is selected from 0, 1, 2, 3 or 4, said R g is selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 3-12 cycloalkyl, C 1-6 alkylamino, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, said C 1-6 alkyl, C 3-12 cycloalkyl, C 1-6 alkylamino, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl can be optionally further substituted by one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfone or 3-8 membered heterocyclyl.

23. The compound of any one of claims 1-16, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein, said R1is selected from -(CH2) q OR g -, said q is selected from 0, 1, 2, 3 or 4, said R g is selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, said C 1-6 alkyl, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl can be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfone or 3-8 membered heterocyclyl.

24. The compound of any one of claims 17-23, or a stereoisomer, tautomer, deuterated analog, or pharmaceutically acceptable salt thereof, wherein, said R1 is selected from 25. The compound of any one of claims 17-23, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein, said R1 is selected from 26. The compound of any one of claims 1-25, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein, The compound is selected from the following compounds:

27. A pharmaceutical composition comprising, The pharmaceutical composition contains a therapeutically effective amount of the compound of any one of claims 1-26 or a stereoisomer, a tautomer, a deuterated analog, or a pharmaceutically acceptable salt thereof.

28. Use of the compound of any one of claims 1-26 or a stereoisomer, a tautomer, a deuterated analog, or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 27 in the manufacture of a medicament for treating a POLQ-mediated disease or disorder and related diseases or disorders.

29. The compound of any one of claims 1-26 or a stereoisomer, a tautomer, a deuterated analog, or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 27 for use in treating a POLQ-mediated disease or disorder and related diseases or disorders.

30. A method of treating and / or preventing a disease, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of claims 1-26 or a stereoisomer, a tautomer, a deuterated analog, or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 27; the disease to be treated and / or prevented is selected from a POLQ-mediated disease or disorder and related diseases or disorders.

31. Use as claimed in claim 28 or 29, or method as claimed in claim 30, characterised in that, The POLQ-mediated disease or disorder and related diseases or disorders is selected from a tumor or a cancer.

32. The use or method of claim 31, wherein the compound is of formula (I) ###0009### (I) or a pharmaceutically acceptable salt thereof. The cancer is characterized by any one or more of the following in combination: 1) the cancer is characterized by homologous recombination (HR) deficiency, reduction or loss of HR-associated gene expression; 2) the cancer is characterized by reduction or loss of BRCA gene expression, loss of BRAC gene or reduced function of BRCA protein; 3) the cancer is characterized by loss of 53BP1 / Shieldin complex; 4) the cancer is characterized by increased dependence on MMEJ DSB repair; 5) the cancer is characterized by receiving or not receiving PARPi drug treatment, having resistance to PARPi treatment.

33. The use or method of claim 31 or 32, wherein the compound is of formula (Ia) ###00010### (Ia) or a pharmaceutically acceptable salt thereof. The tumor or cancer is selected from a hematological tumor or a solid tumor, the solid tumor includes but is not limited to soft tissue cancer, rhabdoid cancer, multiple myeloma, uterine cancer, gastric cancer, peripheral nervous system cancer, rhabdoid cancer, bone cancer, colorectal cancer, mesothelioma, breast cancer, ovarian cancer, lung cancer, fibroblast, central nervous system cancer, urinary tract cancer, upper gastrointestinal cancer, kidney cancer, skin cancer, esophageal cancer, and pancreatic cancer; the hematological tumor includes but is not limited to lymphoma and leukemia.

34. A compound of Formula (M): or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof. wherein, R M1 is selected from iodine, a pinacolato boronic acid group (Bpin) or a ring A, the ring A being as defined in claim 1 ; R M2 selected from hydrogen or C 1-6 alkyl; The compound of formula (M) is preferably The definition of ring A is as described in claim 1.

35. Use of the compound of claim 34 or a stereoisomer, a tautomer, a deuterated analog, or a pharmaceutically acceptable salt thereof in the manufacture of the compound of any one of claims 1-26 or a stereoisomer, a tautomer, a deuterated analog, or a pharmaceutically acceptable salt thereof.

Images